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Sample records for cells reveals early-stage

  1. Signs of Early-stage Disk Growth Revealed with ALMA

    NASA Astrophysics Data System (ADS)

    Yen, Hsi-Wei; Koch, Patrick M.; Takakuwa, Shigehisa; Krasnopolsky, Ruben; Ohashi, Nagayoshi; Aso, Yusuke

    2017-01-01

    We present ALMA 1.3 mm continuum, 12CO, C18O, and SO data for the Class 0 protostars Lupus 3 MMS, IRAS 15398-3559, and IRAS 16253-2429 at resolutions of ˜100 au. By measuring a rotational profile in C18O, a 100 au Keplerian disk around a 0.3 M⊙ protostar is observed in Lupus 3 MMS. No 100 au Keplerian disks are observed in IRAS 15398-3559 and IRAS 16253-2429. Nevertheless, embedded compact (<30 au) continuum components are detected. The C18O emission in IRAS 15398-3559 shows signatures of infall with a constant angular momentum. IRAS 16253-2429 exhibits signatures of infall and rotation, but its rotational profile is unresolved. By fitting the C18O data with our kinematic models, the protostellar masses and the disk radii are inferred to be 0.01 M⊙ and 20 au in IRAS 15398-3559, and 0.03 M⊙ and 6 au in IRAS 16253-2429. By comparing the specific angular momentum profiles from 10,000 au to 100 au in eight Class 0 and I protostars, we find that the evolution of envelope rotation can be described with conventional inside-out collapse models. In comparison with a sample of 18 protostars with known disk radii, our results reveal signs of disk growth, with the disk radius increasing as {{M}* }0.8+/- 0.14 or {t}1.09+/- 0.37 in the Class 0 stage, where M* is the protostellar mass and t is the age. The disk growth rate slows down in the Class I stage. In addition, we find a hint that the mass accretion rate declines as {t}-0.26+/- 0.04 from the Class 0 to the Class I stages.

  2. Isolation and transplantation of sturgeon early-stage germ cells.

    PubMed

    Pšenička, Martin; Saito, Taiju; Linhartová, Zuzana; Gazo, Ievgeniia

    2015-04-01

    We report, for the first time, a series of baseline techniques comprising isolation and transplantation of female and male early-stage germ cells in sturgeon to generate a germline chimera as a potential tool for surrogate reproduction and gene banking. Cells were dissociated from testis, characterized by mostly spermatogonia, and from ovary, exclusively comprising oogonia and previtellogenic oocytes, of Acipenser baerii, using 0.3% trypsin (2 hours, 23 °C) dissolved in PBS, isotonic with blood plasma. The dissociated germ cells were sorted by Percoll gradient centrifugation followed by immunolabeling with germ cell-specific vasa antibody DDX4, while 10% to 30% Percoll solution contained 79.4% and 70.8% labeled testicular and ovarian cells. Sorted germ cells were transplanted into a cavity close to a presumptive genital ridge of newly hatched heterospecific Acipenser ruthenus larvae with fluorescein isothiocyanate-labeled endogenous primordial germ cells. The transplanted germ cells were randomly distributed in the body cavity through 30-day posttransplantation (dpt). Subsequently, the cells were organized into genital ridges 50 dpt and proliferated 90 dpt. The number of both transplanted and endogenous germ cells significantly increased from 18.1, 22.2, and 29.1 (30 dpt) to 108.5, 90.8, and 118.5 (90 dpt) in ovarian, testicular, and endogenous germ cells, respectively (P < 0.05). The efficiency of transplantation was 60% (counted 90 dpt). Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Early-stage primary signet ring cell carcinoma of the colon.

    PubMed

    Kim, Jae Hyun; Park, Seun Ja; Park, Moo In; Moon, Won; Kim, Sung Eun

    2013-06-28

    Primary signet ring cell carcinoma of the colorectum detected at an early stage is very rare; most cases are detected at an advanced stage. Therefore, its prognosis is poorer than that of ordinary colorectal cancer. A 56-year-old Korean man was seen at this hospital for management of signet ring cell carcinoma of the colon. Colonoscopic examination revealed a IIa-like, ill-defined and flatly elevated 9-mm residual tumor in the cecum. Endoscopic mucosal resection was preformed. Pathological examination of the resected specimen revealed signet ring cell carcinoma that had invaded the lamina propria without venous or perineural invasion. Abdominal computed tomography (CT) and positron CT showed no evidence of primary lesions or distant metastasis. An additional laparoscopic right-hemicolectomy was performed; no residual tumor or lymph node metastasis was found. We report a case of primary signet ring cell carcinoma of the colon detected at an early stage and provide a review of the literature.

  4. Early-stage primary signet ring cell carcinoma of the colon

    PubMed Central

    Kim, Jae Hyun; Park, Seun Ja; Park, Moo In; Moon, Won; Kim, Sung Eun

    2013-01-01

    Primary signet ring cell carcinoma of the colorectum detected at an early stage is very rare; most cases are detected at an advanced stage. Therefore, its prognosis is poorer than that of ordinary colorectal cancer. A 56-year-old Korean man was seen at this hospital for management of signet ring cell carcinoma of the colon. Colonoscopic examination revealed a IIa-like, ill-defined and flatly elevated 9-mm residual tumor in the cecum. Endoscopic mucosal resection was preformed. Pathological examination of the resected specimen revealed signet ring cell carcinoma that had invaded the lamina propria without venous or perineural invasion. Abdominal computed tomography (CT) and positron CT showed no evidence of primary lesions or distant metastasis. An additional laparoscopic right-hemicolectomy was performed; no residual tumor or lymph node metastasis was found. We report a case of primary signet ring cell carcinoma of the colon detected at an early stage and provide a review of the literature. PMID:23840131

  5. Radiotherapy Alone for Early-Stage Squamous Cell Carcinoma of the Larynx and Hypopharynx

    SciTech Connect

    Foote, Robert L.

    2007-10-01

    Purpose: To describe and illustrate examples of early-stage larynx and hypopharynx cancer that can be successfully treated with radiotherapy alone. Methods and Materials: Review of the NCCN and ASCO practice guidelines. Representative examples are included. Results: Early-stage larynx and hypopharynx cancer is defined by tumor extent based on physical and imaging examination. Conclusions: Radiotherapy alone is appropriate treatment for properly selected early-stage squamous cell carcinoma of the larynx and hypopharynx. The NCCN and ASCO practice guidelines can be an aid to the clinician in identifying favorable cancers that can be successfully treated with radiotherapy alone with preservation of organ function.

  6. Decreased numbers of endothelial progenitor cells in patients in the early stages of systemic sclerosis.

    PubMed

    Andrigueti, Fernando V; Arismendi, Maria I; Ebbing, Pâmela C C; Kayser, Cristiane

    2015-03-01

    Microangiopathy and endothelial dysfunction are present in the early stages of systemic sclerosis (SSc). Defective vasculogenesis mediated by bone marrow-derived endothelial progenitor cells (EPCs) might be involved in the vascular abnormalities found in SSc. To evaluate the circulating EPC levels and EPC subtypes via flow cytometry and early outgrowth colony-forming units (CFUs) in patients with SSc compared to healthy subjects. Thirty-nine female SSc patients (30 in the early stages of SSc) and 44 age-matched healthy women were included. Peripheral blood EPCs were quantified using flow cytometry and by counting the early outgrowth CFUs. The EPCs quantified with flow cytometry and the CFU numbers were significantly lower in SSc patients than in control subjects (155.1 ± 95.1 vs. 241.3 ± 184.2 EPC/10(6) lymphomononuclear cells, p=0.011; 15.4 ± 8.6 vs. 23.5 ± 10.9 CFU, p<0.001; respectively), as well as in the group of patients in the early stages of SSc compared to the controls. Patients with digital ulcers had significantly higher CFU counts than those without ulcers (p=0.013). Among patients with the scleroderma pattern on nailfold capillaroscopy, patients with the late pattern had significantly lower EPC levels than those with the early and active patterns (p=0.046). There were no significant correlations of EPCs or CFU levels with RP duration. The present study revealed decreased EPCs in SSc patients, including those with early disease onset. These findings suggest that defective vasculogenesis occurs in the early phases of the disease. Therefore, EPCs might be an important therapeutic target for the prevention of vascular complications in SSc patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Single-virus tracking approach to reveal the interaction of Dengue virus with autophagy during the early stage of infection

    NASA Astrophysics Data System (ADS)

    Chu, Li-Wei; Huang, Yi-Lung; Lee, Jin-Hui; Huang, Long-Ying; Chen, Wei-Jun; Lin, Ya-Hsuan; Chen, Jyun-Yu; Xiang, Rui; Lee, Chau-Hwang; Ping, Yueh-Hsin

    2014-01-01

    Dengue virus (DENV) is one of the major infectious pathogens worldwide. DENV infection is a highly dynamic process. Currently, no antiviral drug is available for treating DENV-induced diseases since little is known regarding how the virus interacts with host cells during infection. Advanced molecular imaging technologies are powerful tools to understand the dynamics of intracellular interactions and molecular trafficking. This study exploited a single-virus particle tracking technology to address whether DENV interacts with autophagy machinery during the early stage of infection. Using confocal microscopy and three-dimensional image analysis, we showed that DENV triggered the formation of green fluorescence protein-fused microtubule-associated protein 1A/1B-light chain 3 (GFP-LC3) puncta, and DENV-induced autophagosomes engulfed DENV particles within 15-min postinfection. Moreover, single-virus particle tracking revealed that both DENV particles and autophagosomes traveled together during the viral infection. Finally, in the presence of autophagy suppressor 3-methyladenine, the replication of DENV was inhibited and the location of DENV particles spread in cytoplasma. In contrast, the numbers of newly synthesized DENV were elevated and the co-localization of DENV particles and autophagosomes was detected while the cells were treated with autophagy inducer rapamycin. Taken together, we propose that DENV particles interact with autophagosomes at the early stage of viral infection, which promotes the replication of DENV.

  8. Cell proliferation during the early stages of human eye development.

    PubMed

    Bozanić, Darka; Saraga-Babić, Mirna

    2004-08-01

    The distribution as well as the ultrastructural and biochemical characteristics of proliferating cells in the human eye were investigated in five conceptuses of 5-9 postovulatory weeks, using morphological techniques and Ki-67 immunostaining. The Ki-67 nuclear protein was used as a proliferation marker because of its expression in all phases of the cell cycle except the resting phase (G0). The labelling indices of Ki-67-positive cells were analysed by means of the Kruskal-Wallis ANOVA test and the Wilcoxon matched-pairs test. In the 5th week, mitotic cells were the most numerous between the two layers of the optic cup, the optic cup and stalk, and between the lens pit and the surface ectoderm. During the 6th week, cells were observed in the lens epithelium covering the whole cavity of the lens vesicle as well as in the neuroblast zone and the pigmented epithelium of the retina. At later stages (7th-9th weeks), Ki-67-positive cells were restricted to the anterior lens epithelium, the outer neuroblast zone, and the pigmented retina. Throughout all stages examined, mitotic figures were found lying exclusively adjacent to the intraretinal space. Early in the lens pit, they were confined to the free epithelial surface, and later were facing the cavity of the lens vesicle. The proliferative activity was the most intensive in the 6th week, whereas it decreased significantly in the later stages. Additionally, when proliferative activities were compared, the peripheral retina appeared to be less mature than the central before the 9th week. In the earliest analysed stage, cell proliferation might be associated with the sculpturing of the optic cup and stalk, the cornea, and the lens. In the 6th week, the most intensive proliferation seems to be involved not only in the further morphogenesis of the optic cup and the lens vesicle but also in the retinal neurogenesis. At later stages, the decreased proliferation might participate in the neurogenesis of the outer neuroblast zone

  9. Proteomics Identification of Potential Candidates Involved in Cell Proliferation for Early Stage of Brain Regeneration in the Adult Zebrafish.

    PubMed

    Lim, Fei Tieng; Ogawa, Satoshi; Smith, A Ian; Parhar, Ishwar S

    2017-02-01

    The central nervous system (CNS) of the non-mammalian vertebrates has better neuroregenerative capability as compared with the mammalian CNS. Regeneration of habenula was observed 40 days after damage in zebrafish. During the early stage of regeneration, we found a significant increase of apoptotic cells on day-1 post-damage and of proliferative cells on day-3 post-damage. To identify the molecular factor(s) involved in the early stages of neuroregeneration, differentially expressed proteins during sham, 20- and 40-h post-habenula damage were investigated by proteomic approach by using two-dimensional differential gel electrophoresis (2D-DIGE) coupled with Matrix-Assisted Laser Desorption/Ionization-Time-of-Flight (MALDI-ToF) and tandem mass spectrometry. Protein profiles revealed 17 differentially (>1.5-fold) expressed proteins: 10 upregulated, 4 downregulated, 2 proteins were found to be downregulated at the early stage but upregulated at a later stage, and 1 protein was found to be upregulated at 2 different time points. All proteins identified can be summarized under few molecular processes involved in the early stages of neuroregeneration in zebrafish CNS: apoptosis regulation (Wnt inhibitory factor 1 [WIF1]), neuroprotection (metallothionein), cell proliferation (Spred2, ependymin, Lhx1, and Wnts), differentiation (Spred2, Lhx9, and Wnts), and morphogenesis (cytoplasmic actins and draculin). These protein profiling results suggest that drastic molecular changes occur in the neuroregenerative process during this period, which includes cell proliferation, differentiation, and protection.

  10. beta-Adrenergic activation reveals impaired cardiac calcium handling at early stage of diabetes.

    PubMed

    op den Buijs, Jorn; Miklós, Zsuzsanna; van Riel, Natal A W; Prestia, Christina M; Szenczi, Orsolya; Tóth, András; Van der Vusse, Ger J; Szabó, Csaba; Ligeti, László; Ivanics, Tamás

    2005-01-21

    Cardiac function is known to be impaired in diabetes. Alterations in intracellular calcium handling have been suggested to play a pivotal role. This study aimed to test the hypothesis that beta-adrenergic activation can reveal the functional derangements of intracellular calcium handling of the 4-week diabetic heart. Langendorff perfused hearts of 4-week streptozotocin-induced diabetic rats were subjected to the beta-adrenoceptor agonist isoproterenol. Cyclic changes in [Ca(2+)](i) levels were measured throughout the cardiac cycle using Indo-1 fluorescent dye. Based on the computational analysis of the [Ca(2+)](i) transient the kinetic parameters of the sarcoplasmic reticulum Ca(2+)-ATPase and the ryanodine receptor were determined by minimizing the squared error between the simulated and the experimentally obtained [Ca(2+)](i) transient. Under unchallenged conditions, hemodynamic parameters were comparable between control and diabetic hearts. Isoproterenol administration stimulated hemodynamic function to a greater extent in control than in diabetic hearts, which was exemplified by more pronounced increases in rate of pressure development and decline. Under unchallenged conditions, [Ca(2+)](i) amplitude and rate of rise and decline of [Ca(2+)](i) as measured throughout the cardiac cycle were comparable between diabetic and control hearts. Differences became apparent under beta-adrenoceptor stimulation. Upon beta-activation the rate-pressure product showed a blunted response, which was accompanied by a diminished rise in [Ca(2+)](i) amplitude in diabetic hearts. Computational analysis revealed a reduced function of the sarcoplasmic reticulum Ca(2+)-ATPase and Ca(2+)-release channel in response to beta-adrenoceptor challenge. Alterations in Ca(2+)(i) handling may play a causative role in depressed hemodynamic performance of the challenged heart at an early stage of diabetes.

  11. Survival after community diagnosis of early-stage non-small cell lung cancer.

    PubMed

    Kanarek, Norma F; Hooker, Craig M; Mathieu, Luckson; Tsai, Hua-Ling; Rudin, Charles M; Herman, James G; Brock, Malcolm V

    2014-05-01

    "Rush to surgery" among patients with worse symptoms, delays related to morbidity, and inclusion of patients with advanced disease in study populations have produced a mixed picture of importance of time to treatment to survival of non-small cell lung cancer. Our objective was to assess the contribution of diagnosis to first surgery interval to survival among patients diagnosed in the community with early-stage non-small cell lung cancer. Patients with early-stage lung cancer (N = 174) at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins who were diagnosed and treated from 2003 to 2009 and followed through 2011 made up a prospective study of overall survival. Diagnosis to first surgery interval was examined overall, as 2 segments (referral interval and treatment interval), as short and longer intervals, and as a continuous variable. The majority of patients were female (55%) and aged more than 65 years (61%). The average mean referral and treatment delays were 61.2 and 5.9 days, respectively. Cox method hazard analysis revealed that older age (years) at diagnosis (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00-1.05), stage IIB (HR, 2.17; 95% CI, 1.12-4.21), large (>4 cm) (HR, 3.68; 95% CI, 1.05-12.93) or unknown tumor size (HR, 4.45; 95% CI, 1.21-16.38), and weeks from diagnosis to first surgery interval (HR, 1.04; 95% CI, 1.00-1.09) predicted worse overall survival. The threshold period of less than 42 days from diagnosis to surgery did not reach statistical significance. Patients seem to benefit from rapid reduction of tumor burden with surgery. Reasons for delay were not available. Nevertheless, referral delay experienced in the community is unduly long. In addition to patient choices, an unconscious patient or physician bias that lung cancer is untreatable or an inevitable consequence of smoking may be operating and needs further investigation. Copyright © 2014. Published by Elsevier Inc.

  12. The Osteogenic Niche Promotes Early-Stage Bone Colonization of Disseminated Breast Cancer Cells

    PubMed Central

    Wang, Hai; Yu, Cuijuan; Gao, Xia; Welte, Thomas; Muscarella, Aaron M.; Tian, Lin; Zhao, Hong; Zhao, Zhen; Du, Shiyu; Tao, Jianning; Lee, Brendan; Westbrook, Thomas F.; Wong, Stephen T. C.; Jin, Xin; Rosen, Jeffrey M.; Osborne, C. Kent; Zhang, Xiang H.-F.

    2014-01-01

    Summary Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We further elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human datasets analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases. Significance In advanced stages, breast cancer bone metastases are driven by paracrine crosstalk among cancer cells, osteoblasts, and osteoclasts, which constitute a vicious osteolytic cycle. Current therapies targeting this process limit tumor progression, but do not improve patient survival. On the other hand, bone micrometastases may remain indolent for years before activating the vicious cycle, providing a therapeutic opportunity to prevent macrometastases. Here, we show that bone colonization is initiated in a microenvironment niche exhibiting active osteogenesis. Cancer and osteogenic cells form heterotypic adherens junctions, which enhance mTOR activity and drive early-stage bone colonization prior to osteolysis. These results reveal a strong connection between osteogenesis and micrometastasis and suggest potential therapeutic targets to prevent bone macrometastases. PMID:25600338

  13. A Model of Isotope Separation in Cells at the Early Stages of Evolution.

    PubMed

    Melkikh, A V; Bokunyaeva, A O

    2016-03-01

    The separation of the isotopes of certain ions can serve as an important criterion for the presence of life in the early stages of its evolution. A model of the separation of isotopes during their transport through the cell membrane is constructed. The dependence of the selection coefficient on various parameters is found. In particular, it is shown that the maximum efficiency of the transport of ions corresponds to the minimum enrichment coefficient. At the maximum enrichment, the efficiency of the transport system approaches ½. Calculated enrichment coefficients are compared with experimentally obtained values for different types of cells, and the comparison shows a qualitative agreement between these quantities.

  14. Development of Valpha4+ NK T cells in the early stages of embryogenesis.

    PubMed Central

    Makino, Y; Kanno, R; Koseki, H; Taniguchi, M

    1996-01-01

    The majority of T lymphocytes start to develop at around day 15 of gestation (d15)-d17 in the thymus and comprise the peripheral repertoire characterized by the expression of polymorphic T-cell antigen receptors (TCRs). Contrary to these conventional T cells, a subset of T cells, called natural killer (NK) T cells (most of them expressing an invariant TCR encoded by the Valpha14Jalpha281 gene with a 1-nt N-region), preferentially differentiates extrathymically and dominates the peripheral T-cell population at a high frequency (5% in splenic T cells and 40% in bone marrow T cells). Here, we investigated the development of NK T cells and found that the invariant Valpha14+ TCR transcripts and the circular DNA created by Valpha14 and Jalpha281 gene rearrangements can be detected in the embryo body at d9.5 of gestation and in the yolk sac and the fetal liver at d11.5-d13.5 of gestation, but not in the thymus, whereas T cells with Valpha1+ TCR expression, a major population in the thymus, were not observed at these early stages of gestation. Fluorescence-activated cell sorter analysis also demonstrated that there exist CD3+ alpha beta+ T cells, almost all of which are Valpha14/Vbeta8+ NK+ T cells, during early embryogenesis. To our knowledge, this demonstrates for the first time that a T lymphocyte subset develops in extrathymic tissues during the early stages of embryogenesis. Images Fig. 1 Fig. 4 PMID:8692847

  15. Morphological and proteomic analysis of early stage of osteoblast differentiation in osteoblastic progenitor cells

    SciTech Connect

    Hong, Dun; Chen, Hai-Xiao; Yu, Hai-Qiang; Liang, Yong; Wang, Carrie; Lian, Qing-Quan; Deng, Hai-Teng; Ge, Ren-Shan

    2010-08-15

    Bone remodeling relies on a dynamic balance between bone formation and resorption, mediated by osteoblasts and osteoclasts, respectively. Under certain stimuli, osteoprogenitor cells may differentiate into premature osteoblasts and further into mature osteoblasts. This process is marked by increased alkaline phosphatase (ALP) activity and mineralized nodule formation. In this study, we induced osteoblast differentiation in mouse osteoprogenitor MC3T3-E1 cells and divided the process into three stages. In the first stage (day 3), the MC3T3-E1 cell under osteoblast differentiation did not express ALP or deposit a mineralized nodule. In the second stage, the MC3T3-E1 cell expressed ALP but did not form a mineralized nodule. In the third stage, the MC3T3-E1 cell had ALP activity and formed mineralized nodules. In the present study, we focused on morphological and proteomic changes of MC3T3-E1 cells in the early stage of osteoblast differentiation - a period when premature osteoblasts transform into mature osteoblasts. We found that mean cell area and mean stress fiber density were increased in this stage due to enhanced cell spreading and decreased cell proliferation. We further analyzed the proteins in the signaling pathway of regulation of the cytoskeleton using a proteomic approach and found upregulation of IQGAP1, gelsolin, moesin, radixin, and Cfl1. After analyzing the focal adhesion signaling pathway, we found the upregulation of FLNA, LAMA1, LAMA5, COL1A1, COL3A1, COL4A6, and COL5A2 as well as the downregulation of COL4A1, COL4A2, and COL4A4. In conclusion, the signaling pathway of regulation of the cytoskeleton and focal adhesion play critical roles in regulating cell spreading and actin skeleton formation in the early stage of osteoblast differentiation.

  16. Gene expression profiling reveals underlying molecular mechanisms of the early stages of tamoxifen-induced rat hepatocarcinogenesis

    SciTech Connect

    Pogribny, Igor P. Bagnyukova, Tetyana V.; Tryndyak, Volodymyr P.; Muskhelishvili, Levan; Rodriguez-Juarez, Rocio; Kovalchuk, Olga; Han Tao; Fuscoe, James C.; Ross, Sharon A.; Beland, Frederick A.

    2007-11-15

    Tamoxifen is a widely used anti-estrogenic drug for chemotherapy and, more recently, for the chemoprevention of breast cancer. Despite the indisputable benefits of tamoxifen in preventing the occurrence and re-occurrence of breast cancer, the use of tamoxifen has been shown to induce non-alcoholic steatohepatitis, which is a life-threatening fatty liver disease with a risk of progression to cirrhosis and hepatocellular carcinoma. In recent years, the high-throughput microarray technology for large-scale analysis of gene expression has become a powerful tool for increasing the understanding of the molecular mechanisms of carcinogenesis and for identifying new biomarkers with diagnostic and predictive values. In the present study, we used the high-throughput microarray technology to determine the gene expression profiles in the liver during early stages of tamoxifen-induced rat hepatocarcinogenesis. Female Fisher 344 rats were fed a 420 ppm tamoxifen containing diet for 12 or 24 weeks, and gene expression profiles were determined in liver of control and tamoxifen-exposed rats. The results indicate that early stages of tamoxifen-induced liver carcinogenesis are characterized by alterations in several major cellular pathways, specifically those involved in the tamoxifen metabolism, lipid metabolism, cell cycle signaling, and apoptosis/cell proliferation control. One of the most prominent changes during early stages of tamoxifen-induced hepatocarcinogenesis is dysregulation of signaling pathways in cell cycle progression from the G{sub 1} to S phase, evidenced by the progressive and sustained increase in expression of the Pdgfc, Calb3, Ets1, and Ccnd1 genes accompanied by the elevated level of the PI3K, p-PI3K, Akt1/2, Akt3, and cyclin B, D1, and D3 proteins. The early appearance of these alterations suggests their importance in the mechanism of neoplastic cell transformation induced by tamoxifen.

  17. Genome-Wide Analysis of Survival in Early-Stage Non–Small-Cell Lung Cancer

    PubMed Central

    Huang, Yen-Tsung; Heist, Rebecca S.; Chirieac, Lucian R.; Lin, Xihong; Skaug, Vidar; Zienolddiny, Shanbeh; Haugen, Aage; Wu, Michael C.; Wang, Zhaoxi; Su, Li; Asomaning, Kofi; Christiani, David C.

    2009-01-01

    Purpose Lung cancer, of which 85% is non–small-cell (NSCLC), is the leading cause of cancer-related death in the United States. We used genome-wide analysis of tumor tissue to investigate whether single nucleotide polymorphisms (SNPs) in tumors are prognostic factors in early-stage NSCLC. Patients and Methods One hundred early-stage NSCLC patients from Massachusetts General Hospital (MGH) were used as a discovery set and 89 NSCLC patients collected by the National Institute of Occupational Health, Norway, were used as a validation set. DNA was extracted from flash-frozen lung tissue with at least 70% tumor cellularity. Genome-wide genotyping was done using the high-density SNP chip. Copy numbers were inferred using median smoothing after intensity normalization. Cox models were used to screen and validate significant SNPs associated with the overall survival. Results Copy number gains in chromosomes 3q, 5p, and 8q were observed in both MGH and Norwegian cohorts. The top 50 SNPs associated with overall survival in the MGH cohort (P ≤ 2.5 × 10−4) were selected and examined using the Norwegian cohort. Five of the top 50 SNPs were validated in the Norwegian cohort with false discovery rate lower than 0.05 (P < .016) and all five were located in known genes: STK39, PCDH7, A2BP1, and EYA2. The numbers of risk alleles of the five SNPs showed a cumulative effect on overall survival (Ptrend = 3.80 × 10−12 and 2.48 × 10−7 for MGH and Norwegian cohorts, respectively). Conclusion Five SNPs were identified that may be prognostic of overall survival in early-stage NSCLC. PMID:19414679

  18. VEGF polymorphisms and survival in early-stage non-small-cell lung cancer.

    PubMed

    Heist, Rebecca Suk; Zhai, Rihong; Liu, Geoffrey; Zhou, Wei; Lin, Xihong; Su, Li; Asomaning, Kofi; Lynch, Thomas J; Wain, John C; Christiani, David C

    2008-02-20

    Polymorphisms in the VEGF gene have been identified that are believed to have functional activity. We hypothesized that such polymorphisms may affect survival outcomes among early-stage non-small-cell lung cancer (NSCLC) patients. We evaluated the relationship between VEGF polymorphisms and overall survival (OS) among patients with early-stage NSCLC treated with surgical resection at Massachusetts General Hospital from 1992 to 2001. We specifically investigated the VEGF polymorphisms +936C>T (rs3025039), -460T>C (rs833061), and +405G>C (rs2010963). Analyses of genotype associations with survival outcomes were performed using Cox proportional hazards models, Kaplan-Meier methods, and the log-rank test. There were 462 patients and 237 deaths. Patients carrying the variant C allele of the VEGF +405G>C polymorphism had significantly improved survival (crude hazard ratio [HR] = 0.70; 95% CI, 0.54 to 0.90; P = .006; adjusted HR = 0.70; 95% CI, 0.54 to 0.91; P = .008). Five-year OS for patients carrying the variant C allele of the VEGF +405G>C polymorphism was 61% (95% CI, 54% to 67%) versus 51% (95% CI, 43% to 59%) for those who had the wild-type variant. There was a trend toward improved survival among patients carrying the variant T allele of the VEGF +936C>T polymorphism (crude HR = 0.74; 95% CI, 0.53 to 1.03; P = .07; adjusted HR = 0.73; 95% CI, 0.52 to 1.03; P = .07). Moreover, patients with higher number of variant alleles of the +405G>C and +936C>T polymorphisms had better survival. There was no association found with the -460T>C polymorphism. Polymorphisms in VEGF may affect survival in early-stage lung cancer.

  19. Genome-wide analysis of survival in early-stage non-small-cell lung cancer.

    PubMed

    Huang, Yen-Tsung; Heist, Rebecca S; Chirieac, Lucian R; Lin, Xihong; Skaug, Vidar; Zienolddiny, Shanbeh; Haugen, Aage; Wu, Michael C; Wang, Zhaoxi; Su, Li; Asomaning, Kofi; Christiani, David C

    2009-06-01

    Lung cancer, of which 85% is non-small-cell (NSCLC), is the leading cause of cancer-related death in the United States. We used genome-wide analysis of tumor tissue to investigate whether single nucleotide polymorphisms (SNPs) in tumors are prognostic factors in early-stage NSCLC. One hundred early-stage NSCLC patients from Massachusetts General Hospital (MGH) were used as a discovery set and 89 NSCLC patients collected by the National Institute of Occupational Health, Norway, were used as a validation set. DNA was extracted from flash-frozen lung tissue with at least 70% tumor cellularity. Genome-wide genotyping was done using the high-density SNP chip. Copy numbers were inferred using median smoothing after intensity normalization. Cox models were used to screen and validate significant SNPs associated with the overall survival. Copy number gains in chromosomes 3q, 5p, and 8q were observed in both MGH and Norwegian cohorts. The top 50 SNPs associated with overall survival in the MGH cohort (P < or = 2.5 x 10(-4)) were selected and examined using the Norwegian cohort. Five of the top 50 SNPs were validated in the Norwegian cohort with false discovery rate lower than 0.05 (P < .016) and all five were located in known genes: STK39, PCDH7, A2BP1, and EYA2. The numbers of risk alleles of the five SNPs showed a cumulative effect on overall survival (P(trend) = 3.80 x 10(-12) and 2.48 x 10(-7) for MGH and Norwegian cohorts, respectively). Five SNPs were identified that may be prognostic of overall survival in early-stage NSCLC.

  20. Overlapping DNA Methylation Dynamics in Mouse Intestinal Cell Differentiation and Early Stages of Malignant Progression

    PubMed Central

    Forn, Marta; Díez-Villanueva, Anna; Merlos-Suárez, Anna; Muñoz, Mar; Lois, Sergi; Carriò, Elvira; Jordà, Mireia; Bigas, Anna; Batlle, Eduard; Peinado, Miguel A.

