Cediranib for Metastatic Alveolar Soft Part Sarcoma

PubMed Central

Kummar, Shivaani; Allen, Deborah; Monks, Anne; Polley, Eric C.; Hose, Curtis D.; Ivy, S. Percy; Turkbey, Ismail B.; Lawrence, Scott; Kinders, Robert J.; Choyke, Peter; Simon, Richard; Steinberg, Seth M.; Doroshow, James H.; Helman, Lee

2013-01-01

Purpose Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs). Patients and Methods We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging. Results Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis. Conclusion In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib. PMID:23630200

Promoter CpG island hypermethylation of the DNA repair enzyme MGMT predicts clinical response to dacarbazine in a phase II study for metastatic colorectal cancer.

PubMed

Amatu, Alessio; Sartore-Bianchi, Andrea; Moutinho, Catia; Belotti, Alessandro; Bencardino, Katia; Chirico, Giuseppe; Cassingena, Andrea; Rusconi, Francesca; Esposito, Anna; Nichelatti, Michele; Esteller, Manel; Siena, Salvatore

2013-04-15

O(6)-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein removing mutagenic and cytotoxic adducts from O(6)-guanine in DNA. Approximately 40% of colorectal cancers (CRC) display MGMT deficiency due to the promoter hypermethylation leading to silencing of the gene. Alkylating agents, such as dacarbazine, exert their antitumor activity by DNA methylation at the O(6)-guanine site, inducing base pair mismatch; therefore, activity of dacarbazine could be enhanced in CRCs lacking MGMT. We conducted a phase II study with dacarbazine in CRCs who had failed standard therapies (oxaliplatin, irinotecan, fluoropyrimidines, and cetuximab or panitumumab if KRAS wild-type). All patients had tumor tissue assessed for MGMT as promoter hypermethylation in double-blind for treatment outcome. Patients received dacarbazine 250 mg/m(2) intravenously every day for four consecutive days, every 21 days, until progressive disease or intolerable toxicity. We used a Simon two-stage design to determine whether the overall response rate would be 10% or more. Secondary endpoints included association of response, progression-free survival, and disease control rate with MGMT status. Sixty-eight patients were enrolled from May 2011 to March 2012. Patients received a median of three cycles of dacarbazine (range 1-12). Grades 3 and 4 toxicities included: fatigue (41%), nausea/vomiting (29%), constipation (25%), platelet count decrease (19%), and anemia (18%). Overall, two patients (3%) achieved partial response and eight patients (12%) had stable disease. Disease control rate (partial response + stable disease) was significantly associated with MGMT promoter hypermethylation in the corresponding tumors. Objective clinical responses to dacarbazine in patients with metastatic CRC are confined to those tumors harboring epigenetic inactivation of the DNA repair enzyme MGMT.

Benefit from autologous stem cell transplantation in primary refractory myeloma? Different outcomes in progressive versus stable disease

PubMed Central

Rosiñol, Laura; García-Sanz, Ramón; Lahuerta, Juan José; Hernández-García, Miguel; Granell, Miquel; de la Rubia, Javier; Oriol, Albert; Hernández-Ruiz, Belén; Rayón, Consuelo; Navarro, Isabel; García-Ruiz, Juan Carlos; Besalduch, Joan; Gardella, Santiago; Jiménez, Javier López; Díaz-Mediavilla, Joaquín; Alegre, Adrián; Miguel, Jesús San; Bladé, Joan

2012-01-01

Background Several studies of autologous stem cell transplantation in primary refractory myeloma have produced encouraging results. However, the outcome of primary refractory patients with stable disease has not been analyzed separately from the outcome of patients with progressive disease. Design and Methods In the Spanish Myeloma Group 2000 trial, 80 patients with primary refractory myeloma (49 with stable disease and 31 with progressive disease), i.e. who were refractory to initial chemotherapy, were scheduled for tandem transplants (double autologous transplant or a single autologous transplant followed by an allogeneic transplant). Patients with primary refractory disease included those who never achieved a minimal response (≥25% M-protein decrease) or better. Responses were assessed using the European Bone Marrow Transplant criteria. Results There were no significant differences in the rates of partial response or better between patients with stable or progressive disease. However, 38% of the patients with stable disease at the time of transplantation remained in a stable condition or achieved a minimal response after transplantation versus 7% in the group with progressive disease (P=0.0017) and the rate of early progression after transplantation was significantly higher among the group with progressive disease at the time of transplantation (22% versus 2%; P=0.0043). After a median follow-up of 6.6 years, the median survival after first transplant of the whole series was 2.3 years. Progression-free and overall survival from the first transplant were shorter in patients with progressive disease (0.6 versus 2.3 years, P=0.00004 and 1.1 versus 6 years, P=0.00002, respectively). Conclusions Our results show that patients with progressive refractory myeloma do not benefit from autologous transplantation, while patients with stable disease have an outcome comparable to those with chemosensitive disease. (ClinicalTrials.gov:NCT00560053) PMID:22058223

TU-G-BRA-06: PET-Based Treatment Response Assessement for Neoadjuvent Chemoradiation for Pancreatic Adenocarcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dalah, E; Tai, A; Oshima, K

Purpose: To address the limitations of the conventional response evaluation criteria in solid tumors (RECIST), and validate PET response criteria in solid tumors (PERCIST1.0). We analyze the relationship between the pathological treatment response (PTR) and PERCIST1.0 for patients treated with neoadjuvent chemoradiation (nCR) for pancreatic adenocarcinoma. Methods: The pre- and post-nCR CT and PET data for a total of 8 patients with resectable, or borderline resectable pancreatic head adenocarcinoma treated with nCR were retrospectively analyzed. These data were compared with the PTR which were graded according to tumor cell destruction (cellularity), with Grade1, 2 or 3 (G1, G2 or G3)more » for good, moderate, and poor responses, respectively. RECIST-based PET (RECISTPET), and PERCIST1.0 were defined using lean body mass normalized SUV (nSUVlb). RECIST-based CT (RECISTCT) was defined by contouring the whole pancreas head (CTPH). Pre- and post-nSUVlb and SUVbw, PERCIST 1.0, were correlated with PTR using Pearson’s correlation coefficient test. Results: The average mean and SD in nSUVlb for all 8 patients analyzed were lower in post-nCR (1.35±0.34) compared to those at pre-nCR (1.38±0.20). Using PERCIST1.0, 5/8 patients showed stable metabolic disease (SMD), 2/8 partial metabolic response (PMR), and 1/8 progressive metabolic disease (PMD). Using RECISTPET 4/8 showed stable disease (STD), 4/8 partial response (PR), whereas 8/8 showed stable disease (STD) using RECISTCT. PTR were correlated with PERCIST1.0 (R=0.3780/P=0.6071). Pathological tumor size was correlated with RECISTCT (R=0.0727/P=0.8679), and RECISTPET, R=−0.3333/P=0.3798. Conclusion: Chemoradiation treatment response assessment based on metabolic tumor activities using PRECIST1.0 and RECISTPET appears to provide better agreement with pathological assessment as compared to the conventional CT-based assessment using RECISTCT. The integration of these additional radiographic metrics in assessing treatment response to nCR for pancreatic adenocarcinoma may provide a promising strategy to better select those patients most suitable for therapeutic intensification.« less

Treatment of advanced soft tissue sarcomas with ifosfamide and doxorubicin combination chemotherapy.

PubMed

Barişta, I; Tekuzman, G; Yalçin, S; Güllü, I; Güler, N; Ozişik, Y; Kars, A; Celik, I; Türker, A; Altundağ, K; Zengin, N; Uner, A; Baltali, E; Firat, D

2000-01-01

Our objective was to assess the efficacy of a standard dose ifosfamide and doxorubicin containing regimen in the treatment of advanced soft tissue sarcomas. Forty consecutive patients with a median age of 35.5 years were treated. Ifosfamide was administered at a dose of 2.5 g/m(2)/day as 72-hour continuous infusion with mesna at the same dosage and schedule. Doxorubicin was given at the dose of 60 mg/m(2)/day as 2-hour infusion on day 1. Six patients had a complete response (15%), and 9 (22.5%) had a partial response, fourteen patients (35%) stable disease, and 11 (27.5%) did not respond to chemotherapy. The median duration of response was 13 and 5 months for the complete and partial responders, respectively. The median survival was 37 months. Febrile neutropenia was encountered in 9 cases (22.5%). The present ifosfamide and doxorubicin combination is a moderately effective and well-tolerable regimen in the treatment of advanced soft tissue sarcomas. Copyright 2000 Wiley-Liss, Inc.

Social and Sexual Behaivours of Mice in Partial Gravity

NASA Astrophysics Data System (ADS)

Aou, Shuji; Hasegawa, Katsuya; Kumei, Yasuhiro; Inoue, Katarzyna; Zeredo, Jorge; Narikiyo, Kimiya; Watanabe, Yuuki

2012-07-01

We examined social and sexual behaviours in normal ICR mice, C57BL mice and obese db/db mice lacking leptin receptors in low gravity conditions using parabolic-flight to generate graded levels of partial gravity. Although both normal and obese mice floated with vigorous limb and tail movements when a floor is smooth in microgravity but they were rather stable if a floor is cover by carpet. Obese mice were more stable and socially contacted longer with a partner in low-gravity conditions. When they returned to the home cage after parabolic flights, obese mice started to eat sooner without restless behaviour, while control mice showed restless behaviour without eating. Face grooming, an indicator of stress response, was found more often in the control mice than the obese mice. Obese mice returned to resting condition faster than the control. We also analysed sexual behaviour of ICR mice and C57BL mice but not db/db mice since they are sexually inactive. Social and sexual behaviour could be evaluated in partial gravity conditions to get basic data concerning whether rodents can communicate and reproduce in Moon, Mars and space or not. Supported by Grant-in-Aid for Exploratory Research (JSPS) to S Aou and FY2010 grants from JAXA and Japan Society for Promotion of Science to Y. Kumei.

Regular approximate factorization of a class of matrix-function with an unstable set of partial indices

PubMed Central

Rogosin, S.

2018-01-01

From the classic work of Gohberg & Krein (1958 Uspekhi Mat. Nauk. XIII, 3–72. (Russian).), it is well known that the set of partial indices of a non-singular matrix function may change depending on the properties of the original matrix. More precisely, it was shown that if the difference between the largest and the smallest partial indices is larger than unity then, in any neighbourhood of the original matrix function, there exists another matrix function possessing a different set of partial indices. As a result, the factorization of matrix functions, being an extremely difficult process itself even in the case of the canonical factorization, remains unresolvable or even questionable in the case of a non-stable set of partial indices. Such a situation, in turn, has became an unavoidable obstacle to the application of the factorization technique. This paper sets out to answer a less ambitious question than that of effective factorizing matrix functions with non-stable sets of partial indices, and instead focuses on determining the conditions which, when having known factorization of the limiting matrix function, allow to construct another family of matrix functions with the same origin that preserves the non-stable partial indices and is close to the original set of the matrix functions. PMID:29434502

Regular approximate factorization of a class of matrix-function with an unstable set of partial indices.

PubMed

Mishuris, G; Rogosin, S

2018-01-01

From the classic work of Gohberg & Krein (1958 Uspekhi Mat. Nauk. XIII , 3-72. (Russian).), it is well known that the set of partial indices of a non-singular matrix function may change depending on the properties of the original matrix. More precisely, it was shown that if the difference between the largest and the smallest partial indices is larger than unity then, in any neighbourhood of the original matrix function, there exists another matrix function possessing a different set of partial indices. As a result, the factorization of matrix functions, being an extremely difficult process itself even in the case of the canonical factorization, remains unresolvable or even questionable in the case of a non-stable set of partial indices. Such a situation, in turn, has became an unavoidable obstacle to the application of the factorization technique. This paper sets out to answer a less ambitious question than that of effective factorizing matrix functions with non-stable sets of partial indices, and instead focuses on determining the conditions which, when having known factorization of the limiting matrix function, allow to construct another family of matrix functions with the same origin that preserves the non-stable partial indices and is close to the original set of the matrix functions.

Analytic computation of energy derivatives - Relationships among partial derivatives of a variationally determined function

NASA Technical Reports Server (NTRS)

King, H. F.; Komornicki, A.

1986-01-01

Formulas are presented relating Taylor series expansion coefficients of three functions of several variables, the energy of the trial wave function (W), the energy computed using the optimized variational wave function (E), and the response function (lambda), under certain conditions. Partial derivatives of lambda are obtained through solution of a recursive system of linear equations, and solution through order n yields derivatives of E through order 2n + 1, extending Puley's application of Wigner's 2n + 1 rule to partial derivatives in couple perturbation theory. An examination of numerical accuracy shows that the usual two-term second derivative formula is less stable than an alternative four-term formula, and that previous claims that energy derivatives are stationary properties of the wave function are fallacious. The results have application to quantum theoretical methods for the computation of derivative properties such as infrared frequencies and intensities.

Effects of surface hydroxylation on adhesion at zinc/silica interfaces.

PubMed

Le, Ha-Linh Thi; Goniakowski, Jacek; Noguera, Claudine; Koltsov, Alexey; Mataigne, Jean-Michel

2018-06-06

The weak interaction between zinc and silica is responsible for the poor performance of anti-corrosive galvanic zinc coatings on modern advanced high-strength steels, which are fundamental in the automotive industry, and important for rail transport, shipbuilding, and aerospace. With the goal of identifying possible methods for its improvement, we report an ab initio study of the effect of surface hydroxylation on the adhesion characteristics of model zinc/β-cristobalite interfaces, representative of various surface hydroxylation/hydrogenation conditions. We show that surface silanols resulting from dissociative water adsorption at the most stable stoichiometric (001) and (111) surfaces prevent strong zinc-silica interactions. However, dehydrogenation of such interfaces produces oxygen-rich zinc/silica contacts with excellent adhesion characteristics. These are due to partial zinc oxidation and the formation of strong iono-covalent Zn-O bonds between zinc atoms and the under-coordinated excess anions, remnant of the hydroxylation layer. Interestingly, these interfaces appear as the most thermodynamically stable in a wide range of realistic oxygen-rich and hydrogen-lean environments. We also point out that the partial oxidation of zinc atoms in direct contact with the oxide substrate may somewhat weaken the cohesion in the zinc deposit itself. This fundamental analysis of the microscopic mechanisms responsible for the improved zinc wetting on pre-hydroxylated silica substrates provides useful guidelines towards practical attempts to improve adhesion.

Exercise capacity is associated with endothelin-1 release during emotional excitement in coronary artery disease patients.

PubMed

Tulppo, Mikko P; Piira, Olli-Pekka; Hautala, Arto J; Kiviniemi, Antti M; Miettinen, Johanna A; Huikuri, Heikki V

2014-08-01

Endothelin-1 (ET-1), a potent vasoconstrictor, IL-6, and catecholamines are increased and heart rate variability [SD of normal to normal R-R intervals (SDNN)] decreased during emotional excitement, but individual responses vary. We tested the hypothesis that exercise capacity is associated with physiological responses caused by real-life emotional excitement. We measured the plasma levels of ET-1, IL-6, catecholamines, heart rate, and SDNN in enthusiastic male ice hockey spectators (n = 51; age, 59 ± 9 years) with stable coronary artery disease (CAD) at baseline and during the Finnish National Ice Hockey League's final play-off matches. Maximal exercise capacity (METs) by bicycle exercise test and left ventricular ejection fraction (LVEF) were measured on a separate day. ET-1 response from baseline to emotional excitement correlated with maximal METs (r = -0.30; P = 0.040). In a linear stepwise regression analysis age, body mass index (BMI), METs, LVEF, basal ET-1, and subjective experience of excitement were entered the model as independent variables to explain ET-1 response. This model explained 27% of ET-1 response (P = 0.003). Maximal METs were most strongly correlated with ET-1 response (β = -0.45; partial correlation r = -0.43; P = 0.002), followed by BMI (β = -0.31; partial correlation r = -0.31; P = 0.033) and LVEF (β = -0.30; partial correlation r = -0.33; P = 0.023). Exercise capacity may protect against further cardiovascular events in CAD patients, because it is associated with reduced ET-1 release during emotional excitement. Copyright © 2014 the American Physiological Society.

First follow-up radiographic response is one of the predictors of local tumor progression and radiation necrosis after stereotactic radiosurgery for brain metastases.

PubMed

Sharma, Mayur; Jia, Xuefei; Ahluwalia, Manmeet; Barnett, Gene H; Vogelbaum, Michael A; Chao, Samuel T; Suh, John H; Murphy, Erin S; Yu, Jennifer S; Angelov, Lilyana; Mohammadi, Alireza M

2017-09-01

Local progression (LP) and radiation necrosis (RN) occur in >20% of cases following stereotactic radiosurgery (SRS) for brain metastases (BM). Expected outcomes following SRS for BM include tumor control/shrinkage, local progression and radiation necrosis. 1427 patients with 4283 BM lesions were treated using SRS at Cleveland Clinic from 2000 to 2012. Clinical, imaging and radiosurgery data were collected from the database. Local tumor progression and RN were the primary end points and correlated with patient and tumor-related variables. 5.7% of lesions developed radiographic RN and 3.6% showed local progression at 6 months. Absence of new extracranial metastasis (P < 0.001), response to SRS at first follow-up scan (local progression versus stable size (P < 0.001), partial resolution versus complete resolution at first follow up [P = 0.009]), prior SRS to the same lesion (P < 0.001), IDL% (≤55; P < 0.001), maximum tumor diameter (>0.9 cm; P < 0.001) and MD/PD gradient index (≤1.8, P < 0.001) were independent predictors of high risk of local tumor progression. Absence of systemic metastases (P = 0.029), good neurological function at 1st follow-up (P ≤ 0.001), no prior SRS to other lesion (P = 0.024), low conformity index (≤1.9) (P = 0.009), large maximum target diameter (>0.9 cm) (P = 0.003) and response to SRS (tumor progression vs. stable size following SRS [P < 0.001]) were independent predictors of high risk of radiographic RN. Complete tumor response at first follow-up, maximum tumor diameter <0.9 cm, tumor volume <2.4 cc and no prior SRS to the index lesion are good prognostic factors with reduced risk of LP following SRS. Complete tumor response to SRS, poor neurological function at first follow-up, prior SRS to other lesions and high conformity index are favorable factors for not developing RN. Stable or partial response at first follow-up after SRS have same impact on local progression and RN compared to those with complete resolution or progression. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Efficacy and safety of retreatment with nivolumab in metastatic melanoma patients previously treated with nivolumab.

PubMed

Nomura, Motoo; Otsuka, Atsushi; Kondo, Tomohiro; Nagai, Hiroki; Nonomura, Yumi; Kaku, Yo; Matsumoto, Shigemi; Muto, Manabu

2017-11-01

Nivolumab is a monoclonal antibody directed against programmed death-1 that has been shown to improve survival in patients with metastatic melanoma. However, the efficacy of nivolumab and other agents in melanoma remains limited. The objective of this study was to evaluate the efficacy and safety of retreatment with nivolumab in metastatic melanoma patients who previously progressed on nivolumab. A retrospective review was performed on eight consecutive metastatic melanoma patients retreated with nivolumab who progressed on previous nivolumab. These patients received nivolumab 2 mg/kg every 3 weeks. Best responses to each treatment were assessed using RECIST 1.1. Of eight metastatic melanoma patients, three patients received chemotherapy before first nivolumab. The median first nivolumab treatment period was 4.1 months. During first nivolumab, 3 (37.5%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. First nivolumab was discontinued due to disease progression in seven patients and grade 3 colitis in 1 patient. Patients were subsequently treated with ipilimumab (n = 6), vemurafenib (n = 1), or no other medical treatment (n = 1). The median treatment period between first and second nivolumab was 3.0 months. Four patients received radiation therapy between first and second nivolumab. The median second nivolumab treatment period was 4.3 months. Among the eight patients who received second nivolumab, 2 (25%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. Second nivolumab was discontinued due to disease progression in seven patients. One patient continues to receive second nivolumab. Among the four patients treated with ipilimumab and radiotherapy between first and second nivolumab, the response rate was 50% and the disease control rate was 75%. This study showed that retreatment with nivolumab is an option for select metastatic melanoma patients after previous nivolumab treatment.

Phase II trial of cystemustine, a new nitrosourea, as treatment of high-grade brain tumors in adults.

PubMed

Roche, H; Cure, H; Adenis, A; Fargeot, P; Terret, C; Lentz, M A; Madelmont, J C; Fumoleau, P; Hanausk, A; Chollet, P

2000-09-01

This study included 39 patients (37 evaluable, of whom 30 patients with recurrent gliomas and 7 patients with gliomas untreated by radiotherapy); they were enrolled into a phase II trial using a new nitrosourea, cystemustine, administrated every 2 weeks at 60 mg/m2 as a 15 min-infusion. Pathology at inclusion was (WHO classification): 14 glioblastomas, 20 grade 3-4 astrocytomas and 3 grade 3 oligodendrogliomas. Four partial responses have been obtained, giving an overall response rate of 10.8%. Four additional patients had a partial response, which for various reasons was not confirmed 4 weeks later; 12 patients had a stable disease for at least 8 weeks, 15 patients had progressive disease. Of the 4 responses, 2 were with a grade 3 oligodendroglioma and 2 glioblastoma. Toxicity (WHO grading) was mainly hematological: leukopenia (16.2% grade 3-4), neutropenia (29.7% grade 3-4), thrombopenia (27% grade 3-4). No other toxicity greater than grade 2 was observed. In conclusion, cystemustine at 60 mg/m2 has moderate clinical activity in relapsing glioma. Our results warrant further investigation of this agent with an increased dose or modified scheme.

Ifosfamide, mesna and epirubicin as second-line chemotherapy in advanced breast cancer.

PubMed

Kiraz, S; Baltali, E; Güler, N; Barista, I; Benekli, M; Celik, I; Güllü, I H; Kars, A; Tekuzman, G; Firat, D

1996-08-01

The ifosfamide, mesna and epirubicin (IMEpi) combination is administered to 16 patients having advanced metastatic breast carcinoma as second-line chemotherapy. We observed complete response in 6%, partial response in 44% (total overall response rate of 50%), stable disease in 12% and progressive disease in the remaining 38% of the patients. The median remission duration in responders was calculated to be 9.6 months. IMEpi regimen had a tolerable toxicity profile including alopecia, nausea and vomiting, microscopic hematuria, leukopenia and neurotoxicity in which serious complications necessitating discontinuation of the chemotherapy were not encountered. It might be concluded that IMEpi chemotherapy combination is an effective alternative among schedules in the management of patients with stage IV breast carcinoma without serious side effects.

Phase 1 and 2 study of carboplatin and pralatrexate in patients with recurrent, platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.

PubMed

Del Carmen, Marcela G; Supko, Jeff G; Horick, Nora K; Rauh-Hain, J Alejandro; Clark, Rachel M; Campos, Susana M; Krasner, Carolyn N; Atkinson, Tina; Birrer, Michael J

2016-11-15

The objective of this phase 1 and 2 trial was to identify the appropriate dose of combined carboplatin and pralatrexate for patients with recurrent, platinum-sensitive ovarian, fallopian tube, and primary peritoneal cancer. In phase 1, patients received carboplatin (at an area under the curve of 5) and increasing doses of pralatrexate until the maximum-tolerated dose (MTD) of pralatrexate was achieved. The primary endpoint was the response rate. Additional endpoints were safety, response duration, progression-free survival, overall survival, and pharmacokinetics. Thirty patients were enrolled in phase 1, and 20 were enrolled in phase 2. Of all 50 patients, 49 completed the study. The mean patient age was 59 years, and patients completed a median of 6 cycles. The MTD for pralatrexate was 105 mg/m 2 . The clinical benefit rate (complete responses plus partial responses plus stable disease) was 86%. Of 26 patients who received the MTD, 12 had a partial response, 11 had stable disease, and 2 had disease progression. The progression-free survival rate at 3 and 6 months was 87% and 79%, respectively; and the overall survival rate was 98% at 6 and 12 months and 66% at 24 months. Of 30 patients, 18 (60%) in phase 1 experienced an adverse event of any grade; and, of those, 4 patients (13%) had a grade 3 or greater adverse event. In phase 2, 12 patients (60%) had an adverse event of any grade, and 4 (20%) had grade 3 or greater toxicity. There was a significant reduction in the total body clearance of pralatrexate when it was received concurrently with carboplatin. Most patients responded to carboplatin-pralatrexate combination. This regimen is well tolerated and effective in this patient population. Cancer 2016;122:3297-3306. © 2016 American Cancer Society. © 2016 American Cancer Society.

Removable partial denture on osseointegrated implants and natural teeth.

PubMed

Chang, Li-Ching; Wang, Jen-Chyan; Tasi, Chi-Cheng

2007-01-01

Implants have been designed to provide edentulous patients with fixed prostheses or overdentures. Recently, implant-supported fixed partial prostheses and single crowns have become successful treatment alternatives to removable and fixed partial dentures. However, few researchers have examined "removable partial dentures on implants and natural teeth". In this article, we report two patients fitted with "removable partial dentures on implants and natural teeth". The patients were satisfied with their dentures in terms of function and aesthetics. Regular follow-up visits revealed that the periodontal and peri-implant conditions were stable. There was no evidence of excessive intrusion or mobility of the teeth, nor were any visible changes in the bone levels of the natural teeth or implants noted on radiographs. Since the average duration of observation was about 38 months, further follow-up examinations are necessary to determine whether these dentures remain stable long-term.

Investigating the principles of recrystallization from glyceride melts.

PubMed

Windbergs, Maike; Strachan, Clare J; Kleinebudde, Peter

2009-01-01

Different lipids were melted and resolidified as model systems to gain deeper insight into the principles of recrystallization processes in lipid-based dosage forms. Solid-state characterization was performed on the samples with differential scanning calorimetry and X-ray powder diffraction. Several recrystallization processes could be identified during storage of the lipid layers. Pure triglycerides that generally crystallize to the metastable alpha-form from the melt followed by a recrystallization process to the stable beta-form with time showed a chain-length-dependent behavior during storage. With increasing chain length, the recrystallization to the stable beta-form was decelerated. Partial glycerides exhibited a more complex recrystallization behavior due to the fact that these substances are less homogenous. Mixtures of a long-chain triglyceride and a partial glyceride showed evidence of some interaction between the two components as the partial glyceride hindered the recrystallization of the triglyceride to the stable beta-form. In addition, the extent of this phenomenon depended on the amount of partial glyceride in the mixture. Based on these results, changes in solid dosage forms based on glycerides during processing and storage can be better understood.

A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer.

PubMed

Miles, D W; Towlson, K E; Graham, R; Reddish, M; Longenecker, B M; Taylor-Papadimitriou, J; Rubens, R D

1996-10-01

Studies in animal models of mouse mammary carcinoma have shown that ovine submaxillary mucin, which carries multiple sialyl-Tn (STn) epitopes, is effective in stimulating an immune response and inhibiting tumour growth. In similar studies using carbohydrate antigens, pretreatment with low-dose cyclophosphamide has been shown to be important in modulating the immune response to antigen possibly by inhibiting suppresser T-cell activity. In a clinical trial assessing the efficacy and toxicity of synthetic STn, patients with metastatic breast cancer were randomised to receive 100 micrograms STn linked to keyhole limpet haemocyanin (KLH) with DETOX-B adjuvant given by subcutaneous injection at weeks 0, 2, 5 and 9 with or without low-dose cyclophosphamide (CTX, 300 mg m-2) pretreatment, 3 days before the start of immunotherapy. Patients with responding or stable disease after the first four injections were eligible to receive STn-KLH at 4 week intervals. The main toxicity noted was the development of subcutaneous granulomata at injection sites. Of 23 patients randomised, 18 received four injections, 5 patients having developed progressive disease during the initial 12 week period. Two minor responses were noted in the 18 patients who received four active specific immunotherapy (ASI) injections and a further five patients had stable disease. Six patients continued ASI at 4 week intervals and a partial response was noted in a patient who had previously had stable disease. All patients developed IgG and IgM responses to sialyl-Tn and levels of IgM antibodies were significantly higher in those patients who were pretreated with CTX. Measurable tumour responses have been recorded following ASI with STn-KLH plus DETOX and the immunomodulatory properties of low-dose CTX have been confirmed.

A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer.

PubMed Central

Miles, D. W.; Towlson, K. E.; Graham, R.; Reddish, M.; Longenecker, B. M.; Taylor-Papadimitriou, J.; Rubens, R. D.

1996-01-01

Studies in animal models of mouse mammary carcinoma have shown that ovine submaxillary mucin, which carries multiple sialyl-Tn (STn) epitopes, is effective in stimulating an immune response and inhibiting tumour growth. In similar studies using carbohydrate antigens, pretreatment with low-dose cyclophosphamide has been shown to be important in modulating the immune response to antigen possibly by inhibiting suppresser T-cell activity. In a clinical trial assessing the efficacy and toxicity of synthetic STn, patients with metastatic breast cancer were randomised to receive 100 micrograms STn linked to keyhole limpet haemocyanin (KLH) with DETOX-B adjuvant given by subcutaneous injection at weeks 0, 2, 5 and 9 with or without low-dose cyclophosphamide (CTX, 300 mg m-2) pretreatment, 3 days before the start of immunotherapy. Patients with responding or stable disease after the first four injections were eligible to receive STn-KLH at 4 week intervals. The main toxicity noted was the development of subcutaneous granulomata at injection sites. Of 23 patients randomised, 18 received four injections, 5 patients having developed progressive disease during the initial 12 week period. Two minor responses were noted in the 18 patients who received four active specific immunotherapy (ASI) injections and a further five patients had stable disease. Six patients continued ASI at 4 week intervals and a partial response was noted in a patient who had previously had stable disease. All patients developed IgG and IgM responses to sialyl-Tn and levels of IgM antibodies were significantly higher in those patients who were pretreated with CTX. Measurable tumour responses have been recorded following ASI with STn-KLH plus DETOX and the immunomodulatory properties of low-dose CTX have been confirmed. PMID:8883420

On the Micrometeorology of the Southern Great Plains. 2: Turbulence Statistics

NASA Astrophysics Data System (ADS)

Hicks, Bruce B.; Pendergrass, W. R.; Vogel, C. A.; Keener, R. N.; Leyton, S. M.

2015-03-01

Fast-response micrometeorological data obtained from an instrumented 32-m tower at an arid site near Ocotillo, Texas are used to examine the daily time evolution of the lower atmosphere. Correlation coefficients between turbulence properties (fast response wind-speed components and temperature) confirm that over this sparsely vegetated site the effects of convection are observed soon after sunrise, well ahead of the morning transition from stable to unstable stratification. Details of this kind are obscured when results are considered as functions of conventional stability parameters, since such standard analytical methods combine features of the morning and evening transitions into a single presentation. Partial correlation coefficients and semi-partials indicate that the local turbulent kinetic energy is mainly associated with local fluxes of heat and momentum near neutral and in most stable conditions, but decreases substantially during the times of strongest instability (possibly reflecting the scatter introduced by sampling infrequent convective episodes using a single tower). For many of the variables considered here, the standard deviations are about the same as the linear averages, indicating that the distributions are close to log-normal. The present data indicate that if the intent is to address some specific situation then 10 % error bounds on turbulence quantities (e.g. fluxes) correspond to averaging over a distance scale of the order of 10 km and a time scale of about 3 h. As the distance and time scales become smaller, the uncertainties due to factors external to the local surface increase.

Achieving nitritation in a continuous moving bed biofilm reactor at different temperatures through ratio control.

PubMed

Bian, Wei; Zhang, Shuyan; Zhang, Yanzhuo; Li, Wenjing; Kan, Ruizhe; Wang, Wenxiao; Zheng, Zhaoming; Li, Jun

2017-02-01

A ratio control strategy was implemented in a continuous moving bed biofilm reactor (MBBR) to investigate the response to different temperatures. The control strategy was designed to maintain a constant ratio between dissolved oxygen (DO) and total ammonia nitrogen (TAN) concentrations. The results revealed that a stable nitritation in a biofilm reactor could be achieved via ratio control, which compensated the negative influence of low temperatures by stronger oxygen-limiting conditions. Even with a temperature as low as 6°C, stable nitritation could be achieved when the controlling ratio did not exceed 0.17. Oxygen-limiting conditions in the biofilm reactor were determined by the DO/TAN concentrations ratio, instead of the mere DO concentration. This ratio control strategy allowed the achievement of stable nitritation without complete wash-out of NOB from the reactor. Through the ratio control strategy full nitritation of sidestream wastewater was allowed; however, for mainstream wastewater, only partial nitritation was recommended. Copyright © 2016 Elsevier Ltd. All rights reserved.

Anammox-zeolite system acting as buffer to achieve stable effluent nitrogen values.

PubMed

Yapsakli, Kozet; Aktan, Cigdem Kalkan; Mertoglu, Bulent

2017-02-01

For a successful nitrogen removal, Anammox process needs to be established in line with a stable partial nitritation pretreatment unit since wastewater influent is mostly unsuitable for direct treatment by Anammox. Partial nitritation is, however, a critical bottleneck for the nitrogen removal since it is often difficult to maintain the right proportions of NO 2 -N and NH 4 -N during long periods of time for Anammox process. This study investigated the potential of Anammox-zeolite biofilter to buffer inequalities in nitrite and ammonium nitrogen in the influent feed. Anammox-zeolite biofilter combines the ion-exchange property of zeolite with the biological removal by Anammox process. Continuous-flow biofilter was operated for 570 days to test the response of Anammox-zeolite system for irregular ammonium and nitrite nitrogen entries. The reactor demonstrated stable and high nitrogen removal efficiencies (approximately 95 %) even when the influent NO 2 -N to NH 4 -N ratios were far from the stoichiometric ratio for Anammox reaction (i.e. NO 2 -N to NH 4 -N ranging from 0 to infinity). This is achieved by the sorption of surplus NH 4 -N by zeolite particles in case ammonium rich influent came in excess with respect to Anammox stoichiometry. Similarly, when ammonium-poor influent is fed to the reactor, ammonium desorption took place due to shifts in ion-exchange equilibrium and deficient amount were supplied by previously sorbed NH 4 -N. Here, zeolite acted as a preserving reservoir of ammonium where both sorption and desorption took place when needed and this caused the Anammox-zeolite system to act as a buffer system to generate a stable effluent.

Intra-Arterial Chemotherapy with Osmotic Blood-Brain Barrier Disruption for Aggressive Oligodendroglial tumors: Results of a Phase I Study

PubMed Central

Guillaume, Daniel J.; Doolittle, Nancy D.; Gahramanov, Seymur; Hedrick, Nancy A.; Delashaw, Johnny B.; Neuwelt, Edward A.

2009-01-01

Objective Refractory anaplastic oligodendroglioma (AO) and oligoastrocytoma (OA) tumors are challenging to treat. This trial primarily evaluated toxicity and estimated the maximum tolerated dose (MTD) of intra-arterial (IA) melphalan, IA carboplatin and intravenous (IV) etoposide phosphate in conjunction with blood-brain barrier disruption (BBBD) in these tumors. The secondary measure was efficacy. Methods Thirteen subjects with temozolomide (TMZ) - refractory AO (11) or OA (2) underwent BBBD with carboplatin (IA, 200 mg/m2/day), etoposide phosphate (IV, 200 mg/m2/day), and melphalan (IA, dose escalation) every 4 weeks, for up to 1 year. Subjects underwent melphalan dose escalation (4, 8, 12, 16, and 20 mg/m2/day) until the MTD (one level below that producing grade 4 toxicity) was determined. Toxicity and efficacy were assessed. Results Two of four subjects receiving IA melphalan at 8 mg/m2/day developed grade 4 thrombocytopenia, thus the melphalan MTD was 4 mg/m2/day. Adverse events included asymptomatic subintimal tear (1 subject) and grade 4 thrombocytopenia (3 subjects). Two subjects demonstrated complete response, 3 had partial responses, 5 demonstrated stable disease and 3 progressed. Median overall PFS was 11 months. Subjects with complete or partial response demonstrated deletion of chromosomes 1p and 19q. In the 5 subjects with stable disease, 2 demonstrated 1p and 19q deletion and 3 demonstrated 19q deletion only. Conclusion In these patients with AO or OA tumors who failed TMZ, osmotic BBBD with IA carboplatin, IV etoposide phosphate, and IA melphalan (4mg/m2/day for 2 days) shows acceptable toxicity and encouraging efficacy, especially in subjects demonstrating 1p and/or 19q deletion. PMID:20023537

Towards a General Theory of Extremes for Observables of Chaotic Dynamical Systems.

PubMed

Lucarini, Valerio; Faranda, Davide; Wouters, Jeroen; Kuna, Tobias

2014-01-01

In this paper we provide a connection between the geometrical properties of the attractor of a chaotic dynamical system and the distribution of extreme values. We show that the extremes of so-called physical observables are distributed according to the classical generalised Pareto distribution and derive explicit expressions for the scaling and the shape parameter. In particular, we derive that the shape parameter does not depend on the chosen observables, but only on the partial dimensions of the invariant measure on the stable, unstable, and neutral manifolds. The shape parameter is negative and is close to zero when high-dimensional systems are considered. This result agrees with what was derived recently using the generalized extreme value approach. Combining the results obtained using such physical observables and the properties of the extremes of distance observables, it is possible to derive estimates of the partial dimensions of the attractor along the stable and the unstable directions of the flow. Moreover, by writing the shape parameter in terms of moments of the extremes of the considered observable and by using linear response theory, we relate the sensitivity to perturbations of the shape parameter to the sensitivity of the moments, of the partial dimensions, and of the Kaplan-Yorke dimension of the attractor. Preliminary numerical investigations provide encouraging results on the applicability of the theory presented here. The results presented here do not apply for all combinations of Axiom A systems and observables, but the breakdown seems to be related to very special geometrical configurations.

Towards a General Theory of Extremes for Observables of Chaotic Dynamical Systems

NASA Astrophysics Data System (ADS)

Lucarini, Valerio; Faranda, Davide; Wouters, Jeroen; Kuna, Tobias

2014-02-01

In this paper we provide a connection between the geometrical properties of the attractor of a chaotic dynamical system and the distribution of extreme values. We show that the extremes of so-called physical observables are distributed according to the classical generalised Pareto distribution and derive explicit expressions for the scaling and the shape parameter. In particular, we derive that the shape parameter does not depend on the chosen observables, but only on the partial dimensions of the invariant measure on the stable, unstable, and neutral manifolds. The shape parameter is negative and is close to zero when high-dimensional systems are considered. This result agrees with what was derived recently using the generalized extreme value approach. Combining the results obtained using such physical observables and the properties of the extremes of distance observables, it is possible to derive estimates of the partial dimensions of the attractor along the stable and the unstable directions of the flow. Moreover, by writing the shape parameter in terms of moments of the extremes of the considered observable and by using linear response theory, we relate the sensitivity to perturbations of the shape parameter to the sensitivity of the moments, of the partial dimensions, and of the Kaplan-Yorke dimension of the attractor. Preliminary numerical investigations provide encouraging results on the applicability of the theory presented here. The results presented here do not apply for all combinations of Axiom A systems and observables, but the breakdown seems to be related to very special geometrical configurations.

Evaluation of ifosfamide salvage therapy for metastatic canine osteosarcoma.

PubMed

Batschinski, K; Dervisis, N G; Kitchell, B E

2014-12-01

A retrospective study was performed to assess toxicity and response rate of ifosfamide salvage treatment for dogs diagnosed with metastatic osteosarcoma (OSA). Dogs diagnosed with OSA and previously treated with standard chemotherapy were included in the study. Nineteen dogs met the inclusion criteria, and 17 dogs were evaluable for response. Ifosfamide doses ranged from 375 to 425 mg m(-2) (median dose 375 mg m(-2)), with a median of two doses administered per dog (range 1-7 doses). The overall response to ifosfamide was 11.8% [complete response (CR) = 1/17, partial response (PR) = 1/17, stable disease (SD) = 2/17, progressive disease (PD) = 13/17]. Two dogs were hospitalized due to ifosfamide toxicosis. The median survival duration from the first dose of ifosfamide to death was 95 days. Ifosfamide was well tolerated, but minor anti-tumour activity was observed. © 2012 Blackwell Publishing Ltd.

Stable isotope ratios of carbon and nitrogen and mercury concentrations in 13 toothed whale species taken from the western Pacific Ocean off Japan.

PubMed

Endo, Tetsuya; Hisamichi, Yohsuke; Kimura, Osamu; Haraguchi, Koichi; Lavery, Shane; Dalebout, Merel L; Funahashi, Naoko; Baker, C Scott

2010-04-01

Stable isotope ratios of carbon (partial differential(13)C) and nitrogen (partial differential(15)N) and total mercury (T-Hg) concentrations were measured in red meat samples from 11 odontocete species (toothed whales, dolphins, and porpoises) sold in Japan (n = 96) and in muscle samples from stranded killer whales (n = 6) and melon-headed whales (n = 15), and the analytical data for these species were classified into three regions (northern, central, and southern Japan) depending on the locations in which they were caught or stranded. The partial differential(15)N in the samples from southern Japan tended to be lower than that in samples from the north, whereas both partial differential(13)C and T-Hg concentrations in samples from the south tended to higher than those in samples from northern Japan. Negative correlations were found between the partial differential(13)C and partial differential(15)N values and between the partial differential(15)N value and T-Hg concentrations in the combined samples all three regions (gamma= -0.238, n = 117, P < 0.01). The partial differential(13)C, partial differential(15)N, and T-Hg concentrations in the samples varied more by habitat than by species. Spatial variations in partial differential(13)C, partial differential(15)N, and T-Hg concentrations in the ocean may be the cause of these phenomena.

Differences in the accommodation stimulus response curves of adult myopes and emmetropes: a summary and update.

PubMed

Schmid, Katrina L; Strang, Niall C

2015-11-01

To provide a summary of the classic paper "Differences in the accommodation stimulus response curves of adult myopes and emmetropes" published in Ophthalmic and Physiological Optics in 1998 and to provide an update on the topic of accommodation errors in myopia. The accommodation responses of 33 participants (10 emmetropes, 11 early onset myopes and 12 late onset myopes) aged 18-31 years were measured using the Canon Autoref R-1 free space autorefractor using three methods to vary the accommodation demand: decreasing distance (4 m to 0.25 cm), negative lenses (0 to -4 D at 4 m) and positive lenses (+4 to 0 D at 0.25 m). We observed that the greatest accommodation errors occurred for the negative lens method whereas minimal errors were observed using positive lenses. Adult progressing myopes had greater lags of accommodation than stable myopes at higher demands induced by negative lenses. Progressing myopes had shallower response gradients than the emmetropes and stable myopes; however the reduced gradient was much less than that observed in children using similar methods. This paper has been often cited as evidence that accommodation responses at near may be primarily reduced in adults with progressing myopia and not in stable myopes and/or that challenging accommodation stimuli (negative lenses with monocular viewing) are required to generate larger accommodation errors. As an analogy, animals reared with hyperopic errors develop axial elongation and myopia. Retinal defocus signals are presumably passed to the retinal pigment epithelium and choroid and then ultimately the sclera to modify eye length. A number of lens treatments that act to slow myopia progression may partially work through reducing accommodation errors. © 2015 The Authors Ophthalmic & Physiological Optics © 2015 The College of Optometrists.

Responses to crizotinib in patients with ALK-positive lung adenocarcinoma who tested immunohistochemistry (IHC)-positive and fluorescence in situ hybridization (FISH)-negative.

PubMed

Ma, Di; Wang, Zheng; Yang, Lin; Mu, Xinlin; Wang, Yan; Zhao, Xinming; Li, Junling; Lin, Dongmei

2016-09-27

Although the Ventana immunohistochemistry (IHC) platform for detecting anaplastic lymphoma kinase gene (ALK) (D5F3) expression was recently approved by the US Food and Drugs Administration (FDA), fluorescence in situ hybridization (FISH) is still the "gold-standard" method recommended by the US National Comprehensive Cancer Network (NCCN) guideline for NSCLC. We evaluated 6 ALK-positive lung adenocarcinoma patients who tested Ventana IHC-positive and FISH-negative and assessed their clinical responses to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Histologic and cytologic specimens from the 6 patients were stained with Ventana anti-ALK(D5F3) rabbit monoclonal primary antibody using the OptiView™ DAB IHC detection kit and OptiView™ amplification kit on a Ventana BenchMark XT processor. In addition, they were also tested by FISH, qRT-PCR, next-generation sequencing (NGS), and RNAscope ISH analysis. All patients received crizotinib treatment and their follow-up clinical data were recorded. The objective response rate achieved with crizotinib therapy was 66.7% (4/6 partial responses and 2/6 stable disease). One patient in whom a new fusion type (EML4->EXOC6B->ALK fusion) was identified obtained a partial response. These findings indicate that patients with ALK-positive lung adenocarcinoma who test Ventana IHC-positive and FISH-negative may still respond to crizotinib therapy.

A qualitative systematic review of the evidence base for non-cross-resistance between steroidal and non-steroidal aromatase inhibitors in metastatic breast cancer.

PubMed

Beresford, M; Tumur, I; Chakrabarti, J; Barden, J; Rao, N; Makris, A

2011-04-01

The most effective sequence of tamoxifen and both steroidal (SAIs) and non-steroidal aromatase inhibitors (NSAIs) has been extensively studied in the adjuvant setting. However, treatments for women who have failed initial aromatase inhibitor therapy in the metastatic setting have received relatively little attention. A systematic review was undertaken to assess the use of SAIs and NSAIs in metastatic breast cancer. Medline, Embase and the Cochrane library were searched using free text and MeSH terms. Studies assessing the cross-resistance, efficacy and safety of SAIs and NSAIs for postmenopausal women with advanced metastatic breast cancer confirmed by histology/cytology were included. Patients had progressed/relapsed from previous adjuvant, first- or second-line aromatase inhibitor treatment and had undergone treatment with at least two regimens consisting of aminoglutethimide, anastrozole, letrozole and/or exemestane. Nine studies reported results for patients treated with an SAI after treatment failure with an NSAI. For SAI after NSAI, clinical benefit was the most frequently reported outcome. The clinical benefit for exemestane (SAI) after any NSAI failure or before treatment ranged from 12% (complete response not recorded, partial response 2%, stable disease 10%) to 55% (complete response 6%, partial response 13%, stable disease 35%) Survival outcomes were infrequently reported; four studies reported disease progression. The time to progression ranged from 3.7 to 5.2 months. Only one study reported a median overall survival with exemestane at 15.2 months. Only one study reported information for an NSAI after SAI and an NSAI followed by another NSAI. This review suggests that switching from an NSAI to an SAI is a reasonable option. This would be particularly important for patients who would probably respond to further endocrine manoeuvres; strongly oestrogen receptor-positive disease, non-visceral disease, a good prior response or a long duration of response. Further research to optimise the sequence of endocrine therapies in metastatic breast cancer is needed. Copyright © 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Plant family identity distinguishes patterns of carbon and nitrogen stable isotope abundance and nitrogen concentration in mycoheterotrophic plants associated with ectomycorrhizal fungi

PubMed Central

Hynson, Nicole A.; Schiebold, Julienne M.-I.; Gebauer, Gerhard

2016-01-01

Background and Aims Mycoheterotrophy entails plants meeting all or a portion of their carbon (C) demands via symbiotic interactions with root-inhabiting mycorrhizal fungi. Ecophysiological traits of mycoheterotrophs, such as their C stable isotope abundances, strongly correlate with the degree of species’ dependency on fungal C gains relative to C gains via photosynthesis. Less explored is the relationship between plant evolutionary history and mycoheterotrophic plant ecophysiology. We hypothesized that the C and nitrogen (N) stable isotope compositions, and N concentrations of fully and partially mycoheterotrophic species differentiate them from autotrophs, and that plant family identity would be an additional and significant explanatory factor for differences in these traits among species. We focused on mycoheterotrophic species that associate with ectomycorrhizal fungi from plant families Ericaceae and Orchidaceae. Methods Published and unpublished data were compiled on the N concentrations, C and N stable isotope abundances (δ13C and δ15N) of fully (n = 18) and partially (n = 22) mycoheterotrophic species from each plant family as well as corresponding autotrophic reference species (n = 156). These data were used to calculate site-independent C and N stable isotope enrichment factors (ε). Then we tested for differences in N concentration, 13C and 15N enrichment among plant families and trophic strategies. Key Results We found that in addition to differentiating partially and fully mycoheterotrophic species from each other and from autotrophs, C and N stable isotope enrichment also differentiates plant species based on familial identity. Differences in N concentrations clustered at the plant family level rather than the degree of dependency on mycoheterotrophy. Conclusions We posit that differences in stable isotope composition and N concentrations are related to plant family-specific physiological interactions with fungi and their environments. PMID:27451987

Ladder polymers for use as high temperature stable resins or coatings

NASA Technical Reports Server (NTRS)

Meador, Mary Ann (Inventor)

1990-01-01

An object of the invention is to synthesize a new class of ladder and partial ladder polymers. In accordance with the invention, the new class of ladder and partial ladder polymers are synthesized by polymerizing a bis-dienophile with a bis-diene. Another object of the invention is to provide a fabricated, electrically conducting, void free composite comprising the new class of the ladder and partial ladder polymers described above. The novelty of the invention relates to a new class of ladder and partial ladder polymers and a process for synthesizing these polymers. These polymers are soluble in common organic solvents and are characterized with a unique dehydration property at temperatures of 300 to 400 C to provide thermo-oxidatively stable pentiptycene units along the polymeric backbone. These polymers are further characterized with high softening points and good thermo-oxidative stability properties. Thus these polymers have potential as processable, matrix resins for high temperature composite applications.

Phase I studies of treatment of malignant gliomas and neoplastic meningitis with 131I-radiolabeled monoclonal antibodies anti-tenascin 81C6 and anti-chondroitin proteoglycan sulfate Me1-14 F (ab')2--a preliminary report.

PubMed

Bigner, D D; Brown, M; Coleman, R E; Friedman, A H; Friedman, H S; McLendon, R E; Bigner, S H; Zhao, X G; Wikstrand, C J; Pegram, C N

1995-01-01

The advent of monoclonal antibody (MAb) technology has made Ehrlich's postulate of the 'magic bullet' an attainable goal. Although specific localization of polyvalent antibodies to human gliomas was demonstrated in the 1960s, the lack of specific, high affinity antibody populations and of defined target antigens of sufficient density precluded therapeutic applications. Not until the identification of operationally specific tumor-associated antigens (present in tumor tissue but not normal central nervous system tissue); production of homogeneous, high affinity MAbs to such antigens; and the use of compartmental administration (intrathecal or intracystic), has the promise of passive immunotherapy of primary and metastatic central nervous system neoplasms been recognized. We report here preliminary data from Phase I studies of the compartmental administration of the anti-tenascin MAb 81C6 and F(ab2)2 fragments of MAb Me1-14, which recognizes the proteoglycan chondroitin sulfate-associated protein of gliomas and melanomas, to patients with primary central nervous system tumors or tumors metastatic to the central nervous system. Phase I dose escalation studies of intracystically administered 131I-labeled anti-tenascin MAb 81C6 to either spontaneous cysts of recurrent gliomas or surgically created cystic resection cavities have resulted in striking responses. Of five patients with recurrent cystic gliomas treated, four had partial responses, clinically or radiographically. Similarly, in patients with surgically created resection cavities, a partial response at the treatment site and extended stable disease status has been obtained following intracystic administration of 131I-labeled 81C6. No evidence of hematologic or neurologic toxicity has been observed in either patient population, with the exception of transient exacerbation of a pre-existing seizure disorder in a single patient. Dosimetry calculations indicated high intracystic retention for four to six weeks with little or no systemic dissemination; estimated total doses intracystically ranged from 12,700-70,290 rad. Intrathecal administration of labeled MAbs to patients with neoplastic meningitis is more difficult to assess in terms of clinical responsiveness. Of patients so treated with either 131I-labeled 81C6 or 131I-labeled Me1-14 (F(ab)2, cerebrospinal fluid and radiographic responses have been achieved, and survival prolongation through maintenance of stable disease has been observed in several cases. Initial results from pHase I dose escalation trials are encouraging in terms of the proportion of cases of disease stabilization and partial and complete responses obtained. Importantly, neurotoxicity has been virtually nonexistent, and hematologic toxicity rare and rapidly responsive to treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Chemotherapy for neuroendocrine tumors: the Beatson Oncology Centre experience.

PubMed

Hatton, M Q; Reed, N S

1997-01-01

The role of chemotherapy in malignant neuroendocrine tumours is difficult to assess because of their rarity and variation in biological behaviour. We present a retrospective review of chemotherapy given to 18 patients with metastatic and one with locally advanced neuroendocrine tumours. There were eight poorly differentiated neuroendocrine tumours, six thyroid medullary carcinomas, two phaeochromocytomas, two pancreatic islet cell tumours and one undifferentiated neuroblastoma. Four patients were given 3-weekly dacarbazine, vincristine and cyclophosphamide (DOC) chemotherapy. In eight patients, this regimen was modified by substituting the dacarbazine and cisplatin and etoposide (OPEC). A further six patients were treated with dacarbazine reintroduced into the 3-weekly regimen (DOPEC). The remaining patient received cisplatin and etoposide. There were two complete responses (both with OPEC) and eight partial responses (two with DOC, three with OPEC and three with DOPEC). Five patients had stable disease and four progressed. Four received further chemotherapy on relapse, producing one complete and one partial response. The median response duration to initial chemotherapy was 10 months (range 3-34). The median survival was 12 months (range 1-42). The main toxicity was haematological, with grade 3-4 neutropenia in 12 patients; eight suffered episodes of sepsis. One death was treatment related. Other toxicity was mild although three patients discontinued vincristine with grade 2 neurotoxicity. The response rate and side effects of these three regimens appear comparable. We conclude that, although these patient numbers are small, combination chemotherapy produces an encouraging response rate (53%; 95% CI 30-75) in malignant neuroendocrine tumours, with acceptable toxicity.

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

PubMed

Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C; Fecher, Leslie A; Schuchter, Lynn M; Kramer, Amy; Tan, Kay-See; Heitjan, Daniel F; Rodgers, Glenda; Gallagher, Maryann; Piao, Shengfu; Troxel, Andrea B; Evans, Tracey L; DeMichele, Angela M; Nathanson, Katherine L; O'Dwyer, Peter J; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; Amaravadi, Ravi K

2014-08-01

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.

Induction therapy with carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal radiotherapy in the treatment of locally advanced, unresectable non-small cell lung cancer: preliminary report of a phase I trial.

PubMed

Socinski, M A; Clark, J A; Halle, J; Steagall, A; Kaluzny, B; Rosenman, J G

1997-08-01

Locally advanced non-small cell lung cancer is optimally managed with chemotherapy and thoracic irradiation, although the most appropriate strategy is not yet defined. In this phase I trial, we use two 21-day cycles of induction chemotherapy with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (225 mg/m2 over 3 hours) and carboplatin (area under the concentration-time curve = 6) followed by concurrent weekly paclitaxel (45 mg/m2/wk x 6) and carboplatin (area under the concentration-time curve = 2/wk x 6) and thoracic irradiation. Patients undergo three-dimensional treatment planning (conformal radiotherapy) to define the cancer target volume precisely. The phase I question being addressed in this study is the maximum tolerated radiation dose given concurrently with low-dose paclitaxel and carboplatin. The initial radiation dose is 60 Gy, with dose escalations to 66 Gy, 70 Gy, and 74 Gy being planned. Ten patients have been entered thus far (eight men and two women). Their median age is 67 years (range, 59 to 78 years), and none of the patients has had greater than 5% pretreatment weight loss. Seven of 10 are evaluable for response to induction carboplatin and paclitaxel, with a response rate of 57% (three partial responses and one minor response). Three patients had stable disease and none of the patients had evidence of progressive disease during induction chemotherapy. Three patients have completed all treatment at 60 Gy and one has completed all treatment at 66 Gy. Three of the four patients have had partial responses (75%), with the remaining patient having stable disease. Toxicity in the concurrent chemoradiotherapy portion of the trial thus far has consisted of grade 3 neutropenia in one patient and grade 4 lymphocytopenia in all four patients. No grade 3 or 4 nonhematologic toxicity has been seen. The trial data are not yet mature enough to report on survival. Accrual and treatment is continuing at the 66 Gy radiation dose level.

Stable multi-domain spectral penalty methods for fractional partial differential equations

NASA Astrophysics Data System (ADS)

Xu, Qinwu; Hesthaven, Jan S.

2014-01-01

We propose stable multi-domain spectral penalty methods suitable for solving fractional partial differential equations with fractional derivatives of any order. First, a high order discretization is proposed to approximate fractional derivatives of any order on any given grids based on orthogonal polynomials. The approximation order is analyzed and verified through numerical examples. Based on the discrete fractional derivative, we introduce stable multi-domain spectral penalty methods for solving fractional advection and diffusion equations. The equations are discretized in each sub-domain separately and the global schemes are obtained by weakly imposed boundary and interface conditions through a penalty term. Stability of the schemes are analyzed and numerical examples based on both uniform and nonuniform grids are considered to highlight the flexibility and high accuracy of the proposed schemes.

Optimization of the AGS superconducting helical partial snake strength.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin,F.; Huang, H.; Luccio, A.U.

2008-06-23

Two helical partial snakes, one super-conducting (a.k.a cold snake) and one normal conducting (a.k.a warm snake), have preserved the polarization of proton beam up to 65% in the Brookhaven Alternating Gradient Synchrotron (AGS) at the extraction energy from 85% at injection. In order to overcome spin resonances, stronger partial snakes would be required. However, the stronger the partial snake, the more the stable spin direction tilted producing a stronger horizontal intrinsic resonance. The balance between increasing the spin tune gap generated by the snakes and reducing the tilted stable spin direction has to be considered to maintain the polarization. Becausemore » the magnetic field of the warm snake has to be a constant, only the cold snake with a maximum 3T magnetic field can be varied to find out the optimum snake strength. This paper presents simulation results by spin tracking with different cold snake magnetic fields. Some experimental data are also analyzed.« less

Clinical characteristics of non-small cell lung cancer harboring mutations in exon 20 of EGFR or HER2.

PubMed

Takeda, Masayuki; Sakai, Kazuko; Hayashi, Hidetoshi; Tanaka, Kaoru; Tanizaki, Junko; Takahama, Takayuki; Haratani, Koji; Nishio, Kazuto; Nakagawa, Kazuhiko

2018-04-20

Unlike common epidermal growth factor receptor gene ( EGFR ) mutations that confer sensitivity to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), mutations in exon 20 of either EGFR or the human EGFR2 gene ( HER2 ) are associated with insensitivity to EGFR-TKIs, with treatment options for patients with such mutations being limited. Clinical characteristics, outcome of EGFR-TKI or nivolumab treatment, and the presence of coexisting mutations were reviewed for NSCLC patients with exon-20 mutations of EGFR or HER2 as detected by routine application of an amplicon-based next-generation sequencing panel. Between July 2013 and June 2017, 206 patients with pathologically confirmed lung cancer were screened for genetic alterations including HER2 and EGFR mutations. Ten patients harbored HER2 exon-20 insertions (one of whom also carried an exon-19 deletion of EGFR ), and 12 patients harbored EGFR exon-20 mutations. Five of the 13 patients with EGFR mutations were treated with EGFR-TKIs, two of whom manifested a partial response, two stable disease, and one progressive disease. Among the seven patients treated with nivolumab, one patient manifested a partial response, three stable disease, and three progressive disease, with most (86%) of these patients discontinuing treatment as a result of disease progression within 4 months. The H1047R mutation of PIK3CA detected in one patient was the only actionable mutation coexisting with the exon-20 mutations of EGFR or HER2 . Potentially actionable mutations thus rarely coexist with exon-20 mutations of EGFR or HER2 , and EGFR-TKIs and nivolumab show limited efficacy in patients with such exon-20 mutations.

Isolation and partial characterization of a second myotropic peptide from the hindgut of the cockroach, Leucophaea maderae.

PubMed

Holman, G M; Cook, B J

1983-01-01

Proctolin and a second myotropic peptide were extracted from the hindgut of the cockroach Leucophaea maderae with methanol-water-acetic acid (90:9:1). The two peptides were easily separated by HPLC on a mu-Bondapak-phenyl column. Like proctolin, the second peptide was heat stable and was inactivated by the exopeptidases aminopeptidase M and carboxypeptidase Y. The response of the isolated hindgut to the new peptide was distinguishable from the response to proctolin by the following features: (a) a longer interval following application (1-4 min) to reach a maximum contraction, and (b) a much larger amplitude for single phasic contractions. Like proctolin, the new peptide could cause a protracted stimulation of the hindgut for more than 2 hr.

A dose escalation feasibility study of lenalidomide for treatment of symptomatic, relapsed chronic lymphocytic leukemia☆

PubMed Central

Maddocks, Kami; Ruppert, Amy S.; Browning, Rebekah; Jones, Jeffrey; Flynn, Joseph; Kefauver, Cheryl; Gao, Yue; Jiang, Yao; Rozewski, Darlene M.; Poi, Ming; Phelps, Mitch A.; Harper, Erica; Johnson, Amy J.; Byrd, John C.; Andritsos, Leslie A.

2015-01-01

Adequate dosing of lenalidomide in Chronic Lymphocytic Leukemia (CLL) remains unclear. This study determined maximum tolerated dose (MTD) in relapsed CLL patients (Cohort A) and patients achieving a partial response (PR) or better to recent therapy (Cohort B). Thirty-seven patients were enrolled. MTD was 2.5 mg followed by 5.0 mg continuous. In Cohort A, tumor flare grade 1–2 occurred in 15 patients (50%) and grade 3 in 1 patient (3%). Cohort A had 19 of 23 evaluable (83%) patients, 4 PR (17%) and 15 (65%) stable disease (SD), Cohort B had 6 of 7 patients (86%) with SD. Despite overall response rate not being high, many patients remained on therapy several months with SD. PMID:25082342

Erlotinib as a single agent in select subsets of patients with advanced non-small-cell lung cancer.

PubMed

Carrión, Ramón Pérez; Gracián, Antonio Cubillo; Hernandez, Pedro Salinas

2007-07-01

Erlotinib is an orally active inhibitor of the epidermal growth factor receptor that is effective for the treatment of non-small-cell lung cancer (NSCLC). Patients with a poor performance status (PS) of 2 constitute up to 40% of advanced NSCLC. This group of patients have a lower life expectancy and are thought to have a greater degree of treatment-related toxicity. The clinical benefit on 238 patients with poor PS included in an open-label, nonrandomized, phase II trial of erlotinib in advanced/metastatic NSCLC was 57.58% defined as complete response plus partial response plus stable disease. Median time to progression was 2.9 months. This review will summarize available data about erlotinib on patients with a PS of 2.

Plant family identity distinguishes patterns of carbon and nitrogen stable isotope abundance and nitrogen concentration in mycoheterotrophic plants associated with ectomycorrhizal fungi.

PubMed

Hynson, Nicole A; Schiebold, Julienne M-I; Gebauer, Gerhard

2016-09-01

Mycoheterotrophy entails plants meeting all or a portion of their carbon (C) demands via symbiotic interactions with root-inhabiting mycorrhizal fungi. Ecophysiological traits of mycoheterotrophs, such as their C stable isotope abundances, strongly correlate with the degree of species' dependency on fungal C gains relative to C gains via photosynthesis. Less explored is the relationship between plant evolutionary history and mycoheterotrophic plant ecophysiology. We hypothesized that the C and nitrogen (N) stable isotope compositions, and N concentrations of fully and partially mycoheterotrophic species differentiate them from autotrophs, and that plant family identity would be an additional and significant explanatory factor for differences in these traits among species. We focused on mycoheterotrophic species that associate with ectomycorrhizal fungi from plant families Ericaceae and Orchidaceae. Published and unpublished data were compiled on the N concentrations, C and N stable isotope abundances (δ(13)C and δ(15)N) of fully (n = 18) and partially (n = 22) mycoheterotrophic species from each plant family as well as corresponding autotrophic reference species (n = 156). These data were used to calculate site-independent C and N stable isotope enrichment factors (ε). Then we tested for differences in N concentration, (13)C and (15)N enrichment among plant families and trophic strategies. We found that in addition to differentiating partially and fully mycoheterotrophic species from each other and from autotrophs, C and N stable isotope enrichment also differentiates plant species based on familial identity. Differences in N concentrations clustered at the plant family level rather than the degree of dependency on mycoheterotrophy. We posit that differences in stable isotope composition and N concentrations are related to plant family-specific physiological interactions with fungi and their environments. © The Author 2016. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Stable, Ultra-Low Residence Time Partial Oxidation

DOEpatents

Schmidt, Lanny D.; Hickman, Daniel A.

1997-07-15

A process for the catalytic partial oxidation of methane in gas phase at very short residence time (800,000 to 12,000,000 hr.sup.-1) by contacting a gas stream containing methane and oxygen with a metal supported catalyst, such as platinum deposited on a ceramic monolith.

Intraperitoneal implant of recombinant encapsulated cells overexpressing alpha-L-iduronidase partially corrects visceral pathology in mucopolysaccharidosis type I mice.

PubMed

Baldo, Guilherme; Mayer, Fabiana Quoos; Martinelli, Barbara; Meyer, Fabiola Schons; Burin, Maira; Meurer, Luise; Tavares, Angela Maria Vicente; Giugliani, Roberto; Matte, Ursula

2012-08-01

Mucopolysaccharidosis type I (MPS I) is characterized by deficiency of the enzyme alpha-L-iduronidase (IDUA) and storage of glycosaminoglycans (GAG) in several tissues. Current available treatments present limitations, thus the search for new therapies. Encapsulation of recombinant cells within polymeric structures combines gene and cell therapy and is a promising approach for treating MPS I. We produced alginate microcapsules containing baby hamster kidney (BHK) cells overexpressing IDUA and implanted these capsules in the peritoneum of MPS I mice. An increase in serum and tissue IDUA activity was observed at early time-points, as well as a reduction in GAG storage; however, correction in the long term was only partially achieved, with a drop in the IDUA activity being observed a few weeks after the implant. Analysis of the capsules obtained from the peritoneum revealed inflammation and a pericapsular fibrotic process, which could be responsible for the reduction in IDUA levels observed in the long term. In addition, treated mice developed antibodies against the enzyme. The results suggest that the encapsulation process is effective in the short term but improvements must be achieved in order to reduce the immune response and reach a stable correction.

Stable, synthetic analogs of diadenosine tetraphosphate inhibit rat and human P2X3 receptors and inflammatory pain.

PubMed

Viatchenko-Karpinski, Viacheslav; Novosolova, Natalia; Ishchenko, Yevheniia; Azhar, M Ameruddin; Wright, Michael; Tsintsadze, Vera; Kamal, Ahmed; Burnashev, Nail; Miller, Andrew D; Voitenko, Nana; Giniatullin, Rashid; Lozovaya, Natalia

2016-01-01

A growing body of evidence suggests that ATP-gated P2X3 receptors (P2X3Rs) are implicated in chronic pain. We address the possibility that stable, synthetic analogs of diadenosine tetraphosphate (Ap4A) might induce antinociceptive effects by inhibiting P2X3Rs in peripheral sensory neurons. The effects of two stable, synthetic Ap4A analogs (AppNHppA and AppCH2ppA) are studied firstly in vitro on HEK293 cells expressing recombinant rat P2XRs (P2X2Rs, P2X3Rs, P2X4Rs, and P2X7Rs) and then using native rat brain cells (cultured trigeminal, nodose, or dorsal root ganglion neurons). Thereafter, the action of these stable, synthetic Ap4A analogs on inflammatory pain and thermal hyperalgesia is studied through the measurement of antinociceptive effects in formalin and Hargreaves plantar tests in rats in vivo. In vitro inhibition of rat P2X3Rs (not P2X2Rs, P2X4Rs nor P2X7Rs) is shown to take place mediated by high-affinity desensitization (at low concentrations; IC50 values 100-250 nM) giving way to only weak partial agonism at much higher concentrations (EC50 values ≥ 10 µM). Similar inhibitory activity is observed with human recombinant P2X3Rs. The inhibitory effects of AppNHppA on nodose, dorsal root, and trigeminal neuron whole cell currents suggest that stable, synthetic Ap4A analogs inhibit homomeric P2X3Rs in preference to heteromeric P2X2/3Rs. Both Ap4A analogs mediate clear inhibition of pain responses in both in vivo inflammation models. Stable, synthetic Ap4A analogs (AppNHppA and AppCH2ppA) being weak partial agonist provoke potent high-affinity desensitization-mediated inhibition of homomeric P2X3Rs at low concentrations. Therefore, both analogs demonstrate clear potential as potent analgesic agents for use in the management of chronic pain associated with heightened P2X3R activation. © The Author(s) 2016.

Stable, synthetic analogs of diadenosine tetraphosphate inhibit rat and human P2X3 receptors and inflammatory pain

PubMed Central

Viatchenko-Karpinski, Viacheslav; Novosolova, Natalia; Ishchenko, Yevheniia; Azhar, M Ameruddin; Wright, Michael; Tsintsadze, Vera; Kamal, Ahmed; Burnashev, Nail; Voitenko, Nana; Giniatullin, Rashid; Lozovaya, Natalia

2016-01-01

Background A growing body of evidence suggests that ATP-gated P2X3 receptors (P2X3Rs) are implicated in chronic pain. We address the possibility that stable, synthetic analogs of diadenosine tetraphosphate (Ap4A) might induce antinociceptive effects by inhibiting P2X3Rs in peripheral sensory neurons. Results The effects of two stable, synthetic Ap4A analogs (AppNHppA and AppCH2ppA) are studied firstly in vitro on HEK293 cells expressing recombinant rat P2XRs (P2X2Rs, P2X3Rs, P2X4Rs, and P2X7Rs) and then using native rat brain cells (cultured trigeminal, nodose, or dorsal root ganglion neurons). Thereafter, the action of these stable, synthetic Ap4A analogs on inflammatory pain and thermal hyperalgesia is studied through the measurement of antinociceptive effects in formalin and Hargreaves plantar tests in rats in vivo. In vitro inhibition of rat P2X3Rs (not P2X2Rs, P2X4Rs nor P2X7Rs) is shown to take place mediated by high-affinity desensitization (at low concentrations; IC50 values 100–250 nM) giving way to only weak partial agonism at much higher concentrations (EC50 values ≥ 10 µM). Similar inhibitory activity is observed with human recombinant P2X3Rs. The inhibitory effects of AppNHppA on nodose, dorsal root, and trigeminal neuron whole cell currents suggest that stable, synthetic Ap4A analogs inhibit homomeric P2X3Rs in preference to heteromeric P2X2/3Rs. Both Ap4A analogs mediate clear inhibition of pain responses in both in vivo inflammation models. Conclusions Stable, synthetic Ap4A analogs (AppNHppA and AppCH2ppA) being weak partial agonist provoke potent high-affinity desensitization-mediated inhibition of homomeric P2X3Rs at low concentrations. Therefore, both analogs demonstrate clear potential as potent analgesic agents for use in the management of chronic pain associated with heightened P2X3R activation. PMID:27030723

End-of-Treatment Positron Emission Tomography After Uniform First-Line Therapy of B-Cell Posttransplant Lymphoproliferative Disorder Identifies Patients at Low Risk of Relapse in the Prospective German PTLD Registry.

PubMed

Zimmermann, Heiner; Denecke, Timm; Dreyling, Martin H; Franzius, Christiane; Reinke, Petra; Subklewe, Marion; Amthauer, Holger; Kneba, Michael; Riess, Hanno; Trappe, Ralf U

2018-05-01

Fluorine-18 fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) is a recommended standard in the staging and response assessment of 18F-FDG-avid lymphoma. Posttransplant lymphoproliferative disorder (PTLD) can be detected by 18F-FDG-PET at diagnosis with high sensitivity and specificity. However, the role of response assessment by end-of-treatment (EOT) PET has only been addressed in small case series. We performed a retrospective, multicenter study of 37 patients with CD20-positive PTLD after solid organ transplantation treated with uniform, up-to-date, first-line protocols in the prospective German PTLD registry who had received EOT 18F-FDG-PET between 2006 and 2014. Median follow-up was 5.0 years. Any nonphysiological 18F-FDG uptake (Deauville score greater 2) was interpreted as PET-positive. By computed tomography (CT) final staging, 18 of 37 patients had a complete response, 18 had a partial response and 1 patient had stable disease. EOT PET was negative in 24 of 37 patients and positive in 13 of 37 patients. The positive predictive value of EOT PET for PTLD relapse was 38%, and the negative predictive value was 92%. Time to progression (TTP) and progression-free-survival were significantly longer in the PET negative group (P = 0.019 and P = 0.013). In the 18 patients in a partial response by CT staging, we noted highly significant differences in overall survival (P = 0.001), time to progression (P = 0.007), and progression-free survival (P < 0.001) by EOT PET. Even without baseline imaging, EOT PET in PTLD identifies patients at low risk of relapse and offers clinically relevant information, particularly in patients in a partial remission by CT staging.

Formestane, a steroidal aromatase inhibitor after failure of non-steroidal aromatase inhibitors (anastrozole and letrozole): is a clinical benefit still achievable?

PubMed

Carlini, P; Frassoldati, A; De Marco, S; Casali, A; Ruggeri, E M; Nardi, M; Papaldo, P; Fabi, A; Paoloni, F; Cognetti, F

2001-11-01

There are few clinical data on the sequential use of aromatase inhibitors (AI). This paper focuses on the relevance of clinical benefit CB (CR + PR + SD > or = 6 months) in postmenopausal metastatic breast cancer (MBC) patients treated with the steroidal aromatase inhibitor (SAI) formestane (FOR). who had already received non-steroidal aromatase inhibitor (nSAI): letrozole (LTZ) or anastrozole (ANZ). Twenty postmenopausal women with MBC were analysed in this retrospective two-centre study with the sequence nSAI-FOR. When receiving ANZ, 1 of 11 achieved a complete response and 9 of 11 a stable disease > or = 6 months, and receiving LTZ 1 of 9 achieved a partial response and 4 of 9 a stable disease > or = 6 months. The analysis of the entire population treated with FOR showed an overall CB of 55% (11 of 20) with a median duration of 15 months and median time to progression (TTP) of 6 months. Formestane 250 mg once bi-weekly seems to be an attractive alternative third-line hormonal therapy for the treatment of patients with MBC, previously treated with nSAI.

Pattern of Retained Contrast on Immediate Postprocedure Computed tomography (CT) After Particle Embolization of Liver Tumors Predicts Subsequent Treatment Response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang Xiaodong, E-mail: wangxde@gmail.com; Erinjeri, Joseph P., E-mail: erinjerj@mskcc.org; Jia Xiaoyu, E-mail: jiax@mskcc.org

2013-08-01

PurposeTo determine if the pattern of retained contrast on immediate postprocedure computed tomography (CT) after particle embolization of hepatic tumors predicts modified Response Evaluation Criteria in Solid Tumors (mRECIST) response.Materials and MethodsThis study was approved by the Institutional Review Board with a waiver of authorization. One hundred four liver tumors were embolized with spherical embolic agents (Embospheres, Bead Block, LC Bead) and polyvinyl alcohol. Noncontrast CT was performed immediately after embolization to assess contrast retention in the targeted tumors, and treatment response was assessed by mRECIST criteria on follow-up CT (average time 9.0 {+-} 7.7 weeks after embolization). Tumor contrastmore » retention (TCR) was determined based on change in Hounsfield units (HUs) of the index tumors between the preprocedure and immediate postprocedure scans; vascular contrast retention (VCR) was rated; and defects in contrast retention (DCR) were also documented. The morphology of residual enhancing tumor on follow-up CT was described as partial, circumferential, or total. Association between TCR variables and tumor response were assessed using multivariate logistic regression.ResultsOf 104 hepatic tumors, 51 (49 %) tumors had complete response (CR) by mRECIST criteria; 23 (22.1 %) had partial response (PR); 21 (20.2 %) had stable disease (SD); and 9 (8.7 %) had progressive disease (PD). By multivariate analysis, TCR, VCR, and tumor size are independent predictors of CR (p = 0.02, 0.05, and 0.005 respectively). In 75 tumors, DCR was found to be an independent predictor of failure to achieve complete response (p < 0.0001) by imaging criteria.ConclusionTCR, VCR, and DCR on immediate posttreatment CT are independent predictors of CR by mRECIST criteria.« less

Feasibility and performance of an adaptive contrast-oriented FDG PET/CT quantification technique for global disease assessment of malignant pleural mesothelioma and a brief review of the literature.

PubMed

Marin-Oyaga, Victor A; Salavati, Ali; Houshmand, Sina; Pasha, Ahmed Khurshid; Gharavi, Mohammad; Saboury, Babak; Basu, Sandip; Torigian, Drew A; Alavi, Abass

2015-01-01

Treatment of malignant pleural mesothelioma (MPM) remains very challenging. Assessment of response to treatment is necessary for modifying treatment and using new drugs. Global disease assessment (GDA) by implementing image processing methods to extract more information out of positron emission tomography (PET) images may provide reliable information. In this study we show the feasibility of this method of semi-quantification in patients with mesothelioma, and compare it with the conventional methods. We also present a review of the literature about this topic. Nineteen subjects with histologically proven MPM who had undergone fluoride-18-fluorodeoxyglucose PET/computed tomography ((18)F-FDG PET/CT) before and after treatment were included in this study. An adaptive contrast-oriented thresholding algorithm was used for the image analysis and semi-quantification. Metabolic tumor volume (MTV), maximum and mean standardized uptake volume (SUVmax, SUVmean) and total lesion glycolysis (TLG) were calculated for each region of interest. The global tumor glycolysis (GTG) was obtained by summing up all TLG. Treatment response was assessed by the European Organisation for Research and Treatment of Cancer (EORTC) criteria and the changes of GTG. Agreement between global disease assessment and conventional method was also determined. In patients with progressive disease based on EORTC criteria, GTG showed an increase of 150.7 but in patients with stable or partial response, GTG showed a decrease of 433.1. The SUVmax of patients before treatment was 5.95 (SD: 2.93) and after the treatment it increased to 6.38 (SD: 3.19). Overall concordance of conventional method with GDA method was 57%. Concordance of progression of disease based on conventional method was 44%, stable disease was 85% and partial response was 33%. Discordance was 55%, 14% and 66%. Adaptive contrast-oriented thresholding algorithm is a promising method to quantify the whole tumor glycolysis in patients with mesothelioma. We are able to assess the total metabolic lesion volume, lesion glycolysis, SUVmax, tumor SUVmean and GTG for this particular tumor. Also we were able to demonstrate the potential use of this technique in the monitoring of treatment response. More studies comparing this technique with conventional and other global disease assessment methods are needed in order to clarify its role in the assessment of treatment response and prognosis of these patients.

Inferring the source of evaporated waters using stable H and O isotopes

EPA Science Inventory

Stable isotope ratios of H and O are widely used to identify the source of water, e.g., in aquifers, river runoff, soils, plant xylem, and plant-based beverages. In situations where the sampled water is partially evaporated, its isotope values will have evolved along an evaporati...

Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart.

PubMed

Levitan, Bryana M; Manning, Janet R; Withers, Catherine N; Smith, Jeffrey D; Shaw, Robin M; Andres, Douglas A; Sorrell, Vincent L; Satin, Jonathan

2016-12-01

Sympathetic stimulation modulates L-type calcium channel (LTCC) gating to contribute to increased systolic heart function. Rad is a monomeric G-protein that interacts with LTCC. Genetic deletion of Rad (Rad -/- ) renders LTCC in a sympathomimetic state. The study goal was to use a clinically inspired pharmacological stress echocardiography test, including analysis of global strain, to determine whether Rad -/- confers tonic positive inotropic heart function. Sarcomere dynamics and strain showed partial parallel isoproterenol (ISO) responsiveness for wild-type (WT) and for Rad -/- . Rad -/- basal inotropy was elevated compared to WT but was less responsiveness to ISO. Rad protein levels were lower in human patients with end-stage non-ischemic heart failure. These results show that Rad reduction provides a stable inotropic response rooted in sarcomere level function. Thus, reduced Rad levels in heart failure patients may be a compensatory response to need for increased output in the setting of HF. Rad deletion suggests a future therapeutic direction for inotropic support.

Qualitative radiology assessment of tumor response: does it measure up?

PubMed

Gottlieb, Ronald H; Litwin, Alan; Gupta, Bhavna; Taylor, John; Raczyk, Cheryl; Mashtare, Terry; Wilding, Gregory; Fakih, Marwan

2008-01-01

Our purpose was to assess whether a simpler qualitative evaluation of tumor response by computed tomography is as reproducible and predictive of clinical outcome as the Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) methods. This study was a two-reader retrospective evaluation in which qualitative assessment resulted in agreement in 21 of 23 patients with metastatic colorectal carcinoma (91.3%, kappa=0.78; 95% CI, 0.51-1.00). Hepatic metastases were classified as increased, decreased, or unchanged, compared with agreement in 20 of 23 patients (87.0%) for RECIST (kappa=0.62; 95% CI, 0.23-1.00) and WHO (kappa=0.67; 95% CI, 0.34-1.00) methods. Patients were placed into partial response, stable disease, and disease progression categories. Time to progression of disease was better predicted qualitatively than by RECIST or WHO. Our pilot data suggest that our qualitative scoring system is more reproducible and predictive of patient clinical outcome than the RECIST and WHO methods.

Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart

PubMed Central

Levitan, Bryana M.; Manning, Janet R.; Withers, Catherine N.; Smith, Jeffrey D.; Shaw, Robin M.; Andres, Douglas A.; Sorrell, Vincent L.

2016-01-01

Sympathetic stimulation modulates L-type calcium channel (LTCC) gating to contribute to increased systolic heart function. Rad is a monomeric G-protein that interacts with LTCC. Genetic deletion of Rad (Rad−/−) renders LTCC in a sympathomimetic state. The study goal was to use a clinically inspired pharmacological stress echocardiography test, including analysis of global strain, to determine whether Rad−/− confers tonic positive inotropic heart function. Sarcomere dynamics and strain showed partial parallel isoproterenol (ISO) responsiveness for wild-type (WT) and for Rad−/−. Rad−/− basal inotropy was elevated compared to WT but was less responsiveness to ISO. Rad protein levels were lower in human patients with end-stage non-ischemic heart failure. These results show that Rad reduction provides a stable inotropic response rooted in sarcomere level function. Thus, reduced Rad levels in heart failure patients may be a compensatory response to need for increased output in the setting of HF. Rad deletion suggests a future therapeutic direction for inotropic support. PMID:27798760

A retrospective analysis of hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis

PubMed Central

Yuan, Meiqin; Wang, Zeng; Hu, Guinv; Yang, Yunshan; Lv, Wangxia; Lu, Fangxiao; Zhong, Haijun

2016-01-01

Peritoneal metastasis (PM) is a poor prognostic factor in patients with gastric cancer. The aim of this study was to evaluate the efficacy and safety of hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with advanced gastric cancer with PM by retrospective analysis. A total of 54 gastric cancer patients with positive ascitic fluid cytology were included in this study: 23 patients were treated with systemic chemotherapy combined with HIPEC (HIPEC+ group) and 31 received systemic chemotherapy alone (HIPEC- group). The patients were divided into 4 categories according to the changes of ascites, namely disappear, decrease, stable and increase. The disappear + decrease rate in the HIPEC+ group was 82.60%, which was statistically significantly superior to that of the HIPEC- group (54.80%). The disappear + decrease + stable rate was 95.70% in the HIPEC+ group and 74.20% in the HIPEC- group, but the difference was not statistically significant. In 33 patients with complete survival data, including 12 from the HIPEC+ and 21 from the HIPEC- group, the median progression-free survival was 164 and 129 days, respectively, and the median overall survival (OS) was 494 and 223 days, respectively. In patients with ascites disappear/decrease/stable, the OS appeared to be better compared with that in patients with ascites increase, but the difference was not statistically significant. Further analysis revealed that patients with controlled disease (complete response + partial response + stable disease) may have a better OS compared with patients with progressive disease, with a statistically significant difference. The toxicities were well tolerated in both groups. Therefore, HIPEC was found to improve survival in advanced gastric cancer patients with PM, but the difference was not statistically significant, which may be attributed to the small number of cases. Further studies with larger samples are required to confirm our data. PMID:27446587

Stable carbonous catalyst particles and method for making and utilizing same

DOEpatents

Ganguli, Partha S.; Comolli, Alfred G.

2005-06-14

Stable carbonous catalyst particles composed of an inorganic catalytic metal/metal oxide powder and a carbonaceous binder material are formed having a basic inner substantially uniform-porous carbon coating of the catalytic powder, and may include an outer porous carbon coating layer. Suitable inorganic catalytic powders include zinc-chromite (ZnO/Cr.sub.2 03) and suitable carbonaceous liquid binders having molecular weight of 200-700 include partially polymerized furfuryl alcohol, which are mixed together, shaped and carbonized and partially oxidized at elevated temperature. Such stable carbonous catalyst particles such as 0.020-0.100 inch (0.51-2.54 mm) diameter extrudates, have total carbon content of 2-25 wt. % and improved crush strength of 1.0-5 1b/mn, 50-300 m.sup.2 /g surface area, and can be advantageously utilized in fixed bed or ebullated/fluidized bed reactor operations. This invention also includes method steps for making the stable carbonous catalyst particles having improved particle strength and catalytic activity, and processes for utilizing the active stable carbonous carbon-coated catalysts such as for syn-gas reactions in ebullated/fluidized bed reactors for producing alcohol products and Fischer-Tropsch synthesis liquid products.

Structure of β- N-dimethylamino-4-dodecyloxypropiophenone complexes with di- and polycarboxylic acids

NASA Astrophysics Data System (ADS)

Lebedeva, Tamara L.; Shandryuk, George A.; Sycheva, Tatyana I.; Bezborodov, Vladimir S.; Talroze, Raissa V.; Platé, Nicolai A.

1995-07-01

The type of bonds responsible for the complexation of di- and polyacids with the tertiary amine β- N-dimethylamino-4-dodecyloxypropiophenone is studied by means of FTIR spectroscopy. The complexes are shown to be stable due to strong H-bonding with partial charge transfer. The characteristic composition for complexes of polyacrylic, polymethacrylic and malonic acids is calculated as 2:1 (number of carboxylic groups per number of amine molecules) whereas glutaric acid forms complexes of different composition including 1:1. The characteristic composition results from the structure of the initial acid. The structures of both the characteristic complex and "excess" acid are also discussed.

Effect of surface texture and structure on the development of stable fluvial armors

NASA Astrophysics Data System (ADS)

Bertin, Stephane; Friedrich, Heide

2018-04-01

Stable fluvial armors are found in river systems under conditions of partial sediment transport and limited sediment supply, a common occurrence in nature. Stable armoring is also readily recreated in experimental flumes. Initially, this bed stabilizing phenomenon was examined for different flow discharges and solely related to surface coarsening and bedload transport reduction. The models developed suggest a specific armor composition (i.e., texture) dependent on the parent bed material and formative discharge. Following developments in topographic remote sensing, recent research suggests that armor structure is an important control on bed stability and roughness. In this paper, replicated flume runs during which digital elevation models (DEMs) were collected from both exposed and flooded gravel beds are used to interpret armoring manifestations and to assess their replicability. A range of methodologies was used for the analysis, providing information on (i) surface grain size and orientation, (ii) bed-elevation distributions, (iii) the spatial coherence of the elevations at the grain-scale, (iv) surface slope and aspect, (v) grain imbrication and (vi) the spatial variability in DEM properties. The bed-surface topography was found to be more responsive than bed-material size to changes in flow strength. Our experimental results also provide convincing evidence that gravel-beds' response to water-work during parallel degradation is unique (i.e., replicable) given the formative parameters. Based on this finding, relationships between the armors' properties and formative parameters are proposed, and are supported by adding extensive data from previous research.

Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE for Metastatic Neuroendocrine Tumor Occurring in Association with Multiple Endocrine Neoplasia Type 1 and Cushing's Syndrome.

PubMed

Naik, Chinna; Basu, Sandip

2017-01-01

Neuroendocrine tumor (NET) occurring in association with other endocrine syndromes forms a distinct entity. The aim was to assess the therapy response profile of the routine peptide receptor radionuclide therapy (PRRT) in this relatively uncommon but clinically challenging subgroup of patients. A retrospective analysis was undertaken from the case records from those who were treated with 177 Lu-DOTATATE for metastatic NET. In addition to assessing the therapeutic efficacy, emphasis was also given to study lesional sites and scan pattern. A total of 5 cases were found: In this series of five cases, four belonged to multiple endocrine neoplasia type 1 (MEN1) syndrome; in these four MEN1 syndrome patients, the primary site of NET was thymic region ( n = 1), duodenum ( n = 1), and pancreas ( n = 2). The fifth case was of Cushing's syndrome with the primary site of NET in the thymus. A good symptomatic response was observed in all MEN1 syndrome cases (100%) and progression of symptoms in the patient with Cushing's syndrome. The biochemical response (assessed by measurement of tumor marker serum chromogranin A) demonstrated very good partial response (defined by more than 75% reduction of tumor marker) in 2 MEN1 cases and Cushing's syndrome, good partial response (25-75% reduction of tumor marker) in the remaining 2 MEN1 cases. Scan wise (assessed by technetium [ 99m Tc]-hydrazinonicotinamide [HYNIC]-tektrotyd [TOC]/ 68 Ga-DOTA-NOC/TATE positron emission tomography-computed tomography [PET-CT] and fluorodeoxyglucose [FDG] PET-CT) partial response was observed in 3 MEN1 cases, stable disease was noted in one MEN1 case and disease progression was noted in the patient with Cushing's syndrome. The change in FDG uptake was found to be an important sensitive scan parameter in the treatment evaluation of NETs compared to somatostatin receptor-based imaging in the cases with low MiB1 index. In our series, good palliative response to 177 Lu-DOTA-octreotate (DOTATATE) PRRT was observed in most NET patients associated with MEN1 syndrome without any major hematological or renal toxicity.

Eribulin mesylate (halichondrin B Analog E7389) in platinum-resistant and platinum-sensitive ovarian cancer: a two-cohort, phase II study

PubMed Central

Hensley, Martee L.; Kravetz, Sara; Jia, Xiaoyu; Iasonos, Alexia; Tew, William; Pereira, Lauren; Sabbatini, Paul; Whalen, Christin; Aghajanian, Carol A.; Zarwan, Corinne; Berlin, Suzanne

2011-01-01

Background Eribulin mesylate is a tubulin inhibitor with activity superior to paclitaxel in NIH:OVCAR-3 human epithelial ovarian cancer xenograft models. We sought to assess the efficacy of eribulin in platinum-resistant and platinum-sensitive recurrent ovarian cancer. Methods Patients with recurrent measurable epithelial ovarian cancer, ≤2 prior cytotoxic regimens, and adequate organ function were enrolled into two separate cohorts: 1) Platinum resistant (progression-free interval from last platinum-based therapy <6 months); and 2) Platinum sensitive (progression-free interval from last platinum-based therapy ≥6 months). Treatment: Eribulin 1.4 mg/m2 over 15 minutes by vein on days 1 and 8, every 21 days. Efficacy was determined by objective response by computed tomography. Results Platinum-resistant cohort: Thirty-seven patients enrolled. Thirty-six patients were evaluable for response and toxicity. Two patients achieved partial response (PR, 5.5%). Sixteen (44%) had a best response of stable disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.4–2.8 months). Platinum-sensitive cohort: Thirty-seven patients enrolled, and all were evaluable for response. Seven patients achieved partial response (PR, 19%). Median progression-free survival was 4.1 months (95% confidence interval, 2.8–5.8 months). The major toxicity was grade 3 or 4 neutropenia (42% in platinum-resistant patients; 54% in platinum-sensitive patients). Conclusions Eribulin achieved objective response in 5.5% of women with platinum-resistant recurrent ovarian cancer and in 19% of women with platinum-sensitive disease. Median progression-free survival was 1.8 months in the platinum-resistant group and 4.1 months in the platinum-sensitive group. PMID:21935916

Efficacy of Capecitabine Plus Oxaliplatin Combination Chemotherapy for Advanced Pancreatic Cancer after Failure of First-Line Gemcitabine-Based Therapy.

PubMed

Chung, Kwang Hyun; Ryu, Ji Kon; Son, Jun Hyuk; Lee, Jae Woo; Jang, Dong Kee; Lee, Sang Hyub; Kim, Yong-Tae

2017-03-15

Second-line chemotherapy in patients with advanced pancreatic ductal adenocarcinoma (PDAC) that progresses following gemcitabine-based treatment has not been established. This study aimed to investigate the efficacy and safety of second-line combination chemotherapy with capecitabine and oxaliplatin (XELOX) in these patients. Between August 2011 and May 2014, all patients who received at least one cycle of XELOX (capecitabine, 1,000 mg/m 2 twice daily for 14 days; oxaliplatin, 130 mg/m 2 on day 1 of a 3-week cycle) combination chemotherapy for unresectable or recurrent PDAC were retrospectively recruited. The response was evaluated every 9 weeks, and the tumor response rate, progression-free survival and overall survival, and adverse events were assessed. Sixty-two patients were included; seven patients (11.3%) had a partial tumor response, and 20 patients (32.3%) had stable disease. The median progression-free and overall survival were 88 days (range, 35.1 to 140.9 days) and 158 days (range, 118.1 to 197.9 days), respectively. Patients who remained stable longer with frontline therapy (≥120 days) exhibited significantly longer progression-free and overall survival. The most common grade 3 to 4 adverse events in patients were vomiting (8.1%) and anorexia (6.5%). There was one treatment-related mortality caused by severe neutropenia and typhlitis. Second-line XELOX combination chemotherapy demonstrated an acceptable response and survival rate in patients with advanced PDAC who had failed gemcitabine-based chemotherapy.

How to build stable geochemical reservoirs on Mars?

NASA Astrophysics Data System (ADS)

Plesa, Ana-Catalina; Tosi, Nicola; Breuer, Doris

2014-05-01

To explain the complex thermo-chemical processes needed for the formation of distinct and stable geochemical reservoirs early in the thermo-chemical evolution of Mars, most geochemical studies argue that fractional crystallization of a global magma ocean may reproduce the isotopic characteristic of the SNCs [1, 2]. However, geodynamical models show that such scenario is difficult to reconcile with other observations like late volcanic activity and crustal density values as obtained from gravity and topography modelling [3, 4]. The stable density gradient, which establishes after the mantle overturn has completed, inhibits thermal convection. Albeit capable to provide stable reservoirs, this scenario suggests a conductive mantle after the overturn which on the one hand fails to sample deep regions of the mantle and on the other hand is clearly at odds with the volcanic history of Mars. This is best explained by assuming a convective mantle and partial melting as the principal agents responsible for the generation and evolution of Martian volcanism. Therefore, in this work an alternative scenario for the formation of early stable geochemical reservoirs is presented similar to the model of [5]. We investigate the influence of partial melting on mantle dynamics, crustal formation, and volcanic outgassing of a one-plate planet using a 2D mantle convection code. When melt is extracted to form crust, the mantle material left behind is more buoyant than its parent material and depleted in radioactive heat sources. The extracted heat-producing elements are then enriched in the crust, which also has an insulating effect due to its lower thermal conductivity compared to the mantle. In addition, partial melting can influence the mantle rheology through the dehydration (water depletion) of the mantle material by volcanic outgassing. As a consequence, the viscosity of water-depleted regions increases more than two orders of magnitude compared to water-saturated rocks resulting in slower cooling rates. The most important parameter influencing the thermo-chemical evolution is the assumed density difference between the primitive and the depleted mantle material (i.e., between peridotite and harzburgite). With small or negligible values of compositional buoyancy, crustal formation including crustal delamination is very efficient, also resulting in efficient processing and degassing of the mantle. The entire convecting mantle below the stagnant lid depletes continuously with time. In contrast, with increasing compositional buoyancy, crustal formation and mantle degassing are strongly suppressed although partial melting is substantially prolonged in the thermal evolution. The crust shows strong lateral variations in thickness, and crustal delamination is reduced and occurs only locally. Furthermore, two to four different mantle reservoirs can form depending on the initial temperature distribution [6]. Some of these reservoirs can be sustained during the entire evolution whereas others change with time - a scenario possibly valid for Mars as it may explain the isotope characteristic of the Martian meteorites. References: [1] Elkins-Tanton et al., 2005, EPSL; [2] Debaille et al., 2009, Nature; [3] Tosi et al., 2013, JGR; [4] Plesa et al., submitted to EPSL; [5] Ogawa and Yanagisawa 2011, JGR; [6] Plesa and Breuer, 2013, PSS.

Repeated iodine-125 seed implantations combined with external beam radiotherapy for the treatment of locally recurrent or metastatic stage III/IV non-small cell lung cancer: a retrospective study.

PubMed

Li, Wei; Dan, Gang; Jiang, Jianqing; Zheng, Yifeng; Zheng, Xiushan; Deng, Dan

2016-09-13

Recurrent or metastatic lung cancer is difficult to manage. This retrospective study aimed to assess the efficacy of repeated iodine-125 seed implantations combined with external beam radiotherapy (EBRT) for locally recurrent or metastatic stage-III/IV non-small cell lung cancer (NSCLC). Eighteen previously treated stage-III/IV NSCLC patients with local or metastatic recurrences underwent 1-to-3 iodine-125 implantations. Six of these patients received palliative EBRT and six patients received combined chemotherapy using gemcitabine and cisplatin. Near-term treatment efficacy was evaluated 3 months after seed implantation by comparing changes in tumor size on computed tomography images; the evaluated outcomes were complete response, partial response, stable disease, and local tumor control rate. Long-term efficacy was assessed based on 1- and 2-year survival rates. Patients were followed up for 6 to 50 months. The overall (i.e., complete + partial) response rate was 87.4 %. The local control rates after the first, second, and third years were 94.1, 58.8 and 41.2 %, respectively. The results of this study demonstrated that repeated implantation of radioactive particles combined with EBRT is a safe treatment that effectively controlled local recurrence and metastasis of stage III/IV NSCLC.

Toxicity and response in cats with neoplasia treated with toceranib phosphate.

PubMed

Harper, Aaron; Blackwood, Laura

2017-06-01

Objectives Toceranib phosphate is a tyrosine kinase inhibitor licensed for the treatment of non-resectable Patnaik grade II/III recurrent cutaneous mast cell tumours in dogs. There is no information in cats regarding the tolerated dose, toxicity or tumour response of this drug. The aim of this study was to analyse retrospectively a cohort of cats with advanced neoplasia treated with toceranib to identify toxicity and response. Methods The medical records of the Small Animal Teaching Hospital were reviewed. Cats were included if they had received toceranib for at least 2 weeks for the treatment of histologically or cytologically confirmed neoplastic disease, and had at least one set of monitoring blood tests (haematology, biochemistry) performed after baseline tests. Toxicity was graded according to the Veterinary Comparative Oncology Group - common terminology criteria for adverse events(VCOG-CTCAE) and response was measured according to Response Evaluation In Solid Tumors (RECIST) criteria. Results Fourteen cats met the inclusion criteria, the majority of which (13/14) had received previous therapy (surgery, radiotherapy, chemotherapy). The most common tumour types were mast cell tumours or malignant epithelial tumours. Toxicity occurred in 10/14 cats - 10 cats had mild myelosuppression or gastrointestinal effects. Two cats developed severe hepatoxicity. One cat died from congestive heart failure, although whether this was related to toceranib therapy is unknown. Regarding response, one cat achieved complete response; two cats achieved partial response and five cats achieved stable disease: overall biological response rate was 57.1%. All of the cats that achieved either partial or complete response were treated for mast cell disease. Overall median duration of response was 90 days (range 14-570 days). None of the cats with squamous cell carcinoma achieved a response. Conclusions and relevance Toceranib phosphate is generally well tolerated in cats, with toxicity limited to mild gastrointestinal or myelosuppressive effects in the majority of cases (10/14) in this study; however, hepatotoxicity is a concern. Response to treatment in this small cohort was similar to that reported in dogs.

Performance of 177Lu-DOTATATE-based peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumor: a multiparametric response evaluation correlating with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics.

PubMed

Thapa, Pradeep; Ranade, Rohit; Ostwal, Vikas; Shrikhande, Shailesh V; Goel, Mahesh; Basu, Sandip

2016-10-01

To assess the performance of Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in metastatic gastroenteropancreatic neuroendocrine tumor (GEP-NET) and correlate it with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics. Fifty patients (M : F 33 : 17, age: 26-71 years) with histopathologically confirmed metastatic/inoperable NETs who had undergone at least three cycles of PRRT with Lu-DOTATATE were included in the analysis. As part of the pretreatment evaluation, they underwent either Tc-HYNIC TOC (n=40)/Ga-DOTATATE PET (n=10) or fluorine-18-fluorodeoxyglucose (F-FDG) PET-computed tomography (CT). Response was assessed after three and five cycles PRRT on the basis of three parameters: (a) symptomatic and subjective scale, (b) biochemical tumor marker level, and (c) objective imaging (F-FDG/Ga DOTATATE PET/CT, Tc-HYNIC TOC, ceCT), and was categorized using predefined criteria (detailed in methods). Stable disease on imaging assessment with response on symptomatic or biochemical tumor marker scales or both were included in the responder group. The study population was broadly classified into (a) metastatic GEP-NET with known primary (n=43 i.e. 86%), which was further subclassified according to the site of primary and (b) those with unknown primary (n=7 i.e. 14%). Symptomatic response: 96% of patients showed a symptomatic response or improvement in health-related quality of life, irrespective of tumor proliferation index, dual tracer imaging characteristics, and response or progression of disease in the scan. Biochemical tumor marker response: 83% of scan responders showed a decrease, 10% showed a stable value, and 7% showed an increase in tumor marker levels. Among the scan nonresponders, 67% patients showed a corresponding increase in the tumor marker level, 22% patient showed a decrease, whereas 11% showed stable values. Scan response: 31 out of total 50 patients (62%) showed a partial scan response with either a decrease in the number of somatostatin receptor (SSTR)-positive lesions or metabolic activity in F-FDG/Ga-DOTATATE PET-CT or both, 10 patients (20%) showed stable disease, and nine patients (18%) showed progressive disease. The higher objective partial scan response documented can be explained by the introduction of the F-FDG-PET/CT parameter as a determinant criterion. Among the responders category (n=41), 32 (78.04%) showed discordance between F-FDG-PET/CT-based and SSTR-based imaging, whereas eight out of nine patients with nonresponse category (88.89%) showed concordance between SSTR-based imaging and F-FDG-PET/CT. Conversely, 32 of 33 patients (96.97%) with SSTR/F-FDG discordance and nine out of 17 (52.94%) with concordance were finally classified as responders, whereas the remaining, that is, 1/33 (3.03%) in the 'discordant' category and 8/17 (47.06%) with imaging concordance were classified as nonresponders, respectively. Our data show that high pretherapy F-FDG maximum standardized uptake values were associated with increased chances of treatment refractoriness in GEP-NETs. However, symptomatic improvement was observed in most cases irrespective of grade and F-FDG uptake. High pretherapy F-FDG maximum standardized uptake value in both low-grade and high-grade NET predicted a poor outcome and was associated with disease progression. Introduction of F-FDG-PET/CT parameter as a determinant of response classification increases the percentage of objective scan responders among patients with grades I and II GEP-NETs as F-FDG activity was observed to decrease before SSTR-based imaging and more frequently compared with the latter.

Modified Organosilica Core-Shell Nanoparticles for Stable pH Sensing in Biological Solutions.

PubMed

Robinson, Kye J; Huynh, Gabriel T; Kouskousis, Betty P; Fletcher, Nicholas L; Houston, Zachary H; Thurecht, Kristofer J; Corrie, Simon R

2018-04-19

Continuous monitoring using nanoparticle-based sensors has been successfully employed in complex biological systems, yet the sensors still suffer from poor long-term stability partially because of the scaffold materials chosen to date. Organosilica core-shell nanoparticles containing a mixture of covalently incorporated pH-sensitive (shell) and pH-insensitive (core) fluorophores is presented as a continuous pH sensor for application in biological media. In contrast to previous studies focusing on similar materials, we sought to investigate the sensor characteristics (dynamic range, sensitivity, response time, stability) as a function of material properties. The ratio of the fluorescence intensities at specific wavelengths was found to be highly sensitive to pH over a physiologically relevant range (4.5-8) with a response time of <100 ms, significantly faster than that of previously reported response times using silica-based particles. Particles produced stable, pH-specific signals when stored at room temperature for more than 80 days. Finally, we demonstrated that the nanosensors successfully monitored the pH of a bacterial culture over 15 h and that pH changes in the skin of mouse cadavers could also be observed via in vivo fluorescence imaging following subcutaneous injection. The understanding gained from linking sensor characteristics and material properties will inform the next generation of optical nanosensors for continuous-monitoring applications.

Subcellular glucose exposure biases the spatial distribution of insulin granules in single pancreatic beta cells.

PubMed

Terao, Kyohei; Gel, Murat; Okonogi, Atsuhito; Fuke, Ariko; Okitsu, Teru; Tada, Takashi; Suzuki, Takaaki; Nagamatsu, Shinya; Washizu, Masao; Kotera, Hidetoshi

2014-02-18

In living tissues, a cell is exposed to chemical substances delivered partially to its surface. Such a heterogeneous chemical environment potentially induces cell polarity. To evaluate this effect, we developed a microfluidic device that realizes spatially confined delivery of chemical substances at subcellular resolution. Our microfluidic device allows simple setup and stable operation for over 4 h to deliver chemicals partially to a single cell. Using the device, we showed that subcellular glucose exposure triggers an intracellular [Ca(2+)] change in the β-cells. In addition, the imaging of a cell expressing GFP-tagged insulin showed that continuous subcellular exposure to glucose biased the spatial distribution of insulin granules toward the site where the glucose was delivered. Our approach illustrates an experimental technique that will be applicable to many biological experiments for imaging the response to subcellular chemical exposure and will also provide new insights about the development of polarity of β-cells.

Subcellular glucose exposure biases the spatial distribution of insulin granules in single pancreatic beta cells

PubMed Central

Terao, Kyohei; Gel, Murat; Okonogi, Atsuhito; Fuke, Ariko; Okitsu, Teru; Tada, Takashi; Suzuki, Takaaki; Nagamatsu, Shinya; Washizu, Masao; Kotera, Hidetoshi

2014-01-01

In living tissues, a cell is exposed to chemical substances delivered partially to its surface. Such a heterogeneous chemical environment potentially induces cell polarity. To evaluate this effect, we developed a microfluidic device that realizes spatially confined delivery of chemical substances at subcellular resolution. Our microfluidic device allows simple setup and stable operation for over 4 h to deliver chemicals partially to a single cell. Using the device, we showed that subcellular glucose exposure triggers an intracellular [Ca2+] change in the β-cells. In addition, the imaging of a cell expressing GFP-tagged insulin showed that continuous subcellular exposure to glucose biased the spatial distribution of insulin granules toward the site where the glucose was delivered. Our approach illustrates an experimental technique that will be applicable to many biological experiments for imaging the response to subcellular chemical exposure and will also provide new insights about the development of polarity of β-cells. PMID:24535122

Identification and partial characterization of a latent ATP, Mg-dependent protein phosphatase in rabbit skeletal muscle cytosol.

PubMed

Vandenheede, J R; Staquet, S; Merlevede, W

1989-05-04

Fractionation of rabbit skeletal muscle cytosol on Aminohexyl-Sepharose has resulted in the identification of a latent ATP, Mg-dependent protein phosphatase whose catalytic subunit is in the active conformation, but is inhibited by the presence of more than one modulator unit. The partially purified enzyme is converted to an inactive, kinase FA-dependent form upon incubation at 30 degrees C unless modulator-specific polyclonal antibodies are added to the preparation. The immunoglobulins also relieve the inhibition which is responsible for the low basal phosphatase activity of the enzyme, and they counteract all of the heat-stable inhibitor activity present in the preparation. Addition of free catalytic subunit abolishes the inhibition of the latent enzyme in a dose-dependent way, but cannot prevent the inactivation process. The inactivated phosphatase and the original latent enzyme exhibit the same apparent Mr in sucrose density-gradient centrifugation (70,000) and in gel filtration (110,000).

Activity and safety of the antiestrogen EM-800, the orally active precursor of acolbifene, in tamoxifen-resistant breast cancer.

PubMed

Labrie, Fernand; Champagne, Pierre; Labrie, Claude; Roy, Jean; Laverdière, Jacques; Provencher, Louise; Potvin, Martin; Drolet, Yvan; Pollak, Michael; Panasci, Lawrence; L'Espérance, Bernard; Dufresne, Jean; Latreille, Jean; Robert, Jean; Samson, Benoît; Jolivet, Jacques; Yelle, Louise; Cusan, Lionel; Diamond, Pierre; Candas, Bernard

2004-03-01

To determine the efficacy and safety of EM-800 (SCH-57050), the precursor of acolbifene, a new, highly potent, orally active, pure antiestrogen in the mammary gland and endometrium, for the treatment of tamoxifen-resistant breast cancer. Forty-three post menopausal/ovariectomized women with breast cancer who had received tamoxifen, either for metastatic disease or as adjuvant to surgery for > or = 1 year, and had relapsed were treated in a prospective, multicenter, phase II study with EM-800 (20 mg/d [n = 21] or 40 mg/d [n = 22] orally). Results Thirty-seven patients had estrogen receptor (ER)-positive tumors (>10 fmol/mg; mean, 146 fmol/mg cytosolic protein), three patients had ER-negative/progesterone receptor-positive tumors, and three patients had undetermined ER status. The objective response rate to EM-800 was 12%, with one complete response and four partial responses. Ten patients (23%) had stable disease for > or = 3 months, and 7 patients (16%) had stable disease for > or = 6 months. With a median follow-up of 29 months, median duration of response was 8 months (range, 7 to 71+ months). Treatment with EM-800 was well tolerated. No significant adverse events related to the study drug were observed clinically or biochemically. EM-800 produced responses in a significant proportion of patients with tamoxifen-resistant breast cancer, thus showing that this highly potent, selective estrogen receptor modulator, which lacks estrogenic activity in the mammary gland and endometrium, has incomplete cross-resistance with tamoxifen, thus suggesting additional benefits in the treatment of breast cancer.

Bartonella spp. DNA Associated with Biting Flies from California

PubMed Central

Chung, Crystal Y.; Kasten, Rickie W.; Paff, Sandra M.; Van Horn, Brian A.; Vayssier-Taussat, Muriel; Boulouis, Henri-Jean

2004-01-01

Bartonella DNA was investigated in 104 horn flies (Haematobia spp.), 60 stable flies (Stomoxys spp.), 11 deer flies (Chrysops spp.), and 11 horse flies (Tabanus spp.) collected on cattle in California. Partial sequencing indicated B. bovis DNA in the horn fly pool and B. henselae type M DNA in one stable fly. PMID:15324557

Stability and growth of continental shields in mantle convection models including recurrent melt production

NASA Astrophysics Data System (ADS)

de Smet, J. H.; van den Berg, A. P.; Vlaar, N. J.

1998-10-01

The long-term growth and stability of compositionally layered continental upper mantle has been investigated by numerical modelling. We present the first numerical model of a convecting mantle including differentiation through partial melting resulting in a stable compositionally layered continental upper mantle structure. This structure includes a continental root extending to a depth of about 200 km. The model covers the upper mantle including the crust and incorporates physical features important for the study of the continental upper mantle during secular cooling of the Earth since the Archaean. Among these features are: a partial melt generation mechanism allowing consistent recurrent melting, time-dependent non-uniform radiogenic heat production, and a temperature- and pressure-dependent rheology. The numerical results reveal a long-term growth mechanism of the continental compositional root. This mechanism operates through episodical injection of small diapiric upwellings from the deep layer of undepleted mantle into the continental root which consists of compositionally distinct depleted mantle material. Our modelling results show the layered continental structure to remain stable during at least 1.5 Ga. After this period mantle differentiation through partial melting ceases due to the prolonged secular cooling and small-scale instabilities set in through continental delamination. This stable period of 1.5 Ga is related to a number of limitations in our model. By improving on these limitations in the future this stable period will be extended to more realistic values.

Partially coherent axiconic surface plasmon polariton fields

NASA Astrophysics Data System (ADS)

Chen, Yahong; Norrman, Andreas; Ponomarenko, Sergey A.; Friberg, Ari T.

2018-04-01

We introduce a class of structured polychromatic surface electromagnetic fields, reminiscent of conventional optical axicon fields, through a judicious superposition of partially correlated surface plasmon polaritons. We show that such partially coherent axiconic surface plasmon polariton fields are structurally stable and statistically highly versatile with regard to spectral density, polarization state, energy flow, and degree of coherence. These fields can be created by plasmon coherence engineering and may prove instrumental broadly in surface physics and in various nanophotonics applications.

TU-C-12A-02: Development of a Multiparametric Statistical Response Map for Quantitative Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bosca, R; The University of Texas MD Anderson Cancer Center, Houston, TX; Mahajan, A

2014-06-15

Purpose: Quantitative imaging biomarkers (QIB) are becoming increasingly utilized in early phase clinical trials as a means of non-invasively assessing treatment response and associated response heterogeneity. The aim of this study was to develop a flexible multiparametric statistical framework to predict voxel-by-voxel response of several potential MRI QIBs. Methods: Patients with histologically proven glioblastomas (n=11) were treated with chemoradiation (with/without bevacizumab) and underwent one baseline and two mid-treatment (3–4wks) MRIs. Dynamic contrast-enhanced (3D FSPGR, 6.3sec/phase, 0.1 mmol/kg Gd-DTPA), dynamic susceptibility contrast (2D GRE-EPI, 1.5sec/phase, 0.2mmol/kg Gd-DTPA), and diffusion tensor (2D DW-EPI, b=0, 1200 s/mm{sup 2}, 27 directions) imaging acquisitions weremore » obtained during each study. Mid-treatment and pre-treatment images were rigidly aligned, and regions of partial response (PR), stable disease (SD), and progressive disease (PD) were contoured in consensus by two experienced radiation oncologists. Voxels in these categories were used to train ordinal (PR« less

A phase I study of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors potentially responsive to mitoxantrone

PubMed Central

Resta, Lee P.; Pili, Roberto; Eisenberger, Mario A.; Spitz, Avery; King, Serina; Porter, Jennifer; Franke, Amy; Boinpally, Ramesh; Sweeney, Christopher J.

2010-01-01

Purpose To find the maximum tolerated dose (MTD) of OSI-461 in combination with mitoxantrone in patients with advanced solid tumors. Methods This was a Phase I study using cohort dose escalation of OSI-461 dosed orally twice daily in combination with mitoxantrone 12 mg/m2 given on Day 1 of each 21-day cycle. Results OSI-461 dose was escalated to 1,000 mg po bid. One patient experienced a dose-limiting toxicity (DLT). Three patients discontinued the study due to adverse events (AE). Two patients (10%) had a partial response, and ten patients (50%) had stable disease as best response. Conclusion The combination of OSI-461 and mitoxantrone was well tolerated. Dose escalation was stopped because of toxicities in a concurrent Phase I trial. The response rate seen in patients with prostate cancer was comparable to response rates seen in trials of mitoxantrone and prednisone alone, and further studies of the combination of OSI-461 and mitoxantrone were not pursued. PMID:20445979

Response Assessment in Paediatric Phase I Trials According to RECIST Guidelines: Survival Outcomes, Patterns of Progression and Relevance of Changes in Tumour Measurements.

PubMed

Carceller, Fernando; Bautista, Francisco J; Fowkes, Lucy A; Marshall, Lynley V; Sirvent, Sara I; Chisholm, Julia C; Pearson, Andrew D J; Koh, Dow-Mu; Moreno, Lucas

2016-08-01

RECIST guidelines constitute the reference for radiological response assessment in most paediatric trials of anticancer agents. However, these criteria have not been validated in children. We evaluated the outcomes and patterns of progression of children/adolescents enrolled in phase I trials in two paediatric drug development units. Patients aged ≤21 assessed with RECIST (v1.0 or v1.1) were eligible. Clinico-radiological data were analysed using Mann-Whitney U and log-rank tests to correlate response categories and sum of longest diameters (SLD) with time-to-event variables and overall survival (OS). Sixty-one patients (71 enrolments) were evaluated; median age: 12.7 years (range, 3.1-20.9). Overall, 7% achieved complete/partial response (n = 5) and 31% disease stabilisation (n = 22). Median (95% CI) OS (in months) was 29.1 (27.6-30.6) with complete/partial response, 8.9 (2.0-15.8) with stable disease and 2.8 (2.3-3.3) with disease progression (P < 0.001); 32.6% patients with measurable disease presented exclusive progression of existing non-target lesions and/or new lesions. The change in SLD at best response showed a linear correlation with duration of response (r = -0.605; P = 0.004) and time on trial (r = -0.61; P = 0.003), but the change in SLD at progression did not correlate with time to progression (r = -0.219; P = 0.206). Response assessment according to RECIST correlated with OS in children/adolescents treated on phase I trials. The reduction in SLD at best response correlated with more prolonged responses. Tumour size did not constitute an optimal method to assess disease progression in one third of patients with measurable disease. Further refinement of current response assessment guidelines will enable the development of paediatric-specific radiological criteria. © 2016 Wiley Periodicals, Inc.

Chemoembolization for Hepatocellular Carcinoma Supplied by a Lumbar Artery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Han Myun, E-mail: seoul49@naver.com; Kim, Hyo-Cheol, E-mail: angiointervention@gmail.com; Woo, Sungmin, E-mail: j-crew7@hotmail.com

PurposeTo describe the radiologic findings and imaging response of hepatocellular carcinoma (HCC) supplied by the lumbar artery.MethodsBetween April 2004 and December 2012, we encountered HCC supplied by a lumbar artery in 21 patients. Two investigators retrospectively reviewed clinical and radiological findings of HCC supplied by the lumbar artery using computed tomography (CT) scans and digital subtraction angiograms.ResultsPatients had received 1–27 sessions of previous chemoembolization procedures (mean 7.7 sessions, median 4 sessions). Mean tumor size was 5.3 cm. The locations of HCC supplied by lumbar artery were the bare area (n = 14, 67 %) and segment VI (n = 7, 33 %). Tumor-feeding arteries arose from themore » main lumbar artery (n = 7), proximal anterior division (n = 4), and distal anterior division (n = 14). In 20 patients, selective chemoembolization through the tumor-feeding arteries of the lumbar artery was achieved. In 1 patient, nonselective embolization at the main lumbar artery was performed. There was no complication such as skin necrosis or paralysis. On the first follow-up enhanced CT scan, target tumors fed by the lumbar artery showed complete response (n = 6), partial response (n = 4), stable disease (n = 3), and progressive disease (n = 8), but overall tumor response was partial response (n = 1) and progressive disease (n = 20).ConclusionWhen HCC is located in the inferior tip or bare area of the liver, a lumbar artery may supply the tumor. Although selective chemoembolization via the tumor-feeding vessel of the lumbar artery can be achieved in most cases, overall tumor response is commonly unfavorable.« less

Semiquantitative visual approach to scoring lung cancer treatment response using computed tomography: a pilot study.

PubMed

Gottlieb, Ronald H; Kumar, Prasanna; Loud, Peter; Klippenstein, Donald; Raczyk, Cheryl; Tan, Wei; Lu, Jenny; Ramnath, Nithya

2009-01-01

Our objective was to compare a newly developed semiquantitative visual scoring (SVS) method with the current standard, the Response Evaluation Criteria in Solid Tumors (RECIST) method, in the categorization of treatment response and reader agreement for patients with metastatic lung cancer followed by computed tomography. The 18 subjects (5 women and 13 men; mean age, 62.8 years) were from an institutional review board-approved phase 2 study that evaluated a second-line chemotherapy regimen for metastatic (stages III and IV) non-small cell lung cancer. Four radiologists, blinded to the patient outcome and each other's reads, evaluated the change in the patients' tumor burden from the baseline to the first restaging computed tomographic scan using either the RECIST or the SVS method. We compared the numbers of patients placed into the partial response, the stable disease (SD), and the progressive disease (PD) categories (Fisher exact test) and observer agreement (kappa statistic). Requiring the concordance of 3 of the 4 readers resulted in the RECIST placing 17 (100%) of 17 patients in the SD category compared with the SVS placing 9 (60%) of 15 patients in the partial response, 5 (33%) of the 15 patients in the SD, and 1 (6.7%) of the 15 patients in the PD categories (P < 0.0001). Interobserver agreement was higher among the readers using the SVS method (kappa, 0.54; P < 0.0001) compared with that of the readers using the RECIST method (kappa, -0.01; P = 0.5378). Using the SVS method, the readers more finely discriminated between the patient response categories with superior agreement compared with the RECIST method, which could potentially result in large differences in early treatment decisions for advanced lung cancer.

Peptide vaccine immunotherapy biomarkers and response patterns in pediatric gliomas

PubMed Central

Müller, Sören; Agnihotri, Sameer; Shoger, Karsen E.; Myers, Max I.; Chaparala, Srilakshmi; Villanueva, Clarence R.; Chattopadhyay, Ansuman; Butterfield, Lisa H.; Okada, Hideho; Pollack, Ian F.

2018-01-01

Low-grade gliomas (LGGs) are the most common brain tumor affecting children. We recently reported an early phase clinical trial of a peptide-based vaccine, which elicited consistent antigen-specific T cell responses in pediatric LGG patients. Additionally, we observed radiologic responses of stable disease (SD), partial response (PR), and near-complete/complete response (CR) following therapy. To identify biomarkers of clinical response in peripheral blood, we performed RNA sequencing on PBMC samples collected at multiple time points. Patients who showed CR demonstrated elevated levels of T cell activation markers, accompanied by a cytotoxic T cell response shortly after treatment initiation. At week 34, patients with CR demonstrated both IFN signaling and Poly-IC:LC adjuvant response patterns. Patients with PR demonstrated a unique, late monocyte response signature. Interestingly, HLA-V expression, before or during therapy, and an early monocytic hematopoietic response were strongly associated with SD. Finally, low IDO1 and PD-L1 expression before treatment and early elevated levels of T cell activation markers were associated with prolonged progression-free survival. Overall, our data support the presence of unique peripheral immune patterns in LGG patients associated with different radiographic responses to our peptide vaccine immunotherapy. Future clinical trials, including our ongoing phase II LGG vaccine immunotherapy, should monitor these response patterns. PMID:29618666

Cerebral blood flow during paroxysmal EEG activation induced by sleep in patients with complex partial seizures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gozukirmizi, E.; Meyer, J.S.; Okabe, T.

1982-01-01

Cerebral blood flow (CBF) measurements were combined with sleep polysomnography in nine patients with complex partial seizures. Two methods were used: the 133Xe method for measuring regional (rCBF) and the stable xenon CT method for local (LCBF). Compared to nonepileptic subjects, who show diffuse CBF decreases during stages I-II, non-REM sleep onset, patients with complex partial seizures show statistically significant increases in CBF which are maximal in regions where the EEG focus is localized and are predominantly seen in one temporal region but are also propagated to other cerebral areas. Both CBF methods gave comparable results, but greater statistical significancemore » was achieved by stable xenon CT methodology. CBF increases are more diffuse than predicted by EEG paroxysmal activity recorded from scalp electrodes. An advantage of the 133Xe inhalation method was achievement of reliable data despite movement of the head. This was attributed to the use of a helmet which maintained the probes approximated to the scalp. Disadvantages were poor resolution (7 cm3) and two-dimensional information. The advantage of stable xenon CT method is excellent resolution (80 mm3) in three dimensions, but a disadvantage is that movement of the head in patients with seizure disorders may limit satisfactory measurements.« less

Signature program: a platform of basket trials.

PubMed

Slosberg, Eric D; Kang, Barinder P; Peguero, Julio; Taylor, Matthew; Bauer, Todd M; Berry, Donald A; Braiteh, Fadi; Spira, Alexander; Meric-Bernstam, Funda; Stein, Steven; Piha-Paul, Sarina A; Salvado, August

2018-04-20

Investigating targeted therapies can be challenging due to diverse tumor mutations and slow patient accrual for clinical studies. The Signature Program is a series of 8 phase 2, agent-specific basket protocols using a rapid study start-up approach involving no predetermined study sites. Each protocol evaluated 1 agent (buparlisib, dovitinib, binimetinib, encorafenib, sonidegib, BGJ398, ceritinib, or ribociclib) in patients with solid or hematologic malignancies and an actionable mutation. The primary endpoint of each study was the clinical benefit rate (ie, complete or partial response, or stable disease) at 16 weeks. A total of 192 individual sites were opened in the United States, with a median start-up time of 3.6 weeks. The most common tumor types among the 595 treated patients were colorectal (9.2%), non-small cell lung adenocarcinoma (9.1%), and ovarian (8.4%). Frequent genetic alterations were in PIK3CA , RAS , p16 , and PTEN . Overall, 30 partial or complete responses were observed with 6 compounds in 16 tumor types. The Signature Program presents a unique and successful approach for rapid signal finding across multiple tumors and allowed various agents to be evaluated in patients with rare alterations. Incorporating these program features in conventional studies could lead to improved trial efficiencies and patient outcomes.

Signature program: a platform of basket trials

PubMed Central

Peguero, Julio; Taylor, Matthew; Bauer, Todd M.; Berry, Donald A.; Braiteh, Fadi; Spira, Alexander; Meric-Bernstam, Funda; Stein, Steven; Piha-Paul, Sarina A.; Salvado, August

2018-01-01

Investigating targeted therapies can be challenging due to diverse tumor mutations and slow patient accrual for clinical studies. The Signature Program is a series of 8 phase 2, agent-specific basket protocols using a rapid study start-up approach involving no predetermined study sites. Each protocol evaluated 1 agent (buparlisib, dovitinib, binimetinib, encorafenib, sonidegib, BGJ398, ceritinib, or ribociclib) in patients with solid or hematologic malignancies and an actionable mutation. The primary endpoint of each study was the clinical benefit rate (ie, complete or partial response, or stable disease) at 16 weeks. A total of 192 individual sites were opened in the United States, with a median start-up time of 3.6 weeks. The most common tumor types among the 595 treated patients were colorectal (9.2%), non-small cell lung adenocarcinoma (9.1%), and ovarian (8.4%). Frequent genetic alterations were in PIK3CA, RAS, p16, and PTEN. Overall, 30 partial or complete responses were observed with 6 compounds in 16 tumor types. The Signature Program presents a unique and successful approach for rapid signal finding across multiple tumors and allowed various agents to be evaluated in patients with rare alterations. Incorporating these program features in conventional studies could lead to improved trial efficiencies and patient outcomes. PMID:29765547

Changes in microbial communities, photosynthesis and calcification of the coral Acropora gemmifera in response to ocean acidification.

PubMed

Zhou, Guowei; Yuan, Tao; Cai, Lin; Zhang, Weipeng; Tian, Renmao; Tong, Haoya; Jiang, Lei; Yuan, Xiangcheng; Liu, Sheng; Qian, Peiyuan; Huang, Hui

2016-10-27

With the increasing anthropogenic CO 2 concentration, ocean acidification (OA) can have dramatic effects on coral reefs. However, the effects of OA on coral physiology and the associated microbes remain largely unknown. In the present study, reef-building coral Acropora gemmifera collected from a reef flat with highly fluctuating environmental condition in the South China Sea were exposed to three levels of partial pressure of carbon dioxide (pCO 2 ) (i.e., 421, 923, and 2070 μatm) for four weeks. The microbial community structures associated with A. gemmifera under these treatments were analyzed using 16S rRNA gene barcode sequencing. The results revealed that the microbial community associated with A. gemmifera was highly diverse at the genus level and dominated by Alphaproteobacteria. More importantly, the microbial community structure remained rather stable under different pCO 2 treatments. Photosynthesis and calcification in A. gemmifera, as indicated by enrichment of δ 18 O and increased depletion of δ 13 C in the coral skeleton, were significantly impaired only at the high pCO 2 (2070 μatm). These results suggest that A. gemmifera can maintain a high degree of stable microbial communities despite of significant physiological changes in response to extremely high pCO 2 .

Changes in microbial communities, photosynthesis and calcification of the coral Acropora gemmifera in response to ocean acidification

NASA Astrophysics Data System (ADS)

Zhou, Guowei; Yuan, Tao; Cai, Lin; Zhang, Weipeng; Tian, Renmao; Tong, Haoya; Jiang, Lei; Yuan, Xiangcheng; Liu, Sheng; Qian, Peiyuan; Huang, Hui

2016-10-01

With the increasing anthropogenic CO2 concentration, ocean acidification (OA) can have dramatic effects on coral reefs. However, the effects of OA on coral physiology and the associated microbes remain largely unknown. In the present study, reef-building coral Acropora gemmifera collected from a reef flat with highly fluctuating environmental condition in the South China Sea were exposed to three levels of partial pressure of carbon dioxide (pCO2) (i.e., 421, 923, and 2070 μatm) for four weeks. The microbial community structures associated with A. gemmifera under these treatments were analyzed using 16S rRNA gene barcode sequencing. The results revealed that the microbial community associated with A. gemmifera was highly diverse at the genus level and dominated by Alphaproteobacteria. More importantly, the microbial community structure remained rather stable under different pCO2 treatments. Photosynthesis and calcification in A. gemmifera, as indicated by enrichment of δ18O and increased depletion of δ13C in the coral skeleton, were significantly impaired only at the high pCO2 (2070 μatm). These results suggest that A. gemmifera can maintain a high degree of stable microbial communities despite of significant physiological changes in response to extremely high pCO2.

Changes in microbial communities, photosynthesis and calcification of the coral Acropora gemmifera in response to ocean acidification

PubMed Central

Zhou, Guowei; Yuan, Tao; Cai, Lin; Zhang, Weipeng; Tian, Renmao; Tong, Haoya; Jiang, Lei; Yuan, Xiangcheng; Liu, Sheng; Qian, Peiyuan; Huang, Hui

2016-01-01

With the increasing anthropogenic CO2 concentration, ocean acidification (OA) can have dramatic effects on coral reefs. However, the effects of OA on coral physiology and the associated microbes remain largely unknown. In the present study, reef-building coral Acropora gemmifera collected from a reef flat with highly fluctuating environmental condition in the South China Sea were exposed to three levels of partial pressure of carbon dioxide (pCO2) (i.e., 421, 923, and 2070 μatm) for four weeks. The microbial community structures associated with A. gemmifera under these treatments were analyzed using 16S rRNA gene barcode sequencing. The results revealed that the microbial community associated with A. gemmifera was highly diverse at the genus level and dominated by Alphaproteobacteria. More importantly, the microbial community structure remained rather stable under different pCO2 treatments. Photosynthesis and calcification in A. gemmifera, as indicated by enrichment of δ18O and increased depletion of δ13C in the coral skeleton, were significantly impaired only at the high pCO2 (2070 μatm). These results suggest that A. gemmifera can maintain a high degree of stable microbial communities despite of significant physiological changes in response to extremely high pCO2. PMID:27786309

Collective phase description of oscillatory convection

NASA Astrophysics Data System (ADS)

Kawamura, Yoji; Nakao, Hiroya

2013-12-01

We formulate a theory for the collective phase description of oscillatory convection in Hele-Shaw cells. It enables us to describe the dynamics of the oscillatory convection by a single degree of freedom which we call the collective phase. The theory can be considered as a phase reduction method for limit-cycle solutions in infinite-dimensional dynamical systems, namely, stable time-periodic solutions to partial differential equations, representing the oscillatory convection. We derive the phase sensitivity function, which quantifies the phase response of the oscillatory convection to weak perturbations applied at each spatial point, and analyze the phase synchronization between two weakly coupled Hele-Shaw cells exhibiting oscillatory convection on the basis of the derived phase equations.

Active lamp pulse driver circuit. [optical pumping of laser media

NASA Technical Reports Server (NTRS)

Logan, K. E. (Inventor)

1983-01-01

A flashlamp drive circuit is described which uses an unsaturated transistor as a current mode switch to periodically subject a partially ionized gaseous laser excitation flashlamp to a stable, rectangular pulse of current from an incomplete discharge of an energy storage capacitor. A monostable multivibrator sets the pulse interval, initiating the pulse in response to a flash command by providing a reference voltage to a non-inverting terminal of a base drive amplifier; a tap on an emitter resistor provides a feedback signal sensitive to the current amplitude to an inverting terminal of amplifier, thereby controlling the pulse amplitude. The circuit drives the flashlamp to provide a squarewave current flashlamp discharge.

A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hiniker, Susan M., E-mail: shiniker@stanford.edu; Reddy, Sunil A.; Maecker, Holden T.

Purpose: Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte–associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses. Methods and Materials: In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles. RT to 1 to 2 disease sites was initiated within 5 days after starting ipilimumab. Patients had ≥1 nonirradiated metastasismore » measuring ≥1.5 cm available for response assessment. Tumor imaging studies were obtained at baseline, 2 to 4 weeks after cycle 4 of ipilimumab, and every 3 months until progression. Laboratory immune response parameters were measured before and during treatment. Results: Combination therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%) experienced clinical benefit from therapy, including complete and partial responses and stable disease at median follow-up of 55 weeks. Three patients (27.3%) achieved an ongoing systemic complete response at a median follow-up of 55 weeks (range 32-65), and 3 (27.3%) had an initial partial response for a median of 40 weeks. Analysis of immune response data suggested a relationship between elevated CD8-activated T-cells and response. Conclusion: This is the second prospective clinical trial of treatment of metastatic melanoma using the combination of RT and systemic immunotherapy and the first using this sequence of therapy. The results from the present trial demonstrate that a subset of patients may benefit from combination therapy, arguing for continued clinical investigation of the use of RT combined with immunotherapy, including programmed cell death 1 inhibitors, which might have the potential to be even more effective in combination with RT.« less

A Case of Recurrent Anaplastic Meningioma of the Skull Base with Radiologic Response to Hydroxyurea

PubMed Central

Gurberg, Joshua; Bouganim, Nathaniel; Shenouda, George; Zeitouni, Anthony

2014-01-01

Anaplastic meningiomas are rare and aggressive tumors with a high propensity for local recurrence. Surgical resection and postoperative radiotherapy are the standard of care for primary disease and local recurrences. Refractory disease is managed with chemotherapy with limited success. A highly efficacious, well-tolerated chemotherapeutic agent has yet to be found for this disease entity. Hydroxyurea is currently receiving renewed attention because of its efficacy in inducing apoptosis of meningioma cells in vitro and its favorable side-effect profile. Thus far, in humans, this agent has only induced stable disease. We describe the first patient showing a near complete/partial clinical and radiological regression after 5 months of 25 mg/kg of hydroxyurea once daily, given within 1 month after stereotactic fractionated reirradiation of a previously irradiated and operated anaplastic meningioma of the skull base. Magnetic resonance imaging showed a significant and sustained response with tumor shrinkage and cavitation. PMID:25083390

In vivo tissue response following implantation of shape memory polyurethane foam in a porcine aneurysm model

PubMed Central

Rodriguez, Jennifer N.; Clubb, Fred J.; Wilson, Thomas S.; Miller, Matthew W.; Fossum, Theresa W.; Hartman, Jonathan; Tuzun, Egemen; Singhal, Pooja; Maitland, Duncan J.

2014-01-01

Cerebral aneurysms treated by traditional endovascular methods using platinum coils have a tendency to be unstable, either due to chronic inflammation, compaction of coils, or growth of the aneurysm. We propose to use alternate filling methods for the treatment of intracranial aneurysms using polyurethane based shape memory polymer (SMP) foams. SMP polyurethane foams were surgically implanted in a porcine aneurysm model to determine biocompatibility, localized thrombogenicity, and their ability to serve as a stable filler material within an aneurysm. The degree of healing was evaluated via gross observation, histopathology and low vacuum scanning electron microscopy (LV-SEM) imaging after zero, thirty and ninety days. Clotting was initiated within the SMP foam at time zero (less than one hour exposure to blood prior to euthanization), partial healing was observed at thirty days, and almost complete healing had occurred at ninety days in vivo, with minimal inflammatory response. PMID:23650278

In vivo response to an implanted shape memory polyurethane foam in a porcine aneurysm model.

PubMed

Rodriguez, Jennifer N; Clubb, Fred J; Wilson, Thomas S; Miller, Matthew W; Fossum, Theresa W; Hartman, Jonathan; Tuzun, Egemen; Singhal, Pooja; Maitland, Duncan J

2014-05-01

Cerebral aneurysms treated by traditional endovascular methods using platinum coils have a tendency to be unstable, either due to chronic inflammation, compaction of coils, or growth of the aneurysm. We propose to use alternate filling methods for the treatment of intracranial aneurysms using polyurethane-based shape memory polymer (SMP) foams. SMP polyurethane foams were surgically implanted in a porcine aneurysm model to determine biocompatibility, localized thrombogenicity, and their ability to serve as a stable filler material within an aneurysm. The degree of healing was evaluated via gross observation, histopathology, and low vacuum scanning electron microscopy imaging after 0, 30, and 90 days. Clotting was initiated within the SMP foam at time 0 (<1 h exposure to blood before euthanization), partial healing was observed at 30 days, and almost complete healing had occurred at 90 days in vivo, with minimal inflammatory response. Copyright © 2013 Wiley Periodicals, Inc.

Application of partially coherent modes for studying generation of a Gaussian partially coherent laser beam

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suvorov, A A

2010-10-15

The problem of steady-state generation of a Gaussian partially coherent beam in a stable-cavity laser is considered within the framework of the method of expansion of the radiation coherence function in partially coherent modes. We discuss the conditions whose fulfilment makes it possible to neglect the intermode beatings of the radiation field and the effect of the gain dispersion on the steady-state generation of multimode partially coherent radiation. Based on the simplified model, we solve the self-consistent problem of generation of a Gaussian partially coherent beam for the given laser pump conditions and the resonator parameters. The dependence of themore » beam characteristics (power, radius, etc.) on the active medium properties and the resonator parameters is obtained. (laser beams)« less

A computer-controlled, closed-loop infusion system for infusing muscle relaxants: its use during motor-evoked potential monitoring.

PubMed

Stinson, L W; Murray, M J; Jones, K A; Assef, S J; Burke, M J; Behrens, T L; Lennon, R L

1994-02-01

A microcomputer-controlled closed-loop infusion system (MCCLIS) has been developed that provides stable intraoperative levels of partial neuromuscular blockade. Complete neuromuscular blockade interferes with intraoperative motor-evoked potential (MEP) monitoring used for patients undergoing surgical procedures that place them at risk for spinal cord ischemia. Nine patients were studied during which the MCCLIS maintained stable levels of partial neuromuscular blockade and allowed transcranial magnetic motor-evoked potential (TcM-MEP) monitoring during thoracoabdominal aortic aneurysmectomy. The use of TcM-MEP for monitoring intraoperative spinal cord function was balanced against surgical considerations for muscle relaxation with 80% to 90% neuromuscular blockade fulfilling each requirement. Intraoperative adjustment of partial neuromuscular blockade to facilitate TcM-MEP monitoring was also possible with the MCCLIS. The MCCLIS should allow for further investigation into the sensitivity, specificity, and predictability of TcM-MEP monitoring for any patient at risk for intraoperative spinal cord ischemia including those undergoing thoracoabdominal aortic aneurysmectomy.

Everolimus in Combination with Octreotide Long-Acting Repeatable in a First-Line Setting for Patients with Neuroendocrine Tumors: A 5-Year Update.

PubMed

Bajetta, Emilio; Catena, Laura; Pusceddu, Sara; Spada, Francesca; Iannacone, Claudio; Sarno, Italo; Di Menna, Giandomenico; Dottorini, Lorenzo; Marte, Anna Maria

2018-01-01

We previously presented data of this multicentric, phase II study showing that everolimus plus octreotide long-acting repeatable (LAR) for advanced neuroendocrine neoplasms (NENs), in the first line setting, is an active and safe treatment. We now present updated data at 5 years. Patients with advanced well-differentiated, previously untreated neuroendocrine tumors of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg plus everolimus 10 mg/day. The primary endpoint was the objective response rate (ORR). We performed an analysis of "long responder" patients and of time to progression (TTP) and overall survival (OS) at 5 years. Fifty patients were enrolled; the primary tumor site was: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum/duodenum (2 patients), and unknown (14 patients). Seventeen (34%) of these patients have received treatment for more than 2 years. The median exposure to study drugs was 519.5 days (range 48-2,024). Currently 3 patients are still in treatment. The ORR (partial response + complete response) was 18% (95% confidence interval [CI] 7.4-28.6): complete response 1 patient (2%), partial response 8 patients (16%), stable disease 37 patients (74%). The median TTP was 33.6 months (95% CI 18.7-41.2) and the median OS was 61.0 months (95% CI 49.8-not reached). In this update of clinical outcome at 5-year follow-up, everolimus plus octreotide has been shown to be active in advanced NENs. The current analysis showed a further prolongation of TTP and a long exposure to the study drug without major side effects in the long term. © 2017 S. Karger AG, Basel.

Comparison of the effects of the antiestrogens EM-800 and tamoxifen on the growth of human breast ZR-75-1 cancer xenografts in nude mice.

PubMed

Couillard, S; Gutman, M; Labrie, C; Bélanger, A; Candas, B; Labrie, F

1998-01-01

Although estrone supplementation in ovariectomized (OVX) nude mice bearing ZR-75-1 xenografts caused a 365% increase in average tumor size during the 4-month treatment period, administration of the antiestrogen EM-800 at the daily oral doses of 50, 150, or 400 microg completely prevented estrogen-stimulated tumor growth. At the same doses of tamoxifen, tumor size was inhibited to 189, 117, and 120% above pretreatment values. However, when EM-800 (150 microg/day) was added to the daily 150- and 400-microg doses of tamoxifen, final tumor size was decreased further to 12 and 38% above pretreatment values, respectively. EM-800 (400 microg daily) administered to estrone-supplemented OVX mice caused complete, partial, and stable responses in 11, 22, and 49% of estrone-stimulated tumors, respectively, whereas 19% (7 of 37) progressed. At the same dose of tamoxifen, the corresponding responses were 3% (complete response), 3% (partial response), and 25% (no change), whereas 69% (22 of 32) of tumors progressed. In the absence of estrone supplementation, tamoxifen (400 microg) alone administered to OVX mice stimulated tumor growth to 161% compared with initial size whereas the same dose of EM-800 reduced tumor size by 55%, a value superimposable to that observed in OVX control animals. The agonistic effect of tamoxifen is thus illustrated by the observation that 73% of tumors progressed when tamoxifen was administered alone to OVX animals whereas no tumor progressed with EM-800. The present data strongly suggest that at least part of the initial lack of response and resistance to tamoxifen during tamoxifen treatment in women is due to the estrogenic activity of this compound, whereas the new antiestrogen EM-800 exerts pure antagonistic action.

Microwave Ablation in Combination with Chemotherapy for the Treatment of Advanced Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wei, Zhigang, E-mail: weizhigang321321@163.com; Ye, Xin, E-mail: yexintaian@aliyun.com; Yang, Xia, E-mail: yangxjinan@163.com

2015-02-15

PurposeTo verify whether microwave ablation (MWA) used as a local control treatment had an improved outcome regarding advanced non-small cell lung cancer (NSCLC) when combined with chemotherapy.MethodsThirty-nine patients with histologically verified advanced NSCLC and at least one measurable site other than the ablative sites were enrolled. Primary tumors underwent MWA followed by platinum-based doublet chemotherapy. Modified response evaluation criteria in solid tumors (mRECIST) and RECIST were used to evaluate therapeutic response. Complications were assessed using the National Cancer Institute Common Toxicity Criteria (version 3.0).ResultsMWA was administered to 39 tumors in 39 patients. The mean and median diameters of the primarymore » tumor were 3.84 cm and 3.30 cm, respectively, with a range of 1.00–9.00 cm. Thirty-three (84.6 %) patients achieved a partial response. No correlation was found between MWA efficacy and clinicopathologic characteristics. For chemotherapy, 11 patients (28.2 %) achieved a partial response, 18 (46.2 %) showed stable disease, and 10 (25.6 %) had progressive disease. The overall objective response rate and disease control rate were 28.2 and 74.4 %, respectively. The median progression-free survival time was 8.7 months (95 % CI 5.5–11.9). The median overall survival time was 21.3 months (95 % CI 17.0–25.4). Complications were observed in 22 (56.4 %) patients, and grade 3 adverse events were observed in 3 (7.9 %) patients.ConclusionsPatients with advanced NSCLC could benefit from MWA in combination with chemotherapy. Complications associated with MWA were common but tolerable.« less

Second-line chemotherapy of disseminated malignant melanoma with cystemustine at 60 mg/m2: a phase II trial.

PubMed

Thivat, Emilie; Durando, Xavier; D'Incan, Michel; Cure, Hervé; Mouret-Reynier, Marie-Ange; Madelmont, Jean-Claude; Souteyrand, Pierre; Chollet, Philippe

2005-10-01

Nitrosoureas possess some anti-tumor activity as a single agent in metastatic melanoma (MM). In a phase II trial, we evaluated the anti-tumor effects of cystemustine chemotherapy, a new nitrosourea, as a second-line treatment. Patients were required to have histologic evidence of disseminated MM and had failed in first-line chemotherapy. Treatment comprised cystemustine given at a dose of 60 mg/m every 2 weeks by a 15-min infusion. From February 1997 to September 1999, 22 patients (median age 66 years) were enrolled and were assessable. Two complete responses, one partial response, three stable diseases and 16 progressions were observed, giving an overall response rate of 13.6%. Median duration of response was 10 months (range 4-63). Median survival of responders and non-responders was 11 and 4 months, respectively. However, hematological toxicity, particularly thrombopenia, was a limiting factor for one-third of patients. We conclude that cystemustine at 60 mg/m is active in patients who progressed after one line of chemotherapy in advanced disease, and offers the possibility of complete responses and long durations of these responses.

High-dose ifosfamide by infusion with Mesna in advanced refractory sarcomas.

PubMed

Güllü, I; Yalçin, S; Tekuzman, G; Barişta, I; Alkiş, N; Celik, I; Zengin, N; Güler, N; Kars, A; Baltali, E

1996-01-01

Twenty patients with advanced sarcomas entered a pilot study with ifosfamide (IF) and mercaptoethane sulfonate sodium (Mesna) as a second-line treatment for six planned cycles. All patients had received prior doxorubicin- and cyclophosphamide-based chemotherapies. IF was administered at a dose of 3 g/m2 given as continuous intravenous infusion for 24 hr on day 1-5 with Mesna. In the absence of disease progression, chemotherapy was planned to be repeated every 4 weeks for six consecutive cycles. Following chemotherapy, only 2 patients (11%) achieved partial response with response durations of 6 and 9 months. There was no complete response. When considered for only high-grade tumors, the response rate reached up to 22%. Toxicity was reported for 48 cycles and the dose-limiting toxicities were myelosuppression (22%) and encephalopathy (17%). Chemotherapy protocol was changed after two or three courses in 16 patients with stable or progressive disease. IF/Mesna chemotherapy at this dose and schedule was not found to be very promising in refractory sarcomas as a second-line chemotherapy.

Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase II study.

PubMed

Brandes, Alba A; Ermani, Mario; Basso, Umberto; Paris, Myriam K; Lumachi, Franco; Berti, Franco; Amistà, Pietro; Gardiman, Marina; Iuzzolino, Paolo; Turazzi, Sergio; Monfardini, Silvio

2002-01-01

To investigate the efficacy of temozolomide (TMZ) in relationship to progression free survival at 6 months (PFS-6), median time to progression (TTP), response rate and toxicity, a phase II study was conducted in patients with recurrent glioblastoma multiforme (GBM) following surgery plus radiotherapy and a first-line regimen based on nitrosourea, procarbazine and vincristine. Forty-two patients with GBM were administered TMZ at the dose of 150 mg/m(2)/daily for 5 days every 4 weeks. The PFS-6 and at 12 months (PFS-12) was 24% (95% Confidence Interval [CI] = 14-42%) and 8% (CI = 2-27%), respectively, with a median TTP of 11.7 weeks (CI = 9-22 weeks). The response was assessed in all 42 patients; we observed 2 complete responses (CR) (4.7%), 6 partial responses (PR) (14.3%), and 9 stable disease (SD) (21.4%), with CR+PR = 19% (CI = 7-31%). TMZ as a second line regimen is a valid option in patients with heavily pretreated GBM. Copyright 2002 S. Karger AG, Basel

A phase ii study of gemcitabine and capecitabine in patients with advanced renal cell cancer: Southwest Oncology Group Study S0312.

PubMed

Van Veldhuizen, Peter J; Hussey, Michael; Lara, Primo N; Mack, Philip C; Gandour-Edwards, Regina; Clark, Joseph I; Lange, Marianne K; Crawford, David E

2009-10-01

Gemcitabine plus capecitabine has moderate efficacy in patients with advanced renal cell cancer (RCC) but has considerable toxicity. We evaluated the efficacy and toxicity of a modified dose-schedule of this doublet in patients with metastatic RCC. Chemotherapy-naive patients were treated with gemcitabine at 900 mg/m2 on days 1, 8, and 15 and with capecitabine at 625 mg/m2 twice daily on days 1 through 21, and every 28 days thereafter. The primary end point was response rate (RR). No further evaluation of this regimen would be pursued if the RR was ≤ 5%. In an exploratory analysis, we also evaluated potential markers of prognosis and treatment response, including thymidylate synthase, PTEN, pAKT, pmTOR, XRCC1, and ERCC1. Of 43 patients, 1 was ineligible and 2 were not analyzable. There was 1 complete response and 3 partial responses, for an overall RR of 10% (95% CI = 3, 24). Nineteen patients (48%) had stable disease. The 6-month freedom-from-treatment-failure and overall survival rates were 20% (95% CI = 8, 32) and 75% (95% CI = 62, 88), respectively. Median survival time was 23 months (95% CI = 10, 37). One patient each experienced grade 4 neutropenia, fatigue, thrombocytopenia, and hemolysis with renal failure. The most common grade 3 toxicities were neutropenia (12 patients), fatigue (5), and leucopenia (4). Patients with a best response of stable disease or better were more likely to have decreased expression of PTEN and increased expression of pmTOR. Gemcitabine plus capecitabine at this reduced dose-schedule benefits a small percentage of patients with RCC with an acceptable toxicity profile.

Probabilistic Learning by Rodent Grid Cells

PubMed Central

Cheung, Allen

2016-01-01

Mounting evidence shows mammalian brains are probabilistic computers, but the specific cells involved remain elusive. Parallel research suggests that grid cells of the mammalian hippocampal formation are fundamental to spatial cognition but their diverse response properties still defy explanation. No plausible model exists which explains stable grids in darkness for twenty minutes or longer, despite being one of the first results ever published on grid cells. Similarly, no current explanation can tie together grid fragmentation and grid rescaling, which show very different forms of flexibility in grid responses when the environment is varied. Other properties such as attractor dynamics and grid anisotropy seem to be at odds with one another unless additional properties are assumed such as a varying velocity gain. Modelling efforts have largely ignored the breadth of response patterns, while also failing to account for the disastrous effects of sensory noise during spatial learning and recall, especially in darkness. Here, published electrophysiological evidence from a range of experiments are reinterpreted using a novel probabilistic learning model, which shows that grid cell responses are accurately predicted by a probabilistic learning process. Diverse response properties of probabilistic grid cells are statistically indistinguishable from rat grid cells across key manipulations. A simple coherent set of probabilistic computations explains stable grid fields in darkness, partial grid rescaling in resized arenas, low-dimensional attractor grid cell dynamics, and grid fragmentation in hairpin mazes. The same computations also reconcile oscillatory dynamics at the single cell level with attractor dynamics at the cell ensemble level. Additionally, a clear functional role for boundary cells is proposed for spatial learning. These findings provide a parsimonious and unified explanation of grid cell function, and implicate grid cells as an accessible neuronal population readout of a set of probabilistic spatial computations. PMID:27792723

Effects of pumpless extracorporeal lung assist on hemodynamics, gas exchange and inflammatory cascade response during experimental lung injury

PubMed Central

Ju, Zhihai; Ma, Jinhui; Wang, Chen; Yu, Jie; Qiao, Yeru; Hei, Feilong

2018-01-01

Pumpless extracorporeal lung assist (pECLA) has been reported to efficiently remove the systemic CO2 production and provide mild to moderate oxygenation, thereby allowing for ventilator settings and modes prioritizing oxygenation and lung protection. However, an adequate bypass flow, the capacity to provide respiratory support and the effect on the inflammatory cascade response and tissue perfusion require further study to be determined. After induction of acute lung injury (ALI) by oleic acid injection, pECLA was implemented in 12 anaesthetized and mechanically ventilated dogs for 48 h. Improved oxygenation [partial oxygen pressure (PaO2) and oxygen saturation (SaO2) was measured by arterial blood gas analysis, and increased by 29 and 18%, respectively] and CO2 elimination (partial CO2 pressure decreased by 43.35%) were obtained after pECLA implementation. A maximum arterio-venous shunt flow of up to 25% of the foundational CO resulted in stable hemodynamics. The pECLA procedure did not elicit any further increase in the concentration of tumor necrosis factor-α, interleukin (IL)-6, IL-8 and endothelin-1 compared with that in the group subjected to oleic acid injection only. In addition, the pECLA procedure had no effect on lactate levels and urine production. In conclusion, pECLA is an efficient and promising strategy for providing a mild to moderate oxygenation and adequate decarboxylation, while avoiding excessive inflammatory cascade response and tissue hypoperfusion in an experimental ALI model. PMID:29434789

Estimating of aquifer parameters from the single-well water-level measurements in response to advancing longwall mine by using particle swarm optimization

NASA Astrophysics Data System (ADS)

Buyuk, Ersin; Karaman, Abdullah

2017-04-01

We estimated transmissivity and storage coefficient values from the single well water-level measurements positioned ahead of the mining face by using particle swarm optimization (PSO) technique. The water-level response to the advancing mining face contains an semi-analytical function that is not suitable for conventional inversion shemes because the partial derivative is difficult to calculate . Morever, the logaritmic behaviour of the model create difficulty for obtaining an initial model that may lead to a stable convergence. The PSO appears to obtain a reliable solution that produce a reasonable fit between water-level data and model function response. Optimization methods have been used to find optimum conditions consisting either minimum or maximum of a given objective function with regard to some criteria. Unlike PSO, traditional non-linear optimization methods have been used for many hydrogeologic and geophysical engineering problems. These methods indicate some difficulties such as dependencies to initial model, evolution of the partial derivatives that is required while linearizing the model and trapping at local optimum. Recently, Particle swarm optimization (PSO) became the focus of modern global optimization method that is inspired from the social behaviour of birds of swarms, and appears to be a reliable and powerful algorithms for complex engineering applications. PSO that is not dependent on an initial model, and non-derivative stochastic process appears to be capable of searching all possible solutions in the model space either around local or global optimum points.

The role of interim 18F-FDG PET/CT in prediction of response to ipilimumab treatment in metastatic melanoma.

PubMed

Sachpekidis, Christos; Anwar, Hoda; Winkler, Julia; Kopp-Schneider, Annette; Larribere, Lionel; Haberkorn, Uwe; Hassel, Jessica C; Dimitrakopoulou-Strauss, Antonia

2018-07-01

The aim of the present study was to assess the value of interim 18 F-FDG PET/CT performed after the first two cycles of ipilimumab treatment in the prediction of the final clinical response to this type of immunotherapy. The study group comprised 41 patients with unresectable metastatic melanoma scheduled for ipilimumab therapy. Whole-body 18 F-FDG PET/CT was performed before the start of ipilimumab treatment (baseline PET/CT) and after the initial two cycles of ipilimumab treatment (interim PET/CT). Evaluation of patient response to treatment was based on the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria for PET as well as the recently proposed PET Response Evaluation Criteria for Immunotherapy (PERCIMT). The patients' best clinical response, assessed at a median of 21.4 months (range 6.3-41.9 months) was used as reference. According to their best clinical response, the patients were divided into two groups: those showing clinical benefit (CB) including stable disease, partial response and complete response (31 patients), and those showing no clinical benefit (no-CB including progressive disease (10 patients). According to the EORTC criteria, interim PET/CT demonstrated progressive metabolic disease (PMD) in 20 patients, stable metabolic disease (SMD) in 11 patients, partial metabolic response (PMR) in 8 patients, and complete metabolic response (CMR) in 2 patients. According to the PERCIMT, interim PET/CT demonstrated PMD in 9 patients, SMD in 24 patients, PMR in 6 patients and CMR in 2 patients. On the basis of the interim PET, the patients were divided in a similar manner to the division according to clinical response into those showing metabolic benefit (MB) including SMD, PMR and CMR, and those showing no metabolic benefit (no-MB) including PMD. According to this dichotomization, the EORTC criteria showed a sensitivity (correctly predicting CB) of 64.5%, a specificity (correctly predicting no-CB) of 90.0%, a positive predictive value (PPV) of 95.2%, a negative predictive value (NPV) of 45.0% and an accuracy of 70.7% in predicting best clinical response. The PERCIMT showed a sensitivity of 93.6%, a specificity of 70.0%, a PPV of 90.6%, a NPV of 77.8% and an accuracy of 87.8%. The McNemar test showed that the PERCIMT had a significantly higher sensitivity than EORTC criteria (p = 0.004), while there was no significant difference in specificity (p = 0.5). The agreement between the two sets of criteria was poor (McNemar test p = 0.001, and accordingly kappa = 0.46). The application of the recently proposed PERCIMT to interim 18 F-FDG PET/CT provides a more sensitive predictor of final clinical response to immunotherapy than the application of the EORTC criteria in patients with metastatic melanoma.

Stabilization of gold nanoparticle films on glass by thermal embedding.

PubMed

Karakouz, Tanya; Maoz, Ben M; Lando, Gilad; Vaskevich, Alexander; Rubinstein, Israel

2011-04-01

The poor adhesion of gold nanoparticles (NPs) to glass has been a known obstacle to studies and applications of NP-based systems, such as glass/Au-NP optical devices. Here we present a simple scheme for obtaining stable localized surface plasmon resonance (LSPR) transducers based on Au NP films immobilized on silanized glass and annealed. The procedure includes high-temperature annealing of the Au NP film, leading to partial embedding in the glass substrate and stabilization of the morphology and optical properties. The method is demonstrated using citrate-stabilized Au NPs, 20 and 63 nm mean diameter, immobilized electrostatically on glass microscope cover slides precoated with an aminosilane monolayer. Partial thermal embedding of the Au NPs in the glass occurs at temperatures in the vicinity of the glass transition temperature of the substrate. Upon annealing in air the Au NPs gradually settle into the glass and become encircled by a glass rim. In situ transmission UV-vis spectroscopy carried out during the annealing in a specially designed optical oven shows three regions: The most pronounced change of the surface plasmon (SP) band shape occurs in the first ca. 15 min of annealing; this is followed by a blue-shift of the SP band maximum (up to ca. 5 h), after which a steady red-shift of the SP band is observed (up to ca. 70 h, when the experiment was terminated). The development of the SP extinction spectrum was correlated to changes in the system structure, including thermal modification of the NP film morphology and embedding in the glass. The partially embedded Au NP films pass successfully the adhesive-tape test, while their morphology and optical response are stable toward immersion in solvents, drying, and thiol self-assembly. The enhanced adhesion is attributed to the metal NP embedding and rim formation. The stabilized NP films display a refractive index sensitivity (RIS) of 34-48 nm/RIU and 0.1-0.4 abs.u./RIU in SP band shift and extinction change, respectively. The RIS can be improved significantly by electroless deposition of Au on the embedded NPs, while the system stability is maintained. The method presented provides a simple route to obtaining stable Au NP film transducers. © 2011 American Chemical Society

Space Shuttle Transportation (Roll-Out) Loads Diagnostics

NASA Technical Reports Server (NTRS)

Elliott, Kenny B.; Buehrle, Ralph D.; James, George H.; Richart, Jene A.

2005-01-01

The Space Transportation System (STS) consists of three primary components; an Orbiter Vehicle, an External Fuel Tank, and two Solid Rocket Boosters. The Orbiter Vehicle and Solid Rocket Boosters are reusable components, and as such, they are susceptible to durability issues. Recently, the fatigue load spectra for these components have been updated to include load histories acquired during the rollout phase of the STS processing for flight. Using traditional program life assessment techniques, the incorporation of these "rollout" loads produced unacceptable life estimates for certain Orbiter structural members. As a result, the Space Shuttle System Engineering and Integration Office has initiated a program to re-assess the method used for developing the "rollout" loads and performing the life assessments. In the fall of 2003 a set of tests were preformed to provide information to either validate existing load spectra estimation techniques or generate new load spectra estimation methods. Acceleration and strain data were collected from two rollouts of a partial-stack configuration of the Space Shuttle. The partial stack configuration consists of two Solid Rocket Boosters tied together at the upper External Tank attachment locations mounted on the Mobile Launch Platform carried by a Crawler Transporter (CT). In the current analysis, the data collected from this test is examined for consistency in speed, surface condition effects, and the characterization of the forcing function. It is observed that the speed of the CT is relatively stable. The dynamic response acceleration of the partial-stack is slightly sensitive to the surface condition of the road used for transport, and the dynamic response acceleration of the partial-stack generally increases as the transport speed increases. However, the speed sensitivity is dependent on the measurement location. Finally, the character of the forcing function is narrow-banded with the primary drivers being harmonics of two CT speed dependent excitations. One source is an excitation due to the CT treads striking the road surface, and the second is unknown.

Human-murine transthyretin heterotetramers are kinetically stable and non-amyloidogenic. A lesson in the generation of transgenic models of diseases involving oligomeric proteins.

PubMed

Reixach, Natàlia; Foss, Ted R; Santelli, Eugenio; Pascual, Jaime; Kelly, Jeffery W; Buxbaum, Joel N

2008-01-25

The transthyretin amyloidoses appear to be caused by rate-limiting tetramer dissociation and partial monomer unfolding of the human serum protein transthyretin, resulting in aggregation and extracellular deposition of amorphous aggregates and amyloid fibrils. Mice transgenic for few copies of amyloid-prone human transthyretin variants, including the aggressive L55P mutant, failed to develop deposits. Silencing the murine transthyretin gene in the presence of the L55P human gene resulted in enhanced tissue deposition. To test the hypothesis that the murine protein interacted with human transthyretin, preventing the dissociation and partial unfolding required for amyloidogenesis, we produced recombinant murine transthyretin and human/murine transthyretin heterotetramers and compared their structures and biophysical properties to recombinant human transthyretin. We found no significant differences between the crystal structures of murine and human homotetramers. Murine transthyretin is not amyloidogenic because the native homotetramer is kinetically stable under physiologic conditions and cannot dissociate into partially unfolded monomers, the misfolding and aggregation precursor. Heterotetramers composed of murine and human subunits are also kinetically stable. These observations explain the lack of transthyretin deposition in transgenics carrying a low copy number of human transthyretin genes. The incorporation of mouse subunits into tetramers otherwise composed of human amyloid-prone transthyretin subunits imposes kinetic stability, preventing dissociation and subsequent amyloidogenesis.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rose, Brian E. J.; Cronin, Timothy W.; Bitz, Cecilia M., E-mail: brose@albany.edu

Planetary obliquity determines the meridional distribution of the annual mean insolation. For obliquity exceeding 55°, the weakest insolation occurs at the equator. Stable partial snow and ice cover on such a planet would be in the form of a belt about the equator rather than polar caps. An analytical model of planetary climate is used to investigate the stability of ice caps and ice belts over the widest possible range of parameters. The model is a non-dimensional diffusive Energy Balance Model, representing insolation, heat transport, and ice−albedo feedback on a spherical planet. A complete analytical solution for any obliquity ismore » given and validated against numerical solutions of a seasonal model in the “deep-water” regime of weak seasonal ice line migration. Multiple equilibria and unstable transitions between climate states (ice-free, Snowball, or ice cap/belt) are found over wide swaths of parameter space, including a “Large Ice-Belt Instability” and “Small Ice-Belt Instability” at high obliquity. The Snowball catastrophe is avoided at weak radiative forcing in two different scenarios: weak albedo feedback and inefficient heat transport (favoring stable partial ice cover), or efficient transport at high obliquity (favoring ice-free conditions). From speculative assumptions about distributions of planetary parameters, three-fourths to four-fifths of all planets with stable partial ice cover should be in the form of Earth-like polar caps.« less

Safety and efficacy of targeted hyperthermia treatment utilizing gold nanorod therapy in spontaneous canine neoplasia.

PubMed

Schuh, Elizabeth M; Portela, Roberta; Gardner, Heather L; Schoen, Christian; London, Cheryl A

2017-10-02

Hyperthermia is an established anti-cancer treatment but is limited by tolerance of adjacent normal tissues. Parenteral administration of gold nanorods (NRs) as a photosensitizer amplifies the effects of hyperthermia treatment while sparing normal tissues. This therapy is well tolerated and has demonstrated anti-tumor effects in mouse models. The purpose of this phase 1 study was to establish the safety and observe the anti-tumor impact of gold NR enhanced (plasmonic) photothermal therapy (PPTT) in client owned canine patients diagnosed with spontaneous neoplasia. Seven dogs underwent gold NR administration and subsequent NIR PPTT. Side effects were mild and limited to local reactions to NIR laser. All of the dogs enrolled in the study experienced stable disease, partial remission or complete remission. The overall response rate (ORR) was 28.6% with partial or complete remission of tumors at study end. PPTT utilizing gold nanorod therapy can be safely administered to canine patients. Further studies are needed to determine the true efficacy in a larger population of canine cancer patients and to and identify those patients most likely to benefit from this therapy.

Cytokine-enhanced vaccine and interferon-β plus suicide gene as combined therapy for spontaneous canine sarcomas.

PubMed

Finocchiaro, Liliana M E; Villaverde, Marcela S; Gil-Cardeza, María L; Riveros, María D; Glikin, Gerardo C

2011-10-01

Eleven soft tissue- and five osteosarcoma canine patients were subjected to: (i) periodic subcutaneous injection of irradiated xenogeneic cells secreting hGM-CSF and hIL-2 mixed with allogeneic or autologous tumor homogenates; and (ii) injections of cIFN-β and HSVtk-carrying lipoplexes and ganciclovir, marginal (after surgery) and/or intratumoral (in the case of partial tumor resection, local relapse or small surface tumors). This treatment alone (4 patients) or as surgery adjuvant (12 patients), was safe and well tolerated. In those patients presenting local disease (6/11), the suicide gene plus cIFN-β treatment induced local antitumor activity evidenced by the objective responses (3 complete, 2 partial) and stable diseases (2). In addition, the treatment prevented or delayed local relapse, regional metastases (lymph nodes developed only in 3/16) and distant metastases (0/16), suggesting a strong systemic antitumor immunity. The most encouraging result was the long survival times of 10 patients (>1 year, with good quality of life). Copyright © 2011 Elsevier Ltd. All rights reserved.

Transient dichroism in photoreceptor membranes indicates that stable oligomers of rhodopsin do not form during excitation.

PubMed Central

Downer, N W; Cone, R A

1985-01-01

If a photoexcited rhodopsin molecule initiates the formation of rhodopsin oligomers during the process of visual excitation, the rate of rotational diffusion of the rhodopsin molecules involved should change markedly. Using microsecond-flash photometry, we have observed the rotational diffusion of rhodopsin throughout the time period of visual excitation and found that no detectable change occurs in its rotational diffusion rate. Partial chemical cross-linking of the retina yields oligomers of rhodopsin and causes a significant decrease in the rotational diffusion rate of rhodopsin even when as little as 20% of rhodopsin is dimeric. Moreover, the pattern of oligomers formed by cross-linking, taken together with the magnitude of decreases in rotational diffusion rate accompanying the cross-linking reaction, suggests that rhodopsin is a monomer in the dark-adapted state. The experiments reported here show that photoexcited rhodopsin molecules do not irreversibly associate with unbleached neighbors during the time course of the receptor response. Hence, it is not likely that stable oligomers of rhodopsin trigger the excitation of the photoreceptor cell. Images FIGURE 1 PMID:3919778

N2 and P3 modulation during partial inhibition in a modified go/nogo task.

PubMed

Nguyen, An T; Moyle, Jonson J; Fox, Allison M

2016-09-01

The neural response following the partial inhibition of responses can provide insight into the processes underlying response inhibition. We examined the N2 and P3 on trials where participants correctly responded to go stimuli, successfully inhibited their response to nogo stimuli, and nogo trials where they initiated but did not complete their response (partial inhibitions) in an adult sample (N=24, M(age)=21.17, SD(age)=3.52). An enhanced and delayed N2 was observed on partially inhibited compared to successfully inhibited nogo trials. Further analysis showed that this modulation was error-related. An enhanced central P3 was observed following successful inhibitions compared to correct go trials, but not following partial inhibitions. The results suggest that the central P3 enhancement is specific to the complete and successful inhibition of responses. Therefore, the absence of a central P3 on partial inhibitions could reflect insufficient inhibition or a monitored failure in inhibiting the response. Although, our findings provide support for the role of P3 in response inhibition, it raises questions about the processes involved in the subsequent inhibition or correction of the erroneous response. Further research examining the neural response following both partial and unsuccessful inhibitions could provide insight regarding these processes. Copyright © 2016 Elsevier B.V. All rights reserved.

Aggressive fibromatosis response to tamoxifen: lack of correlation between MRI and symptomatic response.

PubMed

Libertini, M; Mitra, I; van der Graaf, W T A; Miah, A B; Judson, I; Jones, R L; Thomas, K; Moskovic, E; Szucs, Z; Benson, C; Messiou, C

2018-01-01

One of the commonly used systemic agents for the treatment of aggressive fibromatosis is the anti-oestrogen drug tamoxifen. However, data on efficacy and optimum methods of response assessment are limited, consisting mainly of small case series and reports. A retrospective database was used to identify consecutive patients diagnosed with aggressive fibromatosis (AF) and treated with tamoxifen plus/minus non-steroidal anti-inflammatory drugs at our tertiary referral centre between 2007 and 2014. MRI and symptom changes were recorded. Thirty-two patients (13 male 19 female, median age 41 years) were included. Median duration of treatment with tamoxifen was 316 days. Of 9 patients with progressive disease by RECIST 1.1 (28%): 4 patients experienced worsening symptoms; 3 patients had improved symptoms and 2 had no change in symptoms. Of 22 patients with stable disease (69%): 11 had no change in symptoms; 6 had improved symptoms and 5 patients had worsening symptoms. One patient achieved a partial response with improved symptoms. No relationship was identified between symptomatic benefit and response by RECIST 1.1 on MRI. Prospective studies in AF should incorporate endpoints focusing on patient symptoms.

Phase 2 trial of BCNU plus irinotecan in adults with malignant glioma1

PubMed Central

Reardon, David A.; Quinn, Jennifer A.; Rich, Jeremy N.; Gururangan, Sridharan; Vredenburgh, James; Sampson, John H.; Provenzale, James M.; Walker, Amy; Badruddoja, Michael; Tourt-Uhlig, Sandra; Herndon, James E.; Dowell, Jeannette M.; Affronti, Mary Lou; Jackson, Susanne; Allen, Deborah; Ziegler, Karen; Silverman, Steven; Bohlin, Cindy; Friedman, Allan H.; Bigner, Darell D.; Friedman, Henry S.

2004-01-01

In preclinical studies, BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, plus CPT-11 (irinotecan) exhibits schedule-dependent, synergistic activity against malignant glioma (MG). We previously established the maximum tolerated dose of CPT-11 when administered for 4 consecutive weeks in combination with BCNU administered on the first day of each 6-week cycle. We now report a phase 2 trial of BCNU plus CPT-11 for patients with MG. In the current study, BCNU (100 mg/m2) was administered on day 1 of each 6-week cycle. CPT-11 was administered on days 1, 8, 15, and 22 at 225 mg/m2 for patients receiving CYP3A1- or CYP3A4-inducing anticonvulsants and at 125 mg/m2 for those not on these medications. Newly diagnosed patients received up to 3 cycles before radiotherapy, while recurrent patients received up to 8 cycles. The primary end point of this study was radiographic response, while time to progression and overall survival were also assessed. Seventy-six patients were treated, including 37 with newly diagnosed tumors and 39 with recurrent disease. Fifty-six had glioblastoma multiforme, 18 had anaplastic astrocytoma, and 2 had anaplastic oligodendroglioma. Toxicities (grade ⩾3) included infections (13%), thromboses (12%), diarrhea (10%), and neutropenia (7%). Interstitial pneumonitis developed in 4 patients. Five newly diagnosed patients (14%; 95% CI, 5%–29%) achieved a radiographic response (1 complete response and 4 partial responses). Five patients with recurrent MG also achieved a response (1 complete response and 4 partial responses; 13%; 95% CI, 4%–27%). More than 40% of both newly diagnosed and recurrent patients achieved stable disease. Median time to progression was 11.3 weeks for recurrent glioblastoma multiforme patients and 16.9 weeks for recurrent anaplastic astrocytoma/anaplastic oligodendroglioma patients. We conclude that the activity of BCNU plus CPT-11 for patients with MG appears comparable to that of CPT-11 alone and may be more toxic. PMID:15134628

mRECIST criteria and contrast-enhanced US for the assessment of the response of hepatocellular carcinoma to transarterial chemoembolization

PubMed Central

Moschouris, Hippocrates; Malagari, Katerina; Papadaki, Marina G.; Kornezos, Ioannis; Stamatiou, Konstantinos; Anagnostopoulos, Antonios; Chatzimichael, Katerina; Kelekis, Nikolaos

2014-01-01

PURPOSE We aimed to evaluate the combination of the modified Response Evaluation Criteria In Solid Tumors (mRECIST) and contrast-enhanced ultrasonography (CEUS) as a tool for the assessment of hepatocellular carcinoma treated with transarterial chemoembolization. MATERIALS AND METHODS Forty-seven hepatocellular carcinoma patients (80 target tumors suitable for mRECIST measurements) were studied. They were treated with scheduled transarterial chemoembolization with doxorubicin-eluting microspheres every 5–7 weeks. Imaging follow-up (performed one month after each transarterial chemoembolization) included a standard, contrast-enhanced modality (computed tomography [CT] in 12 patients or magnetic resonance imaging [MRI] in 35 patients) and CEUS. The study focused on response evaluation after the third transarterial chemoembolization. CEUS required a bolus injection of an echo-enhancer and imaging with a dedicated, low mechanical index technique. The longest diameters of the enhancing target tumors were measured on the CEUS or CT/MRI, and mRECIST criteria were applied. Radiologic responses were correlated with overall survival and time to progression. RESULTS The measurements of longest diameters of the enhancing target tumors were easily performed in all patients. According to mRECIST-CEUS and mRECIST-CT/MRI, complete response was recorded in five and six patients, partial response in 22 and 21 patients, stable disease in 16 and 14 patients, and progressive disease in four and six patients, respectively. There was a high degree of concordance between CEUS and CT/MRI (kappa coefficient=0.84, P < 0.001). Responders (complete+partial response) according to mRECIST-CEUS had a significantly longer mean overall survival and time to progression compared to nonresponders (37.1 vs. 11.0 months, P < 0.001 and 24.6 vs. 10.9 months, P = 0.007, respectively). CONCLUSION The mRECIST-CEUS combination is feasible and has prognostic value in the assessment of hepatocellular carcinoma following transarterial chemoembolization. PMID:24317334

Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1-Positive Cervical Cancer: Results From the Phase Ib KEYNOTE-028 Trial.