    2015-01-01

    Mouse models of intestinal crypt cell differentiation and tumorigenesis have been used to characterize the molecular mechanisms underlying both processes. DNA methylation is a key epigenetic mark and plays an important role in cell identity and differentiation programs and cancer. To get insights into the dynamics of cell differentiation and malignant transformation we have compared the DNA methylation profiles along the mouse small intestine crypt and early stages of tumorigenesis. Genome-scale analysis of DNA methylation together with microarray gene expression have been applied to compare intestinal crypt stem cells (EphB2high), differentiated cells (EphB2negative), ApcMin/+ adenomas and the corresponding non-tumor adjacent tissue, together with small and large intestine samples and the colon cancer cell line CT26. Compared with late stages, small intestine crypt differentiation and early stages of tumorigenesis display few and relatively small changes in DNA methylation. Hypermethylated loci are largely shared by the two processes and affect the proximities of promoter and enhancer regions, with enrichment in genes associated with the intestinal stem cell signature and the PRC2 complex. The hypermethylation is progressive, with minute levels in differentiated cells, as compared with intestinal stem cells, and reaching full methylation in advanced stages. Hypomethylation shows different signatures in differentiation and cancer and is already present in the non-tumor tissue adjacent to the adenomas in ApcMin/+ mice, but at lower levels than advanced cancers. This study provides a reference framework to decipher the mechanisms driving mouse intestinal tumorigenesis and also the human counterpart. PMID:25933092

  1. Carbon Ion Therapy for Early-Stage Non-Small-Cell Lung Cancer

    PubMed Central

    Demizu, Yusuke; Fujii, Osamu; Iwata, Hiromitsu; Fuwa, Nobukazu

    2014-01-01

    Carbon ion therapy is a type of radiotherapies that can deliver high-dose radiation to a tumor while minimizing the dose delivered to the organs at risk; this profile differs from that of photon radiotherapy. Moreover, carbon ions are classified as high-linear energy transfer radiation and are expected to be effective for even photon-resistant tumors. Recently, high-precision radiotherapy modalities such as stereotactic body radiotherapy (SBRT), proton therapy, and carbon ion therapy have been used for patients with early-stage non-small-cell lung cancer, and the results are promising, as, for carbon ion therapy, local control and overall survival rates at 5 years are 80–90% and 40–50%, respectively. Carbon ion therapy may be theoretically superior to SBRT and proton therapy, but the literature that is currently available does not show a statistically significant difference among these treatments. Carbon ion therapy demonstrates a better dose distribution than both SBRT and proton therapy in most cases of early-stage lung cancer. Therefore, carbon ion therapy may be safer for treating patients with adverse conditions such as large tumors, central tumors, and poor pulmonary function. Furthermore, carbon ion therapy may also be suitable for dose escalation and hypofractionation. PMID:25295269

  2. DPEP1, expressed in the early stages of colon carcinogenesis, affects cancer cell invasiveness.

    PubMed

    Toiyama, Yuji; Inoue, Yasuhiro; Yasuda, Hiromi; Saigusa, Susumu; Yokoe, Takeshi; Okugawa, Yoshinaga; Tanaka, Koji; Miki, Chikao; Kusunoki, Masato

    2011-02-01

    We investigated changes in the gene expression profile in colon cancer in order to identify gene markers that may be useful in the management of this disease. The Cancer Genome Anatomy Project was used to detect differences in gene expression between normal and cancer tissue. The overexpression of dipeptidase-1 (DPEP1) in cancer tissue was confirmed in a sample of 76 patients by real-time PCR. To identify the function of DPEP1, RNA interference (RNAi) was used to inactivate this gene in the colon cancer cell line. Immunohistochemical analysis was performed to characterize the pattern of DPEP1 expression in colon cancer. DPEP1 expression in cancer was significantly higher than that in normal tissue. However, DPEP1 expression decreased with pathological differentiation, lymph-node and distant metastasis. Patients with tumors with decreased DPEP1 expression showed a poorer prognosis, and this was also true of patients with tumors who are treated with curative intent. RNAi-mediated DPEP1 reduction in the colon cancer cell line did not result in cell proliferation or apoptosis, but was associated with an increased invasive ability. DPEP1 protein was observed on the apical side of the cancer cells, and is expressed in the early stages of carcinogenesis, even in adenomas of both sporadic colorectal cancer and familial adenomatous polyposis patients. DPEP1 expression in normal colonic mucosa is very low, but it is highly expressed in colorectal adenoma and cancer specimens and is negatively correlated with parameters of pathological aggressiveness and poor prognosis. DPEP1 is expressed in the early stages of colon carcinogenesis and affects cancer cell invasiveness.

  3. Characterization of early stages of human B cell development by gene expression profiling.

    PubMed

    Hystad, Marit E; Myklebust, June H; Bø, Trond H; Sivertsen, Einar A; Rian, Edith; Forfang, Lise; Munthe, Else; Rosenwald, Andreas; Chiorazzi, Michael; Jonassen, Inge; Staudt, Louis M; Smeland, Erlend B

    2007-09-15

    We have characterized several stages of normal human B cell development in adult bone marrow by gene expression profiling of hemopoietic stem cells, early B (E-B), pro-B, pre-B, and immature B cells, using RNA amplification and Lymphochip cDNA microarrays (n = 6). Hierarchical clustering of 758 differentially expressed genes clearly separated the five populations. We used gene sets to investigate the functional assignment of the differentially expressed genes. Genes involved in VDJ recombination as well as B lineage-associated transcription factors (TCF3 (E2A), EBF, BCL11A, and PAX5) were turned on in E-B cells, before acquisition of CD19. Several transcription factors with unknown roles in B lymphoid cells demonstrated interesting expression patterns, including ZCCHC7 and ZHX2. Compared with hemopoietic stem cells and pro-B cells, E-B cells had increased expression of 18 genes, and these included IGJ, IL1RAP, BCL2, and CD62L. In addition, E-B cells expressed T/NK lineage and myeloid-associated genes including CD2, NOTCH1, CD99, PECAM1, TNFSF13B, and MPO. Expression of key genes was confirmed at the protein level by FACS analysis. Several of these Ags were heterogeneously expressed, providing a basis for further subdivision of E-B cells. Altogether, these results provide new information regarding expression of genes in early stages of human B cell development.

  4. [Extracranial stereotactic radiotherapy for early-stage non-small cell lung cancer and oligometastases].

    PubMed

    Riesterer, Oliver

    2013-10-16

    Stereotactic body radiotherapy (SBRT) is a new radiation technique that combines improvements in radiotherapy planning, intensity modulation and image guidance. The use of SBRT enables radiotherapy to be delivered instead of in six weeks in only a few days and with ablative total dose. Prospective phase II studies in patients with inoperable early stage non-small cell lung cancer demonstrate that the use of SBRT results in local control rates of 85-95% with acceptable toxicity. SBRT is also increasingly used for treatment of metastases in the lung, liver, retroperitoneum and in bones. Because SBRT enables a locally curative dose to be delivered in a time efficient manner this technique also opens up new perspectives for the treatment of patients with oligometastases.

  5. Vaginal brachytherapy for early stage uterine papillary serous and clear cell endometrial cancer.

    PubMed

    Townamchai, Kanokpis; Berkowitz, Ross; Bhagwat, Mandar; Damato, Antonio L; Friesen, Scott; Lee, Larissa J; Matulonis, Ursula; O'Farrell, Desmond; Viswanathan, Akila N

    2013-04-01

    To report clinical outcomes following adjuvant high-dose-rate (HDR) vaginal brachytherapy (VB) for early-stage uterine papillary serous (UPSC) and clear cell (CC) endometrial cancer. A retrospective study of Stage I and II papillary serous and clear cell endometrial cancer treated with post-operative HDR VB between October 2005 and May 2012 was performed. A total of 37 patients were identified, 26 with UPSC, 9 with CC and 2 with mixed UPSC/CC. After total hysterectomy and bilateral salpingo-oophorectomy, VB was administered without external-beam radiation with a dose of 24 Gy in 6 fractions prescribed to the vaginal surface. Chemotherapy was given to 30 patients (75%). The median follow up time was 24.8 months (range, 2.0 to 71.5 months). Four patients relapsed, 2 with UPSC and 2 with CC. The initial site of relapse was concurrent vagina, pelvic/para-aortic nodes and abdominal wall (1), pelvic/para-aortic nodes (1) and para-aortic nodes alone (2). The 2-year vaginal-control rate was 96.8%. The pelvic-control rate including vaginal and nodal relapse was 93.5%. The 2-year disease-free and overall survival rates were 89.3% and 100%, respectively. HDR VB as the sole adjuvant treatment modality for early-stage UPSC/CC is associated with a low rate of vaginal relapse and excellent survival outcomes. This novel low-dose regimen for VB is safe and effective. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. High dose rate brachytherapy in early stage squamous-cell carcinoma of the lip.

    PubMed

    Mut, Alejandro; Guinot, José Luis; Arribas, Leoncio; Díez-Presa, Lorena; Tortajada, María Isabel; Santos, Miguel Ángel; Samper, Josefa; Santamaría, Paula; Vendrell, Juan Bosco

    2016-01-01

    To analyze the results obtained after treatment of early stage (T1-T2) squamous cell carcinoma of the lip with high dose rate brachytherapy and evaluate the efficacy of this treatment in both local and regional control. Retrospective analysis of the treatments performed at our department from March 1999 to March 2013 with high dose rate brachytherapy with rigid needles. We included 68 patients, 63 men and 5 women; 37 patients (54.4%) presented a T1 tumour, less than or equal to 2cm, while the other 31 (45.6%) were classified as T2. Median total dose was 45Gy, with a median dose per fraction of 5Gy x 9 fractions twice a day for 5 days. With a mean follow-up of 56.4 months, local control was 96.9%. Stratifying by tumour size, local control of T1 cases was 100%, while T2 achieved 93.2% (2 local recurrences). Regional control at 5 years was 93.8% for T1, and 80.8% for T2. In 11 cases with elective cervical treatment, no regional failure happened. As for toxicity, no patient presented soft tissue, or bone, necrosis. All patients achieved good or excellent cosmetic and functional results. High dose rate brachytherapy allows effective, safe treatments for squamous cell carcinoma of the lip, with good aesthetic and functional results. It can be considered a valid alternative for surgery in early stage tumours. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. All rights reserved.

  7. Smoking cessation before diagnosis and survival in early stage non-small cell lung cancer patients.

    PubMed

    Zhou, Wei; Heist, Rebecca Suk; Liu, Geoffrey; Park, Sohee; Neuberg, Donna S; Asomaning, Kofi; Wain, John C; Lynch, Thomas J; Christiani, David C

    2006-09-01

    Smoking cessation decreases the risk of lung cancer. However, little is known about how smoking cessation affects lung cancer survival. We examined the association between smoking cessation and overall survival (OS) and recurrence-free survival (RFS) in 543 early stage non-small cell lung cancer (NSCLC) patients. The data were analyzed using log-rank test and Cox proportional hazard models, adjusting for age, gender, stage, and smoking intensity. The median follow-up time was 57 months (range 0.2-140 months). There were 191 recurrences and 285 deaths. The 5-year OS rates were 50% (95% confidence interval (CI), 43-58%) for current smokers, 54% (44-65%) for ex-smokers who quit 1-8 years, 59% (49-70%) for ex-smokers who quit 9-17 years, 58% (47-69%) for ex-smokers who quit > or =18 years prior to diagnosis, and 76% (63-90%) for never smokers (P=0.09, log-rank test). The adjusted hazard ratios for ex-smokers who quit 1-8, 9-17, > or =18 years, and never smokers were 0.82 (95% CI, 0.59-1.13), 0.69 (0.49-0.97), 0.66 (0.45-0.95), and 0.54 (0.29-0.996), respectively, when compared with current smokers (P(trend)=0.004). Similar associations were found among ever smokers-only, when smoking cessation time was treated as a continuous variable, and for RFS. The significantly beneficial effects of smoking cessation on OS and RFS were observed among women only, while not among men (P=0.01 for interactions between gender and smoking cessation). In conclusion, smoking cessation is associated with improved survival in early stage NSCLC patients. The longer the time since cessation of smoking, the better the survival outcome.

  8. Circulating and tissue biomarkers in early-stage non-small cell lung cancer

    PubMed Central

    Fumagalli, Caterina; Bianchi, Fabrizio; Raviele, Paola Rafaniello; Vacirca, Davide; Bertalot, Giovanni; Rampinelli, Cristiano; Lazzeroni, Matteo; Bonanni, Bernardo; Veronesi, Giulia; Fusco, Nicola; Barberis, Massimo; Guerini-Rocco, Elena

    2017-01-01

    Objective We sought to characterise circulating and tissue tumour biomarkers of patients who developed early-stage non-small cell lung cancer (NSCLC) during long-term follow-up of a chemoprevention trial (NCT00321893). Materials and Methods Blood and sputum samples were collected from 202 high-risk asymptomatic individuals with CT-detected stable lung nodules. Real-time PCR was performed on plasma to quantify free circulating DNA. Baseline serum was investigated with a previously validated test based on 13 circulating miRNAs (miR-Test). Promoter methylation status of p16, RASSF1a and RARβ2 and telomerase activity were assessed in sputum samples. DNA was extracted from each tumour developed during follow-up and subjected to a mutation survey using the LungCarta panel on the Sequenom MassARRAY platform. Results During follow-up (9 years) six individuals underwent surgery for stage I NSCLC with a median time of disease onset of 20.5 months. MiR-Test scores were positive (range: 0.14–7.24) in four out of six baseline pre-disease onset sera. No association was identified between free circulating DNA or sputum biomarkers and disease onset. All tumours harboured at least one somatic mutation in well-known cancer genes, including KRAS (n = 4), BRAF (n = 1), and TP53 (n = 3). Conclusion Circulating miRNA tests may represent valuable tools to detect clinically-silent tumours. Early-stage lung adenocarcinomas harbour recurrent genetic events similar to those described in advanced-stage NSCLCs. PMID:28194229

  9. Increased Endothelial Progenitor Cell Number in Early Stage of Endometrial Cancer.

    PubMed

    Paprocka, Maria; Kieda, Claudine; Kantor, Aneta; Bielawska-Pohl, Aleksandra; Dus, Danuta; Czekanski, Andrzej; Heimrath, Jerzy

    2017-06-01

    It is generally believed that circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) reflect the state of the endothelium, its injury and/or repair possibilities. In different types of cancers, increased numbers of CECs and EPCs were found, suggesting their participation in cancer angiogenesis. The objective of this study was to determine whether, in the blood circulation of women with early endometrial cancer, CEC and EPC levels differ from those of healthy women of similar age. For CEC number evaluation, samples of peripheral blood cells of women with endometrial carcinoma and control subjects were labeled with anti-CD31 and anti-CD45 antibodies; for EPCs, with anti-VEGFR2 (vascular-endothelium growth factor receptor 2)/KDR and anti-CD34 antibodies. The CEC and EPC cells were then quantified by flow cytometry. Endothelial progenitor cell numbers (CD34, VEGFR2/KDR) in the peripheral blood of women with endometrial carcinoma were significantly augmented as compared with those of control healthy women and CEC numbers (CD31, CD45) were similar in both groups. Cancer patients were divided according to the grading into G1 and G2 groups and according to the stage into International Federation of Gynecology and Obstetrics (FIGO) stage IA and FIGO IB groups. Statistically significant augmented EPC numbers were demonstrated only in G1 and FIGO IA patients. These results strongly suggest new vessel formation from recruited endothelial precursors as being involved mainly at the early stages of tumor progression.

  10. Citrullination as early-stage indicator of cell response to Single-Walled Carbon Nanotubes

    NASA Astrophysics Data System (ADS)

    Mohamed, Bashir Mustafa; Movia, Dania; Knyazev, Anton; Langevin, Dominique; Davies, Anthony Mitchell; Prina-Mello, Adriele; Volkov, Yuri

    2013-01-01

    Single-walled carbon nanotubes (SWCNTs) have been widely explored as potential technologies for information systems and medical applications. The impact of SWCNTs on human health is of prime concern, if SWCNTs have a future in the manufacturing industry. This study proposes a novel, inflammation-independent paradigm of toxicity for SWCNTs, identifying the protein citrullination process as early-stage indicator of inflammatory responses of macrophages (THP-1) and of subtle phenotypic damages of lung epithelial (A549) cells following exposure to chemically-treated SWCNTs. Our results showed that, while most of the cellular responses of A549 cells exposed to SWCNTs are different to those of similarly treated THP-1 cells, the protein citrullination process is triggered in a dose- and time-dependent manner in both cell lines, with thresholds comparable between inflammatory (THP-1) and non-inflammatory (A549) cell types. The cellular mechanism proposed herein could have a high impact in predicting the current risk associated with environmental exposure to SWCNTs.

  11. Citrullination as early-stage indicator of cell response to Single-Walled Carbon Nanotubes

    PubMed Central

    Mohamed, Bashir Mustafa; Movia, Dania; Knyazev, Anton; Langevin, Dominique; Davies, Anthony Mitchell; Prina-Mello, Adriele; Volkov, Yuri

    2013-01-01

    Single-walled carbon nanotubes (SWCNTs) have been widely explored as potential technologies for information systems and medical applications. The impact of SWCNTs on human health is of prime concern, if SWCNTs have a future in the manufacturing industry. This study proposes a novel, inflammation-independent paradigm of toxicity for SWCNTs, identifying the protein citrullination process as early-stage indicator of inflammatory responses of macrophages (THP-1) and of subtle phenotypic damages of lung epithelial (A549) cells following exposure to chemically-treated SWCNTs. Our results showed that, while most of the cellular responses of A549 cells exposed to SWCNTs are different to those of similarly treated THP-1 cells, the protein citrullination process is triggered in a dose- and time-dependent manner in both cell lines, with thresholds comparable between inflammatory (THP-1) and non-inflammatory (A549) cell types. The cellular mechanism proposed herein could have a high impact in predicting the current risk associated with environmental exposure to SWCNTs. PMID:23350031

  12. Electrostatic Force Microscopic Characterization of Early Stage Carbon Deposition on Nickel Anodes in Solid Oxide Fuel Cells.

    PubMed

    Park, Hyungmin; Li, Xiaxi; Lai, Samson Y; Chen, Dongchang; Blinn, Kevin S; Liu, Mingfei; Choi, Sinho; Liu, Meilin; Park, Soojin; Bottomley, Lawrence A

    2015-09-09

    Carbon deposition on nickel anodes degrades the performance of solid oxide fuel cells that utilize hydrocarbon fuels. Nickel anodes with BaO nanoclusters deposited on the surface exhibit improved performance by delaying carbon deposition (i.e., coking). The goal of this research was to visualize early stage deposition of carbon on nickel surface and to identify the role BaO nanoclusters play in coking resistance. Electrostatic force microscopy was employed to spatially map carbon deposition on nickel foils patterned with BaO nanoclusters. Image analysis reveals that upon propane exposure initial carbon deposition occurs on the Ni surface at a distance from the BaO features. With continued exposure, carbon deposits penetrate into the BaO-modified regions. After extended exposure, carbon accumulates on and covers BaO. The morphology and spatial distribution of deposited carbon was found to be sensitive to experimental conditions.

  13. Early stages of carbonate mineralization revealed from molecular simulations: Implications for biomineral formation

    NASA Astrophysics Data System (ADS)

    Wallace, A. F.; DeYoreo, J.; Banfield, J. F.

    2011-12-01

    calcite-type lattice is also apparent. Continued growth results in expansion of the dehydrated core, however, complete desolvation and incorporation of cations into the growing carbonate phase is not achieved until the cluster grows to ~1.2 nm. Exploration of the system free energy along the crystallization path reveals "special" cluster sizes that correlate with ion desolvation milestones. The formation of these species comprise critical bottlenecks on the energy landscape and for the establishment of order within the growing clusters.

  14. Coherent Brightfield Microscopy Provides the Spatiotemporal Resolution To Study Early Stage Viral Infection in Live Cells.

    PubMed

    Huang, Yi-Fan; Zhuo, Guan-Yu; Chou, Chun-Yu; Lin, Cheng-Hao; Chang, Wen; Hsieh, Chia-Lung

    2017-03-28

    Viral infection starts with a virus particle landing on a cell surface followed by penetration of the plasma membrane. Due to the difficulty of measuring the rapid motion of small-sized virus particles on the membrane, little is known about how a virus particle reaches an endocytic site after landing at a random location. Here, we use coherent brightfield (COBRI) microscopy to investigate early stage viral infection with ultrahigh spatiotemporal resolution. By detecting intrinsic scattered light via imaging-based interferometry, COBRI microscopy allows us to track the motion of a single vaccinia virus particle with nanometer spatial precision (<3 nm) in 3D and microsecond temporal resolution (up to 100,000 frames per second). We explore the possibility of differentiating the virus signal from cell background based on their distinct spatial and temporal behaviors via digital image processing. Through image postprocessing, relatively stationary background scattering of cellular structures is effectively removed, generating a background-free image of the diffusive virus particle for precise localization. Using our method, we unveil single virus particles exploring cell plasma membranes after attachment. We found that immediately after attaching to the membrane (within a second), the virus particle is locally confined within hundreds of nanometers where the virus particle diffuses laterally with a very high diffusion coefficient (∼1 μm(2)/s) at microsecond time scales. Ultrahigh-speed scattering-based optical imaging may provide opportunities for resolving rapid virus-receptor interactions with nanometer clarity.

  15. Is surgery indicated for elderly patients with early stage nonsmall cell lung cancer, in the era of stereotactic body radiotherapy?

    PubMed Central

    Nguyen, Nam P.; Godinez, Juan; Shen, Wei; Vinh-Hung, Vincent; Gorobets, Helena; Thariat, Juliette; Ampil, Fred; Vock, Jacqueline; Karlsson, Ulf; Chi, Alexander

    2016-01-01

    Abstract Background: The aim of this article is to assess the influence of comorbidities among elderly patients (at least 70 year old) undergoing surgery for early stage nonsmall cell lung cancer (NSCLC) and to explore the tolerability and efficacy of surgery in relation to stereotactic body radiotherapy (SBRT) in this patient population. Methods: A review of the literature on the prevalence of comorbidities among elderly patients with early stage NSCLC, and the impact of comorbidity factors on survival following surgery was conducted. Survival rates and the incidence of complications following SBRT for this patient population were also identified. Results: Comorbidities in elderly patients with early stage NSCLC may preclude surgery or lead to poor survival following surgery. However, chronological age alone should not be used as a deciding factor to deny curative treatment in elderly, but fit patients. Stereotactic body radiotherapy is well tolerated by elderly lung cancer patients and may result in survival rates similar to that following surgery. Conclusion: SBRT should be the treatment of choice for early stage NSCLC in elderly patients with multiple comorbidities that preclude surgery. The roles of surgery and SBRT for elderly, -fit patients with early stage NSCLC needs to be further defined in future prospective trials. PMID:27787380

  16. Stereotactic radiotherapy for early stage non-small cell lung cancer

    PubMed Central

    Badellino, Serena; Filippi, Andrea Riccardo

    2015-01-01

    Stereotactic body radiotherapy (SBRT) represents a consolidated treatment option for patients with medically inoperable early stage non-small cell lung cancer (NSCLC). The clinical evidence accumulated in the past decade supports its use as an alternative to surgery with comparable survival outcomes. Due to its limited toxicity, SBRT is also applicable to elderly patients with very poor baseline pulmonary function or other severe comorbidities. Recent comparative studies in operable patients raised the issue of the possible use of SBRT also for this subgroup, with quite promising results that still should be fully confirmed by prospective trials with long-term follow-up. Aim of this review is to summarize and discuss the major studies conducted over the years on SBRT and to provide data on the efficacy and toxicity of this radiotherapy technique for stage I NSCLC. Technical aspects and quality of life related issues are also discussed, with the goal to provide information on the current role and limitations of SBRT in clinical practice. PMID:26157674

  17. Norvaline and norleucine may have been more abundant protein components during early stages of cell evolution.

    PubMed

    Alvarez-Carreño, Claudia; Becerra, Arturo; Lazcano, Antonio

    2013-10-01

    The absence of the hydrophobic norvaline and norleucine in the inventory of protein amino acids is readdressed. The well-documented intracellular accumulation of these two amino acids results from the low-substrate specificity of the branched-chain amino acid biosynthetic enzymes that act over a number of related α-ketoacids. The lack of absolute substrate specificity of leucyl-tRNA synthase leads to a mischarged norvalyl-tRNA(Leu) that evades the translational proofreading activities and produces norvaline-containing proteins, (cf. Apostol et al. J Biol Chem 272:28980-28988, 1997). A similar situation explains the presence of minute but detectable amounts of norleucine in place of methionine. Since with few exceptions both leucine and methionine are rarely found in the catalytic sites of most enzymes, their substitution by norvaline and norleucine, respectively, would have not been strongly hindered in small structurally simple catalytic polypeptides during the early stages of biological evolution. The report that down-shifts of free oxygen lead to high levels of intracellular accumulation of pyruvate and the subsequent biosynthesis of norvaline (Soini et al. Microb Cell Factories 7:30, 2008) demonstrates the biochemical and metabolic consequences of the development of a highly oxidizing environment. The results discussed here also suggest that a broader definition of biomarkers in the search for extraterrestrial life may be required.

  18. Discovery of a dual-targeting organometallic ruthenium complex with high activity inducing early stage apoptosis of cancer cells.

    PubMed

    Du, Jun; Zhang, Erlong; Zhao, Yao; Zheng, Wei; Zhang, Yang; Lin, Yu; Wang, Zhaoying; Luo, Qun; Wu, Kui; Wang, Fuyi

    2015-12-01

    Ruthenium based complexes are promising antitumour candidates due to their lower toxicity and better water-solubility compared to the platinum antitumour complexes. An epidermal growth factor receptor (EGFR) has been found to be overexpressed in a large set of tumour cells. In this work, a series of organoruthenium complexes containing EGFR-inhibiting 4-anilinoquinazoline pharmacophores were synthesised and characterised. These complexes exhibited excellent inhibitory activity against EGFR and high affinity to interact with DNA via minor groove binding, featuring dual-targeting properties. In vitro screening demonstrated that the as-prepared ruthenium complexes are anti-proliferating towards a series of cancer cell lines, in particular the non-small-cell lung cancer cell line A549. Fluorescence-activated cell sorting analysis and fluorescence microscopy revealed that the most active complex 3 induced much more early-stage cell apoptosis than its cytotoxic arene ruthenium analogue and the EGFR-inhibiting 4-anilinoquinazolines, verifying the synergetic effect of the two mono-functional pharmacophores.

  19. Transcriptome Profiles Using Next-Generation Sequencing Reveal Liver Changes in the Early Stage of Diabetes in Tree Shrew (Tupaia belangeri chinensis)

    PubMed Central

    Xu, Haibo; Zhang, Zhiguo; Chang, Qing; Liao, Shasha; Zhang, Linqiang; Li, Yunhai; Wu, Dongdong

    2016-01-01

    Determining the liver changes during the early stages of diabetes is critical to understand the nature of the disease and development of novel treatments for it. Advances in the use of animal models and next-generation sequencing technologies offer a powerful tool in connection between liver changes and the diabetes. Here, we created a tree shrew diabetes model akin to type 1 diabetes by using streptozotocin to induce hyperglycemia and hyperlipidemia. Using RNA-seq, we compiled liver transcriptome profiles to determine the differentially expressed genes and to explore the role of hyperglycemia in liver changes. Our results, respectively, identified 14,060 and 14,335 genes in healthy tree shrews and those with diabetes, with 70 genes differentially expressed between the two groups. Gene orthology and KEGG annotation revealed that several of the main biological processes of these genes were related to translational processes, steroid metabolic processes, oxidative stress, inflammation, and hypertension, all of which are highly associated with diabetes and its complications. These results collectively suggest that STZ induces hyperglycemia in tree shrew and that hyperglycemia induced oxidative stress led to high expression of aldose reductase, inflammation, and even cell death in liver tissues during the early stage of diabetes. PMID:27069931

  20. Early stage colon cancer.

    PubMed

    Freeman, Hugh James

    2013-12-14

    Evidence has now accumulated that colonoscopy and removal of polyps, especially during screening and surveillance programs, is effective in overall risk reduction for colon cancer. After resection of malignant pedunculated colon polyps or early stage colon cancers, long-term repeated surveillance programs can also lead to detection and removal of asymptomatic high risk advanced adenomas and new early stage metachronous cancers. Early stage colon cancer can be defined as disease that appears to have been completely resected with no subsequent evidence of involvement of adjacent organs, lymph nodes or distant sites. This differs from the clinical setting of an apparent "curative" resection later pathologically upstaged following detection of malignant cells extending into adjacent organs, peritoneum, lymph nodes or other distant sites, including liver. This highly selected early stage colon cancer group remains at high risk for subsequent colon polyps and metachronous colon cancer. Precise staging is important, not only for assessing the need for adjuvant chemotherapy, but also for patient selection for continued surveillance. With advanced stages of colon cancer and a more guarded outlook, repeated surveillance should be limited. In future, novel imaging technologies (e.g., confocal endomicroscopy), coupled with increased pathological recognition of high risk markers for lymph node involvement (e.g., "tumor budding") should lead to improved staging and clinical care.

  1. Probiotic lactobacilli inhibit early stages of Candida albicans biofilm development by reducing their growth, cell adhesion, and filamentation.

    PubMed

    Matsubara, Victor Haruo; Wang, Yi; Bandara, H M H N; Mayer, Marcia Pinto Alves; Samaranayake, Lakshman P

    2016-07-01

    We evaluated the inhibitory effects of the probiotic Lactobacillus species on different phases of Candida albicans biofilm development. Quantification of biofilm growth and ultrastructural analyses were performed on C. albicans biofilms treated with Lactobacillus rhamnosus, Lactobacillus casei, and Lactobacillus acidophilus planktonic cell suspensions as well as their supernatants. Planktonic lactobacilli induced a significant reduction (p < 0.05) in the number of biofilm cells (25.5-61.8 %) depending on the probiotic strain and the biofilm phase. L. rhamnosus supernatants had no significant effect on the mature biofilm (p > 0.05), but significantly reduced the early stages of Candida biofilm formation (p < 0.01). Microscopic analyses revealed that L. rhamnosus suspensions reduced Candida hyphal differentiation, leading to a predominance of budding growth. All lactobacilli negatively impacted C. albicans yeast-to-hyphae differentiation and biofilm formation. The inhibitory effects of the probiotic Lactobacillus on C. albicans entailed both cell-cell interactions and secretion of exometabolites that may impact on pathogenic attributes associated with C. albicans colonization on host surfaces and yeast filamentation. This study clarifies, for the first time, the mechanics of how Lactobacillus species may antagonize C. albicans host colonization. Our data elucidate the inhibitory mechanisms that define the probiotic candicidal activity of lactobacilli, thus supporting their utility as an adjunctive therapeutic mode against mucosal candidal infections.

  2. Characterization of xylan in the early stages of secondary cell wall formation in tobacco bright yellow-2 cells.

    PubMed

    Ishii, Tadashi; Matsuoka, Keita; Ono, Hiroshi; Ohnishi-Kameyama, Mayumi; Yaoi, Katsuro; Nakano, Yoshimi; Ohtani, Misato; Demura, Taku; Iwai, Hiroaki; Satoh, Shinobu

    2017-11-15

    The major polysaccharides present in the primary and secondary walls surrounding plant cells have been well characterized. However, our knowledge of the early stages of secondary wall formation is limited. To address this, cell walls were isolated from differentiating xylem vessel elements of tobacco bright yellow-2 (BY-2) cells induced by VASCULAR-RELATED NAC-DOMAIN7 (VND7). The walls of induced VND7-VP16-GR BY-2 cells consisted of cellulose, pectic polysaccharides, hemicelluloses, and lignin, and contained more xylan and cellulose compared with non-transformed BY-2 and uninduced VND7-VP16-GR BY-2 cells. A reducing end sequence of xylan containing rhamnose and galaturonic acid- residues is present in the walls of induced, uninduced, and non-transformed BY-2 cells. Glucuronic acid residues in xylan from walls of induced cells are O-methylated, while those of xylan in non-transformed BY-2 and uninduced cells are not. Our results show that xylan changes in chemical structure and amounts during the early stages of xylem differentiation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Growth pattern switch of renal cells and expression of cell cycle related proteins at the early stage of diabetic nephropathy

    SciTech Connect

    Zhang Yanling; Shi Yonghong; Liu Yaling; Dong Hui; Liu, Maodong; Li Ying; Duan Huijun

    2007-11-09

    Renal hypertrophy, partly due to cell proliferation and hypertrophy, has been found correlated to renal function deterioration in diabetes mellitus. We screened the up-regulated cell cycle related genes to investigate cell growth and the expression of cell cycle regulating proteins at the early stage of diabetic nephropathy using STZ-induced diabetic rats. Cyclin E, CDK{sub 2} and P{sup 27} were found significantly up-regulated in diabetic kidney. Increased cell proliferation in the kidney was seen at day 3, peaked at day 5, and returned to normal level at day 30. Cyclin E and CDK{sub 2} expression also peeked at day 5 and P{sup 27} activity peaked at day 14. These findings indicate that a hyperplastic growth period of renal cells is followed by a hypertrophic growth period at the early stage of diabetes. The growth pattern switch may be regulated by cell cycle regulating proteins, Cyclin E, CDK{sub 2}, and P{sup 27}.

  4. Circulating micro-RNA expression profiles in early stage nonsmall cell lung cancer.

    PubMed

    Heegaard, Niels H H; Schetter, Aaron J; Welsh, Judith A; Yoneda, Mitsuhiro; Bowman, Elise D; Harris, Curtis C

    2012-03-15

    Circulating micro-RNA (miR) profiles have been proposed as promising diagnostic and prognostic biomarkers for cancer, including lung cancer. We have developed methods to accurately and reproducibly measure micro-RNA levels in serum and plasma. Here, we study paired serum and plasma samples from 220 patients with early stage nonsmall cell lung cancer (NSCLC) and 220 matched controls. We use qRT-PCR to measure the circulating levels of 30 different miRs that have previously been reported to be differently expressed in lung cancer tissue. Duplicate RNA extractions were performed for 10% of all samples, and micro-RNA measurements were highly correlated among those duplicates. This demonstrates high reproducibility of our assay. The expressions of miR-146b, miR-221, let-7a, miR-155, miR-17-5p, miR-27a and miR-106a were significantly reduced in the serum of NSCLC cases, while miR-29c was significantly increased. No significant differences were observed in plasma of patients compared with controls. Overall, expression levels in serum did not correlate well with levels in plasma. In secondary analyses, reduced plasma expression of let-7b was modestly associated with worse cancer-specific mortality in all patients, and reduced serum expression of miR-223 was modestly associated with cancer-specific mortality in stage IA/B patients. MiR profiles also showed considerable differences comparing African American and European Americans. In summary, we found significant differences in miR expression when comparing cases and controls and find evidence that expression of let-7b is associated with prognosis in NSCLC.

  5. NUCLEAR EGFR PROTEIN EXPRESSION PREDICTS POOR SURVIVAL IN EARLY STAGE NON-SMALL CELL LUNG CANCER

    PubMed Central

    Traynor, Anne M.; Weigel, Tracey L.; Oettel, Kurt R.; Yang, David T.; Zhang, Chong; Kim, KyungMann; Salgia, Ravi; Iida, Mari; Brand, Toni M.; Hoang, Tien; Campbell, Toby C.; Hernan, Hilary R.; Wheeler, Deric L.

    2013-01-01

    Introduction Nuclear EGFR (nEGFR) has been identified in various human tumor tissues, including cancers of the breast, ovary, oropharynx, and esophagus, and has predicted poor patient outcomes. We sought to determine if protein expression of nEGFR is prognostic in early stage non-small cell lung cancer (NSCLC). Methods Resected stage I and II NSCLC specimens were evaluated for nEGFR protein expression using immunohistochemistry (IHC). Cases with at least one replicate core containing ≥5% of tumor cells demonstrating strong dot-like nucleolar EGFR expression were scored as nEGFR positive. Results Twenty-three (26.1% of the population) of 88 resected specimens stained positively for nEGFR. Nuclear EGFR protein expression was associated with higher disease stage (45.5% of stage II vs. 14.5% of stage I; p=0.023), histology (41.7% in squamous cell carcinoma vs. 17.1% in adenocarcinoma; p=0.028), shorter progression-free survival (PFS) (median PFS 8.7 months [95% CI 5.1–10.7 mo] for nEGFR positive vs. 14.5 months [95% CI 9.5–17.4 mo] for nEGFR negative; hazard ratio (HR) of 1.89 [95% CI 1.15–3.10]; p=0.011), and shorter overall survival (OS) (median OS 14.1 months [95% CI 10.3–22.7 mo] for nEGFR positive vs. 23.4 months [95% CI 20.1–29.4 mo] for nEGFR negative; HR of 1.83 [95% CI 1.12–2.99]; p=0.014). Conclusions Expression of nEGFR protein was associated with higher stage and squamous cell histology, and predicted shorter PFS and OS, in this patient cohort. Nuclear EGFR serves as a useful independent prognostic variable and as a potential therapeutic target in NSCLC. PMID:23628526

  6. Phase 0 Trial of Itraconazole for Early-Stage Non-Small Cell Lung Cancer

    DTIC Science & Technology

    2015-10-01

    and by targeting the Hedgehog developmental/survival pathway. In this clinical trial, 15 patients with early-stage lung cancer planned for surgical ...Determine the effect of itraconazole pharmacokinetics (PK) on the pharmacodynamic profile of itraconazole. On- treatment serum, tumor tissue, and...itraconazole 600 mg orally daily for 7-10 days followed by repeat skin biopsy, blood sampling, and MRI studies, followed by surgical resection. Baseline

  7. Human Adipose-derived Mesenchymal Stem Cells Attenuate Early Stage of Bleomycin Induced Pulmonary Fibrosis: Comparison with Pirfenidone

    PubMed Central

    Reddy, Manoj; Fonseca, Lyle; Gowda, Shashank; Chougule, Basavraj; Hari, Aarya; Totey, Satish

    2016-01-01

    Background and Objectives Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, invariably fatal fibrotic lung disease with no lasting option for therapy. Mesenchymal stem cells (MSCs) could be a promising modality for the treatment of IPF. Aim of the study was to investigate improvement in survivability and anti-fibrotic efficacy of human adipose-derived mesenchymal stem cells (AD-MSCs) in comparison with pirfenidone in the bleomycin-induced pulmonary fibrosis model. Methods Human AD-MSCs were administered intravenously on day 3, 6 and 9 after an intra-tracheal challenge with bleomycin, whereas, pirfenidone was given orally in drinking water at the rate of 100 mg/kg body weight three times a day daily from day 3 onward. AD-MSCs were labelled with PKH-67 before administration to detect engraftment. Disease severity and improvement was assessed and compared between sham control and vehicle control groups using Kaplan-Meier survival analysis, biochemical and molecular analysis, histopathology and high resolution computed tomography (HRCT) parameters at the end of study. Results Results demonstrated that AD-MSCs significantly increase survivability; reduce organ weight and collagen deposition better than pirfenidone group. Histological analyses and HRCT of the lung revealed that AD-MSCs afforded protection against bleomycin induced fibrosis and protect architecture of the lung. Gene expression analysis revealed that AD-MSCs potently suppressed pro-fibrotic genes induced by bleomycin. More importantly, AD-MSCs were found to inhibit pro-inflammatory related transcripts. Conclusions Our results provided direct evidence that AD-MSC-mediated immunomodulation and anti-fibrotic effect in the lungs resulted in marked protection in pulmonary fibrosis, but at an early stage of disease. PMID:27871152

  8. Cryopreservation of early stage Siberian sturgeon Acipenser baerii germ cells, comparison of whole tissue and dissociated cells.

    PubMed

    Pšenička, Martin; Saito, Taiju; Rodina, Marek; Dzyuba, Boris

    2016-04-01

    Several sturgeon species are near extinction; therefore an efficient conservation strategy is required. Germ stem cells can be used for long-term storage and restoration of genetic information using surrogate reproduction. This study compared cryopreservation procedures of early stages of Siberian sturgeon Acipenser baerii testicular and ovarian cells. Whole gonad tissue or dissociated cells were frozen at a cooling rate of 1 °C/min in phosphate buffered saline with 0.5% bovine serum albumin, 50 mM glucose, and one of four different 1.5 M cryoprotectants: dimethyl sulfoxide, glycerol, ethylene glycol, or dimethyl sulfoxide with propanediol. The number of living cells obtained from 0.1 g of gonadal tissue after freeze/thaw of both whole tissue and dissociated cells was higher using ethylene glycol than with other cryoprotectants. Although there were no differences in the number of living cells in cryopreserved whole tissue vs. dissociated cells, the number of dead cells was lower with whole tissue cryopreservation, indicating that cells that died during freeze/thaw were digested during subsequent enzymatic dissociation. This resulted in more than 90% live cells after freeze/thaw and dissociation. The thawed tissue cryopreserved using ethylene glycol as protectant as well as fresh gonadal tissue were dissociated, and the cells were labelled by PKH26 and transplanted into larvae of sterlet Acipenser ruthenus. Ninety days post-transplant of both fresh and cryopreserved cells, introduced cells proliferated in more than half of the recipients.

  9. Photoluminescence due to early stage of oxygen precipitation in multicrystalline Si for solar cells

    NASA Astrophysics Data System (ADS)

    Higuchi, Fumito; Tajima, Michio; Ogura, Atsushi

    2017-07-01

    To analyze the early stage of oxygen precipitation in n-type multicrytalline Si, the spectral change of photoluminescence (PL) induced by thermal treatment at 450-650 °C was investigated in relation to the changes in excess donor and interstitial oxygen concentrations. We observed the characteristic PL bands in the near-band-edge region and sharp lines in the deep-level region in correspondence with the generation of thermal donors and new donors. The observed PL spectral variation is essentially the same as that in Czochralski-grown Si annealed at 450-650 °C.

  10. [Treatment of non-small cell lung carcinoma in early stages].

    PubMed

    Meneses, José Carlos; Avila Martínez, Régulo J; Ponce, Santiago; Zuluaga, Mauricio; Bartolomé, Adela; Gámez, Pablo

    2013-12-01

    Treatment of lung carcinoma is multidisciplinary. There are different therapeutic strategies available, although surgery shows the best results in those patients with lung carcinoma in early stages. Other options such as stereotactic radiation therapy are relegated to patients with small tumors and poor cardiopulmonary reserve or to those who reject surgery. Adjuvant chemotherapy is not justified in patients with stage i of the disease and so double adjuvant chemotherapy should be considered. This adjuvant chemotherapy should be based on cisplatin after surgery in those patients with stages ii and IIIA.

  11. Early-stage esophageal squamous cell carcinoma treated with californium-252 neutron brachytherapy: clinical report on 16 cases.

    PubMed

    Liu, Huiming; Wang, Qifeng; Jia, Xitang; Liu, Bo; Wang, C-K Chris

    2013-01-01

    Californium-252 (²⁵²Cf) neutron brachytherapy is a form of high linear energy transfer radiotherapy, which has proven effective when used in combination with external beam radiotherapy to treat intracavitary cancers of the cervix, colon/rectum and esophagus. No study has been reported for treatment of intracavitary cancers with neutron brachytherapy alone. The aim of the study was to observe and analyze the long-term curative effects and complications for early stage thoracic esophageal cancer patients treated with neutron brachytherapy alone. From December 2001 to August 2006, 16 patients of early stage squamous cell carcinoma underwent neutron brachytherapy. The total radiation dose to the reference point was 20-28 Gy-eq in 5 to 7 fractions with 4 Gy-eq/fraction. The 1-, 3-, and 5-year follow-up rates were 100%. The 2-, 3-, 4-, and 5-year survival rates were 100%, 87.5%, 87.5%, and 75%, respectively. The early complication rates for grades 1 and 2 radiation esophagitis were 75% and 25%, respectively. The late complication rates for grades 0 and 1 (according to the RTOG/EORTC standard) were 87.5% and 12.5%, respectively. Barium esophagography after treatments confirmed that the complete response rate was 100%. Fourteen patients were confirmed by endoscopy to have either normal mucosa or inflammation change. Neutron brachytherapy alone was an effective and safe treatment for early stage esophageal squamous cell cancer.

  12. Identification of c-Yes expression in the nuclei of hepatocellular carcinoma cells: involvement in the early stages of hepatocarcinogenesis.

    PubMed

    Nonomura, Takako; Masaki, Tsutomu; Morishita, Asahiro; Jian, Gong; Uchida, Naohito; Himoto, Takashi; Izuishi, Kunihiko; Iwama, Hisakazu; Yoshiji, Hitoshi; Watanabe, Seishiro; Kurokohchi, Kazutaka; Kuriyama, Shigeki

    2007-01-01

    It is thought that the subcellular distribution of Src-family tyrosine kinases, including c-Yes binding to the cellular membrane, is membranous and/or cytoplasmic. c-Yes protein tyrosine kinase is known to be related to malignant transformation. However, the expression patterns of c-Yes in hepatocellular carcinoma (HCC) remains unknown. In the present study, we report that c-Yes is expressed not only in the membrane and cytoplasm, but also in the nuclei of cancer cells in some human HCC tissues and in a human HCC cell line. We examined the expression and localization of c-Yes in human HCC cell lines (HLE, HLF, PLC/PRF/5 and Hep 3B) by Western blotting and immunohistochemical analyses; we also examined the expression of c-Yes by immunohistochemistry and Western blotting in the tissues of various liver diseases, including 39 samples from HCC patients. We used an antibody array to detect proteins that bind to nuclear c-Yes in PLC/PRF/5 cell line. c-Yes was found to be expressed in the membranes and cytoplasm of HLE, HLF and Hep 3B HCC cells; it was also detected in the nuclei in addition to the membranes and cytoplasm of PLC/PRF/5 HCC cells. HCC with nuclear c-Yes was detected in 5 of 39 cases (13.0%), and nuclear c-Yes expression was not detected in normal, chronic hepatitis or cirrhotic livers. All HCCs with nuclear c-Yes expression were well-differentiated, small tumors at the early stages. In the PLC/PRF/5 cell line, the nuclear localization of c-Yes with cyclin-dependent kinase 1 was confirmed by a protein antibody array. In conclusion, nuclear c-Yes expression was found in cancer cells at the early stages of hepatocarcinogenesis, suggesting that nucleus-located c-Yes may be a useful marker to detect early-stage HCC.

  13. Upregulation of MAGEA4 correlates with poor prognosis in patients with early stage of esophageal squamous cell carcinoma

    PubMed Central

    Tang, Wei-Wei; Liu, Zi-Hao; Yang, Tong-Xin; Wang, Han-Jin; Cao, Xiu-Feng

    2016-01-01

    Esophageal cancer is a common type of cancer in the People’s Republic of China. Many genes have been reported to be linked with it. Melanoma antigen gene family A (MAGEA) genes are frequently highly expressed in various types of carcinoma. However, the specific role of MAGEA gene expression in esophageal squamous cell carcinoma (ESCC) still remains unclear. MAGEA4 is a member of MAGEA genes. We aimed to investigate the expression and prognosis of MAGEA4 expression in ESCC. MAGEA4 messenger RNA expression levels of 120 pairs of tumor and nontumor tissues of patients with ESCC were measured by quantitative real-time polymerase chain reaction. The results showed that MAGEA4 messenger RNA was significantly elevated in tumor tissues of patients with ESCC compared to nontumor ones. In addition, overexpression of MAGEA4 messenger RNA was significantly correlated with poorer overall survival (P=0.018) in early stage of patients with ESCC (I–IIA). In conclusion, MAGEA4 played an important role in the early stage of ESCC and overexpression of MAGEA4 was expected to become a potential prognostic marker for patients with early stage of ESCC. PMID:27478386

  14. Stereotactic body radiation therapy versus no treatment for early stage non-small cell lung cancer in medically inoperable elderly patients: A National Cancer Data Base analysis.

    PubMed

    Nanda, Ronica H; Liu, Yuan; Gillespie, Theresa W; Mikell, John L; Ramalingam, Suresh S; Fernandez, Felix G; Curran, Walter J; Lipscomb, Joseph; Higgins, Kristin A

    2015-12-01

    Stereotactic body radiation therapy (SBRT) has demonstrated high rates of local control with low morbidity and has now emerged as the standard of care for medically inoperable, early stage non-small cell lung cancer (NSCLC). However, the impact of lung SBRT on survival in the elderly population is less clear given competing comorbid conditions. An analysis of the National Cancer Data Base (NCDB) was undertaken to determine whether definitive SBRT improves survival relative to observation alone patients ages 70 years and older. The NCDB, a retrospective national database that captures approximately 70% of all patients treated for cancer, was queried for patients aged 70 years or older with early stage (T1-T3N0M0) NSCLC from 2003 to 2006. Overall survival was compared between patients who received stereotactic body radiotherapy alone and those who received no treatment. An extended Cox proportional hazards model was applied to estimate the treatment effect of SBRT. In total, 3147 patients met the selection criteria for this analysis. SBRT was delivered to 258 patients (8.2%), and 2889 patients (91.8%) received no treatment. There was no significant difference in the distribution of Charlson/Deyo comorbidity index scores between the 2 groups (P = .076). Multivariable analysis revealed improved overall survival with SBRT compared with observation for the entire cohort (hazard ratio, 0.64; P < .001). SBRT is associated with improved survival in elderly patients with early stage NSCLC who have concurrent comorbid conditions compared with observation alone. The current data support the use of SBRT for the treatment of elderly patients with early stage NSCLC who have limiting comorbid conditions. © 2015 American Cancer Society.

  15. Robotic stereotactic body radiation therapy for elderly medically inoperable early-stage non-small cell lung cancer

    PubMed Central

    Karam, Sana D; Horne, Zachary D; Hong, Robert L; Baig, Nimrah; Gagnon, Gregory J; McRae, Don; Duhamel, David; Nasr, Nadim M

    2013-01-01

    Introduction Stereotactic body radiation therapy (SBRT) is being increasingly applied in the treatment of non-small cell lung cancer (NSCLC) because of its high local efficacy. This study aims to examine survival outcomes in elderly patients with inoperable stage I NSCLC treated with SBRT. Methods A total of 31 patients with single lesions treated with fractionated SBRT from 2008 to 2011 were retrospectively analyzed. A median prescribed dose of 48 Gy was delivered to the prescription isodose line, over a median of four treatments. The median biologically effective dose (BED) was 105.6 (range 37.50–180), and the median age was 73 (65–90 years). No patient received concurrent chemotherapy. Results With a median follow up of 13 months (range, 4–40 months), the actuarial median overall survival (OS) and progression-free survival (PFS) were 32 months, and 19 months, respectively. The actuarial median local control (LC) time was not reached. The survival outcomes at median follow up of 13 months were 80%, 68%, and 70% for LC, PFS, and OS, respectively. Univariate analysis revealed a BED of >100 Gy was associated with improved LC rates (P = 0.02), while squamous cell histology predicted for worse LC outcome at median follow up time of 13 months (P = 0.04). Increased tumor volume was a worse prognostic indicator of both LC and OS outcomes (P < 0.05). Finally, female gender was a better prognostic factor for OS than male gender (P = 0.006). There were no prognostic indicators of PFS that reached statistical significance. No acute or subacute high-grade toxicities were documented. Conclusion SBRT is a safe, feasible, and effective treatment option for elderly patients with inoperable early stage NSCLC. BED, histology, and tumor size are predictors of local control, while tumor size and gender predict OS. PMID:28210133

  16. VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma.

    PubMed

    Lessi, Francesca; Mazzanti, Chiara Maria; Tomei, Sara; Di Cristofano, Claudio; Minervini, Andrea; Menicagli, Michele; Apollo, Alessandro; Masieri, Lorenzo; Collecchi, Paola; Minervini, Riccardo; Carini, Marco; Bevilacqua, Generoso

    2014-03-01

    Von Hipple-Lindau gene (VHL) inactivation represents the most frequent abnormality in clear cell renal cell carcinoma (ccRCC). Hypoxia-inducible factor-1α (HIF-1α) expression is regulated by O2 level. In normal O2 conditions, VHL binds HIF-1α and allows HIF-1α proteasomal degradation. A single-nucleotide polymorphism (SNP) has been found located in the oxygen-dependent degradation domain at codon 582 (C1772T, rs11549465, Pro582Ser). In hypoxia, VHL/HIF-1α interaction is abolished and HIF-1α activates target genes in the nucleus. This study analyzes the impact of genetic alterations and protein expression of VHL and the C1772T SNP of HIF-1α gene (HIF-1α) on prognosis in early-stage ccRCC (pT1a, pT1b, and pT2). Mutational analysis of the entire VHL sequence and the genotyping of HIF-1α C1772T SNP were performed together with VHL promoter methylation analysis and loss of heterozygosis (LOH) analysis at (3p25) locus. Data obtained were correlated with VHL and HIF-1α protein expression and with tumor-specific survival (TSS). VHL mutations, methylation status, and LOH were detected in 51, 11, and 12% of cases, respectively. Our results support the association between biallelic alterations and/or VHL silencing with a worse TSS. Moreover, we found a significant association between the HIF-1α C1772C genotype and a worse TSS. The same association was found when testing the presence of HIF-1α protein in the nucleus. Our results highlight the role of VHL/HIF-1α pathway in RCC and support the molecular heterogeneity of early-stage ccRCC. More important, we show the involvement of HIF-1α C1772T SNP in ccRCC progression.

  17. Apoptosis in Macrophages and Alveolar Epithelial Cells during Early Stages of Infection by Legionella pneumophila and Its Role in Cytopathogenicity

    PubMed Central

    Gao, Lian-Yong; Abu Kwaik, Yousef

    1999-01-01

    The hallmark of Legionnaires’ disease is intracellular replication of Legionella pneumophila within cells in the alveolar spaces. Cytopathogenicity of this bacterium to the host cell has been well demonstrated, but the mechanisms of host cell death due to infection by L. pneumophila are not well understood. In this study, induction of apoptosis in macrophages and alveolar epithelial cells by L. pneumophila during early stages of infection was confirmed by using multiple criteria, including DNA fragmentation by agarose gel electrophoresis, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, surface exposure of phosphatidylserine, and cellular morphology by transmission electron microscopy. Induction of nuclear apoptosis in L. pneumophila-infected macrophages is mediated by activation of the caspase cascade death machinery. We provide genetic and biochemical evidence that L. pneumophila-induced apoptosis in macrophages and alveolar epithelial cells does not require intracellular bacterial replication or new protein synthesis. In addition, extracellular L. pneumophila is capable of inducing apoptosis. Furthermore, induction of apoptosis by L. pneumophila correlates with cytopathogenicity. We conclude that L. pneumophila-induced apoptosis in macrophages and alveolar epithelial cells plays an important role in cytopathogenicity to the host cell during early stages of infection. PMID:9916101

  18. Phylogeographic structure and outbreeding depression reveal early stages of reproductive isolation in the neotropical orchid Epidendrum denticulatum.

    PubMed

    Pinheiro, Fábio; Cozzolino, Salvatore; de Barros, Fábio; Gouveia, Tiago M Z M; Suzuki, Rogério M; Fay, Michael F; Palma-Silva, Clarisse

    2013-07-01

    Phylogeographic studies provide an important framework for investigating the mechanisms operating during the earliest stages of speciation, as reproductive barriers can be examined among divergent lineages in a geographic context. We investigated the evolution of early stages of intrinsic postmating isolation among different populations and lineages of Epidendrum denticulatum, a Neotropical orchid distributed across different biomes in South America. We estimated genetic diversity and structure for both nuclear and plastid markers, using a haplotype network, differentiation tests, Bayesian assignment analysis, and divergence time estimates of the main lineages. Reproductive barriers among divergent lineages were examined by analyzing seed viability following reciprocal crossing experiments. Strong plastid phylogeographic structure was found, indicating that E. denticulatum was restricted to multiple refuges during South American forest expansion events. In contrast, significant phylogeographic structure was not found for nuclear markers, suggesting higher gene flow by pollen than by seeds. Large asymmetries in seed set were observed among different plastid genetic groups, suggesting the presence of polymorphic genic incompatibilities associated with cytonuclear interactions. Our results confirm the importance of phylogeographic studies associated with reproductive isolation experiments and suggest an important role for outbreeding depression during the early stages of lineage diversification. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

  19. Phase-based x-ray scattering—A possible method to detect cancer cells in a very early stage

    SciTech Connect

    Feye-Treimer, U. Treimer, W.

    2014-05-15

    Purpose: This theoretical work contains a detailed investigation of the potential and sensitivity of phase-based x-ray scattering for cancer detection in biopsies if cancer is in a very early stage of development. Methods: Cancer cells in their early stage of development differ from healthy ones mainly due to their faster growing cell nuclei and the enlargement of their densities. This growth is accompanied by an altered nucleus–plasma relation for the benefit of the cell nuclei, that changes the physical properties especially the index of refraction of the cell and the one of the cell nuclei. Interaction of radiation with matter is known to be highly sensitive to small changes of the index of refraction of matter; therefore a detection of such changes of volume and density of cell nuclei by means of high angular resolved phase-based scattering of x rays might provide a technique to distinguish malignant cells from healthy ones ifthe cell–cell nucleus system is considered as a coherent phase shifting object. Then one can observe from a thin biopsy which represents a monolayer of cells (no multiple scattering) that phase-based x-ray scattering curves from healthy cells differ from those of cancer cells in their early stage of development. Results: Detailed calculations of x-ray scattering patterns from healthy and cancer cell nuclei yield graphs and numbers with which one can distinguish healthy cells from cancer ones, taking into account that both kinds of cells occur in a tissue within a range of size and density. One important result is the role and the influence of the (lateral) coherence width of the radiation on the scattering curves and the sensitivity of phase-based scattering for cancer detection. A major result is that a larger coherence width yields a larger sensitivity for cancer detection. Further import results are calculated limits for critical sizes and densities of cell nuclei in order to attribute the investigated tissue to be healthy or

  20. Identification of circulating tumour cells in early stage breast cancer patients using multi marker immunobead RT-PCR

    PubMed Central

    Raynor, Michael P; Stephenson, Sally-Anne; Pittman, Kenneth B; Walsh, David CA; Henderson, Michael A; Dobrovic, Alexander

    2009-01-01

    Introduction The ability to screen blood of early stage operable breast cancer patients for circulating tumour cells is of potential importance for identifying patients at risk of developing distant relapse. We present the results of a study of the efficacy of the immunobead RT-PCR method in identifying patients with circulating tumour cells. Results Immunomagnetic enrichment of circulating tumour cells followed by RT-PCR (immunobead RT-PCR) with a panel of five epithelial specific markers (ELF3, EPHB4, EGFR, MGB1 and TACSTD1) was used to screen for circulating tumour cells in the peripheral blood of 56 breast cancer patients. Twenty patients were positive for two or more RT-PCR markers, including seven patients who were node negative by conventional techniques. Significant increases in the frequency of marker positivity was seen in lymph node positive patients, in patients with high grade tumours and in patients with lymphovascular invasion. A strong trend towards improved disease free survival was seen for marker negative patients although it did not reach significance (p = 0.08). Conclusion Multi-marker immunobead RT-PCR analysis of peripheral blood is a robust assay that is capable of detecting circulating tumour cells in early stage breast cancer patients. PMID:19500345

  1. Contribution of mammary epithelial cells to the immune response during early stages of a bacterial infection to Staphylococcus aureus

    PubMed Central

    2014-01-01

    To differentiate between the contribution of mammary epithelial cells (MEC) and infiltrating immune cells to gene expression profiles of mammary tissue during early stage mastitis, we investigated in goats the in vivo transcriptional response of MEC to an experimental intra mammary infection (IMI) with Staphylococcus aureus, using a non-invasive RNA sampling method from milk fat globules (MFG). Microarrays were used to record gene expression patterns during the first 24 hours post-infection (hpi). This approach was combined with laser capture microdissection of MEC from frozen slides of mammary tissue to analyze some relevant genes at 30 hpi. During the early stages post-inoculation, MEC play an important role in the recruitment and activation of inflammatory cells through the IL-8 signalling pathway and initiate a sharp induction of innate immune genes predominantly associated with the pro-inflammatory response. At 30 hpi, MEC express genes encoding different acute phase proteins, including SAA3, SERPINA1 and PTX3 and factors, such as S100A12, that contribute directly to fighting the infection. No significant change in the expression of genes encoding caseins was observed until 24 hpi, thus validating our experimental model to study early stages of infection before the occurrence of tissue damage, since the milk synthesis function is still operative. This is to our knowledge the first report showing in vivo, in goats, how MEC orchestrate the innate immune response to an IMI challenge with S. aureus. Moreover, the non-invasive sampling method of mammary representative RNA from MFG provides a valuable tool to easily follow the dynamics of gene expression in MEC to search for sensitive biomarkers in milk for early detection of mastitis and therefore, to successfully improve the treatment and thus animal welfare. PMID:24521038

  2. Cytosolic Sequestration of Prep1 Influences Early Stages of T Cell Development

    PubMed Central

    Penkov, Dmitry; Palazzolo, Martina; Mondino, Anna; Blasi, Francesco

    2008-01-01

    Objective Prep1 and Pbx2 are the main homeodomain DNA-binding proteins of the TALE (three amino acid loop extension) family expressed in the thymus. We previously reported reduced Pbx2 expression and defective thymocyte maturation in Prep1 hypomorphic mice. To further investigate the role of this homeodomain DNA-binding protein in T cell development, we generated transgenic mice expressing the N-terminal fragment of Pbx1 (Pbx1NT) under the control of the Lck proximal promoter. Principal Findings Pbx1NT causes Prep1 cytosolic sequestration, abolishes Prep1-dependent DNA-binding activity and results in reduced Pbx2 expression in developing thymocytes. Transgenic thymi reveal increased numbers of CD4− CD8− CD44− (DN3 and DN4) thymocytes, due to a higher frequency of DN2 and DN4 Pbx1NT thymocytes in the S phase. Transgenic thymocytes however do not accumulate at later stages, as revealed by a normal representation of CD4/CD8 double positive and single positive thymocytes, due to a higher rate of apoptotic cell death of DN4 Pbx1NT thymocytes. Conclusion The results obtained by genetic (Prep1 hypomorphic) and functional (Pbx1NT transgenic) inactivation of Prep1 support nonredundant roles for this homeodomain protein during different stages of T cell development. PMID:18560600

  3. Supraependymal cells and fibers during the early stages of chick rhombencephalic development.

    PubMed

    Ojeda, J L; Piedra, S

    1998-09-01

    Supraependymal cellular elements are a constant feature in the adult cerebroventricular system. However, there has been no analysis of their distribution and morphology during the embryonic stages of the chick brain. The ultrastructural features of the rhombencephalic luminal surface of chick embryos ranging from stage 10 to 22 were studied with both scanning and transmission electron microscopy. In addition, immunocytochemistry and confocal laser microscopy were used to examine the presence of 68 kD neurofilaments in supraependymal elements. The ultrastructural observations revealed significant morphological differences in the apical cell surface between the cells at rhombomere boundaries and those in the rhombomere bodies. These differences support the idea that the boundary and the body of rhombomeres contain two morphologically distinct cell types. Supraependymal (SE) cells and SE fibers were present in the rhombencephalon of all embryos studied from stage 12 to 22. The cells were bipolar spindle-shaped. The SE fibers showed a characteristic spatial pattern within the rhombencephalon, following a straight course parallel to the rhombomere boundaries. The SE fibers showed varicosities and their endings contained small vesicles. Both SE cells and SE fibers were positive for 68 kD neurofilaments. Their morphology and reactivity for neurofilaments indicate a neuronal function. The constant presence of SE cells and SE fibers on the surface of the developing rhombencephalon, their special pattern and close relationship with the neural tube fluid (NTF) suggest that these supraependymal elements may be involved in a neuronal signalling pathway between different parts of the same rhombomere and also in chemical communication and integration within the ventricular system, linking distant parts of the developing central nervous system by means of NTF.

  4. Loss of vhl in the zebrafish pronephros recapitulates early stages of human clear cell renal cell carcinoma.

    PubMed

    Noonan, Haley R; Metelo, Ana M; Kamei, Caramai N; Peterson, Randall T; Drummond, Iain A; Iliopoulos, Othon

    2016-08-01

    Patients with von Hippel-Lindau (VHL) disease harbor a germline mutation in the VHL gene leading to the development of several tumor types including clear cell renal cell carcinoma (ccRCC). In addition, the VHL gene is inactivated in over 90% of sporadic ccRCC cases. 'Clear cell' tumors contain large, proliferating cells with 'clear cytoplasm', and a reduced number of cilia. VHL inactivation leads to the stabilization of hypoxia inducible factors 1a and 2a [HIF1a and HIF2a (HIF2a is also known as EPAS1)] with consequent up-regulation of specific target genes involved in cell proliferation, angiogenesis and erythropoiesis. A zebrafish model with a homozygous inactivation in the VHL gene (vhl(-/-)) recapitulates several aspects of the human disease, including development of highly vascular lesions in the brain and the retina and erythrocytosis. Here, we characterize for the first time the epithelial abnormalities present in the kidney of the vhl(-/-) zebrafish larvae as a first step in building a model of ccRCC in zebrafish. Our data show that the vhl(-/-) zebrafish kidney is characterized by an increased tubule diameter, disorganized cilia, the dramatic formation of cytoplasmic lipid vesicles, glycogen accumulation, aberrant cell proliferation and abnormal apoptosis. This phenotype of the vhl(-/-) pronephros is reminiscent of clear cell histology, indicating that the vhl(-/-) mutant zebrafish might serve as a model of early stage RCC. Treatment of vhl(-/-) zebrafish embryos with a small-molecule HIF2a inhibitor rescued the pronephric abnormalities, underscoring the value of the zebrafish model in drug discovery for treatment of VHL disease and ccRCC.

  5. Loss of vhl in the zebrafish pronephros recapitulates early stages of human clear cell renal cell carcinoma

    PubMed Central

    Noonan, Haley R.; Metelo, Ana M.; Kamei, Caramai N.; Peterson, Randall T.; Drummond, Iain A.