PubMed

Frenel, Jean-Sebastien; Le Tourneau, Christophe; O'Neil, Bert; Ott, Patrick A; Piha-Paul, Sarina A; Gomez-Roca, Carlos; van Brummelen, Emilie M J; Rugo, Hope S; Thomas, Shari; Saraf, Sanatan; Rangwala, Reshma; Varga, Andrea

2017-12-20

Purpose The KEYNOTE-028 trial ( ClinicalTrials.gov identifier: NCT02054806) was designed to assess the safety and efficacy of pembrolizumab in 20 programmed death ligand 1-positive, advanced solid tumor cohorts. Here, we present the results from the cohort of patients with advanced cervical cancer. Methods Patients were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end point was overall response rate per Response Evaluation Criteria in Solid Tumors, version 1.1, by investigator review. Safety was a secondary end point. Results Twenty-four patients were enrolled in the cervical cancer cohort. The median age was 42 years (range, 26 to 62 years), 22 patients (92%) had received prior radiation therapy, and 15 patients (63%) had received two or more lines of therapy, including bevacizumab (10 of 24 patients), for advanced disease. At the data cutoff, median follow-up duration was 11.0 months (range, 1.3 to 32.2 months). Overall response rate was 17% (95% CI, 5% to 37%); four patients (17%) achieved a confirmed partial response, and three patients (13%) had stable disease. Median duration of response for the four patients who achieved a partial response was 5.4 months (4.1 to 7.5 months). Treatment related adverse events (AEs) were experienced by 18 patients (75%); only rash (n = 5; 21%) and pyrexia (n = 4; 17%) and occurred in ≥ 10% of patients. Five patients experienced grade 3 treatment-related AEs. No grade 4 treatment-related AEs or deaths were observed. Conclusion In patients with programmed death ligand 1-positive advanced cervical cancer, pembrolizumab demonstrated antitumor activity and exhibited a safety profile consistent with that seen in other tumor types.

Evidence that inhibitory factor extracted from bovine retractor penis is nitrite, whose acid-activated derivative is stabilized nitric oxide.

PubMed Central

Martin, W.; Smith, J. A.; Lewis, M. J.; Henderson, A. H.

1988-01-01

1. Unactivated extracts of bovine retractor penis (BRP) contains 3-7 microM nitrite. Acid-activation of these extracts at pH 2 for 10 min followed by neutralization generates the active form of inhibitory factor (IF; assayed by its vasodilator action on rabbit aorta), and is associated with partial loss of nitrite. 2. Increasing the time of acid-activation at pH 2 from 10 to 60 min with intermittent vortex mixing generates greater vasodilator activity and increases nitrite loss. 3. When acid-activated and neutralized extracts are incubated at 37 degrees C or 30 min or boiled for 5 min, vasodilator activity is lost and nitrite content increased. Reactivation of these samples at pH 2 for 10 min followed by neutralization leads to partial recoveries of vasodilator activity with loss in nitrite content. 4. Addition of sodium nitrite to BRP extracts increases acid-activatable vasodilator activity pro rata. 5. Acid-activation of aqueous sodium nitrite solutions results in less loss of nitrite and generation of less vasodilator activity than BRP extracts. Vasodilatation is only transient and is rapidly abolished on neutralization, whereas responses to acid-activated BRP extracts are more prolonged and activity is stable on ice. 6. Bovine aortic endothelial cells yield vasodilator activity that is indistinguishable from that isolated from BRP. It is activated by acid, stable on ice, abolished by boiling or by haemoglobin, and appears to be due to the generation of nitric oxide (NO) from nitrite.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2897219

T-Cell Therapy Using Interleukin-21–Primed Cytotoxic T-Cell Lymphocytes Combined With Cytotoxic T-Cell Lymphocyte Antigen-4 Blockade Results in Long-Term Cell Persistence and Durable Tumor Regression

PubMed Central

Chapuis, Aude G.; Roberts, Ilana M.; Thompson, John A.; Margolin, Kim A.; Bhatia, Shailender; Lee, Sylvia M.; Sloan, Heather L.; Lai, Ivy P.; Farrar, Erik A.; Wagener, Felecia; Shibuya, Kendall C.; Cao, Jianhong; Wolchok, Jedd D.; Greenberg, Philip D.

2016-01-01

Purpose Peripheral blood–derived antigen-specific cytotoxic T cells (CTLs) provide a readily available source of effector cells that can be administered with minimal toxicity in an outpatient setting. In metastatic melanoma, this approach results in measurable albeit modest clinical responses in patients resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity of adoptively transferred CTLs. Patients and Methods Autologous MART1-specific CTLs were generated by priming with peptide-pulsed dendritic cells in the presence of interleukin-21 and enriched by peptide-major histocompatibility complex multimer-guided cell sorting. This expeditiously yielded polyclonal CTL lines uniformly expressing markers associated with an enhanced survival potential. In this first-in-human strategy, 10 patients with stage IV melanoma received the MART1-specific CTLs followed by a standard course of anti–CTLA-4 (ipilimumab). Results The toxicity profile of the combined treatment was comparable to that of ipilimumab monotherapy. Evaluation of best responses at 12 weeks yielded two continuous complete remissions, one partial response (PR) using RECIST criteria (two PRs using immune-related response criteria), and three instances of stable disease. Infused CTLs persisted with frequencies up to 2.9% of CD8+ T cells for as long as the patients were monitored (up to 40 weeks). In patients who experienced complete remissions, PRs, or stable disease, the persisting CTLs acquired phenotypic and functional characteristics of long-lived memory cells. Moreover, these patients also developed responses to nontargeted tumor antigens (epitope spreading). Conclusion We demonstrate that combining antigen-specific CTLs with CTLA-4 blockade is safe and produces durable clinical responses, likely reflecting both enhanced activity of transferred cells and improved recruitment of new responses, highlighting the promise of this strategy. PMID:27269940

T-Cell Therapy Using Interleukin-21-Primed Cytotoxic T-Cell Lymphocytes Combined With Cytotoxic T-Cell Lymphocyte Antigen-4 Blockade Results in Long-Term Cell Persistence and Durable Tumor Regression.

PubMed

Chapuis, Aude G; Roberts, Ilana M; Thompson, John A; Margolin, Kim A; Bhatia, Shailender; Lee, Sylvia M; Sloan, Heather L; Lai, Ivy P; Farrar, Erik A; Wagener, Felecia; Shibuya, Kendall C; Cao, Jianhong; Wolchok, Jedd D; Greenberg, Philip D; Yee, Cassian

2016-11-01

Purpose Peripheral blood-derived antigen-specific cytotoxic T cells (CTLs) provide a readily available source of effector cells that can be administered with minimal toxicity in an outpatient setting. In metastatic melanoma, this approach results in measurable albeit modest clinical responses in patients resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity of adoptively transferred CTLs. Patients and Methods Autologous MART1-specific CTLs were generated by priming with peptide-pulsed dendritic cells in the presence of interleukin-21 and enriched by peptide-major histocompatibility complex multimer-guided cell sorting. This expeditiously yielded polyclonal CTL lines uniformly expressing markers associated with an enhanced survival potential. In this first-in-human strategy, 10 patients with stage IV melanoma received the MART1-specific CTLs followed by a standard course of anti-CTLA-4 (ipilimumab). Results The toxicity profile of the combined treatment was comparable to that of ipilimumab monotherapy. Evaluation of best responses at 12 weeks yielded two continuous complete remissions, one partial response (PR) using RECIST criteria (two PRs using immune-related response criteria), and three instances of stable disease. Infused CTLs persisted with frequencies up to 2.9% of CD8 + T cells for as long as the patients were monitored (up to 40 weeks). In patients who experienced complete remissions, PRs, or stable disease, the persisting CTLs acquired phenotypic and functional characteristics of long-lived memory cells. Moreover, these patients also developed responses to nontargeted tumor antigens (epitope spreading). Conclusion We demonstrate that combining antigen-specific CTLs with CTLA-4 blockade is safe and produces durable clinical responses, likely reflecting both enhanced activity of transferred cells and improved recruitment of new responses, highlighting the promise of this strategy.

On-orbit performance of the Landsat-7 ETM+ radiometric calibrators

USGS Publications Warehouse

Markham, Brian L; Barker, J. L.; Kaita, E.; Seiferth, J.; Morfitt, Ron

2003-01-01

The Landsat-7 Enhanced Thematic Mapper Plus (ETM+) incorporates two new devices to improve its absolute radiometric calibration: a Full Aperture Solar Calibrator (FASC) and a Partial Aperture Solar Calibrator (PASC). The FASC is a diffuser panel, typically deployed once per month. Initial FASC absolute calibration results were within 5% of the pre-launch calibrations. Over time, the responses of the ETM+ to the FASC have varied with the location viewed on the panel, suggesting a localized degradation or contamination of the panel. On the best part of the panel, the trends in response range from m 1.4% y m 1 (band 4) to +0.6% y m 1 (band 7), with band 5 showing the least change at m 0.4% y m 1 . Changes in the panel reflectance due to UV exposure are believed to be the origin of these trends. The PASC is a set of auxiliary optics that allows the ETM+ to image the Sun through reduced apertures. PASC data have normally been acquired on a daily basis. Unlike the FASC, the PASC has exhibited significant anomalies. During the first six months of operation, responses to the PASC increased up to 60%, sending bands 2, 3 and 8 into saturation (band 1 was saturated at launch). The short-wave infrared (SWIR) band individual detectors have shown variations up to - 20% in response to the PASC. The variation is different for each detector. After the first six months, the responses to the PASC have become more stable, with much of the variation related to the within-scan position of the solar image. Overall results to date for all calibrators and comparisons with vicarious calibrations indicate that most of the response variations have been due to the calibrators themselves and suggest that the instrument has been stable with changes in response of less than 0.5% y m 1 .

Collective phase description of oscillatory convection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kawamura, Yoji, E-mail: ykawamura@jamstec.go.jp; Nakao, Hiroya

We formulate a theory for the collective phase description of oscillatory convection in Hele-Shaw cells. It enables us to describe the dynamics of the oscillatory convection by a single degree of freedom which we call the collective phase. The theory can be considered as a phase reduction method for limit-cycle solutions in infinite-dimensional dynamical systems, namely, stable time-periodic solutions to partial differential equations, representing the oscillatory convection. We derive the phase sensitivity function, which quantifies the phase response of the oscillatory convection to weak perturbations applied at each spatial point, and analyze the phase synchronization between two weakly coupled Hele-Shawmore » cells exhibiting oscillatory convection on the basis of the derived phase equations.« less

Large-Scale Partial-Duplicate Image Retrieval and Its Applications

DTIC Science & Technology

2016-04-23

SECURITY CLASSIFICATION OF: The explosive growth of Internet Media (partial-duplicate/similar images, 3D objects, 3D models, etc.) sheds bright...light on many promising applications in forensics, surveillance, 3D animation, mobile visual search, and 3D model/object search. Compared with the...and stable spatial configuration. Compared with the general 2D objects, 3D models/objects consist of 3D data information (typically a list of

(11)C-Choline PET/CT as a guide to radiation treatment planning of lymph-node relapses in prostate cancer patients.

PubMed

Picchio, M; Berardi, G; Fodor, A; Busnardo, E; Crivellaro, C; Giovacchini, G; Fiorino, C; Kirienko, M; Incerti, E; Messa, C; Gianolli, L; Di Muzio, N

2014-07-01

To evaluate, in prostate cancer (PCa) patients the potential of (11)C-choline PET/CT as a guide to helical tomotherapy (HTT) of lymph-node (LN) relapses with simultaneous integrated boost (SIB). The efficacy and feasibility of HTT in terms of acute toxicity were assessed. We enrolled 83 PCa patients (mean age 68 years, range 51 - 82 years) with biochemical recurrence after radical primary treatment (mean serum PSA 7.61 ng/ml, range 0.37 - 187.00 ng/ml; PSA0) who showed pathological findings on (11)C-choline PET/CT only at the LN site. (11)C-Choline PET/CT was performed for restaging and then for radiation treatment planning (PET/CT0). Of the 83 patients, 8 experienced further LN relapse, of whom 5 were retreated once and 3 were retreated twice (total 94 radiotherapy treatments). All pelvic and/or abdominal LNs positive on PET/CT0 were treated with high doses using SIB. Doses were in the range 36 - 74 Gy administered in 28 fractions. After the end of HTT (mean 83 days, range 16 - 365 days), serum PSA was measured in all patients (PSA1) and compared with PSA0 to evaluate early biochemical response. In 47 patients PET/CT was repeated (PET/CT1) to assess metabolic responses at the treated areas. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) were used to assess acute toxicity. PET/CT0 revealed pathological LNs in the pelvis in 49 patients, pathological LNs in the abdomen in 15 patients pathological LNs in both the pelvis and abdomen in 18 patients, and pathological LNs in the pelvis or abdomen and other sites in 12 patients. All these sites were treated with HTT. With respect to PSA0, PSA1 (mean 6.28 ng/ml, range 0.00 - 220.46 ng/ml) showed a complete biochemical response after 66 of the 94 HTT treatments, a partial response after 12 treatments, stable disease after 1 treatment and progression of disease after 15 treatments. Of the 47 patients receiving PET/CT1, 20 showed a complete metabolic response at the treated area, 22 a partial metabolic response, 3 progression of disease and 2 stable disease. HTT with SIB was well tolerated in all patients. Grade 3 acute toxicity in the genitourinary tract was observed in two patients. (11)C-Choline PET/CT is a valuable tool for planning and monitoring HTT in LN relapse after primary treatment. High-dose hypofractionated (11)C-choline PET/CT-guided HTT with SIB is well tolerated and is associated with a high early biochemical response rate.

A phase 1 study of the heat shock protein 90 inhibitor retaspimycin hydrochloride (IPI-504) in patients with gastrointestinal stromal tumors or soft tissue sarcomas

PubMed Central

Wagner, Andrew J.; Chugh, Rashmi; Rosen, Lee S.; Morgan, Jeffrey A.; George, Suzanne; Gordon, Michael; Dunbar, Joi; Normant, Emmanuel; Grayzel, David; Demetri, George D.

2015-01-01

Purpose Heat shock protein 90 (Hsp90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRα) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase 1 study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective Hsp90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS). Experimental Design IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m2 twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging. Results Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m2 twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26/37) of patients with GIST and 59% (10/17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11/29 (38%) of GIST patients. Conclusions In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of anti-tumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy. PMID:24045182

High-resolution, terrestrial radar velocity observations and model results reveal a strong bed at stable, tidewater Rink Isbræ, West Greenland

NASA Astrophysics Data System (ADS)

Bartholomaus, T. C.; Walker, R. T.; Stearns, L. A.; Fahnestock, M. A.; Cassotto, R.; Catania, G. A.; Felikson, D.; Fried, M.; Sutherland, D.; Nash, J. D.; Shroyer, E.

2015-12-01

At tidewater Rink Isbræ, on the central west coast of Greenland, satellite observations reveal that glacier velocities and terminus positions have remained stable, while the lowest 25 km have thinned 30 m since 1985. Over this same time period, other tidewater glaciers in central west Greenland have retreated, thinned and accelerated. Here we present field observations and model results to show that the flow of Rink Isbræ is resisted by unusually high basal shear stresses. Terrestrial radar interferometry (TRI) observations over 9 days in summer 2014 demonstrate weak velocity response to 4 km wide, full thickness calving events. Velocities at the terminus change by +/- 10% in response to rising and falling tides within a partial-width, 2.5-km-long floating ice tongue; however these tidal perturbations damp out within 2 km of the grounding line. Inversions for basal shear stress and force balance analyses together show that basal shear stresses in excess of 300 kPa support the majority of the driving stress at thick, steep Rink Isbræ. These observational and modeling results tell a consistent story in which a strong bed may limit the unstable tidewater glacier retreats observed elsewhere. Rink Isbræ has an erosion resistant quartzite bed with low fracture density. We hypothesize that this geology may play a major role in the bed strength.

Deciphering Systemic Wound Responses of the Pumpkin Extrafascicular Phloem by Metabolomics and Stable Isotope-Coded Protein Labeling1[C][W

PubMed Central

Gaupels, Frank; Sarioglu, Hakan; Beckmann, Manfred; Hause, Bettina; Spannagl, Manuel; Draper, John; Lindermayr, Christian; Durner, Jörg

2012-01-01

In cucurbits, phloem latex exudes from cut sieve tubes of the extrafascicular phloem (EFP), serving in defense against herbivores. We analyzed inducible defense mechanisms in the EFP of pumpkin (Cucurbita maxima) after leaf damage. As an early systemic response, wounding elicited transient accumulation of jasmonates and a decrease in exudation probably due to partial sieve tube occlusion by callose. The energy status of the EFP was enhanced as indicated by increased levels of ATP, phosphate, and intermediates of the citric acid cycle. Gas chromatography coupled to mass spectrometry also revealed that sucrose transport, gluconeogenesis/glycolysis, and amino acid metabolism were up-regulated after wounding. Combining ProteoMiner technology for the enrichment of low-abundance proteins with stable isotope-coded protein labeling, we identified 51 wound-regulated phloem proteins. Two Sucrose-Nonfermenting1-related protein kinases and a 32-kD 14-3-3 protein are candidate central regulators of stress metabolism in the EFP. Other proteins, such as the Silverleaf Whitefly-Induced Protein1, Mitogen Activated Protein Kinase6, and Heat Shock Protein81, have known defensive functions. Isotope-coded protein labeling and western-blot analyses indicated that Cyclophilin18 is a reliable marker for stress responses of the EFP. As a hint toward the induction of redox signaling, we have observed delayed oxidation-triggered polymerization of the major Phloem Protein1 (PP1) and PP2, which correlated with a decline in carbonylation of PP2. In sum, wounding triggered transient sieve tube occlusion, enhanced energy metabolism, and accumulation of defense-related proteins in the pumpkin EFP. The systemic wound response was mediated by jasmonate and redox signaling. PMID:23085839

Adriamycin and cis-platinum as first-line treatment in unresectable locally advanced or metastatic adult soft-tissue sarcomas.

PubMed

Kalofonos, Haralabos P; Bafaloukos, Dimitrios; Kourelis, Theodoros G; Karamouzis, Michalis V; Megas, Panagiotis; Iconomou, Grigorios; Tsiata, Ekaterini; Dimitropoulos, Dimitrios; Kosmidis, Paris; Lampiris, E

2004-06-01

Standard chemotherapy in advanced adult soft-tissue sarcomas (STS) has not yet been established. We evaluated the efficacy and toxicity of the combination of adriamycin (ADR) and cis-platinum (CDDP) as first-line treatment in nonoperable locally advanced or metastatic adult STS. Thirty patients were treated with CDDP 100 mg/m2 on day 1 and ADR 75 mg/m2 equally divided on days 1 to 3, every 3 weeks for 6 cycles. Patients were evaluated for response, toxicity, and survival, while resectability of residual disease was also assessed after the third cycle and the end of chemotherapy. No complete response was observed. Five patients (16.7%, 95% CI: 2.5%-31%) achieved partial response, 16 patients (53.3%, 95% CI: 34%-72%) had stable disease and 9 patients (30%, 95% CI: 13%-47%) had progressive disease. The overall median survival was 11.5 months (range, 4-96 months), and the median time to disease progression was 6 months (range, 0-96 months). Furthermore, two patients with PR and six patients with stable disease underwent further surgery followed by radiotherapy in four of them. At present, 5 patients remain free of relapse for 96, 90, 72, 60, and 48 months, respectively. Treatment-related toxicity was acceptable, with moderate myelosuppression and alopecia as the main adverse events. The ADR/CDDP regimen was well tolerated, but it did not achieve a high response rate. However, patients with resectable disease after chemotherapy achieved long-term survival. Further studies are needed to evaluate the role of combined-modality treatments in the management of patients with advanced STS.

Single-arm, open label study of pemetrexed plus cisplatin in chemotherapy naïve patients with malignant pleural mesothelioma: outcomes of an expanded access program.

PubMed

Obasaju, Coleman K; Ye, Zhishen; Wozniak, Antoinette J; Belani, Chandra P; Keohan, Mary-Louise; Ross, Helen J; Polikoff, Jonathan A; Mintzer, David M; Monberg, Matthew J; Jänne, Pasi A

2007-02-01

An expanded access program (EAP) provided patient access to pemetrexed prior to its commercial availability. The current report consists of US patients in the EAP who had chemotherapy naïve pleural mesothelioma. Eligible patients had a histologic or cytologic diagnosis of malignant mesothelioma that was not amenable to curative treatment with surgery. Study treatment consisted of pemetrexed 500mg/m(2) in combination with cisplatin 75mg/m(2) once every 21 days. Vitamin B12, folic acid, and dexamethasone were administered as prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmacovigilance database for all patients enrolled in the EAP. Of 1056 patients receiving at least one dose of pemetrexed in the EAP, 728 had chemotherapy naïve pleural mesothelioma. Median age of this group was 70 years (range 23-89 years) and 84% were male. Among 615 patients, overall response rate was 20.5%, including 12 complete responses (2.0%) and 114 partial responses (18.5%). An additional 290 patients (47.2%) had stable disease. Median survival for all 728 patients was 10.8 months (95% CI=9.8, 12.3; 60.3% censorship) and 1 year survival was 45.4%. The most commonly reported SAEs in the overall EAP irrespective of causality were dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%). In this large cohort, 67.7% of patients treated with first-line chemotherapy experienced a response or stable disease. Survival time and toxicity from this EAP were promising for this difficult-to-treat disease.

Female sea lamprey shift orientation toward a conspecific chemical cue to escape a sensory trap

USGS Publications Warehouse

Brant, Cory O.; Johnson, Nicholas; Li, Ke; Buchinger, Tyler J.; Li, Weiming

2016-01-01

The sensory trap model of signal evolution hypothesizes that signalers adapt to exploit a cue used by the receiver in another context. Although exploitation of receiver biases can result in conflict between the sexes, deceptive signaling systems that are mutually beneficial drive the evolution of stable communication systems. However, female responses in the nonsexual and sexual contexts may become uncoupled if costs are associated with exhibiting a similar response to a trait in both contexts. Male sea lamprey (Petromyzon marinus) signal with a mating pheromone, 3-keto petromyzonol sulfate (3kPZS), which may be a match to a juvenile cue used by females during migration. Upstream movement of migratory lampreys is partially guided by 3kPZS, but females only move toward 3kPZS with proximal accuracy during spawning. Here, we use in-stream behavioral assays paired with gonad histology to document the transition of female preference for juvenile- and male-released 3kPZS that coincides with the functional shift of 3kPZS as a migratory cue to a mating pheromone. Females became increasingly biased toward the source of synthesized 3kPZS as their maturation progressed into the reproductive phase, at which point, a preference for juvenile odor (also containing 3kPZS naturally) ceased to exist. Uncoupling of female responses during migration and spawning makes the 3kPZS communication system a reliable means of synchronizing mate search. The present study offers a rare example of a transition in female responses to a chemical cue between nonsexual and sexual contexts, provides insights into the origins of stable communication signaling systems.

Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: a report from the Children's Oncology Group.

PubMed

Villablanca, Judith G; London, Wendy B; Naranjo, Arlene; McGrady, Patrick; Ames, Matthew M; Reid, Joel M; McGovern, Renee M; Buhrow, Sarah A; Jackson, Hollie; Stranzinger, Enno; Kitchen, Brenda J; Sondel, Paul M; Parisi, Marguerite T; Shulkin, Barry; Yanik, Gregory A; Cohn, Susan L; Reynolds, C Patrick

2011-11-01

To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma. Patients received 7 days of fenretinide: 2,475 mg/m(2)/d divided TID (<18 years) or 1,800 mg/m(2)/d divided BID (≥18 years) every 21 days for a maximum of 30 courses. Patients with stable or responding disease after course 30 could request additional compassionate courses. Best response by course 8 was evaluated in stratum 1 (measurable disease on CT/MRI ± bone marrow and/or MIBG avid sites) and stratum 2 (bone marrow and/or MIBG avid sites only). Sixty-two eligible patients, median age 5 years (range 0.6-19.9), were treated in stratum 1 (n = 38) and stratum 2 (n = 24). One partial response (PR) was seen in stratum 2 (n = 24 evaluable). No responses were seen in stratum 1 (n = 35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in stratum 1 and 6 patients in stratum 2 for 4 to 45+ (median 15) courses. Median time to progression was 40 days (range 17-506) for stratum 1 and 48 days (range 17-892) for stratum 2. Mean 4-HPR steady-state trough plasma concentrations were 7.25 μmol/L (coefficient of variation 40-56%) at day 7 course 1. Toxicities were mild and reversible. Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric phase I studies. ©2011 AACR

Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: A report from the Children’s Oncology Group NSC #374551; IND# 40294

PubMed Central

Villablanca, Judith G.; London, Wendy B.; Naranjo, Arlene; McGrady, Patrick; Ames, Matthew M.; Reid, Joel M.; McGovern, Renee M.; Buhrow, Sarah A.; Jackson, Hollie; Stranzinger, Enno; Kitchen, Brenda J.; Sondel, Paul M.; Parisi, Marguerite T.; Shulkin, Barry; Yanik, Gregory A.; Cohn, Susan L.; Reynolds, C. Patrick

2011-01-01

Purpose To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma. Experimental Design Patients received 7 days of fenretinide: 2475 mg/m2/day divided TID (<18 years) or 1800 mg/m2/day divided BID (≥18 years) every 21 days for a maximum of 30 courses. Patients with stable or responding disease after course 30 could request additional compassionate courses. Best response by course 8 was evaluated in Stratum 1 (measurable disease on CT/MRI +/− bone marrow and/or MIBG avid sites) and Stratum 2 (bone marrow and/or MIBG avid sites only). Results Sixty-two eligible patients, median age 5 years (range 0.6–19.9), were treated in Stratum 1 (n=38) and Stratum 2 (n=24). One partial response (PR) was seen in Stratum 2 (n=24 evaluable). No responses were seen in Stratum 1 (n=35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in Stratum 1 and 6 patients in Stratum 2 for 4–45+ (median 15) courses. Median time to progression was 40 days (range 17–506) for Stratum 1 and 48 days (range 17–892) for Stratum 2. Mean 4-HPR steady state trough plasma concentrations were 7.25 µM (coefficient of variation 40–56%) at day 7 course 1. Toxicities were mild and reversible. Conclusions Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric Phase I studies. PMID:21908574

Vertical Mixing in the Dead Sea

NASA Astrophysics Data System (ADS)

Gertman, Isaac; Ozer, Tal; Katsenelson, Boris; Lensky, Nadav

2015-04-01

For hundreds of years, the Dead Sea was characterized by a stable haline stratification, supported by runoff. The penetration of the winter convection was limited to an upper mixed layer (UML) of about 30-50 m. Below the UML, a stable halocline prevented the mixing. As a result of the runoff reduction, the UML salinity increased and the gravitational stability diminished. During the winter of 1978-1979, the sea water overturned, ending the long-term stable hydrological regime. Since 1979, the haline stratification structure reoccurred twice after extremely rainy winters, in 1980-82 and 1992-1995. In other years, the sea was entirely mixed by winter thermal convection ( which occurs from November to March ) and had a seasonal pycnocline beneath the UML during summer. Profiles of temperature and quasi-salinity (density anomaly from 1000 kg/m3 for the chosen reference temperature of 32° C) during the last 19 years, show the formation of summer ``overturning halocline'' beneath the UML, and the thermocline that supports the stable stratification. Another warm and saline layer is formed also during the summer period near the bottom. This layer spreads from the southern part of the sea, where end-brine is discharged to the sea from the Israeli and Jordanian salt plants' evaporation ponds. The end-brine has extremely high salinity (˜ 350 g/kg) and, in spite of the high temperatures ( ˜ 45° C), high density (1350 kg/m^3), it therefore spreads as a gravitational current in the Dead Sea deep basin. Estimation of the density ratio (Rρ) for the Dead Sea water (where measurements of water salinity is quite difficult) was done using quasi-salinity (σ32) and potential temperature (θ): Rρ= [α(partialθ/partial z)]/[β(partial σ32/partial z)], where α and β are temperature expansion and quasi-salinity contraction coefficients respectively. The values of α and β for the Dead Sea water were defined from water samples collected during 2008. The Rρ values confirm that the summer Dead Sea thermohaline structure is appropriate for double diffusion mixing. A salt fingers regime beneath the UML (1.3< Rρ

Camera Based Closed Loop Control for Partial Penetration Welding of Overlap Joints

NASA Astrophysics Data System (ADS)

Abt, F.; Heider, A.; Weber, R.; Graf, T.; Blug, A.; Carl, D.; Höfler, H.; Nicolosi, L.; Tetzlaff, R.

Welding of overlap joints with partial penetration in automotive applications is a challenging process, since the laser power must be set very precisely to achieve a proper connection between the two joining partners without damaging the backside of the sheet stack. Even minor changes in welding conditions can lead to bad results. To overcome this problem a camera based closed loop control for partial penetration welding of overlap joints was developed. With this closed loop control it is possible to weld such configurations with a stable process result even under changing welding conditions.

Induction chemotherapy in head and neck squamous cell carcinoma of the paranasal sinus and nasal cavity: a role in organ preservation

PubMed Central

Ock, Chan-Young; Keam, Bhumsuk; Kim, Tae Min; Han, Doo Hee; Won, Tae-Bin; Lee, Se-Hoon; Hah, J. Hun; Kwon, Tack-Kyun; Kim, Dong-Wan; Kim, Dong-Young; Rhee, Chae-Seo; Wu, Hong-Gyun; Sung, Myung-Whun; Heo, Dae Seog

2016-01-01

Background/Aims: The role of induction chemotherapy (IC) for eyeball preservation has not been established in head and neck squamous cell carcinoma (HNSCC) of the paranasal sinus and nasal cavity (PNSNC). Periorbital involvement frequently leads to eyeball exenteration with a margin of safety. We evaluated the treatment outcomes, including survival and eyeball preservation, of patients who received IC for HNSCC of the PNSNC. Methods: We reviewed 21 patients diagnosed with HNSCC of the PNSNC who were treated with IC. We analyzed response, eyeball preservation rate, and overall survival. Results: Tumors were located in the paranasal sinus (n = 14) or nasal cavity (n = 7). Most patients had stage T4a (n = 10) or T4b (n = 7) disease. More than half of the patients received a chemotherapy regimen of docetaxel, fluorouracil, and cisplatin (n = 11). Thirteen patients (61.9%) achieved a partial response after IC and 15 patients (71.4%) achieved T down-staging. Among 17 patients with stage T4 disease, which confers a high risk of orbital exenteration, 14 (82.4%) achieved preservation of the involved eye. The 3-year overall survival (OS) rate of patients who achieved a partial response to IC was 84.6%. The 3-year OS rate of patients with stable disease or disease progression after IC was 25.0% (p = 0.038). Conclusions: IC could be considered for down-staging patients with advanced T-stage disease. It could also be a reasonable option for eyeball preservation in locally advanced HNSCC of the PNSNC. PMID:26976150

MOPP chemotherapy for treatment of resistant lymphoma in dogs: a retrospective study of 117 cases (1989-2000).

PubMed

Rassnick, Kenneth M; Mauldin, Glenna E; Al-Sarraf, Renee; Mauldin, G Neal; Moore, Antony S; Mooney, Samantha C

2002-01-01

The purpose of this retrospective study was to evaluate the efficacy and toxicity of the MOPP chemotherapy protocol (mechlorethamine, vincristine, procarbazine, and prednisone) as a rescue regimen in dogs with lymphoma. One hundred seventeen dogs that had resistance to previously administered chemotherapy were evaluated. Before treatment with MOPP, all dogs received a median of 6 chemotherapy drugs for a median duration of 213 days. Thirty-one percent (36 of 117) had a complete response (CR) to MOPP for a median of 63 days, and 34% (40 of 117) had a partial response (PR) for a median of 47 days. Sixteen percent (19 of 117) had stable disease (SD) for a median of 33 days. Predictors for response to MOPP were not identified. Gastrointestinal (GI) toxicity occurred in 28% (33 of 117) of the dogs, and 13% (15 dogs) required hospitalization. Five dogs developed septicemia, and 2 died as a result. MOPP was an effective treatment for dogs with resistant lymphoma and was well tolerated by the majority of affected dogs.

Phase-II trials in osteosarcoma recurrences: A systematic review of past experience.

PubMed

Omer, Natacha; Le Deley, Marie-Cécile; Piperno-Neumann, Sophie; Marec-Berard, Perrine; Italiano, Antoine; Corradini, Nadège; Bellera, Carine; Brugières, Laurence; Gaspar, Nathalie

2017-04-01

The most appropriate design of Phase-II trials evaluating new therapies in osteosarcoma remains poorly defined. To study consistency in phase-II clinical trials evaluating new therapies for osteosarcoma recurrences with respect to eligibility criteria, response assessment, end-points, statistical design and reported results. Systematic review of clinical trials registered on clinicaltrials.gov, clinicaltrialsregister.eu and French National Cancer Institute website or referenced in PubMed and American Society of Clinical Oncology websites, between 2003 and 2016, using the following criteria: (osteosarcoma OR bone sarcoma) AND (Phase-II). Among the 99 trials identified, 80 were Phase-II, 17 I/II and 2 II/III, evaluating mostly targeted therapy (n = 40), and chemotherapy alone (n = 26). Results were fully (n = 28) or partially (abstract, n = 6) published. Twenty-four trials were dedicated to osteosarcoma, 22 had an osteosarcoma stratum. Twenty-eight out of 99 trials refer to the age range observed at recurrence (28%). Overall, 65 trials were run in multicentre settings, including 17 international trials. Only 9 trials were randomised. The primary end-point was tumour response in 71 trials (response rate, n = 40 or best response, n = 31), with various definitions (complete + partial ± minor response and stable disease), mainly evaluated with RECIST criteria (n = 69); it was progression-free survival in 24 trials and OS in 3. In single-arm trials evaluating response rate, the null hypothesis tested (when available, n = 12) varied from 5% to 25%. No robust historical data can currently be derived from past efficacy Phase-II trials. There is an urgent need to develop international randomised Phase-II trials across all age ranges with standardised primary end-point. Copyright © 2017 Elsevier Ltd. All rights reserved.

Final report of a phase 2 clinical trial of lenalidomide monotherapy for patients with T-cell lymphoma.

PubMed

Toumishey, Ethan; Prasad, Angeli; Dueck, Greg; Chua, Neil; Finch, Daygen; Johnston, James; van der Jagt, Richard; Stewart, Doug; White, Darrell; Belch, Andrew; Reiman, Tony

2015-03-01

Patients with T-cell lymphomas face a poorer prognosis compared with patients with B-cell lymphomas. New therapeutic approaches need to be developed to improve outcomes for these patients. Forty patients with recurrent and refractory T-cell lymphomas other than mycosis fungoides and patients with untreated T-cell lymphoma who were not candidates for combination chemotherapy were prescribed oral lenalidomide at a dose of 25 mg daily on days 1 to 21 of each 28-day cycle, with standardized dose reductions for toxicity. The primary endpoint was overall response rate (ORR), and secondary endpoints were complete and partial response rates, progression-free survival (PFS), overall survival (OS), and safety. The authors also determined duration of response (DoR). A total of 40 patients were enrolled in the current study; 1 patient was subsequently deemed ineligible. The ORR was 10 of 39 patients (26%); 3 patients (8%) achieved complete responses and 7 patients achieved partial responses. Three patients had stable disease for ≥5 cycles. The median OS was 12 months (range <1 month to ≥69 months), the median PFS was 4 months (range, <1 month to ≥50 months), and the median DoR was 13 months (range 2 months to ≥37 months), including 5 responses that lasted >1 year. Toxicity was in keeping with the known safety profile of lenalidomide. Among the patients who had recurrent/refractory peripheral T-cell lymphoma (29 patients), the ORR was 24%, the median OS was 12 months, the median PFS was 4 months, and the median DoR was 5 months (range, 2 months to ≥37 months). In the current study, the use of oral lenalidomide monotherapy demonstrated clinically relevant efficacy among patients with systemic T-cell lymphomas. It appears to have excellent potential as an agent in combination therapy for patients with T-cell lymphoma. © 2014 American Cancer Society.

Application of a statistically enhanced, novel, organic solvent stable lipase from Bacillus safensis DVL-43.

PubMed

Kumar, Davender; Parshad, Rajinder; Gupta, Vijay Kumar

2014-05-01

This paper presents the molecular identification of a newly isolated bacterial strain producing a novel and organic solvent stable lipase, statistical optimization of fermentation medium, and its application in the synthesis of ethyl laurate. On the basis of nucleotide homology and phylogenetic analysis of 16S rDNA sequence, the strain was identified as Bacillus safensis DVL-43 (Gen-bank accession number KC156603). Optimization of fermentation medium using Plackett-Burman design and response surface methodology led to 11.4-fold increase in lipase production. The lipase from B. safensis DVL-43 exhibited excellent stability in various organic solvents. The enzyme retained 100% activity after 24h incubation in xylene, DMSO and toluene, each solvent being used at a concentration of 25% (v/v). The use of partially purified DVL-43 lipase as catalyst in the synthesis of ethyl laurate, an esterification product of lauric acid and ethanol, resulted in 80% esterification in 12h under optimized conditions. The formation of ethyl laurate was confirmed using TLC and (1)H NMR. Organic solvent stable lipases exhibiting potential application in enzymatic esterification are in great demand in flavor, fine chemicals and pharma industries. We could not find any report on lipase production from B. safensis strain and its application in esterification. Copyright © 2014 Elsevier B.V. All rights reserved.

Why do the lonely stay lonely? Chronically lonely adolescents' attributions and emotions in situations of social inclusion and exclusion.

PubMed

Vanhalst, Janne; Soenens, Bart; Luyckx, Koen; Van Petegem, Stijn; Weeks, Molly S; Asher, Steven R

2015-11-01

The goal of this study was to identify mechanisms associated with chronic loneliness by examining the effect of adolescents' accumulated history of loneliness on responses to new social situations. Specifically, this study investigated whether attributions and emotions in situations of social inclusion and exclusion differ between chronically lonely adolescents and adolescents with a different loneliness history. A total of 730 adolescents (Mage at Wave 1 = 15.43 years) participated in a 4-wave longitudinal study with annual loneliness assessments. A chronic loneliness trajectory was identified, in addition to low-stable, moderate-stable, moderate-increasing, and high-decreasing loneliness trajectories. At Wave 4, vignettes depicting social inclusion and exclusion were presented, and participants rated a set of attributions and emotions following each vignette. Compared with individuals following other trajectories, chronically lonely adolescents were characterized by hypersensitivity to social exclusion (i.e., higher levels of negative emotions) and hyposensitivity to social inclusion (i.e., lower levels of enthusiasm). Further, chronically lonely adolescents had a stronger tendency to attribute social inclusion to circumstantial factors and social exclusion to internal and stable characteristics. This maladaptive attribution style partially mediated their emotional experiences. Together, results indicate that chronically lonely individuals respond to social situations in ways that may perpetuate rather than reduce their loneliness. (c) 2015 APA, all rights reserved).

PRospective Imaging of CErvical cancer and neoadjuvant treatment (PRICE) study: role of ultrasound to predict partial response in locally advanced cervical cancer patients undergoing chemoradiation and radical surgery.

PubMed

Testa, A C; Ferrandina, G; Moro, F; Pasciuto, T; Moruzzi, M C; De Blasis, I; Mascilini, F; Foti, E; Autorino, R; Collarino, A; Gui, B; Zannoni, G F; Gambacorta, M A; Valentini, A L; Rufini, V; Scambia, G

2018-05-01

Chemoradiation-based neoadjuvant treatment followed by radical surgery is an alternative therapeutic strategy for locally advanced cervical cancer (LACC), but ultrasound variables used to predict partial response to neoadjuvant treatment are not well defined. Our goal was to analyze prospectively the potential role of transvaginal ultrasound in early prediction of partial pathological response, assessed in terms of residual disease at histology, in a large, single-institution series of LACC patients triaged to neoadjuvant treatment followed by radical surgery. Between October 2010 and June 2014, we screened 108 women with histologically documented LACC Stage IB2-IVA, of whom 88 were included in the final analysis. Tumor volume, three-dimensional (3D) power Doppler indices and contrast parameters were obtained before (baseline examination) and after 2 weeks of treatment. The pathological response was defined as complete (absence of any residual tumor after treatment) or partial (microscopic and/or macroscopic residual tumor at pathological examination). Complete-response and partial-response groups were compared and receiver-operating characteristics (ROC) curves were generated for ultrasound variables that were statistically significant on univariate analysis to evaluate their diagnostic ability to predict partial pathological response. There was a complete pathological response to neoadjuvant therapy in 40 (45.5%) patients and a partial response in 48 (54.5%). At baseline examination, tumor volume did not differ between the two groups. However, after 2 weeks of neoadjuvant treatment, the tumor volume was significantly greater in patients with partial response than it was in those with complete response (P = 0.019). Among the 3D vascular indices, the vascularization index (VI) was significantly lower in the partial-response compared with the complete-response group, both before and after 2 weeks of treatment (P = 0.037 and P = 0.024, respectively). At baseline examination in the contrast analysis, women with partial response had lower tumor peak enhancement (PE) as well as lower tumor wash-in rate (WiR) and longer tumor rise time (RT) compared with complete responders (P = 0.006, P = 0.003, P = 0.038, respectively). There was no difference in terms of contrast parameters after 2 weeks of treatment. ROC-curve analysis of baseline parameters showed that the best cut-offs for predicting partial pathological response were 41.5% for VI (sensitivity, 63.6%; specificity, 66.7%); 16123.5 auxiliary units for tumor PE (sensitivity, 47.9%; specificity, 84.2%); 7.8 s for tumor RT (sensitivity, 68.8%; specificity, 57.9%); and 4902 for tumor WiR (sensitivity, 77.1%; specificity, 60.5%). ROC curves of parameters after 2 weeks of treatment showed that the best cut-off for predicting partial pathological response was 18.1 cm 3 for tumor volume (sensitivity, 70.8%; specificity 60.0%) and 39.5% for VI (sensitivity; 62.5%; specificity, 73.5%). Ultrasound and contrast parameters differ between LACC patients with complete response and those with partial response before and after 2 weeks of neoadjuvant treatment. However, neither ultrasound parameters before treatment nor those after 2 weeks of treatment had cut-off values with acceptable sensitivity and specificity for predicting partial pathological response to neoadjuvant therapy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

The nucleotide-free state of heterotrimeric G proteins α-subunit adopts a highly stable conformation.

PubMed

Andhirka, Sai Krishna; Vignesh, Ravichandran; Aradhyam, Gopala Krishna

2017-08-01

Deciphering the mechanism of activation of heterotrimeric G proteins by their cognate receptors continues to be an intriguing area of research. The recently solved crystal structure of the ternary complex captured the receptor-bound α-subunit in an open conformation, without bound nucleotide has improved our understanding of the activation process. Despite these advancements, the mechanism by which the receptor causes GDP release from the α-subunit remains elusive. To elucidate the mechanism of activation, we studied guanine nucleotide-induced structural stability of the α-subunit (in response to thermal/chaotrope-mediated stress). Inherent stabilities of the inactive (GDP-bound) and active (GTP-bound) forms contribute antagonistically to the difference in conformational stability whereas the GDP-bound protein is able to switch to a stable intermediate state, GTP-bound protein loses this ability. Partial perturbation of the protein fold reveals the underlying influence of the bound nucleotide providing an insight into the mechanism of activation. An extra stable, pretransition intermediate, 'empty pocket' state (conformationally active-state like) in the unfolding pathway of GDP-bound protein mimics a gating system - the activation process having to overcome this stable intermediate state. We demonstrate that a relatively more complex conformational fold of the GDP-bound protein is at the core of the gating system. We report capturing this threshold, 'metastable empty pocket' conformation (the gate) of α-subunit of G protein and hypothesize that the receptor activates the G protein by enabling it to achieve this structure through mild structural perturbation. © 2017 Federation of European Biochemical Societies.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Checco, A.; Hofmann, T.; DiMasi, E.

The details of air nanobubble trapping at the interface between water and a nanostructured hydrophobic silicon surface are investigated using X-ray scattering and contact angle measurements. Large-area silicon surfaces containing hexagonally packed, 20 nm wide hydrophobic cavities provide ideal model surfaces for studying the morphology of air nanobubbles trapped inside cavities and its dependence on the cavity depth. Transmission small-angle X-ray scattering measurements show stable trapping of air inside the cavities with a partial water penetration of 5-10 nm into the pores, independent of their large depth variation. This behavior is explained by consideration of capillary effects and the cavitymore » geometry. For parabolic cavities, the liquid can reach a thermodynamically stable configuration - a nearly planar nanobubble meniscus - by partially penetrating into the pores. This microscopic information correlates very well with the macroscopic surface wetting behavior.« less

Treatment of advanced refractory sarcomas with ifosfamide and etoposide combination chemotherapy.

PubMed

Yalçin, S; Güllü, I; Barişta, I; Tekuzman, G; Ozişik, Y; Celik, I; Kars, A

1998-01-01

Chemotherapy options for resistant advanced-stage sarcomas are limited and in most cases disappointing. In a phase II study, we treated 26 consecutive patients with refractory advanced sarcoma with ifosfamide and etoposide combination chemotherapy. All patients had received prior doxorubicin- and/or cyclophosphamide-based chemotherapies. Seventeen patients were male and 9 were female. The patients' median age was 35 years (range: 19-67 years). A total of 24 patients were eligible for evaluation of responses. Seven patients had a complete response (CR) (29.1%), 3 had a partial response (PR) (12.5%), 3 had stable disease (SD) (12.5%), and 11 had progressive disease (PD) (45.9%). An overall 41.6% objective response was achieved. Median time to treatment failure was 13.3 months. A total of 108 cycles of therapy were evaluable for evaluation of toxicity. Myelosuppression, observed in 55.5% of the treatment courses, was the major dose-limiting toxicity. Nausea and vomiting, seen in 64% of the courses, were the most important nonhematological side effects. Alopecia was almost universal. Hemorrhagic cystitis was observed in only 1 patient. We have concluded that the combination of ifosfamide, mesna, and etoposide is effective in advanced refractory sarcomas, and has acceptable toxicity.

Spontaneous switching among multiple spatio-temporal patterns in three-oscillator systems constructed with oscillatory cells of true slime mold

NASA Astrophysics Data System (ADS)

Takamatsu, Atsuko

2006-11-01

Three-oscillator systems with plasmodia of true slime mold, Physarum polycephalum, which is an oscillatory amoeba-like unicellular organism, were experimentally constructed and their spatio-temporal patterns were investigated. Three typical spatio-temporal patterns were found: rotation ( R), partial in-phase ( PI), and partial anti-phase with double frequency ( PA). In pattern R, phase differences between adjacent oscillators were almost 120 ∘. In pattern PI, two oscillators were in-phase and the third oscillator showed anti-phase against the two oscillators. In pattern PA, two oscillators showed anti-phase and the third oscillator showed frequency doubling oscillation with small amplitude. Actually each pattern is not perfectly stable but quasi-stable. Interestingly, the system shows spontaneous switching among the multiple quasi-stable patterns. Statistical analyses revealed a characteristic in the residence time of each pattern: the histograms seem to have Gamma-like distribution form but with a sharp peak and a tail on the side of long period. That suggests the attractor of this system has complex structure composed of at least three types of sub-attractors: a “Gamma attractor”-involved with several Poisson processes, a “deterministic attractor”-the residence time is deterministic, and a “stable attractor”-each pattern is stable. When the coupling strength was small, only the Gamma attractor was observed and switching behavior among patterns R, PI, and PA almost always via an asynchronous pattern named O. A conjecture is as follows: Internal/external noise exposes each pattern of R, PI, and PA coexisting around bifurcation points: That is observed as the Gamma attractor. As coupling strength increases, the deterministic attractor appears then followed by the stable attractor, always accompanied with the Gamma attractor. Switching behavior could be caused by regular existence of the Gamma attractor.

Role of Nonsteroidal Anti-inflammatory Drug in Treatment of Extra-abdominal Desmoid Tumors.

PubMed

Cho, Ja Young; Gupta, Sanjay; Cho, Hwan Seong; Park, Min Suk; Mok, Su Jung; Han, Ilkyu; Kim, Han-Soo

2018-06-01

We retrospectively reviewed the outcomes of patients who had been treated with meloxicam for the extra-abdominal desmoid tumors and evaluated the correlation between clinical outcome and clinic pathological variables. Twenty patients treated with meloxicam were followed up every 3 to 6 months. Meloxicam administration was planned at 15 mg/day orally for 6 months. Of the 20 patients evaluated, according to Response Evaluation Criteria in Solid Tumors criteria, there were five patients with partial response (25.0%), eight with stable disease (40.0%), and seven with tumor progression (35.0%). The cumulative probability of dropping out from our nonsurgical strategy using meloxicam was 35.0% at 1 year and 35.0% at 5 years. The present study suggests that conservative treatment would be a primary treatment option for this perplexing disease even though we were not able to determine that the use of a cyclooxygenase-2 inhibitor would have an additional influence on the natural course of a desmoid tumor.

A phase II study of bortezomib in patients with MALT lymphoma

PubMed Central

Troch, Marlene; Jonak, Constanze; Müllauer, Leonhard; Püspök, Andreas; Formanek, Michael; Hauff, Wolfgang; Zielinski, Christoph C.; Chott, Andreas; Raderer, Markus

2009-01-01

We have performed a phase II study to evaluate bortezomib in patients with MALT-lymphoma. Sixteen patients entered the trial, 4 had gastric MALT-lymphoma, 7 of the ocular adnexa, one of the colon, and 2 of the parotid, and one patient each the lung and the breast. Bortezomib was given at 1.5 mg/m2 days 1, 4, 8 and 11; repeated every 21 days. The overall response rate was 80% (13/16); 7 patients achieved complete remission (43%), 6 partial response (37%) and 3 stable disease. After a median follow-up of 23 months (range; 8–26), all patients are alive and 4 have relapsed. Fifteen patients required dose reductions due to either neuropathy (7 patients) or diarrhea (8 patients). Bortezomib appears to be active in patients with MALT-lymphoma. However, an unexpectedly high rate of toxicities was seen, warranting assessment of combination schedules with bortezomib at a lower dose than given in our study (ClinicalTrials.govIdentifier: NCT 00373906). PMID:19336742

Production of Escherichia coli heat labile toxin (LT) B subunit in soybean seed and analysis of its immunogenicity as an oral vaccine.

PubMed

Moravec, Tomas; Schmidt, Monica A; Herman, Eliot M; Woodford-Thomas, Terry

2007-02-19

The B subunit of the heat labile toxin of enterotoxigenic Escherichia coli (LTB) was used as a model immunogen for production in soybean seed. LTB expression was directed to the endoplasmic reticulum (ER) of seed storage parenchyma cells for sequestration in de novo synthesized inert protein accretions derived from the ER. Pentameric LTB accumulated to 2.4% of the total seed protein at maturity and was stable in desiccated seed. LTB-soybean extracts administered orally to mice induced both systemic IgG and IgA, and mucosal IgA antibody responses, and was particularly efficacious when used in a parenteral prime-oral gavage boost immunization strategy. Sera from immunized mice blocked ligand binding in vitro and immunized mice exhibited partial protection against LT challenge. Moreover, soybean-expressed LTB stimulated the antibody response against a co-administered antigen by 500-fold. These results demonstrate the utility of soybean as an efficient production platform for vaccines that can be used for oral delivery.

Long-term survival in primary CNS lymphoma treated by high-dose methotrexate monochemotherapy: role of STAT6 activation as prognostic determinant.

PubMed

Yang, Seung-Ho; Lee, Kun Soo; Kim, Il Sup; Hong, Jae Taek; Sung, Jae Hoon; Son, Byung Chul; Lee, Sang Won; Hong, Yong-Kil

2009-03-01

We report a single-center experience of 16 immunocompetent patients diagnosed with primary central nervous system lymphoma and treated with monochemotherapy with high-dose methotrexate (MTX) and deferred radiotherapy. MTX was given at a dose of 8.0 g/m2 for induction and at a dose of 3.5-8.0 g/m2 for maintenance. There were eight complete responses (CR), one partial response, one stable disease, and six patients whose tumors progressed in spite of the chemotherapy. At final follow-up, five of five CRs were alive and well without radiotherapy, with median follow-up of 26 months. Overall survival in eight non-CRs treated with the subsequent radiotherapy was 36 months. In the immunohistochemical study, STAT6 was positively expressed in 8 out of 13 cases. They included all non-CRs and two CRs. This observation suggests that STAT6 expression can be used as a prognostic determinant for MTX chemotherapy.

Malignant pilomatricoma in a dog with local and distant metastases treated with chemotherapy and bisphosphonates

PubMed Central

Treggiari, Elisabetta; Elliott, James W.

2017-01-01

A ten-year-old male neutered cross breed dog presented for evaluation of a mass associated with the left scapular bone, identified as a carcinoma. The dog had a malignant pilomatricoma removed from the left lateral thigh 6 months earlier. Histopathology review of the cutaneous and scapular mass identified the same tumour type, confirming metastatic disease; additional metastases to the inguinal lymph node, liver and lungs were identified. Chemotherapy resulted in partial responses/stable disease of very short duration. Bisphosphonates were administered due to lack of a measurable response and worsening of the associated lameness. The patient ultimately developed a symptomatic vertebral metastasis and was euthanased. The dog survived 255 days since medical treatment was started and 455 days since surgical removal of the primary tumour. This case report suggests that medical treatment with the addition of analgesia may be able to palliate clinical signs and possibly extend survival in dogs with metastatic epithelial cancer. PMID:28795016

A partial pressure monitor and controller for stable ozone flow from a silica gel trap

NASA Astrophysics Data System (ADS)

Stevens, R. E.; Hsiao, C.-W.; Le, Linh; Curro, N. J.; Monton, B. J.; Chang, B.-Y.; Kung, C.-Y.; Kittrell, C.; Kinsey, J. L.

1998-06-01

A new ozone trapping system designed for safe and consistent delivery to a reaction vessel is described. Silica gel is used to trap the ozone because of its known safety advantages over traps that store ozone in liquid form. The new design is free of any liquid baths, such as freon or flammable solvents. A circuit design for monitoring and controlling the ozone partial pressure of 6-25 Torr is also described.

Multi-scale simulation of lithium diffusion in the presence of a 30° partial dislocation and stacking fault in Si

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Chao-Ying; Li, Chen-liang; Wu, Guo-Xun

The multi-scale simulation method is employed to investigate how defects affect the performances of Li-ion batteries (LIBs). The stable positions, binding energies and dynamics properties of Li impurity in Si with a 30° partial dislocation and stacking fault (SF) have been studied in comparison with the ideal crystal. It is found that the most table position is the tetrahedral (T{sub d}) site and the diffusion barrier is 0.63 eV in bulk Si. In the 30° partial dislocation core and SF region, the most stable positions are at the centers of the octagons (Oct-A and Oct-B) and pentahedron (site S), respectively. Inmore » addition, Li dopant may tend to congregate in these defects. The motion of Li along the dislocation core are carried out by the transport among the Oct-A (Oct-B) sites with the barrier of 1.93 eV (1.12 eV). In the SF region, the diffusion barrier of Li is 0.91 eV. These two types of defects may retard the fast migration of Li dopant that is finally trapped by them. Thus, the presence of the 30° partial dislocation and SF may deactivate the Li impurity and lead to low rate capability of LIB.« less

Coexistence of stable stationary behavior and partial synchrony in an all-to-all coupled spiking neural network

NASA Astrophysics Data System (ADS)

de Smet, Filip; Aeyels, Dirk

2010-12-01

We consider the stationary and the partially synchronous regimes in an all-to-all coupled neural network consisting of an infinite number of leaky integrate-and-fire neurons. Using analytical tools as well as simulation results, we show that two threshold values for the coupling strength may be distinguished. Below the lower threshold, no synchronization is possible; above the upper threshold, the stationary regime is unstable and partial synchrony prevails. In between there is a range of values for the coupling strength where both regimes may be observed. The assumption of an infinite number of neurons is crucial: simulations with a finite number of neurons indicate that above the lower threshold partial synchrony always prevails—but with a transient time that may be unbounded with increasing system size. For values of the coupling strength in a neighborhood of the lower threshold, the finite model repeatedly builds up toward synchronous behavior, followed by a sudden breakdown, after which the synchronization is slowly built up again. The “transient” time needed to build up synchronization again increases with increasing system size, and in the limit of an infinite number of neurons we retrieve stationary behavior. Similarly, within some range for the coupling strength in this neighborhood, a stable synchronous solution may exist for an infinite number of neurons.

Complex symmetric matrices with strongly stable iterates

NASA Technical Reports Server (NTRS)

Tadmor, E.

1985-01-01

Complex-valued symmetric matrices are studied. A simple expression for the spectral norm of such matrices is obtained, by utilizing a unitarily congruent invariant form. A sharp criterion is provided for identifying those symmetric matrices whose spectral norm is not exceeding one: such strongly stable matrices are usually sought in connection with convergent difference approximations to partial differential equations. As an example, the derived criterion is applied to conclude the strong stability of a Lax-Wendroff scheme.

Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis.

PubMed

Marty, Francisco M; Ostrosky-Zeichner, Luis; Cornely, Oliver A; Mullane, Kathleen M; Perfect, John R; Thompson, George R; Alangaden, George J; Brown, Janice M; Fredricks, David N; Heinz, Werner J; Herbrecht, Raoul; Klimko, Nikolai; Klyasova, Galina; Maertens, Johan A; Melinkeri, Sameer R; Oren, Ilana; Pappas, Peter G; Ráčil, Zdeněk; Rahav, Galia; Santos, Rodrigo; Schwartz, Stefan; Vehreschild, J Janne; Young, Jo-Anne H; Chetchotisakd, Ploenchan; Jaruratanasirikul, Sutep; Kanj, Souha S; Engelhardt, Marc; Kaufhold, Achim; Ito, Masanori; Lee, Misun; Sasse, Carolyn; Maher, Rochelle M; Zeiher, Bernhardt; Vehreschild, Maria J G T

2016-07-01

Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. In a single-arm open-label trial (VITAL study), adult patients (≥18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response-ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)-according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19-179, range 2-882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary-treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B-treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0·595). Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. Astellas Pharma Global Development, Basilea Pharmaceutica International. Copyright © 2016 Elsevier Ltd. All rights reserved.

A semigroup approach to the strong ergodic theorem of the multistate stable population process.

PubMed

Inaba, H

1988-01-01

"In this paper we first formulate the dynamics of multistate stable population processes as a partial differential equation. Next, we rewrite this equation as an abstract differential equation in a Banach space, and solve it by using the theory of strongly continuous semigroups of bounded linear operators. Subsequently, we investigate the asymptotic behavior of this semigroup to show the strong ergodic theorem which states that there exists a stable distribution independent of the initial distribution. Finally, we introduce the dual problem in order to obtain a logical definition for the reproductive value and we discuss its applications." (SUMMARY IN FRE) excerpt

Radiographic and magnetic resonance imaging predicts severity of cruciate ligament fiber damage and synovitis in dogs with cranial cruciate ligament rupture

PubMed Central

Racette, Molly A.; Hans, Eric C.; Volstad, Nicola J.; Holzman, Gerianne; Bleedorn, Jason A.; Schaefer, Susan L.; Waller, Kenneth R.; Hao, Zhengling; Block, Walter F.

2017-01-01

Cruciate ligament rupture (CR) and associated osteoarthritis (OA) is a common condition in dogs. Dogs frequently develop a second contralateral CR. This study tested the hypothesis that the degree of stifle synovitis and cranial cruciate ligament (CrCL) matrix damage in dogs with CR is correlated with non-invasive diagnostic tests, including magnetic resonance (MR) imaging. We conducted a prospective cohort study of 29 client-owned dogs with an unstable stifle due to complete CR and stable contralateral stifle with partial CR. We evaluated correlation of stifle synovitis and CrCL fiber damage with diagnostic tests including bilateral stifle radiographs, 3.0 Tesla MR imaging, and bilateral stifle arthroscopy. Histologic grading and immunohistochemical staining for CD3+ T lymphocytes, TRAP+ activated macrophages and Factor VIII+ blood vessels in bilateral stifle synovial biopsies were also performed. Serum and synovial fluid concentrations of C-reactive protein (CRP) and carboxy-terminal telopeptide of type I collagen (ICTP), and synovial total nucleated cell count were determined. Synovitis was increased in complete CR stifles relative to partial CR stifles (P<0.0001), although total nucleated cell count in synovial fluid was increased in partial CR stifles (P<0.01). In partial CR stifles, we found that 3D Fast Spin Echo Cube CrCL signal intensity was correlated with histologic synovitis (SR = 0.50, P<0.01) and that radiographic OA was correlated with CrCL fiber damage assessed arthroscopically (SR = 0.61, P<0.001). Taken together, results of this study show that clinical diagnostic tests predict severity of stifle synovitis and cruciate ligament matrix damage in stable partial CR stifles. These data support use of client-owned dogs with unilateral complete CR and contralateral partial CR as a clinical trial model for investigation of disease-modifying therapy for partial CR. PMID:28575001

Radiographic and magnetic resonance imaging predicts severity of cruciate ligament fiber damage and synovitis in dogs with cranial cruciate ligament rupture.

PubMed

Sample, Susannah J; Racette, Molly A; Hans, Eric C; Volstad, Nicola J; Holzman, Gerianne; Bleedorn, Jason A; Schaefer, Susan L; Waller, Kenneth R; Hao, Zhengling; Block, Walter F; Muir, Peter

2017-01-01

Cruciate ligament rupture (CR) and associated osteoarthritis (OA) is a common condition in dogs. Dogs frequently develop a second contralateral CR. This study tested the hypothesis that the degree of stifle synovitis and cranial cruciate ligament (CrCL) matrix damage in dogs with CR is correlated with non-invasive diagnostic tests, including magnetic resonance (MR) imaging. We conducted a prospective cohort study of 29 client-owned dogs with an unstable stifle due to complete CR and stable contralateral stifle with partial CR. We evaluated correlation of stifle synovitis and CrCL fiber damage with diagnostic tests including bilateral stifle radiographs, 3.0 Tesla MR imaging, and bilateral stifle arthroscopy. Histologic grading and immunohistochemical staining for CD3+ T lymphocytes, TRAP+ activated macrophages and Factor VIII+ blood vessels in bilateral stifle synovial biopsies were also performed. Serum and synovial fluid concentrations of C-reactive protein (CRP) and carboxy-terminal telopeptide of type I collagen (ICTP), and synovial total nucleated cell count were determined. Synovitis was increased in complete CR stifles relative to partial CR stifles (P<0.0001), although total nucleated cell count in synovial fluid was increased in partial CR stifles (P<0.01). In partial CR stifles, we found that 3D Fast Spin Echo Cube CrCL signal intensity was correlated with histologic synovitis (SR = 0.50, P<0.01) and that radiographic OA was correlated with CrCL fiber damage assessed arthroscopically (SR = 0.61, P<0.001). Taken together, results of this study show that clinical diagnostic tests predict severity of stifle synovitis and cruciate ligament matrix damage in stable partial CR stifles. These data support use of client-owned dogs with unilateral complete CR and contralateral partial CR as a clinical trial model for investigation of disease-modifying therapy for partial CR.

Evaluation of the response of concurrent high dose rate intracavitary brachytherapy with external beam radiotherapy in management of early stage carcinoma cervix.

PubMed

Patidar, Arvind Kumar; Kumar, H S; Walke, Rahul V; Hirapara, Pushpendra H; Jakhar, Shankar Lal; Bardia, M R

2012-10-01

To evaluate local disease control and early complications of concomitant brachytherapy with external beam-radiotherapy in early stage carcinoma cervix. Fifty patients of early stage carcinoma cervix (FIGO-IB/IIA) were randomly divided into study group concomitant external beam irradiation (EBRT) and HDR-ICBT (intra-cavitary brachytherapy, xrt = 50 Gy/25 Fr, HDR 5.2 Gy*5 Fr) and the control group EBRT followed by HDR-ICBT (xrt = 50 Gy/25 Fr, HDR 7.5 Gy*3 Fr). Acute reactions and local disease response were compared between treatment and at 6-month follow up. Median overall treatment times were 38 and 61 days in the study and the control groups, respectively. Acute skin reactions and diarrhea were more in the study but manageable. At the completion of the study, there were 80 and 68 % complete responses, 16 and 20 % partial responses, 0 and 8 % stable diseases in the study group and the control group, respectively. Response was better in the study group but statistically insignificant. Larger number of patients and longer follow up are required to arrive at concrete conclusion.

Dyslexia risk gene relates to representation of sound in the auditory brainstem.

PubMed

Neef, Nicole E; Müller, Bent; Liebig, Johanna; Schaadt, Gesa; Grigutsch, Maren; Gunter, Thomas C; Wilcke, Arndt; Kirsten, Holger; Skeide, Michael A; Kraft, Indra; Kraus, Nina; Emmrich, Frank; Brauer, Jens; Boltze, Johannes; Friederici, Angela D

2017-04-01

Dyslexia is a reading disorder with strong associations with KIAA0319 and DCDC2. Both genes play a functional role in spike time precision of neurons. Strikingly, poor readers show an imprecise encoding of fast transients of speech in the auditory brainstem. Whether dyslexia risk genes are related to the quality of sound encoding in the auditory brainstem remains to be investigated. Here, we quantified the response consistency of speech-evoked brainstem responses to the acoustically presented syllable [da] in 159 genotyped, literate and preliterate children. When controlling for age, sex, familial risk and intelligence, partial correlation analyses associated a higher dyslexia risk loading with KIAA0319 with noisier responses. In contrast, a higher risk loading with DCDC2 was associated with a trend towards more stable responses. These results suggest that unstable representation of sound, and thus, reduced neural discrimination ability of stop consonants, occurred in genotypes carrying a higher amount of KIAA0319 risk alleles. Current data provide the first evidence that the dyslexia-associated gene KIAA0319 can alter brainstem responses and impair phoneme processing in the auditory brainstem. This brain-gene relationship provides insight into the complex relationships between phenotype and genotype thereby improving the understanding of the dyslexia-inherent complex multifactorial condition. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Epoxy resin

DOEpatents

Wilson, Glenn R.; Salyer, Ival O.; Ball, III, George L.

1976-07-13

By mixing one part of a prepolymer containing a polyamine partially polymerized with an organic epoxide and subsequently reacted with a fatty acid containing from 8 to 32 carbon atoms, and then reacting this prepolymer mixture with 3 parts of an organic epoxide, a composition was obtained which made a gas frothable, shear-stable, room temperature curing, low density foam. A particularly advantageous prepolymer was prepared using a polyamine selected from the group consisting of diethylenetriamine, triethylenetetramine, and tetraethylenepentamine, partially polymerized with an organic epoxide having an average molecular weight of about 350 and having an epoxide equivalent of 185 to 192, and reacted with 2-10 weight percent linoleic acid. When one part of this prepolymer was reacted with about three parts of epoxy, and frothed by whipping in air or nitrogen an epoxy foam was produced which could be troweled onto surfaces and into corners or crevices, and subsequently cured, at near ambient temperature, to a strong dimensionally stable foam product.

Treatment of transmissible venereal tumors in dogs with intratumoral interleukin-2 (IL-2). A pilot study.

PubMed

Den Otter, Willem; Hack, Margot; Jacobs, John J L; Tan, Jurgen F V; Rozendaal, Lawrence; Van Moorselaar, R Jeroen A

2015-02-01

To improve the treatment of transmissible venereal tumors (TVTs) in dogs with intratumoral injections of interleukin-2 (IL-2). We treated 13 dogs with 18 natural TVTs with IL-2. The tumors were treated with intratumoral application of 2×10(6) units IL-2. Three months after injection of IL-2, the tumors in 2/13 dogs had regressed completely, those in 1/13 had regressed partially, and 4/13 dogs had stable disease. Local IL-2 treatment of TVT is therapeutically effective, as indicated by complete regression (CR), partial regression (PR) and stable disease (SD) of the tumors of 7 out of 13 dogs. In addition, we observed that the intratumoral treatment with IL-2 did not cause any toxic side-effects. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Characterizing the Effects of Inorganic Acid and Alkaline Shock on the Staphylococcus aureus Transcriptome and Messenger RNA Turnover

PubMed Central

Anderson, Kelsi L.; Roux, Christelle M.; Olson, Matthew W.; Luong, Thanh T.; Lee, Chia Y.; Olson, Robert; Dunman, Paul M.

2010-01-01

Staphylococcus aureus pathogenesis can be partially attributed to its ability to adapt to otherwise deleterious host-associated stresses. Here, Affymetrix GeneChips® were used to examine the S. aureus responses to inorganic acid and alkaline shock and to assess whether stress dependent changes in mRNA turnover are likely to facilitate the organism’s ability to tolerate pH challenge. Results indicate that S. aureus adapts to pH shock by eliciting responses expected of cells coping with pH alteration, including neutralizing cellular pH, DNA repair, amino acid biosynthesis and virulence factor expression. Further, the S. aureus response to alkaline conditions is strikingly similar to that of stringent response induced cells. Indeed, we show that alkaline shock stimulates accumulation of the stringent response activator (p)ppGpp. Results also revealed that pH shock significantly alters the mRNA properties of the cell. A comparison of the mRNA degradation properties of transcripts whose titers either increased or decreased in response to sudden pH change revealed that alterations in mRNA degradation may, in part, account for the changes in the mRNA levels of factors predicted to mediate pH tolerance. A set of small stable RNA molecules were induced in response to acid or alkaline shock conditions and may mediate adaptation to pH stress. PMID:21039920

Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector.

PubMed

Herzog, R W; Yang, E Y; Couto, L B; Hagstrom, J N; Elwell, D; Fields, P A; Burton, M; Bellinger, D A; Read, M S; Brinkhous, K M; Podsakoff, G M; Nichols, T C; Kurtzman, G J; High, K A

1999-01-01

Hemophilia B is a severe X-linked bleeding diathesis caused by the absence of functional blood coagulation factor IX, and is an excellent candidate for treatment of a genetic disease by gene therapy. Using an adeno-associated viral vector, we demonstrate sustained expression (>17 months) of factor IX in a large-animal model at levels that would have a therapeutic effect in humans (up to 70 ng/ml, adequate to achieve phenotypic correction, in an animal injected with 8.5x10(12) vector particles/kg). The five hemophilia B dogs treated showed stable, vector dose-dependent partial correction of the whole blood clotting time and, at higher doses, of the activated partial thromboplastin time. In contrast to other viral gene delivery systems, this minimally invasive procedure, consisting of a series of percutaneous intramuscular injections at a single timepoint, was not associated with local or systemic toxicity. Efficient gene transfer to muscle was shown by immunofluorescence staining and DNA analysis of biopsied tissue. Immune responses against factor IX were either absent or transient. These data provide strong support for the feasibility of the approach for therapy of human subjects.

Identification of key nitrous oxide production pathways in aerobic partial nitrifying granules.

PubMed

Ishii, Satoshi; Song, Yanjun; Rathnayake, Lashitha; Tumendelger, Azzaya; Satoh, Hisashi; Toyoda, Sakae; Yoshida, Naohiro; Okabe, Satoshi

2014-10-01

The identification of the key nitrous oxide (N2O) production pathways is important to establish a strategy to mitigate N2O emission. In this study, we combined real-time gas-monitoring analysis, (15)N stable isotope analysis, denitrification functional gene transcriptome analysis and microscale N2O concentration measurements to identify the main N2O producers in a partial nitrification (PN) aerobic granule reactor, which was fed with ammonium and acetate. Our results suggest that heterotrophic denitrification was the main contributor to N2O production in our PN aerobic granule reactor. The heterotrophic denitrifiers were probably related to Rhodocyclales bacteria, although different types of bacteria were active in the initial and latter stages of the PN reaction cycles, most likely in response to the presence of acetate. Hydroxylamine oxidation and nitrifier denitrification occurred, but their contribution to N2O emission was relatively small (20-30%) compared with heterotrophic denitrification. Our approach can be useful to quantitatively examine the relative contributions of the three pathways (hydroxylamine oxidation, nitrifier denitrification and heterotrophic denitrification) to N2O emission in mixed microbial populations. © 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.

Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors.

PubMed

Zhao, Qiong; Shentu, Jianzhong; Xu, Nong; Zhou, Jianya; Yang, Guangdie; Yao, Yinan; Tan, Fenlai; Liu, Dongyang; Wang, Yingxiang; Zhou, Jianying

2011-08-01

The goal of this study was to assess the safety and tolerability of icotinib hydrochloride (BPI-2009H), a new selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), and to explore its pharmacokinetics (PK) and clinical activity in patients with advanced solid tumors, mainly those with non-small-cell lung cancer (NSCLC) after the failure of the prior platinum-based chemotherapy. Different doses of oral icotinib were administered once every 8 h (Q8H) for a 28-continuous-day cycle until disease progression and or undue toxicity was observed. PK studies of subjects' blood were performed during cycle one (day 1 through 28). Patients aged ≥18 and ≤70 years with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and adequate organ functions eligible for the study. Tumor responses were assessed by Response Evaluation Criteria in Solid Tumors (RECIST). K-ras and EGFR mutations in the extracted DNA of fourteen specimens were examined using PCR-based direct sequencing assay. Thirty-six patients were enrolled in the study. PK analysis demonstrated that the mean elimination half-life of icotinib was 6 h, and the T(max) was around 2 h. The steady-state concentration of icotinib administered at a dose of 125 mg once every 8 h (Q8H) was significantly higher than that achieved by a dose of 100mg Q8H. The most frequent treatment-related adverse events (TRAEs) were an acne-like (folliculitis) rash (16/36, 44.4%), diarrhea (8/36, 22.2%) and a decrease in white blood cells (4/36, 11.1%). The maximum-tolerated dose (MTD) was not reached. Among 33 patients with NSCLC, 7 patients exhibited a partial response, 7 showed stable disease at the 24 weeks. Among 14 patients undergoing DNA sequence for K-ras and EGFR mutations, 3 with K-ras mutation presented 2 stable disease (SD) and 1 partial response (PR), 5 with EGFR exon 19 or 21 mutation 2 PR and 3 SD within 4 weeks. Oral icotinib was generally well tolerated, with manageable and reversible adverse events (AEs) and showed positive clinical anti-tumor activities in patients with advanced NSCLC. The recommended dose for phase II/III studies with icotinib is 125 mg or 150 mg Q8H. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Kinematically stable bipedal locomotion using ionic polymer-metal composite actuators

NASA Astrophysics Data System (ADS)

Hosseinipour, Milad; Elahinia, Mohammad

2013-08-01

Ionic conducting polymer-metal composites (abbreviated as IPMCs) are interesting actuators that can act as artificial muscles in robotic and microelectromechanical systems. Various black or gray box models have modeled the electrochemical-mechanical behavior of these materials. In this study, the governing partial differential equation of the behavior of IPMCs is solved using finite element methods to find the critical actuation parameters, such as strain distribution, maximum strain, and response time. One-dimensional results of the FEM solution are then extended to 2D to find the tip displacement of a flap actuator and experimentally verified. A model of a seven-degree-of-freedom biped robot, actuated by IPMC flaps, is then introduced. The possibility of fast and stable bipedal locomotion using IPMC artificial muscles is the main motivation of this study. Considering the actuator limits, joint path trajectories are generated to achieve a fast and smooth motion. The stability of the proposed gait is then evaluated using the ZMP criterion and motion simulation. The fabrication parameters of each actuator, such as length, platinum plating thickness and installation angle, are then determined using the generated trajectories. A discussion on future studies on force-torque generation of IPMCs for biped locomotion concludes this paper.

Kinetic 15N-isotope effects on algal growth

NASA Astrophysics Data System (ADS)

Andriukonis, Eivydas; Gorokhova, Elena

2017-03-01

Stable isotope labeling is a standard technique for tracing material transfer in molecular, ecological and biogeochemical studies. The main assumption in this approach is that the enrichment with a heavy isotope has no effect on the organism metabolism and growth, which is not consistent with current theoretical and empirical knowledge on kinetic isotope effects. Here, we demonstrate profound changes in growth dynamics of the green alga Raphidocelis subcapitata grown in 15N-enriched media. With increasing 15N concentration (0.37 to 50 at%), the lag phase increased, whereas maximal growth rate and total yield decreased; moreover, there was a negative relationship between the growth and the lag phase across the treatments. The latter suggests that a trade-off between growth rate and the ability to adapt to the high 15N environment may exist. Remarkably, the lag-phase response at 3.5 at% 15N was the shortest and deviated from the overall trend, thus providing partial support to the recently proposed Isotopic Resonance hypothesis, which predicts that certain isotopic composition is particularly favorable for living organisms. These findings confirm the occurrence of KIE in isotopically enriched algae and underline the importance of considering these effects when using stable isotope labeling in field and experimental studies.

Radioembolization for Unresectable Intrahepatic Cholangiocarcinoma: Review of Safety, Response Evaluation Criteria in Solid Tumors 1.1 Imaging Response and Survival.

PubMed

Swinburne, Nathaniel C; Biederman, Derek M; Besa, Cecilia; Tabori, Nora E; Fischman, Aaron M; Patel, Rahul S; Nowakowski, Francis Scott; Gunasekaran, Ganesh; Schwartz, Myron E; Lookstein, Robert A; Kim, Edward

2017-06-01

The optimal palliative treatment for unresectable intrahepatic cholangiocarcinoma (ICC) remains controversial. While selective internal radiation therapy (SIRT) using yttrium-90 microspheres is a well-accepted treatment for hepatocellular carcinoma, data related to its use for locally advanced ICC remain relatively scarce. Twenty-nine patients (mean age 66 ± 11 years; 15 female) with unresectable biopsy-proven ICC treated with SIRT between June 2008 and April 2015 were retrospectively evaluated for post-treatment toxicity, overall survival, and imaging response using response evaluation criteria in solid tumors (RECIST) 1.1 criteria. RECIST 1.1 response was evaluable following 26 treatments [complete response (CR):0, partial response (PR):3; stable disease (SD):16, progression of disease (PD):7]. Objective response rate (CR+PR) was 12%. Disease control rate (CR+PR+SD) was 73%. Median time to progression was 5.6 [95% confidence interval (CI): 0-12.0] months. Median survival following SIRT was 9.1 (95% CI: 1.7-16.4) months. Post-treatment survival was prolonged in patients with absence of extrahepatic disease (p = 0.03) and correlated with RECIST 1.1 response (p = 0.02). Toxicities were limited to grade I severity and occurred following 27% of treatments. These findings support the safe, effective use of SIRT for unresectable ICC. Post-treatment survival is prolonged in patients with absence of extrahepatic disease at baseline. RECIST 1.1 response following SIRT for ICC is predictive of survival.

Explicit finite difference predictor and convex corrector with applications to hyperbolic partial differential equations

NASA Technical Reports Server (NTRS)

Dey, C.; Dey, S. K.

1983-01-01

An explicit finite difference scheme consisting of a predictor and a corrector has been developed and applied to solve some hyperbolic partial differential equations (PDEs). The corrector is a convex-type function which is applied at each time level and at each mesh point. It consists of a parameter which may be estimated such that for larger time steps the algorithm should remain stable and generate a fast speed of convergence to the steady-state solution. Some examples have been given.

Antinociceptive effect of cyclic phosphatidic acid and its derivative on animal models of acute and chronic pain.

PubMed

Kakiuchi, Yasutaka; Nagai, Jun; Gotoh, Mari; Hotta, Harumi; Murofushi, Hiromu; Ogawa, Tomoyo; Ueda, Hiroshi; Murakami-Murofushi, Kimiko

2011-05-14

Cyclic phosphatidic acid (cPA) is a structural analog of lysophosphatidic acid (LPA), but possesses different biological functions, such as the inhibition of autotaxin (ATX), an LPA-synthesizing enzyme. As LPA is a signaling molecule involved in nociception in the peripheral and central systems, cPA is expected to possess analgesic activity. We characterized the effects of cPA and 2-carba-cPA (2ccPA), a chemically stable cPA analog, on acute and chronic pain. (1) The systemic injection of 2ccPA significantly inhibited somato-cardiac and somato-somatic C-reflexes but not the corresponding A-reflexes in anesthetized rats. (2) 2ccPA reduced sensitivity measured as the paw withdrawal response to electrical stimulation applied to the hind paws of mice through the C-fiber, but not Aδ or Aβ. (3) In mice, pretreatment with 2ccPA dose-dependently inhibited the second phase of formalin-induced licking and biting responses. (4) In mice, pretreatment and repeated post-treatments with 2ccPA significantly attenuated thermal hyperalgesia and mechanical allodynia following partial ligation of the sciatic nerve. (5) In rats, repeated post-treatments with 2ccPA also significantly attenuated thermal hyperalgesia and mechanical allodynia following chronic sciatic nerve constriction. Our results suggest that cPA and its stable analog 2ccPA inhibit chronic and acute inflammation-induced C-fiber stimulation, and that the central effects of 2ccPA following repeated treatments attenuate neuropathic pain.

Phase I study of temozolomide in paediatric patients with advanced cancer. United Kingdom Children's Cancer Study Group.

PubMed Central

Estlin, E. J.; Lashford, L.; Ablett, S.; Price, L.; Gowing, R.; Gholkar, A.; Kohler, J.; Lewis, I. J.; Morland, B.; Pinkerton, C. R.; Stevens, M. C.; Mott, M.; Stevens, R.; Newell, D. R.; Walker, D.; Dicks-Mireaux, C.; McDowell, H.; Reidenberg, P.; Statkevich, P.; Marco, A.; Batra, V.; Dugan, M.; Pearson, A. D.

1998-01-01

A phase I study of temozolomide administered orally once a day, on 5 consecutive days, between 500 and 1200 mg m(-2) per 28-day cycle was performed. Children were stratified according to prior craniospinal irradiation or nitrosourea therapy. Sixteen of 20 patients who had not received prior craniospinal irradiation or nitrosourea therapy were evaluable. Myelosuppression was dose limiting, with Common Toxicity Criteria (CTC) grade 4 thrombocytopenia occurring in one of six patients receiving 1000 mg m(-2) per cycle, and two of four patients treated at 1200 mg m(-2) per cycle. Therefore, the maximum-tolerated dose (MTD) was 1000 mg m(-2) per cycle. The MTD was not defined for children with prior craniospinal irradiation because of poor recruitment. Plasma pharmacokinetic analyses showed temozolomide to be rapidly absorbed and eliminated, with linear increases in peak plasma concentrations and systemic exposure with increasing dose. Responses (CR and PR) were seen in two out of five patients with high-grade astrocytomas, and one patient had stable disease. One of ten patients with diffuse intrinsic brain stem glioma achieved a long-term partial response, and a further two patients had stable disease. Therefore, the dose recommended for phase II studies in patients who have not received prior craniospinal irradiation or nitrosoureas is 1000 mg m(-2) per cycle. Further evaluation in diffuse intrinsic brain stem gliomas and other high-grade astrocytomas is warranted. Images Figure 5 p658-b Figure 6 p659-b PMID:9744506

Effects of partial reinforcement and time between reinforced trials on terminal response rate in pigeon autoshaping.

PubMed

Gottlieb, Daniel A

2006-03-01

Partial reinforcement often leads to asymptotically higher rates of responding and number of trials with a response than does continuous reinforcement in pigeon autoshaping. However, comparisons typically involve a partial reinforcement schedule that differs from the continuous reinforcement schedule in both time between reinforced trials and probability of reinforcement. Two experiments examined the relative contributions of these two manipulations to asymptotic response rate. Results suggest that the greater responding previously seen with partial reinforcement is primarily due to differential probability of reinforcement and not differential time between reinforced trials. Further, once established, differences in responding are resistant to a change in stimulus and contingency. Secondary response theories of autoshaped responding (theories that posit additional response-augmenting or response-attenuating mechanisms specific to partial or continuous reinforcement) cannot fully accommodate the current body of data. It is suggested that researchers who study pigeon autoshaping train animals on a common task prior to training them under different conditions.

Time domain convergence properties of Lyapunov stable penalty methods

NASA Technical Reports Server (NTRS)

Kurdila, A. J.; Sunkel, John

1991-01-01

Linear hyperbolic partial differential equations are analyzed using standard techniques to show that a sequence of solutions generated by the Liapunov stable penalty equations approaches the solution of the differential-algebraic equations governing the dynamics of multibody problems arising in linear vibrations. The analysis does not require that the system be conservative and does not impose any specific integration scheme. Variational statements are derived which bound the error in approximation by the norm of the constraint violation obtained in the approximate solutions.

Autologous Bone Marrow-Derived Mesenchymal Stem Cells Modulate Molecular Markers of Inflammation in Dogs with Cruciate Ligament Rupture.

PubMed

Muir, Peter; Hans, Eric C; Racette, Molly; Volstad, Nicola; Sample, Susannah J; Heaton, Caitlin; Holzman, Gerianne; Schaefer, Susan L; Bloom, Debra D; Bleedorn, Jason A; Hao, Zhengling; Amene, Ermias; Suresh, M; Hematti, Peiman

2016-01-01

Mid-substance rupture of the canine cranial cruciate ligament rupture (CR) and associated stifle osteoarthritis (OA) is an important veterinary health problem. CR causes stifle joint instability and contralateral CR often develops. The dog is an important model for human anterior cruciate ligament (ACL) rupture, where rupture of graft repair or the contralateral ACL is also common. This suggests that both genetic and environmental factors may increase ligament rupture risk. We investigated use of bone marrow-derived mesenchymal stem cells (BM-MSCs) to reduce systemic and stifle joint inflammatory responses in dogs with CR. Twelve dogs with unilateral CR and contralateral stable partial CR were enrolled prospectively. BM-MSCs were collected during surgical treatment of the unstable CR stifle and culture-expanded. BM-MSCs were subsequently injected at a dose of 2x106 BM-MSCs/kg intravenously and 5x106 BM-MSCs by intra-articular injection of the partial CR stifle. Blood (entry, 4 and 8 weeks) and stifle synovial fluid (entry and 8 weeks) were obtained after BM-MSC injection. No adverse events after BM-MSC treatment were detected. Circulating CD8+ T lymphocytes were lower after BM-MSC injection. Serum C-reactive protein (CRP) was decreased at 4 weeks and serum CXCL8 was increased at 8 weeks. Synovial CRP in the complete CR stifle was decreased at 8 weeks. Synovial IFNγ was also lower in both stifles after BM-MSC injection. Synovial/serum CRP ratio at diagnosis in the partial CR stifle was significantly correlated with development of a second CR. Systemic and intra-articular injection of autologous BM-MSCs in dogs with partial CR suppresses systemic and stifle joint inflammation, including CRP concentrations. Intra-articular injection of autologous BM-MSCs had profound effects on the correlation and conditional dependencies of cytokines using causal networks. Such treatment effects could ameliorate risk of a second CR by modifying the stifle joint inflammatory response associated with cranial cruciate ligament matrix degeneration or damage.

Autologous Bone Marrow-Derived Mesenchymal Stem Cells Modulate Molecular Markers of Inflammation in Dogs with Cruciate Ligament Rupture

PubMed Central

Muir, Peter; Hans, Eric C.; Racette, Molly; Volstad, Nicola; Sample, Susannah J.; Heaton, Caitlin; Holzman, Gerianne; Schaefer, Susan L.; Bloom, Debra D.; Bleedorn, Jason A.; Hao, Zhengling; Amene, Ermias; Suresh, M.; Hematti, Peiman

2016-01-01

Mid-substance rupture of the canine cranial cruciate ligament rupture (CR) and associated stifle osteoarthritis (OA) is an important veterinary health problem. CR causes stifle joint instability and contralateral CR often develops. The dog is an important model for human anterior cruciate ligament (ACL) rupture, where rupture of graft repair or the contralateral ACL is also common. This suggests that both genetic and environmental factors may increase ligament rupture risk. We investigated use of bone marrow-derived mesenchymal stem cells (BM-MSCs) to reduce systemic and stifle joint inflammatory responses in dogs with CR. Twelve dogs with unilateral CR and contralateral stable partial CR were enrolled prospectively. BM-MSCs were collected during surgical treatment of the unstable CR stifle and culture-expanded. BM-MSCs were subsequently injected at a dose of 2x106 BM-MSCs/kg intravenously and 5x106 BM-MSCs by intra-articular injection of the partial CR stifle. Blood (entry, 4 and 8 weeks) and stifle synovial fluid (entry and 8 weeks) were obtained after BM-MSC injection. No adverse events after BM-MSC treatment were detected. Circulating CD8+ T lymphocytes were lower after BM-MSC injection. Serum C-reactive protein (CRP) was decreased at 4 weeks and serum CXCL8 was increased at 8 weeks. Synovial CRP in the complete CR stifle was decreased at 8 weeks. Synovial IFNγ was also lower in both stifles after BM-MSC injection. Synovial/serum CRP ratio at diagnosis in the partial CR stifle was significantly correlated with development of a second CR. Systemic and intra-articular injection of autologous BM-MSCs in dogs with partial CR suppresses systemic and stifle joint inflammation, including CRP concentrations. Intra-articular injection of autologous BM-MSCs had profound effects on the correlation and conditional dependencies of cytokines using causal networks. Such treatment effects could ameliorate risk of a second CR by modifying the stifle joint inflammatory response associated with cranial cruciate ligament matrix degeneration or damage. PMID:27575050

Many-body Green’s function theory for electron-phonon interactions: The Kadanoff-Baym approach to spectral properties of the Holstein dimer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Säkkinen, Niko; Peng, Yang; Fritz-Haber-Institut der Max-Planck-Gesellschaft, Faradayweg 4-6, 14195 Berlin-Dahlem

2015-12-21

We present a Kadanoff-Baym formalism to study time-dependent phenomena for systems of interacting electrons and phonons in the framework of many-body perturbation theory. The formalism takes correctly into account effects of the initial preparation of an equilibrium state and allows for an explicit time-dependence of both the electronic and phononic degrees of freedom. The method is applied to investigate the charge neutral and non-neutral excitation spectra of a homogeneous, two-site, two-electron Holstein model. This is an extension of a previous study of the ground state properties in the Hartree (H), partially self-consistent Born (Gd) and fully self-consistent Born (GD) approximationsmore » published in Säkkinen et al. [J. Chem. Phys. 143, 234101 (2015)]. Here, the homogeneous ground state solution is shown to become unstable for a sufficiently strong interaction while a symmetry-broken ground state solution is shown to be stable in the Hartree approximation. Signatures of this instability are observed for the partially self-consistent Born approximation but are not found for the fully self-consistent Born approximation. By understanding the stability properties, we are able to study the linear response regime by calculating the density-density response function by time-propagation. This amounts to a solution of the Bethe-Salpeter equation with a sophisticated kernel. The results indicate that none of the approximations is able to describe the response function during or beyond the bipolaronic crossover for the parameters investigated. Overall, we provide an extensive discussion on when the approximations are valid and how they fail to describe the studied exact properties of the chosen model system.« less

Radioembolization of Symptomatic, Unresectable Neuroendocrine Hepatic Metastases Using Yttrium-90 Microspheres

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paprottka, Philipp M., E-mail: philipp.paprottka@med.uni-muenchen.de; Hoffmann, Ralf-T.; Haug, Alexander

2012-04-15

Purpose: To evaluate safety, efficacy, and symptom-control of radioembolization in patients with unresectable liver metastases from neuroendocrine tumors (NETLMs). Materials and Methods: Forty-two patients (mean age of 62 years) with treatment-refractory NETLMs underwent radioembolization using yttrium-90 ({sup 90}Y) resin microspheres. Posttreatment tumor response was assessed by cross-sectional imaging using the Response Evaluation Criteria in Solid Tumors (RECIST) and tumor-marker levels. Laboratory and clinical toxicities and clinical symptoms were monitored. Results: The median activity delivered was 1.63 GBq (range 0.63-2.36). Imaging follow-up using RECIST at 3-month follow-up demonstrated partial response, stable disease, and progressive disease in 22.5, 75.0, and 2.5% ofmore » patients, respectively. In 97.5% of patients, the liver lesions appeared hypovascular or partially necrotic. The mean follow-up was 16.2 months with 40 patients (95.2%) remaining alive. The median decrease in tumor-marker levels at 3 months was 54.8% (chromogranin A) and 37.3% (serotonin), respectively. There were no acute or delayed toxicities greater than grade 2 according to Common Terminology Criteria for Adverse Events [CTCAE (v3.0)]. No radiation-induced liver disease was noted. Improvement of clinical symptoms 3 months after treatment was observed in 36 of 38 symptomatic patients. Conclusion: Radioembolization with {sup 90}Y-microspheres is a safe and effective treatment option in patients with otherwise treatment-refractory NETLMs. Antitumoral effect is supported by good local tumor control, decreased tumor-marker levels, and improved clinical symptoms. Further investigation is warranted to define the role of radioembolization in the treatment paradigm for NETLMs.« less

An Emerging Entity: Pancreatic Adenocarcinoma Associated with a Known BRCA Mutation: Clinical Descriptors, Treatment Implications, and Future Directions

PubMed Central

Lowery, Maeve A.; Kelsen, David P.; Stadler, Zsofia K.; Yu, Kenneth H.; Janjigian, Yelena Y.; Ludwig, Emmy; D'Adamo, David R.; Salo-Mullen, Erin; Robson, Mark E.; Allen, Peter J.; Kurtz, Robert C.

2011-01-01

Background. BRCA1 and BRCA2 germline mutations are associated with an elevated risk for pancreas adenocarcinoma (PAC). Other BRCA-associated cancers have been shown to have greater sensitivity to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors with better clinical outcomes than in sporadic cases; however, outcomes in BRCA-associated PAC have not been reported. Methods. Patients with a known BRCA1 or BRCA2 mutation and a diagnosis of PAC were identified from the Gastrointestinal Oncology Service, Familial Pancreas Cancer Registry, and Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center. Results. Fifteen patients, five male, with a BRCA1 (n = 4) or BRCA2 (n = 11) mutation and PAC and one patient with a BRCA1 mutation and acinar cell carcinoma of the pancreas were identified. Seven female patients (70%) had a prior history of breast cancer. Four patients received a PARP inhibitor alone or in combination with chemotherapy; three demonstrated an initial radiographic partial response by Response Evaluation Criteria in Solid Tumors whereas one patient had stable disease for 6 months. Six patients received platinum-based chemotherapy first line for metastatic disease; five of those patients had a radiographic partial response. Conclusion. BRCA mutation–associated PAC represents an underidentified, but clinically important, subgroup of patients. This is of particular relevance given the ongoing development of therapeutic agents targeting DNA repair, which may potentially offer a significant benefit to a genetically selected population. We anticipate that further study and understanding of the clinical and biologic features of BRCA-mutant PAC will aid in the identification of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC. PMID:21934105

Systemic therapy of aggressive fibromatosis in children and adolescents: Report of the Cooperative Weichteilsarkom Studiengruppe (CWS).

PubMed

Sparber-Sauer, Monika; Seitz, Guido; von Kalle, Thekla; Vokuhl, Christian; Leuschner, Ivo; Scheer, Monika; Münter, Marc; Ljungman, Gustaf; Bielack, Stefan S; Niggli, Felix; Ladenstein, Ruth; Klingebiel, Thomas; Fuchs, Joerg; Koscielniak, Ewa

2018-05-01

Treatment algorithms for patients with aggressive fibromatosis (AF) are challenging. There are limited data available about the use of systemic therapy (ST) in pediatric patients with AF. Patient-, tumor-, and treatment-related factors of 90 children and adolescents with AF treated on multiple prospective trials of the Cooperative Weichteilsarkom Studiengruppe (1981-2015) were analyzed with focus on response and outcome of ST. Median age was 9.48 years (0.02-18.05). Primary resection was performed in 54 patients and ST was administered in 29 of 54 patients because of disease progression or relapse. In 35 patients, ST was the initial treatment modality. A secondary resection was performed in 21 of 35 patients after ST. A total of 64 patients received ST, mainly methotrexate and vinblastine (40%) with a median duration of 380 days. The most frequent radiological response to ST was stable disease at 3 months (39%) and partial response at 6 months (53%). Radiotherapy was administered to 15 of 90 patients. One patient remained on observation only. The 5-year overall survival was 100% and the 5-year event-free survival (EFS) was 44%. Patients who had a primary resection showed a 5-year EFS of 35% versus 59% in patients who had received primary ST (P = 0.08). Functional deficiencies as long-term sequelae following resection occurred in 11 patients. At a median follow-up of 5.05 years (0.25-14.88), complete remission was achieved in 51 patients and partial remission in 28 patients. ST seems appropriate if a primary complete resection is not feasible and at relapse/progression after resection. © 2018 Wiley Periodicals, Inc.

Development of a New Subclavian Arterial Infusion Chemotherapy Method for Locally or Recurrent Advanced Breast Cancer Using an Implanted Catheter-Port System After Redistribution of Arterial Tumor Supply

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takizawa, Kenji, E-mail: taki-lrl@vy.catv.ne.jp; Shimamoto, Hiroshi, E-mail: hshima@k8.dion.ne.jp; Ogawa, Yukihisa, E-mail: yukky-p406c@nifty.com

Locally or recurrent advanced breast cancers can receive arterial blood supply from various arteries, such as the internal thoracic artery (ITA), the lateral thoracic artery, and the other small arterial branches originating from the subclavian artery. Failure to catheterize and subsequent formation of collateral arterial blood supply from various arteries are some of the reasons why the response to conventional selective transarterial infusion chemotherapy is limited and variable. To overcome this problem, we developed a new subclavian arterial infusion chemotherapy method using an implanted catheter-port system after redistribution of arterial tumor blood supply by embolizing the ITA. We named thismore » technique ('redistributed subclavian arterial infusion chemotherapy' (RESAIC)). Using RESAIC, patients can be treated on an outpatient basis for extended periods of time. Eleven patients underwent RESAIC, and the complete remission and partial response rate in 10 evaluable patients was 90%: complete remission [CR] n = 4, partial remission n = 4, stable disease n = 1, and not evaluable n = 1. Three of four patients with CR had no distant metastasis, and modified radical mastectomy was performed 1 month after conclusion of RESAIC. The resected specimens showed no residual cancer cells, and pathologically confirmed complete remission was diagnosed in each of these cases. Although temporary grade-3 myelosuppression was seen in three patients who were previously treated by systemic chemotherapy, there was no other drug-induced toxicity or procedure-related complications. RESAIC produced a better response and showed no major complications compared with other studies despite the advanced stage of the cancers.« less

Bevacizumab plus fotemustine as first-line treatment in metastatic melanoma patients: clinical activity and modulation of angiogenesis and lymphangiogenesis factors.

PubMed

Del Vecchio, Michele; Mortarini, Roberta; Canova, Stefania; Di Guardo, Lorenza; Pimpinelli, Nicola; Sertoli, Mario R; Bedognetti, Davide; Queirolo, Paola; Morosini, Paola; Perrone, Tania; Bajetta, Emilio; Anichini, Andrea

2010-12-01

To assess the clinical and biological activity of the association of bevacizumab and fotemustine as first-line treatment in advanced melanoma patients. Previously untreated, metastatic melanoma patients (n = 20) received bevacizumab (at 15 mg/kg every 3 weeks) and fotemustine (100 mg/m² by intravenous administration on days 1, 8, and 15, repeated after 4 weeks) in a multicenter, single-arm, open-label, phase II study. Primary endpoint was the best overall response rate; other endpoints were toxicity, time to progression (TTP), and overall survival (OS). Serum cytokines, angiogenesis, and lymphangiogenesis factors were monitored by multiplex arrays and by in vitro angiogenesis assays. Effects of fotemustine on melanoma cells, in vitro, on vascular endothelial growth factor (VEGF)-C release and apoptosis were assessed by ELISA and flow cytometry, respectively. One complete response, 2 partial responses (PR), and 10 patients with stable disease were observed. TTP and OS were 8.3 and 20.5 months, respectively. Fourteen patients experienced adverse events of toxicity grade 3-4. Serum VEGF-A levels in evaluated patients (n = 15) and overall serum proangiogenic activity were significantly inhibited. A significant reduction in VEGF-C levels was found in several post-versus pretherapy serum samples. In vitro, fotemustine inhibited VEGF-C release by melanoma cells without inducing significant cell death. Serum levels of interleukin (IL)-10 and IL-12p70 showed the highest levels in sera of PR patients, compared with patients with stable or progressive disease whereas IL-23 showed the opposite pattern. The combination of bevacizumab plus fotemustine has clinical activity in advanced melanoma and promotes systemic modulation of angiogenesis and lymphangiogenesis factors. ©2010 AACR.

Phase II study of cisplatin/pemetrexed combined with bevacizumab followed by pemetrexed/bevacizumab maintenance therapy in patients with EGFR-wild advanced non-squamous non-small cell lung cancer.

PubMed

Fukushima, Toshirou; Wakatsuki, Yuuki; Kobayashi, Takashi; Sonehara, Kei; Tateishi, Kazunari; Yamamoto, Manabu; Masubuchi, Takeshi; Yoshiike, Fumiaki; Hirai, Kazuya; Hachiya, Tsutomu; Koizumi, Tomonobu

2018-06-01

This phase II study was performed to evaluate the efficacy and safety of cisplatin/pemetrexed combined with 15 mg/kg of bevacizumab followed by pemetrexed/bevacizumab maintenance therapy as first-line chemotherapy in advanced non-squamous non-small cell lung cancer (NSCLC) limited to epidermal growth factor receptor (EGFR)-wild type. Fifty patients with advanced or metastatic EGFR-wild type NSCLC aged < 75 years old were enrolled in the study. The patients were treated with four cycles of cisplatin (75 mg/m 2 , day 1), pemetrexed (500 mg/m 2 , days 1), and bevacizumab (15 mg/kg, day 1), every 3 weeks, followed by pemetrexed plus bevacizumab maintenance until progression for achieving a response over stable disease after induction chemotherapy. Partial response and stable disease were observed in 35 (objective response rate: 70, 95% CI: 55.4-82.1%) and 9 patients, respectively, and 39 (78%) patients received pemetrexed plus bevacizumab maintenance therapy. Median progression-free survival and overall survival periods were 12.0 months (95% CI: 7.5-16.5 months) and 31.0 months (95% CI: 22.2-39.8 months), respectively. Grade 3 adverse events included neutropenia (14%), nausea (10%), anorexia (18%), and hypertension (8%). Coagulation disorder was observed in one patient, but all of these events were reversible and resulted in no treatment-related deaths. The combination of cisplatin/pemetrexed/bevacizumab followed by pemetrexed/bevacizumab maintenance therapy exhibited favorable efficacy and manageable toxicity profiles in patients with EGFR-wild type non-squamous NSCLC (UMIN-CTR number: UMIN000003645).

Stable carbon isotope fractionation of organic cyst-forming dinoflagellates: Evaluating the potential for a CO2 proxy

NASA Astrophysics Data System (ADS)

Hoins, Mirja; Van de Waal, Dedmer B.; Eberlein, Tim; Reichart, Gert-Jan; Rost, Björn; Sluijs, Appy

2015-07-01

Over the past decades, significant progress has been made regarding the quantification and mechanistic understanding of stable carbon isotope fractionation (13C fractionation) in photosynthetic unicellular organisms in response to changes in the partial pressure of atmospheric CO2 (pCO2). However, hardly any data is available for organic cyst-forming dinoflagellates while this is an ecologically important group with a unique fossil record. We performed dilute batch experiments with four harmful dinoflagellate species known for their ability to form organic cysts: Alexandrium tamarense, Scrippsiella trochoidea, Gonyaulax spinifera and Protoceratium reticulatum. Cells were grown at a range of dissolved CO2 concentrations characterizing past, modern and projected future values (∼5-50 μmol L-1), representing atmospheric pCO2 of 180, 380, 800 and 1200 μatm. In all tested species, 13C fractionation depends on CO2 with a slope of up to 0.17‰ (μmol L)-1. Even more consistent correlations were found between 13C fractionation and the combined effects of particulate organic carbon quota (POC quota; pg C cell-1) and CO2. Carbon isotope fractionation as well as its response to CO2 is species-specific. These results may be interpreted as a first step towards a proxy for past pCO2 based on carbon isotope ratios of fossil organic dinoflagellate cysts. However, additional culture experiments focusing on environmental variables other than pCO2, physiological underpinning of the recorded response, testing for possible offsets in 13C values between cells and cysts, as well as field calibration studies are required to establish a reliable proxy.

Augmentation of Chemotherapeutic Infusion Effect by TSU-68, an Oral Targeted Antiangiogenic Agent, in a Rabbit VX2 Liver Tumor Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Hyo-Cheol; Chung, Jin Wook, E-mail: chungjw@snu.ac.kr; Choi, Seung Hong

Purpose: This study was designed to investigate the in vivo effects of combination therapy with TSU-68 and chemotherapeutic infusion in a rabbit VX2 liver tumor model. Methods: This study was approved by the animal care committee at our institute. Three weeks before chemotherapeutic infusion, VX2 carcinoma was implanted into the livers of 32 rabbits. One week after chemotherapeutic infusion, vehicle was administered orally for 3 weeks in the control group (n = 16), and TSU-68 was administered orally at a daily dose of 200 mg/kg for 3 weeks in the treated group (n = 16). Computed tomography (CT) was performedmore » before and 1, 2, 3, and 4 weeks after chemotherapeutic infusion. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) on CT scan. The maximum thickness of viable tumor was measured on microscopic sections. Results: According to the RECIST, stable disease was observed in 9 (56%) rabbits and progressive disease in 7 (44%) in the control group, whereas partial response was observed in 1 (6%) rabbit and stable disease in 15 (94%) in the treated group. On pathologic examination, a viable lesion was present in 12 (75%) rabbits in the control group and in 6 (38%) rabbits in the treated group (P = 0.073). The mean maximum thickness of viable tumor in the treated group was significantly smaller than that in the control group (0.74 mm vs. 3.39 mm; P = 0.02). Conclusions: Oral administration of TSU-68 augmented the effect of chemotherapeutic infusion in a rabbit VX2 liver tumor model.« less

Sequential measurements of serum matrix metalloproteinase 9 to monitor chemotherapy responses in patients with advanced non-small-cell lung cancer.

PubMed

Qiao, Xiaojuan; Zhai, Xiaoran; Wang, Jinghui; Zhao, Xiaoting; Yang, Xinjie; Lv, Jialin; Ma, Li; Zhang, Lina; Wang, Yue; Zhang, Shucai; Yue, Wentao

2016-01-01

Matrix metalloproteinase 9 (MMP-9) plays an important role in tumor invasion and metastasis, including lung cancer. However, whether variations in serum MMP-9 levels can serve as a biomarker for monitoring chemotherapy curative effect remains unclear. This study was designed to investigate the association between variations in serum MMP-9 levels and chemotherapy curative effect in patients with lung cancer. A total of 82 patients with advanced lung cancer were included. All newly diagnosed patients were treated with platinum-based doublet chemotherapy. Serial measurements of serum MMP-9 levels were performed by enzyme-linked immunosorbent assay. In this manner, we chose four time points to examine the association, including before chemotherapy, and 3 weeks after the beginning of the first, second, and fourth cycles of chemotherapy. Compared with the serum level of MMP-9 before progressive disease, patients with progressive disease had elevated serum levels of MMP-9. Compared with the previous time point of collecting specimens, the serum levels of MMP-9 in the patients with a complete response/partial response/stable disease decreased or were maintained stable. The differences of variation in serum MMP-9 levels in patients with different chemotherapy curative effects were all statistically significant after one cycle, two cycles, and four cycles (after one cycle: P<0.001; after two cycles: P<0.001; after four cycles: P=0.01). However, patients with small-cell lung cancer did not exhibit similar test results. The variation in serum MMP-9 levels in patients with non-small-cell lung cancer during chemotherapy was closely related to chemotherapy curative effect and could be useful to monitor chemotherapy curative effect for a small portion of patients.

Intratumor heterogeneity characterized by textural features on baseline 18F-FDG PET images predicts response to concomitant radiochemotherapy in esophageal cancer.

PubMed

Tixier, Florent; Le Rest, Catherine Cheze; Hatt, Mathieu; Albarghach, Nidal; Pradier, Olivier; Metges, Jean-Philippe; Corcos, Laurent; Visvikis, Dimitris

2011-03-01

(18)F-FDG PET is often used in clinical routine for diagnosis, staging, and response to therapy assessment or prediction. The standardized uptake value (SUV) in the primary or regional area is the most common quantitative measurement derived from PET images used for those purposes. The aim of this study was to propose and evaluate new parameters obtained by textural analysis of baseline PET scans for the prediction of therapy response in esophageal cancer. Forty-one patients with newly diagnosed esophageal cancer treated with combined radiochemotherapy were included in this study. All patients underwent pretreatment whole-body (18)F-FDG PET. Patients were treated with radiotherapy and alkylatinlike agents (5-fluorouracil-cisplatin or 5-fluorouracil-carboplatin). Patients were classified as nonresponders (progressive or stable disease), partial responders, or complete responders according to the Response Evaluation Criteria in Solid Tumors. Different image-derived indices obtained from the pretreatment PET tumor images were considered. These included usual indices such as maximum SUV, peak SUV, and mean SUV and a total of 38 features (such as entropy, size, and magnitude of local and global heterogeneous and homogeneous tumor regions) extracted from the 5 different textures considered. The capacity of each parameter to classify patients with respect to response to therapy was assessed using the Kruskal-Wallis test (P < 0.05). Specificity and sensitivity (including 95% confidence intervals) for each of the studied parameters were derived using receiver-operating-characteristic curves. Relationships between pairs of voxels, characterizing local tumor metabolic nonuniformities, were able to significantly differentiate all 3 patient groups (P < 0.0006). Regional measures of tumor characteristics, such as size of nonuniform metabolic regions and corresponding intensity nonuniformities within these regions, were also significant factors for prediction of response to therapy (P = 0.0002). Receiver-operating-characteristic curve analysis showed that tumor textural analysis can provide nonresponder, partial-responder, and complete-responder patient identification with higher sensitivity (76%-92%) than any SUV measurement. Textural features of tumor metabolic distribution extracted from baseline (18)F-FDG PET images allow for the best stratification of esophageal carcinoma patients in the context of therapy-response prediction.

Production and characterisation of glycolipid biosurfactant by Halomonas sp. MB-30 for potential application in enhanced oil recovery.

PubMed

Dhasayan, Asha; Kiran, G Seghal; Selvin, Joseph

2014-12-01

Biosurfactant-producing Halomonas sp. MB-30 was isolated from a marine sponge Callyspongia diffusa, and its potency in crude oil recovery from sand pack column was investigated. The biosurfactant produced by the strain MB-30 reduced the surface tension to 30 mN m(-1) in both glucose and hydrocarbon-supplemented minimal media. The critical micelle concentration of biosurfactant obtained from glucose-based medium was at 0.25 mg ml(-1) at critical micelle dilution 1:10. The chemical structure of glycolipid biosurfactant was characterised by infrared spectroscopy and proton magnetic resonance spectroscopy. The emulsification activity of MB-30 biosurfactant was tested with different hydrocarbons, and 93.1 % emulsification activity was exhibited with crude oil followed by kerosene (86.6 %). The formed emulsion was stable for up to 1 month. To identify the effectiveness of biosurfactant for enhanced oil recovery in extreme environments, the interactive effect of pH, temperature and salinity on emulsion stability with crude oil and kerosene was evaluated. The stable emulsion was formed at and above pH 7, temperature >80 °C and NaCl concentration up to 10 % in response surface central composite orthogonal design model. The partially purified biosurfactant recovered 62 % of residual crude oil from sand pack column. Thus, the stable emulsifying biosurfactant produced by Halomonas sp. MB-30 could be used for in situ biosurfactant-mediated enhanced oil recovery process and hydrocarbon bioremediation in extreme environments.

Reestablishment of occlusion through overlay removable partial dentures: a case report.

PubMed

Bataglion, César; Hotta, Takami Hirono; Matsumoto, Wilson; Ruellas, Carlos Ventura de Oliveira

2012-01-01

Loss of posterior teeth may cause an imbalance in the stomatognathic system. Overlay removable partial dentures (ORPD) are a reversible and relatively inexpensive treatment for patients with severely worn teeth. This paper presents a treatment with ORPD in a 55-year-old male patient who had severe attrition in the maxillary and mandibular teeth, temporomandibular joint pain and reduced vertical dimension of occlusion (VDO). The treatment consisted in the reestablishment of the VDO using Lucia's jig, fabricating removable partial denture with reconstruction of the worn teeth without preparation. This therapy can be used as an alternative treatment to provide esthetic, function and stable occlusion in patients with severely worn teeth.

Murine and math models for the level of stable mixed chimerism to cure beta-thalassemia by nonmyeloablative bone marrow transplantation.

PubMed

Roberts, Carla; Kean, Leslie; Archer, David; Balkan, Can; Hsu, Lewis L

2005-01-01

Stable mixed chimeric stem cell transplantation in hemoglobinopathies exploits shorter erythroid survival in hemolytic anemias, providing normal donor red blood cells with a competitive survival advantage. This study examined the level of stable mixed chimerism necessary for complete hematological cure of the thalassemic phenotype, using a nonmyeloablative busulfan chemotherapeutic preparation. Thalassemic mice transplanted from congenic wild-type donors developed partial mixed chimerism. Hematologic cure required >80% donor red blood cells and only >13% donor white blood cells. Murine and human transplant results were compared with a math model for survival advantage of donor peripheral blood cells produced by steady-state chimeric marrow.

Morphological response contributes to patient selection for rescue liver resection in chemotherapy patients with initially un-resectable colorectal liver metastasis.

PubMed

Suzuki, Koichi; Muto, Yuta; Ichida, Kosuke; Fukui, Taro; Takayama, Yuji; Kakizawa, Nao; Kato, Takaharu; Hasegawa, Fumi; Watanabe, Fumiaki; Kaneda, Yuji; Kikukawa, Rina; Saito, Masaaki; Tsujinaka, Shingo; Futsuhara, Kazushige; Takata, Osamu; Noda, Hiroshi; Miyakura, Yasuyuki; Kiyozaki, Hirokazu; Konishi, Fumio; Rikiyama, Toshiki

2017-08-01

Morphological response is considered an improved surrogate to the Response Evaluation Criteria in Solid Tumors (RECIST) model with regard to predicting the prognosis for patients with colorectal liver metastases. However, its use as a decision-making tool for surgical intervention has not been examined. The present study assessed the morphological response in 50 patients who underwent chemotherapy with or without bevacizumab for initially un-resectable colorectal liver metastases. Changes in tumor morphology between heterogeneous with uncertain borders and homogeneous with clear borders were defined as an optimal response (OR). Patients were also assessed as having an incomplete response (IR), and an absence of marked changes was assessed as no response (NR). No significant difference was observed in progression-free survival (PFS) between complete response/partial response (CR/PR) and stable disease/progressive disease (SD/PD), according to RECIST. By contrast, PFS for OR/IR patients was significantly improved compared with that for NR patients (13.2 vs. 8.7 months; P=0.0426). Exclusion of PD enhanced the difference in PFS between OR/IR and NR patients (15.1 vs. 9.3 months; P<0.0001), whereas no difference was observed between CR/PR and SD. The rate of OR and IR in patients treated with bevacizumab was 47.4% (9/19), but only 19.4% (6/31) for patients that were not administered bevacizumab. Comparison of the survival curves between OR/IR and NR patients revealed similar survival rates at 6 months after chemotherapy, but the groups exhibited different survival rates subsequent to this period of time. Patients showing OR/IR within 6 months appeared to be oncologically stable and could be considered as candidates for surgical intervention, including rescue liver resection. Comparing the pathological and morphological features of the tumor with representative optimal response, living tumor cells were revealed to be distributed within the area of vascular reconstruction induced by bevacizumab, resulting in a predictive value for prognosis in the patients treated with bevacizumab. The present findings provided the evidence for physicians to consider patients with previously un-resectable metastatic colorectal cancer as candidates for surgical treatment. Morphological response is a useful decision-making tool for evaluating these patients for rescue liver resection following chemotherapy.

Stable performance of non‐aerated two‐stage partial nitritation/anammox (PANAM) with minimal process control

PubMed Central

Bagchi, Samik; Biswas, Rima; Vlaeminck, Siegfried E.; Roychoudhury, Kunal; Nandy, Tapas

2012-01-01

Summary Partial nitritation/anammox (PANAM) technologies have rapidly developed over the last decade, but still considerable amounts of energy are required for active aeration. In this study, a non‐aerated two‐stage PANAM process was investigated. In the first‐stage upflow fixed‐film bioreactor, nitratation could not be prevented at ammonium loading rates up to 186 mg N l−1 d−1 and low influent dissolved oxygen (0.1 mg O2 l−1). Yet, increasing the loading rate to 416 and 747 mg N l−1 d−1 by decreasing the hydraulic retention time to 8 and 5 h, respectively, resulted in partial nitritation with the desired nitrite to ammonium nitrogen ratio for the subsequent anammox stage (0.71–1.05). The second‐stage anammox reactor was established with a synthetic feeding based on ammonium and nitrite. After establishing anammox at low biomass content (0.5 g VSS l−1), the anammox influent was switched to partial nitritation effluent at a loading rate of 71 mg N l−1 d−1, of which 78% was removed at the stoichiometrically expected nitrite to ammonium consumption ratios (1.19) and nitrate production to ammonium consumption ratio (0.24). The combined PANAM reactors were operated for 3 months at a stable performance. Overall, PANAM appeals economically, saving about 50% of the energy costs, as well as technically, given straightforward operational principles. PMID:22414169

Blastic transformation in chronic myelogenous leukemia: experience with 50 patients.

PubMed

Marks, S M; McCaffrey, R; Rosenthal, D S; Moloney, W C

1978-01-01

Fifty consecutive patients with blastic chronic myelogenous leukemia were evaluated clinically, morphologically, biochemically, and therapeutically. Forty-five patients had a preceding stable phase (38 Ph'+, 7 Ph'-); five patients presented with de novo Ph+ blast crisis. The most frequent clinical signs of impending blast crisis were weakness, fatigue, increasing splenomegaly, anemia, thrombocytopenia, marrow fibrosis, and a rising neutrophil alkaline phosphatase. Fever (unrelated to infection), skin infiltration, lymphadenopathy, hepatomegaly, thrombocytosis, and basophilia were much less common. The development of aneuploidy occurred in less than one-half of the total group. Myeloblastic morphology at blastic transformation was most frequent with occasional lymphoblastic, promyelocytic, and undifferentiated cases seen. Terminal deoxynucleotidyl transferase was present in one-third of the patients, but had no clear-cut relationship to the morphology. Response to treatment was generally disappointing (two complete and 15 partial remissions in 45 treated patients).

Computer analysis of multicircuit shells of revolution by the field method

NASA Technical Reports Server (NTRS)

Cohen, G. A.

1975-01-01

The field method, presented previously for the solution of even-order linear boundary value problems defined on one-dimensional open branch domains, is extended to boundary value problems defined on one-dimensional domains containing circuits. This method converts the boundary value problem into two successive numerically stable initial value problems, which may be solved by standard forward integration techniques. In addition, a new method for the treatment of singular boundary conditions is presented. This method, which amounts to a partial interchange of the roles of force and displacement variables, is problem independent with respect to both accuracy and speed of execution. This method was implemented in a computer program to calculate the static response of ring stiffened orthotropic multicircuit shells of revolution to asymmetric loads. Solutions are presented for sample problems which illustrate the accuracy and efficiency of the method.

Behavioural responses of stable flies to cattle manure slurry associated odourants

USDA-ARS?s Scientific Manuscript database

Stable flies (Stomoxys calcitrans [Diptera: Muscidae] L.) are blood-feeding synanthropic pests, which cause significant economic losses in livestock. Stable fly antennae contain olfactory sensilla responsive to host and host environment-associated odours. Field observation indicated that the abundan...

Systems and Methods for Implementing High-Temperature Tolerant Supercapacitors

NASA Technical Reports Server (NTRS)

Bugga, Ratnakumar V. (Inventor); Brandon, Erik J. (Inventor); West, William C. (Inventor)

2016-01-01

Systems and methods in accordance with embodiments of the invention implement high-temperature tolerant supercapacitors. In one embodiment, a high-temperature tolerant super capacitor includes a first electrode that is thermally stable between at least approximately 80C and approximately 300C; a second electrode that is thermally stable between at least approximately 80C and approximately 300C; an ionically conductive separator that is thermally stable between at least approximately 80C and 300C; an electrolyte that is thermally stable between approximately at least 80C and approximately 300C; where the first electrode and second electrode are separated by the separator such that the first electrode and second electrode are not in physical contact; and where each of the first electrode and second electrode is at least partially immersed in the electrolyte solution.

Combined autophagy and proteasome inhibition

PubMed Central

Vogl, Dan T; Stadtmauer, Edward A; Tan, Kay-See; Heitjan, Daniel F; Davis, Lisa E; Pontiggia, Laura; Rangwala, Reshma; Piao, Shengfu; Chang, Yunyoung C; Scott, Emma C; Paul, Thomas M; Nichols, Charles W; Porter, David L; Kaplan, Janeen; Mallon, Gayle; Bradner, James E; Amaravadi, Ravi K

2014-01-01

The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy. PMID:24991834

Assessing response to treatment in non--small-cell lung cancer: role of tumor volume evaluated by computed tomography.

PubMed

Knollmann, Friedrich D; Kumthekar, Rohan; Fetzer, David; Socinski, Mark A

2014-03-01

We set out to investigate whether volumetric tumor measurements allow for a prediction of treatment response, as measured by patient survival, in patients with advanced non-small-cell lung cancer (NSCLC). Patients with nonresectable NSCLC (stage III or IV, n = 100) who were repeatedly evaluated for treatment response by computed tomography (CT) were included in a Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study. Tumor response was measured by comparing tumor volumes over time. Patient survival was compared with Response Evaluation Criteria in Solid Tumors (RECIST) using Kaplan-Meier survival statistics and Cox regression analysis. The median overall patient survival was 553 days (standard error, 146 days); for patients with stage III NSCLC, it was 822 days, and for patients with stage IV disease, 479 days. The survival differences were not statistically significant (P = .09). According to RECIST, 5 patients demonstrated complete response, 39 partial response, 44 stable disease, and 12 progressive disease. Patient survival was not significantly associated with RECIST class, the change of the sum of tumor diameters (P = .98), nor the change of the sum of volumetric tumor dimensions (P = .17). In a group of 100 patients with advanced-stage NSCLC, neither volumetric CT measurements of changes in tumor size nor RECIST class significantly predicted patient survival. This observation suggests that size response may not be a sufficiently precise surrogate marker of success to steer treatment decisions in individual patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Treatment-related toxicities in tumor-bearing cats treated with temozolomide alone or in combination with doxorubicin: a pilot assessment.

PubMed

Gagnon, Jerome; Dervisis, Nikolaos G; Kitchell, Barbara E

2012-08-01

A retrospective study assessing treatment-related toxicities in tumor-bearing cats treated with temozolomide (TMZ) alone or in combination with doxorubicin was conducted. TMZ was administered orally once a day for 5 days every 3 weeks at a dose of 20 mg/cat. Tumor response was evaluated with standard World Health Organization criteria and toxicity was monitored using veterinary co-operative oncology group-common terminology criteria for adverse events (VCOG--CTCAE) criteria. Ten tumor-bearing cats with various types of malignancies were treated with TMZ-based chemotherapy. Eight cats were evaluable for response. Two cats achieved a complete response, one achieved stable disease and five achieved a partial response. Four grade III and one grade IV hematological toxicities, and one grade IV gastrointestinal toxicity were observed. Four cats were euthanased as a result of apparent toxicity. One cat was euthanased as a result of severe and prolonged myelosuppression with fever. Three were euthanased for grade III pleural and pericardial effusions. Effusion was seen in cats treated with higher cumulative dose of TMZ (P = 0.0046). Planned additional case accrual was discontinued because of unacceptable levels of toxicity despite evidence of efficacy in some of the cats. Additional investigation is needed to elucidate this unexpected apparent cumulative toxicity.

The natural history of renal function after surgical management of renal cell carcinoma: Results from the Canadian Kidney Cancer Information System.

PubMed

Mason, Ross; Kapoor, Anil; Liu, Zhihui; Saarela, Olli; Tanguay, Simon; Jewett, Michael; Finelli, Antonio; Lacombe, Louis; Kawakami, Jun; Moore, Ronald; Morash, Christopher; Black, Peter; Rendon, Ricardo A

2016-11-01

Patients who undergo surgical management of renal cell carcinoma (RCC) are at risk for chronic kidney disease and its sequelae. This study describes the natural history of renal function after radical and partial nephrectomy and explores factors associated with postoperative decline in renal function. This is a multi-institutional cohort study of patients in the Canadian Kidney Cancer Information System who underwent partial or radical nephrectomy for RCC. Estimated glomerular filtration rate (eGFR) and stage of chronic kidney disease were determined preoperatively and at 3, 12, and 24 months postoperatively. Linear regression was used to determine the association between postoperative eGFR and type of surgery (radical vs. partial), duration of ischemia, ischemia type (warm vs. cold), and tumor size. With a median follow-up of 26 months, 1,379 patients were identified from the Canadian Kidney Cancer Information System database including 665 and 714 who underwent partial and radical nephrectomy, respectively. Patients undergoing radical nephrectomy had a lower eGFR (mean = 19ml/min/1.73m 2 lower) at 3, 12, and 24 months postoperatively (P<0.001). Decline in renal function occurred early and remained stable throughout follow-up. A lower preoperative eGFR and increasing age were also associated with a lower postoperative eGFR (P<0.01). Ischemia type and duration were not predictive of postoperative decline in eGFR (P>0.05). Severe renal failure (eGFR<30ml/min/1.73m 2 ) developed postoperatively in 12.5% and 4.1% of radical and partial nephrectomy patients, respectively (P<0.001). After the initial postoperative decline, renal function remains stable in patients undergoing surgery for RCC. Patients undergoing radical nephrectomy have a greater long-term reduction in renal function compared with those undergoing partial nephrectomy. Ischemia duration and type are not predictive of postoperative renal function when adhering to generally short ischemia durations. Copyright © 2016 Elsevier Inc. All rights reserved.

Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.

PubMed

Gadgeel, Shirish M; Gandhi, Leena; Riely, Gregory J; Chiappori, Alberto A; West, Howard L; Azada, Michele C; Morcos, Peter N; Lee, Ruey-Min; Garcia, Linta; Yu, Li; Boisserie, Frederic; Di Laurenzio, Laura; Golding, Sophie; Sato, Jotaro; Yokoyama, Shumpei; Tanaka, Tomohiro; Ou, Sai-Hong Ignatius

2014-09-01

Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progression-free survival of 8-11 months while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib. We enrolled patients with ALK-rearranged NSCLC who progressed on or were intolerant to crizotinib. We administered various oral doses of alectinib (300-900 mg twice a day) during the dose-escalation portion of the study (phase 1), to ascertain the recommended dose for phase 2. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.1) to investigate the activity of alectinib in all patients with a baseline scan and at least one post-treatment scan (CT or MRI), with central radiological review of individuals with brain metastases. We assessed safety in all patients who received at least one dose of alectinib. Here, we present data for the phase 1 portion of the study, the primary objective of which was to establish the recommended phase 2 dose; phase 2 is ongoing. This trial is registered at ClinicalTrials.gov, number NCT01588028. 47 patients were enrolled. Alectinib was well tolerated, with the most common adverse events being fatigue (14 [30%]; all grade 1-2), myalgia (eight [17%]; all grade 1-2), and peripheral oedema (seven [15%] grade 1-2, one [2%] grade 3). Dose-limiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day; one individual had grade 3 headache and the other had grade 3 neutropenia. The most common grade 3-4 adverse events were increased levels of γ-glutamyl transpeptidase (two [4%]), a reduction in the number of neutrophils (two [4%]), and hypophosphataemia (two [4%]). Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib: acute renal failure; pleural effusion and pericardial effusion; and brain metastasis. At data cut-off (median follow-up 126 days [IQR 84-217]), 44 patients could be assessed for activity. Investigator-assessed objective responses were noted in 24 (55%) patients, with a confirmed complete response in one (2%), a confirmed partial response in 14 (32%), and an unconfirmed partial response in nine (20%). 16 (36%) patients had stable disease; the remaining four (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had an objective response; six (29%) had a complete response (three unconfirmed) and five (24%) had a partial response (one unconfirmed); eight (38%) patients had stable disease and the remaining two (10%) had progressive disease. Pharmacokinetic data indicated that mean exposure (AUC0-10) after multiple doses of alectinib (300-600 mg twice a day) was dose-dependent. Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2. Chugai Pharmaceuticals, F Hoffmann La-Roche. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effect of americium-241 alpha-particles on the dose-response of chromosome aberrations in human lymphocytes analysed by fluorescence in situ hybridization.

PubMed

Barquinero, J F; Stephan, G; Schmid, E

2004-02-01

To evaluate by the fluorescent in-situ hybridization (FISH) technique the dose-response and intercellular distribution of alpha-particle-induced chromosome aberrations. In particular, the validity of using the yield of characteristic types of chromosome abnormalities in stable cells as quantitative indicators for retrospective dose reconstruction has been evaluated. Monolayers of human peripheral lymphocytes were exposed at doses from 0.02 to 1 Gy to alpha-particles emitted from a source of americium-241. The most probable energy of the alpha-particles entering the cells was 2.7 MeV. FISH painting was performed using DNA probes for chromosomes 2, 4 and 8 in combination with a pan-centromeric probe. In complete first-division cells, identified by harlequin staining, aberrations involving painted target chromosomal material were recorded as well as aberrations involving only unpainted chromosomal material. In total, the percentage of complex aberrations was about 35% and no dose dependence was observed. When complex-type exchanges were reduced to simple base types, the different cell distributions were clearly over-dispersed, and the linear coefficients of the dose-effect curves for translocations were significantly higher than for dicentrics. For past dose reconstruction, only a few complex aberrations were in stable cells. The linear coefficient obtained for transmissible aberrations in stable cells was more than seven times lower than that obtained in all analysed cells, i.e. including unstable cells. FISH-based analysis of complex rearrangements allows discrimination between partial-body exposures to low-linear energy transfer radiation and high-linear energy transfer exposures. In assessing past or chronic exposure to alpha-particles, the use of a dose-effect curve obtained by FISH-based translocation data, which had not excluded data determined in unstable cells, would underestimate the dose. Insertions are ineffective biomarkers because their frequency is too low.

C3 glomerulopathy associated with monoclonal Ig is a distinct subtype.

PubMed

Ravindran, Aishwarya; Fervenza, Fernando C; Smith, Richard J H; Sethi, Sanjeev

2018-05-02

Monoclonal immunoglobulins (MIg) may play a causal role in C3 glomerulopathy (C3G) by impairing regulation of the alternative pathway of complement. Ninety-five patients with C3G were tested for MIg of which 36 were positive. Their mean age at diagnosis was 60 years and among patient 50 years and older, 65.1% had a MIg. At presentation, median serum creatinine and proteinuria were 1.9 mg/dL and 3.0 g/24 hours. Hematuria was present in 32 (88.9%) patients. Twelve (34.3%) patients had low C3 levels. C3 nephritic factor was detected in 45.8% patients; pathogenic variants in complement protein genes were rare. Hematologic evaluation revealed monoclonal gammopathy of renal significance in 26 patients, multiple myeloma in five, smoldering multiple myeloma in two, and chronic lymphocytic leukemia, lymphoma, or type I cryoglobulin each in one patient. After a median follow-up of 43.6 months, the median serum creatinine and proteinuria were 1.4 mg/dL and 0.8g/24 hours. Nine patients developed ESRD. Sixteen patients received MIg-targeted treatment, 17 patients received non-targeted treatment while three patients were managed conservatively. Of the 16 patients receiving MIg-targeted treatment, ten achieved complete/very good/partial hematologic response. Of these, seven achieved a complete/partial/stable renal response. Five patients receiving targeted treatment did not achieve hematologic response, none had a renal response. Patients receiving targeted treatment were more likely to have multiple myeloma/smoldering multiple myeloma. Patients receiving non-targeted treatment were more likely to have monoclonal gammopathy of renal significance. Thus, C3G with MIg is seen in older patients, C3 nephritic factor is the most common autoantibody detected, and MIg-targeted treatment may result in remission and stabilization of kidney function in a subset of these patients. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Sarcomatoid Carcinoma of the Lung: The Mayo Clinic Experience in 127 Patients.

PubMed

Maneenil, Kunlatida; Xue, Zhiqiang; Liu, Ming; Boland, Jennifer; Wu, Fengying; Stoddard, Shawn M; Molina, Julian; Yang, Ping

2018-05-01

Pulmonary sarcomatoid carcinoma (PSC) is an unusual form of non-small-cell lung cancer (NSCLC). Because of its rarity and heterogeneity, the treatment and prognosis of PSC have not been clearly described. We retrospectively evaluated all patients with a diagnosis of PSC from 1997 to 2015 at the Mayo Clinic (Rochester, MN). The clinical characteristics, treatment details, and outcomes were collected. The survival rates of the PSC patients were compared with those for other subtypes of NSCLC. We used propensity score matching to minimize the bias resulting from to imbalanced comparison groups. The study included 127 PSC patients. The median age at diagnosis was 68 years (range, 32-89 years), most of whom were men (61%) and smokers (82%). The clinical stage was I, II, III, and IV in 15.9%, 20.6%, 22.2%, and 41.3%, respectively. The median survival time was 9.9 months (95% confidence interval [CI], 7.6-12.6 months). The 1-, 2-, and 5-year survival rates were 42%, 23%, and 15%, respectively. Most patients received multimodality treatment. Of the 3 patients who received neoadjuvant chemotherapy, a partial response was demonstrated in 2. Twenty-five patients who underwent palliative chemotherapy were evaluated for tumor response: 52% experienced progression, 40% stable disease, 8.0% a partial response, and 0% a complete response. Multivariate analysis showed T stage, M stage, and treatment with surgery plus neoadjuvant chemotherapy or surgery plus adjuvant therapy were independent prognostic factors (P < .05). In matched analysis, multivariate models revealed worse overall survival for PSC compared with adenocarcinoma (hazard ratio, 2.38; 95% CI, 1.61-2.53) and squamous cell carcinoma (hazard ratio, 2.20; 95% CI, 1.44-2.34). We found the outcome of PSC to be significantly worse than that of adenocarcinoma and squamous cell carcinoma. Neoadjuvant or adjuvant chemotherapy, in addition to surgical resection, should be considered. Copyright © 2017 Elsevier Inc. All rights reserved.

Oxaliplatin and protracted venous infusion of 5-fluorouracil in patients with advanced or relapsed 5-fluorouracil pretreated colorectal cancer

PubMed Central

Chau, I; Webb, A; Cunningham, D; Hill, M; Waters, J S; Norman, A; Massey, A

2001-01-01

The purpose of this study was to evaluate the activity and safety of oxaliplatin and protracted venous infusion of 5-fluorouracil (PVI 5-FU) in patients with advanced or relapsed 5-FU pretreated colorectal cancer. 38 patients with advanced or metastatic colorectal carcinoma with documented progression on or within 6 months following 5-FU or thymidylate synthase inhibitor containing chemotherapy were recruited between June 1997 and September 2000. Oxaliplatin (100 mg m−2) was given every 2 weeks and PVI 5-FU (300 mg m−2day−1) was administered. Median age of patients was 61 years. 17 patients had >2 sites of disease involvement. 10 had received 5-FU based adjuvant chemotherapy. 16 received oxaliplatin and PVI 5-FU as second-line chemotherapy for advanced disease and 22 as third or subsequent lines. Median follow up was 6.1 months. The best achieved objective tumour response rate was 29% (11 partial responses 95% confidence interval [CI] = 15–46%). 20 patients (52.6%) had stable disease. The median duration of response was 3.9 months. Even for patients who had previously received both 5-FU and irinotecan (n= 22), 27.3% had partial response with oxaliplatin and PVI 5-FU. 37 patients had symptoms on entry into the study. 25 patients had pain, 10 had anorexia and 28 had lethargy. 64%, 70% and 17.9% had symptomatic improvement after treatment respectively. Grade 3–4 toxicities were anaemia 10.6%, neutropenia 2.6%, thrombocytopenia 5.2%, diarrhoea 18.9%, nausea and vomiting 2.7%, infection 5.4% and lethargy 37.8%. The median survival was 9.1 months. Probability of overall survival at 6 months was 58.4% (95% CI = 38.7–73.7%). The median failure-free survival was 4 months. Oxaliplatin and PVI 5FU is an active and well tolerated regimen in patients with heavily pre-treated advanced colorectal cancer. © 2001 Cancer Research Campaign PMID:11720458

A randomized controlled trial of nonoperative treatment versus open reduction and internal fixation for stable, displaced, partial articular fractures of the radial head: the RAMBO trial

PubMed Central

2014-01-01

Background The choice between operative or nonoperative treatment is questioned for partial articular fractures of the radial head that have at least 2 millimeters of articular step-off on at least one radiograph (defined as displaced), but less than 2 millimeter of gap between the fragments (defined as stable) and that are not associated with an elbow dislocation, interosseous ligament injury, or other fractures. These kinds of fractures are often classified as Mason type-2 fractures. Retrospective comparative studies suggest that operative treatment might be better than nonoperative treatment, but the long-term results of nonoperative treatment are very good. Most experts agree that problems like reduced range of motion, painful crepitation, nonunion or bony ankylosis are infrequent with both nonoperative and operative treatment of an isolated displaced partial articular fracture of the radial head, but determining which patients will have problems is difficult. A prospective, randomized comparison would help minimize bias and determine the balance between operative and nonoperative risks and benefits. Methods/Design The RAMBO trial (Radial Head – Amsterdam – Amphia – Boston - Others) is an international prospective, randomized, multicenter trial. The primary objective of this study is to compare patient related outcome defined by the ‘Disabilities of Arm, Shoulder and Hand (DASH) score’ twelve months after injury between operative and nonoperative treated patients. Adult patients with partial articular fractures of the radial head that comprise at least 1/3rd of the articular surface, have ≥ 2 millimeters of articular step-off but less than 2 millimeter of gap between the fragments will be enrolled. Secondary outcome measures will be the Mayo Elbow Performance Index (MEPI), the Oxford Elbow Score (OES), pain intensity through the ‘Numeric Rating Scale’, range of motion (flexion arc and rotational arc), radiographic appearance of the fracture (heterotopic ossification, radiocapitellar and ulnohumeral arthrosis, fracture healing, and signs of implant loosening or breakage) and adverse events (infection, nerve injury, secondary interventions) after one year. Discussion The successful completion of this trial will provide evidence on the best treatment for stable, displaced, partial articular fractures of the radial head. Trial registration The trial is registered at the Dutch Trial Register: NTR3413. PMID:24885637

Electrophysiological Perspectives on the Therapeutic Use of Nicotinic Acetylcholine Receptor Partial AgonistsS⃞

PubMed Central

Trocmé-Thibierge, Caryn; Guendisch, Daniela; Al Rubaiy, Shehd Abdullah Abbas; Bloom, Stephen A.

2011-01-01

Partial agonist therapies rely variously on two hypotheses: the partial agonists have their effects through chronic low-level receptor activation or the partial agonists work by decreasing the effects of endogenous or exogenous full agonists. The relative significance of these activities probably depends on whether acute or chronic effects are considered. We studied nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes to test a model for the acute interactions between acetylcholine (ACh) and weak partial agonists. Data were best-fit to a basic competition model that included an additional factor for noncompetitive inhibition. Partial agonist effects were compared with the nAChR antagonist bupropion in prolonged bath application experiments that were designed to mimic prolonged drug exposure typical of therapeutic drug delivery. A primary effect of prolonged application of nicotine was to decrease the response of all nAChR subtypes to acute applications of ACh. In addition, nicotine, cytisine, and varenicline produced detectable steady-state activation of α4β2* [(α4)2(β2)3, (α4)3(β2)2, and (α4)2(β2)2α5)] receptor subtypes that was not seen with other test compounds. Partial agonists produced no detectable steady-state activation of α7 nAChR, but seemed to show small potentiation of ACh-evoked responses; however, “run-up” of α7 ACh responses was also sometimes observed under control conditions. Potential off-target effects of the partial agonists therefore included the modulation of α7 responses by α4β2 partial agonists and decreases in α4β2* responses by α7-selective agonists. These data indicate the dual effects expected for α4β2* partial agonists and provide models and insights for utility of partial agonists in therapeutic development. PMID:21285282

A PHASE II STUDY OF GEMCITABINE AND CAPECITABINE IN PATIENTS WITH ADVANCED RENAL CELL CANCER (RCC): SOUTHWEST ONCOLOGY GROUP STUDY S0312

PubMed Central

Van Veldhuizen, Peter J.; Hussey, Michael; Lara, Primo N.; Mack, Philip C.; Gandour-Edwards, Regina; Clark, Joseph I.; Lange, Marianne K.; Crawford, E. David

2010-01-01

Background Gemcitabine plus capecitabine has modest efficacy in patients with advanced RCC but has considerable toxicity. We evaluated the efficacy and toxicity of a modified dose-schedule of this doublet in patients with advanced unresectable or metastatic RCC. Methods Chemotherapy-naïve patients were treated with gemcitabine at 900mg/m2 on days 1,8,15 and capecitabine at 625mg/m2 twice daily on days 1 through 21, every 28 days. Eligible patients must have adequate performance status and end-organ function. The primary endpoint was tumor response rate (RR). No further evaluation of this regimen would be pursued if the RR was ≤ 5%. In an exploratory manner using archival specimens, we also evaluated potential markers of prognosis and treatment response including thymidylate synthase (TS) gene polymorphisms and tumor expression of p53, PTEN, pAKT, pmTOR, and ERCC1. Results Of 43 patients registered, 1 was ineligible and 2 were not analyzable. There was 1 confirmed complete response (CR) and three unconfirmed partial responses (PR), for an overall response rate of 10% (95% CI: 3, 24). Nineteen patients (48%) had stable disease (SD). The six-month freedom-from-treatment-failure and overall survival rates were 20% (95% CI: 8, 32) and 75% (95% CI: 62, 88), respectively. Median survival time was 23 months (95% CI: 10, 37). One patient each experienced Grade 4 neutropenia, fatigue, thrombocytopenia and hemolysis with renal failure. The most common Grade 3 toxicities were neutropenia (12 patients), fatigue (5), and leucopenia (4). Patients with a best response of stable disease or better were more likely to have a decrease in expression of PTEN and an increased expression of pmTOR. Conclusions Gemcitabine plus capecitabine at this reduced dose-schedule benefits a small percentage of patients with RCC with an acceptable toxicity profile. The combination of gemcitabine and capecitabine may serve as a base regimen for combination therapy with targeted agents in select RCC patients. PMID:19487915

Inter-Observer Agreement of Whole-Body Computed Tomography in Staging and Response Assessment in Lymphoma: The Lugano Classification.

PubMed

Razek, Ahmed Abdel Khalek Abdel; Shamaa, Sameh; Lattif, Mahmoud Abdel; Yousef, Hanan Hamid

2017-01-01

To assess inter-observer agreement of whole-body computed tomography (WBCT) in staging and response assessment in lymphoma according to the Lugano classification. Retrospective analysis was conducted of 115 consecutive patients with lymphomas (45 females, 70 males; mean age of 46 years). Patients underwent WBCT with a 64 multi-detector CT device for staging and response assessment after a complete course of chemotherapy. Image analysis was performed by 2 reviewers according to the Lugano classification for staging and response assessment. The overall inter-observer agreement of WBCT in staging of lymphoma was excellent ( k =0.90, percent agreement=94.9%). There was an excellent inter-observer agreement for stage I ( k =0.93, percent agreement=96.4%), stage II ( k =0.90, percent agreement=94.8%), stage III ( k =0.89, percent agreement=94.6%) and stage IV ( k =0.88, percent agreement=94%). The overall inter-observer agreement in response assessment after a completer course of treatment was excellent ( k =0.91, percent agreement=95.8%). There was an excellent inter-observer agreement in progressive disease ( k =0.94, percent agreement=97.1%), stable disease ( k =0.90, percent agreement=95%), partial response ( k =0.96, percent agreement=98.1%) and complete response ( k =0.87, Percent agreement=93.3%). We concluded that WBCT is a reliable and reproducible imaging modality for staging and treatment assessment in lymphoma according to the Lugano classification.

Characterizing the effects of inorganic acid and alkaline shock on the Staphylococcus aureus transcriptome and messenger RNA turnover.

PubMed

Anderson, Kelsi L; Roux, Christelle M; Olson, Matthew W; Luong, Thanh T; Lee, Chia Y; Olson, Robert; Dunman, Paul M

2010-12-01

Staphylococcus aureus pathogenesis can be attributed partially to its ability to adapt to otherwise deleterious host-associated stresses. Here, Affymetrix GeneChips® were used to examine the S. aureus responses to inorganic acid and alkaline shock and to assess whether stress-dependent changes in mRNA turnover are likely to facilitate the organism's ability to tolerate a pH challenge. The results indicate that S. aureus adapts to pH shock by eliciting responses expected of cells coping with pH alteration, including neutralizing cellular pH, DNA repair, amino acid biosynthesis, and virulence factor expression. Further, the S. aureus response to alkaline conditions is strikingly similar to that of stringent response-induced cells. Indeed, we show that alkaline shock stimulates the accumulation of the stringent response activator (p)ppGpp. The results also revealed that pH shock significantly alters the mRNA properties of the cell. A comparison of the mRNA degradation properties of transcripts whose titers either increased or decreased in response to a sudden pH change revealed that alterations in mRNA degradation may, in part, account for the changes in the mRNA levels of factors predicted to mediate pH tolerance. A set of small stable RNA molecules were induced in response to acid- or alkaline-shock conditions and may mediate adaptation to pH stress. © 2010 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Open-label Bendamustine Monotherapy for Pediatric Patients With Relapsed or Refractory Acute Leukemia: Efficacy and Tolerability

PubMed Central

Brown, Patrick; Megason, Gail; Ahn, Hyo Seop; Cho, Bin; Kirov, Ivan; Frankel, Lawrence; Aplenc, Richard; Bensen-Kennedy, Debra; Munteanu, Mihaela; Weaver, Jennifer; Harker-Murray, Paul

2014-01-01

This open-label, single-arm, phase I/II, dose-escalation study was designed to determine the recommended phase II dose (RP2D), pharmacokinetics, tolerability, and efficacy of bendamustine in pediatric patients (age ranging from 1 to 20 y) with histologically proven relapsed/refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Patients (27 with ALL, 16 with AML) received intravenous bendamustine on days 1 and 2 of each treatment cycle. Phase I involved planned dose escalation of bendamustine to establish the RP2D for phase II. Objectives included overall response rate, duration of response, and tolerability. Eleven patients were treated in phase I, and the RP2D was 120 mg/m2. In phase II, 32 patients received bendamustine 120 mg/m2. Two patients with ALL (bendamustine 90 mg/m2) experienced complete response (CR). Among patients who received bendamustine 120 mg/m2, 2 experienced partial response (PR); 7 had stable disease. The overall response rate (CR+CR without platelet recovery [CRp]) was 4.7% and biological activity rate (CR+CRp+PR) was 9.3%. No AML patients responded. The most common adverse events were anemia, neutropenia, thrombocytopenia, pyrexia, nausea, vomiting, and diarrhea. Bendamustine monotherapy has acceptable tolerability in heavily pretreated children with relapsed/refractory ALL or AML and appears to have some activity in ALL, warranting further studies in combination trials. PMID:24072240

Partial Cavity Flows at High Reynolds Numbers

NASA Astrophysics Data System (ADS)

Makiharju, Simo; Elbing, Brian; Wiggins, Andrew; Dowling, David; Perlin, Marc; Ceccio, Steven

2009-11-01

Partial cavity flows created for friction drag reduction were examined on a large-scale. Partial cavities were investigated at Reynolds numbers up to 120 million, and stable cavities with frictional drag reduction of more than 95% were attained at optimal conditions. The model used was a 3 m wide and 12 m long flat plate with a plenum on the bottom. To create the partial cavity, air was injected at the base of an 18 cm backwards-facing step 2.1 m from the leading edge. The geometry at the cavity closure was varied for different flow speeds to optimize the closure of the cavity. Cavity gas flux, thickness, frictional loads, and cavity pressures were measured over a range of flow speeds and air injection fluxes. High-speed video was used extensively to investigate the unsteady three dimensional cavity closure, the overall cavity shape and oscillations.

Response of anaerobic membrane bioreactor to the presence of nano-Bi2WO6: reactor performance, supernatant characteristics, and microbial community.

PubMed

Chen, Lin; Wang, Yue; Cao, Chuqing; Liu, Chang; Zhu, Liang

2017-11-01

Considering the increasing incorporation of manufactured nano-material into consumer products, there is a concern about its potential impacts in biological wastewater treatment. In this study, the response of anaerobic sludge to the presence of Bi 2 WO 6 nano-particles (NPs) was investigated in the anaerobic membrane bioreactor (AnMBR). As the concentration of Bi 2 WO 6 in the reactor was controlled around 1 mg/L, there was no significant difference in effluent water quality or bacterial activities before and after NP exposure, partially due to the microbial-induced NP aggregation and stable complex formation. However, with the increasing dosage of Bi 2 WO 6 from 5 to 40 mg/L, great influences on the AnMBR performance were observed, including the reduction of COD removal efficiency, inhibition of the mechanization step, increased production of soluble microbial products, and enhanced secretion of extracellular polymer substrates. Additional investigation with high-throughput sequencing was conducted, clearly demonstrating that Bi 2 WO 6 NPs induced changes in the bacterial community.

Managing neurobehavioral capability when social expediency trumps biological imperatives

PubMed Central

Spaeth, Andrea M.; Goel, Namni; Dinges, David F.

2013-01-01

Sleep, which is evolutionarily conserved across species, is a biological imperative that cannot be ignored or replaced. However, the percentage of habitually sleep-restricted adults has increased in recent decades. Extended work hours and commutes, shift work schedules, and television viewing are particularly potent social factors that influence sleep duration. Chronic partial sleep restriction, a product of these social expediencies, leads to the accumulation of sleep debt over time and consequently increases sleep propensity, decreases alertness, and impairs critical aspects of cognitive functioning. Significant interindividual variability in the neurobehavioral responses to sleep restriction exists—this variability is stable and phenotypic—suggesting a genetic basis. Identifying vulnerability to sleep loss is essential as many adults cannot accurately judge their level of impairment in response to sleep restriction. Indeed, the consequences of impaired performance and the lack of insight due to sleep loss can be catastrophic. In order to cope with the effects of social expediencies on biological imperatives, identification of biological (including genetic) and behavioral markers of sleep loss vulnerability as well as development of technological approaches for fatigue management are critical. PMID:22877676

Ionic liquids as electrolytes for the development of a robust amperometric oxygen sensor.

PubMed

Wang, Zhe; Lin, Peiling; Baker, Gary A; Stetter, Joseph; Zeng, Xiangqun

2011-09-15

A simple Clark-type online electrochemical cell design, consisting of a platinum gauze working electrode and incorporating ionic liquids (IL) as electrolytes, has been successfully applied for the amperometric sensing of oxygen. Studying ILs comprising the bis(trifluoromethylsulfonyl)imide anion, the obtained analytical parameters were found to be strongly dependent on the choice of cation. Compared with a conventional Clark cell design based on an aqueous supporting electrolyte, the modified oxygen sensor achieves substantial improvements in performance and stability. A limit of detection for oxygen as low as 0.05 vol %, linearity over an oxygen partial pressure between 0% and 20%, and a steady-state response time of 2 min was demonstrated, with a stable analytical response shown over the examined period of 90 days with no obvious fouling of the electrode surface. Based on the attractive physical attributes of ionic liquids (e.g., thermal stability beyond 150 °C), one can envision intriguing utility in nonstandard conditions and long-term online applications, as well as extension to the determination of other gases, such as methane and nitric oxide.

A phase I study of ABT-510 plus bevacizumab in advanced solid tumors.

PubMed

Uronis, Hope E; Cushman, Stephanie M; Bendell, Johanna C; Blobe, Gerard C; Morse, Michael A; Nixon, Andrew B; Dellinger, Andrew; Starr, Mark D; Li, Haiyan; Meadows, Kellen; Gockerman, Jon; Pang, Herbert; Hurwitz, Herbert I

2013-06-01

Targeting multiple regulators of tumor angiogenesis have the potential to improve treatment efficacy. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor and ABT-510 is a synthetic analog of thrombospondin, an endogenous angiogenesis inhibitor. Dual inhibition may result in additional benefit. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus ABT-510 in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. Thirty-four evaluable subjects were enrolled and received study drug. Therapy was well tolerated; minimal treatment-related grade 3/4 toxicity was observed. One patient treated at dose level 1 had a partial response and five other patients treated at the recommended phase II dose had prolonged stable disease for more than 1 year. Biomarker evaluation revealed increased levels of D-dimer, von Willebrand factor, placental growth factor, and stromal-derived factor 1 in response to treatment with the combination of bevacizumab and ABT-510. Data suggest that continued evaluation of combination antiangiogenesis therapies may be clinically useful.

The Modelling of Axially Translating Flexible Beams

NASA Astrophysics Data System (ADS)

Theodore, R. J.; Arakeri, J. H.; Ghosal, A.

1996-04-01

The axially translating flexible beam with a prismatic joint can be modelled by using the Euler-Bernoulli beam equation together with the convective terms. In general, the method of separation of variables cannot be applied to solve this partial differential equation. In this paper, a non-dimensional form of the Euler Bernoulli beam equation is presented, obtained by using the concept of group velocity, and also the conditions under which separation of variables and assumed modes method can be used. The use of clamped-mass boundary conditions leads to a time-dependent frequency equation for the translating flexible beam. A novel method is presented for solving this time dependent frequency equation by using a differential form of the frequency equation. The assume mode/Lagrangian formulation of dynamics is employed to derive closed form equations of motion. It is shown by using Lyapunov's first method that the dynamic responses of flexural modal variables become unstable during retraction of the flexible beam, which the dynamic response during extension of the beam is stable. Numerical simulation results are presented for the uniform axial motion induced transverse vibration for a typical flexible beam.

Efficiency of low dosage apatinib in post-first-line treatment of advanced lung adenocarcinoma.

PubMed

Zeng, Da-Xiong; Wang, Chang-Guo; Lei, Wei; Huang, Jian-An; Jiang, Jun-Hong

2017-09-12

Chemotherapy is the standard treatment of in advanced lung adenocarcinoma patients without driver mutation. However, few drugs could be selected when diseases progressed after second-line treatment. As a small molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), apatinib was suggested mainly using in advanced gastric cancer. In this study, we showed the results of apatinib as second-line to fourth-line treatment in EGFR wild-type advanced lung adenocarcinoma patients. 16 EGFR wild-type advanced lung adenocarcinoma patients were administrated apatinib (250-500 mg/d) orally. 3 patients showed partial response and 8 patients showed stable diseases response to apatinib, with a medium progression-free survival (PFS) of 4.4 month (2-10 months). The objective remission rate (ORR) was 18.75%(3/16). The total disease control rate (DCR) was 68.75% (11/16). The main toxicities were hypertension, hand-foot syndrome, proteinuria and thrombocytopenia which were tolerable and manageable. So, apatinib might be an optional choice for post-first-line treatment of EGFR wild-type advanced lung adenocarcinoma patients.

Lattice dynamic properties of Rh2XAl (X=Fe and Y) alloys

NASA Astrophysics Data System (ADS)

Al, Selgin; Arikan, Nihat; Demir, Süleyman; Iyigör, Ahmet

2018-02-01

The electronic band structure, elastic and vibrational spectra of Rh2FeAl and Rh2YAl alloys were computed in detail by employing an ab-initio pseudopotential method and a linear-response technique based on the density-functional theory (DFT) scheme within a generalized gradient approximation (GGA). Computed lattice constants, bulk modulus and elastic constants were compared. Rh2YAl exhibited higher ability to resist volume change than Rh2FeAl. The elastic constants, shear modulus, Young modulus, Poisson's ratio, B/G ratio electronic band structure, total and partial density of states, and total magnetic moment of alloys were also presented. Rh2FeAl showed spin up and spin down states whereas Rh2YAl showed none due to being non-magnetic. The calculated total densities of states for both materials suggest that both alloys are metallic in nature. Full phonon spectra of Rh2FeAl and Rh2YA1 alloys in the L21 phase were collected using the ab-initio linear response method. The obtained phonon frequencies were in the positive region indicating that both alloys are dynamically stable.

Bevacizumab in Combination with Chemotherapy for Colorectal Brain Metastasis.

PubMed

Finkelmeier, Fabian; You, Se-Jong; Waidmann, Oliver; Wolff, Robert; Zeuzem, Stefan; Bähr, Oliver; Trojan, Jörg

2016-03-01

Brain metastases are rare in patients with colorectal cancer, but the incidence is expected to rise due to prolonged survival resulting from more effective regimens including anti-EGF-receptor and anti-angiogenic antibodies. Because of the potential fear of intracranial hemorrhage, patients with colorectal brain metastases have been excluded from clinical trials involving bevacizumab or aflibercept. Five patients with colorectal brain metastases treated with bevacizumab-containing chemotherapy regimen following either neurosurgery, radiosurgery, or whole-brain radiotherapy were identified between 2009 and 2014. The clinicopathological data and outcomes for these patients were reviewed. Mean time to disease progression concerning brain metastases was 14.8 months (range 5-25). Overall survival was 26.2 months (range 7-42 months) and overall survival since diagnosis of brain metastases was 20.6 month (7-42). Best response was a partial response in two and a stable disease in three patients. Treatment-related adverse events were mild hypertension (grade 1), diarrhea (grade 1), and fatigue (grade 1). No intracranial hemorrhage was observed. Bevacizumab in combination with chemotherapy is a feasible option for palliative treatment of patients with colorectal brain metastasis with a good safety profile.

A Generalized Partial Credit Model: Application of an EM Algorithm.

ERIC Educational Resources Information Center

Muraki, Eiji

1992-01-01

The partial credit model with a varying slope parameter is developed and called the generalized partial credit model (GPCM). Analysis results for simulated data by this and other polytomous item-response models demonstrate that the rating formulation of the GPCM is adaptable to the analysis of polytomous item responses. (SLD)

Four-Hour Dives with Exercise While Breathing Oxygen Partial Pressure of 1.3 ATM

DTIC Science & Technology

2006-09-01

carboxyhemoglobin and hemoglobin concentrations, 8 and the samples were chosen to ensure that the analyzer signal was stable when measurements were...Instrumentation Laboratory; Lexington, MA) determined the pretest carboxyhemoglobin and hemoglobin concentrations from a venous blood sample. An autorefractor

A trypsin inhibitor from Sapindus saponaria L. seeds: purification, characterization, and activity towards pest insect digestive enzyme.

PubMed

Macedo, Maria Lígia R; Diz Filho, Eduardo B S; Freire, Mariadas Graças M; Oliva, Maria Luiza V; Sumikawa, Joana T; Toyama, Marcos H; Marangoni, Sérgio

2011-01-01

The present paper describes the purification, characterization and determination of the partial primary structure of the first trypsin inhibitor isolated from the family Sapindaceae. A highly stable, potent trypsin inhibitor (SSTI) was purified to homogeneity. SDS-PAGE analysis revealed that the protein consists of a two-polypeptide chain with molecular masses of approximately 15 and 3 kDa. The purified inhibitor inhibited bovine trypsin at a 1:1 M ratio. Kinetic analysis revealed that the protein is a competitive inhibitor with an equilibrium dissociation constant of 10⁻⁹ M for trypsin. The partial NH₂- terminal sequence of 36 amino acids in SSTI indicates homology with other members of the trypsin-inhibitor family from different sources. This inhibitor is highly stable in the presence of denaturing agents. SSTI showed significant inhibitory activity against trypsin-like proteases present in the larval midgut on Anagasta kuehniella, Corcyra cephalonica, Diatreae saccharalis and Anticarsia gemmatalis.

Almost periodic solutions to difference equations

NASA Technical Reports Server (NTRS)

Bayliss, A.

1975-01-01

The theory of Massera and Schaeffer relating the existence of unique almost periodic solutions of an inhomogeneous linear equation to an exponential dichotomy for the homogeneous equation was completely extended to discretizations by a strongly stable difference scheme. In addition it is shown that the almost periodic sequence solution will converge to the differential equation solution. The preceding theory was applied to a class of exponentially stable partial differential equations to which one can apply the Hille-Yoshida theorem. It is possible to prove the existence of unique almost periodic solutions of the inhomogeneous equation (which can be approximated by almost periodic sequences) which are the solutions to appropriate discretizations. Two methods of discretizations are discussed: the strongly stable scheme and the Lax-Wendroff scheme.

Remanent magnetization stratigraphy of lunar cores

NASA Technical Reports Server (NTRS)

Banerjee, S. K.; Gingrich, D.; Marvin, J. A.

1977-01-01

Depth dependent fluctuations have been observed in the natural remanent magnetizations (NRM) of drive cores and drill strings from Apollo 16 and 17 missions. Partial demagnetization of unstable secondary magnetizations and identification of characteristic error signals from a core which is known to have been recently disturbed allow us to identify and isolate the stable NRM stratigraphy in double drive core 60010/60009 and drill strings 60002-60004. The observed magnetization fluctuations persist after normalization to take into account depth dependent variations in the carriers of stable NRM. We tentatively ascribe the stable NRM stratigraphy to instantaneous records of past magnetic fields at the lunar surface and suggest that the stable NRM stratigraphy technique could develop as a new relative time-stratigraphic tool, to be used with other physical measurements such as relative intensity of ferromagnetic resonance and charged particle track density to study the evolution of the lunar regolith.

Adjoint-based constant-mass partial derivatives

DOE PAGES

Favorite, Jeffrey A.

2017-09-01

In transport theory, adjoint-based partial derivatives with respect to mass density are constant-volume derivatives. Likewise, adjoint-based partial derivatives with respect to surface locations (i.e., internal interface locations and the outer system boundary) are constant-density derivatives. This study derives the constant-mass partial derivative of a response with respect to an internal interface location or the outer system boundary and the constant-mass partial derivative of a response with respect to the mass density of a region. Numerical results are given for a multiregion two-dimensional (r-z) cylinder for three very different responses: the uncollided gamma-ray flux at an external detector point, k effmore » of the system, and the total neutron leakage. Finally, results from the derived formulas compare extremely well with direct perturbation calculations.« less

Spatial and Temporal Variations in the Partial Pressure and Emission of CO2 and CH4 in and Amazon Floodplain Lake

NASA Astrophysics Data System (ADS)

Forsberg, B. R.; Amaral, J. H.; Barbosa, P.; Kasper, D.; MacIntyre, S.; Cortes, A.; Sarmento, H.; Borges, A. V.; Melack, J. M.; Farjalla, V.

2015-12-01

The Amazon floodplain contains a variety of wetland environments which contribute CO2 and CH4 to the regional and global atmospheres. The partial pressure and emission of these greenhouse gases (GHGs) varies: 1) between habitats, 2) seasonally, as the characteristics these habitats changes and 3) diurnally, in response to diurnal stratification. In this study, we investigated the combined influence of these factors on the partial pressure and emission of GHGs in Lago Janauacá, a central Amazon floodplain lake (3o23' S; 60o18' O). All measurements were made between August of 2014 and April of 2015 at two different sites and in three distinct habitats: open water, flooded forest, flooded macrophytes. Concentrations of CO2 and CH4 in air were measured continuously with a cavity enhanced absorption spectrometer, Los Gatos Research´s Ultraportable Greenhouse Gas Analyzer (UGGA). Vertical profiles o pCO2 and pCH4 were measured using the UGGA connected to an electric pump and equilibrator. Diffusive surface emissions were estimated with the UGGA connected to a static floating chamber. To investigate the influence of vertical stratification and mixing on GHG partial pressure and emissions, a meteorological station and submersible sensor chain were deployed at each site. Meteorological sensors included wind speed and direction. The submersible chains included thermistors and oxygen sensors. Depth profiles of partial pressure and diffusive emissions for both CO2 and CH4 varied diurnally, seasonally and between habitats. Both pCO2 and pCH4 were consistently higher in bottom than surface waters with the largest differences occurring at high water when thermal stratification was most stable. Methane emissions and partial pressures were highest at low water while pCO2 and CO2 fluxes were highest during high water periods, with 35% of CO2 fluxes at low water being negative. The highest average surface value of pCO2 (5491 μatm), encountered during rising water, was ~3 times higher than that encountered at low water (1708 μatm). Partial pressures and emissions of both CO2 and CH4 were greatest in open water habitats and consistently higher at night. These patterns reflected the higher levels of wind driven mixing and turbulence in open water environments and higher convective mixing at night which promoted diffusive emission.

Nutritional Control of Chronological Aging and Heterochromatin in Saccharomyces cerevisiae.

PubMed

McCleary, David F; Rine, Jasper

2017-03-01

Calorie restriction extends life span in organisms as diverse as yeast and mammals through incompletely understood mechanisms.The role of NAD + -dependent deacetylases known as Sirtuins in this process, particularly in the yeast Saccharomyces cerevisiae , is controversial. We measured chronological life span of wild-type and sir2 Δ strains over a higher glucose range than typically used for studying yeast calorie restriction. sir2 Δ extended life span in high glucose complete minimal medium and had little effect in low glucose medium, revealing a partial role for Sir2 in the calorie-restriction response under these conditions. Experiments performed on cells grown in rich medium with a newly developed genetic strategy revealed that sir2 Δ shortened life span in low glucose while having little effect in high glucose, again revealing a partial role for Sir2 In complete minimal media, Sir2 shortened life span as glucose levels increased; whereas in rich media, Sir2 extended life span as glucose levels decreased. Using a genetic strategy to measure the strength of gene silencing at HML , we determined increasing glucose stabilized Sir2-based silencing during growth on complete minimal media. Conversely, increasing glucose destabilized Sir-based silencing during growth on rich media, specifically during late cell divisions. In rich medium, silencing was far less stable in high glucose than in low glucose during stationary phase. Therefore, Sir2 was involved in a response to nutrient cues including glucose that regulates chronological aging, possibly through Sir2-dependent modification of chromatin or deacetylation of a nonhistone protein. Copyright © 2017 by the Genetics Society of America.

Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase

PubMed Central

Feun, L G; Marini, A; Walker, G; Elgart, G; Moffat, F; Rodgers, S E; Wu, C J; You, M; Wangpaichitr, M; Kuo, M T; Sisson, W; Jungbluth, A A; Bomalaski, J; Savaraj, N

2012-01-01

Background: Arginine-depleting therapy with pegylated arginine deiminase (ADI-PEG20) was reported to have activity in advanced melanoma in early phase I–II trial, and clinical trials are currently underway in other cancers. However, the optimal patient population who benefit from this treatment is unknown. Methods: Advanced melanoma patients with accessible tumours had biopsy performed before the start of treatment with ADI-PEG20 and at the time of progression or relapse when amenable to determine whether argininosuccinate synthetase (ASS) expression in tumour was predictive of response to ADI-PEG20. Results: Twenty-seven of thirty-eight patients treated had melanoma tumours assessable for ASS staining before treatment. Clinical benefit rate (CBR) and longer time to progression were associated with negative expression of tumour ASS. Only 1 of 10 patients with ASS-positive tumours (ASS+) had stable disease, whereas 4 of 17 (24%) had partial response and 5 had stable disease, when ASS expression was negative (ASS−), giving CBR rates of 52.9 vs 10%, P=0.041. Two responding patients with negative ASS expression before therapy had rebiopsy after tumour progression and the ASS expression became positive. The survival of ASS− patients receiving at least four doses at 320 IU m−2 was significantly better than the ASS+ group at 26.5 vs 8.5 months, P=0.024. Conclusion: ADI-PEG20 is safe and the drug is only efficacious in melanoma patients whose tumour has negative ASS expression. Argininosuccinate synthetase tumour positivity is associated with drug resistance and tumour progression. PMID:22472884

In-situ restoration of one-stage partial nitritation-anammox process deteriorated by nitrate build-up via elevated substrate levels

PubMed Central

Wang, Xiaolong; Gao, Dawen

2016-01-01

The one-stage partial nitritation and anammox process (PN/A) has been a promising microbial process to remove ammonia from wastewater especially with low carbon/nitrogen ratio. The main breakdown was the deterioration caused by overgrowth of nitrite oxidizing bacteria (NOB) resulting effluent nitrate build-up in the PN/A process. This study presented an in-situ restoring strategy for suppressing NOB activity in a one-stage granular PN/A system deteriorated over 2 months, using elevated concentrations of substrates (ammonia and nitrite) under limited dissolved oxygen level. The results showed that the NOB activity was successfully suppressed after 56 days of restoration, and finally the ratio of produced nitrate/consumed ammonium was reduced from 36.8% to 7%. On day 66 the nitrogen removal rate obtained as 1.2 kg N/(m3·d). The high FA level (5–40 mg/L) and low dissolved oxygen (<0.13 mg/L) were responsible for NOB suppression. From quantitative PCR (qPCR) analysis, after this restoration, anammox bacteria had a widely growth, and AOB stay stable, but Nitrospira increase and Nitrobacter declined. High amount of NOB was still persistent in the granules, which was not easy to wash-out and threaten the deammonification performance. PMID:27881860

Effect of Increased Intra-abdominal Pressure on Liver Histology and Hemodynamics: An Experimental Study

PubMed Central

ANTONIOU, EFSTATHIOS A; KAIRI, EVI; MARGONIS, GEORGIOS A; ANDREATOS, NIKOLAOS; SASAKI, KAZUNARI; DAMASKOS, CHRISTOS; GARMPIS, NIKOLAOS; SAMAHA, MARIO; ARGYRA, ERIPHYLI; POLYMENEAS, GEORGE; WEISS, MATTHEW J; PAWLIK, TIMOTHY M; VOROS, DIONYSIOS; KOURAKLIS, GREGORY

2018-01-01

Background: While reduction of portal venous (PV) blood flow has been described in animal models of intra-abdominal hypertension, reports on compensatory changes in hepatic arterial (HA) flow, known as the hepatic arterial buffer response are controversial. Materials and Methods: Pneumoperitoneum with helium was induced in 13 piglets. Hemodynamic measurements and pathological assessment were conducted at baseline and during the three subsequent phases: Phase A: 45 minutes with a stable intra-abdominal pressure of 25 mmHg; phase B: 45 minutes with a stable intra-abdominal pressure of 40 mmHg; and phase C during which the abdomen was re-explored and reperfusion of the liver was allowed to take place. Results: Phase B pressure was significantly greater than phase A pressure in both the PV and the inferior vena cava, demonstrating a positive association between escalating intra-abdominal hypertension and the pressure in these two vessels (all p<0.001). In contrast, HA pressure was comparable between baseline and phase A, while it tended to decrease in phase B. Regarding histology, the most notable abnormality was the presence of inflammatory infiltrates and hepatocyte necrosis. Conclusion: Helium-insufflation increased PV pressure with a partial compensatory decrease of HA pressure. Nonetheless, findings consistent with hepatic ischemia were observed on pathology. PMID:29275303

Spectral methods on arbitrary grids

NASA Technical Reports Server (NTRS)

Carpenter, Mark H.; Gottlieb, David

1995-01-01

Stable and spectrally accurate numerical methods are constructed on arbitrary grids for partial differential equations. These new methods are equivalent to conventional spectral methods but do not rely on specific grid distributions. Specifically, we show how to implement Legendre Galerkin, Legendre collocation, and Laguerre Galerkin methodology on arbitrary grids.