    2016-01-01

    ABSTRACT Patients with von Hippel–Lindau (VHL) disease harbor a germline mutation in the VHL gene leading to the development of several tumor types including clear cell renal cell carcinoma (ccRCC). In addition, the VHL gene is inactivated in over 90% of sporadic ccRCC cases. ‘Clear cell’ tumors contain large, proliferating cells with ‘clear cytoplasm’, and a reduced number of cilia. VHL inactivation leads to the stabilization of hypoxia inducible factors 1a and 2a [HIF1a and HIF2a (HIF2a is also known as EPAS1)] with consequent up-regulation of specific target genes involved in cell proliferation, angiogenesis and erythropoiesis. A zebrafish model with a homozygous inactivation in the VHL gene (vhl−/−) recapitulates several aspects of the human disease, including development of highly vascular lesions in the brain and the retina and erythrocytosis. Here, we characterize for the first time the epithelial abnormalities present in the kidney of the vhl−/− zebrafish larvae as a first step in building a model of ccRCC in zebrafish. Our data show that the vhl−/− zebrafish kidney is characterized by an increased tubule diameter, disorganized cilia, the dramatic formation of cytoplasmic lipid vesicles, glycogen accumulation, aberrant cell proliferation and abnormal apoptosis. This phenotype of the vhl−/− pronephros is reminiscent of clear cell histology, indicating that the vhl−/− mutant zebrafish might serve as a model of early stage RCC. Treatment of vhl−/− zebrafish embryos with a small-molecule HIF2a inhibitor rescued the pronephric abnormalities, underscoring the value of the zebrafish model in drug discovery for treatment of VHL disease and ccRCC. PMID:27491085

  6. Anti-tumor immune response in early stage non small cell lung cancer (NSCLC): implications for adjuvant therapy.

    PubMed

    Butts, Charles A

    2013-10-01

    The demonstration that systemic chemotherapy improves survival in patients who have had resection of early stage non-small cell lung cancer (NSCLC) represents a significant advance. The absolute benefit of adjuvant chemotherapy in this setting is small with an overall survival improvement of 5%. In addition, there are many patients who have contraindications to cisplatin-based adjuvant therapy. Adjuvant chemotherapy is intended to target systemic micrometastases that remain after primary resection. The observation that cancers can relapse months or years after initial surgery implies that the residual micrometastases exist in a latent or dormant state. The concept of tumor dormancy offers therapeutic potential through induction or maintenance of the dormant state in disseminated tumor cells or through eradication of these dormant cells. Cancer dormancy is a complex process with multiple potential mechanisms. This review will focus on some of the evidence for immune related tumor dormancy and the potential for immune therapies to improve outcomes in the adjuvant setting in NSCLC.

  7. Foxp3(+) regulatory T cells are increased in the early stages of halo nevi: clinicopathological features of 30 halo nevi.

    PubMed

    Park, H S; Jin, S A; Choi, Y-D; Shin, M-H; Lee, S E; Yun, S J

    2012-01-01

    There have been few clinical studies of the role of regulatory T cells (Tregs) in halo formation of halo nevus. To evaluate the clinicopathologic features and the presence of Tregs in halo nevi. We analyzed 30 halo nevi and performed immunohistochemical analysis using antibodies against CD4, CD8, CD25 and Foxp3. We also performed double immunohistochemical staining for Foxp3 and CD25. We found significant increases in Foxp3(+) Tregs, and the shorter the halo nevus duration, the more Foxp3(+) Tregs were detected. Also, the ratio of Foxp3 to CD8 T cells was increased in early stages of halo nevi. Double immunohistochemical staining suggested that the Tregs in the halo nevi were CD25(+)Foxp3(+) T cells. Foxp3(+) Tregs were greatly increased in the halo nevi. The shorter the halo nevi duration, the more Foxp3(+) Tregs were involved in the earlier developmental stages of halo nevi. Copyright © 2012 S. Karger AG, Basel.

  8. Circulating Tumor DNA Detection in Early-Stage Non-Small Cell Lung Cancer Patients by Targeted Sequencing

    PubMed Central

    Chen, Ke-Zhong; Lou, Feng; Yang, Fan; Zhang, Jing-Bo; Ye, Hua; Chen, Wei; Guan, Tian; Zhao, Ming-Yu; Su, Xue-Xia; Shi, Rong; Jones, Lindsey; Huang, Xue F.; Chen, Si-Yi; Wang, Jun

    2016-01-01

    Circulating tumor DNA (ctDNA) isolated from peripheral blood has recently been shown to be an alternative source to detect gene mutations in primary tumors; however, most previous studies have focused on advanced stage cancers, and few have evaluated ctDNA detection in early-stage lung cancer. In the present study, blood and tumor samples were collected prospectively from 58 early-stage non-small lung cancer (NSCLC) patients (stages IA, IB, and IIA) and a targeted sequencing approach was used to detect somatic driver mutations in matched tumor DNA (tDNA) and plasma ctDNA. We identified frequent driver mutations in plasma ctDNA and tDNA in EGFR, KRAS, PIK3CA, and TP53, and less frequent mutations in other genes, with an overall study concordance of 50.4% and sensitivity and specificity of 53.8% and 47.3%, respectively. Cell-free (cfDNA) concentrations were found to be significantly associated with some clinical features, including tumor stage and subtype. Importantly, the presence of cfDNA had a higher positive predictive value than that of currently used protein tumor biomarkers. This study demonstrates the feasibility of identifying plasma ctDNA mutations in the earliest stage lung cancer patients via targeted sequencing, demonstrating a potential utility of targeted sequencing of ctDNA in the clinical management of NSCLC. PMID:27555497

  9. FADD Expression as a Prognosticator in Early-Stage Glottic Squamous Cell Carcinoma of the Larynx Treated Primarily With Radiotherapy

    SciTech Connect

    Schrijvers, Michiel L.; Pattje, Wouter J.; Slagter-Menkema, Lorian; Mastik, Mirjam F.; Gibcus, Johan H.; Langendijk, Johannes A.; Wal, Jacqueline E. van der; Laan, Bernard F.A.M. vn der

    2012-07-15

    Purpose: We recently reported on the identification of the Fas-associated death domain (FADD) as a possible driver of the chromosome 11q13 amplicon and the association between increased FADD expression and disease-specific survival in advanced-stage laryngeal carcinoma. The aim of this study was to examine whether expression of FADD and its Ser194-phosphorylated isoform (pFADD) predicts local control in patients with early-stage glottic carcinoma primarily treated with radiotherapy only. Methods and Materials: Immunohistochemical staining for FADD and pFADD was performed on pretreatment biopsy specimens of 92 patients with T1-T2 glottic squamous cell carcinoma primarily treated with radiotherapy between 1996 and 2005. Cox regression analysis was used to correlate expression levels with local control. Results: High levels of pFADD were associated with significantly better local control (hazard ratio, 2.40; 95% confidence interval, 1.04-5.55; p = 0.040). FADD overexpression showed a trend toward better local control (hazard ratio, 3.656; 95% confidence interval, 0.853-15.663; p = 0.081). Multivariate Cox regression analysis showed that high pFADD expression was the best predictor of local control after radiotherapy. Conclusions: This study showed that expression of phosphorylated FADD is a new prognostic biomarker for better local control after radiotherapy in patients with early-stage glottic carcinomas.

  10. Early stage signet ring cell carcinoma of the colon examined by magnifying endoscopy with narrow-band imaging: a case report.

    PubMed

    Ohnita, Ken; Isomoto, Hajime; Akashi, Taro; Hashiguchi, Keiichi; Matsushima, Kayoko; Minami, Hitomi; Akazawa, Yuko; Yamaguchi, Naoyuki; Takeshima, Fuminao; To, Kazuo; Takeshita, Hiroaki; Yasui, Haruna; Abe, Kuniko; Nakao, Kazuhiko

    2015-07-24

    Signet ring cell carcinoma of the colon and rectum is rare, and most cases are detected at an advanced stage. We present a case of primary signet ring cell carcinoma detected at an early stage by magnifying endoscopy with narrow-band imaging (NBI) and crystal violet staining. A 73-year-old man visited our hospital for screening colonoscopy. Six years previously, he had undergone endoscopic submucosal dissection (ESD) for early gastric cancer. The pathological diagnosis was a well-differentiated adenocarcinoma, invading into the mucosa without lymphovascular invasion. Colonoscopy revealed a flat elevated lesion with a slightly depressed area, 20 mm in diameter, in the cecum. Further, magnifying endoscopy with NBI revealed that the surface pattern was slightly irregular and microvessels had a regular diameter and distribution in the margin of the lesion, but in the central part of the lesion, irregularity in the tumor surface pattern and form as well as in the diameter and distribution of microvessels was noted. Additionally, due to mucus, avascular areas were also observed. Magnifying endoscopy combined with 0.05 % crystal violet staining showed IIIL and VI pit patterns in the margin of the lesion, and a VI pit pattern in the central part of the lesion; however, due to mucus exudate, this finding could not be established with certainty. The lesion was successfully removed en bloc using ESD without complications. The tumor was composed mainly of signet ring cell carcinoma, partially mixed with moderately differentiated (tub2) and well-differentiated (tub1) adenocarcinomas. The tumor cells infiltrated 250 μm into the submucosal layer and involved lymphatic vessels. Therefore, the patient underwent an additional laparoscopic ileocecal resection, and the resected specimen revealed no residual carcinoma or lymph node metastasis. In this case report, we present a case of primary signet ring cell carcinoma detected at an early stage and identified by magnifying

  11. Plasma miR-324-3p and miR-1285 as diagnostic and prognostic biomarkers for early stage lung squamous cell carcinoma

    PubMed Central

    Gao, Xujie; Wang, Yang; Zhao, Hua; Wei, Feng; Zhang, Xinwei; Su, Yanjun; Wang, Changli; Li, Hui; Ren, Xiubao

    2016-01-01

    Background Specific biomarkers for early detection and outcome prediction of lung squamous cell carcinoma (LSCC) are still lacking. This study assessed the differentially expressed miRNAs as potential biomarkers for early stage LSCC. Results Base on the results of multi-phase study, we found that miR-324-3p was significantly up-regulated, whereas mir-1285 was significantly down-regulated in plasma of stage I LSCC patients compared to healthy controls. ROC analysis showed that AUC of miR-324-3p and miR-1285 were 0.79 and 0.85, respectively. The combination of these two miRNAs could further improve the diagnostic accuracy (AUC = 0.89). The multivariate analysis revealed that plasma miR-324-3p level was an independent prognostic predictor for early stage LSCC. Methods 395 patients and 195 healthy controls were enrolled in this study. We screened the differentially expressed plasma miRNAs using TaqMan Low Density Arrays (TLDA) followed by three-phase qRT-PCR validation. We also evaluated the association of candidate miRNAs with overall survival of early stage LSCC patients. Finally, the target genes of the candidate miRNAs were analyzed using public available databases and bioinformatics methods. Conclusions The current study suggests that plasma miR-324-3p and miR-1285 levels could serve as LSCC early detection markers while miR-324-3p may serve as a prognostic marker for LSCC patients. PMID:27517633

  12. Impact of Adjuvant External-Beam Radiation Therapy in Early-Stage Uterine Papillary Serous and Clear Cell Carcinoma

    SciTech Connect

    Kim, Anne; Schreiber, David; Rineer, Justin; Choi, Kwang; Rotman, Marvin

    2011-11-15

    Purpose: Adjuvant radiation therapy (RT) in early-stage high- to intermediate-risk endometrioid adenocarcinoma is well established and has been shown to improve locoregional control. Its role in the management of early-stage clear cell carcinoma and uterine papillary serous carcinoma (UPSC) remains controversial. Methods and Materials: Using the Surveillance Epidemiology and End Results database, we identified women with American Joint Committee on Cancer Stage Sixth Edition. Stage IA-IIB clear cell carcinoma or UPSC who underwent hysterectomy with or without adjuvant RT between 1988 and 2003. We used Kaplan-Meier and Cox regression analysis to compare overall survival (OS) for all patients. Results: We identified 1,333 women of whom 451 had clear cell carcinoma and 882 had UPSC. Of those patients, 775 underwent surgery alone and 558 received adjuvant RT as well. For Stages I-IIB disease, the median OS with surgery alone was 106 months, vs. 151 months with adjuvant RT (p = 0.006). On subgroup analysis, we saw the benefit from adjuvant RT only in Stage IB-C patients. For Stage IB disease, patients undergoing surgery alone had a median OS of 117 months, vs. median survival not reached with the addition of RT (p = 0.006). For Stage IC disease, surgery alone had a median OS of 35 months vs. 120 months with RT (p = 0.001). Although the apparent benefit of RT diminished when measured via multivariate analysis, the impact of RT on survival did show a trend toward significance (hazard ration 0.808, confidence interval 95% 0.651-1.002, p = 0.052) Conclusion: In FIGO Stage IB-C papillary serous and clear cell uterine carcinoma, adjuvant RT seems to play an important role in improving survival.

  13. MYC and Human Telomerase Gene (TERC) Copy Number Gain in Early-stage Non–small Cell Lung Cancer

    PubMed Central

    Flacco, Antonella; Ludovini, Vienna; Bianconi, Fortunato; Ragusa, Mark; Bellezza, Guido; Tofanetti, Francesca R.; Pistola, Lorenza; Siggillino, Annamaria; Vannucci, Jacopo; Cagini, Lucio; Sidoni, Angelo; Puma, Francesco; Varella-Garcia, Marileila; Crinò, Lucio

    2015-01-01

    Objectives We investigated the frequency of MYC and TERC increased gene copy number (GCN) in early-stage non–small cell lung cancer (NSCLC) and evaluated the correlation of these genomic imbalances with clinicopathologic parameters and outcome. Materials and Methods Tumor tissues were obtained from 113 resected NSCLCs. MYC and TERC GCNs were tested by fluorescence in situ hybridization (FISH) according to the University of Colorado Cancer Center (UCCC) criteria and based on the receiver operating characteristic (ROC) classification. Results When UCCC criteria were applied, 41 (36%) cases for MYC and 41 (36%) cases for TERC were considered FISH-positive. MYC and TERC concurrent FISH-positive was observed in 12 cases (11%): 2 (17%) cases with gene amplification and 10 (83%) with high polysomy. By using the ROC analysis, high MYC (mean ≥2.83 copies/cell) and TERC (mean ≥2.65 copies/cell) GCNs were observed in 60 (53.1%) cases and 58 (51.3%) cases, respectively. High TERC GCN was associated with squamous cell carcinoma (SCC) histology (P = 0.001). In univariate analysis, increased MYC GCN was associated with shorter overall survival (P = 0.032 [UCCC criteria] or P = 0.02 [ROC classification]), whereas high TERC GCN showed no association. In multivariate analysis including stage and age, high MYC GCN remained significantly associated with worse overall survival using both the UCCC criteria (P = 0.02) and the ROC classification (P = 0.008). Conclusions Our results confirm MYC as frequently amplified in early-stage NSCLC and increased MYC GCN as a strong predictor of worse survival. Increased TERC GCN does not have prognostic impact but has strong association with squamous histology. PMID:25806711

  14. [Submental island flap for repair of oral defects after radical resection of early-stage oral squamous cell carcinoma].

    PubMed

    Liu, Hanqian; Yu, Huiming; Liu, Jiawu

    2013-09-01

    To evaluate the effectiveness of the submental island flap for repair of oral defects after radical resection of early-stage oral squamous cell carcinoma (OSCC). Between February 2010 and August 2011, 15 cases of early-stage OSCC were treated. Of 15 cases, 9 were male and 6 were female, aged from 48 to 71 years (mean, 63 years). The disease duration was 28-73 days (mean, 35 days). Primary lesions included tongue (3 cases), buccal mucosa (8 cases), retromolar area (2 cases), and floor of mouth mucosa (2 cases). According to TNM classification of International Union Against Cancer (UICC, 2002) of oral cancer and oropharyngeal cancer, 2 cases were classified as T1N0M0 and 13 cases as T2N0M0. The results of the pathologic type were high differentiated squamous cell carcinoma in 11 cases and moderately differentiated squamous cell carcinoma in 4 cases. The defect after resection of the lesion ranged from 5 cm x 3 cm to 8 cm x 6 cm. All the cases underwent radical resection of the primary lesion and immediate reconstruction with submental island flap except 1 case with radial forearm free flap because of no definite venous drainage. The sizes of the submental island flap varied from 6 cm x 4 cm to 9 cm x 6 cm. Operation time ranged from 4 hours and 30 minutes to 7 hours and 10 minutes (mean, 5 hours and 53 minutes) in 14 cases undergoing repair with submental island flap. All the flaps survived completely in 13 cases except 1 case having superficial necrosis of the flap, which was cured after conservative treatment. Temporary marginal mandibular nerve palsy occurred in 1 case, and was cured after 3 months; submandibular effusion was observed in 3 cases, and was cured after expectant treatment. The follow-up period ranged from 8 to 15 months (mean, 10.5 months) in 14 cases undergoing repair with submental island flap. Hair growth was seen on the flap and became sparse after 3 months in 2 male cases. The appearance of the face, opening mouth, swallowing, and speech were

  15. Gene Expression Analysis of Early Stage Endometrial Cancers Reveals Unique Transcripts Associated with Grade and Histology but Not Depth of Invasion

    PubMed Central

    Risinger, John I.; Allard, Jay; Chandran, Uma; Day, Roger; Chandramouli, Gadisetti V. R.; Miller, Caela; Zahn, Christopher; Oliver, Julie; Litzi, Tracy; Marcus, Charlotte; Dubil, Elizabeth; Byrd, Kevin; Cassablanca, Yovanni; Becich, Michael; Berchuck, Andrew; Darcy, Kathleen M.; Hamilton, Chad A.; Conrads, Thomas P.; Maxwell, G. Larry

    2013-01-01

    Endometrial cancer is the most common gynecologic malignancy in the United States but it remains poorly understood at the molecular level. This investigation was conducted to specifically assess whether gene expression changes underlie the clinical and pathologic factors traditionally used for determining treatment regimens in women with stage I endometrial cancer. These include the effect of tumor grade, depth of myometrial invasion and histotype. We utilized oligonucleotide microarrays to assess the transcript expression profile in epithelial glandular cells laser microdissected from 79 endometrioid and 12 serous stage I endometrial cancers with a heterogeneous distribution of grade and depth of myometrial invasion, along with 12 normal post-menopausal endometrial samples. Unsupervised multidimensional scaling analyses revealed that serous and endometrioid stage I cancers have similar transcript expression patterns when compared to normal controls where 900 transcripts were identified to be differentially expressed by at least fourfold (univariate t-test, p < 0.001) between the cancers and normal endometrium. This analysis also identified transcript expression differences between serous and endometrioid cancers and tumor grade, but no apparent differences were identified as a function of depth of myometrial invasion. Four genes were validated by quantitative PCR on an independent set of cancer and normal endometrium samples. These findings indicate that unique gene expression profiles are associated with histologic type and grade, but not myometrial invasion among early stage endometrial cancers. These data provide a comprehensive perspective on the molecular alterations associated with stage I endometrial cancer, particularly those subtypes that have the worst prognosis. PMID:23785665

  16. [Morphofunctional status of gonadotropic cells of the adenohypophysis at early stages of age involution].

    PubMed

    Kozak, M V; Teplyĭ, D L

    2007-01-01

    Action of alpha-tocopherol, emoxipinum on functional status of gonadotropic cells was investigated at deficiency of sexual hormones in male and female rats of Wistar line. The alpha-tocopherol slows down aging of gonadotropic cells after gonadectomy.

  17. Chromosome 2p gain in monoclonal B-cell lymphocytosis and in early stage chronic lymphocytic leukemia.

    PubMed

    Fabris, Sonia; Mosca, Laura; Cutrona, Giovanna; Lionetti, Marta; Agnelli, Luca; Ciceri, Gabriella; Barbieri, Marzia; Maura, Francesco; Matis, Serena; Colombo, Monica; Gentile, Massimo; Recchia, Anna Grazia; Anna Pesce, Emanuela; Di Raimondo, Francesco; Musolino, Caterina; Gobbi, Marco; Di Renzo, Nicola; Mauro, Francesca Romana; Brugiatelli, Maura; Ilariucci, Fiorella; Lipari, Maria Grazia; Angrilli, Francesco; Consoli, Ugo; Fragasso, Alberto; Molica, Stefano; Festini, Gianluca; Vincelli, Iolanda; Cortelezzi, Agostino; Federico, Massimo; Morabito, Fortunato; Ferrarini, Manlio; Neri, Antonino

    2013-01-01

    Recent studies have described chromosome 2p gain as a recurrent lesion in chronic lymphocytic leukemia (CLL). We investigated the 2p gain and its relationship with common prognostic biomarkers in a prospective series of 69 clinical monoclonal B-cell lymphocytosis (cMBL) and 218 early stage (Binet A) CLL patients. The 2p gain was detected by FISH in 17 patients (6%, 16 CLL, and 1 cMBL) and further characterized by single nucleotide polymorphism-array. Overall, unfavorable cytogenetic deletions, i.e., del(11)(q23) and del(17)(p13) (P = 0.002), were significantly more frequent in 2p gain cases, as well as unmutated status of IGHV (P < 1 × 10(-4) ) and CD38 (P < 1 × 10(-4) ) and ZAP-70 positive expression (P = 0.003). Furthermore, 2p gain patients had significantly higher utilization of stereotyped B-cell receptors compared with 2p negative patients (P = 0.009), and the incidence of stereotyped subset #1 in 2p gain patients was significantly higher than that found in the remaining CLLs (P = 0.031). Transcriptional profiling analysis identified several genes significantly upregulated in 2p gain CLLs, most of which mapped to 2p. Among these, NCOA1 and ROCK2 are known for their involvement in tumor progression in several human cancers, whereas among those located in different chromosomes, CAV1 at 7q31.1 has been recently identified to play a critical role in CLL progression. Thus, 2p gain can be present since the early stages of the disease, particularly in those cases characterized by other poor prognosis markers. The finding of genes upregulated in the cells with 2p gain provides new insights to define the pathogenic role of this lesion. Copyright © 2012 Wiley Periodicals, Inc.

  18. The softening of human bladder cancer cells happens at an early stage of the malignancy process

    PubMed Central

    Ramos, Jorge R; Pabijan, Joanna

    2014-01-01

    Summary Various studies have demonstrated that alterations in the deformability of cancerous cells are strongly linked to the actin cytoskeleton. By using atomic force microscopy (AFM), it is possible to determine such changes in a quantitative way in order to distinguish cancerous from non-malignant cells. In the work presented here, the elastic properties of human bladder cells were determined by means of AFM. The measurements show that non-malignant bladder HCV29 cells are stiffer (higher Young’s modulus) than cancerous cells (HTB-9, HT1376, and T24 cell lines). However, independently of the histological grade of the studied bladder cancer cells, all cancerous cells possess a similar level of the deformability of about a few kilopascals, significantly lower than non-malignant cells. This underlines the diagnostic character of stiffness that can be used as a biomarker of bladder cancer. Similar stiffness levels, observed for cancerous cells, cannot be fully explained by the organization of the actin cytoskeleton since it is different in all malignant cells. Our results underline that it is neither the spatial organization of the actin filaments nor the presence of stress fibers, but the overall density and their 3D-organization in a probing volume play the dominant role in controlling the elastic response of the cancerous cell to an external force. PMID:24778971

  19. The softening of human bladder cancer cells happens at an early stage of the malignancy process.

    PubMed

    Ramos, Jorge R; Pabijan, Joanna; Garcia, Ricardo; Lekka, Malgorzata

    2014-01-01

    Various studies have demonstrated that alterations in the deformability of cancerous cells are strongly linked to the actin cytoskeleton. By using atomic force microscopy (AFM), it is possible to determine such changes in a quantitative way in order to distinguish cancerous from non-malignant cells. In the work presented here, the elastic properties of human bladder cells were determined by means of AFM. The measurements show that non-malignant bladder HCV29 cells are stiffer (higher Young's modulus) than cancerous cells (HTB-9, HT1376, and T24 cell lines). However, independently of the histological grade of the studied bladder cancer cells, all cancerous cells possess a similar level of the deformability of about a few kilopascals, significantly lower than non-malignant cells. This underlines the diagnostic character of stiffness that can be used as a biomarker of bladder cancer. Similar stiffness levels, observed for cancerous cells, cannot be fully explained by the organization of the actin cytoskeleton since it is different in all malignant cells. Our results underline that it is neither the spatial organization of the actin filaments nor the presence of stress fibers, but the overall density and their 3D-organization in a probing volume play the dominant role in controlling the elastic response of the cancerous cell to an external force.

  20. Polymorphisms of vitamin D receptor and survival in early-stage non-small cell lung cancer patients.

    PubMed

    Zhou, Wei; Heist, Rebecca S; Liu, Geoffrey; Neuberg, Donna S; Asomaning, Kofi; Su, Li; Wain, John C; Lynch, Thomas J; Giovannucci, Edward; Christiani, David C

    2006-11-01

    Our previous analysis suggested that surgery season in the summer time and high vitamin D intake are associated with improved survival in early-stage non-small cell lung cancer (NSCLC) patients. Here, we investigated the associations of vitamin D receptor (VDR) polymorphisms of Cdx-2 G>A, FokI C>T, and BsmI C>T with overall survival (OS) and recurrence-free survival (RFS) in 373 early-stage NSCLC patients. The data were analyzed using log-rank test and Cox proportional hazards models. The median follow-up time was 71 months (range, 0.1-140 months), with 186 deaths and 127 recurrences. There was no association between VDR polymorphisms and survival, overall or among adenocarcinoma patients. Among squamous cell carcinoma (SCC) patients, the G/A+A/A genotype group of the Cdx-2 polymorphism was associated with better OS: the 5-year OS rates were 41% [95% confidence interval (95% CI), 28-53] for the G/G and 55% (95% CI, 39-71) for the G/A+A/A genotypes, respectively (P = 0.04, log-rank test), with the adjusted hazard ratio of 0.56 (95% CI, 0.33-0.95) for G/A+A/A versus G/G. For the joint effects of the three polymorphisms, subjects with two or more "protective" alleles have better OS among SCC patients, with the adjusted hazard ratios of 0.20 (95% CI, 0.09-0.48), 0.40 (95% CI, 0.19-0.87), and 0.43 (95% CI, 0.19-0.97), respectively, for subjects with two, three, and four or more "protective" alleles when compared with subjects with zero or one "protective" allele (P(trend) = 0.71). Similar associations were found in haplotype analysis and for RFS among SCC patients. In conclusion, VDR polymorphisms may be associated with improved survival among SCC patients of early-stage NSCLC.

  1. Ultrastructure of Fibre and Parenchyma Cell Walls During Early Stages of Culm Development in Dendrocalamus asper

    PubMed Central

    GRITSCH, CRISTINA SANCHIS; MURPHY, RICHARD J.

    2005-01-01

    • Background and Aims The anatomy of bamboo culms and the multilayered structure of fibre cell walls are known to be the main determinant factors for its physical and mechanical properties. Studies on the bamboo cell wall have focussed mainly on fully elongated and mature fibres. The main aim of this study was to describe the ultrastructure of primary and secondary cell walls in culm tissues of Dendrocalamus asper at different stages of development. • Methods The development of fibre and parenchyma tissues was classified into four stages based on light microscopy observations made in tissues from juvenile plants. The stages were used as a basis for transmission electron microscopy study on the ultrastructure of the cell wall during the process of primary and early secondary cell wall formation. Macerations and phloroglucinol–HCl staining were employed to investigate fibre cell elongation and fibre cell wall lignification, respectively. • Key Results The observations indicated that the primary wall is formed by the deposition of two distinct layers during the elongation of the internode and that secondary wall synthesis may begin before the complete cessation of internode and fibre elongation. Elongation was followed by a maturation phase characterized by the deposition of multiple secondary wall layers, which varied in number according to the cell type, location in the culm tissue and stage of shoot development. Lignification of fibre cell walls started at the period prior to the cessation of internode elongation. • Conclusions The structure of the primary cell wall was comprised of two layers. The fibre secondary cell wall began to be laid down while the cells were still undergoing some elongation, suggesting that it may act to cause the slow-down and eventual cessation of cell elongation. PMID:15665037

  2. Second hand smoke exposure and survival in early-stage non-small-cell lung cancer patients.

    PubMed

    Zhou, Wei; Heist, Rebecca S; Liu, Geoffrey; Asomaning, Kofi; Miller, David P; Neuberg, Donna S; Wain, John C; Lynch, Thomas J; Christiani, David C

    2006-12-01

    Second hand smoke (SHS) exposure is associated with higher risk of lung cancer. However, the role of SHS in lung cancer survival is not clear. We examined the association between self-reported SHS exposure before diagnosis and overall survival and recurrence-free survival in 393 early-stage non-small-cell lung cancer patients. SHS exposure was analyzed by both duration and location of exposure using log-rank test and Cox proportional hazard models, adjusting for covariates including pack-years of smoking. The median follow-up time was 66 months (range, 0.2-140 months). There were 135 recurrences and 213 deaths. The 5-year overall survival rates were 71% [95% confidence interval (95% CI), 62-81%], 61% (51-72%), 49% (38-60%), and 47% (37-58%), respectively, for patients with the lowest to highest quartile of SHS exposure durations (P < 0.001, log-rank test), with the adjusted hazard ratio (AHR) of 1.57 (95% CI, 1.02-2.41) for the highest versus lowest quartile of SHS exposure durations (P(trend) = 0.04). For different SHS exposure locations, a stronger association was found for SHS exposure at work (AHR of the highest versus lowest quartile, 1.71; 95% CI, 1.12-2.61; P(trend) = 0.03) than for exposure at home (AHR, 1.26; 95% CI, 0.86-1.86; P(trend) = 0.20) or leisure places (AHR, 1.28; 95% CI, 0.83-1.95; P(trend) = 0.16). Similar associations were observed when SHS exposure durations were dichotomized into two or three groups and between SHS exposure and recurrence-free survival. SHS exposure is associated with worse survival in early-stage non-small-cell lung cancer patients, especially for SHS exposure at the work.

  3. High Expression of KIF20A Is Associated with Poor Overall Survival and Tumor Progression in Early-Stage Cervical Squamous Cell Carcinoma

    PubMed Central

    Gu, Haifeng; Li, Min; Liu, Zhimin; Feng, Yanling; Zheng, Nianzhen; Xie, Chuanmiao; Zhang, Yanna

    2016-01-01

    Background The kinesin family member 20a (KIF20A) protein has been implicated in the development and progression of many human cancers; however, its precise function and role in cervical cancer remain largely unclear. This study aimed to investigate the expression profile and prognostic value of KIF20A in patients with early-stage cervical squamous cell carcinoma. Methods We examined the mRNA and protein levels of KIF20A in eight cervical cancer cell lines and eight paired cervical cancer samples, compared with normal cervical epithelial cells and adjacent normal cervical tissues, respectively. Immunohistochemistry was performed to detect the expression of KIF20A in paraffin-embedded specimens from 169 early-stage cervical squamous cell carcinoma patients. Statistical analyses were applied to analyze the association between KIF20A expression and clinical variables, as well with patient survival. Results The mRNA and protein expression levels of KIF20A were significantly elevated in cervical cancer cell lines and lesions compared with normal cells and corresponding normal tissues (P < 0.05). Immunohistochemistry analysis in 169 cervical cancer cases revealed that increased KIF20A expression was strongly associated with human papillomavirus (HPV) infection (P = 0.008), clinical stage (P = 0.001), tumor recurrence (P = 0.016), vital status (P < 0.001), the property of the surgical margin (P = 0.032), the lymphovascular space involvement (P = 0.014), and pelvic lymph node metastasis (P = 0.001). The overall survival and disease-free survival of patients with high levels of KIF20A expression were significantly poorer than those with low KIF20A expression. KIF20A was an independent survival prognostic factor, as evidenced by univariate and multivariate analysis. Conclusions Our results illustrate that elevated KIF20A expression correlates with HPV infection, clinical stage, tumor recurrence, lymphovascular space involvement, pelvic lymph node metastasis, and poor outcome

  4. Circulating 25-hydroxyvitamin D levels predict survival in early-stage non-small-cell lung cancer patients.

    PubMed

    Zhou, Wei; Heist, Rebecca S; Liu, Geoffrey; Asomaning, Kofi; Neuberg, Donna S; Hollis, Bruce W; Wain, John C; Lynch, Thomas J; Giovannucci, Edward; Su, Li; Christiani, David C

    2007-02-10

    Our previous analyses suggested that surgery in the summertime with higher vitamin D intake is associated with improved survival in patients with early-stage non-small-cell lung cancer (NSCLC). We further investigated the results of circulating 25-hydroxyvitamin D (25[OH]D) levels on overall survival (OS) and recurrence-free survival (RFS) in NSCLC patients. Among 447 patients with early-stage NSCLC, data were analyzed using Cox proportional hazards models, adjusting for age, sex, stage, smoking, and treatment. The median follow-up time was 72 months (range, 0.2 to 141), with 161 recurrences and 234 deaths. For OS, the adjusted hazard ratio (AHR) was 0.74 (95% CI, 0.50 to 1.10; Ptrend = .07) for the highest versus lowest quartile of 25(OH)D levels. Stratified by stage, a strong association was observed among stage IB-IIB patients (AHR, 0.45; 95% CI, 0.24 to 0.82; Ptrend = .002), but not among stage IA patients (AHR, 1.10; 95% CI, 0.62 to 1.96; Ptrend = .53). Similar effects of 25(OH)D levels were observed among the 309 patients with dietary information (AHR, 0.74; 95% CI, 0.46 to 1.17; Ptrend = .19). For the joint effects of 25(OH)D level and vitamin D intake, the combined high 25(OH)D levels and high vitamin D intake (by median) were associated with better survival than the combined low 25(OH)D levels and low vitamin D intake (AHR, 0.64; 95% CI, 0.42 to 0.98; Ptrend = .06). Again, stronger associations were observed among stage IB-IIB than IA patients. Similar effects of 25(OH)D levels and vitamin D intake were observed for RFS. Vitamin D may be associated with improved survival of patients with early-stage NSCLC, particularly among stage IB-IIB patients.

  5. Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer

    PubMed Central

    Eruslanov, Evgeniy B.; Bhojnagarwala, Pratik S.; Quatromoni, Jon G.; Stephen, Tom Li; Ranganathan, Anjana; Deshpande, Charuhas; Akimova, Tatiana; Vachani, Anil; Litzky, Leslie; Hancock, Wayne W.; Conejo-Garcia, José R.; Feldman, Michael; Albelda, Steven M.; Singhal, Sunil

    2014-01-01

    Infiltrating inflammatory cells are highly prevalent within the tumor microenvironment and mediate many processes associated with tumor progression; however, the contribution of specific populations remains unclear. For example, the nature and function of tumor-associated neutrophils (TANs) in the cancer microenvironment is largely unknown. The goal of this study was to provide a phenotypic and functional characterization of TANs in surgically resected lung cancer patients. We found that TANs constituted 5%–25% of cells isolated from the digested human lung tumors. Compared with blood neutrophils, TANs displayed an activated phenotype (CD62LloCD54hi) with a distinct repertoire of chemokine receptors that included CCR5, CCR7, CXCR3, and CXCR4. TANs produced substantial quantities of the proinflammatory factors MCP-1, IL-8, MIP-1α, and IL-6, as well as the antiinflammatory IL-1R antagonist. Functionally, both TANs and neutrophils isolated from distant nonmalignant lung tissue were able to stimulate T cell proliferation and IFN-γ release. Cross-talk between TANs and activated T cells led to substantial upregulation of CD54, CD86, OX40L, and 4-1BBL costimulatory molecules on the neutrophil surface, which bolstered T cell proliferation in a positive-feedback loop. Together our results demonstrate that in the earliest stages of lung cancer, TANs are not immunosuppressive, but rather stimulate T cell responses. PMID:25384214

  6. Endoscopic features of early-stage signet-ring-cell carcinoma of the stomach.

    PubMed

    Phalanusitthepha, Chainarong; Grimes, Kevin L; Ikeda, Haruo; Sato, Hiroki; Sato, Chiaki; Hokierti, Chananya; Inoue, Haruhiro

    2015-06-25

    To identify the features of early signet ring cell gastric carcinoma using magnification endoscopy with narrow band imaging (NBI). A retrospective review was conducted of 12 cases of early signet ring cell gastric carcinoma who underwent treatment in a single institution between January 2009 and April 2013. All patients had magnification endoscopy with NBI and indigo carmine contrast to closely examine the mucosal architecture, including the microvasculature and arrangement of gastric pits. Histologic examination of the final endoscopic submucosal dissection or gastrectomy specimen was performed and compared with the endoscopic findings to identify patterns specific to signet ring cell carcinoma. Twelve patients with early signet ring cell gastric carcinoma were identified; 75% were male, and average age was 61 years. Most of the lesions were stage T1a (83%), while the remainder were T1b (17%). The mean lesion size was 1.4 cm(2). On standard endoscopy, all 12 patients had a pale, flat lesion without any evidence of mucosal abnormality such as ulceration, elevation, or depression. On magnification endoscopy with NBI, all of the patients had irregularities in the glands and microvasculature consistent with early gastric cancer. In addition, all 12 patients exhibited the "stretch sign", an elongation or expansion of the architectural structure. Histologic examination of the resected specimens demonstrated an expanded and edematous mucosal layer infiltrated with tumor cells. The "stretch sign" appears to be specific for signet ring cell carcinoma and may aid in the early diagnosis and treatment of this aggressive pathology.

  7. Calreticulin Release at an Early Stage of Death Modulates the Clearance by Macrophages of Apoptotic Cells

    PubMed Central

    Osman, Rim; Tacnet-Delorme, Pascale; Kleman, Jean-Philippe; Millet, Arnaud; Frachet, Philippe

    2017-01-01

    Calreticulin (CRT) is a well-known “eat-me” signal harbored by dying cells participating in their recognition by phagocytes. CRT is also recognized to deeply impact the immune response to altered self-cells. In this study, we focus on the role of the newly exposed CRT following cell death induction. We show that if CRT increases at the outer face of the plasma membrane and is well recognized by C1q even when phosphatidylserine is not yet detected, CRT is also released in the surrounding milieu and is able to interact with phagocytes. We observed that exogenous CRT is endocytosed by THP1 macrophages through macropinocytosis and that internalization is associated with a particular phenotype characterized by an increase of cell spreading and migration, an upregulation of CD14, an increase of interleukin-8 release, and a decrease of early apoptotic cell uptake. Importantly, CRT-induced pro-inflammatory phenotype was confirmed on human monocytes-derived macrophages by the overexpression of CD40 and CD274, and we found that monocyte-derived macrophages exposed to CRT display a peculiar polarization notably associated with a downregulation of the histocompatibility complex of class II molecules hampering its description through the classical M1/M2 dichotomy. Altogether our results highlight the role of soluble CRT with strong possible consequences on the macrophage-mediated immune response to dying cell. PMID:28878781

  8. Imbalance between apoptosis and cell proliferation during early stages of mammary gland carcinogenesis in ACI rats.

    PubMed

    Kutanzi, Kristy R; Koturbash, Igor; Bronson, Roderick T; Pogribny, Igor P; Kovalchuk, Olga

    2010-12-10

    Estrogen and ionizing radiation are well-documented human breast carcinogens, yet the exact mechanisms of their deleterious effects on mammary gland remain to be discerned. Here we analyze the balance between cellular proliferation and apoptosis in the mammary glands of rats exposed to estrogen and X-ray radiation and the combined action of these carcinogenic agents. For the first time, we show that combined exposure to estrogen and radiation has a synergistic effect on cell proliferation in the mammary glands of ACI rats, as evidenced by a substantially greater magnitude of cell proliferation, especially after 12 and 18 weeks of treatment, when compared to mammary glands of rats exposed to estrogen or radiation alone. We also demonstrate that an imbalance between cell proliferation and apoptosis, rather than enhanced cell proliferation or apoptosis suppression alone, may be a driving force for carcinogenesis. Our studies further suggest that compromised functional activity of p53 may be one of the mechanisms responsible for the proliferation/apoptosis imbalance. In sum, the results of our study indicate that evaluation of the extent of cell proliferation and apoptosis before the onset of preneoplastic lesions may be a potential biomarker of breast cancer risk after exposure to breast carcinogens.

  9. Comparative Effectiveness of Five Treatment Strategies for Early-Stage Non-Small Cell Lung Cancer in the Elderly

    PubMed Central

    Shirvani, Shervin M; Jiang, Jing; Chang, Joe Y; Welsh, James W; Gomez, Daniel R; Swisher, Stephen; Buchholz, Thomas A; Smith, Benjamin D

    2013-01-01

    Purpose Early-stage non-small cell lung cancer (NSCLC) incidence among older adults is expected to increase due to demographic trends and CT-based screening, yet optimal treatment in the elderly remains controversial. Using the SEER-Medicare cohort spanning 2001–2007, we compared survival outcomes associated with five strategies used in contemporary practice: lobectomy, sublobar resection, conventional radiation, stereotactic ablative radiotherapy (SABR) and observation. Methods and Materials Treatment strategy and covariates were determined in 10,923 patients age≥66 with stage IA-IB NSCLC. Cox regression, adjusted for patient and tumor factors, compared overall and disease-specific survival for the five strategies. In a second, exploratory analysis, propensity-score matching was used for comparison of SABR with other options. Results Median age was 75 years and 29% had moderate-to-severe comorbidities. Treatment distribution was lobectomy (59%), sublobar resection (11.7%), conventional radiation (14.8%), observation (12.6%), and SABR (1.1%). In Cox regression with median follow up of 3.2 years, SABR was associated with the lowest risk of death within six months of diagnosis (HR 0.48; 95%CI 0.38–0.63; referent is lobectomy). After six months, lobectomy was associated with the best overall and disease-specific survival. In the propensity-score matched analysis, survival after SABR was similar to lobectomy (HR 0.71; 95%CI 0.45–1.12). Conventional radiation and observation were associated with poor outcomes in all analyses. Conclusions In this population-based experience, lobectomy was associated with the best long-term outcomes in fit elderly patients with early-stage NSCLC. Exploratory analysis of SABR early-adopters suggests efficacy comparable to surgery in select populations. Evaluation of these therapies in randomized trials is urgently needed. PMID:22975611

  10. Guideline for radiotherapy with curative intent in patients with early-stage medically inoperable non-small-cell lung cancer

    PubMed Central

    Falkson, C.B.; Vella, E.T.; Yu, E.; El-Mallah, M.; Mackenzie, R.; Ellis, P.M.; Ung, Y.C.

    2017-01-01

    Objectives For this guideline, we investigated the effectiveness of radiotherapy with curative intent in medically inoperable patients with early-stage non-small-cell lung cancer (nsclc). Methods The guideline was developed by Cancer Care Ontario’s Program in Evidence-Based Care and by the Lung Cancer Disease Site Group through a systematic review of mainly retrospective studies, expert consensus, and formal internal and external reviews. Recommendations ■ Stereotactic body radiation therapy (sbrt) with curative intent is an option that should be considered for patients with early-stage, node-negative, medically inoperable nsclc. Qualifying Statements■ Because of the high dose per fraction, the planning process and treatment delivery for sbrt require the use of advanced technology to maintain an appropriate level of safety. Consistent patient positioning and 4-dimensional analysis of tumour and critical structure motion during simulation and treatment delivery are essential.■ Preliminary results for proton-beam therapy have been promising, but the technique requires further clinical study.■ Recommended fractionation schemes for sbrt should result in a biologically effective dose of 100 or greater by the linear quadric model, choosing an α/β value of 10 [bed10(LQ) ≥ 100]. Qualifying Statements■ Because of the increased risk of treatment-related adverse events associated with centrally located tumours, consideration of tumour size and proximity to critical central structures is required when determining the dose and fractionation.■ Examples of dose–fractionation schemes used in the included studies have been provided.■ Based on the current evidence and the opinion of the authors, radiation doses at bed10(LQ) greater than 146 might significantly increase toxicity and should be avoided.■ Determination of the radiation bed by the linear quadratic model has limitations for the extreme hypofractionated schemes used in sbrt. PMID:28270731

  11. Percutaneous microwave ablation for early-stage non-small cell lung cancer (NSCLC) in the elderly: a promising outlook.

    PubMed

    Acksteiner, Christian; Steinke, Karin

    2015-02-01

    Microwave ablation (MWA) is a relatively new minimally invasive treatment option for lung cancer with substantially lower morbidity and mortality than surgery. This retrospective study was performed to evaluate the safety, effectiveness and follow-up imaging of MWA in the elderly aged 75 years and above. Eleven percutaneous computed tomography (CT)-guided MWA of early-stage non-small cell lung cancer (NSCLC) were performed in 10 patients aged 75 years and older. All but one patient were treated with a high-powered MWA system delivering maximally 140 W. Follow-up with CT and fludeoxyglucose-positron emission tomography (FDG-PET) was carried out over a maximum period of 30 months and a median period of 12 months. There were no peri-procedural deaths or major complications. Seven patients were disease free at the time of manuscript submission. Three patients showed growth of the treated lesions, one patient aged 90 years deceased due to unknown cause after approximately 18 months. One patient presented with local progression and disseminated metastatic disease at 12 months; he is still alive. One patient showed increasing soft tissue at the ablation site 15 months post-treatment. Three consecutive core biopsies over 2 months failed to confirm tumour recurrence. MWA therapy is a promising option of treating early-stage NSCLC in the elderly with good treatment outcome and negligible morbidity. Determining successful treatment outcome may be challenging at times as local tissue increase and PET-CT positivity do not seem to necessarily correlate with reccurrence of malignancy. © 2014 The Royal Australian and New Zealand College of Radiologists.

  12. Carotid-Sparing Intensity-Modulated Radiotherapy for Early-Stage Squamous Cell Carcinoma of the True Vocal Cord

    SciTech Connect

    Chera, Bhishamjit S.; Amdur, Robert J.; Morris, Christopher G.; Mendenhall, William M.

    2010-08-01

    Purpose: To compare radiation doses to carotid arteries among various radiotherapy techniques for treatment of early-stage squamous cell carcinoma (SCC) of the true vocal cords. Methods and Materials: Five patients were simulated using computed tomography (CT). Clinical and planning target volumes (PTV) were created for bilateral and unilateral stage T1 vocal cord cancers. Planning risk volumes for the carotid arteries and spinal cord were delineated. For each patient, three treatment plans were designed for bilateral and unilateral target volumes: opposed laterals (LATS), three-dimensional conformal radiotherapy (3DCRT), and intensity-modulated radiotherapy (IMRT), for a total of 30 plans. More than 95% of the PTV received the prescription dose (63Gy at 2.25 Gy per treatment). Results: Carotid dose was lowest with IMRT. With a bilateral vocal cord target, the median carotid dose was 10Gy with IMRT vs. 25 Gy with 3DCRT and 38 Gy with LATS (p < 0.05); with a unilateral target, the median carotid dose was 4 Gy with IMRT vs. 19 Gy with 3DCRT and 39 Gy with LATS (p < 0.05). The dosimetric tradeoff with IMRT is a small area of high dose in the PTV. The worst heterogeneity results were at a maximum point dose of 80 Gy (127%) in a unilateral target that was close to the carotid. Conclusions: There is no question that IMRT can reduce the dose to the carotid arteries in patients with early-stage vocal cord cancer. The question is whether the potential advantage of reducing the carotid dose outweighs the risk of tumor recurrence due to contouring errors and organ motion and the risk of complications from dose heterogeneity.

  13. Comparative Effectiveness of 5 Treatment Strategies for Early-Stage Non-Small Cell Lung Cancer in the Elderly

    SciTech Connect

    Shirvani, Shervin M.; Jiang, Jing; Chang, Joe Y.; Welsh, James W.; Gomez, Daniel R.; Swisher, Stephen; Buchholz, Thomas A.; Smith, Benjamin D.

    2012-12-01

    Purpose: The incidence of early-stage non-small cell lung cancer (NSCLC) among older adults is expected to increase because of demographic trends and computed tomography-based screening; yet, optimal treatment in the elderly remains controversial. Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort spanning 2001-2007, we compared survival outcomes associated with 5 strategies used in contemporary practice: lobectomy, sublobar resection, conventional radiation therapy, stereotactic ablative radiation therapy (SABR), and observation. Methods and Materials: Treatment strategy and covariates were determined in 10,923 patients aged {>=}66 years with stage IA-IB NSCLC. Cox regression, adjusted for patient and tumor factors, compared overall and disease-specific survival for the 5 strategies. In a second exploratory analysis, propensity-score matching was used for comparison of SABR with other options. Results: The median age was 75 years, and 29% had moderate to severe comorbidities. Treatment distribution was lobectomy (59%), sublobar resection (11.7%), conventional radiation (14.8%), observation (12.6%), and SABR (1.1%). In Cox regression analysis with a median follow-up time of 3.2 years, SABR was associated with the lowest risk of death within 6 months of diagnosis (hazard ratio [HR] 0.48; 95% confidence interval [CI] 0.38-0.63; referent is lobectomy). After 6 months, lobectomy was associated with the best overall and disease-specific survival. In the propensity-score matched analysis, survival after SABR was similar to that after lobectomy (HR 0.71; 95% CI 0.45-1.12; referent is SABR). Conventional radiation and observation were associated with poor outcomes in all analyses. Conclusions: In this population-based experience, lobectomy was associated with the best long-term outcomes in fit elderly patients with early-stage NSCLC. Exploratory analysis of SABR early adopters suggests efficacy comparable with that of surgery in select populations

  14. Influence of pulsed magnetic fields on the morphology of bone cells in early stages of growth.

    PubMed

    Noriega-Luna, Berenice; Sabanero, Myrna; Sosa, Modesto; Avila-Rodriguez, Mario

    2011-08-01

    The effect of electromagnetic fields on living systems has been studied both in vivo and in vitro in a wide range of organisms, cells and tissues. However, the mechanism of action of electromagnetic fields is not yet clearly defined. This paper presents the results of applying a pulsed magnetic field of 70ms width, intensity of 0.65mT at 4Hz in human osteoblasts, during 45min. The magnetic field application was conducted on crops of both 24 and 48h of proliferation. The effect of applying magnetic fields was assessed using parameters such as cell density, protein content, distribution of F-actin fibrils and β-tubulin and integrity of nuclear structure. The results indicate no alteration in either protein synthesis or nuclear structure, or in the number of cells. However, we observed that exposure to these fields induces changes in the distribution of cytoskeletal proteins of osteoblasts. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. Endoscopic features of early-stage signet-ring-cell carcinoma of the stomach

    PubMed Central

    Phalanusitthepha, Chainarong; Grimes, Kevin L; Ikeda, Haruo; Sato, Hiroki; Sato, Chiaki; Hokierti, Chananya; Inoue, Haruhiro

    2015-01-01

    AIM: To identify the features of early signet ring cell gastric carcinoma using magnification endoscopy with narrow band imaging (NBI). METHODS: A retrospective review was conducted of 12 cases of early signet ring cell gastric carcinoma who underwent treatment in a single institution between January 2009 and April 2013. All patients had magnification endoscopy with NBI and indigo carmine contrast to closely examine the mucosal architecture, including the microvasculature and arrangement of gastric pits. Histologic examination of the final endoscopic submucosal dissection or gastrectomy specimen was performed and compared with the endoscopic findings to identify patterns specific to signet ring cell carcinoma. RESULTS: Twelve patients with early signet ring cell gastric carcinoma were identified; 75% were male, and average age was 61 years. Most of the lesions were stage T1a (83%), while the remainder were T1b (17%). The mean lesion size was 1.4 cm2. On standard endoscopy, all 12 patients had a pale, flat lesion without any evidence of mucosal abnormality such as ulceration, elevation, or depression. On magnification endoscopy with NBI, all of the patients had irregularities in the glands and microvasculature consistent with early gastric cancer. In addition, all 12 patients exhibited the “stretch sign”, an elongation or expansion of the architectural structure. Histologic examination of the resected specimens demonstrated an expanded and edematous mucosal layer infiltrated with tumor cells. CONCLUSION: The “stretch sign” appears to be specific for signet ring cell carcinoma and may aid in the early diagnosis and treatment of this aggressive pathology. PMID:26140102

  16. The embryonic midbrain directs neuronal specification of embryonic stem cells at early stages of differentiation.

    PubMed

    Baizabal, José-Manuel; Covarrubias, Luis

    2009-01-01

    Specific neuronal differentiation of Embryonic Stem Cells (ESCs) depends on their capacity to interpret environmental cues. At present, it is not clear at which stage of differentiation ESCs become competent to produce multiple neuronal lineages in response to the niche of the embryonic brain. To unfold the developmental potential of ESC-derived precursors, we transplanted these cells into the embryonic midbrain explants, where neurogenesis occurs as in normal midbrain development. Using this experimental design, we show that the transition from ESCs to Embryoid Body (EB) precursors is necessary to differentiate into Lmx1a(+)/Ptx3(+)/TH(+) dopaminergic neurons around the ventral midline of the midbrain. In addition, EB cells placed at other dorsal-ventral levels of the midbrain give rise to Nkx6.1(+) red nucleus (RN) neurons, Nkx2.2(+) ventral interneurons and Pax7(+) dorsal neurons at the correct positions. Notably, differentiation of ESCs into Neural Precursor Cells (NPCs) prior to transplantation markedly reduces specification at the Lmx1a, Nkx6.1 and Pax7 expression domains, without affecting neuronal differentiation. Finally, exposure to Fgf8 and Shh in vitro promotes commitment of some ESC-derived NPCs to differentiate into putative Lmx1a(+) dopaminergic neurons in the midbrain. Our data demonstrate intrinsic developmental potential differences among ESC-derived precursor populations.

  17. Early stage hot spot analysis through standard cell base random pattern generation

    NASA Astrophysics Data System (ADS)

    Jeon, Joong-Won; Song, Jaewan; Kim, Jeong-Lim; Park, Seongyul; Yang, Seung-Hune; Lee, Sooryong; Kang, Hokyu; Madkour, Kareem; ElManhawy, Wael; Lee, SeungJo; Kwan, Joe

    2017-04-01

    Due to limited availability of DRC clean patterns during the process and RET recipe development, OPC recipes are not tested with high pattern coverage. Various kinds of pattern can help OPC engineer to detect sensitive patterns to lithographic effects. Random pattern generation is needed to secure robust OPC recipe. However, simple random patterns without considering real product layout style can't cover patterning hotspot in production levels. It is not effective to use them for OPC optimization thus it is important to generate random patterns similar to real product patterns. This paper presents a strategy for generating random patterns based on design architecture information and preventing hotspot in early process development stage through a tool called Layout Schema Generator (LSG). Using LSG, we generate standard cell based on random patterns reflecting real design cell structure - fin pitch, gate pitch and cell height. The output standard cells from LSG are applied to an analysis methodology to assess their hotspot severity by assigning a score according to their optical image parameters - NILS, MEEF, %PV band and thus potential hotspots can be defined by determining their ranking. This flow is demonstrated on Samsung 7nm technology optimizing OPC recipe and early enough in the process avoiding using problematic patterns.

  18. Shp2 suppresses the adipogenic differentiation of preadipocyte 3T3-L1 cells at an early stage

    PubMed Central

    Tao, J; Zheng, L; Meng, M; Li, Y; Lu, Z

    2016-01-01

    Tyrosine phosphatase protein Shp2 is a potential therapeutic target for obesity. However, the mechanism of Shp2 during adipogenesis is not fully understood. The present study investigated the role of Shp2 in the terminal differentiation of preadipocytes. The results showed that Shp2 suppressed adipocyte differentiation in 3T3-L1 cells; overexpression of Shp2 reduced lipid droplet production in 3T3-L1 cells, whereas Shp2 knockdown increased lipid droplet production in 3T3-L1 cells. Furthermore, inhibition of Shp2 activity also enhanced adipocyte differentiation. Interestingly, Shp2 expression was specifically decreased early during differentiation in response to stimulation with the dexamethasone–methylisobutylxanthine–insulin (DMI) hormone cocktail. During the first 2 days of differentiation, Shp2 overexpression impaired the DMI-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in 3T3-L1 cells and blocked the peak expression of CCAAT/enhancer-binding proteins β and δ during preadipocyte differentiation. In conclusion, Shp2 downregulated the early stages of hormone-induced differentiation of 3T3-L1 cells and inhibited the expression of the first wave of transcription factors by suppressing the DMI-induced STAT3 signaling pathway. These discoveries point to a novel role of Shp2 during adipogenesis and support the hypothesis that Shp2 could be a therapeutic target for the control of obesity. PMID:27551539

  19. Identification of high-risk human papillomavirus (hrHPV)-associated genes in early stage cervical squamous cell carcinomas.

    PubMed

    Hu, Y; Liu, Y; Liu, C-B; Ling, Z-Q

    2011-01-01

    This retrospective study investigated gene expression in tumour samples from 38 patients with early stage human papillomavirus (HPV)-associated cervical squamous cell carcinoma (CSCC). The patients were divided into two groups based on the presence of viral markers of HPV16 or HPV18 infection. Gene expression profiles of tumour samples and the corresponding normal cervical epithelium were analysed using cDNA microarrays. Several genes showed differential expression between the two groups of HPV-infected CSCC patients, although seven genes showed similar changes in both groups. The four genes encoding cyclin-dependent kinase inhibitor 2A, matrix metallopeptidase 9, laminin γ-1, and epidermal growth factor receptor were up-regulated, and the three genes encoding transforming growth factor β receptor 1, interleukin-1α and insulin-like growth factor-binding protein 6 were down-regulated, in both HPV16(+) and HPV18(+) CSCC. These proteins are involved in cell proliferation, cell structure and cell attachment, so their expression might be involved in the mechanism of HPV-induced carcino genesis. A clearer understanding of HPV type-specific gene expression might aid diagnosis and treatment.

  20. Hematopoietic cell crisis: An early stage of evolving myeloid leukemia following radiation exposure

    SciTech Connect

    Seed, T.M.

    1990-01-01

    Under select radiological conditions, chronic radiation exposure elicits a high incidence of myeloproliferative disease, principally myeloid leukemia (ML), in beagles. Previously we demonstrated that for full ML expression, a four-stage preclinical sequence is required, namely (1) suppression, (2) recovery, (3) accommodation, and (4) preleukemic transition. Within this pathological sequence, a critical early event has been identified as the acquisition of radioresistance by hematopoietic progenitors that serves to mediate a newfound regenerative hematopoietic capacity. As such, this event sets the stage'' for preleukemic progression by initiating progression from preclinical phase 1 to 2. Due to the nature of target cell suppression, the induction of crisis, and the outgrowth of progenitors with altered phenotypes, this preleukemic event resembles the immortalization'' step of the in vitro transformation sequence following induction with either physical and chemical carcinogens. The radiological, temporal, and biological dictates governing this event have been extensively evaluated and will be discussed in light of their role in the induction and progression of chronic radiation leukemia. 35 refs., 2 tabs.

  1. Anti-tumor immune response in early stage non small cell lung cancer (NSCLC): implications for adjuvant therapy

    PubMed Central

    2013-01-01

    The demonstration that systemic chemotherapy improves survival in patients who have had resection of early stage non-small cell lung cancer (NSCLC) represents a significant advance. The absolute benefit of adjuvant chemotherapy in this setting is small with an overall survival improvement of 5%. In addition, there are many patients who have contraindications to cisplatin-based adjuvant therapy. Adjuvant chemotherapy is intended to target systemic micrometastases that remain after primary resection. The observation that cancers can relapse months or years after initial surgery implies that the residual micrometastases exist in a latent or dormant state. The concept of tumor dormancy offers therapeutic potential through induction or maintenance of the dormant state in disseminated tumor cells or through eradication of these dormant cells. Cancer dormancy is a complex process with multiple potential mechanisms. This review will focus on some of the evidence for immune related tumor dormancy and the potential for immune therapies to improve outcomes in the adjuvant setting in NSCLC. PMID:25806261

  2. Ptaquiloside-induced, B-cell lymphoproliferative and early-stage urothelial lesions in mice.

    PubMed

    Gil da Costa, Rui M; Oliveira, Paula A; Vilanova, Manuel; Bastos, Margarida M S M; Lopes, Célia C; Lopes, Carlos

    2011-11-01

    Bracken (Pteridium aquilinum) has long been known to cause cancer in farm and laboratory animals. Ptaquiloside, a norsesquiterpene glycoside found in bracken, is considered its main carcinogenic toxin and is capable of inducing tumours in a variety of organ systems, but especially in the urinary bladder, depending on the animal species, the administration route employed and the duration of exposure. In the present study, 12 male CD-1 mice were intraperitoneally administered with 0.5 mg ptaquiloside weekly for 15 weeks, followed by 15 weeks without any treatment. Twelve animals used as controls were administered the vehicle solution (phosphate buffered saline). Two exposed animals died during the experimental work. On necropsy, blood and tissue samples (brain, eyes, thymus, heart, lungs, liver, digestive system, spleen, bladder, kidney, adrenal gland, urinary bladder, sexual accessory glands, testes, muscle, skin and femur) were collected for histological analysis. Leukograms were prepared from blood smears and total WBC counts obtained with a Neubauer chamber. Flow cytometry was used to assess blood T-(CD3(+)) and B-(CD19(+))-lymphocytes, medullary granulocytic (CD11b(+)/Ly-6G(-), CD11b(+)/Ly-6G(+)) and lymphocytic (CD19(+)/IgM(-), CD19+/IgM(+)) populations and thymic lymphoid (CD4(+), CD8(+), CD4(+)/CD8(+)) populations. Lymphoproliferative lesions were analysed immunohistochemically using antibodies against CD45R and CD3. All of the 10 surviving mice developed a lymphoproliferative malignancy. Lymphoproliferative disease was characterized by multifocal B-(CD45(+)/CD3(-))-lymphocytic renal (10/10 animals) and hepatic (2/10 animals) invasion, splenic white pulp hyperplasia (10/10) together with a significant increase in circulating B-(CD19(+))-lymphocytes and the appearance of circulating dysplastic lymphoid cells. Eight out of 10 ptaquiloside-exposed animals developed urothelial dysplasia (six low-grade dysplasia and two high-grade dysplasia). No lesions were

  3. CHD1L Regulated PARP1-Driven Pluripotency and Chromatin Remodeling During the Early-Stage Cell Reprogramming.

    PubMed

    Jiang, Bo-Hua; Chen, Wei-Yi; Li, Hsin-Yang; Chien, Yueh; Chang, Wei-Chao; Hsieh, Pei-Chen; Wu, Ping; Chen, Chieh-Yu; Song, Hui-Yung; Chien, Chian-Shiu; Sung, Yen-Jen; Chiou, Shih-Hwa

    2015-10-01

    PARP1 and poly(ADP-ribosyl)ation (PARylation) have been shown to be essential for the initial steps of cellular reprogramming. However, the mechanism underlying PARP1/PARylation-regulated activation of pluripotency loci remains undetermined. Here, we demonstrate that CHD1L, a DNA helicase, possesses chromatin remodeling activity and interacts with PARP1/PARylation in regulating pluripotency during reprogramming. We found that this interaction is mediated through the interplay of the CHD1L macro-domain and the PAR moiety of PARylated-PARP1. Chromatin immunoprecipitation assays demonstrated the co-occupancy of CHD1L and PARP1 at Pou5f1, Nanog, and Esrrb pluripotency loci. Knockdown of CHD1L significantly blocked the binding activity of PARP1 at pluripotency loci and inhibited the efficiency of PARP1-driven reprogramming. Notably, we found that CHD1L-promoted reprogramming requires both a PARP1-interacting domain and DNA helicase activity, partly contributing to the chromatin-remodeling states of pluripotency loci. Taken together, these results identify CHD1L as a key chromatin remodeler involved in PARP1/PARylation-regulated early-stage reprogramming and pluripotency in stem cells. © 2015 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  4. Prognostic role of PIK3CA mutations of cell-free DNA in early-stage triple negative breast cancer.

    PubMed

    Takeshita, Takashi; Yamamoto, Yutaka; Yamamoto-Ibusuki, Mutsuko; Inao, Toko; Sueta, Aiko; Fujiwara, Saori; Omoto, Yoko; Iwase, Hirotaka

    2015-11-01

    PIK3CA is an oncogene that encodes the p110α component of phosphatidylinositol 3-kinase (PI3K); it is the second most frequently mutated gene following the TP53 gene. In the clinical setting, PIK3CA mutations may have favorable prognostic value for hormone receptor-positive breast cancer patients and, during the past few years, PIK3CA mutations of cell-free DNA (cfDNA) have attracted attention as a potential noninvasive biomarker of cancer. However, there are few reports on the clinical implications of PIK3CA mutations for TNBC patients. We investigated the PIK3CA major mutation status of cfDNA as a noninvasive biomarker of cancer using droplet digital polymerase chain reaction (ddPCR), which has high level sensitivity and specificity for cancer mutation, in early-stage 49 triple negative breast cancer (TNBC) patients. A total of 12 (24.4%) of 49 patients had PIK3CA mutations of cfDNA. In a median follow up of 54.4 months, the presence of PIK3CA mutations of cfDNA had significant impacts on relapse-free survival (RFS; P = 0.0072) and breast cancer-specific survival (BCSS; P = 0.016), according to the log-lank test. In a Cox proportional hazards model, the presence of PIK3CA mutations of cfDNA had significant prognostic value in the univariate and multivariate analysis. Additionally, the presence of PIK3CA mutations of cfDNA was significantly correlated with positive androgen receptor phosphorylated form depending on PI3K signaling pathway (pAR) which is independent favorable prognostic factors of TNBC. We demonstrated that the presence of PIK3CA major mutations of cfDNA could be a discriminatory predictor of RFS and BCSS in early-stage TNBC patients and it was associated with PI3K pathway-dependent AR phosphorylation. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  5. Comparative effectiveness of 5 treatment strategies for early-stage non-small cell lung cancer in the elderly.