Phase I study of liposome-encapsulated c-raf antisense oligodeoxyribonucleotide infusion in combination with radiation therapy in patients with advanced malignancies.

PubMed

Dritschilo, Anatoly; Huang, Chao H; Rudin, Charles M; Marshall, John; Collins, Brian; Dul, Jeanne L; Zhang, Chuanbo; Kumar, Deepak; Gokhale, Prafulla C; Ahmad, Ateeq; Ahmad, Imran; Sherman, Jeffrey W; Kasid, Usha N

2006-02-15

Raf proteins are key elements of growth-related cellular signaling pathways and are a component of cancer cell resistance to radiation therapy. Antisense oligonucleotides to c-raf-1 permit highly selective inhibition of the gene product and offer a strategy for sensitizing cancer cells to radiation therapy. In this dose escalation study, we evaluated the safety of combined liposomal formulation of raf antisense oligonucleotide (LErafAON) and radiation therapy in patients with advanced malignancies. Patients with advanced solid tumors were treated with LErafAON in a phase I dose escalation study while receiving palliative radiation therapy. Drug-related and radiation-related toxicities were monitored. Pharmacokinetics and expression of c-raf-1 mRNA and Raf-1 protein were determined in peripheral blood mononuclear cells. Seventeen patients with palliative indications for radiation therapy were entered into this study. Thirteen patients received daily infusions of LErafAON and four received twice-weekly infusions. Radiation therapy was delivered in daily 300-cGy fractions over 2 weeks. Patients tolerated radiation, and no unexpected radiation-related side effects were observed. Drug-related reactions (grade > or =2), such as back pain, chills, dyspnea, fatigue, fever, flushing, and hypertension, were observed in most patients and were managed by premedication with corticosteroids and antihistamines. Serious adverse events occurred in five patients, including acute infusion-related symptoms, abnormal liver function tests, hypoxia, dehydration, diarrhea, esophagitis, fever, hypokalemia, pharyngitis, and tachypnea. Twelve of 17 patients were evaluable for tumor response at completion of treatment; four showed partial response, four showed stable disease, and four experienced progressive disease. The intact rafAON was detected in plasma for 30 minutes to several hours. Six patients with partial response or stable disease were evaluable for c-raf-1 mRNA and/or Raf-1 protein expression. Inhibition of c-raf-1 mRNA was observed in three of five patients. Raf-1 protein was inhibited in four of five patients. This is the first report of the combined modality treatment using antisense oligonucleotides with radiation therapy in patients with advanced cancer. A dose of 2.0 mg/kg of LErafAON administered twice weekly is tolerated with premedication and does not enhance radiation toxicity in patients. The observation of dose-dependent, infusion-related reactions has led to further modification of the liposomal composition for use in future clinical trials.

Transport and Transformation of Selenium and Other Constituents of Flue-Gas Desulfurization Wastewater in Water-Saturated Soil Materials.

PubMed

Galkaduwa, Madhubhashini B; Hettiarachchi, Ganga M; Kluitenberg, Gerard J; Hutchinson, Stacy L; Davis, Lawrence; Erickson, Larry E

2017-03-01

Constructed wetland treatment systems are used to remove selenium (Se) from flue-gas desulfurization (FGD) wastewater (WW). However, direct confirmation of the mechanism responsible for FGD WW Se retention in soil is lacking. A laboratory-based soil column study was performed to develop an evidence-based mechanism of Se retention and to study the behavior and the retention capacity of FGD WW constituents in water-saturated soil. A deoxygenated 1:1 mixture of FGD WW and raw water was delivered to the columns bottom-up at a flux of 1.68 cm d for 100 d. Some of the columns were flushed with the raw water at the same rate for an additional 100 d. Column effluent was analyzed for constituents of concern. Results showed a complete retention of FGD WW Se in the soil materials. Boron and fluorine were partially retained; however, sulfur, sodium, and chlorine retention was poor, agreeing with field observations. The FGD WW Se was retained in soil near the inlet end of the columns, indicating its limited mobility under reduced conditions. Sequential extraction procedure revealed that retained Se was mainly sequestered as stable/residual forms. Bulk- and micro-X-ray absorption near-edge structure spectroscopy confirmed that Se was mainly retained as reduced/stable species [Se(IV), organic Se, and Se(0)]. This study provides direct evidence for FGD WW Se retention in water-saturated soil via the transformation of oxidized Se into reduced/stable forms. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

Treatment of metastatic uveal melanoma with intravenous fotemustine.

PubMed

Spagnolo, Francesco; Grosso, Marco; Picasso, Virginia; Tornari, Elena; Pesce, Marianna; Queirolo, Paola

2013-06-01

The purpose of the present study was to retrospectively evaluate the safety and activity of intravenous fotemustine in patients with metastatic uveal melanoma. We report on a series of 25 consecutive patients diagnosed with metastatic uveal melanoma. Fotemustine was administered intravenously as a first-line treatment to all patients. Thrombocytopenia and leukopenia (any grade) were observed in 60 and 52% of patients, respectively. Only two patients discontinued treatment because of toxicity (G3 thrombocytopenia), whereas all other patients were discontinued for progressive disease. Two partial responses were observed. Nine patients had stable disease (disease control rate=44%). The median survival duration was 13.9 months, and the 1-year survival rate was 60%. Intravenous fotemustine is well tolerated and could improve the outcome of metastatic uveal melanoma patients with or without liver involvement, although a randomized prospective trial is required to confirm these results.

The use of 99mTc-HYNIC-TOC and 18F-FDG PET/CT in the evaluation of duodenal neuroendocrine tumor with atypical and extensive metastasis responding dramatically to a single fraction of PRRT with 177Lu-DOTATATE.

PubMed

Basu, Sandip; Abhyankar, Amit

2014-12-01

This report describes a case of extensive diffuse bone marrow involvement with bilateral breast metastases from duodenal neuroendocrine tumor giving rise to a superscan-like appearance on somatostatin receptor-targeted (99m)Tc-hydrazinonicotinamide-TOC scintigraphy. The metastatic lesions demonstrated partial concordance with (18)F-FDG PET/CT findings, signifying varying tumor biology and heterogeneity among metastatic lesions in the same individual, as illustrated with a dual-tracer approach. There was a dramatic symptomatic and biochemical response and better health-related quality of life with a single fraction of peptide receptor radionuclide therapy with (177)Lu-DOTATATE, and radiologically there was stable disease at that point. © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

An efficient plant viral expression system generating orally immunogenic Norwalk virus-like particles.

PubMed

Santi, Luca; Batchelor, Lance; Huang, Zhong; Hjelm, Brooke; Kilbourne, Jacquelyn; Arntzen, Charles J; Chen, Qiang; Mason, Hugh S

2008-03-28

Virus-like particles (VLPs) derived from enteric pathogens like Norwalk virus (NV) are well suited to study oral immunization. We previously described stable transgenic plants that accumulate recombinant NV-like particles (rNVs) that were orally immunogenic in mice and humans. The transgenic approach suffers from long generation time and modest level of antigen accumulation. We now overcome these constraints with an efficient tobacco mosaic virus (TMV)-derived transient expression system using leaves of Nicotiana benthamiana. We produced properly assembled rNV at 0.8 mg/g leaf 12 days post-infection (dpi). Oral immunization of CD1 mice with 100 or 250 microg/dose of partially purified rNV elicited systemic and mucosal immune responses. We conclude that the plant viral transient expression system provides a robust research tool to generate abundant quantities of rNV as enriched, concentrated VLP preparations that are orally immunogenic.

An efficient plant viral expression system generating orally immunogenic Norwalk virus-like particles

PubMed Central

Santi, Luca; Batchelor, Lance; Huang, Zhong; Hjelm, Brooke; Kilbourne, Jacquelyn; Arntzen, Charles J.; Chen, Qiang; Mason, Hugh S.

2009-01-01

Virus like particles (VLPs) derived from enteric pathogens like Norwalk virus (NV) are well suited to study oral immunization. We previously described stable transgenic plants that accumulate recombinant NV-like particles (rNV) that were orally immunogenic in mice and humans. The transgenic approach suffers from long generation time and modest level of antigen accumulation. We now overcome these constraints with an efficient tobacco mosaic virus (TMV)-derived transient expression system using leaves of Nicotiana benthamiana. We produced properly assembled rNV at 0.8 mg/g leaf 12 days post infection. Oral immunization of CD1 mice with 100 or 250 μg/dose of partially purified rNV elicited systemic and mucosal immune responses. We conclude that the plant viral transient expression system provides a robust research tool to generate abundant quantities of rNV as enriched, concentrated VLP preparations that are orally immunogenic. PMID:18325641

Entropic contributions enhance polarity compensation for CeO2(100) surfaces

NASA Astrophysics Data System (ADS)

Capdevila-Cortada, Marçal; López, Núria

2017-03-01

Surface structure controls the physical and chemical response of materials. Surface polar terminations are appealing because of their unusual properties but they are intrinsically unstable. Several mechanisms, namely metallization, adsorption, and ordered reconstructions, can remove thermodynamic penalties rendering polar surfaces partially stable. Here, for CeO2(100), we report a complementary stabilization mechanism based on surface disorder that has been unravelled through theoretical simulations that: account for surface energies and configurational entropies; show the importance of the ion distribution degeneracy; and identify low diffusion barriers between conformations that ensure equilibration. Disordered configurations in oxides might also be further stabilized by preferential adsorption of water. The entropic stabilization term will appear for surfaces with a high number of empty sites, typically achieved when removing part of the ions in a polar termination to make the layer charge zero. Assessing the impact of surface disorder when establishing new structure-activity relationships remains a challenge.

2015 update on the diagnosis and management of neoplastic pericardial disease.

PubMed

Lestuzzi, Chiara; Berretta, Massimiliano; Tomkowski, Witold

2015-04-01

The best approach in diagnosis and treatment of neoplastic pericardial disease has not been defined yet. The authors report the most recent literature about the new diagnostic techniques that are useful to improve the diagnosis. The literature about the therapeutic options is critically reviewed, in order to give suggestions of use to the clinical practice. Pericardial effusion may require urgent drainage; the solid component, however, becomes predominant in some cases. Neoplastic pericardial disease should be assessed following oncologic criteria evaluation of the neoplastic burden; outcome classified as complete or partial response, stable or progressive disease and - in cases with progression - event-free survival. Systemic chemotherapy may be effective in lymphomas and possibly in breast carcinomas. Intrapericardial chemotherapy with systemic chemotherapy is the treatment of choice in lung cancer. Pericardial window with systemic chemotherapy is also effective in preventing the accumulation of large amount of fluid.

Phase I/II Clinical Trial of Hyaluronan-Cisplatin Nanoconjugate for the Treatment of Spontaneous Canine Cancers

PubMed Central

Cai, Shuang; Zhang, Ti; Forrest, W.C.; Yang, Qiuhong; Groer, Chad; Mohr, Eva; Aires, Daniel J.; Axiak-Bechtel, Sandra M.; Flesner, Brian K.; Henry, Carolyn J.; Selting, Kimberly A.; Tate, Deborah; Swarz, Jeffrey A.; Bryan, Jeffrey N.; Forrest, M. Laird

2015-01-01

Objective To conduct an open label, multi-dose Phase I/II clinical study in spontaneous canine cancers and evaluate the pharmacokinetics, safety, and efficacy of the hyaluronan-based cisplatin formulation (HA-Pt). Animals 13 dogs with heterogeneous, naturally occurring cancers. Procedures The dogs received up to four injections of 10-30 mg/m2 HA-Pt into the tumor or peritumoral sub-mucosa at three-week intervals. Blood sample (2 mL) was collected from the jugular catheter at 0.5, 1, 2, 4, and 24 hours following drug administration. A complete blood count and renal profile with urinalysis were conducted prior to and one week after each treatment. Tumor measurements were collected three weeks following each administration to assess response. Results Of the 13 dogs with heterogeneous, naturally occurring cancers, 23% had complete response and 15% had partial response or stable disease. Among the dogs that received drug with low diaquated content, the complete response rate for SCC was 3/7 (43%). Myelosuppression and cardiac toxicity were observed for 38% and 19% of the dogs, respectively. The formulation did not cause nephrotoxicity, the dose-limiting toxicity of standard cisplatin, in any dogs. Conclusions and Clinical Relevance The HA-Pt formulation demonstrated positive response in spontaneous canine squamous cell carcinomas. It did not cause nephrotoxicity in any patients. Canine oral SCC is very homogenous in progression and drug response to human HNSCC, and these results could be useful in developing human treatments. PMID:27580113

Simultaneous PET/MRI in assessing the response to chemo/radiotherapy in head and neck carcinoma: initial experience.

PubMed

Romeo, Valeria; Iorio, Brigida; Mesolella, Massimo; Ugga, Lorenzo; Verde, Francesco; Nicolai, Emanuele; Covello, Mario

2018-06-19

The purpose of the study was to assess by simultaneous positron emission tomography/magnetic resonance imaging (PET/MRI) the response to chemotherapy (CHT) and/or radiotherapy (RT) in patients with head and neck squamous cell carcinoma (HNSCC). Five patients with HNSCC underwent simultaneous PET/MRI examination before and after CHT and/or RT. Standard uptake volume (SUV), apparent diffusion coefficient (ADC), Ktrans, Kep, Ve, and iAUC pre- and post-treatment values were extracted and compared. The response to treatment was assessed according to RECIST criteria and classified as complete response (CR), partial response (PR), stable disease (SD), and progression disease (PD). In patient 1, PR was observed with increased ADC, Ktrans, and Ve values and reduction of SUV, iAUC, and Kep values; during clinical and instrumental follow-up, the patient experienced disease progression. Patient 2, classified as PR, showed increased ADC values and reduction of SUV and all perfusion parameters; follow-up demonstrated disease stability. Patient 3, considered as SD, showed increase of ADC and all perfusion values with a mild decrease of SUV; PD was observed during clinical and instrumental follow-up. Patients 4 and 5 showed a CR with no detectable tumor lesions at post-treatment PET/MRI examination, confirmed by 1-year follow-up. Multiparametric evaluation with simultaneous PET/MRI could be a useful tool to assess and predict the response to CHT and/or RT in patients with HNSCC.

Rapid and early α-fetoprotein and des-γ-carboxy prothrombin responses to initial arterial infusion chemotherapy predict treatment outcomes of advanced hepatocellular carcinoma

PubMed Central

OYAMA, KENJI; KODA, MASAHIKO; SUGIHARA, TAKAAKI; KISHINA, MANABU; MIYOSHI, KENICHI; OKAMOTO, TOSHIAKI; HODOTSUKA, MASANORI; FUJISE, YUKI; MATONO, TOMOMITSU; TOKUNAGA, SHIHO; OKAMOTO, KINYA; HOSHO, KEIKO; OKANO, JUNICHI; MURAWAKI, YOSHIKAZU

2015-01-01

The aim of the present study was to predict the effects of transarterial infusion (TAI) chemotherapy based on early changes in α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) in patients with advanced hepatocellular carcinoma (HCC). Seventy-four patients who underwent TAI with cisplatin, 5-fluorouracil, mitomycin C and epirubicin for advanced HCC were enrolled. Antitumor responses were evaluated 6 months after TAI. Rapid and early responses were defined as the ratio of AFP or DCP after 1 week and 1 month compared to baseline. A total of 5, 10, 17 and 42 patients had complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD), respectively. Early AFP response was significantly lower in the CR+PR compared to the SD+PD groups (P<0.01). The early DCP response was significantly lower in the CR+PR compared to the SD+PD. The sensitivity and specificity of rapid and early AFP responses in the CR+PR were 0.78 and 0.72, and 0.80 and 0.73, respectively, and those of rapid and early DCP responses were 0.67 and 0.65, and 0.77 and 0.71, respectively. The combination of AFP and DCP responses had higher specificity compared to AFP or DCP alone responses. Patients were divided into responder and non-responder groups to evaluate the prediction of survival outcome. Early responders of AFP, DCP and AFP+DCP, who were divided based on the cut-off values of CR+PR survived significantly longer than the non-responders (P<0.05). In conclusion, rapid or early responses of AFP and/or DCP levels 1 and 4 weeks after TAI chemotherapy helped to predict the treatment effects. PMID:26137283

Response assessment of bevacizumab therapy in GBM with integrated 11C-MET-PET/MRI: a feasibility study.

PubMed

Deuschl, Cornelius; Moenninghoff, Christoph; Goericke, Sophia; Kirchner, Julian; Köppen, Susanne; Binse, Ina; Poeppel, Thorsten D; Quick, Harald H; Forsting, Michael; Umutlu, Lale; Herrmann, Ken; Hense, Joerg; Schlamann, Marc

2017-08-01

The objective of this study was to evaluate the potential of integrated 11C-MET PET/MR for response assessment of relapsed glioblastoma (GBM) receiving bevacizumab treatment. Eleven consecutive patients with relapsed GBM were enrolled for an integrated 11C-MET PET/MRI at baseline and at follow-up. Treatment response for MRI was evaluated according to Response Assessment in Neuro-oncology (RANO) criteria and integrated 11C-MET PET was assessed by the T/N ratio. MRI showed no patient with complete response (CR), six of 11 patients with PR, four of 11 patients with SD, and one of 11 patients with progressive disease (PD). PET revealed metabolic response in five of the six patients with partial response (PR) and in two of the four patients with stable disease (SD), whereas metabolic non-response was detected in one of the six patients with PR, in two of the four patients with SD, and in the one patient with PD. Morphological imaging was predictive for PFS and OS when response was defined as CR, PR, SD, and non-response as PD. Metabolic imaging was predictive when using T/N ratio reduction of >25 as discriminator. Based on the morphologic and metabolic findings of this study a proposal for applying integrated PET/MRI for treatment response in relapsed GBM was developed, which was significantly predictive for PFS and OS (P = 0.010 respectively 0,029, log). This study demonstrates the potential of integrated 11C-MET-PET/MRI for response assessment of GBM and the utility of combined assessment of morphologic and metabolic information with the proposal for assessing relapsed GBM.

A Comparison of Three Polytomous Item Response Theory Models in the Context of Testlet Scoring.

ERIC Educational Resources Information Center

Cook, Karon F.; Dodd, Barbara G.; Fitzpatrick, Steven J.

1999-01-01

The partial-credit model, the generalized partial-credit model, and the graded-response model were compared in the context of testlet scoring using Scholastic Assessment Tests results (n=2,548) and a simulated data set. Results favor the partial-credit model in this context; considerations for model selection in other contexts are discussed. (SLD)

Potential of MR histogram analyses for prediction of response to chemotherapy in patients with colorectal hepatic metastases.

PubMed

Liang, He-Yue; Huang, Ya-Qin; Yang, Zhao-Xia; Ying-Ding; Zeng, Meng-Su; Rao, Sheng-Xiang

2016-07-01

To determine if magnetic resonance imaging (MRI) histogram analyses can help predict response to chemotherapy in patients with colorectal hepatic metastases by using response evaluation criteria in solid tumours (RECIST1.1) as the reference standard. Standard MRI including diffusion-weighted imaging (b=0, 500 s/mm(2)) was performed before chemotherapy in 53 patients with colorectal hepatic metastases. Histograms were performed for apparent diffusion coefficient (ADC) maps, arterial, and portal venous phase images; thereafter, mean, percentiles (1st, 10th, 50th, 90th, 99th), skewness, kurtosis, and variance were generated. Quantitative histogram parameters were compared between responders (partial and complete response, n=15) and non-responders (progressive and stable disease, n=38). Receiver operator characteristics (ROC) analyses were further analyzed for the significant parameters. The mean, 1st percentile, 10th percentile, 50th percentile, 90th percentile, 99th percentile of the ADC maps were significantly lower in responding group than that in non-responding group (p=0.000-0.002) with area under the ROC curve (AUCs) of 0.76-0.82. The histogram parameters of arterial and portal venous phase showed no significant difference (p>0.05) between the two groups. Histogram-derived parameters for ADC maps seem to be a promising tool for predicting response to chemotherapy in patients with colorectal hepatic metastases. • ADC histogram analyses can potentially predict chemotherapy response in colorectal liver metastases. • Lower histogram-derived parameters (mean, percentiles) for ADC tend to have good response. • MR enhancement histogram analyses are not reliable to predict response.

Clinical and biological effects of demethylating agents on solid tumours - A systematic review.

PubMed

Linnekamp, J F; Butter, R; Spijker, R; Medema, J P; van Laarhoven, H W M

2017-03-01

It is assumed that DNA methylation plays a key role in both tumour development and therapy resistance. Demethylating agents have been shown to be effective in the treatment of haematological malignancies. Based on encouraging preclinical results, demethylating agents may also be effective in solid tumours. This systematic review summarizes the evidence of the effect of demethylating agents on clinical response, methylation and the immune system in solid tumours. We conducted a systematic literature search from 1949 to December 2016, according to the PRISMA guidelines. Studies which evaluated treatment with azacitidine, decitabine, guadecitabine, hydralazine, procaine, MG98 and/or zebularine in patients with solid tumours were included. Data on clinical response, effects on methylation and immune response were extracted. Fifty-eight studies were included: in 13 studies complete responses (CR) were observed, 35 studies showed partial responses (PR), 47 studies stable disease (SD) and all studies except two showed progressive disease (PD). Effects on global methylation were observed in 11/15 studies and demethylation/re-expression of tumour specific genes was seen in 15/17 studies. No clear correlation between (de)methylation and clinical response was observed. In 14 studies immune-related responses were reported, such as re-expression of cancer-testis antigens and upregulation of interferon genes. Demethylating agents are able to improve clinical outcome and alter methylation status in patients with solid tumours. Although beneficial effect has been shown in individual patients, overall response is limited. Further research on biomarker predicting therapy efficacy is indicated, particularly in earlier stage and highly methylated tumours. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Rockets and spacecraft: Sine qua non of space science

NASA Technical Reports Server (NTRS)

1980-01-01

The evolution of the national launch vehicle stable is presented along with lists of launch vehicles used in NASA programs. A partial list of spacecraft used throughout the world is also given. Scientific spacecraft costs are presented along with an historial overview of project development and funding in NASA.

Regions of absolute ultimate boundedness for discrete-time systems.

NASA Technical Reports Server (NTRS)

Siljak, D. D.; Weissenberger, S.

1972-01-01

This paper considers discrete-time systems of the Lur'e-Postnikov class where the linear part is not asymptotically stable and the nonlinear characteristic satisfies only partially the usual sector condition. Estimates of the resulting finite regions of absolute ultimate boundedness are calculated by means of a quadratic Liapunov function.

Transtendon, Double-Row, Transosseous-Equivalent Arthroscopic Repair of Partial-Thickness, Articular-Surface Rotator Cuff Tears

PubMed Central

Dilisio, Matthew F.; Miller, Lindsay R.; Higgins, Laurence D.

2014-01-01

Arthroscopic transtendinous techniques for the arthroscopic repair of partial-thickness, articular-surface rotator cuff tears offer the advantage of minimizing the disruption of the patient's remaining rotator cuff tendon fibers. In addition, double-row fixation of full-thickness rotator cuff tears has shown biomechanical advantages. We present a novel method combining these 2 techniques for transtendon, double-row, transosseous-equivalent arthroscopic repair of partial-thickness, articular-surface rotator cuff tears. Direct visualization of the reduction of the retracted articular tendon layer to its insertion on the greater tuberosity is the key to the procedure. Linking the medial-row anchors and using a double-row construct provide a stable repair that allows early shoulder motion to minimize the risk of postoperative stiffness. PMID:25473606

Transtendon, double-row, transosseous-equivalent arthroscopic repair of partial-thickness, articular-surface rotator cuff tears.

PubMed

Dilisio, Matthew F; Miller, Lindsay R; Higgins, Laurence D

2014-10-01

Arthroscopic transtendinous techniques for the arthroscopic repair of partial-thickness, articular-surface rotator cuff tears offer the advantage of minimizing the disruption of the patient's remaining rotator cuff tendon fibers. In addition, double-row fixation of full-thickness rotator cuff tears has shown biomechanical advantages. We present a novel method combining these 2 techniques for transtendon, double-row, transosseous-equivalent arthroscopic repair of partial-thickness, articular-surface rotator cuff tears. Direct visualization of the reduction of the retracted articular tendon layer to its insertion on the greater tuberosity is the key to the procedure. Linking the medial-row anchors and using a double-row construct provide a stable repair that allows early shoulder motion to minimize the risk of postoperative stiffness.

Rotor-to-stator Partial Rubbing and Its Effects on Rotor Dynamic Response

NASA Technical Reports Server (NTRS)

Muszynska, Agnes; Franklin, Wesley D.; Hayashida, Robert D.

1991-01-01

Results from experimental and analytical studies on rotor to stationary element partial rubbings at several locations and their effects on rotor dynamic responses are presented. The mathematical model of a rubbing rotor is given. The computer program provides numerical results which agree with experimentally obtained rotor responses.

Removable partial denture supported by implants with prefabricated telescopic abutments - a case report.

PubMed

Kumar, Lalit; Sehgal, Komal

2014-06-01

Implants have been designed to rehabilitate edentulous patients with fixed prosthesis or implant supported overdentures. Implant-supported single crowns and fixed partial dentures have become successful treatment alternatives to removable and fixed partial dentures. However, it is common to have clinical situations which make it impossible to use conventional as well as implant supported fixed partial dentures. The implant supported removable partial dentures can be a treatment modality that offers the multitude of benefits of implant-based therapy-biologic, biomechanical, social, and psychological to such patients. The aim of this article is to present a case report describing the fabrication and advantages of removable partial denture supported by teeth and implants for a patient with long edentulous span. The patient was satisfied with his dentures in terms of function and aesthetics. Regular follow-up visits over a period of three years revealed that the periodontal condition of remaining natural dentition and peri-implant conditions were stable. There was no evidence of excessive residual ridge resorption or mobility of the teeth, nor were any visible changes in the bone levels of the natural teeth or implants noted on radiographs.

Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy.

PubMed

Grimaldi, Antonio M; Simeone, Ester; Giannarelli, Diana; Muto, Paolo; Falivene, Sara; Borzillo, Valentina; Giugliano, Francesca Maria; Sandomenico, Fabio; Petrillo, Antonella; Curvietto, Marcello; Esposito, Assunta; Paone, Miriam; Palla, Marco; Palmieri, Giuseppe; Caracò, Corrado; Ciliberto, Gennaro; Mozzillo, Nicola; Ascierto, Paolo A

2014-01-01

Cancer radiotherapy (RT) may induce what is referred to as the "abscopal effect," a regression of non-irradiated metastatic lesions distant from the primary tumor site directly subject to irradiation. This clinical response is rare, but has been surmised to be an immune-mediated phenomenon, suggesting that immunotherapy and RT could potentially synergize. Here, we report the outcome of patients with advanced melanoma treated with the immune checkpoint blockade monoclonal antibody antagonist, ipilimumab followed by RT. Patients were selected for enrollment at the National Cancer Institute "Fondazione G.Pascale" through the expanded access program in Italy. Those who experienced disease progression after ipilimumab thus received subsequent RT and were selected for analysis. Among 21 patients, 13 patients (62%) received RT to treat metastases in the brain and 8 received RT directed at extracranial sites. An abscopal response was observed in 11 patients (52%), 9 of whom had partial responses (43%) and 2 had stable disease (10%). The median time from RT to an abscopal response was 1 month (range 1-4). Median overall survival (OS) for all 21 patients was 13 months (range 6-26). Median OS for patients with abscopal responses was extended to 22.4 months (range 2.5-50.3) vs. 8.3 months (range 7.6-9.0) without. A local response to RT was detected in 13 patients (62%) and, of these, 11 patients (85%) had an abscopal response and abscopal effects were only observed among patients exhibiting a local response. These results suggest RT after ipilimumab may lead to abscopal responses in some patients with advanced melanoma correlating with prolonged OS. Our data also suggest that local responses to RT may be predictive of abscopal responses. Further research in larger randomized trials is needed to validate these results.

Stable Tearing and Buckling Responses of Unstiffened Aluminum Shells with Long Cracks

NASA Technical Reports Server (NTRS)

Starnes, James H., Jr.; Rose, Cheryl A.

1999-01-01

The results of an analytical and experimental study of the nonlinear response of thin, unstiffened, aluminum cylindrical shells with a long longitudinal crack are presented. The shells are analyzed with a nonlinear shell analysis code that accurately accounts for global and local structural response phenomena. Results are presented for internal pressure and for axial compression loads. The effect of initial crack length on the initiation of stable crack growth and unstable crack growth in typical shells subjected to internal pressure loads is predicted using geometrically nonlinear elastic-plastic finite element analyses and the crack-tip-opening angle (CTOA) fracture criterion. The results of these analyses and of the experiments indicate that the pressure required to initiate stable crack growth and unstable crack growth in a shell subjected to internal pressure loads decreases as the initial crack length increases. The effects of crack length on the prebuckling, buckling and postbuckling responses of typical shells subjected to axial compression loads are also described. For this loading condition, the crack length was not allowed to increase as the load was increased. The results of the analyses and of the experiments indicate that the initial buckling load and collapse load for a shell subjected to axial compression loads decrease as the initial crack length increases. Initial buckling causes general instability or collapse of a shell for shorter initial crack lengths. Initial buckling is a stable local response mode for longer initial crack lengths. This stable local buckling response is followed by a stable postbuckling response, which is followed by general or overall instability of the shell.

Stable Tearing and Buckling Responses of Unstiffened Aluminum Shells with Long Cracks

NASA Technical Reports Server (NTRS)

Starnes, James H., Jr.; Rose, Cheryl A.

1998-01-01

The results of an analytical and experimental study of the nonlinear response of thin, unstiffened, aluminum cylindrical shells with a long longitudinal crack are presented. The shells are analyzed with a nonlinear shell analysis code that accurately accounts for global and local structural response phenomena. Results are presented for internal pressure and for axial compression loads. The effect of initial crack length on the initiation of stable crack growth and unstable crack growth in typical shells subjected to internal pressure loads is predicted using geometrically nonlinear elastic-plastic finite element analyses and the crack-tip-opening angle (CTOA) fracture criterion. The results of these analyses and of the experiments indicate that the pressure required to initiate stable crack growth and unstable crack growth in a shell subjected to internal pressure loads decreases as the initial crack length increases. The effects of crack length on the prebuckling, buckling and postbuckling responses of typical shells subjected to axial compression loads are also described. For this loading condition, the crack length was not allowed to increase as the load was increased. The results of the analyses and of the experiments indicate that the initial buckling load and collapse load for a shell subjected to axial compression loads decrease as the initial crack length increases. Initial buckling causes general instability or collapse of a shell for shorter initial crack lengths. Initial buckling is a stable local response mode for longer initial crack lengths. This stable local buckling response is followed by a stable postbuckling response, which is followed by general or overall instability of the shell.

Sutureless amniotic membrane transplantation for partial limbal stem cell deficiency.

PubMed

Kheirkhah, Ahmad; Casas, Victoria; Raju, Vadrevu K; Tseng, Scheffer C G

2008-05-01

To evaluate the results of sutureless amniotic membrane (AM) transplantation using fibrin glue for reconstructing corneal surfaces with partial limbal stem cell deficiency (LSCD). Retrospective noncomparative interventional case series. Eleven eyes of nine patients that had LSCD with 120 degrees to almost 360 degrees of limbal involvement underwent superficial keratectomy to remove the conjunctivalized pannus followed by AM transplantation using fibrin glue. Additional sutureless AM patch (ProKera; Bio-Tissue, Inc, Miami, Florida, USA) was used in seven patients, and mitomycin C was applied on the cornea in four eyes and during fornix reconstruction in seven eyes. The surgery was repeated in three eyes for residual pannus. During a mean follow-up of 14.2 +/- 7.7 months (range, six to 26 months), all eyes maintained a smooth and stable corneal epithelial surface without recurrent erosion or persistent epithelial defect, and showed less stromal cloudiness and vascularization. Best-corrected visual acuity improved in nine eyes (81.8%). Corneal epithelialization proceeded by epithelial growth over AM (n = 4), accompanied by dissolution of AM (n = 4) or a combination of both (n = 3). No complication was noted regarding initial or repeated uses of fibrin glue. AM transplantation using fibrin glue appears to be a safe and effective method of restoring a stable corneal epithelium for cases with partial LSCD. This approach avoids the need of transplanting limbal epithelial stem cells.

Quantitative trait locus analysis of heterosis for plant height and ear height in an elite maize hybrid zhengdan 958 by design III.

PubMed

Li, Hongjian; Yang, Qingsong; Fan, Nannan; Zhang, Ming; Zhai, Huijie; Ni, Zhongfu; Zhang, Yirong

2017-04-17

Plant height (PH) and ear height (EH) are two important agronomic traits in maize selection breeding. F 1 hybrid exhibit significant heterosis for PH and EH as compared to their parental inbred lines. To understand the genetic basis of heterosis controlling PH and EH, we conducted quantitative trait locus (QTL) analysis using a recombinant inbreed line (RIL) based design III population derived from the elite maize hybrid Zhengdan 958 in five environments. A total of 14 environmentally stable QTLs were identified, and the number of QTLs for Z 1 and Z 2 populations was six and eight, respectively. Notably, all the eight environmentally stable QTLs for Z 2 were characterized by overdominance effect (OD), suggesting that overdominant QTLs were the most important contributors to heterosis for PH and EH. Furthermore, 14 environmentally stable QTLs were anchored on six genomic regions, among which four are trait-specific QTLs, suggesting that the genetic basis for PH and EH is partially different. Additionally, qPH.A-1.3, modifying about 10 centimeters of PH, was further validated in backcross populations. The genetic basis for PH and EH is partially different, and overdominant QTLs are important factors for heterosis of PH and EH. A major QTL qPH.A-1.3 may be a desired target for genetic improvement of maize plant height.

Systemic gemcitabine combined with intra-arterial low-dose cisplatin and 5-fluorouracil for advanced hepatocellular carcinoma: Seven cases

PubMed Central

Uka, Kiminori; Aikata, Hiroshi; Takaki, Shintaro; Kawaoka, Tomokazu; Saneto, Hiromi; Miki, Daiki; Takahashi, Shoichi; Toyota, Naoyuki; Ito, Katsuhide; Chayama, Kazuaki

2008-01-01

The combination of intra-arterial low-dose cisplatin and 5-fluorouracil (5-FU) is effective against advanced hepatocellular carcinoma (HCC). Systemic gemcitabine chemotherapy seems effective in many cancers. We report the results of combination therapy with systemic gemcitabine, intra-arterial low-dose cisplatin and 5-FU (GEMFP). Seven patients with non-resectable advanced HCC were treated with GEMFP. One course of chemotherapy consisted of daily intra-arterial cisplatin (20 mg/body weight/hour on d 1, 10 mg/body weight per 0.5 h on d 2-5 and 8-12), followed by 5-FU (250 mg/body weight per 5 h on d 1-5 and 8-12) via an injection port. Gemcitabine at 1000 mg/m2 was administered intravenously at 0.5 h on d 1 and 8. The objective response was 57%. The response to GEMFP was as follows: complete response (no patients), partial response (four patients), stable disease (three patients), and progressive disease (no patients). The median survival period was 8 mo (range, 5-55). With regard to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 3 or 4 adverse reactions, seven (100%), seven, six (86%) and one (14%) patients developed leukopenia, neutropenia, thrombocytopenia and anemia, respectively. GEMFP may potentially be effective for non-resectable advanced HCC, but it has severe hematologic toxicity. PMID:18442216

A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study.

PubMed

Biagi, J J; Oza, A M; Chalchal, H I; Grimshaw, R; Ellard, S L; Lee, U; Hirte, H; Sederias, J; Ivy, S P; Eisenhauer, E A

2011-02-01

Sunitinib is a multitargeted receptor tyrosine kinase inhibitor. We conducted a two-stage phase II study to evaluate the objective response rate of oral sunitinib in recurrent epithelial ovarian cancer. Eligibility required measurable disease and one or two prior chemotherapies, at least one platinum based. Platinum-sensitive or -resistant disease was allowed. Initial dose schedule was sunitinib 50 mg daily, 4 of 6 weeks. Observation of fluid accumulations during off-treatment periods resulted in adoption of continuous 37.5 mg daily dosing in the second stage of accrual. Of 30 eligible patients, most had serous histology (67%), were platinum sensitive (73%) and had two prior chemotherapies (60%). One partial response (3.3%) and three CA125 responses (10%) were observed, all in platinum-sensitive patients using intermittent dosing. Sixteen (53%) had stable disease. Five had >30% decrease in measurable disease. Overall median progression-free survival was 4.1 months. Common adverse events included fatigue, gastrointestinal symptoms, hand-foot syndrome and hypertension. No gastrointestinal perforation occurred. Single-agent sunitinib has modest activity in recurrent platinum-sensitive ovarian cancer, but only at the 50 mg intermittent dose schedule, suggesting that dose and schedule may be vital considerations in further evaluation of sunitinib in this cancer setting.

Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma.

PubMed

Vogl, Dan T; Stadtmauer, Edward A; Tan, Kay-See; Heitjan, Daniel F; Davis, Lisa E; Pontiggia, Laura; Rangwala, Reshma; Piao, Shengfu; Chang, Yunyoung C; Scott, Emma C; Paul, Thomas M; Nichols, Charles W; Porter, David L; Kaplan, Janeen; Mallon, Gayle; Bradner, James E; Amaravadi, Ravi K

2014-08-01

The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.

Antitumor effects of deracoxib treatment in 26 dogs with transitional cell carcinoma of the urinary bladder.

PubMed

McMillan, Sarah K; Boria, Pedro; Moore, George E; Widmer, William R; Bonney, Patty L; Knapp, Deborah W

2011-10-15

OBJECTIVE-To evaluate the antitumor activity and toxic effects of deracoxib, a selective cyclooxygenase-2 inhibitor, in dogs with transitional cell carcinoma (TCC) of the urinary bladder. DESIGN-Clinical trial. Animals-26 client-owned dogs with naturally occurring, histologically confirmed, measurableTCC of the urinary bladder. PROCEDURES-Dogs were treated PO with deracoxib at a dosage of 3 mg/kg/d (1.36 mg/lb/d) as a single-agent treatment for TCC. Tumor response was assessed via radiography, abdominal ultrasonography, and ultrasonographic mapping of urinary bladder masses. Toxic effects of deracoxib administration in dogs were assessed through clinical observations and hematologic and biochemical analyses. RESULTS-Of 24 dogs for which tumor response was assessed, 4 (17%) had partial remission, 17 (71%) had stable disease, and 3 (13%) had progressive disease; initial response could not be assessed in 2 of 26 dogs. The median survival time was 323 days. Median time to progressive disease was 133 days. Renal, hepatic, and gastrointestinal abnormalities attributed to deracoxib administration were noted in 4% (1/26), 4% (1/26), and 19% (5/26) of dogs, respectively. CONCLUSIONS AND CLINICAL RELEVANCE-Results indicated that deracoxib was generally well tolerated by dogs and had antitumor activity against TCC.

Sleep restriction undermines cardiovascular adaptation during stress, contingent on emotional stability.

PubMed

Lü, Wei; Hughes, Brian M; Howard, Siobhán; James, Jack E

2018-02-01

Sleep loss is associated with increased cardiovascular disease, but physiological mechanisms accounting for this relationship are largely unknown. One possible mechanism is that sleep restriction exerts effects on cardiovascular stress responses, and that these effects vary between individuals. Emotional stability (ES) is a personality trait pertinent to sleep restriction and stress responding. However, no study to date has explored how ES and sleep-restriction interactively affect cardiovascular stress responses or processes of adaptation during stress. The present study sought to investigate the association between ES and impact of sleep restriction on cardiovascular function during stress, with particular regard to the trajectory of cardiovascular function change across time. Ninety female university students completed a laboratory vigilance stress task while undergoing continuous cardiovascular (SBP, DBP, HR, SV, CO, TPR) monitoring, after either a night of partial sleep restriction (40% of habitual sleep duration) or a full night's rest. Individuals high in ES showed stable and adaptive cardiovascular (SBP, SV, CO) responses throughout stress exposure, regardless of sleep. In contrast, individuals low in ES exhibited cardiovascular adaptation during stress exposure while rested, but disrupted adaption while sleep-restricted. These findings suggest that sleep-restriction undermines healthful cardiovascular adaptation to stress for individuals low in ES. Copyright © 2017 Elsevier B.V. All rights reserved.

Icotinib and whole-brain radiotherapy for the treatment in patients with brain metastases from EGFR-mutant nonsmall cell lung cancer

PubMed Central

Jiang, Ai-Ying; Zhang, Jing; Luo, Hai-Long; Gao, Feng; Lv, Yu-Feng

2018-01-01

Abstract This study aimed to explore the effect and toxicity of icotinib and whole-brain radiotherapy (IWBRT) for the treatment of brain metastases from nonsmall cell lung cancer (BMNSCLC) with epidermal growth factor receptor (EGFR)-mutant among Chinese Han population. A total of 55 patients with EGFR-mutant BMNSCLC were included. They received orally icotinib (125 mg/tablet, 125 mg each time, 3 times daily) until disease progression. In addition, they also underwent whole-brain radiotherapy (3-Gy fractions once daily, 5 days weekly for a total dose of 30 Gy) in an attempt to extend their survival time. The outcomes consisted of complete response (CR), partial response (PR), stable disease (SD), progress disease (PD), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). In addition, toxicity was also recorded in this study. The CR, PR, SD, PD, ORR, PFS, and OS were 38.2%, 52.8%, 5.4%, 3.6%, 90.1%, 12.5%, and 48.0% months, respectively. In addition, mild toxicity was observed in this study. This study demonstrated that IWBRT is efficacious with acceptable toxicity for patients with EGFR-mutant BMNSCLC among Chinese Han population. PMID:29642161

Icotinib and whole-brain radiotherapy for the treatment in patients with brain metastases from EGFR-mutant nonsmall cell lung cancer: A retrospective study.

PubMed

Jiang, Ai-Ying; Zhang, Jing; Luo, Hai-Long; Gao, Feng; Lv, Yu-Feng

2018-04-01

This study aimed to explore the effect and toxicity of icotinib and whole-brain radiotherapy (IWBRT) for the treatment of brain metastases from nonsmall cell lung cancer (BMNSCLC) with epidermal growth factor receptor (EGFR)-mutant among Chinese Han population.A total of 55 patients with EGFR-mutant BMNSCLC were included. They received orally icotinib (125 mg/tablet, 125 mg each time, 3 times daily) until disease progression. In addition, they also underwent whole-brain radiotherapy (3-Gy fractions once daily, 5 days weekly for a total dose of 30 Gy) in an attempt to extend their survival time. The outcomes consisted of complete response (CR), partial response (PR), stable disease (SD), progress disease (PD), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). In addition, toxicity was also recorded in this study.The CR, PR, SD, PD, ORR, PFS, and OS were 38.2%, 52.8%, 5.4%, 3.6%, 90.1%, 12.5%, and 48.0% months, respectively. In addition, mild toxicity was observed in this study.This study demonstrated that IWBRT is efficacious with acceptable toxicity for patients with EGFR-mutant BMNSCLC among Chinese Han population.

Spatial changes in acid secretion from isolated stomach tissue using a pH-histamine sensing microarray.

PubMed

Bitziou, Eleni; O'Hare, Danny; Patel, Bhavik Anil

2010-03-01

The acid secretion mechanism can be studied by measuring a series of metabolic markers and neurotransmitters from in vitro isolated tissue. A microelectrode array was used to monitor proton concentration and histamine levels from isolated guinea pig stomach tissue. The device was partially modified using iridium oxide to form a series of pH sensors, whereas unmodified gold microelectrodes were used to measure the level of histamine in the gut. Real-time measurements in the presence of the H2-receptor antagonist ranitidine produced significant decreases in the overall Delta pH response, as expected. Also, a significant variation in the Delta pH response in between pH sensors was observed in the presence of pharmacological treatment due to structural features of the tissue. No significant differences in Delta i(H) were detected in the presence of ranitidine as expected. More significantly, clear variations in Delta pH responses between animals in control conditions and those in the presence of ranitidine was observed highlighting possible variation in parietal cell density and/or variations in tissue activity. These results identify great possibilities in applying these multi-sensing devices as a long-term stable personalised diagnostic tool for pharmacological screening and disease status.

Combined local and systemic bleomycin administration in electrochemotherapy to reduce the number of treatment sessions

PubMed Central

Tellado, Matias; Olaiz, Nahuel; Michinski, Sebastian; Marshall, Guillermo

2016-01-01

Background Electrochemotherapy (ECT), a medical treatment widely used in human patients for tumor treatment, increases bleomycin toxicity by 1000 fold in the treated area with an objective response rate of around 80%. Despite its high response rate, there are still 20% of cases in which the patients are not responding. This could be ascribed to the fact that bleomycin, when administered systemically, is not reaching the whole tumor mass properly because of the characteristics of tumor vascularization, in which case local administration could cover areas that are unreachable by systemic administration. Patients and methods We propose combined bleomycin administration, both systemic and local, using companion animals as models. We selected 22 canine patients which failed to achieve a complete response after an ECT treatment session. Eleven underwent another standard ECT session (control group), while 11 received a combined local and systemic administration of bleomycin in the second treatment session. Results According to the WHO criteria, the response rates in the combined administration group were: complete response (CR) 54% (6), partial response (PR) 36% (4), stable disease (SD) 10% (1). In the control group, these were: CR 0% (0), PR 19% (2), SD 63% (7), progressive disease (PD) 18% (2). In the combined group 91% objective responses (CR+PR) were obtained. In the control group 19% objective responses were obtained. The difference in the response rate between the treatment groups was significant (p < 0.01). Conclusions Combined local and systemic bleomycin administration was effective in previously to ECT non responding canine patients. The results indicate that this approach could be useful and effective in specific population of patients and reduce the number of treatment sessions needed to obtain an objective response. PMID:27069450

Long-Term Response and Remission with Pixantrone in Patients with Relapsed or Refractory Aggressive Non-Hodgkin Lymphoma: Post-Hoc Analysis of the Multicenter, Open-Label, Randomized PIX301 Trial.

PubMed

Pettengell, Ruth; Coiffier, Bertrand; Egorov, Anton; Singer, Jack; Sivcheva, Lilia

2018-06-01

Pixantrone is recommended in relapsed and refractory non-Hodgkin lymphoma (NHL) or heavily pretreated NHL patients. Its conditional approval in Europe was based on results from the open-label, randomized, phase 3 PIX301 study, comparing pixantrone monotherapy with physician's choice of treatment in 140 patients with relapsed or refractory aggressive NHL. This post-hoc analysis of the PIX301 study investigated possible correlations between patient characteristics and clinical response in 17 patients (24%) treated with pixantrone who achieved a complete response (CR) or an unconfirmed complete response (CRu) at study end. These patients (10 male and 7 female) had a median age of 61 (range 41-75) years, and the most common diagnoses were diffuse large B-cell lymphoma (n = 10) and transformed indolent lymphoma (n = 4). Most had received two prior lines of therapy (n = 12). There was wide variation in the time from diagnosis to study entry (219-4777 days). Among the 17 patients who achieved a CR/CRu with pixantrone, 6 had stable or progressive disease as a response to their last regimen, 7 had a partial response, and 4 had a CR/CRu. Four patients from the pixantrone group survived without progression for more than 400 days. Prior response to previous therapies did not appear to affect long-term response to pixantrone. These observations suggest that pixantrone monotherapy in patients with multiply relapsed or refractory aggressive NHL who had received at least two prior therapies can be associated with durable responses and long-term remission, and this may be unrelated to the clinical response to the last therapy.

Impacts of motivational valence on the error-related negativity elicited by full and partial errors.

PubMed

Maruo, Yuya; Schacht, Annekathrin; Sommer, Werner; Masaki, Hiroaki

2016-02-01

Affect and motivation influence the error-related negativity (ERN) elicited by full errors; however, it is unknown whether they also influence ERNs to correct responses accompanied by covert incorrect response activation (partial errors). Here we compared a neutral condition with conditions, where correct responses were rewarded or where incorrect responses were punished with gains and losses of small amounts of money, respectively. Data analysis distinguished ERNs elicited by full and partial errors. In the reward and punishment conditions, ERN amplitudes to both full and partial errors were larger than in the neutral condition, confirming participants' sensitivity to the significance of errors. We also investigated the relationships between ERN amplitudes and the behavioral inhibition and activation systems (BIS/BAS). Regardless of reward/punishment condition, participants scoring higher on BAS showed smaller ERN amplitudes in full error trials. These findings provide further evidence that the ERN is related to motivational valence and that similar relationships hold for both full and partial errors. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Production, characterization, and immobilization of partially purified surfactant-detergent and alkali-thermostable protease from newly isolated Aeromonas caviae.

PubMed

Datta, Sumitra; Menon, Gopalakrishnan; Varughese, Bincy

2017-04-21

Proteolytic Aeromonas caviae P-1-1 growing at wide-ranging pH (7.0-11.0) and moderate salinity (0-5% NaCl) was isolated from cattle shed of Thanjavur, India. It produced lipase, gelatinase, and polyhydroxybutyrate. Different culture conditions, incubation time, carbon and nitrogen sources, vitamins, amino acids, surfactants, and metal ions for optimal growth and protease production of P-1-1 were examined. Maximum protease (0.128 U/mL) production was achieved with 1% fructose, 1% yeast extract, 0.1% ammonium sulfate, 3% NaCl, 0.1% CaCl 2  · 2H 2 O, 1% glycine, 0.1% vitamin E, and 0.1% Tween-40 at pH 8.0 after 42 hr of incubation at 37°C. It was active over broad range of pH (7.0-12.0), temperature (15-100°C), and salinity (0-9% NaCl) with optima at pH 10.0, 55°C, and 3% NaCl. It retained 65 and 48% activities at pH 12.0 and 100°C, respectively. Partially purified protease was highly stable (100%) within pH range 7.0-12.0 and salinities of 0-5% NaCl for 48 hr. Cu 2+ , Mn 2+ , Co 2+ , and Ca 2+ did not inhibit its activity. Its stability at extreme pHs, temperatures, and in the presence of surfactants and commercial detergents suggests its possible application in laundry detergents. Partially purified protease was immobilized and reused. This is the first report of alkali-thermotolerant, surfactant-detergent-stable partially purified extracellular protease from A. caviae.

The puzzle of partial migration: Adaptive dynamics and evolutionary game theory perspectives.

PubMed

De Leenheer, Patrick; Mohapatra, Anushaya; Ohms, Haley A; Lytle, David A; Cushing, J M

2017-01-07

We consider the phenomenon of partial migration which is exhibited by populations in which some individuals migrate between habitats during their lifetime, but others do not. First, using an adaptive dynamics approach, we show that partial migration can be explained on the basis of negative density dependence in the per capita fertilities alone, provided that this density dependence is attenuated for increasing abundances of the subtypes that make up the population. We present an exact formula for the optimal proportion of migrants which is expressed in terms of the vital rates of migrant and non-migrant subtypes only. We show that this allocation strategy is both an evolutionary stable strategy (ESS) as well as a convergence stable strategy (CSS). To establish the former, we generalize the classical notion of an ESS because it is based on invasion exponents obtained from linearization arguments, which fail to capture the stabilizing effects of the nonlinear density dependence. These results clarify precisely when the notion of a "weak ESS", as proposed in Lundberg (2013) for a related model, is a genuine ESS. Secondly, we use an evolutionary game theory approach, and confirm, once again, that partial migration can be attributed to negative density dependence alone. In this context, the result holds even when density dependence is not attenuated. In this case, the optimal allocation strategy towards migrants is the same as the ESS stemming from the analysis based on the adaptive dynamics. The key feature of the population models considered here is that they are monotone dynamical systems, which enables a rather comprehensive mathematical analysis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Magnetar giant flares in multipolar magnetic fields. I. Fully and partially open eruptions of flux ropes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Lei; Yu, Cong, E-mail: muduri@shao.ac.cn, E-mail: cyu@ynao.ac.cn

2014-04-01

We propose a catastrophic eruption model for the enormous energy release of magnetars during giant flares, in which a toroidal and helically twisted flux rope is embedded within a force-free magnetosphere. The flux rope stays in stable equilibrium states initially and evolves quasi-statically. Upon the loss of equilibrium, the flux rope cannot sustain the stable equilibrium states and erupts catastrophically. During the process, the magnetic energy stored in the magnetosphere is rapidly released as the result of destabilization of global magnetic topology. The magnetospheric energy that could be accumulated is of vital importance for the outbursts of magnetars. We carefullymore » establish the fully open fields and partially open fields for various boundary conditions at the magnetar surface and study the relevant energy thresholds. By investigating the magnetic energy accumulated at the critical catastrophic point, we find that it is possible to drive fully open eruptions for dipole-dominated background fields. Nevertheless, it is hard to generate fully open magnetic eruptions for multipolar background fields. Given the observational importance of the multipolar magnetic fields in the vicinity of the magnetar surface, it would be worthwhile to explore the possibility of the alternative eruption approach in multipolar background fields. Fortunately, we find that flux ropes may give rise to partially open eruptions in the multipolar fields, which involve only partial opening of background fields. The energy release fractions are greater for cases with central-arcaded multipoles than those with central-caved multipoles that emerged in background fields. Eruptions would fail only when the centrally caved multipoles become extremely strong.« less

Deformation of interface in a partially miscible system during favorable displacement

NASA Astrophysics Data System (ADS)

Suzuki, Ryuta; Nagatsu, Yuichiro; Mishra, Manoranjan; Ban, Takahiko

2017-11-01

The Saffman-Taylor instability triggers a well-known viscous fingering (VF, called unfavorable displacement), occurring when a less viscous fluid displaces a more viscous one in porous media or in a Hele-Shaw cell because the boundary of the two fluids becomes hydrodynamically unstable. In the reverse situation (called favorable displacement) in which a more viscous fluid displaces a less viscous one, no instabilities occur due to hydrodynamically stable system. It has been reported that the favorable displacements become unstable by several physicochemical effects. So far, studies of both displacements have focused on fluids that are either fully miscible or immiscible. However, little attention has been paid to displacements in partially miscible system. Here, we have discovered that a partial miscibility triggers fingering instability in a favorable displacement without any chemical reactions. The occurrence of this new instability is induced by not hydrodynamic effects but a thermodynamic effect that is so-called Korteweg effect in which convection is induced during phase separation process in a partially miscible system.

Temozolomide is an active agent in children with recurrent medulloblastoma/primitive neuroectodermal tumor: an Italian multi-institutional phase II trial.

PubMed

Cefalo, Graziella; Massimino, Maura; Ruggiero, Antonio; Barone, Giuseppe; Ridola, Vita; Spreafico, Filippo; Potepan, Paolo; Abate, Massimo E; Mascarin, Maurizio; Garrè, Maria Luisa; Perilongo, Giorgio; Madon, Enrico; Colosimo, Cesare; Riccardi, Riccardo

2014-05-01

The aim of this study was to assess the objective response rate (ORR) of children and young adults with recurrent medulloblastoma/primitive neuroectodermal tumor (MB/PNET) treated with temozolomide (TMZ). The secondary purpose was to analyze the toxicity profile of TMZ when administered orally for 5 days in 3 divided daily doses every 28 days. Forty-two patients with recurrent MB/PNET, aged 21 years and younger, were recruited. Patients were treated with oral TMZ. Starting doses ranged from 120 to 200 mg/m(2)/day based on previous treatments. A craniospinal MRI was performed prior to the first cycle of TMZ and following every 2 cycles of treatment. Median age was 10 years (range, 2-21 years). Forty of 42 patients were assessed for response and toxicity. The objective response rate was 42.5%: 6 patients achieved a complete response, 11 had a partial response, and 10 had stable disease. Progression-free survival rates for all patients at 6 and 12 months were 30% and 7.5%, respectively. Their median overall survival rates at 6 and 12 months were 42.5% and 17.5%, respectively. No major extrahematological effects or life-threatening events were reported. The most common grade 3/4 toxicity included thrombocytopenia (17.5%), neutropenia (7.5%), and anemia (2.5%). TMZ proved to be an effective agent in children and young adults with MB/PNET, heavily pre-treated, with a tolerable toxicity profile.

Impaired consciousness in partial seizures is bimodally distributed

PubMed Central

Cunningham, Courtney; Chen, William C.; Shorten, Andrew; McClurkin, Michael; Choezom, Tenzin; Schmidt, Christian P.; Chu, Victoria; Bozik, Anne; Best, Cameron; Chapman, Melissa; Furman, Moran; Detyniecki, Kamil; Giacino, Joseph T.

2014-01-01

Objective: To investigate whether impaired consciousness in partial seizures can usually be attributed to specific deficits in the content of consciousness or to a more general decrease in the overall level of consciousness. Methods: Prospective testing during partial seizures was performed in patients with epilepsy using the Responsiveness in Epilepsy Scale (n = 83 partial seizures, 30 patients). Results were compared with responsiveness scores in a cohort of patients with severe traumatic brain injury evaluated with the JFK Coma Recovery Scale–Revised (n = 552 test administrations, 184 patients). Results: Standardized testing during partial seizures reveals a bimodal scoring distribution, such that most patients were either fully impaired or relatively spared in their ability to respond on multiple cognitive tests. Seizures with impaired performance on initial test items remained consistently impaired on subsequent items, while other seizures showed spared performance throughout. In the comparison group, we found that scores of patients with brain injury were more evenly distributed across the full range in severity of impairment. Conclusions: Partial seizures can often be cleanly separated into those with vs without overall impaired responsiveness. Results from similar testing in a comparison group of patients with brain injury suggest that the bimodal nature of Responsiveness in Epilepsy Scale scores is not a result of scale bias but may be a finding unique to partial seizures. These findings support a model in which seizures either propagate or do not propagate to key structures that regulate overall arousal and thalamocortical function. Future investigations are needed to relate these behavioral findings to the physiology underlying impaired consciousness in partial seizures. PMID:24727311

Impaired consciousness in partial seizures is bimodally distributed.

PubMed

Cunningham, Courtney; Chen, William C; Shorten, Andrew; McClurkin, Michael; Choezom, Tenzin; Schmidt, Christian P; Chu, Victoria; Bozik, Anne; Best, Cameron; Chapman, Melissa; Furman, Moran; Detyniecki, Kamil; Giacino, Joseph T; Blumenfeld, Hal

2014-05-13

To investigate whether impaired consciousness in partial seizures can usually be attributed to specific deficits in the content of consciousness or to a more general decrease in the overall level of consciousness. Prospective testing during partial seizures was performed in patients with epilepsy using the Responsiveness in Epilepsy Scale (n = 83 partial seizures, 30 patients). Results were compared with responsiveness scores in a cohort of patients with severe traumatic brain injury evaluated with the JFK Coma Recovery Scale-Revised (n = 552 test administrations, 184 patients). Standardized testing during partial seizures reveals a bimodal scoring distribution, such that most patients were either fully impaired or relatively spared in their ability to respond on multiple cognitive tests. Seizures with impaired performance on initial test items remained consistently impaired on subsequent items, while other seizures showed spared performance throughout. In the comparison group, we found that scores of patients with brain injury were more evenly distributed across the full range in severity of impairment. Partial seizures can often be cleanly separated into those with vs without overall impaired responsiveness. Results from similar testing in a comparison group of patients with brain injury suggest that the bimodal nature of Responsiveness in Epilepsy Scale scores is not a result of scale bias but may be a finding unique to partial seizures. These findings support a model in which seizures either propagate or do not propagate to key structures that regulate overall arousal and thalamocortical function. Future investigations are needed to relate these behavioral findings to the physiology underlying impaired consciousness in partial seizures.

Evolution of cooperation with shared costs and benefits

PubMed Central

Brown, Joel S; Vincent, Thomas L

2008-01-01

The quest to determine how cooperation evolves can be based on evolutionary game theory, in spite of the fact that evolutionarily stable strategies (ESS) for most non-zero-sum games are not cooperative. We analyse the evolution of cooperation for a family of evolutionary games involving shared costs and benefits with a continuum of strategies from non-cooperation to total cooperation. This cost–benefit game allows the cooperator to share in the benefit of a cooperative act, and the recipient to be burdened with a share of the cooperator's cost. The cost–benefit game encompasses the Prisoner's Dilemma, Snowdrift game and Partial Altruism. The models produce ESS solutions of total cooperation, partial cooperation, non-cooperation and coexistence between cooperation and non-cooperation. Cooperation emerges from an interplay between the nonlinearities in the cost and benefit functions. If benefits increase at a decelerating rate and costs increase at an accelerating rate with the degree of cooperation, then the ESS has an intermediate level of cooperation. The game also exhibits non-ESS points such as unstable minima, convergent-stable minima and unstable maxima. The emergence of cooperative behaviour in this game represents enlightened self-interest, whereas non-cooperative solutions illustrate the Tragedy of the Commons. Games having either a stable maximum or a stable minimum have the property that small changes in the incentive structure (model parameter values) or culture (starting frequencies of strategies) result in correspondingly small changes in the degree of cooperation. Conversely, with unstable maxima or unstable minima, small changes in the incentive structure or culture can result in a switch from non-cooperation to total cooperation (and vice versa). These solutions identify when human or animal societies have the potential for cooperation and whether cooperation is robust or fragile. PMID:18495622

When Can Information from Ordinal Scale Variables Be Integrated?

ERIC Educational Resources Information Center

Kemp, Simon; Grace, Randolph C.

2010-01-01

Many theoretical constructs of interest to psychologists are multidimensional and derive from the integration of several input variables. We show that input variables that are measured on ordinal scales cannot be combined to produce a stable weakly ordered output variable that allows trading off the input variables. Instead a partial order is…

Purification and partial characterization of an exo-polygalacturonase from Paecilomyces variotii liquid cultures.

PubMed

de Lima Damásio, Andre Ricardo; da Silva, Tony Márcio; Maller, Alexandre; Jorge, João Atílio; Terenzi, Hector Francisco; Polizeli, Maria de Lourdes Teixeira de Moraes

2010-03-01

An extracellular polygalacturonase (PG) produced from Paecilomyces variotii was purified to homogeneity through two chromatography steps using DEAE-Fractogel and Sephadex G-100. The molecular weight of P. variotii PG was 77,300 Da by gel filtration and SDS-PAGE. PG had isoelectric point of 4.37 and optimum pH 4.0. PG was very stable from pH 3.0 to 6.0. The extent of hydrolysis of different pectins by the purified enzyme was decreased with an increase in the degree of esterification. PG had no activity toward non-pectic polysaccharides. The apparent K(m) and V(max) values for hydrolyzing sodium polypectate were 1.84 mg/mL and 432 micromol/min/mg, respectively. PG was found to have temperature optimum at 65 degrees Celsius and was totally stable at 45 degrees Celsius for 90 min. Half-life at 55 degrees Celsius was 50.6 min. Almost all the examined metal cations showed partial inhibitory effects under enzymatic activity, except for Na(+1), K(+1), and Co(+2) (1 mM) and Cu(+2) (1 and 10 mM).

Thermoradiation therapy in combined modality treatment for locally advanced laryngeal and hypopharyngeal cancer

NASA Astrophysics Data System (ADS)

Choynzonov, E. L.; Startseva, Zh. A.; Gribova, O. V.; Mukhamedov, M. R.; Spivakova, I. O.

2017-09-01

The article presents the results of combined modality treatment for stage III-IV (T3N0-2M0) laryngeal and hypopharyngeal cancers. All patients (55) were divided into 2 groups. Group I patients (n = 25) received pre-operative thermoradiation therapy and Group II patients (n = 30) received pre-operative radiation therapy alone. The follow-up period was 6-24 months. In Group I patients, partial tumor regression was achieved in 21 (84%) patients and stable disease was observed in 4 (16%) patients. In group II patients, partial tumor regression and stable disease were diagnosed in 18 (60%) and 12 (49%) patients, respectively. Local and regional recurrences occurred in 1 patient (4%) of Group I within the first year of follow-up and in 11 patients of Group II (7 within the first year and 4 within two years of follow-up). The 2-year overall survival rate was 100% in Group I patients and 76.7% ± 10.1% in Group II patients. Disease-free survival rates were 96.6 ± 3.5% and 63.3 ± 13.9%, respectively.

Management of metastatic phaeochromocytoma and paraganglioma: use of iodine-131-meta-iodobenzylguanidine therapy in a tertiary referral centre.

PubMed

Rutherford, M A; Rankin, A J; Yates, T M; Mark, P B; Perry, C G; Reed, N S; Freel, E M

2015-05-01

Phaeochromocytoma (phaeo) and paraganglioma (PGL) are rare conditions, which are malignant in up to 30%. Optimal treatment is controversial, but in patients with metastatic iodine-131-meta-iodobenzylguanidine ((123)I-MIBG) avid tumours, we offer (131)I-MIBG therapy. We summarize response rates, survival and safety in a cohort of such patients treated with (131)I-MIBG in our centre from 1986 to 2012. Retrospective analysis of the case notes of patients with metastatic phaeo/PGL who received (131)I-MIBG was undertaken; patients underwent clinical, biochemical and radiological evaluation within 6 months of each course of (131)I-MIBG therapy. Twenty-two patients (9 males) were identified, 12 with metastatic PGL and 10 with phaeo. Overall median follow-up time after first dose of (131)I-MIBG was 53 months. In total, 68 doses of (131)I-MIBG were administered; average dose was 9967 MBq (269.4 mCi). After the first dose, >50% of patients demonstrated disease stability or partial response; progressive disease was seen in 9%. A subset of patients underwent repeated treatment with the majority demonstrating partial response or stable disease. No life-threatening adverse events were reported, but three patients developed hypothyroidism and two developed ovarian failure after repeated dosing. Five-year survival after original diagnosis was 68% and median (+inter quartile range) survival from date of diagnosis was 17 years (7.6-26.4) with no difference in survival according to diagnosis (P < 0.1). (131)I-MIBG is well tolerated and associates with disease stabilization or improvement in the majority of patients with metastatic phaeo/PGL. However, stronger conclusions on treatment effectiveness are limited by lack of a directly comparable 'control group' as well as an alternative 'gold standard' treatment. © The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors.

PubMed

Herbst, Roy S; Hong, David; Chap, Linnea; Kurzrock, Razelle; Jackson, Edward; Silverman, Jeffrey M; Rasmussen, Erik; Sun, Yu-Nien; Zhong, Don; Hwang, Yuying C; Evelhoch, Jeffrey L; Oliner, Jonathan D; Le, Ngocdiep; Rosen, Lee S

2009-07-20

PURPOSE AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors. PATIENTS AND METHODS Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg. Results Thirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum AMG 386 levels appeared to reach steady-state after four weekly doses, and there was minimal accumulation. No anti-AMG 386 neutralizing antibodies were detected. Reductions in volume transfer constant (K(trans); measured by dynamic contrast-enhanced magnetic resonance imaging) were observed in 10 patients (13 lesions) 48 hours to 8 weeks after treatment. One patient with refractory ovarian cancer achieved a confirmed partial response (ie, 32.5% reduction by Response Evaluation Criteria in Solid Tumors) and withdrew from the study with a partial response after 156 weeks of treatment; four patients experienced stable disease for at least 16 weeks. CONCLUSION Weekly AMG 386 appeared well tolerated, and its safety profile appeared distinct from that of vascular endothelial growth factor-axis inhibitors. AMG 386 also appeared to impact tumor vascularity and showed antitumor activity in this patient population.

Comparison of RECIST version 1.0 and 1.1 in assessment of tumor response by computed tomography in advanced gastric cancer.

PubMed

Jang, Gil-Su; Kim, Min-Jeong; Ha, Hong-Il; Kim, Jung Han; Kim, Hyeong Su; Ju, Sung Bae; Zang, Dae Young

2013-12-01

Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.0 (RECIST 1.0) was proposed as a new guideline for evaluating tumor response and has been widely accepted as a standardized measure. With a number of issues being raised on RECIST 1.0, however, a revised RECIST guideline version 1.1 (RECIST 1.1) was proposed by the RECIST Working Group in 2009. This study was conducted to compare CT tumor response based on RECIST 1.1 vs. RECIST 1.0 in patients with advanced gastric cancer (AGC). We reviewed 61 AGC patients with measurable diseases by RECIST 1.0 who were enrolled in other clinical trials between 2008 and 2010. These patients were retrospectively re-analyzed to determine the concordance between the two response criteria using the κ statistic. The number and sum of tumor diameters of the target lesions by RECIST 1.1 were significantly lower than those by RECIST 1.0 (P<0.0001). However, there was excellent agreement in tumor response between RECIST 1.1 and RECIST 1.0 (κ=0.844). The overall response rates (ORRs) according to RECIST 1.0 and RECIST 1.1 were 32.7% (20/61) and 34.5% (20/58), respectively. One patient with partial response (PR) based on RECIST 1.0 was reclassified as stable disease (SD) by RECIST 1.1. Of two patients with SD by RECIST 1.0, one was downgraded to progressive disease and the other was upgraded to PR by RECIST 1.1. RECIST 1.1 provided almost perfect agreement with RECIST 1.0 in the CT assessment of tumor response of AGC.

Comparison of continuous versus categorical tumor measurement-based metrics to predict overall survival in cancer treatment trials.

PubMed

An, Ming-Wen; Mandrekar, Sumithra J; Branda, Megan E; Hillman, Shauna L; Adjei, Alex A; Pitot, Henry C; Goldberg, Richard M; Sargent, Daniel J

2011-10-15

The categorical definition of response assessed via the Response Evaluation Criteria in Solid Tumors has documented limitations. We sought to identify alternative metrics for tumor response that improve prediction of overall survival. Individual patient data from three North Central Cancer Treatment Group trials (N0026, n = 117; N9741, n = 1,109; and N9841, n = 332) were used. Continuous metrics of tumor size based on longitudinal tumor measurements were considered in addition to a trichotomized response [TriTR: response (complete or partial) vs. stable disease vs. progression). Cox proportional hazards models, adjusted for treatment arm and baseline tumor burden, were used to assess the impact of the metrics on subsequent overall survival, using a landmark analysis approach at 12, 16, and 24 weeks postbaseline. Model discrimination was evaluated by the concordance (c) index. The overall best response rates for the three trials were 26%, 45%, and 25%, respectively. Although nearly all metrics were statistically significantly associated with overall survival at the different landmark time points, the concordance indices (c-index) for the traditional response metrics ranged from 0.59 to 0.65; for the continuous metrics from 0.60 to 0.66; and for the TriTR metrics from 0.64 to 0.69. The c-indices for TriTR at 12 weeks were comparable with those at 16 and 24 weeks. Continuous tumor measurement-based metrics provided no predictive improvement over traditional response-based metrics or TriTR; TriTR had better predictive ability than best TriTR or confirmed response. If confirmed, TriTR represents a promising endpoint for future phase II trials. ©2011 AACR.

Portal vein thrombosis and arterioportal shunts: Effects on tumor response after chemoembolization of hepatocellular carcinoma

PubMed Central

Vogl, Thomas J; Nour-Eldin, Nour-Eldin; Emad-Eldin, Sally; Naguib, Nagy NN; Trojan, Joerg; Ackermann, Hans; Abdelaziz, Omar

2011-01-01

AIM: To evaluate the effect of portal vein thrombosis and arterioportal shunts on local tumor response in advanced cases of unresectable hepatocellular carcinoma treated by transarterial chemoembolization. METHODS: A retrospective study included 39 patients (mean age: 66.4 years, range: 45-79 years, SD: 7) with unresectable hepatocellular carcinoma (HCC) who were treated with repetitive transarterial chemoembolization (TACE) in the period between March 2006 and October 2009. The effect of portal vein thrombosis (PVT) (in 19 out of 39 patients), the presence of arterioportal shunt (APS) (in 7 out of 39), the underlying liver pathology, Child-Pugh score, initial tumor volume, number of tumors and tumor margin definition on imaging were correlated with the local tumor response after TACE. The initial and end therapy local tumor responses were evaluated according to the response evaluation criteria in solid tumors (RECIST) and magnetic resonance imaging volumetric measurements. RESULTS: The treatment protocols were well tolerated by all patients with no major complications. Local tumor response for all patients according to RECIST criteria were partial response in one patient (2.6%), stable disease in 34 patients (87.1%), and progressive disease in 4 patients (10.2%). The MR volumetric measurements showed that the PVT, APS, underlying liver pathology and tumor margin definition were statistically significant prognostic factors for the local tumor response (P = 0.018, P = 0.008, P = 0.034 and P = 0.001, respectively). The overall 6-, 12- and 18-mo survival rates from the initial TACE were 79.5%, 37.5% and 21%, respectively. CONCLUSION: TACE may be exploited safely for palliative tumor control in patients with advanced unresectable HCC; however, tumor response is significantly affected by the presence or absence of PVT and APS. PMID:21455325

Magmatism during the accretion of the late Archaean Dharwar Craton (South India): sanukitoids and related rocks in their geological context.

NASA Astrophysics Data System (ADS)

Moyen, J.-F.; Martin, H.; Jayananda, M.; Peucat, J.-J.

2003-04-01

The South Indian Dharwar Craton assembled during the late-Archaean (ca. 2.5 Ga). This event was associated with intense granite genesis and emplacement. Based on petrography and geochemistry, 4 main types of late Archaean granitoids were distinguished: (1) Anatectic granites (and diatexites), formed by partial melting of TTG gneisses; (2) Classical TTGs; (3) Sanukitoids, generated by interaction between slab melts (TTG) and mantle peridotite; (4) The high HFSE Closepet granite, interpreted as derived from partial melting of a mantle metasomatized by slab melts (TTG). While the 3 later groups all are interpreted as resulting from slab melt/mantle wedge interactions, their differences are related to decreasing felsic melt/peridotite ratios during the ascent “slab melts” in the mantle wedge above an active subduction zone. Field data together with geochronology and isotope geochemistry allow to subdivide the Dharwar craton into three main domains: (1) The Western Dharwar Craton (WDC) is an old (3.3 2.9 Ga ), stable continental block with limited amounts of 2.5 Ga old anatectic granites. (2) The Eastern Dharwar Craton (EDC) is subdivided into two parts: (2a) West of Kolar Schist Belt, a region of 3.0-2.7 Ga old basement intruded by 2.5 Ga old anatectic granites; (2b) East of Kolar, an area featuring mainly 2.5 Ga old diatexites and granites, derived of partial melting of a newly accreted TTG crust. Anatectic granites are ubiquitous, and late in the cratonic evolution; they witnessed generalized melting of a juvenile crust. In contrast, deep-originated granites emplaced before this melting and are restricted to the boundaries between the blocks. This structure of distinct terranes separated by narrow bands operating as channels for deep-originated magmas provides independent evidences for a two-stage evolution: an arc accretion context for the TTG, sanukitoids and related rocks, immediately followed by high temperature reworking of the newly accreted craton, yielding diatexites and anatectic granites. From West to East, granitoids emplaced during the subduction stage evidence increasing slab-melt/peridotite interactions, from Closepet granite to TTG gneisses East of Kolar. These features are consistent with a model of westward subduction/accretion against a stable cratonic nucleus: partial melting along the subducting slab takes place at deeper and deeper levels from East to West, thus resulting in increasing melt/mantle interactions. Sanukitoids and Closepet type granites thus appear to be related to slab melt/mantle wedge interactions similar to those responsible for the secular evolution of TTG (Martin and Moyen, this session), but with still lower melt/peridotite ratios.

Effect of systemic nitric oxide synthase inhibition on optic disc oxygen partial pressure in normoxia and in hypercapnia.

PubMed

Petropoulos, Ioannis K; Pournaras, Jean-Antoine C; Stangos, Alexandros N; Pournaras, Constantin J

2009-01-01

To investigate the effect of systemic nitric oxide synthase (NOS) inhibition on optic disc oxygen partial pressure (PO(2)) in normoxia and hypercapnia. Intervascular optic disc PO(2) was measured in 12 anesthetized minipigs by using oxygen-sensitive microelectrodes placed <50 microm from the optic disc. PO(2) was measured continuously during 10 minutes under normoxia, hyperoxia (100% O(2)), carbogen breathing (95% O(2), 5% CO(2)), and hypercapnia (increased inhaled CO(2)). Measurements were repeated after intravenous injection of N(omega)-nitro-L-arginine methyl ester (L-NAME) 100 mg/kg. Intravenous L-arginine 100 mg/kg was subsequently given to three animals. Before L-NAME injection, an increase was observed in optic disc PO(2) during hypercapnia (DeltaPO(2) = 3.2 +/- 1.7 mm Hg; 18%; P = 0.001) and carbogen breathing (DeltaPO(2) = 12.8 +/- 5.1 mm Hg; 69%; P < 0.001). Optic disc PO(2) in normoxia remained stable for 30 minutes after L-NAME injection (4% decrease from baseline; P > 0.1), despite a 21% increase of mean arterial pressure. Optic disc PO(2) increase under hypercapnia was blunted after L-NAME injection (DeltaPO(2) = 0.6 +/- 1.1 mm Hg; 3%; P > 0.1), and this effect was reversible by L-arginine. Moreover, L-NAME reduced the response to carbogen by 29% (DeltaPO(2) = 9.1 +/- 4.4 mm Hg; 49%; P = 0.01 versus before L-NAME). The response to hyperoxia was not affected. Whereas systemic NOS inhibition did not affect optic disc PO(2) in normoxia, a blunting effect was noted on the CO(2)-induced optic disc PO(2) increase. Nitric oxide appears to mediate the hypercapnic optic disc PO(2) increase.

Gemcitabine in combination with EGF-Receptor antibody (Cetuximab) as a treatment of cholangiocarcinoma: a case report

PubMed Central

Sprinzl, Martin F; Schimanski, Carl C; Moehler, Markus; Schadmand-Fischer, Simin; Galle, Peter R; Kanzler, Stephan

2006-01-01

Background Extensive disease of cholangiocarcinoma (CC) determines the overall outcome and limits curative resection. Despite chemotherapy, which has been introduced to improve the outcome of biliary tract malignancies, the benefit in survival is still marginal. Case presentation We report a 69-year-old patient with non-resectable CC showing hepatic metastasis and peritoneal carcinomatosis. Diagnosis was based on computed tomography, mini-laparoscopy and bioptic specimens. Histology revealed an adenocarcinoma of the biliary tract with expression of epithelial growth factor receptor. After informed consent the patient received experimental gemcitabine (1000 mg/m2) every other week and cetuximab (250 mg/m2) weekly for palliative chemotherapy. During the reported follow up (since time of first presentation) 20 cycles of chemotherapy were administered. Relevant chemotherapy-related toxicity was limited on gemcitabine-associated side effects. Predominantly, haematological toxicity (CTC, grade 3) and neutropenic fever (CTC, grade 3) promoted by catheter-related sepsis were observed. Cetuximab caused only mild skin toxicity (CTC, grade 1). Chemotherapy led to a partial response (> 30% reduction, according to RECIST) of the target lesions and disappearance of the peritoneal carcinomatosis as shown by computed tomography. Partial response occurred after 17 weeks of treatment and remained stable during the entire course of chemotherapy for 9.7 months. In parallel, Ca 19-9 serum levels, which were elevated 5-fold at time of diagnosis, returned to normal after 16 weeks of treatment. The performance status stabilized and intravenous alimentation could be discontinued. Conclusion Our experience from one patient with CC suggests, that a combination of cytotoxic chemotherapy together with cetuximab may show promising efficacy in respect to survival and quality of life. Therefore cetuximab, as a component of palliative chemotherapy in biliary tract cancer, needs further evaluation in prospective randomized trials. PMID:16846514

Pharmacokinetics and tolerability of human mouse chimeric anti-CD22 monoclonal antibody in Chinese patients with CD22-positive non-Hodgkin lymphoma.

PubMed

Li, Su; Zhang, Dongsheng; Sun, Jian; Li, Zhinming; Deng, Liting; Zou, Benyan; Zhan, Jing; Jiang, Wenqi

2012-01-01

The safety and pharmacokinetics assessment of antibodies targeting CD22 (e.g., epratuzumab) have been established in western Caucasian populations, but there are no reports of the effects in Chinese populations. This dose-escalation study examines the safety, pharmacokinetics and biologic effects of multiple doses of anti-CD22 human-murine chimeric monoclonal antibody SM03 in 21 Chinese patients with CD22-positive non-Hodgkin lymphoma. Most of drug-related adverse events (AEs) were mild and reversible. Two patients experienced serious AEs (hemorrhage); one patient had grade 4 neutropenia; one patient had asymptomatic grade III prolongation of activated partial thromboplastin time (APTT). Major AEs included fever (71%), prolongation of APTT (42.8%), leukocytopenia (44.4%), alanine transaminase elevation (28.6%), elevated serum creatinine (23.8%) and injection site skin redness (14.3%). Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. Pharmacokinetic data revealed that mean maximum observed SM03 concentration and mean AUC from time zero to infinity increased in a dose-dependent manner up to 360 mg/m (2) SM03. Mean clearance was similar at doses ≤ 360 mg/m (2) and decreased significantly at dose 480 mg/m (2), supporting saturation of B-cell binding at 360 mg/m (2). Across all dose levels and histologies, one patient achieved partial response at 480 mg/m (2) dose; 14 patients had stable disease as best response and four patients progressed. Overall, SM03 was tolerated at doses ranging from 60-480 mg/m (2) and had potential efficacy in Chinese patients with follicular lymphoma.

A phase I trial of the novel farnesyl protein transferase inhibitor, BMS-214662, in combination with paclitaxel and carboplatin in patients with advanced cancer.

PubMed

Dy, Grace K; Bruzek, Laura M; Croghan, Gary A; Mandrekar, Sumithra; Erlichman, Charles; Peethambaram, Prema; Pitot, Henry C; Hanson, Lorelei J; Reid, Joel M; Furth, Alfred; Cheng, Shinta; Martell, Robert E; Kaufmann, Scott H; Adjei, Alex A

2005-03-01

This phase I study was conducted to determine the toxicities, pharmacokinetics, and pharmacodynamics of BMS-214662, a farnesyl transferase inhibitor, in combination with paclitaxel and carboplatin, in patients with advanced solid tumors. Patients with solid tumors received one of six escalating dose levels of BMS-214662 infused over 1 hour given following paclitaxel and carboplatin on the first day of a 21-day cycle. Toxicities were graded by the National Cancer Institute common toxicity criteria and recorded as maximum grade per patient for each treatment cycle. Inhibition of farnesyl transferase activity in peripheral blood mononuclear cells (PBMCs) was evaluated. Accumulation of unfarnesylated HDJ-2 in PBMCs of patients was evaluated as a marker of farnesyl transferase inhibition by BMS-214662. Thirty patients received 141 cycles of treatment through six dose levels. Dose-limiting toxicities were neutropenia, thrombocytopenia, nausea, and vomiting. There was no pharmacokinetic interaction between BMS-214662 and paclitaxel. The maximum tolerated dose was established as BMS-214662 (160 mg/m(2)), paclitaxel (225 mg/m(2)) and carboplatin (area under the curve = 6 on day 1), every 21 days. Inhibition of HDJ-2 farnesylation in PBMCs of patients was shown. One measurable partial response was observed in a patient with taxane-resistant esophageal cancer. There was partial regression of evaluable disease in two other patients (endometrial and ovarian cancer). Stable disease (> 4 cycles) occurred in eight other patients. The combination of BMS-214662 with paclitaxel and carboplatin was well tolerated, with broad activity in solid tumors. There was no correlation between dose level and accumulation of unfarnesylated HDJ-2 in PBMCs nor tumor response.

A Comparison of Graded Response and Rasch Partial Credit Models with Subjective Well-Being.

ERIC Educational Resources Information Center

Baker, John G.; Rounds, James B.; Zevon, Michael A.

2000-01-01

Compared two multiple category item response theory models using a data set of 52 mood terms with 713 undergraduate psychology students. Comparative model fit for the Samejima (F. Samejima, 1966) logistic model for graded responses and the Masters (G. Masters, 1982) partial credit model favored the former model for this data set. (SLD)

Partially Testing a Process Model for Understanding Victim Responses to an Anticipated Worksite Closure

ERIC Educational Resources Information Center

Blau, Gary

2007-01-01

This study partially tested a recent process model for understanding victim responses to worksite/function closure (W/FC) proposed by Blau [Blau, G. (2006). A process model for understanding victim responses to worksite/function closure. "Human Resource Management Review," 16, 12-28], in a pharmaceutical manufacturing site. Central to the model…

Effect of Preexercise Ingestion of Modified Amylomaize Starch on Glycemic Response While Cycling.

PubMed

Parks, Rachel B; Angus, Hector F; King, Douglas S; Sharp, Rick L

2018-01-01

Amylomaize-7 is classified as a resistant corn starch and is 68% digestible. When modified by partial hydrolysis in ethanol and hydrochloric acid its digestibility is 92%, yet retains its low glycemic and insulinemic properties. The purpose of this study was to characterize the metabolic response when modified amylomaize-7 or dextrose is consumed in the hour before exercise, and to compare the effect on performance of a brief high-intensity cycling trial. Ten male, trained cyclists were given 1 g/kg body mass of dextrose (DEX) or modified amylomaize-7 (AMY-7) or a flavored water placebo (PL) 45 min prior to exercise on a cycle ergometer. A 15-min ride at 60% W max was immediately followed by a self-paced time trial (TT) equivalent to 15 min at 80% W max . When cyclists consumed DEX, mean serum glucose concentration increased by 3.3 ± 2.1 mmol/L before exercise, compared to stable serum glucose observed for AMY-7 or PL. Glucose concentrations returned to baseline by pre-TT in all treatments. However, the mean post-TT glucose concentration of the DEX group was significantly lower than baseline, AMY-7, or PL. Serum insulin concentration increased nine-fold from baseline to preexercise in the DEX trial, whereas PL or AMY-7 remained unchanged. Time required to complete the performance trial was not significantly different between DEX, AMY-7 or PL. Preexercise ingestion of modified amylomaize-7 compared to dextrose resulted in a more stable serum glucose concentration, but did not offer a performance advantage in this high-intensity cycling trial.

Feasibility Trial of Letrozole in Combination With Bevacizumab in Patients With Metastatic Breast Cancer

PubMed Central

Traina, Tiffany A.; Rugo, Hope S.; Caravelli, James F.; Patil, Sujata; Yeh, Benjamin; Melisko, Michele E.; Park, John W.; Geneus, Stephanie; Paulson, Matthew; Grothusen, Jill; Seidman, Andrew D.; Fornier, Monica; Lake, Diana; Dang, Chau; Robson, Mark; Theodoulou, Maria; Flombaum, Carlos D.; Norton, Larry; Hudis, Clifford A.; Dickler, Maura N.