    PubMed

    Shirvani, Shervin M; Jiang, Jing; Chang, Joe Y; Welsh, James W; Gomez, Daniel R; Swisher, Stephen; Buchholz, Thomas A; Smith, Benjamin D

    2012-12-01

    The incidence of early-stage non-small cell lung cancer (NSCLC) among older adults is expected to increase because of demographic trends and computed tomography-based screening; yet, optimal treatment in the elderly remains controversial. Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort spanning 2001-2007, we compared survival outcomes associated with 5 strategies used in contemporary practice: lobectomy, sublobar resection, conventional radiation therapy, stereotactic ablative radiation therapy (SABR), and observation. Treatment strategy and covariates were determined in 10,923 patients aged ≥ 66 years with stage IA-IB NSCLC. Cox regression, adjusted for patient and tumor factors, compared overall and disease-specific survival for the 5 strategies. In a second exploratory analysis, propensity-score matching was used for comparison of SABR with other options. The median age was 75 years, and 29% had moderate to severe comorbidities. Treatment distribution was lobectomy (59%), sublobar resection (11.7%), conventional radiation (14.8%), observation (12.6%), and SABR (1.1%). In Cox regression analysis with a median follow-up time of 3.2 years, SABR was associated with the lowest risk of death within 6 months of diagnosis (hazard ratio [HR] 0.48; 95% confidence interval [CI] 0.38-0.63; referent is lobectomy). After 6 months, lobectomy was associated with the best overall and disease-specific survival. In the propensity-score matched analysis, survival after SABR was similar to that after lobectomy (HR 0.71; 95% CI 0.45-1.12; referent is SABR). Conventional radiation and observation were associated with poor outcomes in all analyses. In this population-based experience, lobectomy was associated with the best long-term outcomes in fit elderly patients with early-stage NSCLC. Exploratory analysis of SABR early adopters suggests efficacy comparable with that of surgery in select populations. Evaluation of these therapies in randomized trials

  6. Early stages of functional diversification in the Rab GTPase gene family revealed by genomic and localization studies in Paramecium species.

    PubMed

    Bright, Lydia J; Gout, Jean-Francois; Lynch, Michael

    2017-04-15

    New gene functions arise within existing gene families as a result of gene duplication and subsequent diversification. To gain insight into the steps that led to the functional diversification of paralogues, we tracked duplicate retention patterns, expression-level divergence, and subcellular markers of functional diversification in the Rab GTPase gene family in three Paramecium aurelia species. After whole-genome duplication, Rab GTPase duplicates are more highly retained than other genes in the genome but appear to be diverging more rapidly in expression levels, consistent with early steps in functional diversification. However, by localizing specific Rab proteins in Paramecium cells, we found that paralogues from the two most recent whole-genome duplications had virtually identical localization patterns, and that less closely related paralogues showed evidence of both conservation and diversification. The functionally conserved paralogues appear to target to compartments associated with both endocytic and phagocytic recycling functions, confirming evolutionary and functional links between the two pathways in a divergent eukaryotic lineage. Because the functionally diversifying paralogues are still closely related to and derived from a clade of functionally conserved Rab11 genes, we were able to pinpoint three specific amino acid residues that may be driving the change in the localization and thus the function in these proteins. © 2017 Bright et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  7. Early stages of functional diversification in the Rab GTPase gene family revealed by genomic and localization studies in Paramecium species

    PubMed Central

    Bright, Lydia J.; Gout, Jean-Francois; Lynch, Michael

    2017-01-01

    New gene functions arise within existing gene families as a result of gene duplication and subsequent diversification. To gain insight into the steps that led to the functional diversification of paralogues, we tracked duplicate retention patterns, expression-level divergence, and subcellular markers of functional diversification in the Rab GTPase gene family in three Paramecium aurelia species. After whole-genome duplication, Rab GTPase duplicates are more highly retained than other genes in the genome but appear to be diverging more rapidly in expression levels, consistent with early steps in functional diversification. However, by localizing specific Rab proteins in Paramecium cells, we found that paralogues from the two most recent whole-genome duplications had virtually identical localization patterns, and that less closely related paralogues showed evidence of both conservation and diversification. The functionally conserved paralogues appear to target to compartments associated with both endocytic and phagocytic recycling functions, confirming evolutionary and functional links between the two pathways in a divergent eukaryotic lineage. Because the functionally diversifying paralogues are still closely related to and derived from a clade of functionally conserved Rab11 genes, we were able to pinpoint three specific amino acid residues that may be driving the change in the localization and thus the function in these proteins. PMID:28251922

  8. Enoxaparin and rivaroxaban have different effects on human mesenchymal stromal cells in the early stages of bone healing

    PubMed Central

    Fröbel, J.; Prodinger, P. M.; Mrotzek, S. J.; Fischer, J. C.; Zilkens, C.; Bittersohl, B.; Krauspe, R.

    2016-01-01

    Objectives Venous thromboembolism (VTE) is a major potential complication following orthopaedic surgery. Subcutaneously administered enoxaparin has been used as the benchmark to reduce the incidence of VTE. However, concerns have been raised regarding the long-term administration of enoxaparin and its possible negative effects on bone healing and bone density with an increase of the risk of osteoporotic fractures. New oral anticoagulants such as rivaroxaban have recently been introduced, however, there is a lack of information regarding how these drugs affect bone metabolism and post-operative bone healing. Methods We measured the migration and proliferation capacity of mesenchymal stem cells (MSCs) under enoxaparin or rivaroxaban treatment for three consecutive weeks, and evaluated effects on MSC mRNA expression of markers for stress and osteogenic differentiation. Results We demonstrate that enoxaparin, but not rivaroxaban, increases the migration potential of MSCs and increases their cell count in line with elevated mRNA expression of C-X-C chemokine receptor type 4 (CXCR4), tumor necrosis factor alpha (TNFα), and alpha-B-crystallin (CryaB). However, a decrease in early osteogenic markers (insulin-like growth factors 1 and 2 (IGF1, IGF2), bone morphogenetic protein2 (BMP2)) indicated inhibitory effects on MSC differentiation into osteoblasts caused by enoxaparin, but not by rivaroxaban. Conclusions Our findings may explain the adverse effects of enoxaparin treatment on bone healing. Rivaroxaban has no significant impact on MSC metabolism or capacity for osteogenic differentiation in vitro. Cite this article: Dr H. Pilge. Enoxaparin and rivaroxaban have different effects on human mesenchymal stromal cells in the early stages of bone healing. Bone Joint Res 2016;5:95–100. DOI: 10.1302/2046-3758.53.2000595. PMID:26989119

  9. α-Synuclein Protects Against Manganese Neurotoxic Insult During the Early Stages of Exposure in a Dopaminergic Cell Model of Parkinson’s Disease

    PubMed Central

    Harischandra, Dilshan S.; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Arthi; Kanthasamy, Anumantha G.

    2015-01-01

    The pathological role of α-synuclein (α-Syn) aggregation in neurodegeneration is well recognized, but the physiological function of normal α-Syn remains unknown. As α-Syn protein contains multiple divalent metal binding sites, herein we conducted a comprehensive characterization of the role of α-Syn in manganese-induced dopaminergic neurotoxicity. We established transgenic N27 dopaminergic neuronal cells by stably expressing human wild-type α-Syn at normal physiological levels. α-Syn-expressing dopaminergic cells significantly attenuated Mn-induced neurotoxicity for 24-h exposures relative to vector control cells. To further explore cellular mechanisms, we studied the mitochondria-dependent apoptotic pathway. Analysis of a key mitochondrial apoptotic initiator, cytochrome c, revealed that α-Syn significantly reduces the Mn-induced cytochrome c release into cytosol. The downstream caspase cascade, involving caspase-9 and caspase-3 activation, during Mn exposure was also largely attenuated in Mn-treated α-Syn cells in a time-dependent manner. α-Syn cells also showed a dramatic reduction in the Mn-induced proteolytic activation of the pro-apoptotic kinase PKCδ. The generation of Mn-induced reactive oxygen species (ROS) did not differ between α-Syn and vector control cells, indicating that α-Syn exerts its protective effect independent of altering ROS generation. Inductively coupled plasma-mass spectrometry (ICP-MS) revealed no significant differences in intracellular Mn levels between treated vector and α-Syn cells. Notably, the expression of wild-type α-Syn in primary mesencephalic cells also rescued cells from Mn-induced neurotoxicity. However, prolonged exposure to Mn promoted protein aggregation in α-Syn-expressing cells. Collectively, these results demonstrate that wild-type α-Syn exhibits neuroprotective effects against Mn-induced neurotoxicity during the early stages of exposure in a dopaminergic neuronal model of PD. PMID:25416158

  10. De Novo Analysis of Wolfiporia cocos Transcriptome to Reveal the Differentially Expressed Carbohydrate-Active Enzymes (CAZymes) Genes During the Early Stage of Sclerotial Growth.

    PubMed

    Zhang, Shaopeng; Hu, Bingxiong; Wei, Wei; Xiong, Ying; Zhu, Wenjun; Peng, Fang; Yu, Yang; Zheng, Yonglian; Chen, Ping

    2016-01-01

    The sclerotium of Wolfiporia cocos has been used as an edible mushroom and/or a traditional herbal medicine for centuries. W. cocos sclerotial formation is dependent on parasitism of the wood of Pinus species. Currently, the sclerotial development mechanisms of W. cocos remain largely unknown and the lack of pine resources limit the commercial production. The CAZymes (carbohydrate-active enzymes) play important roles in degradation of the plant cell wall to provide carbohydrates for fungal growth, development, and reproduction. In this study, the transcript profiles from W. cocos mycelium and 2-months-old sclerotium, the early stage of sclerotial growth, were specially analyzed using de novo sequencing technology. A total of 142,428,180 high-quality reads of mycelium and 70,594,319 high-quality reads of 2-months-old sclerotium were obtained. Additionally, differentially expressed genes from the W. cocos mycelium and 2-months-old sclerotium stages were analyzed, resulting in identification of 69 CAZymes genes which were significantly up-regulated during the early stage of sclerotial growth compared to that of in mycelium stage, and more than half of them belonged to glycosyl hydrolases (GHs) family, indicating the importance of W. cocos GHs family for degrading the pine woods. And qRT-PCR was further used to confirm the expression pattern of these up-regulated CAZymes genes. Our results will provide comprehensive CAZymes genes expression information during W. cocos sclerotial growth at the transcriptional level and will lay a foundation for functional genes studies in this fungus. In addition, our study will also facilitate the efficient use of limited pine resources, which is significant for promoting steady development of Chinese W. cocos industry.

  11. De Novo Analysis of Wolfiporia cocos Transcriptome to Reveal the Differentially Expressed Carbohydrate-Active Enzymes (CAZymes) Genes During the Early Stage of Sclerotial Growth

    PubMed Central

    Zhang, Shaopeng; Hu, Bingxiong; Wei, Wei; Xiong, Ying; Zhu, Wenjun; Peng, Fang; Yu, Yang; Zheng, Yonglian; Chen, Ping

    2016-01-01

    The sclerotium of Wolfiporia cocos has been used as an edible mushroom and/or a traditional herbal medicine for centuries. W. cocos sclerotial formation is dependent on parasitism of the wood of Pinus species. Currently, the sclerotial development mechanisms of W. cocos remain largely unknown and the lack of pine resources limit the commercial production. The CAZymes (carbohydrate-active enzymes) play important roles in degradation of the plant cell wall to provide carbohydrates for fungal growth, development, and reproduction. In this study, the transcript profiles from W. cocos mycelium and 2-months-old sclerotium, the early stage of sclerotial growth, were specially analyzed using de novo sequencing technology. A total of 142,428,180 high-quality reads of mycelium and 70,594,319 high-quality reads of 2-months-old sclerotium were obtained. Additionally, differentially expressed genes from the W. cocos mycelium and 2-months-old sclerotium stages were analyzed, resulting in identification of 69 CAZymes genes which were significantly up-regulated during the early stage of sclerotial growth compared to that of in mycelium stage, and more than half of them belonged to glycosyl hydrolases (GHs) family, indicating the importance of W. cocos GHs family for degrading the pine woods. And qRT-PCR was further used to confirm the expression pattern of these up-regulated CAZymes genes. Our results will provide comprehensive CAZymes genes expression information during W. cocos sclerotial growth at the transcriptional level and will lay a foundation for functional genes studies in this fungus. In addition, our study will also facilitate the efficient use of limited pine resources, which is significant for promoting steady development of Chinese W. cocos industry. PMID:26870032

  12. Genetic characterization drives personalized therapy for early-stage non-small-cell lung cancer (NSCLC) patients and survivors with metachronous second primary tumor (MST)

    PubMed Central

    Ding, Xingchen; Wang, Linlin; Liu, Xijun; Sun, Xindong; Yu, Jinming; Meng, Xue

    2017-01-01

    Abstract Rationale: The pathogenesis and progression of lung cancer is a complicated process in which many genes take part. But molecular gene testing is typically only performed in advanced-stage non-squamous non-small-cell lung cancer (NSCLC). The value of tyrosine kinase inhibitors (TKI) administration is not widely recognized with respect to early-stage NSCLC. Patient concerns: Here, we present a case of a man, heavy smoker who initially presented with stage IA lung adenocarcinoma (LADC). Three years after a lung lobectomy, he was diagnosed with advanced lung squamous cell carcinoma (SCC), according to laboratory, imaging, and pathological examinations. Diagnoses The case initially had an early-stage LADC with an L858R epidermal growth factor receptor (EGFR) mutation. A subsequent advanced SCC bearing EGFR L858R/T790M mutations occurred 3 years after surgery. Interventions: The comprehensive therapy we utilized, including surgical resection for the early-stage lesion and GP chemotherapy and local radiotherapy as the first line therapy along with gefitinib maintenance treatment for the advanced metachronous second primary tumors (MST). Outcomes: The synthetical therapy, have resulted in our patient with remaining alive and progression free for 4.5 years. Lessons: This case suggests that changes in molecular pathology should be monitored closely throughout cancer progression to guide personalized therapy and improve prognosis. We further review administration of TKI to early-stage NSCLC and to the metachronous second primary tumors (MST) in survivors. PMID:28272214

  13. ALCHEMIST Trials: A Golden Opportunity to Transform Outcomes in Early-Stage Non-Small Cell Lung Cancer.

    PubMed

    Govindan, Ramaswamy; Mandrekar, Sumithra J; Gerber, David E; Oxnard, Geoffrey R; Dahlberg, Suzanne E; Chaft, Jamie; Malik, Shakun; Mooney, Margaret; Abrams, Jeffrey S; Jänne, Pasi A; Gandara, David R; Ramalingam, Suresh S; Vokes, Everett E

    2015-12-15

    The treatment of patients with metastatic non-small cell lung cancer (NSCLC) is slowly evolving from empirical cytotoxic chemotherapy to personalized treatment based on specific molecular alterations. Despite this 10-year evolution, targeted therapies have not been studied adequately in patients with resected NSCLC who have clearly defined actionable mutations. The advent of next-generation sequencing has now made it possible to characterize genomic alterations in unprecedented detail. The efforts begun by The Cancer Genome Atlas project to understand the complexities of the genomic landscape of lung cancer will be supplemented further by studying a large number of tumor specimens. The Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST) is an NCI-sponsored national clinical trials network (NCTN) initiative to address the needs to refine therapy for early-stage NSCLC. This program will screen several thousand patients with operable lung adenocarcinoma to determine whether their tumors contain specific molecular alterations [epidermal growth factor receptor mutation (EGFR) and anaplastic lymphoma kinase rearrangement (ALK)], making them eligible for treatment trials that target these alterations. Patients with EGFR mutation or ALK gene rearrangement in their tumor will be randomized to placebo versus erlotinib or crizotinib, respectively, after completion of their standard adjuvant therapy. ALCHEMIST will also contain a large discovery component that will provide an opportunity to incorporate genomic studies to fully understand the clonal architecture, clonal evolution, and mechanisms of resistance to therapy. In this review, we describe the concept, rationale, and outline of ALCHEMIST and the plan for genomic studies in patients with lung adenocarcinoma. Clin Cancer Res; 21(24); 5439-44. ©2015 AACR.

  14. Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: Phase I study

    SciTech Connect

    McGarry, Ronald C. . E-mail: rmcgarry@iupui.edu; Papiez, Lech; Williams, Mark; Whitford, Tia; Timmerman, Robert D.

    2005-11-15

    Purpose: A Phase I dose escalation study of stereotactic body radiation therapy to assess toxicity and local control rates for patients with medically inoperable Stage I lung cancer. Methods and Materials: All patients had non-small-cell lung carcinoma, Stage T1a or T1b N0, M0. Patients were immobilized in a stereotactic body frame and treated in escalating doses of radiotherapy beginning at 24 Gy total (3 x 8 Gy fractions) using 7-10 beams. Cohorts were dose escalated by 6.0 Gy total with appropriate observation periods. Results: The maximum tolerated dose was not achieved in the T1 stratum (maximum dose = 60 Gy), but within the T2 stratum, the maximum tolerated dose was realized at 72 Gy for tumors larger than 5 cm. Dose-limiting toxicity included predominantly bronchitis, pericardial effusion, hypoxia, and pneumonitis. Local failure occurred in 4/19 T1 and 6/28 T2 patients. Nine local failures occurred at doses {<=}16 Gy and only 1 at higher doses. Local failures occurred between 3 and 31 months from treatment. Within the T1 group, 5 patients had distant or regional recurrence as an isolated event, whereas 3 patients had both distant and regional recurrence. Within the T2 group, 2 patients had solitary regional recurrences, and the 4 patients who failed distantly also failed regionally. Conclusions: Stereotactic body radiation therapy seems to be a safe, effective means of treating early-stage lung cancer in medically inoperable patients. Excellent local control was achieved at higher dose cohorts with apparent dose-limiting toxicities in patients with larger tumors.

  15. Shikonin suppresses ERK 1/2 phosphorylation during the early stages of adipocyte differentiation in 3T3-L1 cells

    PubMed Central

    2013-01-01

    Background The naphthoquinone pigment, shikonin, is a major component of Lithospermum erythrorhizon and has been shown to have various biological functions, including antimicrobial, anti-inflammatory, and antitumor effects. In this study, we investigated the effect of shikonin on adipocyte differentiation and its mechanism of action in 3T3-L1 cells. Methods To investigate the effects of shikonin on adipocyte differentiation, 3T3-L1 cells were induced to differentiate using 3-isobutyl-1-methylzanthine, dexamethasone, and insulin (MDI) for 8 days in the presence of 0–2 μM shikonin. Oil Red O staining was performed to determine the lipid accumulation in 3T3-L1 cells. To elucidate the anti-adipogenic mechanism of shikonin, adipogenic transcription factors, the phosphorylation levels of ERK, and adipogenic gene expression were analyzed by Western blotting and quantitative real-time PCR. To further confirm that shikonin inhibits adipogenic differentiation through downregulation of ERK 1/2 activity, 3T3-L1 cells were treated with shikonin in the presence of FGF-2, an activator, or PD98059, an inhibitor, of the ERK1/2 signaling pathway. Results Shikonin effectively suppressed adipogenesis and downregulated the protein levels of 2 major transcription factors, PPARγ and C/EBPα, as well as the adipocyte specific gene aP2 in a dose-dependent manner. qRT-PCR analysis revealed that shikonin inhibited mRNA expression of adipogenesis-related genes, such as PPARγ, C/EBPα, and aP2. Adipocyte differentiation was mediated by ERK 1/2 phosphorylation, which was confirmed by pretreatment with PD98059 (an ERK 1/2 inhibitor) or FGF-2 (an ERK 1/2 activator). The phosphorylation of ERK1/2 during the early stages of adipogenesis in 3T3-L1 cells was inhibited by shikonin. We also confirmed that FGF-2-stimulated ERK 1/2 activity was attenuated by shikonin. Conclusions These results demonstrate that shikonin inhibits adipogenic differentiation via suppression of the ERK signaling pathway

  16. Survival Advantage With the Addition of Radiation Therapy to Chemotherapy in Early Stage Peripheral T-Cell Lymphoma, Not Otherwise Specified

    SciTech Connect

    Zhang, Xi-Mei; Li, Ye-Xiong; Wang, Wei-Hu; Jin, Jing; Wang, Shu-Lian; Liu, Yue-Ping; Song, Yong-Wen; Fang, Hui; Ren, Hua; Zhou, Li-Qiang; Liu, Xin-Fan; Yu, Zi-Hao

    2013-03-15

    Purpose: Early stage peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is rare. The purpose of this study was to evaluate the outcome of treatment as well as the potential role of radiation therapy in PTCL-NOS. Methods and Materials: Thirty-five patients with early stage PTCL-NOS were included. There were 13 patients with stage I disease and 22 with stage II. All patients except 1 received doxorubicin-based chemotherapy alone (n=13) or a combination of chemotherapy and radiation therapy (CMT) (n=21). Results: The 3-year overall survival (OS) and progression-free survival (PFS) rates for the entire group were 41.3% and 25.7%, respectively. The addition of radiation therapy to chemotherapy significantly improved OS and PFS in early stage PTCL-NOS. The 3-year OS and PFS rates were 49.7% and 33.3% for CMT, compared with 23.1% (P=.042) and 15.4% (P=.035) for chemotherapy alone, respectively. The prognosis for patients who achieved a complete response (CR) was significantly better than that observed in those who did not achieve a CR. Conclusions: Despite the aggressive clinical course of early stage PTCL-NOS, additional radiation therapy has a significant impact on outcome. The integration of local radiation therapy into more effective systemic therapies may further improve survival.

  17. Genetic variants of the Wnt signaling pathway as predictors of recurrence and survival in early-stage non-small cell lung cancer patients.

    PubMed

    Coscio, Angela; Chang, David W; Roth, Jack A; Ye, Yuanqing; Gu, Jian; Yang, Ping; Wu, Xifeng

    2014-06-01

    Early-stage non-small cell lung cancer (NSCLC) is potentially curative. Nevertheless, many patients will show disease recurrence after curative treatment. The Wnt signaling pathway is a developmental and stem cell pathway that plays an important role in tumorigenesis and may affect cancer progression. We hypothesize that genetic variants of the Wnt pathway may influence clinical outcome in early-stage NSCLC patients. We genotyped 441 functional and tagging single nucleotide polymorphisms (SNPs) from 54 genes of the Wnt pathway in 535 early-stage NSCLC patients treated with curative intent therapy including surgery and chemotherapy. For validation, 4 top SNPs were genotyped in 301 early-stage NSCLC patients from the Mayo Clinic. Cox proportional hazard model and combined SNP analyses were performed to identify significant SNPs correlated with recurrence-free and overall survival. Results from discovery group showed a total of 40 SNPs in 20 genes correlated with disease recurrence (P < 0.05). After correction for multiple comparisons, rs2536182 near Wnt16 remained significant (q < 0.1), which was validated in the replication population. Thirty-nine SNPs in 16 genes correlated with overall survival (P < 0.05) in the discovery group, and seven remained significant after multiple comparisons were considered (q < 0.1). In patients receiving surgery-only treatment, rs10898563 of FZD4 gene was associated with both recurrence-free and overall survival. Joint SNP analyses identified predictive markers for recurrence stratified by treatment. Our findings suggest inherited genetic variation in the Wnt signaling pathway may contribute to variable clinical outcomes for patients with early-stage NSCLC. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Neurocognitive Trajectory of Boys Who Received a Hematopoietic Stem Cell Transplant at an Early Stage of Childhood Cerebral Adrenoleukodystrophy.

    PubMed

    Pierpont, Elizabeth I; Eisengart, Julie B; Shanley, Ryan; Nascene, David; Raymond, Gerald V; Shapiro, Elsa G; Ziegler, Rich S; Orchard, Paul J; Miller, Weston P

    2017-06-01

    Untreated childhood cerebral adrenoleukodystrophy (cALD) is a fatal disease associated with progressive cerebral demyelination and rapid, devastating neurologic decline. The standard of care to enhance long-term survival and stabilize cerebral disease is a hematopoietic stem cell transplant (HSCT). Neurologic outcomes are better when HSCT occurs at an earlier stage of cALD, yet there is limited understanding of the neurocognitive trajectory of patients who undergo HSCT. To characterize neurocognitive outcomes of boys with cALD and early-stage cerebral disease who were treated with an allogeneic HSCT and to identify disease- and treatment-related factors associated with long-term functioning. Baseline and follow-up neurocognitive test performance was analyzed for all boys with cALD who received an HSCT at the University of Minnesota between January 1, 1991, and October 20, 2014, and who had a pretransplant magnetic resonance imaging (MRI) severity score of less than 10 (scale range, 0-34; higher scores indicate greater severity). Longitudinal neurocognitive test performance in 4 domains (verbal comprehension, perceptual [visual] reasoning, working memory, and processing speed) were the primary outcome measures. Secondary analysis at the most recent evaluation also included measures of sustained attention, verbal memory, visual-motor integration, and fine motor function. Among the 62 boys in this study (mean [SD] age at transplant, 8.37 [2.80] years; range, 4-16 years), there was a significant association of pretransplant MRI severity and baseline verbal comprehension (r = -0.340; P = .008), perceptual reasoning (r = -0.419; P = .001), and processing speed (r = -0.285; P = .03) scores. Higher pretransplant MRI severity scores were also associated with a steeper decline in neurocognitive functioning during the 5-year follow-up period. Twenty-two of 33 patients (67%) with available long-term follow-up neurocognitive testing had severe impairment

  19. A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands

    PubMed Central

    Qin, Tai; Barron, Lindsey; Xia, Lu; Huang, Haojie; Villarreal, Maria M.; Zwaagstra, John; Collins, Cathy; Yang, Junhua; Zwieb, Christian; Kodali, Ravindra; Hinck, Cynthia S.; Kim, Sun Kyung; Reddick, Robert L.; Shu, Chang; O’Connor-McCourt, Maureen D.; Hinck, Andrew P.; Sun, Lu-Zhe

    2016-01-01

    The effects of transforming growth factor beta (TGF-β) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-β functioning as a tumor suppressor in early stages of disease and as a promoter in later stages. To study in further detail the paradoxical tumor-suppressive and tumor-promoting roles of the TGF-β pathway, we investigated the effect of systemic treatment with a TGF-β inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-β receptor trap, RER, comprised of domains derived from the TGF-β type II and type III receptors. This trap was shown to completely block TβRII binding, to antagonize TGF-β1 and TGF-β3 signaling in cultured epithelial cells at low picomolar concentrations, and it showed equal or better anti-TGF-β activities than a pan TGF-β neutralizing antibody and a TGF-β receptor I kinase inhibitor in various prostate cancer cell lines. Systemic administration of RER inhibited prostate tumor cell proliferation as indicated by reduced Ki67 positive cells and invasion potential of tumor cells in high grade prostatic intraepithelial neoplasia (PIN) lesions in the prostate glands of Pten conditional null mice. These results provide evidence that TGF-β acts as a promoter rather than a suppressor in the relatively early stages of this spontaneous prostate tumorigenesis model. Thus, inhibition of TGF-β signaling in early stages of prostate cancer may be a novel therapeutic strategy to inhibit the progression as well as the metastatic potential in patients with prostate cancer. PMID:27863384

  20. A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands.

    PubMed

    Qin, Tai; Barron, Lindsey; Xia, Lu; Huang, Haojie; Villarreal, Maria M; Zwaagstra, John; Collins, Cathy; Yang, Junhua; Zwieb, Christian; Kodali, Ravindra; Hinck, Cynthia S; Kim, Sun Kyung; Reddick, Robert L; Shu, Chang; O'Connor-McCourt, Maureen D; Hinck, Andrew P; Sun, Lu-Zhe

    2016-12-27

    The effects of transforming growth factor beta (TGF-β) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-β functioning as a tumor suppressor in early stages of disease and as a promoter in later stages. To study in further detail the paradoxical tumor-suppressive and tumor-promoting roles of the TGF-β pathway, we investigated the effect of systemic treatment with a TGF-β inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-β receptor trap, RER, comprised of domains derived from the TGF-β type II and type III receptors. This trap was shown to completely block TβRII binding, to antagonize TGF-β1 and TGF-β3 signaling in cultured epithelial cells at low picomolar concentrations, and it showed equal or better anti-TGF-β activities than a pan TGF-β neutralizing antibody and a TGF-β receptor I kinase inhibitor in various prostate cancer cell lines. Systemic administration of RER inhibited prostate tumor cell proliferation as indicated by reduced Ki67 positive cells and invasion potential of tumor cells in high grade prostatic intraepithelial neoplasia (PIN) lesions in the prostate glands of Pten conditional null mice. These results provide evidence that TGF-β acts as a promoter rather than a suppressor in the relatively early stages of this spontaneous prostate tumorigenesis model. Thus, inhibition of TGF-β signaling in early stages of prostate cancer may be a novel therapeutic strategy to inhibit the progression as well as the metastatic potential in patients with prostate cancer.

  1. IFN-gamma treatment at early stages of influenza virus infection protects mice from death in a NK cell-dependent manner.

    PubMed

    Weiss, Ido D; Wald, Ori; Wald, Hanna; Beider, Katia; Abraham, Michal; Galun, Eithan; Nagler, Arnon; Peled, Amnon

    2010-06-01

    Influenza pandemics are imminent and represent a major world health concern. Since vaccinations are expected to be less efficient in the coming years due to newly emerging influenza virus strains, novel antiviral therapies are urgently needed. Here, we show that influenza-infected mice, capable of clearing the virus in the early stages of infection, failed to control inflammation and death. Sequential administration of Interferon-gamma (IFN-gamma) at early stage of the infection protected infected mice from death in a NK cell-dependent manner. IFN-gamma treatment stimulated NK cell proliferation and function and increased their number in the bone marrow, blood, spleen, and infected lungs, keeping viral clearance intact. In parallel, IFN-gamma treatment significantly reduced the number of T cells and NKT cells in the lungs at the inflammatory phase following infection. Thus, rapidly clearing the virus and reducing inflammation by shaping the cellular and cytokine profiles in the early stages of infection may favorably change the fate of influenza pathogenesis.

  2. Kainic Acid-Induced Golgi Complex Fragmentation/Dispersal Shifts the Proteolysis of Reelin in Primary Rat Neuronal Cells: An In Vitro Model of Early Stage Epilepsy.

    PubMed

    Kaneko, Yuji; Sullivan, Robert; Dailey, Travis; Vale, Fernando L; Tajiri, Naoki; Borlongan, Cesar V

    2016-04-01

    The endoplasmic reticulum-lysosome-Golgi network plays an important role in Reelin glycosylation and its proteolytic processing. Golgi complex fragmentation is associated with the separation of Reelin from this network. Kainic acid (KA) is an excitotoxic agent commonly used to induce epilepsy in rodents. The relationship between KA-induced neuronal damage and Golgi complex fragmentation has not been investigated, leaving a major gap in our understanding of the molecular mechanism underlying the development of pathophysiology in epilepsy. We cultured primary rat cortical neurons eitherin ambient condition (control) or treated with a range of KA doses to reveal whether Golgi complex fragmentation impaired neuronal function. The half-life maximal inhibitory concentration (IC50) value of KA was detected to be approximately 5 μM, whereby at these concentrations, KA impaired neuronal viability, which was closely associated with initial Golgi complex fragmentation and subsequent reduction in both the expression and glycosylation patterns of Reelin. These findings implicate that Golgi complex fragmentation and Reelin dysfunction are key contributors to neuronal cell death in the early stage of epilepsy pathophysiology, thereby representing as novel disease biomarkers, as well as potent therapeutic targets for epilepsy.

  3. Interdisciplinary evidence-based recommendations for the follow-up of early stage seminomatous testicular germ cell cancer patients.

    PubMed

    Souchon, Rainer; Hartmann, Michael; Krege, Susanne; Lorch, Anja; Mayer, Frank; De Santis, Maria; Gillessen, Silke; Beyer, Jörg; Cathomas, Richard

    2011-03-01

    To provide guidance regarding follow-up procedures after initial treatment of early stage testicular seminoma (clinical stages (CS) I-II A/B) based on current published evidence complemented by expert opinion. An interdisciplinary, multinational working group consisting of urologists, medical oncologists, and radiation oncologists analyzed the published evidence regarding follow-up procedures in various stages of seminomatous and nonseminomatous testicular cancers. Focusing on radiooncological aspects, the recommendations contained herein are restricted to early stage seminoma (with radiotherapy being a standard treatment option). In particular, extent, frequency, and duration of imaging at follow-up were analyzed concerning relapse patterns, risk factors, and mode of relapse detection. Active surveillance, adjuvant carboplatin or radiotherapy are equally accepted options for CS I seminoma but they result in different relapse rates and patterns. Usually relapses occur within the first 2(-6) years. Routinely performed follow-up using computerized tomography (CT) after adjuvant treatment yield only low detection rates of recurrences. Therefore, there is no evidence to maintain routine examinations every 3-4 months. After treatment of stage IIA/B, detection rates of relapses or progression identified solely by routinely performed CT during follow-up are low. Considering lifelong cure rates of up to 99% for patients treated for seminoma CS I-IIA/B, the negative impact of unnecessary ionizing radiation exposure has to be considered. The presented recommendations for various follow-up scenarios for early stage seminoma strongly promote the restrictive use of imaging procedures that utilize ionizing radiation (especially CT), due to its potential to induce secondary malignancies.

  4. Direct and Complement Dependent Cytotoxicity in CLL Cells from Patients with High Risk Early Stage Chronic Lymphocytic Leukemia (CLL) Treated with Alemtuzumab and Rituximab

    PubMed Central

    Zent, Clive S.; Secreto, Charla R.; LaPlant, Betsy R.; Bone, Nancy D.; Call, Timothy G.; Shanafelt, Tait D.; Jelinek, Diane F.; Tschumper, Renee C.; Kay, Neil E.

    2008-01-01

    The mechanism of cytotoxicity of alemtuzumab and rituximab in CLL is not well understood. We obtained fresh CLL cells from early stage high risk patients just prior to treatment with alemtuzumab and rituximab to study mechanisms of action and resistance. Alemtuzumab had minimal direct cytotoxicity but caused significant complement dependent cytotoxicity (CDC) although a subpopulation of CLL cells had intrinsic resistance. Rituximab had no direct cytotoxicity and caused minimal CDC in cells from most patients. These data suggest that CDC has a therapeutic role in patients treated with alemtuzumab and that measures to decrease resistance to CDC could increase efficacy. PMID:18584865

  5. “Old people suffer the ravages of the years”: changes of treatments in elderly patients with early stage non-small cell lung cancer

    PubMed Central

    Viti, Andrea; Terzi, Alberto

    2015-01-01

    The increase in life expectancy and the spreading of lung cancer screening led to a further rise of newly detected non-small cell lung cancer (NSCLC) cases. Age, per se, should not be considered a contraindication for treatments in fit patients. Early stage NSCLC is more and more treated with minimally invasive surgery. Stereotactic ablative radiation therapy (SABR) has been developed as an innovative therapy for stage I NSCLC and is now considered a standard treatment option for medically inoperable patients or for patient who refuse operation. Preoperative careful functional evaluations either respiratory or cardiovascular, as well as preoperative staging, are mandatory to pose indication for surgery in elderly. On the other hand, all elderly patients with lung cancer should have some form of assessment of physiologic age. As minimally invasive thoracic surgery has reduced the postoperative morbidity and has led to a decrease in the length of hospital stay, lobectomy remains the treatment of choice for early stage NSCLC in elderly patients. Discussion by experienced multidisciplinary team is the best approach to evaluate the advantages/disadvantages of each treatment modality in elderly patients with early-stage NSCLC. PMID:26207242

  6. Surgery versus stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer: less is not more

    PubMed Central

    Swanson, Scott J.

    2016-01-01

    High level evidence from randomized studies comparing surgery to stereotactic ablative radiotherapy (SABR) is lacking and available retrospective cohort and case control studies are highly variable in how thoroughly they define and stage lung cancer, in how they determine operability, and in the offered surgical approaches to operable lung cancer (open vs. video-assisted). This makes it difficult to compare best radiotherapy and best surgery approaches to treatment and to be confident in conclusions of equipoise between the two modalities. What has become clear from the controversy surrounding surgery versus SABR for early stage lung cancer is the desire to optimize treatment efficacy while minimizing invasiveness and morbidity. This review highlights the ongoing debate in light of these goals. PMID:27195137

  7. Variations in Receipt of Curative-Intent Surgery for Early-Stage Non-Small Cell Lung Cancer (NSCLC) by State.

    PubMed

    Sineshaw, Helmneh M; Wu, Xiao-Cheng; Flanders, W Dana; Osarogiagbon, Raymond Uyiosa; Jemal, Ahmedin

    2016-06-01

    Previous studies reported racial and socioeconomic disparities in receipt of curative-intent surgery for early-stage non-small cell lung cancer (NSCLC) in the United States. We examined variation in receipt of surgery and whether the racial disparity varies by state. Patients in whom stage I or II NSCLC was diagnosed from 2007 to 2011 were identified from 38 state and the District of Columbia population-based cancer registries compiled by the North American Association of Central Cancer Registries. Percentage of patients receiving curative-intent surgery was calculated for each registry. Adjusted risk ratios were generated by using modified Poisson regression to control for sociodemographic (e.g., age, sex, race, insurance) and clinical (e.g., grade, stage) factors. Non-Hispanic (NH) whites and Massachusetts were used as references for comparisons because they had the lowest uninsured rates. In all registries combined, 66.4% of patients with early-stage NSCLC (73,475 of 110,711) received curative-intent surgery. Receipt of curative-intent surgery for early-stage NSCLC varied substantially by state, ranging from 52.2% to 56.1% in Wyoming, Louisiana, and New Mexico to 75.2% to 77.2% in Massachusetts, New Jersey, and Utah. In a multivariable analysis, the likelihood of receiving curative-intent surgery was significantly lower in all but nine states/registries compared with Massachusetts, ranging from 7% lower in California to 25% lower in Wyoming. Receipt of curative-intent surgery for early-stage NSCLC was lower for NH blacks than for NH whites in every state, although statistically significant in Florida and Texas. Receipt of curative-intent surgery for early-stage NSCLC varies substantially across states in the United States, with northeastern states generally showing the highest rates. Further, receipt of treatment appeared to be lower in NH blacks than in NH whites in every state, although statistically significant in Florida and Texas. Copyright © 2016

  8. An analysis of early-stage IL-2 capture times in populations of T cells diffusively interacting in a confined environment.

    PubMed

    Labowsky, M

    2016-12-21

    This numerical analysis examines early-stage Interlukin-2 (IL-2) capture in large populations of secreting T helper (Th) and absorbing T regulatory (Treg) cells in an attempt to provide rational guidelines for when diffusive interactions can affect the Th autocrine cycle, as reflected in capture times. Autocrine and paracrine capture is calculated over a wide range of conditions: the mix of cells in a population; cell size and spacing; antigen activated IL-2 secretion and Th receptor expression rates; receptor dissociation constant; and number of resting Treg receptors. Correlations for quickly estimating IL-2 capture over these conditions are provided. This study suggests that a typical Treg can scavenge a significant amount of IL-2 without affecting autocrine capture by the Th. As a result, Treg influence on autocrine capture is shorter-ranged than previously reported. It is conjectured that high early-stage paracrine relative to autocrine capture leads to faster receptor enhancement for a Treg than a Th. The resulting enhancement time gap is considerably longer and, thus, diffusive suppression more likely, for a weakly- as opposed to strongly-activated Th. The methodology can be extended to later-stage capture to confirm this conjecture and to diffusive interactions in other cell-type populations.

  9. Tumor-targeted SN38 inhibits growth of early stage non-small cell lung cancer (NSCLC) in a KRas/p53 transgenic mouse model.

    PubMed

    Deneka, Alexander Y; Haber, Leora; Kopp, Meghan C; Gaponova, Anna V; Nikonova, Anna S; Golemis, Erica A

    2017-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, with a 5-year survival of only ~16%. Potential strategies to address NSCLC mortality include improvements in early detection and prevention, and development of new therapies suitable for use in patients with early and late stage diagnoses. Controlling the growth of early stage tumors could yield significant clinical benefits for patients with comorbidities that make them poor candidates for surgery: however, many drugs that limit cancer growth are not useful in the setting of long-term use or in comorbid patients, because of associated toxicities. In this study, we explored the use of a recently described small molecule agent, STA-8666, as a potential agent for controlling early stage tumor growth. STA-8666 uses a cleavable linker to merge a tumor-targeting moiety that binds heat shock protein 90 (HSP90) with the cytotoxic chemical SN38, and has been shown to have high efficacy and low toxicity, associated with efficient tumor targeting, in preclinical studies using patient-derived and other xenograft models for pancreatic, bladder, and small cell lung cancer. Using a genetically engineered model of NSCLC arising from induced mutation of KRas and knockout of Trp53, we continuously dosed mice with STA-8666 from immediately after tumor induction for 15 weeks. STA-8666 significantly slowed the rate of tumor growth, and was well tolerated over this extended dosing period. STA-8666 induced DNA damage and apoptosis, and reduced proliferation and phosphorylation of the proliferation-associated protein ERK1/2, selectively in tumor tissue. In contrast, STA-8666 did not affect tumor features, such as degree of vimentin staining, associated with epithelial-mesenchymal transition (EMT), or downregulate tumor expression of HSP90. These data suggest STA-8666 and other similar targeted compounds may be useful additions to control the growth of early stage NSCLC in patient populations.

  10. Single Cell Proteomics Using Frog (Xenopus laevis) Blastomeres Isolated from Early Stage Embryos, Which Form a Geometric Progression in Protein Content.

    PubMed

    Sun, Liangliang; Dubiak, Kyle M; Peuchen, Elizabeth H; Zhang, Zhenbin; Zhu, Guijie; Huber, Paul W; Dovichi, Norman J

    2016-07-05

    Single cell analysis is required to understand cellular heterogeneity in biological systems. We propose that single cells (blastomeres) isolated from early stage invertebrate, amphibian, or fish embryos are ideal model systems for the development of technologies for single cell analysis. For these embryos, although cell cleavage is not exactly symmetric, the content per blastomere decreases roughly by half with each cell division, creating a geometric progression in cellular content. This progression forms a ladder of single-cell targets for the development of successively higher sensitivity instruments. In this manuscript, we performed bottom-up proteomics on single blastomeres isolated by microdissection from 2-, 4-, 8-, 16-, 32-, and 50-cell Xenopus laevis (African clawed frog) embryos. Over 1 400 protein groups were identified in single-run reversed-phase liquid chromatography-electrospray ionization-tandem mass spectrometry from single balstomeres isolated from a 16-cell embryo. When the mass of yolk-free proteins in single blastomeres decreased from ∼0.8 μg (16-cell embryo) to ∼0.2 μg (50-cell embryo), the number of protein group identifications declined from 1 466 to 644. Around 800 protein groups were quantified across four blastomeres isolated from a 16-cell embryo. By comparing the protein expression among different blastomeres, we observed that the blastomere-to-blastomere heterogeneity in 8-, 16-, 32-, and 50-cell embryos increases with development stage, presumably due to cellular differentiation. These results suggest that comprehensive quantitative proteomics on single blastomeres isolated from these early stage embryos can provide valuable insights into cellular differentiation and organ development.

  11. Reduced survival in patients with early-stage non-small-cell lung cancer is associated with high pleural endothelial progenitor cell levels.

    PubMed

    Pirro, Matteo; Cagini, Lucio; Mannarino, Massimo R; Andolfi, Marco; Potenza, Rossella; Paciullo, Francesco; Bianconi, Vanessa; Frangione, Maria Rosaria; Bagaglia, Francesco; Puma, Francesco; Mannarino, Elmo

    2016-12-01

    Endothelial progenitor cells are capable of contributing to neovascularization in tumours. In patients with either malignant or transudative pleural effusion, we tested the presence of pleural endothelial progenitor cells. We also measured the number of endothelial progenitor cells in post-surgery pleural drainage of either patients with early non-small-cell lung cancer or control patients with benign lung disease undergoing pulmonary resection. The prospective influence of post-surgery pleural-drainage endothelial progenitor cells on cancer recurrence/survival was investigated. Pleural endothelial progenitor cell levels were quantified by fluorescence-activated cell sorting analysis in pleural effusion of 15 patients with late-stage non-small-cell lung cancer with pleural involvement and in 15 control patients with congestive heart failure. Also, pleural-drainage endothelial progenitor cells were measured in pleural-drainage fluid 48 h after surgery in 64 patients with early-stage non-small-cell lung cancer and 20 benign lung disease patients undergoing pulmonary resection. Cancer recurrence and survival was evaluated in patients with high pleural-drainage endothelial progenitor cell levels. The number of pleural endothelial progenitor cells was higher in non-small-cell lung cancer pleural effusion than in transudative pleural effusion. Also, pleural-drainage endothelial progenitor cell levels were higher in patients with non-small-cell lung cancer than in patients with benign lung disease undergoing pulmonary resection (P < 0.05). Non-small-cell lung cancer patients with high pleural-drainage endothelial progenitor cell levels had a significantly 4.9 higher rate of cancer recurrence/death than patients with lower pleural-drainage endothelial progenitor cell levels, irrespective of confounders. Endothelial progenitor cells are present in the pleural effusion and are higher in patients with late-stage non-small-cell lung cancer with pleural involvement than in

  12. Recurrence and Survival After Segmentectomy in Patients With Prior Lung Resection for Early-Stage Non-Small Cell Lung Cancer.

    PubMed

    Brown, Lisa M; Louie, Brian E; Jackson, Nicole; Farivar, Alexander S; Aye, Ralph W; Vallières, Eric

    2016-10-01

    Lobectomy is the standard of care for patients with early-stage non-small cell lung cancer (NSCLC). However, the treatment of choice for patients with prior lung resection and a second primary NSCLC has not been established. We compared rates and patterns of recurrence and survival in patients with and without prior lung resection treated by segmentectomy and determined predictors of recurrence. This was a retrospective cohort study of 90 patients who underwent 91 consecutive segmentectomies for early-stage NSCLC between April 2004 and December 2014. Logistic regression was used to determine predictors of recurrence, and Kaplan-Meier curves were used to determine survival. Of the 91 segmentectomies, 21 (23%) had a prior lung cancer resection and 70 (77%) were primary resections. There were 18 recurrences (20%): 9 of 21 (43%) in those with prior lung resection and 9 of 70 (13%) in those without. The 90-day mortality was 0%. The recurrence-free survival and 5-year survival were 61% and 55% in those with prior lung resection (p = 0.09) and 84% and 65% in those without (p = 0.4). Close parenchymal margin and number of lymph nodes examined were significant modifiable predictors of recurrence. Segmentectomy is a reasonable option for patients with early-stage NSCLC who have had a prior lung resection. It results in similar survival but trends toward lower recurrence-free survival compared with patients undergoing primary resection. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  13. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline.

    PubMed

    Videtic, Gregory M M; Donington, Jessica; Giuliani, Meredith; Heinzerling, John; Karas, Tomer Z; Kelsey, Chris R; Lally, Brian E; Latzka, Karen; Lo, Simon S; Moghanaki, Drew; Movsas, Benjamin; Rimner, Andreas; Roach, Michael; Rodrigues, George; Shirvani, Shervin M; Simone, Charles B; Timmerman, Robert; Daly, Megan E

    This guideline presents evidence-based recommendations for stereotactic body radiation therapy (SBRT) in challenging clinical scenarios in early-stage non-small cell lung cancer (NSCLC). The American Society for Radiation Oncology convened a task force to perform a systematic literature review on 4 key questions addressing: (1) application of SBRT to operable patients; (2) appropriate use of SBRT in tumors that are centrally located, large, multifocal, or unbiopsied; (3) individual tailoring of SBRT in "high-risk" clinical scenarios; and (4) SBRT as salvage therapy after recurrence. Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology-approved tools for grading evidence quality and recommendation strength. Although few randomized trials have been completed for SBRT, strong consensus recommendations based on extensive, consistent publications were generated for several questions, including recommendations for fractionation for central tumors and surgery versus SBRT in standard-risk medically operable patients with early-stage NSCLC. Lower quality evidence led to conditional recommendations on use of SBRT for tumors >5 cm, patients with prior pneumonectomy, T3 tumors with chest wall invasion, synchronous multiple primary lung cancer, and as a salvage therapy after prior radiation therapy. These areas of moderate- and low-quality evidence highlight the importance of clinical trial enrollment as well as the role of prospective data registries. SBRT has an important role to play in treating early-stage NSCLC, particularly for medically inoperable patients with limited other treatment options. Shared decision-making with patients should be performed in all cases to ensure the patient understands the risks related to SBRT, the side effects, and the alternative treatments available. Copyright © 2017 American Society for Radiation Oncology. Published by Elsevier Inc. All rights

  14. High-dose-rate Three-dimensional Conformal Radiotherapy Combined with Active Breathing Control for Stereotactic Body Radiotherapy of Early-stage Non-small-cell Lung Cancer.

    PubMed

    Wang, Ruozheng; Yin, Yong; Qin, Yonghui; Yu, Jinming

    2015-12-01

    The purpose of this study was to evaluate the feasibility and benefits of using high-dose-rate three-dimensional conformal radiotherapy (3D-CRT) combined with active breathing control (ABC) for stereotactic body radiotherapy (SBRT) of patients with early-stage non-small-cell lung cancer (NSCLC). Eight patients with early-stage NSCLC underwent CT scans under standard free-breathing (FB) and moderately deep inspiration breath-hold (mDIBH) with ABC. Two high-dose-rate 3D-CRT plans (1000 Mu/min) were designed based on the CT scans with FB and mDIBH. The maximal dose (D1%), minimal dose (D99%), conformity index (CI), and homogeneity index (HI) of the planning target volume (PTV), and dose-volume indices of the organs at risk between each plan were compared. The mean PTV volume decreased from 158.04 cm(3) with FB to 76.90 cm(3) with mDIBH (p < 0.05). When mDIBH was used, increases in the affected lung volume (by 47%), contralateral lung volume (by 55%), and total lung volume (by 50%) were observed compared to FB (p < 0.05). The V5-V40 of the affected lung (Vx represented the percentage volume of organs receiving at least the x Gy), V5-V40 and the mean dose for the total lung, V5-V40 and mean dose of the chest wall, and the maximum dose of the spinal cord were less for mDIBH than FB (p < 0.05). There were no significant differences in CI, HI, D1%, or D99% for the PTV between the plans. In conclusion, high-dose-rate 3D-CRT combined with ABC reduced the radiation dose to the lungs and chest wall without affecting the dose distribution in SBRT of early-stage NSCLC patients.

  15. Does early posttreatment surveillance imaging affect subsequent management following stereotactic body radiation therapy for early-stage non-small cell lung cancer?

    PubMed

    Daly, Megan E; Beckett, Laurel A; Chen, Allen M

    2014-01-01

    Uncertainty exists regarding the optimal surveillance imaging strategy following stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC), particularly with respect to timing. We sought to determine how routine use of early (<6 months) posttreatment imaging affects subsequent management. The records of all patients treated with SBRT between January 2007 and January 2013 for early-stage NSCLC were reviewed. Eligible patients underwent ≥ 1 early (defined as within 6 months following SBRT) surveillance imaging study. Radiographic findings and subsequent diagnostic or therapeutic interventions were identified. Proportions and exact 95% confidence intervals (CI) with early posttreatment surveillance findings and altered treatment were calculated, and cases were examined descriptively. Sixty-two patients with 67 lung tumors underwent 92 early surveillance imaging studies (86 computed tomographic [CT] and 6 positron emission/CT) at a median of 2.1 months (range, 0.1-5.9 months). New lung nodules were identified in 8 patients (13%), leading to a diagnosis of metastatic disease treated with systemic therapy in 2 patients and biopsy proven solitary lung recurrence in 2 patients, both treated successfully with local therapy. Tumor growth meeting Response Evaluation Criteria in Solid Tumors (RECIST) criteria was identified in 1 patient, who was followed with subsequent radiographic regression. In aggregate, the treatment of 4 patients (6.5%, 95% CI 1.7%-15.2%) was altered by early imaging; 2 (3.2%, 95% CI 0.4%-10.8%) with a potentially curative intervention. No predictors for utility of early surveillance were identified. Imaging within 6 months following SBRT for early-stage NSCLC resulted in a definitive intervention in approximately 3% of patients. In the era of cost-effective health care, a first scan at 6 months posttreatment may be adequate for most patients. Larger scale prospective studies are needed to address the optimal

  16. Assessing the Need for Adjuvant Chemotherapy After Stereotactic Body Radiation Therapy in Early-stage Non-small Cell Lung Carcinoma

    PubMed Central

    Bahig, Houda; Filion, Édith; Campeau, Marie-Pierre; Lambert, Louise; Roberge, David; Gorgos, Andrei-Bogdan; Vu, Toni

    2016-01-01

    Purpose Surgery remains the standard treatment for medically operable patients with early-stage non-small cell lung carcinoma (NSCLC). Following surgical resection, adjuvant chemotherapy is recommended for large tumors >4 cm. For unfit patients, stereotactic body radiation therapy (SBRT) has emerged as an excellent alternative to surgery. This study aims to assess patterns of recurrence and discuss the role of chemotherapy after SBRT for NSCLC. Methods We reviewed patients treated with SBRT for primary early-stage NSCLC between 2009 and 2015. Total target doses were between 50 and 60 Gy administered in three to eight fractions. All patients had a staging fluorodeoxyglucose (FDG) positron emission tomography (PET) integrated with computed tomography (CT) scan, and histologic confirmation was obtained whenever possible. Mediastinal staging was performed if lymph node involvement was suspected on CT or PET/CT. Survival outcomes were estimated using the Kaplan-Meier method. Results Among the 559 early-stage NSCLC patients treated with SBRT, 121 patients were stage T2N0. The one-year and three-year overall survival rates were 88% and 70%, respectively, for patients with T2 disease, compared to 95% and 81%, respectively, for the T1 patients (p<0.05). The one-year and three-year local control rates were equal in both groups (98% and 91%, respectively). In T2 patients, 25 (21%) presented a relapse, among which 21 (84%) were nodal or distant. The median survival of T2N0 patients following a relapse was 11 months. Conclusion Lung SBRT provides high local control rates, even for larger tumors. When patients relapse, the majority of them do so at regional or distant sites. These results raise the question as to whether adjuvant treatment should be considered following SBRT for larger tumors.  PMID:28070470

  17. Recurrence Patterns and Second Primary Lung Cancers After Stereotactic Body Radiation Therapy for Early-Stage Non-Small-Cell Lung Cancer: Implications for Surveillance.

    PubMed

    Spratt, Daniel E; Wu, Abraham J; Adeseye, Victoria; Din, Shaun U; Shaikh, Fauzia; Woo, Kaitlin M; Zhang, Zhigang; Foster, Amanda; Rosenzweig, Kenneth E; Gewanter, Richard; Huang, James; Rimner, Andreas

    2016-05-01

    Patients treated with stereotactic body radiation therapy (SBRT) for early-stage non-small-cell lung cancer (NSCLC) are subject to locoregional and distant recurrence, as well as the formation of second primary lung cancers (SPLCs). The optimal surveillance regimen for patients treated with SBRT for early-stage NSCLC remains unclear; we therefore investigated the posttreatment recurrence patterns and development of SPLCs. Three hundred sixty-six patients with pathologically proven inoperable early-stage NSCLC treated with SBRT between 2006 and 2013 were assessed. Patients underwent a computed tomographic (CT) scan of the chest every 3 months during years 1 and 2, every 6 months during years 3 and 4, and annually thereafter. Competing risk analysis was used for all time-to-event analyses. With a median follow-up of 23 months, the 2-year cumulative incidence of local, nodal, and distant treatment failures were 12.2%, 16.1%, and 15.5%, respectively. In patients with disease progression after SBRT (n = 108), 84% (n = 91) of cases occurred within the first 2 years. Five percent (n = 19) of patients experienced SPLCs. The median time to development of an SPLC was 16.5 months (range, 6.5-71.1 months), with 33% (n = 6) of these patients experiencing SPLCs after 2 years. None of the never smokers, but 4% of former tobacco smokers and 15% of current tobacco smokers, experienced an SPLC (P = .005). Close monitoring with routine CT scans within the first 2 years after SBRT is effective in detecting early disease progression. In contrast, the risk for the development of an SPLC remains elevated beyond 2 years, particularly in former and current smokers. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Analysis of GAGE, NY-ESO-1 and SP17 cancer/testis antigen expression in early stage non-small cell lung carcinoma.

    PubMed

    Gjerstorff, Morten F; Pøhl, Mette; Olsen, Karen E; Ditzel, Henrik J

    2013-10-08

    The unique expression pattern and immunogenic properties of cancer/testis antigens make them ideal targets for immunotherapy of cancer. The MAGE-A3 cancer/testis antigen is frequently expressed in non-small cell lung cancer (NSCLC) and vaccination with MAGE-A3 in patients with MAGE-A3-positive NSCLC has shown promising results. However, little is known about the expression of other cancer/testis antigens in NSCLC. In the present study the expression of cancer/testis antigens GAGE, NY-ESO-1 and SP17 was investigated in patients with completely resected, early stage, primary NSCLC. Tumor biopsies from normal lung tissue and from a large cohort (n = 169) of NSCLC patients were examined for GAGE, NY-ESO-1 and SP17 protein expression by immunohistochemical analysis. The expression of these antigens was further matched to clinical and pathological features using univariate cox regression analysis. GAGE and NY-ESO-1 cancer/testis antigens were not expressed in normal lung tissue, while SP17 was expressed in ciliated lung epithelia. The frequency of GAGE, NY-ESO-1 and SP17 expression in NSCLC tumors were 26.0% (44/169), 11.8% (20/169) and 4.7% (8/169), respectively, and 33.1% (56/169) of the tumors expressed at least one of these antigens. In general, the expression of GAGE, NY-ESO-1 and SP17 was not significantly associated with a specific histotype (adenocarcinoma vs. squamous cell carcinoma), but high-level GAGE expression (>50%) was more frequent in squamous cell carcinoma (p = 0.02). Furthermore, the frequency of GAGE expression was demonstrated to be significantly higher in stage II-IIIa than stage I NSCLC (17.0% vs. 35.8%; p = 0.02). Analysis of the relation between tumor expression of GAGE and NY-ESO-1 and survival endpoints revealed no significant associations. Our study demonstrates that GAGE, NY-ESO-1 and SP17 cancer/testis antigens are candidate targets for immunotherapy of NSCLC and further suggest that multi-antigen vaccines may be beneficial.

  19. Impact of cadmium on early stages of flax fibre differentiation: ultrastructural aspects and pectic features of cell walls.

    PubMed

    Douchiche, Olfa; Driouich, Azeddine; Morvan, Claudine

    2011-06-01

    The effect of 0.5mM cadmium (Cd) was studied on the ultrastructural aspects and pectin features of the walls of flax cellulosic fibres when the thickening of secondary wall had just started in the hypocotyl of 10-day old seedlings. As seen by PATAg staining in controls, cell-wall formation displayed two distinct steps, secretion and remodelling, which did not occur simultaneously for all the neighbouring fibres. The inner part of the secondary wall, where the cellulose molecules had just been synthesized, appeared very reactive to PATAg. The outer part, where the cellulose fibrils associated in larger microfibril complexes, became non-reactive to PATAg. Under Cd treatment, we noticed some acceleration of fibre differentiation in terms of fibre number, wall thickness and yield. As revealed by PATAg staining, treated fibres exhibited a disturbed cell-wall texture, indicating a modified adhesion between the matrix polysaccharides and the cellulose microfibrils. The Cd impact on the distribution of highly methylesterified homogalacturonans (recognized by JIM7 antibody) was moderate in the cell junctions and low in the primary wall and outer part of secondary wall. The data meant that no early deesterification occurred in these domains, a behaviour related to the specificity of the CW-II metabolism. No large redistribution of low esterified homogalacturonans (recognized by JIM5 antibody) happened either. In parallel, the amount of uronic acid significantly increased in the so-called H(2)SO(4) cell-wall extract, indicating a Cd impact on pectin structure not detected by JIM5 or JIM7 antibodies.

  20. Squamous cell carcinoma of pancreas: an unusual site of relapse from early-stage lung cancer: 12-month postsurgery

    PubMed Central

    Sharma, Anand; Alfa-Wali, Maryam; Rodriguez-Justo, Manuel; Polychronis, Andreas

    2013-01-01

    A 57-year-old man presented with abdominal pain and backache, weight loss of 10 kg and irregular bowel movements. He was previously diagnosed with Stage IB squamous cell carcinoma of lung and had undergone lobectomy 12 months previously. Investigations including imaging revealed a cystic mass in the body and tail of the pancreas which was biopsied and it was confirmed to be a recurrence of the squamous lung cancer involving the pancreas. He was treated with systemic chemotherapy and has shown a partial response on repeat imaging. This case illustrates a rare and unusual site of relapse in lung cancer after adjuvant therapy and a key message for follow-up surveillance for these patients. PMID:23608858

  1. Endothelial binding of beta toxin to small intestinal mucosal endothelial cells in early stages of experimentally induced Clostridium perfringens type C enteritis in pigs.

    PubMed

    Schumacher, V L; Martel, A; Pasmans, F; Van Immerseel, F; Posthaus, H

    2013-07-01

    Beta toxin (CPB) is known to be an essential virulence factor in the development of lesions of Clostridium perfringens type C enteritis in different animal species. Its target cells and exact mechanism of toxicity have not yet been clearly defined. Here, we evaluate the suitability of a neonatal piglet jejunal loop model to investigate early lesions of C. perfringens type C enteritis. Immunohistochemically, CPB was detected at microvascular endothelial cells in intestinal villi during early and advanced stages of lesions induced by C. perfringens type C. This was first associated with capillary dilatation and subsequently with widespread hemorrhage in affected intestinal segments. CPB was, however, not demonstrated on intestinal epithelial cells. This indicates a tropism of CPB toward endothelial cells and suggests that CPB-induced endothelial damage plays an important role in the early stages of C. perfringens type C enteritis in pigs.

  2. Theobromine inhibits differentiation of 3T3-L1 cells during the early stage of adipogenesis via AMPK and MAPK signaling pathways.

    PubMed

    Jang, Yeon Jeong; Koo, Hyun Jung; Sohn, Eun-Hwa; Kang, Se Chan; Rhee, Dong-Kwon; Pyo, Suhkneung

    2015-07-01

    Obesity is characterized by hypertrophy and/or by the differentiation or adipogenesis of pre-existing adipocytes. In this study, we investigated the inhibitory effects of theobromine, a type of alkaloid in cocoa, on adipocyte differentiation of 3T3-L1 preadipocytes and its mechanisms of action. Theobromine inhibited the accumulation of lipid droplets, the expression of PPARγ and C/EBPα, and the mRNA expression of aP2 and leptin. The inhibition of adipogenic differentiation by theobromine occurred primarily in the early stages of differentiation. In addition, theobromine arrested the cell cycle at the G0/G1 phase and regulated the expressions of CDK2, p27, and p21. Theobromine treatment increased AMPK phosphorylation and knockdown of AMPKα1/α2 prevented the ability of theobromine to inhibit PPARγ expression in the differentiating 3T3-L1 cells. Theobromine reduced the phosphorylation of ERK and JNK. Moreover, the secretion and the mRNA level of TNF-α and IL-6 were inhibited by theobromine treatment. These data suggest that theobromine inhibits adipocyte differentiation during the early stages of adipogenesis by regulating the expression of PPARγ and C/EBPα through the AMPK and ERK/JNK signaling pathways in 3T3-L1 preadipocytes.

  3. Tumor budding correlates with occult cervical lymph node metastasis and poor prognosis in clinical early-stage tongue squamous cell carcinoma.

    PubMed

    Xie, Nan; Wang, Cheng; Liu, Xiqiang; Li, Ruyao; Hou, Jinsong; Chen, Xiaohua; Huang, Hongzhang

    2015-04-01

    Tumor budding has been suggested to be a prognostic factor in various human cancers. However, the prognostic value of tumor budding for early-stage (cT1/2N0) tongue squamous cell carcinoma remains inconclusive. This study analyzed the correlation of tumor budding with the clinicopathologic features, and its prognostic significance for cT1/2N0 stage tongue squamous cell carcinoma. One hundred and ninety-five patients with T1/2 stage tongue squamous cell carcinoma enrolled in the retrospective study. Tumor invasive depth, the intensity of tumor budding, and other clinicopathological features were reviewed. Overall survivals were evaluated by the Kaplan-Meier method. For multivariable analysis, Cox's proportional hazards regression models were performed. The frequency of tumor buds in tongue squamous cell carcinoma is about 85.6% in this study. The intensity of tumor budding showed strong correlations with occult lymph node metastasis (P < 0.05), local relapse (P < 0.01), worse invasive pattern (P < 0.01), and invasive depth (P < 0.05). The invasive depth was significantly associated with T classification (P < 0.01) and lymph node metastasis (P < 0.01). And both high intensity of tumor budding and deeper invasive depth correlated with reduced overall survival. Cox's regression models proved tumor budding to be an independent prognostic factor in clinical early-stage tongue squamous cell carcinoma. Tumor local relapses were also a predictor of tongue squamous cell carcinoma progression. Tumor budding is a frequent event in tongue squamous cell carcinoma. It independently predicted prognosis of patients with T1/2 stage tongue squamous cell carcinoma and may be used for routing pathological diagnosis and the decision of elective lymph node dissection. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Comprehensive dosimetric planning comparison for early-stage, non-small cell lung cancer with SABR: fixed-beam IMRT versus VMAT versus TomoTherapy.