2010-01-01

Purpose Preclinical models suggest that the use of anti–vascular endothelial growth factor (anti-VEGF) therapy with antiestrogens may prevent or delay the development of endocrine therapy resistance. We therefore performed a feasibility study to evaluate the safety of letrozole plus bevacizumab in patients with hormone receptor–positive metastatic breast cancer (MBC). Methods Patients with locally advanced breast cancer or MBC were treated with the aromatase inhibitor (AI) letrozole (2.5 mg orally daily) and the anti-VEGF antibody bevacizumab (15 mg/kg intravenously every 3 weeks). The primary end point was safety, defined by grade 4 toxicity using the National Cancer Institute Common Toxicity Criteria, version 3.0. Secondary end points included response rate, clinical benefit rate, and progression-free survival (PFS). Prior nonsteroidal AIs (NSAIs) were permitted in the absence of progressive disease. Results Forty-three patients were treated. After a median of 13 cycles (range, 1 to 71 cycles), select treatment-related toxicities included hypertension (58%; grades 2 and 3 in 19% and 26%), proteinuria (67%; grades 2 and 3 in 14% and 19%), headache (51%; grades 2 and 3 in 16% and 7%), fatigue (74%; grades 2 and 3 in 19% and 2%), and joint pain (63%; grades 2 and 3 in 19% and 0%). Eighty-four percent of patients had at least stable disease on an NSAI, confounding efficacy results. Partial responses were seen in 9% of patients and stable disease ≥ 24 weeks was noted in 67%. Median PFS was 17.1 months. Conclusion Combination letrozole and bevacizumab was feasible with expected bevacizumab-related events of hypertension, headache, and proteinuria. Phase III proof-of-efficacy trials of endocrine therapy plus bevacizumab are in progress (Cancer and Leukemia Group B 40503). PMID:19841327

Feasibility trial of letrozole in combination with bevacizumab in patients with metastatic breast cancer.

PubMed

Traina, Tiffany A; Rugo, Hope S; Caravelli, James F; Patil, Sujata; Yeh, Benjamin; Melisko, Michele E; Park, John W; Geneus, Stephanie; Paulson, Matthew; Grothusen, Jill; Seidman, Andrew D; Fornier, Monica; Lake, Diana; Dang, Chau; Robson, Mark; Theodoulou, Maria; Flombaum, Carlos D; Norton, Larry; Hudis, Clifford A; Dickler, Maura N

2010-02-01

Preclinical models suggest that the use of anti-vascular endothelial growth factor (anti-VEGF) therapy with antiestrogens may prevent or delay the development of endocrine therapy resistance. We therefore performed a feasibility study to evaluate the safety of letrozole plus bevacizumab in patients with hormone receptor-positive metastatic breast cancer (MBC). Patients with locally advanced breast cancer or MBC were treated with the aromatase inhibitor (AI) letrozole (2.5 mg orally daily) and the anti-VEGF antibody bevacizumab (15 mg/kg intravenously every 3 weeks). The primary end point was safety, defined by grade 4 toxicity using the National Cancer Institute Common Toxicity Criteria, version 3.0. Secondary end points included response rate, clinical benefit rate, and progression-free survival (PFS). Prior nonsteroidal AIs (NSAIs) were permitted in the absence of progressive disease. Forty-three patients were treated. After a median of 13 cycles (range, 1 to 71 cycles), select treatment-related toxicities included hypertension (58%; grades 2 and 3 in 19% and 26%), proteinuria (67%; grades 2 and 3 in 14% and 19%), headache (51%; grades 2 and 3 in 16% and 7%), fatigue (74%; grades 2 and 3 in 19% and 2%), and joint pain (63%; grades 2 and 3 in 19% and 0%). Eighty-four percent of patients had at least stable disease on an NSAI, confounding efficacy results. Partial responses were seen in 9% of patients and stable disease >or= 24 weeks was noted in 67%. Median PFS was 17.1 months. Combination letrozole and bevacizumab was feasible with expected bevacizumab-related events of hypertension, headache, and proteinuria. Phase III proof-of-efficacy trials of endocrine therapy plus bevacizumab are in progress (Cancer and Leukemia Group B 40503).

A phase II trial with anti-Lewis-Y monoclonal antibody (hu3S193) for the treatment of platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma.

PubMed

Smaletz, Oren; Diz, Maria D P E; do Carmo, Claudio C; Sabbaga, Jorge; Cunha-Junior, Geraldo F; Azevedo, Sergio J; Maluf, Fernando C; Barrios, Carlos H; Costa, Ronaldo L; Fontana, Ana G; Madrigal, Vivian; Wainstein, Alberto J; Yeda, Fernanda P; Alves, Venâncio A; Moro, Ana M; Blasbalg, Roberto; Scott, Andrew M; Hoffman, Eric W

2015-08-01

The primary objective was to evaluate the clinical efficacy of hu3S193, a humanized monoclonal antibody against the Lewis-Y antigen, in patients with platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma. Secondary objectives were safety and pharmacokinetics. In addition, we sought to determine the potential interaction of clinical benefit and patient characteristics. This two-stage, multicenter, single arm, phase II trial enrolled eligible patients to receive hu3S193 weekly at a dose of 20mg/m(2) intravenously for 8 weeks (1 cycle) to a maximum of 3 cycles. Efficacy was measured as clinical benefit rate (objective response or stable disease for at least 24 weeks). 26 of 31 patients were eligible for efficacy analysis. No complete/partial responses were observed. Six patients had stable disease for 24+weeks [clinical benefit rate 23% (95% CI=9.77%-46.71%)]. Median PFS was 8.4 weeks (95% CI=6.0 to 16.1). Median PFS differed between patients with no ascites and no visceral disease and patients with ascites and/or visceral disease [16.1 vs. 8.1 weeks (p=0.0058)]. The most commonly reported treatment-related adverse events were fatigue (19.3%) and nausea (16.2%). Allergic reactions occurred in 6 patients (5 with Grade 1/2; 1 with Grade 3). Hu3S193 lacked sufficient activity in the first stage of the study to open enrollment to the second stage. However, based on the longer PFS in patients with no ascites and no visceral disease, consolidation strategies in platinum sensitive disease are currently being tested. Copyright © 2015 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Favorite, Jeffrey A.

In transport theory, adjoint-based partial derivatives with respect to mass density are constant-volume derivatives. Likewise, adjoint-based partial derivatives with respect to surface locations (i.e., internal interface locations and the outer system boundary) are constant-density derivatives. This study derives the constant-mass partial derivative of a response with respect to an internal interface location or the outer system boundary and the constant-mass partial derivative of a response with respect to the mass density of a region. Numerical results are given for a multiregion two-dimensional (r-z) cylinder for three very different responses: the uncollided gamma-ray flux at an external detector point, k effmore » of the system, and the total neutron leakage. Finally, results from the derived formulas compare extremely well with direct perturbation calculations.« less

Thin film devices used as oxygen partial pressure sensors

NASA Technical Reports Server (NTRS)

Canady, K. S.; Wortman, J. J.

1970-01-01

Electrical conductivity of zinc oxide films to be used in an oxygen partial pressure sensor is measured as a function of temperature, oxygen partial pressure, and other atmospheric constituents. Time response following partial pressure changes is studied as a function of temperature and environmental changes.

Source Attribution of Cyanides Using Anionic Impurity Profiling, Stable Isotope Ratios, Trace Elemental Analysis and Chemometrics.

PubMed

Mirjankar, Nikhil S; Fraga, Carlos G; Carman, April J; Moran, James J

2016-02-02

Chemical attribution signatures (CAS) for chemical threat agents (CTAs), such as cyanides, are being investigated to provide an evidentiary link between CTAs and specific sources to support criminal investigations and prosecutions. Herein, stocks of KCN and NaCN were analyzed for trace anions by high performance ion chromatography (HPIC), carbon stable isotope ratio (δ(13)C) by isotope ratio mass spectrometry (IRMS), and trace elements by inductively coupled plasma optical emission spectroscopy (ICP-OES). The collected analytical data were evaluated using hierarchical cluster analysis (HCA), Fisher-ratio (F-ratio), interval partial least-squares (iPLS), genetic algorithm-based partial least-squares (GAPLS), partial least-squares discriminant analysis (PLSDA), K nearest neighbors (KNN), and support vector machines discriminant analysis (SVMDA). HCA of anion impurity profiles from multiple cyanide stocks from six reported countries of origin resulted in cyanide samples clustering into three groups, independent of the associated alkali metal (K or Na). The three groups were independently corroborated by HCA of cyanide elemental profiles and corresponded to countries each having one known solid cyanide factory: Czech Republic, Germany, and United States. Carbon stable isotope measurements resulted in two clusters: Germany and United States (the single Czech stock grouped with United States stocks). Classification errors for two validation studies using anion impurity profiles collected over five years on different instruments were as low as zero for KNN and SVMDA, demonstrating the excellent reliability associated with using anion impurities for matching a cyanide sample to its factory using our current cyanide stocks. Variable selection methods reduced errors for those classification methods having errors greater than zero; iPLS-forward selection and F-ratio typically provided the lowest errors. Finally, using anion profiles to classify cyanides to a specific stock or stock group for a subset of United States stocks resulted in cross-validation errors ranging from 0 to 5.3%.

Chaperonin-based biolayer interferometry to assess the kinetic stability of metastable, aggregation-prone proteins

PubMed Central

Lea, Wendy A.; Naik, Subhashchandra; Chaudhri, Tapan; Machen, Alexandra J.; O’Neil, Pierce T.; McGinn-Straub, Wesley; Tischer, Alexander; Auton, Matthew T.; Burns, Joshua R.; Baldwin, Michael R.; Khar, Karen R.; Karanicolas, John; Fisher, Mark T.

2017-01-01

Stabilizing the folded state of metastable and/or aggregation-prone proteins through exogenous ligand binding is an appealing strategy to decrease disease pathologies brought on by protein folding defects or deleterious kinetic transitions. Current methods of examining ligand binding to these marginally stable native states are limited, because protein aggregation typically interferes with analysis. Here, we describe a rapid method for assessing the kinetic stability of folded proteins and monitoring the effects of ligand stabilization for both intrinsically stable proteins (monomers, oligomers, multi-domain) and metastable proteins (e.g. low Tm) that uses a new GroEL chaperonin-based biolayer interferometry (BLI) denaturant-pulse platform. A kinetically controlled denaturation isotherm is generated by exposing a target protein immobilized on a BLI biosensor to increasing denaturant concentrations (urea or GnHCl) in a pulsatile manner to induce partial or complete unfolding of the attached protein population. Following the rapid removal of the denaturant, the extent of hydrophobic unfolded/partially folded species that remain is detected by increased GroEL binding. Since this kinetic denaturant pulse is brief, the amplitude of the GroEL binding to the immobilized protein depends on the duration of exposure to denaturant, the concentration of denaturant, wash times, and the underlying protein unfolding/refolding kinetics; fixing all other parameters and plotting GroEL binding amplitude versus denaturant pulse concentration results in a kinetically controlled denaturation isotherm. When folding osmolytes or stabilizing ligands are added to the immobilized target proteins before and during the denaturant pulse, the diminished population of unfolded/partially folded protein is manifested by a decreased GroEL binding and/or a marked shift in these kinetically controlled denaturation profiles to higher denaturant concentrations. This particular platform approach can be used to identify small molecules/solution conditions that can stabilize or destabilize thermally stable proteins, multi-domain proteins, oligomeric proteins, and most importantly, aggregation prone metastable proteins. PMID:27505032

The effects of magmatic processes and crustal recycling on the molybdenum stable isotopic composition of Mid-Ocean Ridge Basalts

NASA Astrophysics Data System (ADS)

Bezard, Rachel; Fischer-Gödde, Mario; Hamelin, Cédric; Brennecka, Gregory A.; Kleine, Thorsten

2016-11-01

Molybdenum (Mo) stable isotopes hold great potential to investigate the processes involved in planetary formation and differentiation. However their use is currently hampered by the lack of understanding of the dominant controls driving mass-dependent fractionations at high temperature. Here we investigate the role of magmatic processes and mantle source heterogeneities on the Mo isotope composition of Mid-Ocean Ridges Basalts (MORBs) using samples from two contrasting ridge segments: (1) the extremely fast spreading Pacific-Antarctic (66-41°S) section devoid of plume influence and; (2) the slow spreading Mohns-Knipovich segment (77-71°N) intercepted by the Jan Mayen Plume (71°N). We show that significant variations in Mo stable isotope composition exist in MORBs with δ98/95Mo ranging from - 0.24 ‰ to + 0.15 ‰ (relative to NIST SRM3134). The absence of correlation between δ98/95Mo and indices of magma differentiation or partial melting suggests a negligible impact of these processes on the isotopic variations observed. On the other hand, the δ98/95Mo variations seem to be associated with changes in radiogenic isotope signatures and rare earth element ratios (e.g., (La/Sm)N), suggesting mantle source heterogeneities as a dominant factor for the δ98/95Mo variations amongst MORBs. The heaviest Mo isotope compositions correspond to the most enriched signatures, suggesting that recycled crustal components are isotopically heavy compared to the uncontaminated depleted mantle. The uncontaminated depleted mantle shows slightly sub-chondritic δ98/95Mo, which cannot be produced by core formation and, therefore, more likely result from extensive anterior partial melting of the mantle. Consequently, the primitive δ98/95Mo composition of the depleted mantle appears overprinted by the effects of both partial melting and crustal recycling.

Treatment of resistant glomerular diseases with adrenocorticotropic hormone gel: a prospective trial.

PubMed

Bomback, Andrew S; Canetta, Pietro A; Beck, Laurence H; Ayalon, Rivka; Radhakrishnan, Jai; Appel, Gerald B

2012-01-01

Adrenocorticotropic hormone (ACTH) has shown promising results in glomerular diseases resistant to conventional therapies, but the reported data have solely been from retrospective, observational studies. In this prospective, open-label study (NCT01129284), 15 subjects with resistant glomerular diseases were treated with ACTH gel (80 units subcutaneously twice weekly) for 6 months. Resistant membranous nephropathy (MN), minimal change disease (MCD), and focal segmental glomerulosclerosis (FSGS) were defined as failure to achieve sustained remission of proteinuria off immunosuppressive therapy with at least 2 treatment regimens; resistant IgA nephropathy was defined as >1 g/g urine protein:creatinine ratio despite maximally tolerated RAAS blockade. Remission was defined as stable or improved renal function with ≥50% reduction in proteinuria to <0.5 g/g (complete remission) or 0.5-3.5 g/g (partial remission). The study included 5 subjects with resistant idiopathic MN, 5 subjects with resistant MCD (n = 2)/FSGS (n = 3), and 5 subjects with resistant IgA nephropathy. Two resistant MN subjects achieved partial remission on ACTH therapy, although 3 achieved immunologic remission of disease (PLA(2)R antibody disappeared by 4 months of therapy). One subject with resistant FSGS achieved complete remission on ACTH; one subject with resistant MCD achieved partial remission but relapsed within 4 weeks of stopping ACTH. Two subjects with resistant IgA nephropathy demonstrated >50% reductions in proteinuria while on ACTH, with proteinuria consistently <1 g/g by 6 months. Three of 15 subjects reported significant steroid-like adverse effects with ACTH, including weight gain and hyperglycemia, prompting early termination of therapy without any clinical response. ACTH gel is a promising treatment for resistant glomerular diseases and should be studied further in controlled trials against currently available therapies for resistant disease. Copyright © 2012 S. Karger AG, Basel.

Microstructure and Phase Stability of Single Crystal NiAl Alloyed with Hf and Zr

NASA Technical Reports Server (NTRS)

Locci, I. E.; Dickerson, R. M.; Garg, A.; Noebe, R. D.; Whittenberger, J. D.; Nathal, M. V.; Darolia, R.

1996-01-01

Six near stoichiometric, NiAl single-crystal alloys, with 0.05-1.5 at.% of Hf and Zr additions plus Si impurities, were microstructurally analyzed in the as-cast, homogenized, and aged conditions. Hafnium-rich interdendritic regions, containing the Heusler phase (Ni2AlHf), were found in all the as-cast alloys containing Hf. Homogenization heat treatments partially reduced these interdendritic segregated regions. Transmission electron microscopy (TEM) observations of the as-cast and homogenized microstructures revealed the presence of a high density of fine Hf (or Zr) and Si-rich precipitates. These were identified as G-phase, Nil6X6Si7, or as an orthorhombic NiXSi phase, where X is Hf or Zr. Under these conditions the expected Heusler phase (beta') was almost completely absent. The Si responsible for the formation of the G and NiHfSi phases is the result of molten metal reacting with the Si-containing crucible used during the casting process. Varying the cooling rates after homogenization resulted in the refinement or complete suppression of the G and NiHfSi phases. In some of the alloys studied, long-term aging heat treatments resulted in the formation of Heusler precipitates, which were more stable at the aging temperature and coarsened at the expense of the G-phase. In other alloys, long-term aging resulted in the formation of the NiXSi phase. The stability of the Heusler or NiXSi phases can be traced to the reactive element (Hf or Zr) to silicon ratio. If the ratio is high, then the Heusler phase appears stable after long time aging. If the ratio is low, then the NiHfSi phase appears to be the stable phase.

Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma.

PubMed

Quinn, Jennifer A; Pluda, James; Dolan, M Eileen; Delaney, Shannon; Kaplan, Richard; Rich, Jeremy N; Friedman, Allan H; Reardon, David A; Sampson, John H; Colvin, O Michael; Haglund, Michael M; Pegg, Anthony E; Moschel, Robert C; McLendon, Roger E; Provenzale, James M; Gururangan, Sridharan; Tourt-Uhlig, Sandra; Herndon, James E; Bigner, Darell D; Friedman, Henry S

2002-05-01

We conducted a phase II trial of carmustine (BCNU) plus the O(6)-alkylguanine-DNA alkyltransferase inhibitor O(6)-benzylguanine (O(6)-BG) to define the activity and toxicity of this regimen in the treatment of adults with progressive or recurrent malignant glioma resistant to nitrosoureas. Patients were treated with O(6)-BG at an intravenous dose of 120 mg/m(2) followed 1 hour later by 40 mg/m(2) of BCNU, with cycles repeated at 6-week intervals. Eighteen patients were treated (15 with glioblastoma multiforme, two with anaplastic astrocytoma, and one with malignant glioma). None of the 18 patients demonstrated a partial or complete response. Two patients exhibited stable disease for 12 weeks before their tumors progressed. Three patients demonstrated stable disease for 6, 12, and 18 weeks before discontinuing therapy because of hematopoietic toxicity. Twelve patients experienced reversible > or = grade 3 hematopoietic toxicity. There was no difference in half-lives (0.56 +/- 0.21 hour v 0.54 +/- 0.20 hour) or area under the curve values (4.8 +/- 1.7 microg/mL/h v 5.0 +/- 1.3 microg/mL/h) of O(6)-BG for patients receiving phenytoin and those not treated with this drug. These results indicate that O(6)-BG plus BCNU at the dose schedule used in this trial is unsuccessful in producing tumor regression in patients with nitrosourea-resistant malignant glioma, although stable disease was seen in five patients for 6, 12, 12, 12, and 18 weeks. Future use of this approach will require strategies to minimize dose-limiting toxicity of BCNU such as regional delivery or hematopoietic stem-cell protection.

Density functional theory study of ethylene partial oxidation on Ag 7 clusters

NASA Astrophysics Data System (ADS)

Yu, Hua-Gen

2006-11-01

The partial oxidation reaction of ethylene on neutral and anionic Ag 7 clusters has been studied using the BPW91 hybrid DFT method with the Stuttgart RSC97 relativistic pseudopotential for the 28-electron ionic core of Ag. The atomic oxygen reaction mechanism is mainly addressed. Results show that the reaction occurs via a stable oxametallacycle intermediate ( AgOCH4p, p = 0 or -1), but it involves small reaction barriers along the reaction path. The ZPE-corrected barrier heights are obtained as 0.7-6.5 kcal/mole. In addition, the structure and anionic effects of Ag 7 clusters are also discussed.

Monoclonal Antibodies against the MET/HGF Receptor and Its Ligand: Multitask Tools with Applications from Basic Research to Therapy

PubMed Central

Prat, Maria; Oltolina, Francesca; Basilico, Cristina

2014-01-01

Monoclonal antibodies can be seen as valuable tools for many aspects of basic as well as applied sciences. In the case of MET/HGFR, they allowed the identification of truncated isoforms of the receptor, as well as the dissection of different epitopes, establishing structure–function relationships. Antibodies directed against MET extracellular domain were found to be full or partial receptor agonists or antagonists. The agonists can mimic the effects of the different isoforms of the natural ligand, but with the advantage of being more stable than the latter. Thus, some agonist antibodies promote all the biological responses triggered by MET activation, including motility, proliferation, morphogenesis, and protection from apoptosis, while others can induce only a migratory response. On the other hand, antagonists can inhibit MET-driven biological functions either by competing with the ligand or by removing the receptor from the cell surface. Since MET/HGFR is often over-expressed and/or aberrantly activated in tumors, monoclonal antibodies can be used as probes for MET detection or as “bullets” to target MET-expressing tumor cells, thus pointing to their use in diagnosis and therapy. PMID:28548076

Copeptin in the diagnosis of vasopressin-dependent disorders of fluid homeostasis.

PubMed

Christ-Crain, Mirjam; Fenske, Wiebke

2016-03-01

Copeptin and arginine vasopressin (AVP) are derived from a common precursor molecule and have equimolar secretion and response to osmotic, haemodynamic and stress-related stimuli. Plasma concentrations of copeptin and AVP in relation to serum osmolality are highly correlated. The physiological functions of AVP with respect to homeostasis of fluid balance, vascular tonus and regulation of the endocrine stress response are well known, but the exact function of copeptin is undetermined. Quantification of AVP can be difficult, but copeptin is stable in plasma and can be easily measured with a sandwich immunoassay. For this reason, copeptin has emerged as a promising marker for the diagnosis of AVP-dependent fluid disorders. Copeptin measurements can enable differentiation between various conditions within the polyuria-polydipsia syndrome. In the absence of prior fluid deprivation, baseline copeptin levels >20 pmol/l identify patients with nephrogenic diabetes insipidus. Conversely, copeptin levels measured upon osmotic stimulation differentiate primary polydipsia from partial central diabetes insipidus. In patients with hyponatraemia, low levels of copeptin together with low urine osmolality identify patients with primary polydipsia, and the ratio of copeptin to urinary sodium can distinguish the syndrome of inappropriate antidiuretic hormone secretion from other AVP-dependent forms of hyponatraemia.

Preliminary evidence for biologic activity of toceranib phosphate (Palladia(®)) in solid tumours.

PubMed

London, C; Mathie, T; Stingle, N; Clifford, C; Haney, S; Klein, M K; Beaver, L; Vickery, K; Vail, D M; Hershey, B; Ettinger, S; Vaughan, A; Alvarez, F; Hillman, L; Kiselow, M; Thamm, D; Higginbotham, M L; Gauthier, M; Krick, E; Phillips, B; Ladue, T; Jones, P; Bryan, J; Gill, V; Novasad, A; Fulton, L; Carreras, J; McNeill, C; Henry, C; Gillings, S

2012-09-01

The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia®, Pfizer Animal Health, Madison, NJ, USA) in select solid tumours in dogs. Cases in which toceranib was used to treat dogs with apocrine gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma (OSA), thyroid carcinoma, head and neck carcinoma and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 AGASACA [8 partial response (PR), 20 stable disease (SD)], 11/23 OSAs (1 PR and 10 SD), 12/15 thyroid carcinomas (4 PR and 8 SD), 7/8 head and neck carcinomas [1 complete response (CR), 5 PR and 1 SD] and 5/7 (1 CR and 4 SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg kg(-1) , 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis and 47/63 (74.6%) were treated 4 months or longer. Although these data provide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumours, future prospective studies are necessary to define its true activity. © 2011 Blackwell Publishing Ltd.

Apatinib is effective for treatment of advanced hepatocellular carcinoma.

PubMed

Kong, Yinlong; Sun, Lin; Hou, Zhenyu; Zhang, Yongqiang; Chen, Ping; Cui, Yunlong; Zhu, Xiaolin; Song, Tianqiang; Li, Qiang; Li, Huikai; Zhang, Ti; Qin, Lunxiu

2017-12-01

As treatment options for hepatocellular carcinoma (HCC) are currently limited, we evaluated the efficacy and safety of oral apatinib, a VEGFR-2 inhibitor, on patients with advanced HCC. Twenty-two patients from Tianjin Medical University Cancer Institute and Hospital were enrolled for evaluation. Apatinib was administered at 500 mg/day or 250 mg/day continuously. Clinical endpoints were time to disease progression (TTP), overall survival (OS), and safety. The median TTP of treated patients was 10.4 months (95% CI 3.4 -17.5). At the last follow-up, 50% patients had survived longer than 11.4 months from the first dose. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 0%, 40.9%, 40.9%, and 18.2%, respectively. The most common apatinib-related adverse events were hand-foot skin reaction (HFSR) (81.8%) and diarrhea (77.3%). Hypertension (27.3%) and HFSR (13.6%) were the most frequent grade 3/4 adverse events. In summary, results of this small study indicate that apatinib is well tolerated and extremely effective for the treatment of advanced HCC. It is therefore imperative to design and carry out well-controlled clinical trials to confirm its efficacy.

A pilot study of bendamustine in advanced bile duct cancer.

PubMed

Schoppmeyer, Konrad; Kreth, Florian; Wiedmann, Marcus; Mössner, Joachim; Preiss, Rainer; Caca, Karel

2007-07-01

We performed a pilot study to evaluate the safety and tolerability of bendamustine in patients with advanced hilar bile duct cancer and impaired liver function. Six patients with histologically proven, unresectable adenocarcinoma of the hilar bile duct were treated with bendamustine 140 mg/m intravenously on day 1 of the first cycle and with bendamustine 100 mg/m on days 1 and 2 of the second to fourth cycle. Treatment cycles were repeated every 21 days. Primary endpoint was the safety and tolerability of the treatment; secondary endpoints were response rate, time to progression and overall survival. Transient lymphopenia grade 3 occurred in all six patients. No other grade 3 or 4 toxicities were present. The most common nonhematologic toxicity was mouth dryness grade 2 in six patients. Three patients had stable disease. No partial or complete responses were observed. Median time to progression was 3.3 months; median overall survival was 6 months. Our study demonstrates that bendamustine can be safely administered in patients with hilar bile duct cancer and impaired liver function. A potential role of bendamustine in combination therapies for bile duct cancer will be a subject of further trials.

Management of advanced pancreatic cancer with gemcitabine plus erlotinib: efficacy and safety results in clinical practice.

PubMed

Diaz Beveridge, Robert; Alcolea, Vicent; Aparicio, Jorge; Segura, Ángel; García, Jose; Corbellas, Miguel; Fonfría, María; Giménez, Alejandra; Montalar, Joaquin

2014-01-10

The combination of gemcitabine and erlotinib is a standard first-line treatment for unresectable, locally advanced or metastatic pancreatic cancer. We reviewed our single centre experience to assess its efficacy and toxicity in clinical practice. Clinical records of patients with unresectable, locally advanced or metastatic pancreatic cancer who were treated with the combination of gemcitabine and erlotinib were reviewed. Univariate survival analysis and multivariate analysis were carried out to indentify independent predictors factors of overall survival. Our series included 55 patients. Overall disease control rate was 47%: 5% of patients presented complete response, 20% partial response and 22% stable disease. Median overall survival was 8.3 months). Cox regression analysis indicated that performance status and locally advanced versus metastatic disease were independent factors of overall survival. Patients who developed acne-like rash toxicity, related to erlotinib administration, presented a higher survival than those patients who did not develop this toxicity. Gemcitabine plus erlotinib doublet is active in our series of patients with advanced pancreatic cancer. This study provides efficacy and safety results similar to those of the pivotal phase III clinical trial that tested the same combination.

Accelerated hyperfractionated intensity-modulated radiotherapy for recurrent/unresectable rectal cancer in patients with previous pelvic irradiation: results of a phase II study.

PubMed

Cai, Gang; Zhu, Ji; Hu, Weigang; Zhang, Zhen

2014-12-11

This study was conducted to investigate the local effects and toxicity of accelerated hyperfractionated intensity-modulated radiotherapy for recurrent/unresectable rectal cancer in patients with previous pelvic irradiation. Twenty-two patients with recurrent/unresectable rectal cancer who previously received pelvic irradiation were enrolled in our single-center trial between January 2007 and August 2012. Reirradiation was scheduled for up to 39 Gy in 30 fractions using intensity-modulated radiotherapy plans. The dose was delivered via a hyperfractionation schedule of 1.3 Gy twice daily. Patient follow-up was performed by clinical examination, CT/MRI, or PET/CT every 3 months for the first 2 years and every 6 months thereafter. Tumor response was evaluated 1 month after reirradiation by CT/MRI based on the RECIST criteria. Adverse events were assessed using the National Cancer Institute (NCI) common toxicity criteria (version 3.0). The median time from the end of the initial radiation therapy to reirradiation was 30 months (range, 18-93 months). Overall local responses were observed in 9 patients (40.9%). None of the patients achieved a complete response (CR), and 9 patients (40.9%) had a partial response (PR). Thirteen patients failed to achieve a clinical response: 12 (54.5%) presented with stable disease (SD) and 1 (4.5%) with progressive disease (PD). Among all the patients who underwent reirradiation, partial or complete symptomatic relief was achieved in 6 patients (27.3%) and 13 patients (59.1%), respectively. Grade 4 acute toxicity and treatment-related deaths were not observed. The following grade 3 acute toxicities were observed: diarrhea (2 patients, 9.1%), cystitis (1 patient, 4.5%), dermatitis (1 patient, 4.5%), and intestinal obstruction (1 patient, 4.5%). Late toxicity was infrequent. Chronic severe diarrhea, small bowel obstruction, and dysuria were observed in 2 (9.1%), 1 (4.5%) and 2 (9.1%) of the patients, respectively. This study showed that accelerated hyperfractionated intensity-modulated radiotherapy significantly relieved local symptoms and led to a promising local response with an acceptable toxicity profile in patients with recurrent/unresectable rectal cancer and previous pelvic irradiation. Innovative treatment regimens should be evaluated in future studies to improve the clinical outcome while avoiding excessive toxicity in patients with recurrent rectal cancer and previous pelvic irradiation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Compere, A.L.; Griffith, W.L.; Googin, J.M.

Microemulsions fuels containing fully and partially coconut, palm, and soy fatty acids; varying amounts of C/sub 1/ to C/sub 4/ alcohols; varying amounts of water; and four fuel bases were evaluated between 0 and 60/sup 0/C for stability as a single phase system. In general, ability to form a stable single phase system rose with increasing alcohol chain length, decreasing water, and increasing dispersed phase content. It was possible to form 0 to 60/sup 0/C stable single phase systems in all four fuels tested using 30 to 50% v/v dispersed phase containing 1-butanol and either palm or soy fatty acids.more » 11 refs., 3 tabs.« less

Simultaneous determination of iron, cadmium, zinc, copper, nickel, lead, and uranium in seawater by stable isotope dilution spark source mass spectrometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mykytiuk, A.P.; Russell, D.S.; Sturgeon, R.E.

Trace concentrations (ng/mL) of Fe, Cd, Zn, Cu, Ni, Pb, U, and Co have been determined in seawater by stable isotope dilution spark source mass spectrometry. The seawater samples were preconcentrated on the ion exchanger Chelex-100 and the concentrate was evaporated on a graphite or silver electrode. The results are compared with those obtained by graphite furnace atomic absorption spectrometry and inductively coupled plasma emission spectrometry. The technique avoids the use of calibration standards and is capable of producing results in cases where the analyte is only partially recovered. 2 tables.

Partial polarizer filter

NASA Technical Reports Server (NTRS)

Title, A. M. (Inventor)

1978-01-01

A birefringent filter module comprises, in seriatum. (1) an entrance polarizer, (2) a first birefringent crystal responsive to optical energy exiting the entrance polarizer, (3) a partial polarizer responsive to optical energy exiting the first polarizer, (4) a second birefringent crystal responsive to optical energy exiting the partial polarizer, and (5) an exit polarizer. The first and second birefringent crystals have fast axes disposed + or -45 deg from the high transmitivity direction of the partial polarizer. Preferably, the second crystal has a length 1/2 that of the first crystal and the high transmitivity direction of the partial polarizer is nine times as great as the low transmitivity direction. To provide tuning, the polarizations of the energy entering the first crystal and leaving the second crystal are varied by either rotating the entrance and exit polarizers, or by sandwiching the entrance and exit polarizers between pairs of half wave plates that are rotated relative to the polarizers. A plurality of the filter modules may be cascaded.

A phase II study of flavopiridol in patients with advanced renal cell carcinoma: results of Southwest Oncology Group Trial 0109.

PubMed

Van Veldhuizen, Peter J; Faulkner, James R; Lara, Primo N; Gumerlock, Paul H; Goodwin, J Wendall; Dakhil, Shaker R; Gross, Howard M; Flanigan, Robert C; Crawford, E David

2005-07-01

Flavopiridol is a cyclin-dependent kinase inhibitor that prevents cell cycle progression and tumor growth. In initial phase I studies, encouraging responses were seen in advanced renal cell cancer (RCC). In a phase II study of flavopiridol given as a 72-h continuous infusion every 2 weeks in RCC, a response rate of 6% was seen but with considerable grade 3 or 4 asthenia, diarrhea, and thrombosis. Subsequently, an alternative 1-h bolus schedule was reported to have enhanced tolerability in a phase I trial. We therefore conducted a phase II study of this bolus regimen. A total of 38 patients with advanced RCC were entered into this multi-institutional phase II study. Flavopiridol (50 mg/m(2) per day) was administered by bolus intravenous injection daily for three consecutive days, repeated every 3 weeks. Out of 34 eligible patients, one complete response and three partial responses were observed, for an overall response rate of 12% (95% CI 3-27%). Of the 34 patients, 14 (41%) had stable disease (SD). The probability of not failing treatment by 6 months was 21% (95% CI 9-35%). Median overall survival time was 9 months (95% CI 8-18 months). The most common grade 3 or 4 toxicities were diarrhea (35%) and tumor pain (12%) along with anemia, dyspnea, and fatigue (9% each). Flavopiridol at this dose and schedule is feasible with an acceptable toxicity profile. Flavopiridol has some modest biologic activity against advanced RCC, as evidenced by its single-agent objective response and SD rates.

Prediction of response to neoadjuvant chemotherapy in breast cancer: a radiomic study

NASA Astrophysics Data System (ADS)

Wu, Guolin; Fan, Ming; Zhang, Juan; Zheng, Bin; Li, Lihua

2017-03-01

Breast cancer is one of the most malignancies among women in worldwide. Neoadjuvant Chemotherapy (NACT) has gained interest and is increasingly used in treatment of breast cancer in recent years. Therefore, it is necessary to find a reliable non-invasive assessment and prediction method which can evaluate and predict the response of NACT. Recent studies have highlighted the use of MRI for predicting response to NACT. In addition, molecular subtype could also effectively identify patients who are likely have better prognosis in breast cancer. In this study, a radiomic analysis were performed, by extracting features from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and immunohistochemistry (IHC) to determine subtypes. A dataset with fifty-seven breast cancer patients were included, all of them received preoperative MRI examination. Among them, 47 patients had complete response (CR) or partial response (PR) and 10 had stable disease (SD) to chemotherapy based on the RECIST criterion. A total of 216 imaging features including statistical characteristics, morphology, texture and dynamic enhancement were extracted from DCE-MRI. In multivariate analysis, the proposed imaging predictors achieved an AUC of 0.923 (P = 0.0002) in leave-one-out crossvalidation. The performance of the classifier increased to 0.960, 0.950 and 0.936 when status of HER2, Luminal A and Luminal B subtypes were added into the statistic model, respectively. The results of this study demonstrated that IHC determined molecular status combined with radiomic features from DCE-MRI could be used as clinical marker that is associated with response to NACT.

Gene expression patterns in formalin-fixed, paraffin-embedded core biopsies predict docetaxel chemosensitivity in breast cancer patients.

PubMed

Chang, Jenny C; Makris, Andreas; Gutierrez, M Carolina; Hilsenbeck, Susan G; Hackett, James R; Jeong, Jennie; Liu, Mei-Lan; Baker, Joffre; Clark-Langone, Kim; Baehner, Frederick L; Sexton, Krsytal; Mohsin, Syed; Gray, Tara; Alvarez, Laura; Chamness, Gary C; Osborne, C Kent; Shak, Steven

2008-03-01

Previously, we had identified gene expression patterns that predicted response to neoadjuvant docetaxel. Other studies have validated that a high Recurrence Score (RS) by the 21-gene RT-PCR assay is predictive of worse prognosis but better response to chemotherapy. We investigated whether tumor expression of these 21 genes and other candidate genes can predict response to docetaxel. Core biopsies from 97 patients were obtained before treatment with neoadjuvant docetaxel (4 cycles, 100 mg/m2 q3 weeks). Three 10-microm FFPE sections were submitted for quantitative RT-PCR assays of 192 genes that were selected from our previous work and the literature. Of the 97 patients, 81 (84%) had sufficient invasive cancer, 80 (82%) had sufficient RNA for QRTPCR assay, and 72 (74%) had clinical response data. Mean age was 48.5 years, and the median tumor size was 6 cm. Clinical complete responses (CR) were observed in 12 (17%), partial responses in 41 (57%), stable disease in 17 (24%), and progressive disease in 2 patients (3%). A significant relationship (P<0.05) between gene expression and CR was observed for 14 genes, including CYBA. CR was associated with lower expression of the ER gene group and higher expression of the proliferation gene group from the 21 gene assay. Of note, CR was more likely with a high RS (P=0.008). We have established molecular profiles of sensitivity to docetaxel. RT-PCR technology provides a potential platform for a predictive test of docetaxel chemosensitivity using small amounts of routinely processed material.

Effect of Increased Intra-abdominal Pressure on Liver Histology and Hemodynamics: An Experimental Study.

PubMed

Antoniou, Efstathios A; Kairi, Evi; Margonis, Georgios A; Andreatos, Nikolaos; Sasaki, Kazunari; Damaskos, Christos; Garmpis, Nikolaos; Samaha, Mario; Argyra, Eriphyli; Polymeneas, George; Weiss, Matthew J; Pawlik, Timothy M; Voros, Dionysios; Kouraklis, Gregory

2018-01-01

While reduction of portal venous (PV) blood flow has been described in animal models of intra-abdominal hypertension, reports on compensatory changes in hepatic arterial (HA) flow, known as the hepatic arterial buffer response are controversial. Pneumoperitoneum with helium was induced in 13 piglets. Hemodynamic measurements and pathological assessment were conducted at baseline and during the three subsequent phases: Phase A: 45 minutes with a stable intra-abdominal pressure of 25 mmHg; phase B: 45 minutes with a stable intra-abdominal pressure of 40 mmHg; and phase C during which the abdomen was re-explored and reperfusion of the liver was allowed to take place. Phase B pressure was significantly greater than phase A pressure in both the PV and the inferior vena cava, demonstrating a positive association between escalating intra-abdominal hypertension and the pressure in these two vessels (all p<0.001). In contrast, HA pressure was comparable between baseline and phase A, while it tended to decrease in phase B. Regarding histology, the most notable abnormality was the presence of inflammatory infiltrates and hepatocyte necrosis. Helium-insufflation increased PV pressure with a partial compensatory decrease of HA pressure. Nonetheless, findings consistent with hepatic ischemia were observed on pathology. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Modeling Efficacy of Bevacizumab Treatment for Metastatic Colon Cancer

PubMed Central

Islam, Rezwan; Chyou, Po-Huang; Burmester, James K

2013-01-01

Purpose: Bevacizumab, an FDA-approved adjuvant treatment for metastatic colon cancer, has extended survival for many patients. However, factors predicting response to treatment remain undefined. Patients and Methods: Relevant clinical and environmental data were abstracted from medical records of 149 evaluable patients treated with bevacizumab for metastatic colon cancer at a multi-specialty clinic. Tumor response was calculated from radiologic reports using Response Evaluation Criteria in Solid Tumors (RECIST) criteria and verified by oncologist review. Patients with at least one occurrence of complete or partial response or stable disease were classified as responders; those exhibiting progressive disease were classified as non-responders. Results: Univariate analysis demonstrated that blood in stool (P<0.05), unexplained weight loss (P<0.05), primary colon cancer site (P<0.05), chemotherapy treatment of primary tumor site (P<0.05), and adenocarcinoma versus adenoma subtype (P<0.05) was associated with tumor responsiveness. Factors remaining statistically significant following multivariate modeling included adenocarcinoma as tumor cell type versus other adenocarcinoma subtypes (OR=6.35, 95% CI: 1.08-37.18), chemotherapy treatment applied to primary tumor (OR= 0.07, 95% CI: 0.0-0.76,), tumor localization to cecal/ascending colon (OR=0.061, 95% CI: 0.006-0.588,), and unexplained weight loss (OR=0.1, 95% CI: 0.02-0.56,). Chemotherapy treatment of primary tumor, unexplained weight loss, and cecal/ascending localization of the tumor were associated with poorer outcomes. Adenocarcinoma as cell type compared to other adenocarcinoma subtypes was associated with better response to bevacizumab treatment. Conclusion: Results suggest that response to bevacizumab therapy may be predicted by modeling clinical factors including symptomology on presentation, tumor location and type, and initial response to chemotherapy. PMID:23678369

REOX: Evaluation of the Efficacy of Retreatment With an Oxaliplatin-containing Regimen in Metastatic Colorectal Cancer: A Retrospective Single-center Study.

PubMed

Costa, Talita; Nuñez, Jose; Felismino, Tiago; Boente, Leonardo; Mello, Celso

2017-12-01

Treatment of metastatic colorectal adenocarcinoma (mCRC) has evolved, and survival is over 30 months in contemporary trials. Nevertheless, there is a paucity of effective regimes after the first or second-line treatment. Thus, reexposure to previously used drugs has become a treatment strategy for some patients. We aimed to evaluate the efficacy of retreatment with an oxaliplatin-containing regimen in mCRC and correlate this with clinicopathologic features. We retrospectively analyzed 83 patients with mCRC who underwent reexposure to oxaliplatin (REOX). REOX was defined as a second trial of an oxaliplatin-containing regimen after a previous failure. Primary endpoint was time to treatment failure (TTF). The median age was 53.5 years, and the female/male ratio was 51.8%/48.2%. The site of the primary tumor was colon (67.5%) and rectal (32.5%). KRAS was mutated in 39.8%. Liver-limited metastasis was found in 19.3% of patients. The main regimen was 5-fluorouracil, levoleucovorin, and oxaliplatin (mFOLFOX6) (84.3%). Bevacizumab and cetuximab were used in 42.2% and 6% of patients, respectively. REOX was used in the third and fourth lines in 48.2% and 25.3% of patients, respectively. The median TTF after REOX was 6.04 months. Overall survival (OS) was 10.04 months. Disease control (complete response + partial response + stable disease) was observed in 56.6%, whereas 42.2% had progressive disease. Partial response + complete response to previous oxaliplatin was predictive of prolonged OS. Patients who attained disease control had better median OS compared with those with progressive disease (14.5 vs. 6.24 months; P < .0001). In the setting of heavily pretreated patients with mCRC, REOX was an effective treatment, with mTTF of 6.04 months in our cohort. Selection of patients with the longest time since previous oxaliplatin can translate in better outcome. Further studies should be conducted to confirm our data. Copyright © 2017 Elsevier Inc. All rights reserved.

Random chromosome elimination in synthetic Triticum-Aegilops amphiploids leads to development of a stable partial amphiploid with high grain micro- and macronutrient content and powdery mildew resistance.

PubMed

Tiwari, Vijay K; Rawat, Nidhi; Neelam, Kumari; Kumar, Sundip; Randhawa, Gursharn S; Dhaliwal, Harcharan S

2010-12-01

Synthetic amphiploids are the immortal sources for studies on crop evolution, genome dissection, and introgression of useful variability from related species. Cytological analysis of synthetic decaploid wheat (Triticum aestivum L.) - Aegilops kotschyi Boiss. amphiploids (AABBDDUkUkSkSk) showed some univalents from the C1 generation onward followed by chromosome elimination. Most of the univalents came to metaphase I plate after the reductional division of paired chromosomes and underwent equational division leading to their elimination through laggards and micronuclei. Substantial variation in the chromosome number of pollen mother cells from different tillers, spikelets, and anthers of some plants also indicated somatic chromosome elimination. Genomic in situ hybridization, fluorescence in situ hybridization, and simple sequence repeat markers analysis of two amphiploids with reduced chromosomes indicated random chromosome elimination of various genomes with higher sensitivity of D followed by the Sk and Uk genomes to elimination, whereas 1D chromosome was preferentially eliminated in both the amphiploids investigated. One of the partial amphiploids, C4 T. aestivum 'Chinese Spring' - Ae. kotschyi 396 (2n = 58), with 34 T. aestivum, 14 Uk, and 10 Sk had stable meiosis and high fertility. The partial amphiploids with white glumes, bold seeds, and tough rachis with high grain macro- and micronutrients and resistance to powdery mildew could be used for T. aestivum biofortification and transfer of powdery mildew resistance.

Acquisition with partial and continuous reinforcement in pigeon autoshaping.

PubMed

Gottlieb, Daniel A

2004-08-01

Contemporary time accumulation models make the unique prediction that acquisition of a conditioned response will be equally rapid with partial and continuous reinforcement, if the time between conditioned stimuli is held constant. To investigate this, acquisition of conditioned responding was examined in pigeon autoshaping under conditions of 100% and 25% reinforcement, holding intertrial interval constant. Contrary to what was predicted, evidence for slowed acquisition in partially reinforced animals was observed with several response measures. However, asymptotic performance was superior with 25% reinforcement. A switching of reinforcement contingencies after initial acquisition did not immediately affect responding. After further sessions, partial reinforcement augmented responding, whereas continuous reinforcement did not, irrespective of an animal's reinforcement history. Subsequent training with a novel stimulus maintained the response patterns. These acquisition results generally support associative, rather than time accumulation, accounts of conditioning.

Magnetization reversal of in-plane uniaxial Co films and its dependence on epitaxial alignment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Idigoras, O., E-mail: o.idigoras@nanogune.eu; Suszka, A. K.; Berger, A.

2014-02-28

This work studies the influence of crystallographic alignment onto magnetization reversal in partially epitaxial Co films. A reproducible growth sequence was devised that allows for the continuous tuning of grain orientation disorder in Co films with uniaxial in-plane anisotropy by the controlled partial suppression of epitaxy. While all stable or meta-stable magnetization states occurring during a magnetic field cycle exhibit a uniform magnetization for fully epitaxial samples, non-uniform states appear for samples with sufficiently high grain orientation disorder. Simultaneously with the occurrence of stable domain states during the magnetization reversal, we observe a qualitative change of the applied field anglemore » dependence of the coercive field. Upon increasing the grain orientation disorder, we observe a disappearance of transient domain wall propagation as the dominating reversal process, which is characterized by an increase of the coercive field for applied field angles away from the easy axis for well-ordered epitaxial samples. Upon reaching a certain disorder threshold level, we also find an anomalous magnetization reversal, which is characterized by a non-monotonic behavior of the remanent magnetization and coercive field as a function of the applied field angle in the vicinity of the nominal hard axis. This anomaly is a collective reversal mode that is caused by disorder-induced frustration and it can be qualitatively and even quantitatively explained by means of a two Stoner-Wohlfarth particle model. Its predictions are furthermore corroborated by Kerr microscopy and by Brillouin light scattering measurements.« less

Sparse partial least squares regression for simultaneous dimension reduction and variable selection

PubMed Central

Chun, Hyonho; Keleş, Sündüz

2010-01-01

Partial least squares regression has been an alternative to ordinary least squares for handling multicollinearity in several areas of scientific research since the 1960s. It has recently gained much attention in the analysis of high dimensional genomic data. We show that known asymptotic consistency of the partial least squares estimator for a univariate response does not hold with the very large p and small n paradigm. We derive a similar result for a multivariate response regression with partial least squares. We then propose a sparse partial least squares formulation which aims simultaneously to achieve good predictive performance and variable selection by producing sparse linear combinations of the original predictors. We provide an efficient implementation of sparse partial least squares regression and compare it with well-known variable selection and dimension reduction approaches via simulation experiments. We illustrate the practical utility of sparse partial least squares regression in a joint analysis of gene expression and genomewide binding data. PMID:20107611

Responsive cortical stimulation for the treatment of medically intractable partial epilepsy.

PubMed

Morrell, Martha J

2011-09-27

This multicenter, double-blind, randomized controlled trial assessed the safety and effectiveness of responsive cortical stimulation as an adjunctive therapy for partial onset seizures in adults with medically refractory epilepsy. A total of 191 adults with medically intractable partial epilepsy were implanted with a responsive neurostimulator connected to depth or subdural leads placed at 1 or 2 predetermined seizure foci. The neurostimulator was programmed to detect abnormal electrocorticographic activity. One month after implantation, subjects were randomized 1:1 to receive stimulation in response to detections (treatment) or to receive no stimulation (sham). Efficacy and safety were assessed over a 12-week blinded period and a subsequent 84-week open-label period during which all subjects received responsive stimulation. Seizures were significantly reduced in the treatment (-37.9%, n = 97) compared to the sham group (-17.3%, n = 94; p = 0.012) during the blinded period and there was no difference between the treatment and sham groups in adverse events. During the open-label period, the seizure reduction was sustained in the treatment group and seizures were significantly reduced in the sham group when stimulation began. There were significant improvements in overall quality of life (p < 0.02) and no deterioration in mood or neuropsychological function. Responsive cortical stimulation reduces the frequency of disabling partial seizures, is associated with improvements in quality of life, and is well-tolerated with no mood or cognitive effects. Responsive stimulation may provide another adjunctive treatment option for adults with medically intractable partial seizures. This study provides Class I evidence that responsive cortical stimulation is effective in significantly reducing seizure frequency for 12 weeks in adults who have failed 2 or more antiepileptic medication trials, 3 or more seizures per month, and 1 or 2 seizure foci.

Cytogenetics of melanoma and nonmelanoma skin cancer.

PubMed

Carless, Melanie A; Griffiths, Lyn R

2014-01-01

Cytogenetic analysis of melanoma and nonmelanoma skin cancers has revealed recurrent aberrations, the frequency of which is reflective of malignant potential. Highly aberrant karyotypes are seen in melanoma, squamous cell carcinoma, actinic keratosis, Merkel cell carcinoma and cutaneous lymphomas with more stable karyotypes seen in basal cell carcinoma, keratoacanthoma, Bowen's disease and dermatofibrosarcoma protuberans. Some aberrations are common among a number of skin cancer types including rearrangements and numerical abnormalities of chromosome 1, -3p, +3q, partial or entire trisomy 6, trisomy 7, +8q, -9p, +9q, partial or entire loss of chromosome 10, -17p, +17q and partial or entire gain of chromosome 20. Combination of cytogenetic analysis with other molecular genetic techniques has enabled the identification of not only aberrant chromosomal regions, but also the genes that contribute to a malignant phenotype. This review provides a comprehensive summary of the pertinent cytogenetic aberrations associated with a variety of melanoma and nonmelanoma skin cancers.

Methanol partial oxidation on Ag(111) from first principles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aljama, Hassan; Yoo, Jong Suk; Nørskov, Jens K.

In this work, we examine the thermochemistry and kinetics of the partial oxidation of methanol to formaldehyde on silver surfaces. Periodic density functional theory calculations employing the BEEF-vdW functional are used to identify the most stable phases of the silver surface under relevant reaction conditions and the reaction energetics are obtained on these surfaces. The calculated binding energies and transition state energies are used as input in a mean-field microkinetic model providing the reaction kinetics on silver surfaces under different reaction conditions. Our results show that, under conditions pertaining to methanol partial oxidation, oxygen is present at low concentrations andmore » it plays a critical role in the catalytic reaction. Surface oxygen promotes the reaction by activating the OH bond in methanol, thus forming a methoxy intermediate, which can react further to form formaldehyde. Finally, the dissociation of molecular oxygen is identified as the most critical step.« less

Methanol partial oxidation on Ag(111) from first principles

DOE PAGES

Aljama, Hassan; Yoo, Jong Suk; Nørskov, Jens K.; ...

2016-10-26

In this work, we examine the thermochemistry and kinetics of the partial oxidation of methanol to formaldehyde on silver surfaces. Periodic density functional theory calculations employing the BEEF-vdW functional are used to identify the most stable phases of the silver surface under relevant reaction conditions and the reaction energetics are obtained on these surfaces. The calculated binding energies and transition state energies are used as input in a mean-field microkinetic model providing the reaction kinetics on silver surfaces under different reaction conditions. Our results show that, under conditions pertaining to methanol partial oxidation, oxygen is present at low concentrations andmore » it plays a critical role in the catalytic reaction. Surface oxygen promotes the reaction by activating the OH bond in methanol, thus forming a methoxy intermediate, which can react further to form formaldehyde. Finally, the dissociation of molecular oxygen is identified as the most critical step.« less

Phase-and-amplitude recovery from a single phase-contrast image using partially spatially coherent x-ray radiation

NASA Astrophysics Data System (ADS)

Beltran, Mario A.; Paganin, David M.; Pelliccia, Daniele

2018-05-01

A simple method of phase-and-amplitude extraction is derived that corrects for image blurring induced by partially spatially coherent incident illumination using only a single intensity image as input. The method is based on Fresnel diffraction theory for the case of high Fresnel number, merged with the space-frequency description formalism used to quantify partially coherent fields and assumes the object under study is composed of a single-material. A priori knowledge of the object’s complex refractive index and information obtained by characterizing the spatial coherence of the source is required. The algorithm was applied to propagation-based phase-contrast data measured with a laboratory-based micro-focus x-ray source. The blurring due to the finite spatial extent of the source is embedded within the algorithm as a simple correction term to the so-called Paganin algorithm and is also numerically stable in the presence of noise.

Sustained and transient oscillations and chaos induced by delayed antiviral immune response in an immunosuppressive infection model.

PubMed

Shu, Hongying; Wang, Lin; Watmough, James

2014-01-01

Sustained and transient oscillations are frequently observed in clinical data for immune responses in viral infections such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus. To account for these oscillations, we incorporate the time lag needed for the expansion of immune cells into an immunosuppressive infection model. It is shown that the delayed antiviral immune response can induce sustained periodic oscillations, transient oscillations and even sustained aperiodic oscillations (chaos). Both local and global Hopf bifurcation theorems are applied to show the existence of periodic solutions, which are illustrated by bifurcation diagrams and numerical simulations. Two types of bistability are shown to be possible: (i) a stable equilibrium can coexist with another stable equilibrium, and (ii) a stable equilibrium can coexist with a stable periodic solution.

Stable time filtering of strongly unstable spatially extended systems

PubMed Central

Grote, Marcus J.; Majda, Andrew J.

2006-01-01

Many contemporary problems in science involve making predictions based on partial observation of extremely complicated spatially extended systems with many degrees of freedom and with physical instabilities on both large and small scale. Various new ensemble filtering strategies have been developed recently for these applications, and new mathematical issues arise. Because ensembles are extremely expensive to generate, one such issue is whether it is possible under appropriate circumstances to take long time steps in an explicit difference scheme and violate the classical Courant–Friedrichs–Lewy (CFL)-stability condition yet obtain stable accurate filtering by using the observations. These issues are explored here both through elementary mathematical theory, which provides simple guidelines, and the detailed study of a prototype model. The prototype model involves an unstable finite difference scheme for a convection–diffusion equation, and it is demonstrated below that appropriate observations can result in stable accurate filtering of this strongly unstable spatially extended system. PMID:16682626

Stable time filtering of strongly unstable spatially extended systems.

PubMed

Grote, Marcus J; Majda, Andrew J

2006-05-16

Many contemporary problems in science involve making predictions based on partial observation of extremely complicated spatially extended systems with many degrees of freedom and with physical instabilities on both large and small scale. Various new ensemble filtering strategies have been developed recently for these applications, and new mathematical issues arise. Because ensembles are extremely expensive to generate, one such issue is whether it is possible under appropriate circumstances to take long time steps in an explicit difference scheme and violate the classical Courant-Friedrichs-Lewy (CFL)-stability condition yet obtain stable accurate filtering by using the observations. These issues are explored here both through elementary mathematical theory, which provides simple guidelines, and the detailed study of a prototype model. The prototype model involves an unstable finite difference scheme for a convection-diffusion equation, and it is demonstrated below that appropriate observations can result in stable accurate filtering of this strongly unstable spatially extended system.

[Inhibiting properties of stable nitroxyl radicals in reactions of linoleic acid and linoleyl alcohol oxidation catalyzed by 5-lipoxygenase].

PubMed

Kharchenko, O V; Kharitonenko, A I; Vovk, A I; Kukhar', V P; Babiĭ, L V; Khil'chevskiĭ, A N; Mel'nik, A K

2005-01-01

The inhibiting effects of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and its 4-substituted derivatives in reactions of linoleyl acid or linoleyl alcohol oxidation catalyzed by potato tuber 5-lipoxygenase were investigated. Inhibiting properties of stable nitroxyl radicals in presence of lubrol and SDS were reduced at the transition from TEMPO to 4-hydroxy-TEMPO or 4-amino-TEMPO and increased at use of adamantane-1-carboxylic or 3-methyladamantane-1-carboxylic acid 1-oxyl-2,2,6,6-tetramethylpiperidine-4-yl esters. Enzyme activity at saturating concentrations of inhibitor was not suppressed completely, and decreased up to the certain level determined by the substrate nature. The dependence of partial inhibition efficiency on rotational correlation time of stable nitroxides in model micellar systems were analysed. It was supposed that 5-lipoxygenase inhibition includes the interaction of hydrophobic nitroxide with radical intermediate formed in enzymatic process.

Study on the intrinsic defects in tin oxide with first-principles method

NASA Astrophysics Data System (ADS)

Sun, Yu; Liu, Tingyu; Chang, Qiuxiang; Ma, Changmin

2018-04-01

First-principles and thermodynamic methods are used to study the contribution of vibrational entropy to defect formation energy and the stability of the intrinsic point defects in SnO2 crystal. According to thermodynamic calculation results, the contribution of vibrational entropy to defect formation energy is significant and should not be neglected, especially at high temperatures. The calculated results indicate that the oxygen vacancy is the major point defect in undoped SnO2 crystal, which has a higher concentration than that of the other point defect. The property of negative-U is put forward in SnO2 crystal. In order to determine the most stable defects much clearer under different conditions, the most stable intrinsic defect as a function of Fermi level, oxygen partial pressure and temperature are described in the three-dimensional defect formation enthalpy diagrams. The diagram visually provides the most stable point defects under different conditions.

Stable doping of carbon nanotubes via molecular self assembly

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, B.; Chen, Y.; Podzorov, V., E-mail: podzorov@physics.rutgers.edu

2014-10-14

We report a novel method for stable doping of carbon nanotubes (CNT) based on methods of molecular self assembly. A conformal growth of a self-assembled monolayer of fluoroalkyl trichloro-silane (FTS) at CNT surfaces results in a strong increase of the sheet conductivity of CNT electrodes by 60–300%, depending on the CNT chirality and composition. The charge carrier mobility of undoped partially aligned CNT films was independently estimated in a field-effect transistor geometry (~100 cm²V⁻¹s⁻¹). The hole density induced by the FTS monolayer in CNT sheets is estimated to be ~1.8 ×10¹⁴cm⁻². We also show that FTS doping of CNT anodesmore » greatly improves the performance of organic solar cells. This large and stable doping effect, easily achieved in large-area samples, makes this approach very attractive for applications of CNTs in transparent and flexible electronics.« less

Amplification and overexpression of topoisomerase IIalpha predict response to anthracycline-based therapy in locally advanced breast cancer.

PubMed

Coon, John S; Marcus, Elizabeth; Gupta-Burt, Shalina; Seelig, Steven; Jacobson, Kris; Chen, Shande; Renta, Vivian; Fronda, Geraldo; Preisler, Harvey D

2002-04-01

The putative association between erbB-2 overexpression and favorable response to anthracyline-based therapy in breast cancer is controversial, and the mechanism unclear. We sought to determine whether coamplification and overexpression of the topoisomerase IIalpha gene, near erbB-2 on chromosome 17, and a known anthracycline target, may underlie the association. Thirty-five patients who had locally advanced breast cancer (LABC) and who had received neoadjuvant, anthracycline-based therapy were studied. Copy number of topoisomerase IIalpha and erbB-2 was determined by fluorescence in situ hybridization, and expression by immunohistochemistry. Of 8 patients with erbB-2 amplification, 5 had a complete response (CR) or minimal residual disease (MRD), 3 had a partial response (PR), and none had stable (StD) or progressive disease (PD) at the time of mastectomy, versus 3 CR or MRD, 16 PR, and 8 StD or PD for patients without amplification (P = 0.008). In contrast, erbB-2 overexpression was not significantly associated with response (P = 0.114). Of 6 patients with topoisomerase IIalpha amplification, 4 had CR or MRD, 2 PR, and none StD or PD, versus 4 CR or MRD, 17 PR, and 8 StD or PD for patients without amplification (P = 0.034). All of the tumors with topoisomerase IIalpha amplification also had erbB-2 amplification, but not vice versa. Overexpression of topoisomerase IIalpha (9 patients) was also associated with favorable response (P = 0.021). Coamplification of erbB-2 and topoisomerase IIalpha is significantly associated with favorable local response to anthracycline-based therapy in LABC. The expression data favor a plausible mechanism based on topoisomerase IIalpha biology.

European Research on Electrochemotherapy in Head and Neck Cancer (EURECA) project: Results from the treatment of mucosal cancers.

PubMed

Plaschke, Christina Caroline; Bertino, Giulia; McCaul, James A; Grau, Juan J; de Bree, Remco; Sersa, Gregor; Occhini, Antonio; Groselj, Ales; Langdon, Cristobal; Heuveling, Derrek A; Cemazar, Maja; Strojan, Primoz; Leemans, C Rene; Benazzo, Marco; De Terlizzi, Francesca; Wessel, Irene; Gehl, Julie

2017-12-01

Electrochemotherapy is an effective local treatment for cutaneous tumours and metastases. In this prospective trial, six European institutions investigated electrochemotherapy in recurrent, mucosal head and neck tumours. Forty-three patients with recurrent mucosal head and neck tumours and no further curative or reasonably effective palliative treatment options were enrolled and treated with electrochemotherapy. Patients were treated in general anaesthesia using intravenous or local injection of bleomycin followed by delivery of electric pulses to the tumour area. Primary end-point was local tumour response. Secondary end-points were safety and toxicity, overall and progression free survival, and quality-of-life. Thirty-seven patients were evaluable for tumour response, pain score, side-effects and quality of life questionnaires. Six patients were not evaluable due to lost follow-up, disease progression or death before evaluation. Intention to treat analysis revealed an objective response of 56% (complete response 8 (19%), partial response 16 (37%), stable disease 10 (23%), progressive disease 3 (7%), and not evaluable 6 (14%)). Three patients (7%) remained in complete response at 30, 34, and 84 months post-treatment. The treatment procedure was generally well tolerated. Swelling of the mucosa was observed in the first days after treatment. Pain and use of pain medication rose temporarily; fatigue and dysphagia were also noted in the quality of life assessment. Electrochemotherapy can be applied to mucosal head and neck recurrent tumours accessible to the procedure with promising objective response, survival and toxicity profile. Attention should be paid to post-treatment swelling and planning of pain medication. These favourable results indicate that electrochemotherapy could play a role in patients with recurrent head and neck cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Phase II study of Dovitinib in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma

PubMed Central

Dillon, Patrick M.; Petroni, Gina R.; Horton, Bethany J.; Moskaluk, Christopher A.; Fracasso, Paula M.; Douvas, Michael G; Varhegyi, Nikole; Zaja-Milatovic, Snjezana; Thomas, Christopher Y.

2017-01-01

Purpose Genetic and preclinical studies have implicated fibroblast growth factor receptor (FGFR) signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor FGFR activity, may be active in ACC. Methods In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate (ORR) and change in tumor growth rate (TGR). Progression-free survival (PFS), overall survival (OS), metabolic response, biomarker and QOL were secondary endpoints. Results Of thirty-four evaluable patients, two (6%) had a partial response and 22 (65%) had stable disease >4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on-treatment (p<0.001). Toxicity was moderate; 63% of patients developed grade 3–4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on 18FDG-PET scans was seen in 3/15 patients but did not correlate with RECIST response. MYB gene translocation was observed and significantly correlated with over-expression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib. Conclusion Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably to those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine if FGFR signaling is a valid therapeutic target in ACC. PMID:28377480

Initial characterization of shade avoidance response suggests functional diversity between Populus phytochrome B genes.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karve, Abhijit A; Weston, David; Jawdy, Sara

2012-01-01

Shade avoidance signaling in higher plants involves perception of the incident red/far-red (R/FR) light by phytochromes and the modulation of downstream transcriptional networks to regulate developmental plasticity in relation to heterogeneous light environments. In this study, we characterized the expression and functional features of Populus phytochrome (PHY) gene family as well as the transcriptional responses of Populus to the changes in R/FR light. Expression data indicated that PHYA is the predominant PHY in the dark grown Populus seedling whereas PHYBs are most abundant in mature tissue types. Out of three Populus PHYs, PHYA is light labile and localized to cytosolmore » in dark whereas both PHYB1 and PHYB2 are light stable and are localized to nucleus in mesophyll protoplasts. When expressed in Arabidopsis, PHYB1 rescued Arabidopsis phyB mutant phenotype whereas PHYB2 did not, suggesting functional diversification between these two gene family members. However, phenotypes of transgenic Populus lines with altered expression of PHYB1, PHYB2 or both and the expression of candidate shade response genes in these transgenic lines suggest that PHYB1 and PHYB2 may have distinct yet overlapping functions. The RNAseq results and analysis of Populus exposed to enriched-FR light indicate that genes associated in cell wall modification and brassinosteroid signaling were induced under far red light. Overall our data indicate that Populus transcriptional responses are at least partially conserved with Arabidopsis.« less

Intra-arterial radioembolization of breast cancer liver metastases: a structured review.

PubMed

Smits, Maarten L J; Prince, Jip F; Rosenbaum, Charlotte E N M; van den Hoven, Andor F; Nijsen, J Frank W; Zonnenberg, Bernard A; Seinstra, Beatrijs A; Lam, Marnix G E H; van den Bosch, Maurice A A J

2013-06-05

Radioembolization using yttrium-90 microspheres (⁹⁰Y-RE) is an emerging treatment option for breast cancer liver metastases (BCLM) patients if other locoregional and systemic treatment options fail. The purpose of this study was to provide a systematic overview of the current literature concerning ⁹⁰Y-RE for BCLM patients. A systematic search for relevant articles was performed in MEDLINE, EMBASE, and The Cochrane Library (January 2012) by combining an extensive list of synonyms for the determinants 'radioembolization', 'yttrium-90' and 'microsphere' with synonyms for the domain 'liver'. Data on tumor response, survival and toxicity were extracted and collected from all relevant articles. The search yielded 4078 studies, of which six were finally included for analysis, concerning a total of 198 patients. Tumor response was scored in five studies using either RECIST (n=3) or WHO criteria (n=2). Overall disease control rates (complete response, partial response and stable disease) at 2-4 months post treatment ranged from 78% to 96%. Median survival, available in four studies, ranged from 10.8 to 20.9 months. In total, gastric ulceration was reported in ten patients (5%) and treatment related mortality in three patients (2%). The results from the analyzed studies consistently show that ⁹⁰Y-RE is a safe and effective treatment option for BCLM patients. Comparative studies, especially combining ⁹⁰Y-RE with systemic therapy are strongly encouraged. Copyright © 2013 Elsevier B.V. All rights reserved.

Dacarbazine as single-agent therapy for relapsed lymphoma in dogs.

PubMed

Griessmayr, P C; Payne, S E; Winter, J E; Barber, L G; Shofer, F S

2009-01-01

Multidrug resistance is the most common cause of treatment failure in dogs with multicentric lymphoma. 5-(3,3-Dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) is an atypical alkylator used as standard treatment in human Hodgkin's lymphoma, and has been effective in combination treatment to treat resistant lymphoma in dogs. However, no data are available on the use of DTIC as a single agent in the treatment of relapsed canine lymphoma. Single-agent DTIC is effective and safe in treating dogs with lymphoma that relapsed or failed to respond to previous chemotherapy. Forty client-owned dogs with relapsed lymphoma. Dogs were eligible for the retrospective study if they had a histologically or cytologically confirmed diagnosis of lymphoma and had relapsed. Dogs received DTIC (800-1,000 mg/m(2) every 2-3 weeks as a 4-5-hour IV infusion) and were evaluated for response rate and duration. Hematologic and gastrointestinal toxicity was assessed. The overall response rate for dogs being treated with DTIC was 35% (14 dogs) with a median progression-free interval of 43 days. Thirteen dogs had a partial response and 1 dog had a complete response. Stable disease was achieved in 3 dogs. Mild gastrointestinal toxicity was reported in 3 dogs posttreatment. Thrombocytopenia was the principal toxicity observed 7-14 days after the treatment. Treatments were delayed because of thrombocytopenia. DTIC, when used alone, is effective in the treatment of dogs with relapsed lymphoma.

Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after (177)Lu-octreotate.

PubMed

Kamp, Kimberly; Gumz, Brenda; Feelders, Richard A; Kwekkeboom, Dik J; Kaltsas, Gregory; Costa, Frederico P; de Herder, Wouter W

2013-12-01

Although (177)Lu-octreotate is an effective treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), some patients will fail or develop disease progression necessitating further treatment. We examined whether the safety and efficacy of everolimus after prior treatment with (177)Lu-octreotate is different from the published safety profile of everolimus in GEP-NETs. In this multicenter study, 24 GEP-NET patients were included. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Tumor response was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Major clinical adverse events (grade 3 or 4) during treatment with everolimus were hyperglycemia (20.8%), fatigue (8.3%), thrombocytopenia (8.3%), and elevated alanine transaminase levels (8.3%). By radiological review, there were four partial responses (16.7%), five patients (62.5%) with stable disease, and three patients (12.5%) with progressive disease. For two patients (8.3%), no data on tumor response were available. Median progression-free survival (PFS) was 13.1 months (95% CI, 11.5-21.2). Median PFS of the current study was longer when compared with the RADIANT-3 trial (13.1 vs 11.4 months) and shorter when compared with the RADIANT-1 trial (13.1 vs 16.7 months). In conclusion, the safety profile of everolimus is not influenced by previous treatment with peptide receptor radiotherapy.

Retreatment with pembrolizumab in advanced non-small cell lung cancer patients previously treated with nivolumab: emerging reports of 12 cases.

PubMed

Fujita, Kohei; Uchida, Naohiro; Kanai, Osamu; Okamura, Misato; Nakatani, Koichi; Mio, Tadashi

2018-04-19

After approval of anti-programmed cell death (PD)-1 antibodies, treatment for non-small cell lung cancer (NSCLC) has drastically changed. However, even in patients with favorable effects, therapeutic efficacy does not last long. Recently, retreatment with anti-PD-1 antibody has received attention. The aim of this study was to evaluate the efficacy and safety of retreatment with pembrolizumab in NSCLC patients previously treated with nivolumab. We retrospectively reviewed NSCLC patients retreated with pembrolizumab who were previously treated with nivolumab. We collected the following data: patient characteristics, number of cycles of nivolumab and pembrolizumab, treatment interval between nivolumab and pembrolizumab, best response, and immune-related adverse events. Twelve patients were reviewed. The median number of cycles of nivolumab was 12.5 (range 2-32 cycles). Seven patients (58.3%) achieved a partial response (PR) and two patients (16.7%) achieved stable disease (SD). Eight patients (66.7%) received cytotoxic chemotherapy between nivolumab and pembrolizumab. The median number of cycles of chemotherapy treatment was 4 (range 1-9 cycles). The median number of cycles of pembrolizumab was 3.5 (range 1-17 cycles). One patient (8.3%) achieved PR and four patients (33.3%) achieved SD as their best response to pembrolizumab. All patients showing response to pembrolizumab had very high (≥ 80%) tumor PD-Ligand 1 expression. This study suggested that retreatment with anti-PD-1 antibody is a reasonable option for selected NSCLC patients.

Phase II Study of Bortezomib and Pegylated Liposomal Doxorubicin in the Treatment of Metastatic Breast Cancer

PubMed Central

Irvin, William J.; Orlowski, Robert Z.; Chiu, Wing-Keung; Carey, Lisa A.; Collichio, Frances A.; Bernard, Philip S.; Stijleman, Inge J.; Perou, Charles; Ivanova, Anastasia; Dees, E. Claire

2018-01-01

Background Based on preclinical studies and a phase I trial of the combination of bortezomib and pegylated liposomal doxorubicin (PLD), which both showed activity in breast cancer, we conducted a phase II study of this regimen in patients with metastatic breast cancer. Patients and Methods Patients received bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of an every-21-day cycle, along with PLD 30 mg/m2 on day 4. The primary objective was to evaluate the response rate of this combination, while secondary objectives were to obtain further safety data about this combination, to evaluate the time to disease progression (TTP), and to evaluate response by the breast cancer subtype. Results One of 12 evaluable patients had a partial response (8%), while 3 (25%) had stable disease. At 26 months follow-up, the median overall survival was 4.3 months (95% CI, 1.2–26.2) and the median TTP was 1.3 months (95% CI, 0.8–14.0 months). The combination was well tolerated, with the most common events including low-grade nausea and vomiting, neutropenia, and neuropathy, and no cardiac toxicity was seen. Of the 7 tumors subtyped, no association was seen between intrinsic subtype or receptor status and response. Conclusion The combination of PLD and bortezomib was well tolerated but has minimal activity in heavily pretreated unselected metastatic breast cancer. PMID:21147690

Model Selection Indices for Polytomous Items

ERIC Educational Resources Information Center

Kang, Taehoon; Cohen, Allan S.; Sung, Hyun-Jung

2009-01-01

This study examines the utility of four indices for use in model selection with nested and nonnested polytomous item response theory (IRT) models: a cross-validation index and three information-based indices. Four commonly used polytomous IRT models are considered: the graded response model, the generalized partial credit model, the partial credit…

Revisions to the International Neuroblastoma Response Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning Meeting

PubMed Central

Bagatell, Rochelle; Cohn, Susan L.; Pearson, Andrew D.; Villablanca, Judith G.; Berthold, Frank; Burchill, Susan; Boubaker, Ariane; McHugh, Kieran; Nuchtern, Jed G.; London, Wendy B.; Seibel, Nita L.; Lindwasser, O. Wolf; Maris, John M.; Brock, Penelope; Schleiermacher, Gudrun; Ladenstein, Ruth; Matthay, Katherine K.; Valteau-Couanet, Dominique

2017-01-01

Purpose More than two decades ago, an international working group established the International Neuroblastoma Response Criteria (INRC) to assess treatment response in children with neuroblastoma. However, this system requires modification to incorporate modern imaging techniques and new methods for quantifying bone marrow disease that were not previously widely available. The National Cancer Institute sponsored a clinical trials planning meeting in 2012 to update and refine response criteria for patients with neuroblastoma. Methods Multidisciplinary investigators from 13 countries reviewed data from published trials performed through cooperative groups, consortia, and single institutions. Data from both prospective and retrospective trials were used to refine the INRC. Monthly international conference calls were held from 2011 to 2015, and consensus was reached through review by working group leadership and the National Cancer Institute Clinical Trials Planning Meeting leadership council. Results Overall response in the revised INRC will integrate tumor response in the primary tumor, soft tissue and bone metastases, and bone marrow. Primary and metastatic soft tissue sites will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and iodine-123 (123I) –metaiodobenzylguanidine (MIBG) scans or [18F]fluorodeoxyglucose–positron emission tomography scans if the tumor is MIBG nonavid. 123I-MIBG scans, or [18F]fluorodeoxyglucose–positron emission tomography scans for MIBG-nonavid disease, replace technetium-99m diphosphonate bone scintigraphy for osteomedullary metastasis assessment. Bone marrow will be assessed by histology or immunohistochemistry and cytology or immunocytology. Bone marrow with ≤ 5% tumor involvement will be classified as minimal disease. Urinary catecholamine levels will not be included in response assessment. Overall response will be defined as complete response, partial response, minor response, stable disease, or progressive disease. Conclusion These revised criteria will provide a uniform assessment of disease response, improve the interpretability of clinical trial results, and facilitate collaborative trial designs. PMID:28471719

Bortezomib-Containing Regimens for the Treatment of Newly Diagnosed and Relapsed Amyloid Light Chain Amyloidosis: A Single-Center Experience.

PubMed

Jimenez-Zepeda, Victor H; Duggan, Peter; Neri, Paola; Bahlis, Nizar J

2016-06-01

The proteasome is an exciting target for the development of novel anticancer therapies. Recent evidence has suggested that bortezomib, a dipeptide boronate proteasome inhibitor, exhibits unprecedented single-agent activity in amyloid light chain (AL) amyloidosis. We performed a retrospective review of the use of bortezomib-containing regimens to assess the rapidity and quality of response at our institution. A total of 52 patients with documented newly diagnosed and relapsed AL amyloidosis treated with bortezomib-containing regimens were identified from our institutional database. After a median of 4 cycles (range, 1-22 cycles), a hematologic response was seen in 49 patients (94.2%), including a complete response in 15 (28.8%), a very good partial response in 25 (48.1%), and a partial response in 9 (17.3%). At 6 weeks, 37 patients had already achieved a partial response. An organ response at 6 months was documented in 31 patients (59.6%). With respect to the cardiac response, a > 30% decrease in N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) was observed in 17 of 35 evaluable patients (48.6%; NT-proBNP > 650 ng/L) at a median of 6 months. Overall survival was shorter for the patients with NT-proBNP > 5000 ng/L and for those who achieved less than a very good partial response. Bortezomib is a safe and well-tolerated therapy for patients with AL amyloidosis with a rapid hematologic response and cardiac response, as assessed by the NT-proBNP level. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of treatment response to autologous transplantation of noncultured melanocyte/keratinocyte cell suspension in patients with stable vitiligo.

PubMed

Ramos, Mariana Gontijo; Ramos, Daniel Gontijo; Ramos, Camila Gontijo

2017-01-01

Vitiligo is a chronic disease characterized by the appearance of achromic macules caused by melanocyte destruction. Surgical treatments with melanocyte transplantation can be used for stable vitiligo cases. To evaluate treatment response to the autologous transplantation of noncultured epidermal cell suspension in patients with stable vitiligo. Case series study in patients with stable vitiligo submitted to noncultured epidermal cell suspension transplantation and evaluated at least once, between 3 and 6 months after the procedure, to observe repigmentation and possible adverse effects. The maximum follow-up period for some patients was 24 months. Of the 20 patients who underwent 24 procedures, 25% showed an excellent rate of repigmentation, 50% good repigmentation, 15% regular, and 10% poor response. The best results were observed in face and neck lesions, while the worst in extremity lesions (88% and 33% of satisfactory responses, respectively). Patients with segmental vitiligo had a better response (84%) compared to non-segmental ones (63%). As side effects were observed hyperpigmentation of the treated area and the appearance of Koebner phenomenon in the donor area. Some limitations of the study included the small number of patients, a subjective evaluation, and the lack of long-term follow-up on the results. CONCLUSION: Noncultured epidermal cell suspension transplantation is efficient and well tolerated for stable vitiligo treatment, especially for segmental vitiligo on the face and neck.

Modeling and simulation of deformation of hydrogels responding to electric stimulus.

PubMed

Li, Hua; Luo, Rongmo; Lam, K Y

2007-01-01

A model for simulation of pH-sensitive hydrogels is refined in this paper to extend its application to electric-sensitive hydrogels, termed the refined multi-effect-coupling electric-stimulus (rMECe) model. By reformulation of the fixed-charge density and consideration of finite deformation, the rMECe model is able to predict the responsive deformations of the hydrogels when they are immersed in a bath solution subject to externally applied electric field. The rMECe model consists of nonlinear partial differential governing equations with chemo-electro-mechanical coupling effects and the fixed-charge density with electric-field effect. By comparison between simulation and experiment extracted from literature, the model is verified to be accurate and stable. The rMECe model performs quantitatively for deformation analysis of the electric-sensitive hydrogels. The influences of several physical parameters, including the externally applied electric voltage, initial fixed-charge density, hydrogel strip thickness, ionic strength and valence of surrounding solution, are discussed in detail on the displacement and average curvature of the hydrogels.

MR/PET Imaging of the Cardiovascular System.

PubMed

Robson, Philip M; Dey, Damini; Newby, David E; Berman, Daniel; Li, Debiao; Fayad, Zahi A; Dweck, Marc R

2017-10-01

Cardiovascular imaging has largely focused on identifying structural, functional, and metabolic changes in the heart. The ability to reliably assess disease activity would have major potential clinical advantages, including the identification of early disease, differentiating active from stable conditions, and monitoring disease progression or response to therapy. Positron emission tomography (PET) imaging now allows such assessments of disease activity to be acquired in the heart, whereas magnetic resonance (MR) scanning provides detailed anatomic imaging and tissue characterization. Hybrid MR/PET scanners therefore combine the strengths of 2 already powerful imaging modalities. Simultaneous acquisition of the 2 scans also provides added benefits, including improved scanning efficiency, motion correction, and partial volume correction. Radiation exposure is lower than with hybrid PET/computed tomography scanning, which might be particularly beneficial in younger patients who may need repeated scans. The present review discusses the expanding clinical literature investigating MR/PET imaging, highlights its advantages and limitations, and explores future potential applications. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

[Molecular Dynamics of N- and C-terminal Interactions during Autoinhibition and Activation of Formin mDial].

PubMed

Orshanskiy, I A; Popinako, A V; Volokh, O I; Shaitan, K V; Sokolova, O S

2015-01-01

With the method of molecular dynamics, pairs of amino acid residues have been identified on the surface of the interacting formin mDial domains: DID-DAD, which are responsible for the autoinhibition of formin, and the GTPase Rho-DID domain, and control activation. It was found that the most stable interactions are ionic interactions between Glu178 residue and Arg248 residue, as well as hydrophobic interactions between Thr175 and Phe247. The strongest interactions proved to be between the DID domain with Rho-GTPase. These interactions are mediated by specific triple ionic interactions between positively charged amino acid in Rho, and a triplet of amino acids in DID, consisting of two negatively charged amino acids, separated by one uncharged. Binding sites for Rho-GTPase and DAD partially overlap, but various amino acids on the DID participate in interactions with different domains. We discuss the possible conformational changes in formin domains during activation and inactivation.

Interaction of bombesin and its fragments with gold nanoparticles analyzed using surface-enhanced Raman spectroscopy

NASA Astrophysics Data System (ADS)

Tąta, Agnieszka; Szkudlarek, Aleksandra; Kim, Younkyoo; Proniewicz, Edyta

2017-02-01

This work demonstrates the application of commercially available stable surface composed of gold nanograins with diameters ranging from 70 to 226 nm deposited onto silicon wafer for surface-enhanced Raman scattering investigations of biologically active compounds, such as bombesin (BN) and its fragments. BN is an important neurotransmitter involved in a complex signaling pathways and biological responses; for instance, hypertensive action, contractive on uterus, colon or ileum, locomotor activity, stimulation of gastric and insulin secretion as well as growth promotion of various tumor cell lines, including: lung, prostate, stomach, colon, and breast. It has also been shown that 8-14 BN C-terminal fragment partially retains the biological activity of BN. The SERS results for BN and its fragment demonstrated that (1) three amino acids from these peptides sequence; i.e., L-histidine, L-methionine, and L-tryptophan, are involved in the interaction with gold coated silicon wafer and (2) the strength of these interactions depends upon the aforementioned amino acids position in the peptide sequence.

Treatment of eight dogs with nasal tumours with alternating doses of doxorubicin and carboplatin in conjunction with oral piroxicam.

PubMed

Langova, V; Mutsaers, A J; Phillips, B; Straw, R

2004-11-01

To determine the efficacy and toxicity of chemotherapy in the treatment of canine nasal tumours. Retrospective clinical study Eight dogs with histologically confirmed nasal tumours were staged by means of complete blood count, serum biochemical analysis, cytological analysis of fine needle aspirate of the regional lymph nodes, thoracic radiographs and computed tomography scan of the nasal cavity. All dogs were treated with alternating doses of doxorubicin, carboplatin and oral piroxicam. All dogs were monitored for side effects of chemotherapy and evaluated for response to treatment by computed tomography scan of the nasal cavity after the first four treatments. Complete remission was achieved in four dogs, partial remission occurred in two dogs and two had stable disease on the basis of computed tomography evaluation. There was resolution of clinical signs after one to two doses of chemotherapy in all dogs. This chemotherapy protocol was efficacious and well tolerated in this series of eight cases of canine nasal tumours.

Retrospective evaluation of toceranib (Palladia) treatment for canine metastatic appendicular osteosarcoma.

PubMed

Kim, Changseok; Matsuyama, Arata; Mutsaers, Anthony J; Woods, J Paul

2017-10-01

This retrospective study evaluated the outcomes of dogs with macroscopic pulmonary metastasis of appendicular osteosarcoma (OSA) treated with toceranib. Medical records of 20 dogs with macroscopic pulmonary metastasis of OSA that received toceranib were reviewed. The median dose and duration of toceranib administration were 2.52 mg/kg (range: 2.12 to 2.72 mg/kg) and 60 days (range: 17 to 231 days). The median progression free survival (PFS) and overall survival (OS) were 36 days (range: 17 to 231 days) and 90 days (range: 17 to 433 days), respectively. The clinical benefit rate was 10% (2/20; 1 partial response and 1 stable disease). The longest length of initial pulmonary nodules had significant impact on both PFS ( P = 0.01) and OS ( P = 0.02). The prognosis for dogs with metastatic OSA was poor with only 10% of dogs showing clinical benefit from toceranib. These results suggest that toceranib may not improve outcome in dogs with macroscopic pulmonary metastasis of OSA.

A network meta-analysis on the efficacy of sixteen targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer

PubMed Central

Ba-Sang, Dan-Zeng; Long, Zi-Wen; Teng, Hao; Zhao, Xu-Peng; Qiu, Jian; Li, Ming-Shan

2016-01-01

Objective A network meta-analysis was conducted comparing the short-term efficacies of 16 targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer (CRC). Results Twenty-seven RCTs were ultimately incorporated into this network meta-analysis. Compared with chemotherapy alone, bevacizumab + chemotherapy, panitumumab + chemotherapy and conatumumab + chemotherapy had higher PR rate. Bevacizumab + chemotherapy, cetuximab + chemotherapy, panitumumab + chemotherapy, trebananib + chemotherapy and conatumumab + chemotherapy had higher ORR rate in comparison to chemotherapy alone. Furthermore, bevacizumab + chemotherapy had higher DCR rate than chemotherapy alone. The results of our cluster analysis showed that chemotherapy combined with bevacizumab, cetuximab, panitumumab, conatumumab, ganitumab, or brivanib + cetuximab had better efficacies for the treatment of advanced/metastatic CRC in comparison to chemotherapy alone. Materials and Methods Electronic databases were comprehensively searched for potential and related randomized controlled trials (RCTs). Direct and indirect evidence were incorporated for evaluation of stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR) and overall response ratio (ORR) by calculating odds ratio (OR) and 95% confidence intervals (CI), and using the surface under the cumulative ranking curve (SUCRA). Conclusions These results indicated that bevacizumab + chemotherapy, panitumumab + chemotherapy, conatumumab + chemotherapy and brivanib + cetuximab + chemotherapy may have better efficacies for the treatment of advanced/metastatic CRC. PMID:27806321

Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer.

PubMed

Philip, Philip A; Mahoney, Michelle R; Holen, Kyle D; Northfelt, Donald W; Pitot, Henry C; Picus, Joel; Flynn, Patrick J; Erlichman, Charles

2012-05-01

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC). Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2-stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child's Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point. Twenty-seven patients with advanced HCC (median age, 60 years) were enrolled in this multi-institutional study. The proportion of patients with Child's A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8-7.1). Median survival time was 9.5 months (95% CI, 7.1-17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea. In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression-free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients. Copyright © 2011 American Cancer Society.

Phase 2 Study of Bevacizumab Plus Erlotinib in Patients With Advanced Hepatocellular Cancer

PubMed Central

Philip, Philip A.; Mahoney, Michelle R.; Holen, Kyle D.; Northfelt, Donald W.; Pitot, Henry C.; Picus, Joel; Flynn, Patrick J.; Erlichman, Charles

2013-01-01

BACKGROUND Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC). METHODS Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2-stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child’s Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point. RESULTS Twenty-seven patients with advanced HCC (median age, 60 years) were enrolled in this multi-institutional study. The proportion of patients with Child’s A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8-7.1). Median survival time was 9.5 months (95% CI, 7.1-17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea. CONCLUSIONS In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression-free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients. PMID:21953248

Adaptive, dose-finding phase 2 trial evaluating the safety and efficacy of ABT-089 in mild to moderate Alzheimer disease.

PubMed

Lenz, Robert A; Pritchett, Yili L; Berry, Scott M; Llano, Daniel A; Han, Shu; Berry, Donald A; Sadowsky, Carl H; Abi-Saab, Walid M; Saltarelli, Mario D

2015-01-01

ABT-089, an α4β2 neuronal nicotinic receptor partial agonist, was evaluated for efficacy and safety in mild to moderate Alzheimer disease patients receiving stable doses of acetylcholinesterase inhibitors. This phase 2 double-blind, placebo-controlled, proof-of-concept, and dose-finding study adaptively randomized patients to receive ABT-089 (5, 10, 15, 20, 30, or 35 mg once daily) or placebo for 12 weeks. The primary efficacy endpoint was the Alzheimer's Disease Assessment Scale, cognition subscale (ADAS-Cog) total score. A Bayesian response-adaptive randomization algorithm dynamically assigned allocation probabilities based on interim ADAS-Cog total scores. A normal dynamic linear model for dose-response relationships and a longitudinal model for predicting final ADAS-cog score were employed in the algorithm. Stopping criteria for futility or success were defined. The futility stopping criterion was met, terminating the study with 337 patients randomized. No dose-response relationship was observed and no dose demonstrated statistically significant improvement over placebo on ADAS-Cog or any secondary endpoint. ABT-089 was well tolerated at all dose levels. When administered as adjunctive therapy to acetylcholinesterase inhibitors, ABT-089 was not efficacious in mild to moderate Alzheimer disease. The adaptive study design enabled the examination of a broad dose range, enabled rapid determination of futility, and reduced patient exposure to nonefficacious doses of the investigational compound.

Can a Mathematical Model Predict an Individual’s Trait-like Response to Both Total and Partial Sleep Loss?

DTIC Science & Technology

2015-01-01

Can a mathematical model predict an individual’s trait-like response to both total and partial sleep loss? SR IDHAR RAMAKR I SHNAN 1 , WE I LU 1 , SR...biomathematical model, psychomotor vigilance task, sleep -loss phenotype, trait preservation, two-process model Correspondence Jaques Reifman, PhD...trait-like response to sleep loss. However, it is not known whether this trait-like response can be captured by a mathemat- ical model from only one

Long-term dynamic and pseudo-state modeling of complete partial nitrification process at high nitrogen loading rates in a sequential batch reactor (SBR).

PubMed

Soliman, Moomen; Eldyasti, Ahmed

2017-06-01

Recently, partial nitrification has been adopted widely either for the nitrite shunt process or intermediate nitrite generation step for the Anammox process. However, partial nitrification has been hindered by the complexity of maintaining stable nitrite accumulation at high nitrogen loading rates (NLR) which affect the feasibility of the process for high nitrogen content wastewater. Thus, the operational data of a lab scale SBR performing complete partial nitrification as a first step of nitrite shunt process at NLRs of 0.3-1.2kg/(m 3 d) have been used to calibrate and validate a process model developed using BioWin® in order to describe the long-term dynamic behavior of the SBR. Moreover, an identifiability analysis step has been introduced to the calibration protocol to eliminate the needs of the respirometric analysis for SBR models. The calibrated model was able to predict accurately the daily effluent ammonia, nitrate, nitrite, alkalinity concentrations and pH during all different operational conditions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Oxygen stoichiometry, phase stability, and thermodynamic behavior of the lead-doped Bi-2223 and Ag/Bi-2223 systems

NASA Astrophysics Data System (ADS)

Tetenbaum, M.; Hash, M.; Tani, B. S.; Luo, J. S.; Maroni, V. A.

1995-02-01

Electromotive-force (EMF) measurements of oxygen fugacities as a function of stoichiometry have been made in the lead-doped Bi-2223 superconducting system in the temperature range 700-815°C by means of an oxygen titration technique that employs an yttria-stabilized zirconia electrolyte. The results of our studies indicate that processing or annealing lead-doped Bi-2223 at temperatures ranging from 750 to 815°C and at oxygen partial pressures ranging from ∼ 0.02 to 0.2 atm should preserve Bi-2223 as essentially single-phase material. Thermodynamic assessments of the partial molar quantities ΔS¯( O2) andΔH¯( O2) indicate that the plateau regions in the plot of oxygen partial pressure versus oxygen stoichiometry ( x) can be represented by the diphasic CuOCu 2O system. In accord with the EMF measurements, it was found that lead-doped Bi-2223 in a silver sheath is stable at 815°C for oxygen partial pressures between 0.02 and 0.13 atm.

Thermodynamic and nonstoichiometric behavior of the lead-doped Bi-2223 system

NASA Astrophysics Data System (ADS)

Tetenbaum, M.; Hash, M.; Tani, B. S.; Luo, J. S.; Maroni, V. A.

1994-12-01

Electromotive force (EMF) measurements of oxygen fugacities as a function of stoichiometry have been made in the lead-doped Bi-2223 superconducting system in the temperature range 700-815°C by means of an oxygen titration technique. The results of our studies indicate that processing or annealing lead-doped Bi-2223 at temperatures ranging from 700 to 815°C and at oxygen partial pressures ranging from ∼0.02 to 0.2 atm should tend to preserve Bi-2223 as essentially single-phase material. Thermodynamic assessments of partial molar quantities indicate that the plateau regions can be represented by the diphasic CuOCu 2O system. In accord with the EMF measurements, it was found that lead-doped Bi-2223 in a silver sheath is stable at 815°C for oxygen partial pressures between 0.02 and 0.13 atm. Long-duration post anneals of silver-clad Bi-2223 filaments at 825°C and an oxygen partial pressure of 0.075 atm eliminated Bi-2212 intergrowths with a concomitant increase in the superconducting transition sharpness.

Temozolomide is an active agent in children with recurrent medulloblastoma/primitive neuroectodermal tumor: an Italian multi-institutional phase II trial

PubMed Central

Cefalo, Graziella; Massimino, Maura; Ruggiero, Antonio; Barone, Giuseppe; Ridola, Vita; Spreafico, Filippo; Potepan, Paolo; Abate, Massimo E.; Mascarin, Maurizio; Garrè, Maria Luisa; Perilongo, Giorgio; Madon, Enrico; Colosimo, Cesare; Riccardi, Riccardo

2014-01-01

Background The aim of this study was to assess the objective response rate (ORR) of children and young adults with recurrent medulloblastoma/primitive neuroectodermal tumor (MB/PNET) treated with temozolomide (TMZ). The secondary purpose was to analyze the toxicity profile of TMZ when administered orally for 5 days in 3 divided daily doses every 28 days. Methods Forty-two patients with recurrent MB/PNET, aged 21 years and younger, were recruited. Patients were treated with oral TMZ. Starting doses ranged from 120 to 200 mg/m2/day based on previous treatments. A craniospinal MRI was performed prior to the first cycle of TMZ and following every 2 cycles of treatment. Results Median age was 10 years (range, 2–21 years). Forty of 42 patients were assessed for response and toxicity. The objective response rate was 42.5%: 6 patients achieved a complete response, 11 had a partial response, and 10 had stable disease. Progression-free survival rates for all patients at 6 and 12 months were 30% and 7.5%, respectively. Their median overall survival rates at 6 and 12 months were 42.5% and 17.5%, respectively. No major extrahematological effects or life-threatening events were reported. The most common grade 3/4 toxicity included thrombocytopenia (17.5%), neutropenia (7.5%), and anemia (2.5%). Conclusions TMZ proved to be an effective agent in children and young adults with MB/PNET, heavily pre-treated, with a tolerable toxicity profile. PMID:24482446

Activity of thalidomide and capecitabine in patients with advanced hepatocellular carcinoma.

PubMed

Ang, Soo-Fan; Tan, Sze-Huey; Toh, Han-Chong; Poon, Donald Y H; Ong, Simon Y K; Foo, Kian-Fong; Choo, Su-Pin

2012-06-01

Thalidomide has shown modest activity in advanced hepatocellular carcinomas (HCCs). Single-agent capecitabine has also been used in patients with HCC, with objective responses being reported. In our study, we review the use of thalidomide and capecitabine combination in advanced HCC. From November 2003 and September 2008, 42 patients with advanced HCC who were not eligible for clinical trial or conventional chemotherapy were treated with oral capecitabine (2000 mg/m/d) for 14 days every 3 weeks and oral thalidomide at the doses of 50 to 200 mg/d. Almost 50% of patients had Child-Pugh B or C liver cirrhosis and a history of regional or systemic therapy. Three patients achieved complete responses lasting more than 52 weeks, including 1 patient who achieved pathological complete response and underwent curative resection. There were 3 patients with partial responses and 13 with stable disease. Median overall survival of all 42 patients was 9.9 months. The median progression-free survival was 5.1 months. The presence of ascites, portal vein thrombosis, and poorer Child-Pugh liver cirrhosis status also resulted in significantly poorer survival outcome. Treatment was well tolerated. Fatigue was the most common side effect occurring in 16 (38%) patients, but only 1 patient had grade 3 toxicity and had to stop treatment. Two other patients developed grade 3 palmar-plantar erythrodysesthesia from capecitabine. The combination of thalidomide and capecitabine has activity in advanced HCC and can result in complete pathological response. Treatment is well tolerated even in less-fit patients who have been pretreated and deserve further study.

Computed Tomography Assessment of Hepatic Metastases of Breast Cancer with Revised Response Evaluation Criteria in Solid Tumors (RECIST) Criteria (Version 1.1): Inter-Observer Agreement.

PubMed

Ghobrial, Fady Emil Ibrahim; Eldin, Manal Salah; Razek, Ahmed Abdel Khalek Abdel; Atwan, Nadia Ibrahim; Shamaa, Sameh Sayed Ahmed

2017-01-01

To assess inter-observer agreement of revised RECIST criteria (version 1.1) for computed tomography assessment of hepatic metastases of breast cancer. A prospective study was conducted in 28 female patients with breast cancer and with at least one measurable metastatic lesion in the liver that was treated with 3 cycles of anthracycline-based chemotherapy. All patients underwent computed tomography of the abdomen with 64-row multi- detector CT at baseline and after 3 cycles of chemotherapy for response assessment. Image analysis was performed by 2 observers, based on the RECIST criteria (version 1.1). Computed tomography revealed partial response of hepatic metastases in 7 patients (25%) by one observer and in 10 patients (35.7%) by the other observer, with good inter-observer agreement (k=0.75, percent agreement of 89.29%). Stable disease was detected in 19 patients (67.8%) by one observer and in 16 patients (57.1%) by the other observer, with good agreement (k=0.774, percent agreement of 89.29%). Progressive disease was detected in 2 patients (7.2%) by both observers, with perfect agreement (k=1, percent agreement of 100%). The overall inter-observer agreement in the CT-based response assessment of hepatic metastasis between the two observers was good ( k =0.793, percent agreement of 89.29%). We concluded that computed tomography is a reliable and reproducible imaging modality for response assessment of hepatic metastases of breast cancer according to the RECIST criteria (version 1.1).

Apatinib for advanced nonsmall-cell lung cancer: A retrospective case series analysis.

PubMed

Yang, Chengxi; Feng, Wen; Wu, Di

2018-01-01

Apatinib, a tyrosine kinase inhibitor which selectively inhibits vascular endothelial growth factor receptor-2, has been shown to be beneficial to patients with a variety of cancers, including advanced nonsmall-cell lung cancer (NSCLC). Thus, this study was aimed to retrospectively assess the efficacy and safety of apatinib in patients with advanced/metastatic NSCLC who failed more than two lines of treatment. Twenty-three NSCLC patients were involved in this study, who received oral apatinib at a daily dose of 250/500/750 mg, with the progression after the failure of second-line therapy. Treatment was continued until disease progression. The tumor assessments were determined according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Safety was evaluated with adverse reactions and toxicities based on the Common Terminology Criteria for Adverse Events (version 4.0). Response and safety for the included patients were evaluated every 8 weeks. In this study, 23 NSCLC patients were followed from January 2015 to December 2016. Available image efficacy was obtained in 22 patients, including 4 identified as partial responses, 17 stable disease, and 1 progressive disease; no complete responses was observed. The objective response rate was 18.2%, and the disease control rate was 95.5%. Median progression free survival and overall survival for apatinib were 203 days (95% CI, 120-269) and 227 days (95% CI, 146-294), respectively. The most frequent treatment-related adverse events were hypertension, gastrointestinal reactions, and hand-foot skin reaction. Apatinib exhibited modest activity and acceptable toxicity for advanced NSCLC after the failure of chemotherapy or other targeted therapy.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mimura, Hidefumi, E-mail: mimura@marianna-u.ac.jp; Arai, Yasuaki, E-mail: arai-y3111@mvh.biglobe.ne.jp; Yamakado, Koichiro, E-mail: yama@clin.medic.mie-u.ac.jp

PurposeThis multicenter phase I/II study evaluated the safety, feasibility, and initial efficacy of radiofrequency ablation (RFA) for small malignant renal tumors.MethodsThirty-three patients were enrolled in the study. A single session of RFA was performed in patients with a renal tumor of 1–3 cm in greatest diameter, with the exception of lesions adjacent to the renal hilum. The primary endpoint was the safety of renal RFA, and the secondary endpoints were its feasibility and initial efficacy for local control, as well as the incidence and grade of adverse events. Clinical efficacy was evaluated by CT scans within 1 week and at a furthermore » 4 weeks after the procedure using the criteria adapted from the Response Evaluation Criteria in Solid Tumors.ResultsThe RFA procedure was completed in 100 % (95 % confidence interval [CI] 89–100 %) of all 33 patients. There were no severe adverse events (0 % [95 % CI 0–11 %]). Among the 33 patients, a complete response, partial response, progressive disease, and stable disease were seen in 28 (85 %), 0 (0 %), one (3 %), and one (3 %) patient(s), respectively, with a tumor response rate of 85 % [95 % CI 68–95 %]). Three patients (9 %), including one ineligible patient (3 %), were not evaluable. Out of 30 evaluable patients, a complete response was achieved in 28 (93 %).ConclusionThe current multicenter trial revealed that RFA is a safe, feasible, and effective treatment for small malignant renal tumors in patients who are not candidates for surgery.« less

NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors

PubMed Central

Mansky, Patrick J.; Sannes, Timothy S.; Johnson, Laura Lee; Blackman, Marc R.; Grem, Jean L.; Swain, Sandra M.; Monahan, Brian P.

2013-01-01

Purpose. European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. Methods. Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. Results. DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m2 and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. Conclusion. GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone. PMID:24285980

Down-regulation of heat-shock protein 70 (HSP-70) correlated with responsiveness to neoadjuvant aromatase inhibitor therapy in breast cancer patients.

PubMed

Yiu, Christopher C P; Chanplakorn, Niramol; Chan, Monica S M; Loo, Wings T Y; Chow, Louis W C; Toi, Masakazu; Sasano, Hironobu

2010-09-01

Aromatase inhibitor (AI) has been established as an effective endocrine therapy in estrogen receptor (ER)-positive postmenopausal breast cancer patients. Our recent proteomic analysis demonstrated that ten proteins were significantly altered in their expression levels before and after the therapy in the patients receiving neoadjuvant AI. Among these newly identified proteins, heat-shock protein 70 (HSP-70) was the most significantly correlated with both clinical and pathological responses. Therefore, in this study, we further evaluated the significance of this HSP-70 alteration using immunohistochemistry. A total of 32 patients treated with neoadjuvant exemestane or letrozole in whom pre- and post-treatment tumor tissues were available were included. Immunohistochemical evaluation of ER, progesterone receptor (PgR), Her-2, Ki-67 and HSP-70 was performed. Results obtained were compared to both clinical and biological responses of the patients. The majority of the patients responded to treatment (16 patients with partial response, 14 with stable disease and 2 with progressive disease). The means of ER, Ki-67 and HSP-70 were significantly different between treatment responders and non-responders. Decrement of HSP-70 and Ki-67 after AI treatment and pretreatment Ki-67 labeling index of >10% tumor cells were significantly associated with clinical responsiveness to AI treatment (p<0.0001). There was a significant positive correlation between changes of HSP-70 and Ki-67 before and after the therapy. Decrement of HSP-70 in breast carcinoma cells plays important roles in therapeutic mechanisms of AIs through suppressing tumor cell proliferation in breast cancer patients.

Nitrogen and sulfur co-doping of partially exfoliated MWCNTs as 3-D structured electrocatalysts for the oxygen reduction reaction

DOE PAGES

Wang, Jie; Wu, Zexing; Han, Lili; ...

2016-03-14

Preventing the stacking of graphene sheets is of vital importance for highly efficient and stable fuel cell electrocatalysts. Here, we report a 3-D structured carbon nanotube intercalated graphene nanoribbon with N/S co-doping. The nanocomposite is obtained by using high temperature heat-treated thiourea with partially unzipped multi-walled carbon nanotubes. This unique structure preserves both the properties of carbon nanotubes and graphene, exhibiting excellent catalytic performance for the ORR with similar onset and half-wave potentials to those of Pt/C electrocatalysts. Furthermore, the stereo structured composite exhibits distinct advantages in long-term stability and methanol poisoning tolerance in comparison to Pt/C.

Insight in stable schizophrenia: relations with psychopathology and cognition.

PubMed

Mingrone, Cinzia; Rocca, Paola; Castagna, Filomena; Montemagni, Cristiana; Sigaudo, Monica; Scalese, Mara; Rocca, Giuseppe; Bogetto, Filippo

2013-07-01

This study evaluated the relationship among insight, sociodemographic and clinical variables, symptoms and cognitive functions in a population of outpatients with stable schizophrenia, in order to identify possible contributing factors to awareness. Two-hundred and seventy-six consecutive outpatients with stable schizophrenia were enrolled in a cross-sectional study. All subjects were assessed by psychiatric scales and interview, and a wide neuropsychological battery. A factor analysis was performed to identify cognitive factors and multiple regression analyses were executed to test the contribution of variables considered to insight. Our results showed that positive and negative symptoms, executive functions, verbal memory-learning were contributors of awareness of mental illness; positive and negative symptoms explained variability in awareness of the need for treatment; positive symptoms and executive functions contributed to awareness of the social consequences of disorder. These results suggested that insight was partially influenced by positive and negative symptoms and by cognitive functions. A complex system of overlapping variables may underlie impaired insight, contributing to a different extent to specific dimensions of poor insight in patients with stable schizophrenia. Copyright © 2013 Elsevier Inc. All rights reserved.

Stable and Metastable InGaAs/GaAs Island Shapes and Surfactant-like Suppression of the Wetting Transformation

NASA Technical Reports Server (NTRS)

Leon, R.; Lobo, C.; Zou, J.; Romeo, T.; Cockayne, D. J. H.

1998-01-01

Diverging behaviors are observed in the InGaAs/GaAs Stranski-Krastanow (S-K) island formation during vapor phase epitaxy: varying group V partial pressures gives different critical thicknesses for the onset of the S-K transformation, island surface coverages, ratios between coherent and incoherent islands, and dissimilar morphologies upon annealing.

Hydrogen /Hydride/-air secondary battery

NASA Technical Reports Server (NTRS)

Sarradin, J.; Bronoel, G.; Percheron-Guegan, A.; Achard, J. C.

1979-01-01

The use of metal hydrides as negative electrodes in a hydrogen-air secondary battery seems promising. However, in an unpressurized cell, more stable hydrides that LaNi5H6 must be selected. Partial substitutions of nickel by aluminium or manganese increase the stability of hydrides. Combined with an air reversible electrode, a specific energy close to 100 Wh/kg can be expected.

Dynamics of curved fronts in systems with power-law memory

NASA Astrophysics Data System (ADS)

Abu Hamed, M.; Nepomnyashchy, A. A.

2016-08-01

The dynamics of a curved front in a plane between two stable phases with equal potentials is modeled via two-dimensional fractional in time partial differential equation. A closed equation governing a slow motion of a small-curvature front is derived and applied for two typical examples of the potential function. Approximate axisymmetric and non-axisymmetric solutions are obtained.

Effective Treatment of Transmissible Venereal Tumors in Dogs with Vincristine and IL2.

PubMed

DEN Otter, Willem; Hack, Margot; Jacobs, John J L; Tan, Jurgen F V; Rozendaal, Lawrence; VAN Moorselaar, R Jeroen A

2015-06-01

To improve treatment of inoperable transmissible venereal tumors (TVTs) in dogs. Recently, we showed that TVT is sensitive to intratumoral treatment with interleukin-2 (IL2). In addition it is known that TVT is sensitive to intravenous treatment with vincristine. In the present study we tried to establish the therapeutic effect of intratumoral treatment with vincristine and IL2. We treated 12 dogs with TVT with 1-4 intratumoral treatments with vincristine and IL-2. Per treatment we used vincristine (0.5-0.7 mg/m(2)) and IL2 (2×10(6) units). The injections were given at weekly intervals. Early therapeutic effects were: three complete regressions, four partial regressions, three stable disease, and two progressive disease. Late therapeutic effects were established 45-60 months after the first presentation; there were five complete regressions, no partial regressions, nor stable or progressive diseases. Interestingly, all five dogs with late therapeutic effects were in good health. No tumor recurrence was noted. Intratumoral treatment of TVT with vincristine and IL2 appears to have impressive therapeutic effects. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

The evolution of continental roots in numerical thermo-chemical mantle convection models including differentiation by partial melting

NASA Astrophysics Data System (ADS)

de Smet, J. H.; van den Berg, A. P.; Vlaar, N. J.

1999-09-01

Incorporating upper mantle differentiation through decompression melting in a numerical mantle convection model, we demonstrate that a compositionally distinct root consisting of depleted peridotite can grow and remain stable during a long period of secular cooling. Our modeling results show that in a hot convecting mantle partial melting will produce a compositional layering in a relatively short time of about 50 Ma. Due to secular cooling mantle differentiation finally stops before 1 Ga. The resulting continental root remains stable on a billion year time scale due to the combined effects of its intrinsically lower density and temperature-dependent rheology. Two different parameterizations of the melting phase-diagram are used in the models. The results indicate that during the Archaean melting occurred on a significant scale in the deep regions of the upper mantle, at pressures in excess of 15 GPa. The compositional depths of continental roots extend to 400 km depending on the potential temperature and the type of phase-diagram parameterization used in the model. The results reveal a strong correlation between lateral variations of temperature and the thickness of the continental root. This shows that cold regions in cratons are stabilized by a thick depleted root.

Partial purification and characterization of polyphenol oxidase from banana (Musa sapientum L.) peel.

PubMed

Yang, C P; Fujita, S; Kohno, K; Kusubayashi, A; Ashrafuzzaman, M; Hayashi, N

2001-03-01

Polyphenol oxidase (EC 1.10.3.1, o-diphenol: oxygen oxidoreductase, PPO) of banana (Musa sapientum L.) peel was partially purified about 460-fold with a recovery of 2.2% using dopamine as substrate. The enzyme showed a single peak on Toyopearl HW55-S chromatography. However, two bands were detected by staining with Coomassie brilliant blue on PAGE: one was very clear, and the other was faint. Molecular weight for purified PPO was estimated to be about 41 000 by gel filtration. The enzyme quickly oxidized dopamine, and its Km value (Michaelis constant) for dopamine was 3.9 mM. Optimum pH was 6.5 and the PPO activity was quite stable in the range of pH 5-11 for 48 h. The enzyme had an optimum temperature at 30 degrees C and was stable up to 60 degrees C after heat treatment for 30 min. The enzyme activity was strongly inhibited by sodium diethyldithiocarbamate, potassium cyanide, L-ascorbic acid, and cysteine at 1 mM. Under a low buffer capacity, the enzyme was also strongly inhibited by citric acid and acetic acid at 10 mM.

C and N stable isotope signatures reveal constraints to nutritional modes in orchids from the Mediterranean and Macaronesia.

PubMed

Liebel, Heiko T; Bidartondo, Martin I; Preiss, Katja; Segreto, Rossana; Stöckel, Marcus; Rodda, Michele; Gebauer, Gerhard

2010-06-01

We compared the nutritional modes and habitats of orchids (e.g., autotrophic, partially or fully mycoheterotrophic) of the Mediterranean region and adjacent islands of Macaronesia. We hypothesized that ecological factors (e.g., relative light availability, surrounding vegetation) determine the nutritional modes of orchids and thus impose restrictions upon orchid distribution. Covering habitats from dark forests to open sites, orchid samples of 35 species from 14 genera were collected from 20 locations in the Mediterranean and Macaronesia to test for mycoheterotrophy. Mycorrhizal fungi were identified via molecular analyses, and stable isotope analyses were applied to test whether organic nutrients are gained from the fungal associates. Our results show that orchids with partial or full mycoheterotrophy among the investigated species are found exclusively in Neottieae thriving in light-limited forests. Neottioid orchids are missing in Macaronesia, possibly because mycoheterotrophy is constrained by the lack of suitable ectomycorrhizal fungi. Furthermore, most adult orchids of open habitats in the Mediterranean and Macaronesia show weak or no N gains from fungi and no C gain through mycoheterotrophy. Instead isotope signatures of some of these species indicate net plant-to-fungus C transfer.

Density functional theory study of defects in unalloyed δ-Pu

DOE PAGES

Hernandez, S. C.; Freibert, F. J.; Wills, J. M.

2017-03-19

Using density functional theory, we explore in this paper various classical point and complex defects within the face-centered cubic unalloyed δ-plutonium matrix that are potentially induced from self-irradiation. For plutonium only defects, the most energetically stable defect is a distorted split-interstitial. Gallium, the δ-phase stabilizer, is thermodynamically stable as a substitutional defect, but becomes unstable when participating in a complex defect configuration. Finally, complex uranium defects may thermodynamically exist as uranium substitutional with neighboring plutonium interstitial and stabilization of uranium within the lattice is shown via partial density of states and charge density difference plots to be 5f hybridization betweenmore » uranium and plutonium.« less

Thermodynamic investigations on the growth of CuAlO2 delafossite crystals

NASA Astrophysics Data System (ADS)

Wolff, Nora; Klimm, Detlef; Siche, Dietmar

2018-02-01

Simultaneous differential thermal analysis (DTA) and thermogravimetric (TG) measurements with copper oxide/aluminum oxide mixtures were performed in atmospheres with varying oxygen partial pressures and with crucibles made of different materials. Only sapphire and platinum crucibles proved to be stable under conditions that are useful for the growth of CuAlO2 delafossite single crystals. Then the ternary phase diagram Al2O3-CuO-Cu and its isopleth section Cu2O-Al2O3 were redetermined. Millimeter sized crystals could be obtained from copper oxide melts with 1-2 mol% addition of aluminum oxide that are stable in platinum crucibles held in oxidizing atmosphere containing 15-21% oxygen.

Density functional theory study of defects in unalloyed δ-Pu

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hernandez, S. C.; Freibert, F. J.; Wills, J. M.

Using density functional theory, we explore in this paper various classical point and complex defects within the face-centered cubic unalloyed δ-plutonium matrix that are potentially induced from self-irradiation. For plutonium only defects, the most energetically stable defect is a distorted split-interstitial. Gallium, the δ-phase stabilizer, is thermodynamically stable as a substitutional defect, but becomes unstable when participating in a complex defect configuration. Finally, complex uranium defects may thermodynamically exist as uranium substitutional with neighboring plutonium interstitial and stabilization of uranium within the lattice is shown via partial density of states and charge density difference plots to be 5f hybridization betweenmore » uranium and plutonium.« less

In response to partial plant shading, the lack of phytochrome A does not directly induce leaf senescence but alters the fine-tuning of chlorophyll biosynthesis

PubMed Central

Brouwer, Bastiaan; Gardeström, Per; Keech, Olivier

2014-01-01

Phytochrome is thought to control the induction of leaf senescence directly, however, the signalling and molecular mechanisms remain unclear. In the present study, an ecophysiological approach was used to establish a functional connection between phytochrome signalling and the physiological processes underlying the induction of leaf senescence in response to shade. With shade it is important to distinguish between complete and partial shading, during which either the whole or only a part of the plant is shaded, respectively. It is first shown here that, while PHYB is required to maintain chlorophyll content in a completely shaded plant, only PHYA is involved in maintaining the leaf chlorophyll content in response to partial plant shading. Second, it is shown that leaf yellowing associated with strong partial shading in phyA-mutant plants actually correlates to a decreased biosynthesis of chlorophyll rather than to an increase of its degradation. Third, it is shown that the physiological impact of this decreased biosynthesis of chlorophyll in strongly shaded phyA-mutant leaves is accompanied by a decreased capacity to adjust the Light Compensation Point. However, the increased leaf yellowing in phyA-mutant plants is not accompanied by an increase of senescence-specific molecular markers, which argues against a direct role of PHYA in inducing leaf senescence in response to partial shade. In conclusion, it is proposed that PHYA, but not PHYB, is essential for fine-tuning the chlorophyll biosynthetic pathway in response to partial shading. In turn, this mechanism allows the shaded leaf to adjust its photosynthetic machinery to very low irradiances, thus maintaining a positive carbon balance and repressing the induction of leaf senescence, which can occur under prolonged periods of shade. PMID:24604733

Comparison of qualitative and quantitative CT and MRI parameters for monitoring of longitudinal spine involvement in patients with multiple myeloma.

PubMed

Horger, M; Fritz, J; Thaiss, W M; Ditt, H; Weisel, K; Haap, M; Kloth, Christopher

2018-03-01

To compare qualitative and quantitative computed tomography (CT) and magnetic resonance imaging (MRI) parameters for longitudinal disease monitoring of multiple myeloma (MM) of the axial skeleton. We included 31 consecutive patients (17 m; mean age 59.20 ± 8.08 years) with MM, who underwent all baseline (n = 31) and at least one or more (n = 47) follow-up examinations consisting of multi-parametric non-enhanced whole-body MRI ( WB MRI) and non-enhanced whole-body reduced-dose thin-section MDCT (NEWBMDCT) between 06/2013 and 09/2016. We classified response according to qualitative CT criteria into progression (PD), stable(SD), partial/very good partial (PR/VGPR) and complete response(CR), grouping the latter three together for statistical analysis because CT cannot reliably assess PR and CR. Qualitative MR-response criteria were defined and grouped similarly to CT using longitudinal quantification of signal-intensity changes on T1w/STIR/ T2*w and calculating ADC-values. Standard of reference was the hematological laboratory (M-gradient). Hematological response categories were CR (14/47, 29.7%), PR (2/47, 4.2%), SD (16/47, 34.0%) and PD (15/47, 29.9%). Qualitative-CT-evaluation showed PD in 12/47 (25.5%) and SD/PR/VGPR/CR in 35/47 (74.5%) cases. These results were confirmed by quantitative-CT in all focal lytic lesions (p < 0.001). Quantitative-CT at sites with diffuse bone involvement showed significant increase of maximum bone attenuation (p < 0.001*) and significant decrease of minimal bone (p < 0.002*) in the SD/PR/VGPR/CR group. Qualitative MRI showed PD in 14/47 (29.7%) and SD/PR/VGPR/CR in 33/47 (70.3%). Quantitative MRI diagnosis showed a statistically significant decrease in signal intensity on short tau inversion recovery sequences (STIR) in bone marrow in patients with diffuse bone marrow involvement achieving SD/PR/VGPR/CR (p < 0.001*). Imaging response monitoring using MRI is superior to CT only if qualitative parameters are used, whereas there was no definite benefit from using quantitative parameters with either CT or MRI.

Assessing the outcomes of HIV-infected persons receiving treatment for Kaposi sarcoma in Conakry-Guinea.

PubMed

Bekolo, Cavin E; Soumah, Mohamed M; Tiemtore, Ousseni W; Diallo, Abdourahimi; Yuma, Joseph-Desire; Di Stefano, Letizia; Metcalf, Carol; Cisse, Mohamed

2017-12-02

Médecins Sans Frontières is supporting comprehensive HIV care and treatment for Kaposi Sarcoma (KS) in Guinea, where antiretroviral coverage is low and access to KS treatment is very limited. We aimed to evaluate treatment response and survival outcomes of epidemic KS in this setting. Retrospective survival analysis of routinely collected clinical data of HIV-infected patients with clinically diagnosed KS, receiving ART and chemotherapy consisting of a combination of bleomycin and vincristine at the Donka National Hospital in Conakry between 2012 and 2015. A total of 225 patients were enrolled for KS treatment within the three-year period. Late presentation with stage T1 disease was common (82.7%). At the end of a median of 8 cycles of chemotherapy (IQR: 2-12), complete remission was observed in 65 (28.9%), partial remission in 53 (23.6%), stable disease in 15 (6.7%) and unknown response for all 92 (40.9%) patients who dropped out of care. The chances of achieving complete remission doubled after each additional cycle of chemotherapy (aOR = 2.09 95% CI: 1.44-3.01) but were reduced by about two-thirds for each additional month delay between treatment and onset of KS (aOR = 0.31, 95% CI: 0.11-0.86). Treatment response was seriously compromised in patients with woody skin oedema (aOR = 0.05, 95% CI: 0.01-0.38) and those with prior chemotherapy (aOR = 0.21, 95% CI: 0.05-0.80). The median survival time was 7.6 months (95% CI: 5.9-9.8). Attrition from care was reduced by 22% for every additional cycle of chemotherapy administered (aH0R = 0.78, 95% CI: 0.71-0.84) and was lower in those with complete remission compared with those with partial or no response (aHR = 0.05, 95% CI: 0.007-0.43). There has been an increased access to KS treatment. The overall response rate is 52.4%, which is considered a satisfactory result. Poor outcomes were common and were largely due to late presentation and defaulting on treatment. Efforts towards early HIV/KS diagnosis and adherence to a full round of chemotherapy are needed for optimising outcomes. Newer drugs may be required for patients previously exposed to chemotherapy.

[All-ceramic resin bonded fixed partial denture made of IPS hot-pressed casting porcelain restore anterior missing teeth: a three years clinical observation].

PubMed

Zhou, Tuan feng; Wang, Xin zhi; Zhang, Gui rong

2011-02-18

To clinic observation of IPS Empress2 and IPS e.max all ceramic resin bonded fixed partial dentures used in one anterior teeth lost in upper jaw or less than two anterior tooth lost in lower jaw. 22 patients, 26 restorations had been made, which included 16 single-retainer all ceramic resin bonded fixed partial dentures and 10 two-retainers all ceramic resin bonded fixed partial dentures. Secondary caries of the abutments, shade in the margin of the retainers and the integrity of the restorations had been observed at 3 months, 6 months, 1 year, 2 years and 3 years after all ceramic resin bonded fixed partial dentures having been bonded. In the 3 years of clinic observation of the anterior all ceramic resin bonded fixed partial dentures, 1 two-retainers restoration lost bond after it had been made for 3 months, a retainer of one two-retainers restoration was broken after 6 months, but they are still used after modified as one-retainer all ceramic resin bonded fixed partial dentures, 1 two-retainers restoration lost bond two year later, It was integrity and re-bonded again that was still stable. No secondary carries and no shade in margin of the retainers had been found. Their color matches with the nature teeth excellently. The success rate was 88.5%. IPS Empress 2 and IPS e.max all ceramic resin bonded fixed partial dentures should be a good selection in one or two teeth lose in anterior jaws.

Screening and Characterization of Polygalacturonase as Potential Enzyme for Keprok Garut Orange (Citrus nobilis var. chrysocarpa) Juice Clarification

NASA Astrophysics Data System (ADS)

Widowati, E.; Utami, R.; Kalistyatika, K.

2017-11-01

Use of thermostable enzyme from bacilli for industrial application is significant. This research aimed to isolate thermophilic pectinolytic bacteria from orange peel and vegetable waste which produced thermostable polygalacturonase, to investigate the polygalacturonase ability in clarifying keprok Garut orange juice, and to characterize polygalacturonase based on pH optimum, temperature optimum, enzyme stability, enzyme kinetics KM, and Vmax. Obtained, 14 isolates that further selected to 4 best isolates based on highest polygalacturonase activity and keprok Garut orange juice clarification ability. Four selected enzyme isolates were AR 2, AR 4, KK 4, and KK 5 had ability to increase juice transmittance, decrease juice viscosity and also reduce total soluble solid. Furthermore 4 selected isolates were partially purified by ammonium sulphate precipitation and dialysis method. Four partially purified enzymes were known that enzyme character of AR 2 optimum at pH 6; AR 4 optimum at pH 5.5; KK 4 optimum at pH 6; and KK 5 optimum at pH 4.5. Four enzymes were optimum at temperature 60°C thus stable at temperature 50-60°C, this characteristic indicate that enzymes were thermostable. AR 2 showed active activity stable at pH 4-7; AR 4 showed active activity stable at pH 6-7; KK 4 showed active activity stable at pH 4-6; however KK 5 stable at pH 4-5. Enzyme AR 2 and KK 4 was getting inactive at pH 11, thus AR 4 and KK 5 inactive at pH 12. KM value of AR 2, AR 4, KK 4, and KK 5 was 0.0959; 0.0974; 0.0966; and 0.178 mg/ml respectively. Vmax of AR 2, AR 4, KK 4, and KK 5 was 0.0203; 0.0202; 0.0185; and 0.0229 U/ml respectively. Enzyme AR 2 was the most compatible enzyme to be applied in keprok Garut orange juice clarification for it had the lowest KM value.

Piloting a Polychotomous Partial-Credit Scoring Procedure in a Multiple-Choice Test

ERIC Educational Resources Information Center

Tsopanoglou, Antonios; Ypsilandis, George S.; Mouti, Anna

2014-01-01

Multiple-choice (MC) tests are frequently used to measure language competence because they are quick, economical and straightforward to score. While degrees of correctness have been investigated for partially correct responses in combined-response MC tests, degrees of incorrectness in distractors and the role they play in determining the…

A FLEXIBLE APPROACH FOR EVALUATING FIXED RATIO MIXTURES OF FULL AND PARTIAL AGONISTS FOR MIXTURES OF MANY CHEMICALS.

EPA Science Inventory

Detecting interaction in chemical mixtures can be complicated by differences in the shapes of the dose-response curves of the individual components (e.g. mixtures of full and partial agonists with differing response maxima). We present an analysis scheme where flexible single che...

Constrained and Unconstrained Partial Adjacent Category Logit Models for Ordinal Response Variables

ERIC Educational Resources Information Center

Fullerton, Andrew S.; Xu, Jun

2018-01-01

Adjacent category logit models are ordered regression models that focus on comparisons of adjacent categories. These models are particularly useful for ordinal response variables with categories that are of substantive interest. In this article, we consider unconstrained and constrained versions of the partial adjacent category logit model, which…

Photosynthetic light response of flooded cherrybark oak (Quercus pagoda) seedlings grown in two light regimes

Treesearch

Emile S. Gardiner; Ken W. Krauss

2001-01-01

Two-year-old cherrybark oak (Quercus pagoda Raf.) seedlings raised in full or partial (27 percent) sunlight were flooded for 30 days to study the effects of light availability and root inundation on photosynthetic light response. Compared with seedlings receiving full sunlight, seedlings receiving partial sunlight developed leaves...

Partial CD25 Antagonism Enables Dominance of Antigen-Inducible CD25high FOXP3+ Regulatory T Cells As a Basis for a Regulatory T Cell-Based Adoptive Immunotherapy

PubMed Central

Wilkinson, Daniel S.; Ghosh, Debjani; Nickle, Rebecca A.; Moorman, Cody D.; Mannie, Mark D.

2017-01-01

FOXP3+ regulatory T cells (Tregs) represent a promising platform for effective adoptive immunotherapy of chronic inflammatory disease, including autoimmune diseases such as multiple sclerosis. Successful Treg immunotherapy however requires new technologies to enable long-term expansion of stable, antigen-specific FOXP3+ Tregs in cell culture. Antigen-specific activation of naïve T cells in the presence of TGF-β elicits the initial differentiation of the FOXP3+ lineage, but these Treg lines lack phenotypic stability and rapidly transition to a conventional T cell (Tcon) phenotype during in vitro propagation. Because Tregs and Tcons differentially express CD25, we hypothesized that anti-CD25 monoclonal antibodies (mAbs) would only partially block IL-2 signaling in CD25high FOXP3+ Tregs while completely blocking IL-2 responses of CD25low-intermediate Tcons to enable preferential outgrowth of Tregs during in vitro propagation. Indeed, murine TGF-β-induced MOG-specific Treg lines from 2D2 transgenic mice that were maintained in IL-2 with the anti-CD25 PC61 mAb rapidly acquired and indefinitely maintained a FOXP3high phenotype during long-term in vitro propagation (>90% FOXP3+ Tregs), whereas parallel cultures lacking PC61 rapidly lost FOXP3. These results pertained to TGF-β-inducible “iTregs” because Tregs from 2D2-FIG Rag1−/− mice, which lack thymic or natural Tregs, were stabilized by continuous culture in IL-2 and PC61. MOG-specific and polyclonal Tregs upregulated the Treg-associated markers Neuropilin-1 (NRP1) and Helios (IKZF2). Just as PC61 stabilized FOXP3+ Tregs during expansion in IL-2, TGF-β fully stabilized FOXP3+ Tregs during cellular activation in the presence of dendritic cells and antigen/mitogen. Adoptive transfer of blastogenic CD25high FOXP3+ Tregs from MOG35-55-specific 2D2 TCR transgenic mice suppressed experimental autoimmune encephalomyelitis in pretreatment and therapeutic protocols. In conclusion, low IL-2 concentrations coupled with high PC61 concentrations constrained IL-2 signaling to a low-intensity range that enabled dominant stable outgrowth of suppressive CD25high FOXP3+ Tregs. The ability to indefinitely expand stable Treg lines will provide insight into FOXP3+ Treg physiology and will be foundational for Treg-based immunotherapy. PMID:29312311

Stress responsiveness and anxiety-like behavior: The early social environment differentially shapes stability over time in a small rodent.

PubMed

Sangenstedt, Susanne; Jaljuli, Iman; Sachser, Norbert; Kaiser, Sylvia

2017-04-01

The early social environment can profoundly affect behavioral and physiological phenotypes. We investigated how male wild cavy offspring, whose mothers had either lived in a stable (SE) or an unstable social environment (UE) during pregnancy and lactation, differed in their anxiety-like behavior and stress responsiveness. At two different time points in life, we tested the offspring's anxiety-like behavior in a dark-light test and their endocrine reaction to challenge in a cortisol reactivity test. Furthermore, we analyzed whether individual traits remained stable over time. There was no effect of the early social environment on anxiety-like behavior and stress responsiveness. However, at an individual level, anxiety-like behavior was stable over time in UE- but not in SE-sons. Stress responsiveness, in turn, was rather inconsistent in UE-sons and temporally stable in SE-sons. Conclusively, we showed for the first time that the early social environment differentially shapes the stability of behavioral and endocrine traits. At first glance, these results may be surprising, but they can be explained by the different functions anxiety-like behavior and stress responsiveness have. Copyright © 2017 Elsevier Inc. All rights reserved.

How partial reinforcement of food cues affects the extinction and reacquisition of appetitive responses. A new model for dieting success?

PubMed

van den Akker, Karolien; Havermans, Remco C; Bouton, Mark E; Jansen, Anita

2014-10-01

Animals and humans can easily learn to associate an initially neutral cue with food intake through classical conditioning, but extinction of learned appetitive responses can be more difficult. Intermittent or partial reinforcement of food cues causes especially persistent behaviour in animals: after exposure to such learning schedules, the decline in responding that occurs during extinction is slow. After extinction, increases in responding with renewed reinforcement of food cues (reacquisition) might be less rapid after acquisition with partial reinforcement. In humans, it may be that the eating behaviour of some individuals resembles partial reinforcement schedules to a greater extent, possibly affecting dieting success by interacting with extinction and reacquisition. Furthermore, impulsivity has been associated with less successful dieting, and this association might be explained by impulsivity affecting the learning and extinction of appetitive responses. In the present two studies, the effects of different reinforcement schedules and impulsivity on the acquisition, extinction, and reacquisition of appetitive responses were investigated in a conditioning paradigm involving food rewards in healthy humans. Overall, the results indicate both partial reinforcement schedules and, possibly, impulsivity to be associated with worse extinction performance. A new model of dieting success is proposed: learning histories and, perhaps, certain personality traits (impulsivity) can interfere with the extinction and reacquisition of appetitive responses to food cues and they may be causally related to unsuccessful dieting. Copyright © 2014 Elsevier Ltd. All rights reserved.

Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy

PubMed Central

Grimaldi, Antonio M; Simeone, Ester; Giannarelli, Diana; Muto, Paolo; Falivene, Sara; Borzillo, Valentina; Giugliano, Francesca Maria; Sandomenico, Fabio; Petrillo, Antonella; Curvietto, Marcello; Esposito, Assunta; Paone, Miriam; Palla, Marco; Palmieri, Giuseppe; Caracò, Corrado; Ciliberto, Gennaro; Mozzillo, Nicola; Ascierto, Paolo A

2014-01-01

Cancer radiotherapy (RT) may induce what is referred to as the “abscopal effect,” a regression of non-irradiated metastatic lesions distant from the primary tumor site directly subject to irradiation. This clinical response is rare, but has been surmised to be an immune-mediated phenomenon, suggesting that immunotherapy and RT could potentially synergize. Here, we report the outcome of patients with advanced melanoma treated with the immune checkpoint blockade monoclonal antibody antagonist, ipilimumab followed by RT. Patients were selected for enrollment at the National Cancer Institute “Fondazione G.Pascale” through the expanded access program in Italy. Those who experienced disease progression after ipilimumab thus received subsequent RT and were selected for analysis. Among 21 patients, 13 patients (62%) received RT to treat metastases in the brain and 8 received RT directed at extracranial sites. An abscopal response was observed in 11 patients (52%), 9 of whom had partial responses (43%) and 2 had stable disease (10%). The median time from RT to an abscopal response was 1 month (range 1–4). Median overall survival (OS) for all 21 patients was 13 months (range 6–26). Median OS for patients with abscopal responses was extended to 22.4 months (range 2.5–50.3) vs. 8.3 months (range 7.6–9.0) without. A local response to RT was detected in 13 patients (62%) and, of these, 11 patients (85%) had an abscopal response and abscopal effects were only observed among patients exhibiting a local response. These results suggest RT after ipilimumab may lead to abscopal responses in some patients with advanced melanoma correlating with prolonged OS. Our data also suggest that local responses to RT may be predictive of abscopal responses. Further research in larger randomized trials is needed to validate these results. PMID:25083318

Systemic Therapy in Advanced Cutaneous Squamous Cell Carcinoma (CSCC): The Roswell Park Experience and a Review of the Literature.

PubMed

Jarkowski, Anthony; Hare, Ryan; Loud, Peter; Skitzki, Joseph J; Kane, John M; May, Kilian S; Zeitouni, Nathalie C; Nestico, Jill; Vona, Karen L; Groman, Adrienne; Khushalani, Nikhil I

2016-12-01

Treatment of locally advanced unresectable or metastatic cutaneous squamous cell carcinoma (mCSCC) is suboptimal with a paucity of robust data on systemic therapy. This retrospective study aimed to evaluate the efficacy and outcomes of patients with locally advanced unresectable or mCSCC treated with systemic therapy. Records of patients with CSCC treated with systemic therapy from January 2001 to January 2011 were reviewed. Response was assessed using WHO criteria. Descriptive results were assessed using Wilcoxon rank-sum test for ordinal responses and Pearson χ test for categorical responses. Survival was calculated by the Kaplan-Meier method. Of 28 patients identified, 25 patients (M:F=18:7), median age 66 years (range, 39 to 85 y), had the required data for final analysis. Partial response was 44% and stable disease (SD) was 24%. The median progression-free survival (PFS) and overall survival (OS) were 5.5 months (2.3, 13.2) and 10.9 months (5.3, 21.3) respectively; 3-year OS was 22%. Patients with WHO response had improved PFS (20.8 mo; 4.4, NR) and OS (37.5 mo; 10.3, NR) compared with patients with SD/PD (PFS 2.7 mo; OS 5.9 mo). Use of platinum-based therapy significantly improved PFS and OS, whereas taxanes and cetuximab had no impact in this small cohort. There was no difference in PFS or OS with multiagent versus single-agent therapy. Platinum-based therapy remains as one of the standard options in advanced CSCC management. Agents to improve response rates are needed and future trials should address the use of novel targeted and new chemotherapy combinations in CSCC.

Concomitant treatment of brain metastasis with whole brain radiotherapy [WBRT] and temozolomide [TMZ] is active and improves quality of life.

PubMed

Addeo, Raffaele; Caraglia, Michele; Faiola, Vincenzo; Capasso, Elena; Vincenzi, Bruno; Montella, Liliana; Guarrasi, Rosario; Caserta, Luigi; Del Prete, Salvatore

2007-01-25

Brain metastases (BM) represent one of the most frequent complications related to cancer, and their treatment continues to evolve. We have evaluated the activity, toxicity and the impact on Quality of Life (QoL) of a concomitant treatment with whole brain radiotherapy (WBRT) and Temozolomide (TMZ) in patients with brain metastases from solid tumors in a prospective Simon two stage study. Fifty-nine patients were enrolled and received 30 Gy WBRT with concomitant TMZ (75 mg/m2/day) for ten days, and subsequently TMZ (150 mg/m2/day) for up to six cycles. The primary end points were clinical symptoms and radiologic response. Five patients had a complete response, 21 patients had a partial response, while 18 patients had stable disease. The overall response rate (45%) exceeded the target activity per study design. The median time to progression was 9 months. Median overall survival was 13 months. The most frequent toxicities included grade 3 neutropenia (15%) and anemia (13%), and only one patient developed a grade 4 thrombocytopenia. Age, Karnofsky performance status, presence of extracranial metastases and the recursive partitioning analysis (RPA) were found to be predictive factors for response in patients. Overall survival (OS) and progression-free survival (PFS) were dependent on age and on the RPA class. We conclude that this treatment is well tolerated, with an encouraging objective response rate, and a significant improvement in quality of life (p < 0.0001) demonstrated by FACT-G analysis. All patients answered the questionnaires and described themselves as 'independent' and able to act on their own initiatives. Our study found a high level of satisfaction for QoL, this provides useful information to share with patients in discussions regarding chemotherapy treatment of these lesions.

Transcatheter Arterial Embolization With Spherical Embolic Agent for Pulmonary Metastases From Renal Cell Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seki, Akihiko, E-mail: sekia@igtc.jp; Hori, Shinichi, E-mail: horishin@igtc.jp; Sueyoshi, Satoru, E-mail: sueyoshis@igtc.jp

2013-12-15

Purpose: This retrospective study aimed to evaluate the safety and local efficacy of transcatheter arterial embolization (TAE) with superabsorbent polymer microspheres (SAP-MS) in patients with pulmonary metastases from renal cell carcinoma (RCC). Methods: Sixteen patients with unresectable pulmonary metastases from RCC refractory to standard therapy were enrolled to undergo TAE with the purpose of mass reduction and/or palliation. The prepared SAP-MS swell to approximately two times larger than their dry-state size (100-150 {mu}m [n = 14], 50-100 {mu}m [n = 2]). Forty-nine pulmonary nodules (lung n = 22, mediastinal lymph node n = 17, and hilar lymph node n =more » 10) were selected as target lesions for evaluation. Local tumor response was evaluated 3 months after TAE according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The relationship between tumor enhancement ratio by CT during selective angiography and local tumor response was evaluated. Results: The number of TAE sessions per patient ranged from 1 to 5 (median 2.9). Embolized arteries at initial TAE were bronchial arteries in 14 patients (87.5 %) and nonbronchial systemic arteries in 11 patients (68.8 %). Nodule-based evaluation showed that 5 (10.2 %) nodules had complete response, 17 (34.7 %) had partial response, 15 (30.6 %) had stable disease, and 12 (24.5 %) had progressive disease. The response rate was significantly greater in 22 lesions that had a high tumor enhancement ratio than in 27 lesions that had a slight or moderate ratio (90.9 vs. 7.4 %, p = 0.01). Severe TAE-related adverse events did not occur. Conclusion: TAE with SAP-MS might be a well-tolerated and locally efficacious palliative option for patients with pulmonary metastases from RCC.« less

The Tumour Response to Induction Chemotherapy has Prognostic Value for Long-Term Survival Outcomes after Intensity-Modulated Radiation Therapy in Nasopharyngeal Carcinoma.

PubMed

Peng, Hao; Chen, Lei; Zhang, Yuan; Li, Wen-Fei; Mao, Yan-Ping; Liu, Xu; Zhang, Fan; Guo, Rui; Liu, Li-Zhi; Tian, Li; Lin, Ai-Hua; Sun, Ying; Ma, Jun

2016-04-21

The prognostic value of the tumour response to induction chemotherapy (IC) for long-term survival outcomes after intensity-modulated radiation therapy in nasopharyngeal carcinoma (NPC) remains unknown. We retrospectively reviewed 1811 consecutive patients with newly diagnosed NPC treated using IMRT, and 399 eligible patients with pre- and post-induction chemotherapy magnetic resonance images were recruited. The clinicopathological features of patients with different tumour responses were compared using the Chi-square test or Fisher's exact test. Prognostic value was assessed using a multivariate Cox proportional hazards model. After IC, 101/399 (25.3%) patients had a complete tumour response overall (CR), 262 (65.7%) had a partial response (PR) and 36 (9.0%) had stable disease (SD). The 4-year disease-free survival (DFS), overall survival (OS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRRFS) rates for CR vs. PR vs. SD were 90.0% vs. 79.0% vs. 58.2% (CR vs. PR: P1 = 0.007; CR vs. SD: P2 < 0.001; PR vs. SD: P3 = 0.004), 95.7% vs. 88.7% vs. 70.2% (P1 = 0.017, P2 < 0.001, P3 = 0.005), 92.0% vs. 87.4% vs. 74.3% (P1 = 0.162, P2 = 0.005, P3 = 0.029) and 95.9% vs. 88.8% vs. 81.8% (P1 = 0.024, P2 = 0.006, P3 = 0.268), respectively. Multivariate analysis identified that the tumour response to IC was an independent prognostic factor for DFS, OS and LRRFS.

Assessing a novel immuno-oncology-based combination therapy: Ipilimumab plus electrochemotherapy

PubMed Central

Mozzillo, Nicola; Simeone, Ester; Benedetto, Lucia; Curvietto, Marcello; Giannarelli, Diana; Gentilcore, Giusy; Camerlingo, Rosa; Capone, Mariaelena; Madonna, Gabriele; Festino, Lucia; Caracò, Corrado; Di Monta, Gianluca; Marone, Ugo; Di Marzo, Massimiliano; Grimaldi, Antonio M; Mori, Stefano; Ciliberto, Gennaro; Ascierto, Paolo A

2015-01-01

Melanoma is responsible for most skin cancer-related deaths and is one of the most common cancers diagnosed in young adults. In melanoma, tumors can become established by activation of the negative regulator of cytotoxic T lymphocytes (CTLs), CTL antigen-4 (CTLA-4). Ipilimumab blocks the interaction of CTLA-4 with CD80/CD86 and augments T-cell activation and proliferation. In electrochemotherapy (ECT), local application of short high-voltage pulses renders cell membranes transiently permeable to chemotherapeutic drugs. The combination of ipilimumab and ECT may be beneficial for the treatment of metastatic melanoma; however, no prospective data are available to date. Here, we report the retrospective analysis of patients treated with ipilimumab in an expanded access program (EAP) who also received ECT. Fifteen patients with previously treated metastatic melanoma who received ipilimumab 3 mg/kg every three weeks for four cycles and underwent ECT for local disease control and/or palliation of cutaneous lesions with bleomycin 15 mg/m2 after the first ipilimumab infusion were included in the analysis. Over the study period, a local objective response was observed in 67% of patients (27% complete response [CR] and 40% partial response [PR]). According to immune-related response criteria, a systemic response was observed in nine patients (five PR and four stable disease [SD]), resulting in a disease control rate of 60%. Evaluation of circulating T-regulatory (T-reg) cells demonstrated significant differences between responders and non-responders. Overall, treatment was well-tolerated and without notable toxicity. In conclusion, the combination of ipilimumab and ECT appears to be beneficial to patients with advanced melanoma, warranting further investigation in prospective trials. PMID:26155423

Assessing a novel immuno-oncology-based combination therapy: Ipilimumab plus electrochemotherapy.

PubMed

Mozzillo, Nicola; Simeone, Ester; Benedetto, Lucia; Curvietto, Marcello; Giannarelli, Diana; Gentilcore, Giusy; Camerlingo, Rosa; Capone, Mariaelena; Madonna, Gabriele; Festino, Lucia; Caracò, Corrado; Di Monta, Gianluca; Marone, Ugo; Di Marzo, Massimiliano; Grimaldi, Antonio M; Mori, Stefano; Ciliberto, Gennaro; Ascierto, Paolo A

2015-06-01

Melanoma is responsible for most skin cancer-related deaths and is one of the most common cancers diagnosed in young adults. In melanoma, tumors can become established by activation of the negative regulator of cytotoxic T lymphocytes (CTLs), CTL antigen-4 (CTLA-4). Ipilimumab blocks the interaction of CTLA-4 with CD80/CD86 and augments T-cell activation and proliferation. In electrochemotherapy (ECT), local application of short high-voltage pulses renders cell membranes transiently permeable to chemotherapeutic drugs. The combination of ipilimumab and ECT may be beneficial for the treatment of metastatic melanoma; however, no prospective data are available to date. Here, we report the retrospective analysis of patients treated with ipilimumab in an expanded access program (EAP) who also received ECT. Fifteen patients with previously treated metastatic melanoma who received ipilimumab 3 mg/kg every three weeks for four cycles and underwent ECT for local disease control and/or palliation of cutaneous lesions with bleomycin 15 mg/m 2 after the first ipilimumab infusion were included in the analysis. Over the study period, a local objective response was observed in 67% of patients (27% complete response [CR] and 40% partial response [PR]). According to immune-related response criteria, a systemic response was observed in nine patients (five PR and four stable disease [SD]), resulting in a disease control rate of 60%. Evaluation of circulating T-regulatory (T-reg) cells demonstrated significant differences between responders and non-responders. Overall, treatment was well-tolerated and without notable toxicity. In conclusion, the combination of ipilimumab and ECT appears to be beneficial to patients with advanced melanoma, warranting further investigation in prospective trials.

Treatment of refractory germ cell tumors in children with paclitaxel, ifosfamide, and carboplatin: A report from the Children's Oncology Group AGCT0521 study.

PubMed

Pashankar, Farzana; Frazier, A Lindsay; Krailo, Mark; Xia, Caihong; Pappo, Alberto S; Malogolowkin, Marcio; Olson, Thomas A; Rodriguez-Galindo, Carlos

2018-04-26

Paclitaxel, ifosfamide, cisplatin (TIP) is commonly used as salvage for malignant germ cell tumors (MGCT) in adults; however, additional administration of cisplatin at a young age could cause significant short- and long-term toxicities in a group of patients with high expected salvage. Because carboplatin has been shown to be effective in pediatric MGCT with less toxicity, the TIP regimen was modified by substituting carboplatin for cisplatin. The Children's Oncology Group conducted a phase II trial between November 2007 and June 2011 evaluating "TIC" (paclitaxel 135 mg/m 2 /day Day 1, ifosfamide 1,800 mg/m 2 /dose Days 1-5 and carboplatin with AUC 6.5 Day 1) in children < 21 years with relapsed MGCT. The endpoint of the trial was response after two cycles, incorporating RECIST response and marker decline. Twenty patients (12 male, median age 13.5 years) were enrolled. Seventeen patients had tumor markers ≥10 times above normal. After two cycles, by RECIST criteria, 8 patients achieved a partial response (response rate 40%), 10 had stable disease, and 2 had progressive disease. A ≥ 1 log reduction was achieved in 10/17 patients (58.8%) with elevated markers. By study defined criteria, combining response by RECIST and marker decline, the response rate was 44%. TIC is active in relapsed pediatric MGCT and should be considered for salvage therapy in children. In adolescents and older adults with relapse MGCT, TIP or high-dose chemotherapy with stem cell remain the standard therapy. © 2018 Wiley Periodicals, Inc.

Assessment of tumor response to chemoradiotherapy and predicting prognosis in patients with head and neck squamous cell carcinoma by PERCIST.

PubMed

Katsuura, Takayuki; Kitajima, Kazuhiro; Fujiwara, Masayuki; Terada, Tomonori; Uwa, Nobuhiro; Noguchi, Kazuma; Doi, Hiroshi; Tamaki, Yukihisa; Yoshida, Rika; Tsuchitani, Tatsuya; Fujita, Masahiro; Yamakado, Koichiro

2018-06-01

To evaluate therapeutic response to chemoradiotherapy and prediction of recurrence and death in patients with head and neck squamous cell carcinoma (HNSCC) using Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST). Forty-two patients (mean 63.4, range 20-79 years) with nasopharyngeal (n = 10), oropharyngeal (n = 13), hypopharyngeal (n = 11), or laryngeal (n = 8) cancer underwent fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) before and approximately 3 months (mean 95.0, range 70-119 days) after undergoing concurrent chemoradiotherapy. The effect of PERCIST regarding progression-free survival (PFS) and overall survival (OS) was examined using log-rank and Cox methods. Complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease shown by PERCIST were seen in 30 (71.4%), 9 (21.4%), 3 (7.1%), and 0 patients, respectively. Fourteen (33.3%) developed recurrent disease (median follow-up 27.2, range 8.7-123.1 months) and 9 (21.4%) died (median follow-up 43.6, range 9.6-132.6 months). Furthermore, 4 (13.3%) of 30 patients with CMR developed recurrence, while 7 (77.8%) of 9 with PMR and all 3 (100%) with SMD developed recurrence. Two (6.7%) of 30 patients with CMR, 4 (44.4%) of 9 with PMR, and all 3 (100%) with SMD died. Patients who achieved CMR showed significantly longer PFS and OS as compared to those who did not (PMR and SMD) (both, p < 0.0001). PERCIST is useful for evaluating therapeutic response to chemoradiotherapy and predicting recurrence and death in HNSCC patients.

An observational constraint on stomatal function in forests: evaluating coupled carbon and water vapor exchange with carbon isotopes in the Community Land Model (CLM4.5)

NASA Astrophysics Data System (ADS)

Raczka, Brett; Duarte, Henrique F.; Koven, Charles D.; Ricciuto, Daniel; Thornton, Peter E.; Lin, John C.; Bowling, David R.

2016-09-01

Land surface models are useful tools to quantify contemporary and future climate impact on terrestrial carbon cycle processes, provided they can be appropriately constrained and tested with observations. Stable carbon isotopes of CO2 offer the potential to improve model representation of the coupled carbon and water cycles because they are strongly influenced by stomatal function. Recently, a representation of stable carbon isotope discrimination was incorporated into the Community Land Model component of the Community Earth System Model. Here, we tested the model's capability to simulate whole-forest isotope discrimination in a subalpine conifer forest at Niwot Ridge, Colorado, USA. We distinguished between isotopic behavior in response to a decrease of δ13C within atmospheric CO2 (Suess effect) vs. photosynthetic discrimination (Δcanopy), by creating a site-customized atmospheric CO2 and δ13C of CO2 time series. We implemented a seasonally varying Vcmax model calibration that best matched site observations of net CO2 carbon exchange, latent heat exchange, and biomass. The model accurately simulated observed δ13C of needle and stem tissue, but underestimated the δ13C of bulk soil carbon by 1-2 ‰. The model overestimated the multiyear (2006-2012) average Δcanopy relative to prior data-based estimates by 2-4 ‰. The amplitude of the average seasonal cycle of Δcanopy (i.e., higher in spring/fall as compared to summer) was correctly modeled but only when using a revised, fully coupled An - gs (net assimilation rate, stomatal conductance) version of the model in contrast to the partially coupled An - gs version used in the default model. The model attributed most of the seasonal variation in discrimination to An, whereas interannual variation in simulated Δcanopy during the summer months was driven by stomatal response to vapor pressure deficit (VPD). The model simulated a 10 % increase in both photosynthetic discrimination and water-use efficiency (WUE) since 1850 which is counter to established relationships between discrimination and WUE. The isotope observations used here to constrain CLM suggest (1) the model overestimated stomatal conductance and (2) the default CLM approach to representing nitrogen limitation (partially coupled model) was not capable of reproducing observed trends in discrimination. These findings demonstrate that isotope observations can provide important information related to stomatal function driven by environmental stress from VPD and nitrogen limitation. Future versions of CLM that incorporate carbon isotope discrimination are likely to benefit from explicit inclusion of mesophyll conductance.

Thermo-chemical evolution of a one-plate planet: application to Mars

NASA Astrophysics Data System (ADS)

Plesa, A.-C.; Breuer, D.

2012-04-01

Little attention has been devoted so far to find a modelling framework able to explain the geophysical implications of the Martian meteorites, the so-called SNC meteorites. Geochemical analysis of the SNC meteorites implies the rapid formation, i.e. before ~4.5 Ga, of three to four isotopically distinct reservoirs that did not remix since then [3]. In [4] the authors argue that a fast overturn of an early fractionated magma ocean may have given origin to a stably stratified mantle with a large density gradient capable to keep the mantle heterogeneous and to prevent mixing due to thermal convection. This model, albeit capable to provide a plausible explanation to the SNC meteorites, suggests a conductive mantle after the overturn which is clearly at odds with the volcanic history of Mars. This is best explained by assuming a convective mantle and partial melting as the principal agents responsible for the generation and evolution of Martian volcanism. In this work, we present an alternative scenario assuming a homogeneous mantle and accounting for compositional changes and melting temperature variations due to mantle depletion, dehydration stiffening of the mantle material due to water partitioning from the minerals into the melt, redistribution of radioactive heat sources between mantle and crust and thermal conductivity decrease in crustal regions. We use the 2D cylindrical - 3D spherical convection code Gaia [1, 2] and to model the above mentioned effects of partial melting we use a Lagrangian, particle based method. Simulation results show that chemical reservoirs, which can be formed due to partial melting when accounting for compositional changes and dehydration stiffening, remain stable over the entire thermal evolution of Mars. However, an initially depleted (i.e. buoyant harzburgite) layer of about 200 km is needed. This depleted layer in an otherwise homogeneous mantle may be the consequence of equilibrium fractionation of a freezing magma ocean where only the residual melt rises to the surface. If the heat released by accretion never allowed for a magma ocean to build, a large amount of partial melting of about 20% in the earliest stage is required to form such a buoyant layer. These models show an active convective interior and long lived partial melt production, which agrees with the volcanic history of Mars [5].

Asymptotic analysis of the local potential approximation to the Wetterich equation

NASA Astrophysics Data System (ADS)

Bender, Carl M.; Sarkar, Sarben

2018-06-01

This paper reports a study of the nonlinear partial differential equation that arises in the local potential approximation to the Wetterich formulation of the functional renormalization group equation. A cut-off-dependent shift of the potential in this partial differential equation is performed. This shift allows a perturbative asymptotic treatment of the differential equation for large values of the infrared cut-off. To leading order in perturbation theory the differential equation becomes a heat equation, where the sign of the diffusion constant changes as the space-time dimension D passes through 2. When D  <  2, one obtains a forward heat equation whose initial-value problem is well-posed. However, for D  >  2 one obtains a backward heat equation whose initial-value problem is ill-posed. For the special case D  =  1 the asymptotic series for cubic and quartic models is extrapolated to the small infrared-cut-off limit by using Padé techniques. The effective potential thus obtained from the partial differential equation is then used in a Schrödinger-equation setting to study the stability of the ground state. For cubic potentials it is found that this Padé procedure distinguishes between a -symmetric theory and a conventional Hermitian theory (g real). For an theory the effective potential is nonsingular and has a stable ground state but for a conventional theory the effective potential is singular. For a conventional Hermitian theory and a -symmetric theory (g  >  0) the results are similar; the effective potentials in both cases are nonsingular and possess stable ground states.

Instrument for stable high temperature Seebeck coefficient and resistivity measurements under controlled oxygen partial pressure

DOE PAGES

Ihlefeld, Jon F.; Brown-Shaklee, Harlan James; Sharma, Peter Anand

2015-04-28

The transport properties of ceramic materials strongly depend on oxygen activity, which is tuned by changing the partial oxygen pressure (pO 2) prior to and during measurement. Within, we describe an instrument for highly stable measurements of Seebeck coefficient and electrical resistivity at temperatures up to 1300 K with controlled oxygen partial pressure. An all platinum construction is used to avoid potential materials instabilities that can cause measurement drift. Two independent heaters are employed to establish a small temperature gradient for Seebeck measurements, while keeping the average temperature constant and avoiding errors associated with pO 2-induced drifts in thermocouple readings.more » Oxygen equilibrium is monitored using both an O 2 sensor and the transient behavior of the resistance as a proxy. A pO 2 range of 10 -25–10 0 atm can be established with appropriate gas mixtures. Seebeck measurements were calibrated against a high purity platinum wire, Pt/Pt–Rh thermocouple wire, and a Bi 2Te3 Seebeck coefficient Standard Reference Material. To demonstrate the utility of this instrument for oxide materials we present measurements as a function of pO 2 on a 1 % Nb-doped SrTiO 3 single crystal, and show systematic changes in properties consistent with oxygen vacancy defect chemistry. Thus, an approximately 11% increase in power factor over a pO 2 range of 10 -19–10 -8 atm at 973 K for the donor-doped single crystals is observed.« less

Tumor Response and Survival Predicted by Post-Therapy FDG-PET/CT in Anal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schwarz, Julie K.; Siegel, Barry A.; Dehdashti, Farrokh

2008-05-01

Purpose: To evaluate the response to therapy for anal carcinoma using post-therapy imaging with positron emission tomography (PET)/computed tomography and F-18 fluorodeoxyglucose (FDG) and to compare the metabolic response with patient outcome. Patients and Methods: This was a prospective cohort study of 53 consecutive patients with anal cancer. All patients underwent pre- and post-treatment whole-body FDG-PET/computed tomography. Patients had been treated with external beam radiotherapy and concurrent chemotherapy. Whole-body FDG-PET was performed 0.9-5.4 months (mean, 2.1) after therapy completion. Results: The post-therapy PET scan did not show any abnormal FDG uptake (complete metabolic response) in 44 patients. Persistent abnormal FDGmore » uptake (partial metabolic response) was found in the anal tumor in 9 patients. The 2-year cause-specific survival rate was 94% for patients with a complete vs. 39% for patients with a partial metabolic response in the anal tumor (p = 0.0008). The 2-year progression-free survival rate was 95% for patients with a complete vs. 22% for patients with a partial metabolic response in the anal tumor (p < 0.0001). A Cox proportional hazards model of survival outcome indicated that a complete metabolic response was the most significant predictor of progression-free survival in our patient population (p = 0.0003). Conclusions: A partial metabolic response in the anal tumor as determined by post-therapy FDG-PET is predictive of significantly decreased progression-free and cause-specific survival after chemoradiotherapy for anal cancer.« less

Dissociative Photoionization of the Elusive Vinoxy Radical.

PubMed

Adams, Jonathan D; Scrape, Preston G; Lee, Shih-Huang; Butler, Laurie J

2017-08-24

These experiments report the dissociative photoionization of vinoxy radicals to m/z = 15 and 29. In a crossed laser-molecular beam scattering apparatus, we induce C-Cl bond fission in 2-chloroacetaldehyde by photoexcitation at 157 nm. Our velocity measurements, combined with conservation of angular momentum, show that 21% of the C-Cl photofission events form vinoxy radicals that are stable to subsequent dissociation to CH 3 + CO or H + ketene. Photoionization of these stable vinoxy radicals, identified by their velocities, which are momentum-matched with the higher-kinetic-energy Cl atom photofragments, shows that the vinoxy radicals dissociatively photoionize to give signal at m/z = 15 and 29. We calibrated the partial photoionization cross section of vinoxy to CH 3 + relative to the bandwidth-averaged photoionization cross section of the Cl atom at 13.68 eV to put the partial photoionization cross sections on an absolute scale. The resulting bandwidth-averaged partial cross sections are 0.63 and 1.3 Mb at 10.5 and 11.44 eV, respectively. These values are consistent with the upper limit to the cross section estimated from a study by Savee et al. on the O( 3 P) + propene bimolecular reaction. We note that the uncertainty in these values is primarily dependent on the signal attributed to C-Cl primary photofission in the m/z = 35 (Cl + ) time-of-flight data. While the value is a rough estimate, the bandwidth-averaged partial photoionization cross section of vinoxy to HCO + calculated from the signal at m/z = 29 at 11.53 eV is approximately half that of vinoxy to CH 3 + . We also present critical points on the potential energy surface of the vinoxy cation calculated at the G4//B3LYP/6-311++G(3df,2p) level of theory to support the observation of dissociative ionization of vinoxy to both CH 3 + and HCO + .

Validation of reference genes for quantifying changes in gene expression in virus-infected tobacco.

PubMed

Baek, Eseul; Yoon, Ju-Yeon; Palukaitis, Peter

2017-10-01

To facilitate quantification of gene expression changes in virus-infected tobacco plants, eight housekeeping genes were evaluated for their stability of expression during infection by one of three systemically-infecting viruses (cucumber mosaic virus, potato virus X, potato virus Y) or a hypersensitive-response-inducing virus (tobacco mosaic virus; TMV) limited to the inoculated leaf. Five reference-gene validation programs were used to establish the order of the most stable genes for the systemically-infecting viruses as ribosomal protein L25 > β-Tubulin > Actin, and the least stable genes Ubiquitin-conjugating enzyme (UCE) < PP2A < GAPDH. For local infection by TMV, the most stable genes were EF1α > Cysteine protease > Actin, and the least stable genes were GAPDH < PP2A < UCE. Using two of the most stable and the two least stable validated reference genes, three defense responsive genes were examined to compare their relative changes in gene expression caused by each virus. Copyright © 2017 Elsevier Inc. All rights reserved.

A Multidimensional Partial Credit Model with Associated Item and Test Statistics: An Application to Mixed-Format Tests

ERIC Educational Resources Information Center

Yao, Lihua; Schwarz, Richard D.

2006-01-01

Multidimensional item response theory (IRT) models have been proposed for better understanding the dimensional structure of data or to define diagnostic profiles of student learning. A compensatory multidimensional two-parameter partial credit model (M-2PPC) for constructed-response items is presented that is a generalization of those proposed to…

A Study of Reverse-Worded Matched Item Pairs Using the Generalized Partial Credit and Nominal Response Models

ERIC Educational Resources Information Center

Matlock Cole, Ki Lynn; Turner, Ronna C.; Gitchel, W. Dent

2018-01-01

The generalized partial credit model (GPCM) is often used for polytomous data; however, the nominal response model (NRM) allows for the investigation of how adjacent categories may discriminate differently when items are positively or negatively worded. Ten items from three different self-reported scales were used (anxiety, depression, and…

Context-dependent sequential effects of target selection for action.

PubMed

Moher, Jeff; Song, Joo-Hyun

2013-07-11

Humans exhibit variation in behavior from moment to moment even when performing a simple, repetitive task. Errors are typically followed by cautious responses, minimizing subsequent distractor interference. However, less is known about how variation in the execution of an ultimately correct response affects subsequent behavior. We asked participants to reach toward a uniquely colored target presented among distractors and created two categories to describe participants' responses in correct trials based on analyses of movement trajectories; partial errors referred to trials in which observers initially selected a nontarget for action before redirecting the movement and accurately pointing to the target, and direct movements referred to trials in which the target was directly selected for action. We found that latency to initiate a hand movement was shorter in trials following partial errors compared to trials following direct movements. Furthermore, when the target and distractor colors were repeated, movement time and reach movement curvature toward distractors were greater following partial errors compared to direct movements. Finally, when the colors were repeated, partial errors were more frequent than direct movements following partial-error trials, and direct movements were more frequent following direct-movement trials. The dependence of these latter effects on repeated-task context indicates the involvement of higher-level cognitive mechanisms in an integrated attention-action system in which execution of a partial-error or direct-movement response affects memory representations that bias performance in subsequent trials. Altogether, these results demonstrate that whether a nontarget is selected for action or not has a measurable impact on subsequent behavior.

The Role of High Dose Interleukin-2 in the Era of Targeted Therapy.

PubMed

Gills, Jessie; Parker, William P; Pate, Scott; Niu, Sida; Van Veldhuizen, Peter; Mirza, Moben; Holzbeierlein, Jeffery M; Lee, Eugene K

2017-09-01

We assessed survival outcomes following high dose interleukin-2 in a contemporary cohort of patients during the era of targeted agents. We retrospectively reviewed the records of patients with metastatic renal cell carcinoma treated with high dose interleukin-2 between July 2007 and September 2014. Clinicopathological data were abstracted and patient response to therapy was based on RECIST (Response Evaluation Criteria In Solid Tumors), version 1.1 criteria. The Kaplan-Meier method was used to estimate progression-free and overall survival in the entire cohort, the response to high dose interleukin-2 in regard to previous targeted agent therapy and the response to the targeted agent in relation to the response to high dose interleukin-2. We identified 92 patients, of whom 87 had documentation of a response to high dose interleukin-2. Median overall survival was 34.4 months from the initiation of high dose interleukin-2 therapy in the entire cohort. Patients who received targeted therapy before high dose interleukin-2 had overall survival (median 34.4 and 30.0 months, p = 0.88) and progression-free survival (median 1.5 and 1.7 months, p = 0.8) similar to those in patients who received no prior therapy, respectively. Additionally, patients with a complete or partial response to high dose interleukin-2 had similar outcomes for subsequent targeted agents compared to patients whose best response was stable or progressive disease (median overall survival 30.1 vs 25.4 months, p = 0.4). Our data demonstrate that patient responses to high dose interleukin-2 and to targeted agents before and after receiving high dose interleukin-2 are independent. As such, carefully selected patients should be offered high dose interleukin-2 for the possibility of a complete and durable response without the fear of limiting the treatment benefit of targeted agents. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Neurogenic regulation of proximal bicarbonate and chloride reabsorption.

PubMed

Cogan, M G

1986-01-01

Although a change in renal nerve activity is known to alter proximal reabsorption, it is unclear whether reabsorption of NaHCO3 or NaCl or both are affected. Sprague-Dawley rats (n = 10) were studied using free-flow micropuncture techniques during euvolemia and following acute ipsilateral denervation. Glomerular filtration rate and single nephron glomerular filtration rate were stable. Absolute proximal bicarbonate reabsorption fell following denervation (933 +/- 40 to 817 +/- 30 pmol/min) with a parallel reduction in chloride reabsorption (1,643 +/- 116 to 1,341 +/- 129 peq/min). Urinary sodium, potassium, bicarbonate, and chloride excretion all increased significantly. To further assess the physiological significance of neurogenic modulation of proximal transport, other rats (n = 6) were subjected to acute unilateral nephrectomy (AUN). There is evidence that AUN induces a contralateral natriuresis (renorenal reflex) at least partially by causing inhibition of efferent renal nerve traffic. AUN caused significant changes in proximal NaHCO3 and NaCl reabsorption as well as in whole kidney electrolyte excretion in the same pattern as had denervation. Prior denervation of the remaining kidney prevented the proximal and whole kidney response to AUN (n = 6). In conclusion, depression of renal nerve activity inhibits both NaHCO3 and NaCl reabsorption in the rat superficial proximal convoluted tubule. The data are consistent with the hypothesis that changes in renal nerve activity modify whole kidney electrolyte excretion under physiological conditions at least partially by regulating proximal transport.

Evidence for the Presence of Hn-PAHs in Post AGB Stars

NASA Technical Reports Server (NTRS)

Materese, Christopher K.; Bregman, Jesse D.; Sandford, Scott A.

2017-01-01

Polycyclic aromatic hydrocarbons (PAHs) are believed to be ubiquitous in space therefore represent an important class of molecules for the field of astrochemistry. PAHs are relatively stable under interstellar conditions, account for a significant fraction of the known Universe's molecular carbon inventory, and are believed responsible for numerous telltale interstellar infrared emission bands. PAHs can be subdivided into numerous classes, one of which is Hydrogenated PAHs (Hn-PAHs). Hn-PAHs are multi-ringed partially aromatic compounds with excess hydrogenation, leading to a partial disruption of the aromatic system. The infrared spectra of these compounds produce telltale signatures that make them distinct from ordinary aromatic or aliphatic molecules (or a mixture of both). Hn-PAHs may be an important subclass of PAHs that could explain the spectra of some astronomical objects with anomalously large 3.4 micron features. The 3.4 micron feature observed in these objects may be associated with the aliphatic C-H stretching vibrations of the excess hydrogen. If this presumption is correct, we also expect to observe methylene scissoring modes at 6.9 microns. We have recently conducted a series of follow-up observations to compliment our laboratory experiments into the properties of Hn-PAHs. Here we present our laboratory and observational results in support of the hypothesis that Hn-PAHs are a viable candidate molecule as the emission source for numerous post-asymptotic giant branch objects with abnormally large 3.4 micron features.

On Steady-State Tropical Cyclones

DTIC Science & Technology

2014-01-01

components of the velocity vector, specific humidity, suspended liquid water, perturbation Exner function and perturbation density potential...vorticity and spin-up function, respectively. If the flow is symmetrically stable, the partial differential equation (10) is elliptic with a forcing term...Upper-level inflow jets A prominent feature of the radial velocity component shown in Figure 2(c) is the layered structure of inflow and outflow in the

Role of B19' martensite deformation in stabilizing two-way shape memory behavior in NiTi

DOE PAGES

Benafan, O.; Padula, S. A.; Noebe, R. D.; ...

2012-11-01

Deformation of a B19' martensitic, polycrystallineNi49.9Ti50.1 (at. %) shape memoryalloy and its influence on the magnitude and stability of the ensuing two-way shape memory effect (TWSME) was investigated by combined ex situ mechanical experimentation and in situneutron diffraction measurements at stress and temperature. The microstructural changes (texture, lattice strains, and phase fractions) during room-temperature deformation and subsequent thermal cycling were captured and compared to the bulk macroscopic response of the alloy. With increasing uniaxial strain, it was observed that B19' martensite deformed by reorientation and detwinning with preferred selection of the (1¯50) M and (010) M variants, (201¯) B19' deformationmore » twinning, and dislocation activity. These mechanisms were indicated by changes in bulk texture from the neutron diffraction measurements. Partial reversibility of the reoriented variants and deformation twins was also captured upon load removal and thermal cycling, which after isothermal deformation to strains between 6% and 22% resulted in a strong TWSME. Consequently, TWSME functional parameters including TWSME strain, strain reduction, and transformation temperatures were characterized and it was found that prior martensite deformation to 14% strain provided the optimum condition for the TWSME, resulting in a stable two-way shape memory strain of 2.2%. Thus, isothermal deformation of martensite was found to be a quick and efficient method for creating a strong and stable TWSME in Ni₄₉.₉Ti₅₀.₁.« less

Repellency of a wax-based catnip-oil formulation against stable flies

USDA-ARS?s Scientific Manuscript database

Our significant finds including: 1). EAG recordings showed that volatile catnip compounds elicit significant antennal responses from both sexes of stable flies; 2). The laboratory dispersal bioassay showed that stable flies avoided areas treated with catnip oil; 3). The relative concentration of cat...

Statistical variation in progressive scrambling

NASA Astrophysics Data System (ADS)

Clark, Robert D.; Fox, Peter C.

2004-07-01

The two methods most often used to evaluate the robustness and predictivity of partial least squares (PLS) models are cross-validation and response randomization. Both methods may be overly optimistic for data sets that contain redundant observations, however. The kinds of perturbation analysis widely used for evaluating model stability in the context of ordinary least squares regression are only applicable when the descriptors are independent of each other and errors are independent and normally distributed; neither assumption holds for QSAR in general and for PLS in particular. Progressive scrambling is a novel, non-parametric approach to perturbing models in the response space in a way that does not disturb the underlying covariance structure of the data. Here, we introduce adjustments for two of the characteristic values produced by a progressive scrambling analysis - the deprecated predictivity (Q_s^{ast^2}) and standard error of prediction (SDEP s * ) - that correct for the effect of introduced perturbation. We also explore the statistical behavior of the adjusted values (Q_0^{ast^2} and SDEP 0 * ) and the sensitivity to perturbation (d q 2/d r yy ' 2). It is shown that the three statistics are all robust for stable PLS models, in terms of the stochastic component of their determination and of their variation due to sampling effects involved in training set selection.

Elements of cold hardiness in a littoral population of the land snail Helix aspersa (Gastropoda: Pulmonata).

PubMed

Ansart, A; Vernon, P; Daguzan, J

2002-10-01

The land snail Helix aspersa can be considered partially tolerant to freezing, in the sense it can survive some ice formation within its body for a limited time, and possesses a limited ability to supercool. This study aimed at understanding what factors are responsible for the variation of the temperature of crystallization ( Tc) in a littoral temperate population. The ability to supercool was maximal (ca. -5 degrees C) during dormancy periods (hibernation and aestivation) and minimal (ca. -3 degrees C) during spring and autumn, in relation with the decrease of water mass and the increase of osmolality. Tc decreased in October to remain stable through late autumn and winter; it increased quickly with the awakening of animals in April. Snails with an epiphragm had a significantly higher ability to supercool (ca. -4.8 degrees C) than snails which did not form an epiphragm (ca. -4.2 degrees C). The animals' size had a weak but significant influence on the realization of the Tc. It appeared that there was not a real cold-hardiness strategy in this population; rather a sum of parameters, varying in consequences of the external conditions and of the activity cycle, which are responsible for the enhancement of the supercooling ability during winter.

Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension.

PubMed

Schuster, Cornelia; Eikesdal, Hans P; Puntervoll, Hanne; Geisler, Jürgen; Geisler, Stephanie; Heinrich, Daniel; Molven, Anders; Lønning, Per E; Akslen, Lars A; Straume, Oddbjørn

2012-01-01

VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12-49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab. ClinicalTrials.gov NCT00139360.

Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome.

PubMed

Maslak, P; Chanel, S; Camacho, L H; Soignet, S; Pandolfi, P P; Guernah, I; Warrell, R; Nimer, S

2006-02-01

Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. We designed a pilot study to target DNA methylation and histone deacetylation through the sequential administration of 5-azacytidine followed by sodium phenylbutyrate (PB) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Ten evaluable patients (eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azacytidine at 75 mg/m2 followed by 5 days of sodium PB given intravenously at a dose of 200 mg/kg. Five patients (50%) were able to achieve a beneficial clinical response (partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplantation and is alive without evidence of disease 39 months later. The combination regimen was well tolerated with common toxicities of injection site skin reaction (90% of the patients) from 5-azacytidine, and somnolence/fatigue from the sodium PB infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated. Results from this pilot study demonstrate that a combination approach targeting different mechanisms of transcriptional modulation is clinically feasible with acceptable toxicity and measurable biologic and clinical outcomes.

Phase I study of afatinib combined with nintedanib in patients with advanced solid tumours.

PubMed

Bahleda, Rastislav; Hollebecque, Antoine; Varga, Andrea; Gazzah, Anas; Massard, Christophe; Deutsch, Eric; Amellal, Nadia; Farace, Françoise; Ould-Kaci, Mahmoud; Roux, Flavien; Marzin, Kristell; Soria, Jean-Charles

2015-11-17

This Phase I study evaluated continuous- and intermittent-dosing (every other week) of afatinib plus nintedanib in patients with advanced solid tumours. In the dose-escalation phase (n=45), maximum tolerated doses (MTDs) were determined for continuous/intermittent afatinib 10, 20, 30 or 40 mg once daily plus continuous nintedanib 150 or 200 mg twice daily. Secondary objectives included safety and efficacy. Clinical activity of continuous afatinib plus nintedanib at the MTD was further evaluated in an expansion phase (n=25). The most frequent dose-limiting toxicities were diarrhoea (11%) and transaminase elevations (7%). Maximum tolerated doses were afatinib 30 mg continuously plus nintedanib 150 mg, and afatinib 40 mg intermittently plus nintedanib 150 mg. Treatment-related adverse events (mostly Grade⩽3) included diarrhoea (98%), asthenia (64%), nausea (62%) and vomiting (60%). In the dose-escalation phase, two patients had partial responses (PRs) and 27 (60%) had stable disease (SD). In the expansion phase, one complete response and three PRs were observed (all non-small cell lung cancer), with SD in 13 (52%) patients. No pharmacokinetic interactions were observed. MTDs of continuous or intermittent afatinib plus nintedanib demonstrated a manageable safety profile with proactive management of diarrhoea. Antitumour activity was observed in patients with solid tumours.

Percutaneous Hepatic Perfusion with Melphalan for Unresectable Metastatic Melanoma or Sarcoma to the Liver: A Single Institution Experience

PubMed Central

Forster, Meghan R.; Rashid, Omar M.; Perez, Matthew; Choi, Junsung; Chaudhry, Tariq; Zager, Jonathan S.

2015-01-01

Background Patients with unresectable melanoma or sarcoma hepatic metastasis have a poor prognosis with few therapeutic options. Percutaneous hepatic perfusion (PHP), isolating and perfusing the liver with chemotherapy, provides a promising minimally invasive management option. We reviewed our institutional experience with PHP. Methods We retrospectively reviewed patients with unresectable melanoma or sarcoma hepatic metastasis treated with PHP from 2008 to 2013 and evaluated therapeutic response, morbidity, hepatic progression free survival (hPFS), and overall survival (OS). Results Ten patients were treated with 27 PHPs (median 3). Diagnoses were ocular melanoma (n=5), cutaneous melanoma (n=3), unknown primary melanoma (n=1), and sarcoma (n=1). Median hPFS was 240 days, 9 of 10 patients (90%) demonstrated stable disease or partial response to treatment. At a median follow up of 11.5 months, 4 of 10 (40%) remain alive. There were no perioperative mortalities. Myelosuppresion was the most common morbidity, managed on an outpatient basis with growth factors. The median hospital stay was 3 days. Conclusions Patients with metastatic melanoma and sarcoma to the liver have limited treatment options. Our experience with PHP demonstrates promising results with minimal morbidity and should be considered (pending FDA approval) as a management option for unresectable melanoma or sarcoma hepatic metastasis. PMID:24249545

Re-challenge with pemetrexed in advanced mesothelioma: a multi-institutional experience

PubMed Central

2012-01-01

Background Although first-line therapy for patients affected by advanced mesothelioma is well established, there is a lack of data regarding the impact of second-line treatment. Methods We retrospectively collected data of patients affected by advanced mesothelioma, already treated with first-line therapy based on pemetrexed and platin, with a response (partial response or stable disease) lasting at least 6 months, and re-treated with a pemetrexed-based therapy at progression. The primary objective was to describe time to progression and overall survival after re-treatment. Results Overall across several Italian oncological Institutions we found 30 patients affected by advanced mesothelioma, in progression after a 6-month lasting clinical benefit following a first-line treatment with cisplatin and pemetrexed, and re-challenged with a pemetrexed-based therapy. In these patients we found a disease control rate of 66%, with reduction of pain in 43% of patients. Overall time to progression and survival were promising for a second-line setting of patients with advanced mesothelioma, being 5.1 and 13.6 months, respectively. Conclusions In our opinion, when a patient has a long-lasting benefit from previous treatment with pemetrexed combined with a platin compound, the same treatment should be offered at progression. PMID:22943698

Behavioral and Physiological Consequences of Sleep Restriction

PubMed Central

Banks, Siobhan; Dinges, David F.

2007-01-01

Adequate sleep is essential for general healthy functioning. This paper reviews recent research on the effects of chronic sleep restriction on neurobehavioral and physiological functioning and discusses implications for health and lifestyle. Restricting sleep below an individual's optimal time in bed (TIB) can cause a range of neurobehavioral deficits, including lapses of attention, slowed working memory, reduced cognitive throughput, depressed mood, and perseveration of thought. Neurobehavioral deficits accumulate across days of partial sleep loss to levels equivalent to those found after 1 to 3 nights of total sleep loss. Recent experiments reveal that following days of chronic restriction of sleep duration below 7 hours per night, significant daytime cognitive dysfunction accumulates to levels comparable to that found after severe acute total sleep deprivation. Additionally, individual variability in neurobehavioral responses to sleep restriction appears to be stable, suggesting a traitlike (possibly genetic) differential vulnerability or compensatory changes in the neurobiological systems involved in cognition. A causal role for reduced sleep duration in adverse health outcomes remains unclear, but laboratory studies of healthy adults subjected to sleep restriction have found adverse effects on endocrine functions, metabolic and inflammatory responses, suggesting that sleep restriction produces physiological consequences that may be unhealthy. Citation: Banks S; Dinges DF. Behavioral and physiological consequences of sleep restriction. J Clin Sleep Med 2007;3(5):519-528. PMID:17803017

Motion in partially and fully cross-linked F-actin networks

NASA Astrophysics Data System (ADS)

Morris, Eliza; Ehrlicher, Allen; Weitz, David

2012-02-01

Single molecule experiments have measured stall forces and procession rates of molecular motors on isolated cytoskeletal fibers in Newtonian fluids. But in the cell, these motors are transporting cargo through a highly complex cytoskeletal network. To compare these single molecule results to the forces exerted by motors within the cell, an evaluation of the response of the cytoskeletal network is needed. Using magnetic tweezers and fluorescence confocal microscopy we observe and quantify the relationship between bead motion and filament response in F-actin networks both partially and fully cross-linked with filamin We find that when the transition from full to partial cross-linking is brought about by a decrease in cross-linker concentration there is a simultaneous decline in the elasticity of the network, but the response of the bead remains qualitatively similar. However, when the cross-linking is reduced through a shortening of the F-actin filaments the bead response is completely altered. The characteristics of the altered bead response will be discussed here.

Women's Endorsement of Models of Sexual Response: Correlates and Predictors.

PubMed

Nowosielski, Krzysztof; Wróbel, Beata; Kowalczyk, Robert

2016-02-01

Few studies have investigated endorsement of female sexual response models, and no single model has been accepted as a normative description of women's sexual response. The aim of the study was to establish how women from a population-based sample endorse current theoretical models of the female sexual response--the linear models and circular model (partial and composite Basson models)--as well as predictors of endorsement. Accordingly, 174 heterosexual women aged 18-55 years were included in a cross-sectional study: 74 women diagnosed with female sexual dysfunction (FSD) based on DSM-5 criteria and 100 non-dysfunctional women. The description of sexual response models was used to divide subjects into four subgroups: linear (Masters-Johnson and Kaplan models), circular (partial Basson model), mixed (linear and circular models in similar proportions, reflective of the composite Basson model), and a different model. Women were asked to choose which of the models best described their pattern of sexual response and how frequently they engaged in each model. Results showed that 28.7% of women endorsed the linear models, 19.5% the partial Basson model, 40.8% the composite Basson model, and 10.9% a different model. Women with FSD endorsed the partial Basson model and a different model more frequently than did non-dysfunctional controls. Individuals who were dissatisfied with a partner as a lover were more likely to endorse a different model. Based on the results, we concluded that the majority of women endorsed a mixed model combining the circular response with the possibility of an innate desire triggering a linear response. Further, relationship difficulties, not FSD, predicted model endorsement.

Stability of the Zagreb realization of the Carnegie-Mellon-Berkeley coupled-channels unitary model

NASA Astrophysics Data System (ADS)

Osmanović, H.; Ceci, S.; Švarc, A.; Hadžimehmedović, M.; Stahov, J.

2011-09-01

In Hadžimehmedović [Phys. Rev. CPRVCAN0556-281310.1103/PhysRevC.84.035204 84, 035204 (2011)] we have used the Zagreb realization of Carnegie-Melon-Berkeley coupled-channel, unitary model as a tool for extracting pole positions from the world collection of partial-wave data, with the aim of eliminating model dependence in pole-search procedures. In order that the method is sensible, we in this paper discuss the stability of the method with respect to the strong variation of different model ingredients. We show that the Zagreb CMB procedure is very stable with strong variation of the model assumptions and that it can reliably predict the pole positions of the fitted partial-wave amplitudes.

Hearing results in otosclerosis surgery after partial stapedectomy, total stapedectomy and stapedotomy.

PubMed

Persson, P; Harder, H; Magnuson, B

1997-01-01

Hearing results in a consecutive series of 407 patients with otosclerosis undergoing primary stapes surgery were analysed (437 operated ears). Partial stapedectomy was performed in 70 ears (16%), total stapedectomy in 205 ears (47%), in both groups using the House steel wire prosthesis on fascia in the oval window. The remaining 162 ears (37%) underwent stapedotomy using the Fisch 0.4 mm teflon-platinum piston. No case of cochlear loss (> 15 dB) occurred in the total series. The comparison between the three groups one year postoperatively showed that the air-bone gap was smaller for partial and total stapedectomy for all frequencies except 4 kHz. The air-bone gap was calculated as the difference between the preoperative bone conduction and the postoperative air conduction thresholds. Partial and total stapedectomy also showed larger improvements of bone conduction thresholds compared with stapedotomy for all frequencies but 4 kHz. At the 3-year follow-up, the hearing gain for all frequencies (250-8000 Hz) was larger for partial and total stapedectomy. Yet, when comparing the decline of hearing from 1 to 3 year postoperatively, the hearing gain achieved with partial and total stapedectomy seemed to deteriorate at a higher rate, which was considered to be caused by impaired sensorineural function. Our results show that in the short-term perspective partial or total stapedectomy can still compete for better hearing results even at higher frequencies, but stapedotomy seems to yield more stable hearing results over time and should therefore be considered as the method of choice.

Front and pulse solutions for the complex Ginzburg-Landau equation with higher-order terms.

PubMed

Tian, Huiping; Li, Zhonghao; Tian, Jinping; Zhou, Guosheng

2002-12-01

We investigate one-dimensional complex Ginzburg-Landau equation with higher-order terms and discuss their influences on the multiplicity of solutions. An exact analytic front solution is presented. By stability analysis for the original partial differential equation, we derive its necessary stability condition for amplitude perturbations. This condition together with the exact front solution determine the region of parameter space where the uniformly translating front solution can exist. In addition, stable pulses, chaotic pulses, and attenuation pulses appear generally if the parameters are out of the range. Finally, applying these analysis into the optical transmission system numerically we find that the stable transmission of optical pulses can be achieved if the parameters are appropriately chosen.

Chimera patterns in the Kuramoto-Battogtokh model

NASA Astrophysics Data System (ADS)

Smirnov, Lev; Osipov, Grigory; Pikovsky, Arkady

2017-02-01

Kuramoto and Battogtokh (2002 Nonlinear Phenom. Complex Syst. 5 380) discovered chimera states represented by stable coexisting synchrony and asynchrony domains in a lattice of coupled oscillators. After a reformulation in terms of a local order parameter, the problem can be reduced to partial differential equations. We find uniformly rotating, spatially periodic chimera patterns as solutions of a reversible ordinary differential equation, and demonstrate a plethora of such states. In the limit of neutral coupling they reduce to analytical solutions in the form of one- and two-point chimera patterns as well as localized chimera solitons. Patterns at weakly attracting coupling are characterized by virtue of a perturbative approach. Stability analysis reveals that only the simplest chimeras with one synchronous region are stable.

The significance of major and stable molecular responses in chronic myeloid leukemia in the tyrosine kinase inhibitor era

PubMed Central

Renault, Ilana Zalcberg; Scholl, Vanesa; Hassan, Rocio; Capelleti, Paola; de Lima, Marcos; Cortes, Jorge

2011-01-01

Tyrosine kinase inhibitors have changed the management and outcomes of chronic myeloid leukemia patients. Quantitative polymerase chain reaction is used to monitor molecular responses to tyrosine kinase inhibitors. Molecular monitoring represents the most sensitive tool to judge chronic myeloid leukemia disease course and allows early detection of relapse. Evidence of achieving molecular response is important for several reasons: 1. early molecular response is associated with major molecular response rates at 18-24 months; 2. patients achieving major molecular response are less likely to lose their complete cytogenetic response; 3. a durable, stable major molecular response is associated with increased progression-free survival. However, standardization of molecular techniques is still challenging. PMID:23049363

Prognostic sub-grouping of diffuse large B-cell lymphomas into germinal centre and post germinal centre groups by immunohistochemistry after 6 cycles of chemotherapy.

PubMed

Hassan, Usman; Mushtaq, Sajid; Mamoon, Nadira; Asghar, Asghar Hussain; Ishtiaq, Sheeba

2012-01-01

Diffuse large B-cell lymphomas (DLBCL) can be divided into germinal centre (GC-DLBCL) and post germinal centre (post GC-DLBCL) groups by applying immunohistochemical antibodies. As these subgroups respond differently to chemotherapy, it is possible at diagnosis to select a poor prognostic subgroup for aggressive treatment. To determine the frequencies of GC-DLBCL and post GC-DLBCL in patients by immunohistochemistry (IHC) and the clinical response after six cycles of chemotherapy. In this descriptive study conducted in AFIP and CMH, Rawalpindi and NORI, Islamabad, from September 2010 to September 2011, a total of 75 pretreatment cases of DLBCL diagnosed during the study period were included. Cases were segregated in to GC-DLBCL and post GC-DLBCL groups according to results of immunohistochemistry markers CD10, BCL6 and MUM1. Immediate clinical response was assessed after 6 cycles of chemotherapy. Response was divided into complete response, partial response, stable disease or relapse or progression. The mean age was 54.2 ± 15. Males were 53 (70.7%). Forty (53.3%) cases comprised the GC-DLBCL group; 25(62.5%) of them showed a complete response. Most patients of the post GC-DLBCL 19(54%) showed relapse/progression. Results of immediate clinical response in both prognostic subgroups were significant (p<0.05). Results regarding positivity with immunohistochemical antibodies CD10 (p 0.011), BCL6 (p 0.013) and MUM1 (p 0.000) regarding immediate clinical response were also significant. GC-DLBCL group shows better response to CHOP chemotherapy regimen. Immunohistochemistry should be used to further classify DLBCL as this can enable us to select aggressive group for aggressive treatment. This manuscript is important because the study is the first to becarried out exclusively in Pakistan or our part of the world.

Efficacy and influence factors of icotinib hydrochloride in treating advanced non-small cell lung cancer.

PubMed

Ma, X-H; Tian, T-D; Liu, H-M; Li, Q-J; Gao, Q-L; Li, L; Shi, B

2017-01-01

To evaluate the efficacy and safety of icotinib hydrochloride in the treatment of patients with advanced non-small cell lung cancer (NSCLC) and discuss the influence factors on efficacy. 120 treatment-experienced patients confirmed by pathology or cytology with stage III B-IV non-small cell lung cancer took icotinib hydrochloride and erlotinib orally until the occurrence of disease progression or serious adverse reactions. Then, the efficacy of icotinib hydrochloride and the related influence factors were analyzed. In icotinib hydrochloride group, the response rate and the disease control rate were 30.00% and 65.00%, and the median progression-free survival time was 179 days (95% CI: 103.21-254.78); in erlotinib group, the response rate and the disease control rate were 25.00% and 56.70%, and the median progression-free survival time was 121 days (95% CI: 95.05-146.94). Moreover, the objective response rate and the disease control rate of second-line therapy were both superior to the third-line and above therapy. The objective response rate of patients with complete response/partial response/stable disease after the first-line therapy was higher than that of patients without response after the first-line therapy (p<0.05), and the significant differences existed in the objective response rate and the disease control rate among mutant group, wild-type group, and unknown group (p<0.05). The response rate and the disease control rate of erythra group were higher than those of non-erythra group (p<0.05). It was showed in the univariate analysis that the progression-free survival was correlated with the smoking status and the epidermal growth factor receptor gene mutations. The icotinib hydrochloride is effective and safe in treating the treatment-experienced patients with advanced NSCLC, especially for patients with sensitive mutations.

An improved Armstrong-Frederick-Type Plasticity Model for Stable Cyclic Stress-Strain Responses Considering Nonproportional Hardening

NASA Astrophysics Data System (ADS)

Li, Jing; Zhang, Zhong-ping; Li, Chun-wang

2018-03-01

This paper modified an Armstrong-Frederick-type plasticity model for investigating the stable cyclic deformation behavior of metallic materials with different sensitivity to nonproportional loadings. In the modified model, the nonproportionality factor and nonproportional cyclic hardening coefficient coupled with the Jiang-Sehitoglu incremental plasticity model were used to estimate the stable stress-strain responses of the two materials (1045HR steel and 304 stainless steel) under various tension-torsion strain paths. A new equation was proposed to calculate the nonproportionality factor on the basis of the minimum normal strain range. Procedures to determine the minimum normal strain range were presented for general multiaxial loadings. Then, the modified model requires only the cyclic strain hardening exponent and cyclic strength coefficient to determine the material constants. It is convenient for predicting the stable stress-strain responses of materials in engineering application. Comparisons showed that the modified model can reflect the effect of nonproportional cyclic hardening well.

A model of color vision with a robot system

NASA Astrophysics Data System (ADS)

Wang, Haihui

2006-01-01

In this paper, we propose to generalize the saccade target method and state that perceptual stability in general arises by learning the effects one's actions have on sensor responses. The apparent visual stability of color percept across saccadic eye movements can be explained by positing that perception involves observing how sensory input changes in response to motor activities. The changes related to self-motion can be learned, and once learned, used to form stable percepts. The variation of sensor data in response to a motor act is therefore a requirement for stable perception rather than something that has to be compensated for in order to perceive a stable world. In this paper, we have provided a simple implementation of this sensory-motor contingency view of perceptual stability. We showed how a straightforward application of the temporal difference enhancement learning technique yielding color percepts that are stable across saccadic eye movements, even though the raw sensor input may change radically.

Salinity stress constrains photosynthesis in Fraxinus ornus more when growing in partial shading than in full sunlight: consequences for the antioxidant defence system

PubMed Central

Fini, Alessio; Guidi, Lucia; Giordano, Cristiana; Baratto, Maria Camilla; Ferrini, Francesco; Brunetti, Cecilia; Calamai, Luca; Tattini, Massimiliano

2014-01-01

Background and Aims A major challenge in plant ecophysiology is understanding the effects of multiple sub-optimal environmental conditions on plant performance. In most Mediterranean areas soil salinity builds up during the summer because of low availability of soil water coupled with hot temperatures. Although sunlight and soil salinity may strongly interact in determining a plant's performance, this has received relatively little attention. Methods Two-year-old seedlings of Fraxinus ornus were grown outdoors in pots during a Mediterranean summer in either 45 % (shaded plants) or 100 % (sun plants) sunlight irradiance and were supplied with either deionized water or deionized water plus 75 mm NaCl. Morpho-anatomical traits, water and ionic relations, gas exchange and photosystem II performance, concentrations of individual carotenoids, activity of antioxidant enzymes, concentrations of ascorbic acid and individual polyphenols were measured in leaves. Leaf oxidative stress and damage were estimated by in vivo analysis of stable free radicals and ultrastructural analyses. Key Results Leaf concentrations of potentially toxic ions did not markedly differ in shaded or sun plants in response to salinity. Leaves of sun plants displayed superior water use efficiency compared with leaves of shaded plants, irrespective of salinity treatment, and had both better stomatal control and higher CO2 carboxylation efficiency than leaves of shaded plants. In the salt-treated groups, the adverse effects of excess midday irradiance were greater in shade than in sun plants. The activity of enzymes responsible for detoxifying hydrogen peroxide decreased in shaded plants and increased in sun plants as a result of salinity stress. In contrast, the activity of guaiacol peroxidase and the concentration of phenylpropanoids increased steeply in response to salinity in shaded plants but were unaffected in sun plants. Conclusions It is concluded that salinity may constrain the performance of plants growing under partial shading more severely than that of plants growing under full sun during summer. The results suggest co-ordination within the antioxidant defence network aimed at detoxifying salt-induced generation of reactive oxygen species. PMID:25006177

Can peptide receptor radionuclide therapy be safely applied in florid bone metastases? A pilot analysis of late stage osseous involvement.

PubMed

Sabet, A; Khalaf, F; Yong-Hing, C J; Sabet, A; Haslerud, T; Ahmadzadehfar, H; Guhlke, S; Grünwald, F; Biersack, H-J; Ezziddin, S

2014-01-01

Highly advanced metastatic bone disease with extensive osseous infiltration of neuroendocrine tumours (NET) may preclude patients from treatment with peptide receptor radionuclide therapy (PRRT) in concern about haematotoxicity. This study aims to assess the safety and efficacy of PRRT with 177Lu-octreotate in a patient cohort with this condition. 41 PRRT courses were performed in 11 patients with gastroenteropancreatic neuroendocrine tumours (GEP-NET) and florid bone metastases (severely advanced widespread metastatic bone disease). A mean activity of 6.95 GBq 177Lu-octreotate was administered per treatment cycle, aimed at four courses with standard intervals of 3 months. Haematological parameters were determined prior to each treatment course, in 2-4 weeks intervals between the courses, 8-12 weeks after the last course of PRRT and in 3 monthly intervals thereafter. Toxicity was recorded using Common Terminology Criteria for Adverse Events v3.0. Restaging was performed 3 months after termination of PRRT with CT/MRI and functional imaging (modified MDA criteria). Significant (grade III-IV), reversible haematotoxicity occurred in 4 (35%) patients and after 10 (24%) administrations. It either resolved spontaneously (1 patient) or was controlled by supportive measures (3 patients), such as blood transfusions (3 patients) or deferral of the subsequent therapy cycle (1 patient). Patients returned to baseline blood values within up to 23 months after termination of PRRT. The observed treatment response of bone metastases consisted of a partial response in 2, a minor response in 1, stable disease in 7, and progressive disease in 1 patient. Of the 4 patients with metastatic bone pain, 1 experienced complete and 3 partial resolution of symptoms within 3-10 weeks after commencement of PRRT. These preliminary data indicate that PRRT with 177Lu-octreotate can be safely applied even in florid bone metastases with extensive, severely advanced osseous replacement. The higher myelosuppression rate was not associated with serious complications and should not preclude patients from being treated and potentially experiencing remarkable treatment efficacy despite the very advanced stage.

Mitoguazone therapy in patients with refractory or relapsed AIDS-related lymphoma: results from a multicenter phase II trial.

PubMed

Levine, A M; Tulpule, A; Tessman, D; Kaplan, L; Giles, F; Luskey, B D; Scadden, D T; Northfelt, D W; Silverberg, I; Wernz, J; Espina, B; Von Hoff, D

1997-03-01

Patients with AIDS-related lymphoma usually have extensive lymphomatous disease, with relatively frequent involvement of the CNS. Approximately half may achieve complete remission after chemotherapy. Mitoguazone, an inhibitor of polyamine biosynthesis, has demonstrated efficacy in patients with de novo recurrent lymphoma. The drug is relatively nonmyelotoxic and may cross the blood-brain barrier. The current study was designed to assess the safety and potential efficacy of mitoguazone in patients with relapsed or refractory AIDS-lymphoma. Thirty-five patients were accrued, all of whom had failed one (51%) or multiple (two to six) prior regimens. Mitoguazone (600 mg/m2) was given intravenously on days 1 and 8, and then every 2 weeks, until best response, progression, or toxicity. The median age was 39 years. High-grade lymphoma was diagnosed in 29 patients (83%). Extranodal disease was present in 30 patients (86%), with multiple extranodal sites (two to seven) in 18 (51%). The median CD4 cell count at study entry was 66/dL (range, zero to 549). Twenty-six patients were assessable for response. The objective response rate was 23% (95% confidence interval [CI], 6.9 to 39.3), with complete remission in three patients (11.5%), and partial remission (PR) in three patients (11.5%). Six patients experienced stable disease. Median survival from study entry was 2.6 months for the group as a whole; 21.5 months (range, 3.8 to 29.1) in complete responders, 5.6 months (range, 3.8 to 34.8) in partial responders. The most common toxicities occurred solely during drug infusion and included vasodilation (63%), paresthesia (86%), and somnolence (17%). Fourteen patients (40%) experienced nausea and 16 (46%) vomiting (grade 3 in one). Ten patients (29%) developed stomatitis, including grade 3 in two and grade 4 in one. Seven patients (20%) developed neutropenia, with grade 4 in one. Thrombocytopenia occurred in nine patients (26%). While on study, three patients developed sepsis, four had pneumonia, and two developed opportunistic infections. Mitoguazone is an effective agent in patients with multiply relapsed or refractory AIDS-related lymphoma, with acceptable toxicity. Further study in patients with newly diagnosed disease is warranted.

Synergy between root hydrotropic response and root biomass in maize (Zea mays L.) enhances drought avoidance.

PubMed

Eapen, Delfeena; Martínez-Guadarrama, Jesús; Hernández-Bruno, Oralia; Flores, Leonardo; Nieto-Sotelo, Jorge; Cassab, Gladys I

2017-12-01

Roots of higher plants change their growth direction in response to moisture, avoiding drought and gaining maximum advantage for development. This response is termed hydrotropism. There have been few studies of root hydrotropism in grasses, particularly in maize. Our goal was to test whether an enhanced hydrotropic response of maize roots correlates with a better adaptation to drought and partial/lateral irrigation in field studies. We developed a laboratory bioassay for testing hydrotropic response in primary roots of 47 maize elite DTMA (Drought Tolerant Maize for Africa) hybrids. After phenotyping these hybrids in the laboratory, selected lines were tested in the field. Three robust and three weak hybrids were evaluated employing three irrigation procedures: normal irrigation, partial lateral irrigation and drought. Hybrids with a robust hydrotropic response showed growth and developmental patterns, under drought and partial lateral irrigation, that differed from weak hydrotropic responders. A correlation between root crown biomass and grain yield in hybrids with robust hydrotropic response was detected. Hybrids with robust hydrotropic response showed earlier female flowering whereas several root system traits, such as projected root area, median width, maximum width, skeleton width, skeleton nodes, average tip diameter, rooting depth skeleton, thinner aboveground crown roots, as well as stem diameter, were considerably higher than in weak hydrotropic responders in the three irrigation procedures utilized. These results demonstrate the benefit of intensive phenotyping of hydrotropism in primary roots since maize plants that display a robust hydrotropic response grew better under drought and partial lateral irrigation, indicating that a selection for robust hydrotropism might be a promising breeding strategy to improve drought avoidance in maize. Copyright © 2017 Elsevier B.V. All rights reserved.

Measures of Partial Knowledge and Unexpected Responses in Multiple-Choice Tests

ERIC Educational Resources Information Center

Chang, Shao-Hua; Lin, Pei-Chun; Lin, Zih-Chuan

2007-01-01

This study investigates differences in the partial scoring performance of examinees in elimination testing and conventional dichotomous scoring of multiple-choice tests implemented on a computer-based system. Elimination testing that uses the same set of multiple-choice items rewards examinees with partial knowledge over those who are simply…

Intrinsic dynamics and total energy-shaping control of the ballbot system

NASA Astrophysics Data System (ADS)

Satici, A. C.; Donaire, A.; Siciliano, B.

2017-12-01

Research on bipedal locomotion has shown that a dynamic walking gait is energetically more efficient than a statically stable one. Analogously, even though statically stable multi-wheeled robots are easier to control, they are energetically less efficient and have low accelerations to avoid tipping over. In contrast, the ballbot is an underactuated, nonholonomically constrained mobile robot, whose upward equilibrium point has to be stabilised by active control. In this work, we derive coordinate-invariant, reduced, Euler-Poincaré equations of motion for the ballbot. By means of partial feedback linearisation, we obtain two independent passive outputs with corresponding storage functions and utilise these to come up with energy-shaping control laws which move the system along the trajectories of a new Lagrangian system whose desired equilibrium point is asymptotically stable by construction. The basin of attraction of this controller is shown to be almost global under certain conditions on the design of the mechanism which are reflected directly in the mass matrix of the unforced equations of motion.

Stable Lévy motion with inverse Gaussian subordinator

NASA Astrophysics Data System (ADS)

Kumar, A.; Wyłomańska, A.; Gajda, J.

2017-09-01

In this paper we study the stable Lévy motion subordinated by the so-called inverse Gaussian process. This process extends the well known normal inverse Gaussian (NIG) process introduced by Barndorff-Nielsen, which arises by subordinating ordinary Brownian motion (with drift) with inverse Gaussian process. The NIG process found many interesting applications, especially in financial data description. We discuss here the main features of the introduced subordinated process, such as distributional properties, existence of fractional order moments and asymptotic tail behavior. We show the connection of the process with continuous time random walk. Further, the governing fractional partial differential equations for the probability density function is also obtained. Moreover, we discuss the asymptotic distribution of sample mean square displacement, the main tool in detection of anomalous diffusion phenomena (Metzler et al., 2014). In order to apply the stable Lévy motion time-changed by inverse Gaussian subordinator we propose a step-by-step procedure of parameters estimation. At the end, we show how the examined process can be useful to model financial time series.

Production of surfactant and detergent-stable, halophilic, and alkalitolerant alpha-amylase by a moderately halophilic Bacillus sp. Strain TSCVKK.

PubMed

Kiran, Kondepudi Kanthi; Chandra, T S

2008-01-01

A moderately halophilic alkalitolerant Bacillus sp. Strain TSCVKK, with an ability to produce extracellular halophilic, alkalitolerant, surfactant, and detergent-stable alpha-amylase was isolated from soil samples obtained from a salt-manufacturing industry in Chennai. The culture conditions for higher amylase production were optimized with respect to NaCl, substrate, pH, and temperature. Maximum amylase production of 592 mU/ml was achieved in the medium at 48 h with 10% NaCl, 1% dextrin, 0.4% yeast extract, 0.2% tryptone, and 0.2% CaCl(2) at pH 8.0 at 30 degrees C. The enzyme activity in the culture supernatant was highest with 10% NaCl at pH 7.5 and 55 degrees C. The amylase that was partially purified by acetone precipitation was highly stable in various surfactants and detergents. Glucose, maltose, and maltooligosaccharides were the main end products of starch hydrolysis indicating that it is an alpha-amylase.

Multidisciplinary management of very advanced stage III and IV melanoma: Proof-of-principle.

PubMed

Gutman, Haim; Ben-Ami, Eytan; Shapira-Frommer, Roni; Schachter, Jacob

2012-08-01

Patients with potentially resectable advanced stage III and IV melanoma are a selected subgroup that gain maximal advantage if treated in a melanoma center. Surgery combined with chemo/chemobiotherapy may yield durable remission and long-term palliation. Thirty-seven non-randomly selected patients underwent systemic therapy with the aim of consolidating treatment by surgery. Data were collected prospectively, and analyzed retrospectively. The median follow-up from diagnosis was 50 (3-307) months and 15 (1-156) months when calculated from the last intervention. Twenty-two males and 15 females, with a median age at diagnosis of 44 (20-71) years, with 13 trunk, 13 extremity, 3 head and neck and 8 unknown primary melanomas were included. There were 17 stage III and 20 stage IV patients with a median Breslow thickness of 3.7 (0.45-26) mm. Chemo/chemobiotherapy achieved 7 clinical complete responses (cCRs), 28 partial responses (PRs) and 2 instances of stable disease. Six of the 7 cCRs were operated on, securing pathological complete response in 5 and PR in one. Four of these five and the PR patient still have no evidence of disease (NED). Twenty-one of 30 PR patients were rendered NED by surgery; 14 of these 21 patients succumbed to melanoma, and one is alive with stable disease. Overall, 11 of 37 patients have not succumbed to melanoma, with a median of 72 (14-156) months survival following the last intervention. Of the eight patients with unknown primary melanomas, five have not succumbed to melanoma, with a median of 89 (30-156) months survival following the last intervention. Patients with marginally resectable stage III and IV melanoma have a significant 30% chance, according to this series, for durable remission if treated by a multidisciplinary team in a melanoma center using induction chemobiotherapy and surgery. Results are more favorable for patients with an unknown primary lesion. In view of the currently approved new effective treatments for melanoma, this study may be considered a proof-of-principle investigation, enabling long-term remissions by combining induction therapy and surgery.

A phase II study of axitinib (AG-013736) in patients with incurable adenoid cystic carcinoma.

PubMed

Ho, A L; Dunn, L; Sherman, E J; Fury, M G; Baxi, S S; Chandramohan, R; Dogan, S; Morris, L G T; Cullen, G D; Haque, S; Sima, C S; Ni, A; Antonescu, C R; Katabi, N; Pfister, D G

2016-10-01

Recurrent/metastatic adenoid cystic carcinoma (ACC) is an incurable disease with no standard treatments. The majority of ACCs express the oncogenic transcription factor MYB (also c-myb), often in the context of a MYB gene rearrangement. This phase II trial of the tyrosine kinase inhibitor (TKI) axitinib (Pfizer) tested the hypothesis that targeting pathways activated by MYB can be therapeutically effective for ACC. This is a minimax two-stage, phase II trial that enrolled patients with incurable ACC of any primary site. Progressive or symptomatic disease was required. Patients were treated with axitinib 5 mg oral twice daily; dose escalation was allowed. The primary end point was best overall response (BOR). An exploratory analysis correlating biomarkers to drug benefit was conducted, including next-generation sequencing (NGS) in 11 patients. Thirty-three patients were registered and evaluable for response. Fifteen patients had the axitinib dose increased. Tumor shrinkage was achieved in 22 (66.7%); 3 (9.1%) had confirmed partial responses. Twenty-five (75.8%) patients had stable disease, 10 of whom had disease stability for >6 months. The median progression-free survival (PFS) was 5.7 months (range 0.92-21.8 months). Grade 3 axitinib-related toxicities included hypertension, oral pain and fatigue. A trend toward superior PFS was noted with the MYB/NFIB rearrangement, although this was not statistically significant. NGS revealed three tumors with 4q12 amplification, producing increased copies of axitinib-targeted genes PDGFR/KDR/KIT. Two 4q12 amplified patients achieved stable disease for >6 months, including one with significant tumor reduction and the longest PFS on study (21.8 months). Although the primary end point was not met, axitinib exhibited clinical activity with tumor shrinkage achieved in the majority of patients with progressive disease before trial enrollment. Analysis of MYB biomarkers and genomic profiling suggests the hypothesis that 4q12 amplified ACCs are a disease subset that benefit from TKI therapy. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Multicenter Phase 2 Trial of Sirolimus for Tuberous Sclerosis: Kidney Angiomyolipomas and Other Tumors Regress and VEGF- D Levels Decrease

PubMed Central

Dabora, Sandra L.; Franz, David Neal; Ashwal, Stephen; Sagalowsky, Arthur; DiMario, Francis J.; Miles, Daniel; Cutler, Drew; Krueger, Darcy; Uppot, Raul N.; Rabenou, Rahmin; Camposano, Susana; Paolini, Jan; Fennessy, Fiona; Lee, Nancy; Woodrum, Chelsey; Manola, Judith; Garber, Judy; Thiele, Elizabeth A.

2011-01-01

Background Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. Methods We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. Results 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1–2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). Conclusions Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC. Trial Registration Clinicaltrials.gov NCT00126672 PMID:21915260

Synthesis and in Vitro and in Vivo Characterization of Highly β1-Selective β-Adrenoceptor Partial Agonists

PubMed Central

2013-01-01

β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β1-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),1 a selective β1-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1’s aromatic nitrile afforded 19, a ligand with similar β1-adrenoceptor selectivity and partial agonism (log KD of −7.75 and −5.15 as an antagonist of functional β1- and β2-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β1)). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and β1-selectivity. PMID:23614528

Phase I trial of a yeast-based therapeutic cancer vaccine (GI-6301) targeting the transcription factor brachyury

PubMed Central

Heery, Christopher R.; Singh, B. Harpreet; Rauckhorst, Myrna; Marté, Jennifer L.; Donahue, Renee N.; Grenga, Italia; Rodell, Timothy C.; Dahut, William; Arlen, Philip M.; Madan, Ravi A.; Schlom, Jeffrey; Gulley, James L.

2015-01-01

The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A Phase I dose escalation (3+3 design) trial enrolled 34 patients at 4 dose levels (3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)). Expansion cohorts were enrolled at 40 and 80 YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events were observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising CEA, remains on study for greater than 1 year with stable disease, evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling. PMID:26130065

Mixed-phenotype large granular lymphocytic leukemia (LGLL): a rare subtype in the LGLL Spectrum.

PubMed

Neff, Jadee L; Rangan, Aruna; Jevremovic, Dragan; Nguyen, Phuong L; Chiu, April; Go, Ronald S; Chen, Dong; Morice, William G; Shi, Min

2018-06-24

Large granular lymphocytic leukemia (LGLL) is a chronic proliferation of cytotoxic lymphocytes in which over 70% of patients develop cytopenia(s) requiring therapy. LGLL includes T-cell LGLL (T-LGLL) and chronic lymphoproliferative disorder of NK-cells (CLPD-NK). The neoplastic cells in LGLL usually exhibit a single immunophenotype in a patient, with CD8-positive/αβ T-cell type being the most common, followed by NK-cell, γδ T-cell, and CD4-positive/αβ T-cell types. We investigated a total of 220 LGLL cases and identified 12 mixed-phenotype LGLLs (5%): 7 cases with coexistent αβ T-cell and NK-cell clones and 5 with coexistent αβ and γδ T-cell clones. With a median follow-up of 48months, the clinicopathologic characteristics of these patients appeared similar to those of typical LGLL patients. Treatment was instituted in 9 patients and 5 patients (55%) attained complete hematologic response (CR) or partial response (PR). The therapeutic response rate of this cohort is comparable to the reported overall response rate of 40-60% in typical LGLL patients. Three patients who did not receive any treatment had progressive or persistent cytopenias. Interestingly, inverted proportions of two clones at disease recurrence were identified in 4 patients (36%) and stable clonal proportions in 7 patients (64%). Mixed-phenotype LGLL is rare, and this study underscores the importance of recognizing this rare type of LGLL in patients who may benefit from LGLL treatment. Copyright © 2018. Published by Elsevier Inc.

The clinical features of squamous cell lung carcinoma with sensitive EGFR mutations.

PubMed

Taniguchi, Yuri; Matsumoto, Yoko; Furukawa, Ryutaro; Ohara, Sayaka; Usui, Kazuhiro

2018-06-01

The process of selecting patients on the basis of epidermal growth factor receptor (EGFR) mutations would likely result in a patient population with greater sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, EGFR mutation status is not routinely examined in patients with squamous cell lung cancer (Sq) because of the low incidence of EGFR mutations and the poor clinical response to EGFR-TKIs. We retrospectively reviewed the clinical features of patients at our hospital with Sq who carried EGFR-TKI-sensitive EGFR mutations and assessed their responses to EGFR-TKIs. EGFR mutation status was tested in 23 of 441 patients with Sq (5.2%) admitted to our hospital during the study period. An EGFR mutation (exon 19 deletion 3, L858R 2) was identified in five of the 23 patients (21.7%), all of whom were female never-smokers. Of these five patients, four (4/9; 44.4%) were in the normal lung group, one (1/12; 8.3%) was in the emphysematous lung group, and none (0/2; 0%) in the fibrotic lung group. Two of these five patients with the EGFR mutation received gefitinib and two received afatinib. Although the two patients who were treated with gefitinib did not respond well to treatment (stable disease, 1 patient; progressive disease, 1 patient), the two patients who were treated with afatinib showed a good response (partial response, 2 patients). The administration of afatinib to Sq patients after selecting patients using the EGFR mutation test based on their underlying pulmonary disease and smoking status would likely result in a population with a greater sensitivity to afatinib.

Individualized 131I-mIBG therapy in the management of refractory and relapsed neuroblastoma.

PubMed

George, Sally L; Falzone, Nadia; Chittenden, Sarah; Kirk, Stephanie J; Lancaster, Donna; Vaidya, Sucheta J; Mandeville, Henry; Saran, Frank; Pearson, Andrew D J; Du, Yong; Meller, Simon T; Denis-Bacelar, Ana M; Flux, Glenn D

2016-05-01

Iodine-131-labelled meta-iodobenzylguanidine (I-mIBG) therapy is an established treatment modality for relapsed/refractory neuroblastoma, most frequently administered according to fixed or weight-based criteria. We evaluate response and toxicity following a dosimetry-based, individualized approach. A review of 44 treatments in 25 patients treated with I-mIBG therapy was performed. Patients received I-mIBG therapy following relapse (n=9), in refractory disease (n=12), or with surgically unresectable disease despite conventional treatment (n=4). Treatment schedule (including mIBG dose and number of administrations) was individualized according to the clinical status of the patient and dosimetry data from either a tracer study or previous administrations. Three-dimensional tumour dosimetry was also performed for eight patients. The mean administered activity was 11089±7222 MBq and the mean whole-body dose for a single administration was 1.79±0.57 Gy. Tumour-absorbed doses varied considerably (3.70±3.37 mGy/MBq). CTCAE grade 3/4 neutropenia was documented following 82% treatments and grade 3/4 thrombocytopenia following 71% treatments. Further acute toxicity was found in 49% of patients. All acute toxicities resolved with appropriate therapy. The overall response rate was 58% (complete or partial response), with a further 29% of patients having stable disease. A highly personalized approach combining patient-specific dosimetry and clinical judgement enables delivery of high activities that can be tolerated by patients, particularly with stem cell support. We report excellent response rates and acceptable toxicity following individualized I-mIBG therapy.

Toxic effects and antitumor response of gemcitabine in combination with piroxicam treatment in dogs with transitional cell carcinoma of the urinary bladder.

PubMed

Marconato, Laura; Zini, Eric; Lindner, Donna; Suslak-Brown, Lisa; Nelson, Victoria; Jeglum, Ann K

2011-04-15

To investigate whether combined treatment with gemcitabine and piroxicam in dogs with transitional cell carcinoma (TCC) of the urinary bladder is tolerated and provides an advantage in terms of survival time over previously reported treatments. Clinical trial. Animals-38 dogs with TCC of the urinary bladder. Dogs were treated with gemcitabine (800 mg/m(2), IV over 30 to 60 minutes, q 7 d) and piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h). Complete blood cell counts were monitored prior to each gemcitabine treatment. All toxic effects of gemcitabine in dogs were recorded. Primary tumors were ultrasonographically reevaluated after 4 gemcitabine treatments. Dogs received a median of 8 gemcitabine treatments (range, 1 to 38 treatments/dog). In response to treatment, 10 of 38 (26.3%) dogs had grade 1 gastrointestinal tract signs, 11 (28.9%) had grade 2, and 5 (13.2%) had grade 3. Grade 1 neutropenia developed in 6 (15.8%) dogs and grade 2 and 3 neutropenia in 2 (5.3%) dogs each. Thrombocytopenia was rare. All dogs had improvement of clinical signs of disease. Two dogs had a complete tumor response, 8 had a partial response, 19 had stable disease, and 8 had progressive disease. Median survival time with treatment was 230 days. Administration of gemcitabine in combination with piroxicam treatment failed to provide a longer overall survival time in dogs with TCC of the urinary bladder, compared with previously reported treatment strategies. However, this combination of chemotherapy did provide a new treatment alternative with fewer adverse effects.

The stable Cr isotopic compositions of chondrites and silicate planetary reservoirs

NASA Astrophysics Data System (ADS)

Schoenberg, Ronny; Merdian, Alexandra; Holmden, Chris; Kleinhanns, Ilka C.; Haßler, Kathrin; Wille, Martin; Reitter, Elmar

2016-06-01

The depletion of chromium in Earth's mantle (∼2700 ppm) in comparison to chondrites (∼4400 ppm) indicates significant incorporation of chromium into the core during our planet's metal-silicate differentiation, assuming that there was no significant escape of the moderately volatile element chromium during the accretionary phase of Earth. Stable Cr isotope compositions - expressed as the ‰-difference in 53Cr/52Cr from the terrestrial reference material SRM979 (δ53/52CrSRM979 values) - of planetary silicate reservoirs might thus yield information about the conditions of planetary metal segregation processes when compared to chondrites. The stable Cr isotopic compositions of 7 carbonaceous chondrites, 11 ordinary chondrites, 5 HED achondrites and 2 martian meteorites determined by a double spike MC-ICP-MS method are within uncertainties indistinguishable from each other and from the previously determined δ53/52CrSRM979 value of -0.124 ± 0.101‰ for the igneous silicate Earth. Extensive quality tests support the accuracy of the stable Cr isotope determinations of various meteorites and terrestrial silicates reported here. The uniformity in stable Cr isotope compositions of samples from planetary silicate mantles and undifferentiated meteorites indicates that metal-silicate differentiation of Earth, Mars and the HED parent body did not cause measurable stable Cr isotope fractionation between these two reservoirs. Our results also imply that the accretionary disc, at least in the inner solar system, was homogeneous in its stable Cr isotopic composition and that potential volatility loss of chromium during accretion of the terrestrial planets was not accompanied by measurable stable isotopic fractionation. Small but reproducible variations in δ53/52CrSRM979 values of terrestrial magmatic rocks point to natural stable Cr isotope variations within Earth's silicate reservoirs. Further and more detailed studies are required to investigate whether silicate differentiation processes, such as partial mantle melting and crystal fractionation, can cause stable Cr isotopic fractionation on Earth and other planetary bodies.

Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA.

PubMed

Remon, J; Caramella, C; Jovelet, C; Lacroix, L; Lawson, A; Smalley, S; Howarth, K; Gale, D; Green, E; Plagnol, V; Rosenfeld, N; Planchard, D; Bluthgen, M V; Gazzah, A; Pannet, C; Nicotra, C; Auclin, E; Soria, J C; Besse, B

2017-04-01

Approximately 50% of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) will acquire resistance by the T790M mutation. Osimertinib is the standard of care in this situation. The present study assesses the efficacy of osimertinib when T790M status is determined in circulating cell-free tumour DNA (ctDNA) from blood samples in progressing advanced EGFR-mutant NSCLC patients. ctDNA T790M mutational status was assessed by Inivata InVision™ (eTAm-Seq™) assay in 48 EGFR-mutant advanced NSCLC patients with acquired resistance to EGFR TKIs without a tissue biopsy between April 2015 and April 2016. Progressing T790M-positive NSCLC patients received osimertinib (80 mg daily). The objectives were to assess the response rate to osimertinib according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, the progression-free survival (PFS) on osimertinib, and the percentage of T790M positive in ctDNA. The ctDNA T790M mutation was detected in 50% of NSCLC patients. Among assessable patients, osimertinib gave a partial response rate of 62.5% and a stable disease rate of 37.5%. All responses were confirmed responses. After median follow up of 8 months, median PFS by RECIST criteria was not achieved (95% CI: 4-NA), with 6- and 12-months PFS of 66.7% and 52%, respectively. ctDNA from liquid biopsy can be used as a surrogate marker for T790M in tumour tissue. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Intratumoral Epidermal Growth Factor Receptor Antisense DNA Therapy in Head and Neck Cancer: First Human Application and Potential Antitumor Mechanisms

PubMed Central

Lai, Stephen Y.; Koppikar, Priya; Thomas, Sufi M.; Childs, Erin E.; Egloff, Ann Marie; Seethala, Raja R.; Branstetter, Barton F.; Gooding, William E.; Muthukrishnan, Ashok; Mountz, James M.; Lui, Vivian W.Y.; Shin, Dong M.; Agarwala, Sanjiv S.; Johnson, Rita; Couture, Larry A.; Myers, Eugene N.; Johnson, Jonas T.; Mills, Gordon; Argiris, Athanassios; Grandis, Jennifer R.

2009-01-01

Purpose Squamous cell carcinoma of the head and neck (SCCHN) is characterized by upregulation of the epidermal growth factor receptor (EGFR). We developed a novel strategy to target EGFR by using a therapeutic gene that consisted of an EGFR antisense (AS) gene sequence under U6 promoter control. A phase I clinical trial was conducted to evaluate the safety and biologic effects of EGFR AS. Patients and Methods Patients with advanced SCCHN who were refractory to standard therapies and who had at least one assessable and accessible lesion were enrolled. The EGFR AS dose was escalated in successive cohorts (six dose levels; 60 to 1,920 μg/injection). Patients received four weekly intratumoral EGFR AS injections. Tumor biopsies were performed before and after completion of therapy. Treatment response was assessed by tumor volume measurements (positron emission tomography/computed tomography), and levels of target proteins were assessed by immunohistochemistry. Results Seventeen assessable patients were treated. No grades 3 to 4 or dose-limiting toxicities were noted, and a maximum-tolerated dose was not reached. Five patients (29%) achieved a clinical response, which included two complete responses (CRs) and three partial responses (PRs); two additional patients had stable disease (SD) as the best response. Patients with disease control (CR + PR + SD) had tumors with higher EGFR and lower STAT3 expression at baseline compared with patients who had progressive disease (P = .0312 and P = .095, respectively). Conclusion Intratumoral EGFR AS was safe and resulted in antitumor activity in patients with advanced SCCHN. Baseline levels of high EGFR and low STAT3 may be associated with antitumor effects. PMID:19204206

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoffmann, Ralf-T., E-mail: rthoffma@med.uni-muenchen.de; Paprottka, Philipp M., E-mail: philipp.paprottka@med.uni-muenchen.de; Schoen, Agnes

Introduction: In unresectable intrahepatic cholangiocarcinoma (ICC), systemic chemotherapy often is viewed as the only option, although efficacy is limited. Radioembolization (RE) using yttrium-90 ({sup 90}Y) microspheres is an accepted therapy for patients with hepatocellular-carcinoma or metastatic liver tumors. However, there are limited data on the value of RE in patients with ICC and few data on factors influencing prognosis. The purpose of our retrospective analysis was to establish which factors influenced time-to-progression (TTP) and overall survival (OS). Methods: Patients with unresectable ICC were treated with {sup 90}Y resin-microspheres and assessed at 3-monthly intervals. Radiologic response was evaluated by using Responsemore » Criteria in Solid Tumors (RECIST). Baseline characteristics, biochemical/clinical toxicities, and response were examined for impact on TTP and OS. Results: Thirty-four treatments were administered to 33 patients without major complications. By RECIST, 12 patients had a partial response, 17 had stable disease, and 5 had progressive disease after 3 months. The median OS was 22 months posttreatment and 43.7 months postdiagnosis. Median TTP was 9.8 months. Survival and TTP were significantly prolonged in patients with ECOG 0 (vs. ECOG 1 or 2; median OS: 29.4, 10, and 5.1 months; TTP: 17.5, 6.9, and 2.4 months), tumor burden {<=}25% (OS: 26.7 vs. 6 months; TTP: 17.5 vs. 2.3 months), or tumor response (PR or SD vs. PD; OS: 35.5, 17.7 vs. 5.7 months; TTP: 31.9, 9.8 vs. 2.5 months), respectively (P < 0.001). Conclusions: Radioembolization is an effective and safe option for patients with unresectable ICC. Predictors for prolonged survival are performance status, tumor burden, and RECIST response.« less

Ifosfamide and etoposide in previously treated patients with advanced breast cancer.

PubMed

Kiraz, S; Baltali, E; Güler, N; Barişta, I; Benekli, M; Celik, I; Güllü, I H; Kars, A; Tekuzman, G; Firat, D

1997-01-01

Ifosfamide is an active alkylating agent in the treatment of breast cancer, as a first-line therapy and in advanced disease. Since the combination of etoposide with an alkylating agent produces a synergistic and tolerable activity in various malignancies, in the present study, ifosfamide and etoposide were administered to patients with advanced breast cancer to evaluate the response characteristics and the toxicity profile. The combination of ifosfamide, mesna and etoposide was prospectively administered to 41 previously treated patients with stage IV breast carcinoma. The treatment schedule consisted of ifosfamide, 1500 mg/m2, infused over 24 hrs with 1500 mg/m2 mesna on days 1 to 5 and 120 mg/m2 etoposide, infused over 1 hr on days 1 to 3, to be repeated every 4th week. After a median follow-up of 10 months, an objective response rate of 23% (overall 2.5% complete remission and 20.5% partial remission) and a median response duration of 5.3 months were obtained in 39 assessable patients. The non-responder group consisted of 28.3% stable disease and 48.7% progressive disease. The prior status of chemotherapy was the only significant prognostic factor with an impact on the response rate. The overall toxicity was generally mild, with grade 3 myelotoxicity encountered in 25.7% of patients. The tolerable side effect profile of the ifosfamide and etoposide combination might be advantageous as regards the quality of life. To improve the rate and/or the duration of response and to clarify the precise role of the ifosfamide-etoposide combination in previously treated advanced breast cancer, further trials are warranted.

Phase II trial of capecitabine plus modified cisplatin (mXP) as first-line therapy in Japanese patients with metastatic gastric cancer (KSCC1104).

PubMed

Satake, Hironaga; Iwatsuki, Masaaki; Uenosono, Yoshikazu; Shiraishi, Takeshi; Tanioka, Hiroaki; Saeki, Hiroshi; Sugimachi, Keishi; Kitagawa, Dai; Shimokawa, Mototsugu; Oki, Eiji; Emi, Yasunori; Kakeji, Yoshihiro; Tsuji, Akihito; Akagi, Yoshito; Natsugoe, Shoji; Baba, Hideo; Maehara, Yoshihiko

2017-01-01

Capecitabine plus cisplatin (XP) is a standard therapy for metastatic gastric cancer (mGC). However, while results from previous phase III trials suggested that the cisplatin dosage should be reduced in Japanese patients, no clinical data exist to support this. Here, we conducted a multicenter study to evaluate the efficacy and safety of modified XP (mXP) in Japanese patients with mGC. Patients with previously untreated mGC received mXP (cisplatin 60 mg/m 2 on day 1 plus capecitabine 1000 mg/m 2 twice daily on days 1-14) every 3 weeks. The primary endpoint was the Response Evaluation Criteria in Solid Tumors-confirmed overall response rate (ORR). A sample size of 40 was planned for a threshold ORR of 30% and an expected value of 50%, with a one-sided α of 0.05 and a beta of approximately 0.2. Forty-two patients were enrolled. One patient did not fulfill the eligibility criteria; therefore, a total of 41 patients were assessed. The results were as follows: complete response in 2 patients, partial response in 16, stable disease in 14, progressive disease in 8, and no evaluation in 1. The confirmed ORR was 43.9% (95% confidence interval 28.7-59.1%). The median progression-free survival and median overall survival were 4.6 and 11.3 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (37.5%), anemia (24.4%), anorexia (24.4%), and nausea (12.2%). First-line chemotherapy with mXP in Japanese patients with mGC did not reach its primary objective. However, it did show a promising response rate and an acceptable tolerability profile.

A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG-asparaginase, and doxorubicin.

PubMed

Trucco, Matteo; Barredo, Julio C; Goldberg, John; Leclerc, Gilles M; Hale, Gregory A; Gill, Jonathan; Setty, Bhuvana; Smith, Tiffany; Lush, Richard; Lee, Jae K; Reed, Damon R

2018-06-01

Acute lymphoblastic leukemia (ALL) remains a major cause of death in children. AMP-activated protein kinase (AMPK) affects the unfolded protein response (UPR), leading to increased vulnerability to endoplasmic reticulum (ER) stress in ALL cells. In vitro, metformin causes ALL cell death via AMPK-mediated inhibition of the UPR. It was evaluated whether ER stress could be induced in relapsed ALL through a phase I study investigating the safety and feasibility of metformin in combination with relapse induction chemotherapy. Metformin was administered twice daily for 28 days in addition to vincristine, dexamethasone, PEG-asparaginase and doxorubicin (VXLD). Dose escalation of metformin was evaluated using a 3+3 design. Pharmacokinetics (PK), pharmacodynamic (PD) evaluation of the AMPK and ER stress/UPR pathways, and treatment response were assessed. Fourteen patients were enrolled; all were evaluable for toxicity. The recommended phase 2 dose (RP2D) was Dose level 2, 1,000 mg/m 2 /day. A single dose-limiting toxicity (DLT), hypoglycemia with acidosis, was observed at the RP2D and two DLTs, diarrhea and acidosis, were observed at Dose Level 3. Nine patients were evaluable for response as defined by the protocol, receiving at least 85% of planned metformin doses. Five complete remissions, one partial response, and one stable disease were observed. PD evaluation showed induction of ER stress, activation of AMPK, and inhibition of the UPR. The VXLD with metformin was tolerable with a RP2D for metformin of 1,000 mg/m 2 /day and yielded responses in a heavily pretreated population. ER stress was induced and toxicities attributable to metformin occurred in all dose levels. © 2018 Wiley Periodicals, Inc.

Results of a Phase II Trial of Gemcitabine plus Doxorubicin in Patients with Recurrent Head and Neck Cancers: Serum C18-ceramide as a Novel Biomarker for Monitoring Response

PubMed Central

Saddoughi, Sahar A.; Garrett-Mayer, Elizabeth; Chaudhary, Uzair; O’Brien, Paul; Afrin, Larry; Day, Terry A.; Gillespie, M. Boyd; Sharma, Anand; Wilhoit, Christina; Bostick, Robin; Senkal, Can E.; Hannun, Yusuf A.; Bielawski, Jacek; Simon, George; Shirai, Keisuke; Ogretmen, Besim

2011-01-01

Purpose Here we report a phase II clinical trial, which was designed to test a novel hypothesis that treatment with GEM/DOX would be efficacious via reconstitution of C18-ceramide signaling in HNSCC patients for whom first-line platinum-based therapy failed. Experimental Design Patients received GEM (1,000 mg/m2) and DOX (25 mg/m2) on days 1 and 8, every 21 days, until disease progression. After completion of 2 treatment cycles, patients were assessed radiographically, and serum samples were taken for sphingolipid measurements. Results We enrolled 18 patients in the trial, who were evaluable for toxicity, and 17 for response. The most common toxicity was neutropenia, observed in 9 of 18 patients, and there were no major non-hematological toxicities. Of the 17 patients, 5 patients had progressive disease (PD), 1 had complete response (CR), 3 exhibited partial response (PR), and 8 had stable disease (SD). The median progression-free survival (PFS) was 1.6 months (95% CI, 1.4, 4.2) with a median survival of 5.6 months (95% CI, 3.8, 18.2). Remarkably, serum sphingolipid analysis revealed significant differences in patterns of C18-ceramide elevation in patients with CR/PR/SD in comparison to patients with PD, indicating the reconstitution of tumor suppressor ceramide generation by GEM/DOX treatment. Conclusions Our data suggest that the GEM/DOX combination could represent an effective treatment for some patients with recurrent or metastatic HNSCC, and that serum C18-ceramide elevation might be a novel serum biomarker of chemotherapy response. PMID:21791630

Detection of Somatic Mutations in Gastroenteropancreatic Neuroendocrine Tumors Using Targeted Deep Sequencing.

PubMed

Backman, Samuel; Norlén, Olov; Eriksson, Barbro; Skogseid, Britt; Stålberg, Peter; Crona, Joakim

2017-02-01

Mutations affecting the mechanistic target of rapamycin (MTOR) signalling pathway are frequent in human cancer and have been identified in up to 15% of pancreatic neuroendocrine tumours (NETs). Grade A evidence supports the efficacy of MTOR inhibition with everolimus in pancreatic NETs. Although a significant proportion of patients experience disease stabilization, only a minority will show objective tumour responses. It has been proposed that genomic mutations resulting in activation of MTOR signalling could be used to predict sensitivity to everolimus. Patients with NETs that underwent treatment with everolimus at our Institution were identified and those with available tumour tissue were selected for further analysis. Targeted next-generation sequencing (NGS) was used to re-sequence 22 genes that were selected on the basis of documented involvement in the MTOR signalling pathway or in the tumourigenesis of gastroenterpancreatic NETs. Radiological responses were documented using Response Evaluation Criteria in Solid Tumours. Six patients were identified, one had a partial response and four had stable disease. Sequencing of tumour tissue resulted in a median sequence depth of 667.1 (range=404-1301) with 1-fold coverage of 95.9-96.5% and 10-fold coverage of 87.6-92.2%. A total of 494 genetic variants were discovered, four of which were identified as pathogenic. All pathogenic variants were validated using Sanger sequencing and were found exclusively in menin 1 (MEN1) and death domain associated protein (DAXX) genes. No mutations in the MTOR pathway-related genes were observed. Targeted NGS is a feasible method with high diagnostic yield for genetic characterization of pancreatic NETs. A potential association between mutations in NETs and response to everolimus should be investigated by future studies. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemoembolization of Extrahepatic Collateral Arteries for Treatment of Hepatocellular Carcinoma in the Caudate Lobe of the Liver

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woo, Sungmin; Kim, Hyo-Cheol, E-mail: angiointervention@gmail.com; Chung, Jin Wook

2015-04-15

PurposeThis study was designed to evaluate the efficacy and safety in performing chemoembolization of extrahepatic collateral arteries (EHC) for hepatocellular carcinoma (HCC) located in the caudate lobe.MethodsBetween January 2006 and November 2013, chemoembolization via EHC was performed in 35 patients with 35 caudate HCCs. Preprocedural and follow-up CT or MR scans, angiographic images, and medical records were reviewed retrospectively in consensus. Chi-square analysis was used to evaluate the relationship between tumor characteristics and type of EHC and that between tumor response and the characteristics of the tumor and chemoembolization.ResultsIn 31 (88.6 %) patients, EHCs supplying the caudate HCC originated from themore » right inferior phrenic artery (RIPA). The remaining four HCCs were supplied by the gastroduodenal artery, dorsal pancreatic artery, and right and left gastric arteries. Superselective catheterization of tumor-feeding vessels from the EHC was achieved in 27 patients (77.1 %). There were no major complications. Individual tumor response supplied by the EHC at follow-up contrast-enhanced CT were as follows: complete response (n = 18), partial response (n = 9), stable disease (n = 3), and progressive disease (n = 3). Non-RIPA EHCs were significantly more common in patients who had previously received chemoembolization via the RIPA (50 %) than those who had not (6.5 %; P = 0.01). There was no significant predictive factor associated with tumor response.ConclusionsHCC in the caudate lobe can be supplied by several EHCs. Chemoembolization via these arteries can be performed safely and effectively.« less

Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer.

PubMed

Scagliotti, Giorgio; Kang, Jin Hyoung; Smith, David; Rosenberg, Richard; Park, Keunchil; Kim, Sang-We; Su, Wu-Chou; Boyd, Thomas E; Richards, Donald A; Novello, Silvia; Hynes, Scott M; Myrand, Scott P; Lin, Ji; Smyth, Emily Nash; Wijayawardana, Sameera; Lin, Aimee Bence; Pinder-Schenck, Mary

2016-10-01

Introduction LY2603618 is a selective inhibitor of checkpoint kinase 1 (CHK1) protein kinase, a key regulator of the DNA damage checkpoint, and is predicted to enhance the effects of antimetabolites, such as pemetrexed. This phase II trial assessed the overall response rate, safety, and pharmacokinetics (PK) of LY2603618 and pemetrexed in patients with non-small cell lung cancer (NSCLC). Methods In this open-label, single-arm trial, patients with advanced or metastatic NSCLC progressing after a prior first-line treatment regimen (not containing pemetrexed) and Eastern Cooperative Oncology Group performance status ≤2 received pemetrexed (500 mg/m(2), day 1) and LY2603618 (150 mg/m(2), day 2) every 21 days until disease progression. Safety was assessed using Common Terminology Criteria for Adverse Events v3.0. Serial blood samples were collected for PK analysis after LY2603618 and pemetrexed administration. Expression of p53, as measured by immunohistochemistry and genetic variant analysis, was assessed as a predictive biomarker of response. Results Fifty-five patients were enrolled in the study. No patients experienced a complete response; a partial response was observed in 5 patients (9.1 %; 90 % CI, 3.7-18.2) and stable disease in 20 patients (36.4 %). The median progression-free survival was 2.3 months (range, 0-27.1). Safety and PK of LY2603618 in combination with pemetrexed were favorable. No association between p53 status and response was observed. Conclusions There was no significant clinical activity of LY2603618 and pemetrexed combination therapy in patients with advanced NSCLC. The results were comparable with historical pemetrexed single-agent data, with similar safety and PK profiles being observed.

Atezolizumab in Metastatic Urothelial Carcinoma Outside Clinical Trials: Focus on Efficacy, Safety, and Response to Subsequent Therapies.

PubMed

Barata, Pedro C; Gopalakrishnan, Dhrmesh; Koshkin, Vadim S; Mendiratta, Prateek; Karafa, Matt; Allman, Kimberly; Martin, Allison; Beach, Jennifer; Profusek, Pam; Tyler, Allison; Wood, Laura; Ornstein, Moshe; Gilligan, Timothy; Rini, Brian I; Garcia, Jorge A; Grivas, Petros

2018-04-06

Little is known about the outcomes, safety, and response to subsequent therapies of patients with metastatic urothelial carcinoma (mUC) treated with atezolizumab outside clinical trials. The objectives of the study include to report the clinical efficacy and safety of atezolizumab, and the response to future therapies in clinical practice outside clinical trials. This is a retrospective, single-center study including consecutive patients with confirmed mUC who received at least one dose of atezolizumab 1200 mg every 3 weeks between May 2016 and April 2017. Seventy-nine patients, median age 72 years (range 29-93), 71% men and 76% ECOG PS 0-1, were identified. Most patients (79%) had primary cancer in the bladder, 62% had prior surgery, and 75% received at least one prior line of treatment (34 patients had prior cisplatin-based chemotherapy). Best response included 18% partial response, 29% stable disease, and 53% progressive disease. Patients were on atezolizumab for a median of 2.7 months (95%CI, 1.8-3.6) and median PFS was 3.2 months (95%CI, 1.6-4.8). A total of 33 (42%) patients had significant (any cause) AEs, including grade 4 hyperbilirubinemia in two patients; no toxic deaths were reported. At time of data analysis, only 18% of patients received at least one subsequent line of treatment for a median of 1.8 months (95%CI, 0.0-5.0) while 42% were referred to palliative care/hospice or died. Patients with mUC who progressed on atezolizumab were unlikely to receive subsequent systemic treatments and the benefit of those treatments appeared limited in our cohort. The findings may impact timing and designs of clinical trials in mUC.

A phase II trial of recombinant tumor necrosis factor in patients with metastatic colorectal adenocarcinoma: a Southwest Oncology Group study.

PubMed

Whitehead, R P; Fleming, T; Macdonald, J S; Goodman, P J; Neefe, J; Braun, T J; Swinnen, L J; Hersh, E M

1990-12-01

Tumor necrosis factor (TNF) induces hemorrhagic necrosis in the Meth A mouse tumor model and has shown cytostatic and cytotoxic antitumor effects against a wide range of human tumors both in vitro and as human tumor xenografts in nude mice. Because of in vitro activity against colorectal tumors and antitumor responses in colon cancer patients in phase I trials, this phase II study was undertaken. Patients were treated with TNF administered daily for 5 days/week every other week at a dose of 150 micrograms/m2/day as a 30-min i.v. infusion. One cycle consisted of 4 weeks of treatment over an 8-week period. Twenty-five patients have been entered into this study with three patients ineligible. The 22 eligible patients ranged in age from 38-73 years and had initial performance status of 0 in 10 patients, 1 in 10 patients, and 2 in 2 patients. No complete or partial responses were seen. Two patients had stable disease (no response) and 18 patients progressed. Two patients had no evaluation and were assumed to have had no response. The response rate is therefore 0%, with a 95% exact confidence interval of 0% to 15%. There was one grade 4 toxicity consisting of nausea and vomiting. Most common grade 3 toxicities were chills and fever in four patients, nausea and vomiting in three patients, and anemia and elevated liver enzymes in two patients. Headache, myalgia/arthralgia, and elevated serum triglycerides were frequently seen. Mildly elevated levels of fibrin split products were seen after TNF treatment in 5/13 evaluable patients and one ineligible patient.(ABSTRACT TRUNCATED AT 250 WORDS)

RECIST response and variation of circulating tumour cells in phase 1 trials: A prospective multicentric study.

PubMed

Massard, Christophe; Borget, Isabelle; Farace, Françoise; Aspeslagh, Sandrine; Le Deley, Marie-Cécile; Le Tourneau, Christophe; Bidard, François-Clement; Pierga, Jean-Yves; Dieras, Veronique; Hofman, Paul; Spano, Jean-Philippe; Ferte, Charles; Lacroix, Ludovic; Soria, Jean-Charles

2017-09-01

Circulating tumour cell (CTC) counting could be a new biomarker for better evaluation of tumour response to molecules tested in phase I trials. Consenting patients with advanced metastatic cancer referred to various phase I units were enrolled prospectively in this study. CTCs from 7.5 ml of whole blood drawn at baseline and after starting experimental therapy were counted using the CellSearch system, and tumour response was assessed using RECIST 1.1 criteria at baseline and 2 months after treatment initiation. Between March 2010 and May 2013, a total of 326 patients were enrolled, among whom 214 were evaluable (49% male, median age = 56; main cancer types: lung [28], colon [53], ovarian [18], breast [28]). At baseline, we detected ≥1 CTC/7.5 ml in 113/214 patients (53%), and at day 30, we observed ≥1 CTC/7.5 ml in 103/214 patients (48%). Two months after treatment initiation, 11 (5%) of the 214 patients were classified as having a partial response, with no CTCs in 9 of them or a decrease in the CTC count after therapy. In contrast, among the 104 patients (49%) classified as having progressive disease, 38 patients had a higher CTC count. The remaining 99 patients (49%), 33 of whom (33%) had a lower CTC count, were classified as having stable disease. The sensitivity and specificity of CTC variation for predicting progressive disease were 41% (32-51%) and 80% (73-88%) respectively. An early CTC change following therapy does not correlate with RECIST response in patients with advanced cancer enrolled in phase I trials. Copyright © 2017 Elsevier Ltd. All rights reserved.

Morphological and dietary responses of chipmunks to a century of climate change.

PubMed

Walsh, Rachel E; Aprígio Assis, Ana Paula; Patton, James L; Marroig, Gabriel; Dawson, Todd E; Lacey, Eileen A

2016-09-01

Predicting how individual taxa will respond to climatic change is challenging, in part because the impacts of environmental conditions can vary markedly, even among closely related species. Studies of chipmunks (Tamias spp.) in Yosemite National Park provide an important opportunity to explore the reasons for this variation in response. While the alpine chipmunk (T. alpinus) has undergone a significant elevational range contraction over the past century, the congeneric and partially sympatric lodgepole chipmunk (T. speciosus) has not experienced an elevational range shift during this period. As a first step toward identifying the factors underlying this difference in response, we examined evidence for dietary changes and changes in cranial morphology in these species over the past century. Stable isotope analyses of fur samples from modern and historical museum specimens of these species collected at the same localities indicated that signatures of dietary change were more pronounced in T. alpinus, although diet breadth did not differ consistently between the study species. Morphometric analyses of crania from these specimens revealed significant changes in cranial shape for T. alpinus, with less pronounced changes in shape for T. speciosus; evidence of selection on skull morphology was detected for T. alpinus, but not for T. speciosus. These results are consistent with growing evidence that T. alpinus is generally more responsive to environmental change than T. speciosus, but emphasize the complex and often geographically variable nature of such responses. Accordingly, future studies that make use of the taxonomically and spatially integrative approach employed here may prove particularly informative regarding relationships between environmental conditions, range changes, and patterns of phenotypic variation. © 2016 John Wiley & Sons Ltd.

Highly selective direct determination of chlorate ions by using a newly developed potentiometric electrode based on modified smectite.

PubMed

Topcu, Cihan

2016-12-01

A novel polyvinyl chloride membrane chlorate (ClO 3 - ) selective electrode based on modified smectite was developed for the direct determination of chlorate ions and the potentiometric performance characteristics of its were examined. The best selectivity and sensitivity for chlorate ions were obtained for the electrode membrane containing ionophore/polyvinylchloride/o-nitrophenyloctylether in composition of 12/28/60 (w/w%). The proposed electrode showed a Nernstian response toward chlorate ions at pH=7 in the concentration range of 1×10 -7 -1×10 -1 M and the limit of detection was calculated as 9×10 -8 M from the constructed response plot. The linear slope of the electrode was -61±1mVdecade -1 for chlorate activity in the mentioned linear working range. The selectivity coefficients were calculated according to both the matched potential method and the separate solution method. The calculated selectivity coefficients showed that the electrode performed excellent selectivity for chlorate ions. The potentiometric response of electrode toward chlorate ions was found to be highly reproducible. The electrode potential was stable between pH=4-10 and it had a dynamic response time of <5s. The potentiometric behavior of the electrode in partial non-aqueous medium was also investigated and the obtained results (up to 5% (v/v) alcohol) were satisfactory. The proposed electrode was used during 15 weeks without any significant change in its potential response. Additionally, the electrode was very useful in water analysis studies such as dam water, river water, tap water, and swimming pool water where the direct determination of chlorate ions was required. Copyright © 2016 Elsevier B.V. All rights reserved.

Prognostic significance of O6-methylguanine-DNA methyltransferase protein expression in patients with recurrent glioblastoma treated with temozolomide.

PubMed

Nagane, Motoo; Kobayashi, Keiichi; Ohnishi, Akiko; Shimizu, Saki; Shiokawa, Yoshiaki

2007-12-01

Temozolomide (TMZ) is active against newly diagnosed glioblastoma (GBM), and O(6)-methylguanine-DNA methyltransferase (MGMT) is implicated in resistance to TMZ and nitrosoureas. We evaluated the efficacy and safety of the standard 5-day TMZ regimen in patients with recurrent GBM after initial therapy including nitrosourea-based chemotherapy, in conjunction with an analysis of the prognostic value of MGMT protein expression regarding response to TMZ and survival. From September 2003 to January 2007, 30 patients having recurrent GBM received 150-200 mg/m(2)/day of TMZ for five consecutive days every 28 days. Tumor tissue from 19 patients was analysed for MGMT protein expression using western blotting, and 17 of them were assessable for a response. The overall response rate was 23.5% (one complete response and three partial responses). Six patients had stable disease (35.3%). Median progression-free survival (PFS) time was 2.2 months, and median overall survival (OS) time was 9.9 months from the initiation of TMZ therapy. Patients with low MGMT protein expression had a significantly improved PFS (P = 0.016) and OS (P = 0.019) compared to those with high expression. Both low MGMT expression (P = 0.040) and re-resection at relapse (P = 0.014) persisted as significant independent favorable prognostic factors for OS. The most common grade 3 and 4 hematological toxicity was lymphopenia (22.2%). The standard 5-day TMZ regimen resulted in moderate antitumor activity with an acceptable safety profile in patients with nitrosourea-pretreated recurrent GBM, and protein expression of MGMT is an important prognostic factor for patients treated with TMZ even after recurrence.

Phase II Trial of Full-Dose Gemcitabine and Bevacizumab in Combination With Attenuated Three-Dimensional Conformal Radiotherapy in Patients With Localized Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Small, William, E-mail: wsmall@nmff.or; Mulcahy, Mary F.; Rademaker, Alfred

Purpose: To evaluate response rate, survival, and toxicity in patients with nonmetastatic pancreatic cancer treated with gemcitabine, bevacizumab, and radiotherapy. Methods and Materials: Patients received three cycles of therapy over 10 weeks. In total, treatment consisted of intravenous (IV) gemcitabine, 1,000 mg/m{sup 2}, every 1 to 2 weeks (7 doses), IV bevacizumab, 10 mg/kg every 2 weeks (5 doses), and 36 Gy of radiotherapy (2.4-Gy fractions during cycle two). Response was assessed by cross-sectional imaging and carbohydrate antigen 19-9 (CA 19-9) levels. Patients with resectable tumors underwent surgery 6 to 8 weeks after the last dose of bevacizumab. Maintenance gemcitabinemore » and bevacizumab doses were delivered to patients who had unresected tumors and no progression. Results: Twenty-eight of the 32 enrolled patients completed all three cycles. The median follow-up was 11.07 months. Most grade 3 or 4 toxicities occurred in the initial treatment phase; the most frequent toxicities were leukopenia (21%), neutropenia (17%), and nausea (17%). At week 10, 1 patient (4%) had a complete response, 2 patients (7%) had partial responses, 21 patients (75%) had stable disease, and 4 patients (14%) had progressive disease. The median pretreatment and posttreatment CA 19-9 levels (25 patients) were 184.3 and 57.9 U/ml, respectively (p = 0.0006). One of 10 patients proceeding to surgery experienced a major complication. Two of 6 patients undergoing resection had complete pathologic responses. The median progression-free and overall survival durations were 9.9 months and 11.8 months, respectively. Conclusions: The combination of full-dose gemcitabine, bevacizumab, and radiotherapy was active and was not associated with a high rate of major surgical complications.« less

Salvage radiotherapy in prostate cancer patients. Planning, treatment response and prognosis using (11)C-choline PET/CT.

PubMed

García, J R; Cozar, M; Soler, M; Bassa, P; Riera, E; Ferrer, J

2016-01-01

To assess the prognostic value of the therapeutic response by (11)C-choline PET/CT in prostate cancer patients with biochemical recurrence in which (11)C-choline PET/CT indicated radio-guided radiotherapy. The study included 37 patients initially treated with prostatectomy, who were treated due to biochemical recurrence. (11)C-choline PE/CT detected infra-diaphragmatic lymph-node involvement. All were selected for intensity modulated radiation therapy, escalating the dose according to the PET findings. One year after treatment patients underwent PSA and (11)C-choline PET/CT categorizing response (complete/partial/progression). Clinical/biochemical/image monitoring was performed until appearance of second relapse or 36 months in disease-free patients. (11)C-choline PET/CT could detect lymph nodes in all 37 patients. They were 18 (48.6%) of more than a centimetre in size and 19 (51.3%) with no pathological CT morphology: 9 (24.3%) with positive lymph nodes of around one centimetre and 10 (27.0%) only less than a centimetre in size. The response by (11)C-choline PET/CT was categorised one year after radiotherapy: 16 patients (43.2%) complete response; 15 (40.5%) partial response, and 6 (16.2%) progression. The response was concordant between the PSA result and (11)C-choline PET/CT in 32 patients (86.5%), and discordant in five (13.5%). New recurrence was detected in 12 patients (80%) with partial response, and 5 (31.2%) with complete response. The mean time to recurrence was 9 months after partial response, and 18 months after complete response (significant difference, p<.0001). (11)C-choline PET/CT allows the selection of patients with recurrent prostate cancer candidates for radiotherapy and to plan the technique. The evaluation of therapeutic response by (11)C-choline PET/CT has prognostic significance. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

Workshop on Biophysics of Transmembrane Electric Fields

DTIC Science & Technology

1990-11-15

binding of K (a- ketoglutarate ) to the high energy ER form releases only a part of the energy induced in the system. This partial release accomplishes two...nature (eg. calcium , polyethylene glycol), a specialized protein (eg. influenza HA spike glycoprotein), a natural protein or peptide used under...that alamethicin has a stable alpha -helical conformation of about ten residues long beginning at the N terminus and at least in some solvent systems

Geochemical aspects of some Japanese lavas.

NASA Technical Reports Server (NTRS)

Philpotts, J. A.; Martin, W.; Schnetzler, C. C.

1971-01-01

K, Rb, Sr, Ba and rare-earth concentrations in some Japanese lavas have been determined by mass-spectrometric stable-isotope dilution. The samples fall into three rare-earth groups corresponding to tholeiitic, high alumina and alkali basalts. Japanese tholeiites have trace element characteristics similar to those of oceanic ridge tholeiites except for distinctly higher relative concentrations of Ba. Japanese lavas may result from various degrees of partial fusion of amphibole eclogite.

Growth Trajectories of Mexican-Origin Adolescent Mothers’ Educational Expectations

PubMed Central

Bravo, Diamond Y.; Toomey, Russell B.; Umaña-Taylor, Adriana J.; Updegraff, Kimberly A.; Jahromi, Laudan B.

2015-01-01

Pregnant and parenting adolescents are at significant risk for educational underachievement. Educational expectations play a critical role for understanding subsequent educational attainment; yet, limited empirical attention has been given to changes in educational expectations across the transition to parenthood among adolescent mothers. This longitudinal study explored stability and change in educational expectations across the transition to parenthood among 191 first-time pregnant Mexican-origin adolescents (Mage = 16.76, SD = .98). The current study also examined how several contextually relevant risk and protective factors were associated with differential patterns of educational trajectories across this transition and subsequent educational attainment. Latent class growth analyses revealed three educational expectation trajectories: low and stable (< high school degree), moderate and increasing (≈ associate degree), and high and increasing (≈ bachelor’s degree). Adolescent mothers in the low and stable group encountered several educational risk factors that partially explained their probability of membership in this trajectory and subsequent lower attainment. Conversely, probability of membership in the high and increasing expectations class was partially explained by adolescents’ on-track school status at the time of pregnancy and their mother figures’ educational expectations for their pregnant daughters. These findings have implications for understanding the malleable factors that help to explain why some adolescent mothers describe consistently high educational expectations and subsequent higher attainment, while others do not. PMID:28392610

Dynamo Tests for Stratification Below the Core-Mantle Boundary

NASA Astrophysics Data System (ADS)

Olson, P.; Landeau, M.

2017-12-01

Evidence from seismology, mineral physics, and core dynamics points to a layer with an overall stable stratification in the Earth's outer core, possibly thermal in origin, extending below the core-mantle boundary (CMB) for several hundred kilometers. In contrast, energetic deep mantle convection with elevated heat flux implies locally unstable thermal stratification below the CMB in places, consistent with interpretations of non-dipole geomagnetic field behavior that favor upwelling flows below the CMB. Here, we model the structure of convection and magnetic fields in the core using numerical dynamos with laterally heterogeneous boundary heat flux in order to rationalize this conflicting evidence. Strongly heterogeneous boundary heat flux generates localized convection beneath the CMB that coexists with an overall stable stratification there. Partially stratified dynamos have distinctive time average magnetic field structures. Without stratification or with stratification confined to a thin layer, the octupole component is small and the CMB magnetic field structure includes polar intensity minima. With more extensive stratification, the octupole component is large and the magnetic field structure includes intense patches or high intensity lobes in the polar regions. Comparisons with the time-averaged geomagnetic field are generally favorable for partial stratification in a thin layer but unfavorable for stratification in a thick layer beneath the CMB.

Clinical outcomes of gastrointestinal stromal tumor in southern Thailand

PubMed Central

Pornsuksiri, Kittima; Chewatanakornkul, Siripong; Kanngurn, Samornmas; Maneechay, Wanwisa; Chaiyapan, Walawee; Sangkhathat, Surasak

2012-01-01

AIM: To review a single institutional experience in clinical management of gastrointestinal stromal tumors (GIST) and analyze for factors determining treatment outcome. METHODS: Clinicopathological data of patients with a diagnosis of GIST who were treated at our institute during November 2004 to September 2009 were retrospectively reviewed. RESULTS: Ninety-nine cases were included in the analysis. Primary tumor sites were at the stomach in and small bowel in 44% and 33%, respectively. Thirty-one cases already had metastasis at presentation and the most common metastatic site was the liver. Sixty-four cases (65%) were in the high-risk category. Surgical treatment was performed in 77 cases (78%), 3 of whom received upfront targeted therapy. Complete resection was achieved in 56 cases (73% of operative cases) and of whom 27 developed local recurrence or distant metastasis at a median duration of 2 years. Imatinib was given as a primary therapy in unresectable cases (25 cases) and as an adjuvant in cases with residual tumor (21 cases). Targeted therapy gave partial response in 7 cases (15%), stable disease in 27 cases (57%) and progressive disease in 13 cases (28%). Four-year overall survival was 74% (95% CI: 61%-83%). Univariate survival analysis found that low-risk tumor, gastric site, complete resection and response to imatinib were associated with better survival. CONCLUSION: The overall outcomes of GIST can be predicted by risk-categorization. Surgery alone may not be a curative treatment for GIST. Response to targeted therapy is a crucial survival determinant in these patients. PMID:23444235