    PubMed

    Xhaferllari, Ilma; El-Sherif, Omar; Gaede, Stewart

    2016-09-01

    Volumetric-modulated arc therapy (VMAT) is emerging as a leading technology in treating early-stage, non-small cell lung cancer (NSCLC) with stereotactic ablative radiotherapy (SABR). However, two other modalities capable of delivering intensity-modulated radiation therapy (IMRT) include fixed-beam and helical TomoTherapy (HT). This study aims to provide an extensive dosimetric comparison among these various IMRT techniques for treating early-stage NSCLC with SABR. Ten early-stage NSCLC patients were retrospectively optimized using three fixed-beam techniques via nine to eleven beams (high and low modulation step-and-shoot (SS), and sliding window (SW)), two VMAT techniques via two partial arcs (SmartArc (SA) and RapidArc (RA)), and three HT techniques via three different fan beam widths (1 cm, 2.5 cm, and 5 cm) for 80 plans total. Fixed-beam and VMAT plans were generated using flattening filter-free beams. SS and SA, HT treatment plans, and SW and RA were optimized using Pinnacle v9.1, Tomoplan v.3.1.1, and Eclipse (Acuros XB v11.3 algorithm), respectively. Dose-volume histogram statistics, dose conformality, and treatment delivery efficiency were analyzed. VMAT treatment plans achieved significantly lower values for contralateral lung V5Gy(p≤0.05) compared to the HT plans, and significantly lower mean lung dose (p<0.006) compared to HT 5 cm treatment plans. In the comparison between the VMAT techniques, a significant reduction in the total monitor units (p=0.05) was found in the SA plans, while a significant decrease was observed in the dose falloff parameter, D2cm, (p=0.05), for the RA treatments. The maximum cord dose was significantly reduced (p=0.017) in grouped RA&SA plans compared to SS. Estimated treatment time was significantly higher for HT and fixed-beam plans compared to RA&SA (p<0.001). Although, a significant difference was not observed in the RA vs. SA (p=0.393). RA&SA outperformed HT in all parameters measured. Despite an increase in dose to the

  5. Comprehensive dosimetric planning comparison for early-stage, non-small cell lung cancer with SABR: fixed-beam IMRT versus VMAT versus TomoTherapy.

    PubMed

    Xhaferllari, Ilma; El-Sherif, Omar; Gaede, Stewart

    2016-09-08

    Volumetric-modulated arc therapy (VMAT) is emerging as a leading technology in treating early-stage, non-small cell lung cancer (NSCLC) with stereotactic ablative radiotherapy (SABR). However, two other modalities capable of deliver-ing intensity-modulated radiation therapy (IMRT) include fixed-beam and helical TomoTherapy (HT). This study aims to provide an extensive dosimetric compari-son among these various IMRT techniques for treating early-stage NSCLC with SABR. Ten early-stage NSCLC patients were retrospectively optimized using three fixed-beam techniques via nine to eleven beams (high and low modulation step-and-shoot (SS), and sliding window (SW)), two VMAT techniques via two partial arcs (SmartArc (SA) and RapidArc (RA)), and three HT techniques via three different fan beam widths (1 cm, 2.5 cm, and 5 cm) for 80 plans total. Fixed-beam and VMAT plans were generated using flattening filter-free beams. SS and SA, HT treatment plans, and SW and RA were optimized using Pinnacle v9.1, Tomoplan v.3.1.1, and Eclipse (Acuros XB v11.3 algorithm), respectively. Dose-volume histogram statistics, dose conformality, and treatment delivery efficiency were analyzed. VMAT treatment plans achieved significantly lower values for contralat-eral lung V5Gy (p ≤ 0.05) compared to the HT plans, and significantly lower mean lung dose (p < 0.006) compared to HT 5 cm treatment plans. In the comparison between the VMAT techniques, a significant reduction in the total monitor units (p = 0.05) was found in the SA plans, while a significant decrease was observed in the dose falloff parameter, D2cm, (p = 0.05), for the RA treatments. The maximum cord dose was significantly reduced (p = 0.017) in grouped RA&SA plans com-pared to SS. Estimated treatment time was significantly higher for HT and fixed-beam plans compared to RA&SA (p < 0.001). Although, a significant difference was not observed in the RA vs. SA (p = 0.393). RA&SA outperformed HT in all parameters measured. Despite an

  6. Lung stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer in the very elderly (≥80years old): Extremely safe and effective.

    PubMed

    Kreinbrink, Paul; Blumenfeld, Philip; Tolekidis, George; Sen, Neilayan; Sher, David; Marwaha, Gaurav

    2017-09-01

    Stereotactic body radiotherapy (SBRT) for early-stage non-small-cell lung cancer (NSCLC) is the standard of care in medically inoperable patients. In very elderly patients, previous studies have shown SBRT to offer excellent local control, though with higher toxicities than in younger populations. We report our institutional experience using SBRT in the definitive management of NSCLC in patients ≥80years old. Using an IRB-approved registry of 158 patients treated with definitive-intent lung SBRT for early-stage NSCLC at our institution between 2010 and 2016, 31 consecutively treated patients ≥80years of age were identified. CTCAEv4 scales were prospectively recorded during follow-ups and utilized for toxicity assessments. Kaplan-Meier estimates were utilized for survival analyses. For the 31 patients (with 34 lesions) included, median age was 83 (R: 80-93), median ECOG performance status was 2 (R: 0-3), and median follow-up was 15.8months (R: 3.1-48.3). Median PTV size was 24.0cm(3) (R: 5.83-62.1cm(3)). Median prescription dose was 54Gy in 3 fractions (R: 50-60Gy in 3-8 fractions). Local control was 100% at 1year and 92.3% at 2years. Median survival was 29.1months. There were no grade 2-5 toxicities. Grade 1 toxicities included: fatigue in 5 patients (16.1%), asymptomatic (radiographic) pneumonitis in 12 (38.7%), and dyspnea in 2 (6.5%). Lung SBRT with a BED of ≥100Gy10 for very elderly patients with NSCLC is extremely safe and effective, with inordinately low toxicity rates (zero grade 2-5 toxicities). With stringent dosimetric parameters and planning guidelines, patients ≥80years remain excellent candidates for full-dose SBRT. SBRT for early-stage NSCLC is the accepted standard of care in medically inoperable patients, though in many very elderly patients, dose is either de-intensified or withheld for concern of toxicity in the setting of advanced age and competing risks. In this study of our very elderly (≥80years old) early-stage NSCLC patients, we

  7. Computed tomography-guided percutaneous microwave ablation of patients 75 years of age and older with early-stage nonsmall cell lung cancer.

    PubMed

    Han, X; Yang, X; Ye, X; Liu, Q; Huang, G; Wang, J; Li, W; Zheng, A; Ni, Y; Men, M

    2015-12-01

    We aimed to assess the clinical outcome of computed tomography (CT)-guided percutaneous microwave ablation (MWA) in patients 75 years of age and older with early stage peripheral nonsmall cell lung cancer (NSCLC). Twenty-eight patients, aged ≥ 75 years, with Stage I and lymph node-negative IIa peripheral NSCLC underwent CT-guided percutaneous MWA in our hospital between July 2007 and March 2015. The overall 1-, 2-, 3-, and 4-year survival rates were estimated using Kaplan-Meier analysis. Adverse events were recorded. The median follow-up time was 22.5 months. The overall median survival time (MST) was 35 months (95% confidence interval [CI] 22.3-47.7 months), and the cancer-specific MST was 41.9 months (95% CI 38.8-49.9 months). The 1-, 2-, 3-, and 4-year overall survival rates were 91.7%, 76.5%, 47.9%, and 47.9%, while the cancer-specific survival rates were 94.7%, 73.9%, 64.7%, and 64.7%, respectively. Median time to local progression was 28.0 months (95% CI 17.7-38.3 months). Major complications were included pneumothorax (21.4%, requiring drainage), pleural effusions (3.6%, requiring drainage), and pulmonary infection (3.6%). CT-guided percutaneous MWA is safe and effective for the treatment of patients 75 years of age and older with medically inoperable early stage peripheral NSCLC.

  8. [Intraoperative methylene blue and (99m)Tc-sulfur colloid isotope tracing for sentinel node mapping in early-stage non-small cell lung cancer].

    PubMed

    Hong, Bin; Shen, Xueyuan; Chen, Jiangyong

    2014-06-01

    To compare the accuracy of intaoperative methylene blue alone and in combination with (99m)Tc-sulfur colloid isotopic tracing for detection of sentinel lymph nodes (SLNs) in early-stage non-small cell lung cancer (NSCLC). Sixty-one patients with operable NSCLC who did not receive previous radiotherapy or chemotherapy were enrolled. Methylene blue and (99m)Tc-sulfur colloid were injected into the subserosal layer adjacent to the tumor, and SLNs were defined as those with blue staining or those containing 3 times more radioactivity than the surrounding tissue detected with a gamma probe. The SLN were removed with systematic lymph node dissection. All the removed lymph nodes were examined histopathologically with HE staining and immunohistochemistry. Methylene blue alone showed a low detection rate (60.0%) and sensitivity (58.33%) for SLNs compared with the combination of methylene blue and isotope tracing (96.15% and 92.86%, respectively). The combination of methylene blue and (99m)Tc-sulfur colloid isotopic tracing allows accurate detection of the SLNs in early-stage NSCLC.

  9. A comparison of treatment modalities for nasal extranodal natural killer/T-cell lymphoma in early stages: The efficacy of CHOP regimen based concurrent chemoradiotherapy.

    PubMed

    Cao, Jianzhong; Lan, Shengmin; Shen, Liuhai; Si, Hongwei; Zhang, Ning; Li, Hongwei; Guo, Ruyuan

    2016-11-25

    This study was designed to evaluate the efficacy of several treatment modalities, including CHOP based concurrent chemoradiotherapy (CCRT), for the patients with stage IE or IIE nasal extranodal NK/T-cell lymphoma (nasal ENKL). The cases were retrieved between 2000 and 2010 (n=94), and were followed to the end of February 2016. The patients were grouped into A (chemotherapy alone; CT alone), B (sequential treatment) and C (CCRT). For those with efficacy evaluation for overall treatment (n=90), CR was attained in 60.0% (18/30), 69.8% (30/43) and 76.5% (13/17) patients in the group A, B and C, respectively. The 5-year OS rate was 35.2%, 41.9% and 70.6% in the group A, B and C, respectively. For patients with early stage diseases (IE and IIE), the ECOG performance status and the Ann Arbor stage were significant prognostic factors for both OS and PFS. Among the stage IE patients, besides the ECOG performance status, three prognostic factors which related to treatments (treatment modalities, efficacy of initial and overall treatment) were significant against OS or PFS. In conclusion, compared to chemotherapy alone and sequential treatment, nasal ENKL patients in early stages, especially stage IE, benefit the most from CHOP based concurrent chemoradiotherapy.

  10. Pretreatment prognostic factors in patients with early-stage (I/II) non-small-cell lung cancer treated with hyperfractionated radiation therapy alone

    SciTech Connect

    Jeremic, Branislav . E-mail: b.jeremic@iaea.org; Milicic, Biljana; Dagovic, Aleksandar; Acimovic, Ljubisa; Milisavljevic, Slobodan

    2006-07-15

    Purpose: To investigate influence of various pretreatment prognostic factors in patients with early stage (I/II) non-small-cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy alone. Patients and Methods: One hundred and sixteen patients were treated with tumor doses of 69.6 Gy, 1.2-Gy, twice-daily fractionation. There were 49 patients with Stage I and 67 patients with Stage II. Eighty patients had Karnofsky performance status (KPS) 90-100 and 95 patients had <5% weight loss. Peripheral tumors were observed in 57 patients. Squamous histology was observed in 70 patients and the majority of patients had concomitant disease (n = 72). Results: The median survival time for all patients was 29 months; 5-year survival was 29%. The median time to local progression and the distant metastasis were not achieved, whereas 5-year local progression-free and distant metastasis-free survivals were 50% and 72%, respectively. Multivariate analysis identified KPS, weight loss, location, histology, and the reason for not undergoing surgery as prognostic factors for survival. KPS, location, and histology influenced local progression-free survival, whereas only KPS and weight loss influenced distant metastasis-free survival. Conclusions: This retrospective analysis identified KPS and weight loss as the most important prognostic factors of outcome in patients with early-stage NSCLC treated with hyperfractionation radiation therapy.

  11. Accumulation of genome-specific transcripts, transcription factors and phytohormonal regulators during early stages of fiber cell development in allotetraploid cotton.

    PubMed

    Samuel Yang, S; Cheung, Foo; Lee, Jinsuk J; Ha, Misook; Wei, Ning E; Sze, Sing-Hoi; Stelly, David M; Thaxton, Peggy; Triplett, Barbara; Town, Christopher D; Jeffrey Chen, Z

    2006-09-01

    Gene expression during the early stages of fiber cell development and in allopolyploid crops is poorly understood. Here we report computational and expression analyses of 32 789 high-quality ESTs derived from Gossypium hirsutum L. Texas Marker-1 (TM-1) immature ovules (GH_TMO). The ESTs were assembled into 8540 unique sequences including 4036 tentative consensus sequences (TCs) and 4504 singletons, representing approximately 15% of the unique sequences in the cotton EST collection. Compared with approximately 178 000 existing ESTs derived from elongating fibers and non-fiber tissues, GH_TMO ESTs showed a significant increase in the percentage of genes encoding putative transcription factors such as MYB and WRKY and genes encoding predicted proteins involved in auxin, brassinosteroid (BR), gibberellic acid (GA), abscisic acid (ABA) and ethylene signaling pathways. Cotton homologs related to MIXTA, MYB5, GL2 and eight genes in the auxin, BR, GA and ethylene pathways were induced during fiber cell initiation but repressed in the naked seed mutant (N1N1) that is impaired in fiber formation. The data agree with the known roles of MYB and WRKY transcription factors in Arabidopsis leaf trichome development and the well-documented phytohormonal effects on fiber cell development in immature cotton ovules cultured in vitro. Moreover, the phytohormonal pathway-related genes were induced prior to the activation of MYB-like genes, suggesting an important role of phytohormones in cell fate determination. Significantly, AA sub-genome ESTs of all functional classifications including cell-cycle control and transcription factor activity were selectively enriched in G. hirsutum L., an allotetraploid derived from polyploidization between AA and DD genome species, a result consistent with the production of long lint fibers in AA genome species. These results suggest general roles for genome-specific, phytohormonal and transcriptional gene regulation during the early stages of fiber

  12. Accumulation of genome-specific transcripts, transcription factors and phytohormonal regulators during early stages of fiber cell development in allotetraploid cotton

    PubMed Central

    Yang, S. Samuel; Cheung, Foo; Lee, Jinsuk J.; Ha, Misook; Wei, Ning E.; Sze, Sing-Hoi; Stelly, David M.; Thaxton, Peggy; Triplett, Barbara; Town, Christopher D.; Chen, Z. Jeffrey

    2015-01-01

    Summary Gene expression during early stages of fiber cell development and in allopolyploid crops is poorly understood. Here we report computational and expression analyses of 32,789 high-quality ESTs derived from Gossypium hirsutum L. Texas Marker-1 (TM1) immature ovules (GH_TMO). The ESTs were assembled into 8,540 unique sequences including 4,036 tentative consensus sequences (TCs) and 4,504 singletons, representing ~15% unique sequences in the cotton EST collection. Compared to ~178,000 existing ESTs derived from elongating fibers and non-fiber tissues, GH_TMO ESTs showed a significant increase in the percentage of the genes encoding putative transcription factors such as MYB and WRKY and the genes encoding predicted proteins involved in auxin, brassinosteroid (BR), gibberellic acid (GA), abscisic acid (ABA) and ethylene signaling pathways. Cotton homologues related to MIXTA, MYB5, GL2 and eight genes in auxin, BR, GA and ethylene pathways were induced during fiber cell initiation but repressed in the naked seed mutant (N1N1) that is impaired in fiber formation. The data agree with the known roles of MYB and WRKY transcription factors in Arabidopsis leaf trichome development and the well-documented phytohormonal effects on fiber cell development in immature cotton ovules cultured in vitro. Moreover, the phytohormone-related genes were induced prior to the activation of MYB-like genes, suggesting an important role of phytohormones in cell fate determination. Significantly, AA subgenome ESTs of all functional classifications including cell cycle control and transcription factor activity were selectively enriched in G. hirsutum L., an allotetraploid derived from polyploidization between AA and DD genome species, a result consistent with the production of long lint fibers in AA genome species. These results suggest general roles for genome-specific, phytohormonal and transcriptional gene regulation during early stages of fiber cell development in cotton

  13. Histological features of bone marrow in paediatric patients during the asymptomatic phase of early-stage Black African sickle cell anaemia.

    PubMed

    Mauriello, Alessandro; Giacobbi, Erica; Saggini, Andrea; Isgrò, Antonella; Facchetti, Simone; Anemona, Lucia

    2017-04-01

    Bone marrow histological features of sickle cell anaemia (SCA) patients during early stages and in the asymptomatic phase of the disease appear an interesting area of study, representing early-stage consequences of SCA with a close relation to its pathophysiology. Unfortunately, this field of research has never been specifically addressed before. Bone marrow biopsies from 26 consecutive Black African SCA patients (M:F=1.6:1; age 2-17 years), free of clinical signs of chronic bone marrow damage, with no recent history of symptomatic vaso-occlusive episodes, and waiting for haematopoietic stem cell transplantation (HSCT), underwent morphological, immunohistochemical and electron microscopy evaluation. Additional comparison with three bone marrow specimens from post-HSCT SCA patients and 10 bone marrow specimens from AS healthy carriers was performed. Bone marrow of SCA patients was normocellular or slighly hypercellular in all cases. Erythroid hyperplasia was a common feature. Myeloid lineage was slightly decreased with normal to slightly diminished neutrophilic granulocytes; CD68 positive monocytic-macrophagic cells appeared slightly increased, with a predominant CD163 positive M2/M(Hb) phenotype. A positive correlation was found between haemoglobin values and number of bone marrow erythroid cells (R(2)=0.15, p=0.05). Intravascular and interstitial clusters of erythroid sickle cells were found in bone marrow of pre-HSCT homozygous SS SCA patients, as well as heterozygous AS healthy carriers, and the single post-HSCT patient matched to an AS health carrier donor. Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

  14. Evaluation of early stage human bone marrow stromal proliferation, cell migration and osteogenic differentiation on μ-MIM structured stainless steel surfaces.

    PubMed

    Bitar, Malak; Benini, Fausta; Brose, Claudia; Friederici, Vera; Imgrund, Philipp; Bruinink, Arie

    2013-05-01

    It is well established that surface topography greatly affect cell-surface interactions. In a recent study we showed that microstructured stainless steel surfaces characterized by the presence of defined hexagonally arranged hemisphere-like structures significantly affected cell architecture (shape and focal adhesion size) of primary human bone mesenchymal stromal cells. This study aimed at further investigating the influence these microstructures (microcline protruding hemispheres) on critical aspects of cell behaviour namely; proliferation, migration and osteogenic differentiation. As with previously reported data, we used primary human bone mesenchymal stromal cells to investigate such effects at an early stage in vitro. Cells of different patients were utilised for cell migration studies. Our data showed that an increase in cell proliferation was exhibited as a function of surface topography (hemispheres). Cell migration velocity also varied as a function of surface topography on patient specific basis and seems to relate to the differentiated state of the seeded cell population (as demonstrated by bALP positivity). Osteogenic differentiation, however, did not exhibit significant variations (both up and down-regulation) as a function of both surface topography and time in culture.

  15. FGFR1, 2 and 3 protein overexpression and molecular aberrations of FGFR3 in early stage non‐small cell lung cancer

    PubMed Central

    Mittempergher, Lorenza; Willems, Stefan M; Bosma, Astrid J; Peters, Dennis DGC; van der Noort, Vincent; Japenga, Eva J; Peeters, Ton; Koole, Koos; Šuštić, Tonći; Blaauwgeers, JL; van Noesel, Carel J; Bernards, René

    2016-01-01

    Abstract This study aimed to determine protein expression levels of fibroblast growth factor receptors (FGFR) 1, 2 and 3 in early stage non‐small cell lung cancer (NSCLC). Additionally, a screen to define the frequency of FGFR3‐TACC3 translocation and FGFR3 amplification was performed. Archived tissues from 653 NSCLC samples (adenocarcinoma (AC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC)) were analysed with immunohistochemistry (IHC) for expression of FGFR1, 2 and 3. Expression levels of FGFR1, 2 and 3 were correlated with clinicopathological features. The presence of FGFR3‐TACC3 translocation was detected by RT‐PCR and FGFR3 amplification was detected by fluorescence in situ hybridization. FGFR1, 2 and 3 proteins were highly expressed in 64 (10.6%), 76 (12.9%) and 20 (3.3%) NSCLC tumour samples, respectively. Protein expression of FGFR1 was significantly related to worse overall survival in NSCLC. Furthermore, FGFR1 protein expression was associated with light smoking and histological subtype (AC), FGFR2 protein expression with female gender, younger age, histological subtype (AC) and lower tumour stage, and FGFR3 protein was significantly overexpressed in tumours of older patients and SCC histology. The FGFR3‐TACC3 fusion was detected in 3.0% (6/200) of NSCLC samples and the FGFR3 gene was amplified in 4.7% of IHC positive NSCLC samples (2/43). FGFR1, 2 and 3 proteins are expressed in a high number of early stage NSCLC and FGFR1 protein expression may serve as a prognostic biomarker. Recurrent translocations and amplifications in FGFR3 can be found in NSCLC. This study shows that FGFR family members are frequently aberrant in NSCLC and could be interesting therapeutic targets for the treatment of NSCLC. PMID:27785367

  16. FGFR1, 2 and 3 protein overexpression and molecular aberrations of FGFR3 in early stage non-small cell lung cancer.

    PubMed

    Theelen, Willemijn Sme; Mittempergher, Lorenza; Willems, Stefan M; Bosma, Astrid J; Peters, Dennis Dgc; van der Noort, Vincent; Japenga, Eva J; Peeters, Ton; Koole, Koos; Šuštić, Tonći; Blaauwgeers, J L; van Noesel, Carel J; Bernards, René; van den Heuvel, Michel M

    2016-10-01

    This study aimed to determine protein expression levels of fibroblast growth factor receptors (FGFR) 1, 2 and 3 in early stage non-small cell lung cancer (NSCLC). Additionally, a screen to define the frequency of FGFR3-TACC3 translocation and FGFR3 amplification was performed. Archived tissues from 653 NSCLC samples (adenocarcinoma (AC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC)) were analysed with immunohistochemistry (IHC) for expression of FGFR1, 2 and 3. Expression levels of FGFR1, 2 and 3 were correlated with clinicopathological features. The presence of FGFR3-TACC3 translocation was detected by RT-PCR and FGFR3 amplification was detected by fluorescence in situ hybridization. FGFR1, 2 and 3 proteins were highly expressed in 64 (10.6%), 76 (12.9%) and 20 (3.3%) NSCLC tumour samples, respectively. Protein expression of FGFR1 was significantly related to worse overall survival in NSCLC. Furthermore, FGFR1 protein expression was associated with light smoking and histological subtype (AC), FGFR2 protein expression with female gender, younger age, histological subtype (AC) and lower tumour stage, and FGFR3 protein was significantly overexpressed in tumours of older patients and SCC histology. The FGFR3-TACC3 fusion was detected in 3.0% (6/200) of NSCLC samples and the FGFR3 gene was amplified in 4.7% of IHC positive NSCLC samples (2/43). FGFR1, 2 and 3 proteins are expressed in a high number of early stage NSCLC and FGFR1 protein expression may serve as a prognostic biomarker. Recurrent translocations and amplifications in FGFR3 can be found in NSCLC. This study shows that FGFR family members are frequently aberrant in NSCLC and could be interesting therapeutic targets for the treatment of NSCLC.

  17. T-cell motility in the early stages of the immune response modeled as a random walk amongst targets

    NASA Astrophysics Data System (ADS)

    Preston, S. P.; Waters, S. L.; Jensen, O. E.; Heaton, P. R.; Pritchard, D. I.

    2006-07-01

    The transport process by which a T cell makes high-frequency encounters with antigen-presenting cells following infection is an important element of adaptive immunity. Recent experimental work has allowed in vivo cell motility to be characterized in detail. On the basis of experimental data we develop a quantitative model for encounters between T cells and antigen-presenting cells. We model this as a transport-limited chemical reaction with the dynamics dependent on physical contact between randomly moving reactants. We use asymptotic methods to calculate a time distribution which characterizes the delay before a T cell is activated and use Monte Carlo simulations to verify the analysis. We find that the density of antigen-primed dendritic cells within the lymph node paracortex must be greater than 35cells/mm3 for a T cell to have a more than 50% chance of encountering a dendritic cell within 24h . This density is much larger than existing estimates based on calculations which neglect the transport process. We also use simulations to compare a T cell which re-orients isotropically with a T cell which turns according to an experimentally observed distribution and find that the effects of anisotropy on the solution are small.

  18. Investigation of the effect of α-melanocyte-stimulating hormone on proliferation and early stages of differentiation of human induced pluripotent stem cells.

    PubMed

    Novosadova, E V; Manuilova, E S; Arsenyeva, E L; Andreeva, L A; Lebedeva, O S; Grivennikov, I A; Myasoedov, N F

    2016-03-01

    We have studied the influence of α-melanocyte-stimulating hormone (α-MSH) on proliferation and early stages of differentiation of human induced pluripotent stem cells (iPSc). We have demonstrated that α-MSH receptor genes are expressed in undifferentiated iPSc. The expression levels of MCR1, MCR2, and MCR3 increased at the embryoid body (EB) formation stage. The formation of neural progenitors was accompanied by elevation of MCR2, MCR3, and MCR4 expression. α-MSH had no effect on EB generation and iPSc proliferation at concentrations ranging from 1 nM to 10 μM. At the same time, α-MSH increased the generation of neural rosettes in human iPSc cultures more than twice.

  19. The New Immortalized Uroepithelial Cell Line HBLAK Contains Defined Genetic Aberrations Typical of Early Stage Urothelial Tumors

    PubMed Central

    Hoffmann, Michèle J.; Koutsogiannouli, Evangelia; Skowron, Margaretha A.; Pinkerneil, Maria; Niegisch, Günter; Brandt, Artur; Stepanow, Stefanie; Rieder, Harald; Schulz, Wolfgang A.

    2016-01-01

    Background: Cell culture models of normal urothelial cells are important for studying differentiation, disease mechanisms and anticancer drug development. Beyond primary cultures with their limitations in lifespan, interindividual heterogeneity and supply, few conditionally immortalized cell lines with limited applicability due to partial transformation or impaired differentiation capacity are available. We describe characteristics of the new spontaneously immortalized cell line HBLAK derived from a primary culture of uroepithelial cells. Objective: To characterize utility and limitations of HBLAK cells as an urothelial cell culture model. Methods: Differentiation markers were investigated by immunofluorescence and RT-PCR, genetic changes by standard karyotyping, array-CGH, PCR, RT-PCR and exome sequencing; expression of p53 and p21 by Western blotting. Results: HBLAK cells proliferated for >50 passages without senescing. They expressed cytokeratins of basal urothelial cells. Terminal differentiation markers appeared only after induction of differentiation by specific protocols. The karyotype was stable, with few chromosomal changes, especially gains of chromosomes 5 and 20 and a chromosome 9p21 deletion resulting in p16INK4A loss. A C228T TERT promoter mutation was present, but no other mutation typical of urothelial carcinoma. TP53 was wild-type and the cell cycle was arrested in response to genomic stress. Conclusions: HBLAK cells retain some differentiation potential and respond to cytotoxic agents similar to normal urothelial cells, but contain genetic changes contributing to immortalization in urothelial tumors. HBLAK may be valuable for evaluating the tumor specificity of novel cancer drugs, but may also be applied as an urothelial in vitro carcinogenesis model. PMID:28035326

  20. Expression of late viral proteins is restricted in nasal mucosal leucocytes but not in epithelial cells during early-stage equine herpes virus-1 infection.

    PubMed

    Gryspeerdt, Annick C; Vandekerckhove, Annelies P; Baghi, Hossein Bannazadeh; Van de Walle, Gerlinde R; Nauwynck, Hans J

    2012-08-01

    Equine herpes virus (EHV)-1 replicates in the epithelial cells of the upper respiratory tract and reaches the lamina propria and bloodstream in infected mononuclear cells. This study evaluated expression of the late viral proteins gB, gC, gD and gM in respiratory epithelial and mononuclear cells using: (1) epithelial-like rabbit kidney cells and peripheral blood mononuclear cells infected with EHV-1 in vitro; (2) an equine ex vivo nasal explant system; and (3) nasal mucosa tissue of ponies infected in vivo. The viral proteins were expressed in all late-infected epithelial cells, whereas expression was not observed in infected leucocytes where proteins gB and gM were expressed in 60-90%, and proteins gC and gD in only 20% of infected cells, respectively. The results indicate that expression of these viral proteins during early-stage EHV-1 infection is highly dependent on the cell type infected.

  1. Cost-effectiveness of a 14-gene risk score assay to target adjuvant chemotherapy in early stage non-squamous non-small cell lung cancer.

    PubMed

    Roth, Joshua A; Billings, Paul; Ramsey, Scott D; Dumanois, Robert; Carlson, Josh J

    2014-05-01

    Life Technologies has developed a 14-gene molecular assay that provides information about the risk of death in early stage non-squamous non-small cell lung cancer patients after surgery. The assay can be used to identify patients at highest risk of mortality, informing subsequent treatments. The objective of this study was to evaluate the cost-effectiveness of this novel assay. Patients and Methods. We developed a Markov model to estimate life expectancy, quality-adjusted life years (QALYs), and costs for testing versus standard care. Risk-group classification was based on assay-validation studies, and chemotherapy uptake was based on pre- and post-testing recommendations from a study of 58 physicians. We evaluated three chemotherapy-benefit scenarios: moderately predictive (base case), nonpredictive (i.e., the same benefit for each risk group), and strongly predictive. We calculated the incremental cost-effectiveness ratio (ICER) and performed one-way and probabilistic sensitivity analyses. Results. In the base case, testing and standard-care strategies resulted in 6.81 and 6.66 life years, 3.76 and 3.68 QALYs, and $122,400 and $118,800 in costs, respectively. The ICER was $23,200 per QALY (stage I: $29,200 per QALY; stage II: $12,200 per QALY). The ICER ranged from "dominant" to $92,100 per QALY in the strongly predictive and nonpredictive scenarios. The model was most sensitive to the proportion of high-risk patients receiving chemotherapy and the high-risk hazard ratio. The 14-gene risk score assay strategy was cost-effective in 68% of simulations. Conclusion. Our results suggest that the 14-gene risk score assay may be a cost-effective alternative to standard guideline-based adjuvant chemotherapy decision making in early stage non-small cell lung cancer.

  2. Calcium-sensing receptor-mediated osteogenic and early-stage neurogenic differentiation in umbilical cord matrix mesenchymal stem cells from a large animal model.

    PubMed

    Martino, Nicola Antonio; Reshkin, Stephan Joel; Ciani, Elena; Dell'Aquila, Maria Elena

    2014-01-01

    Umbilical cord matrix mesenchymal stem cells (UCM-MSCs) present a wide range of potential therapeutical applications. The extracellular calcium-sensing receptor (CaSR) regulates physiological and pathological processes. We investigated, in a large animal model, the involvement of CaSR in triggering osteogenic and neurogenic differentiation of two size-sieved UCM-MSC lines, by using AMG641, a novel potent research calcimimetic acting as CaSR agonist. Large (>8 µm in diameter) and small (<8 µm) equine UCM-MSC lines were cultured in medium with high calcium (Ca2+) concentration ([Ca2+]o; 2.87 mM) and dose-response effects of AMG641 (0.01 to 3µM) on cell proliferation were evaluated. Both cell lines were then cultured in osteogenic or neurogenic differentiation medium containing: 1) low [Ca2+]o (0.37 mM); 2) high [Ca2+]o (2.87 mM); 3) AMG641 (0.05, 0.1 or 1 µM) with high [Ca2+]o and 4) the CaSR antagonist NPS2390 (10 mM for 30 min) followed by incubation with AMG641 in high [Ca2+]o. Expression of osteogenic or neurogenic differentiation biomarkers was compared among groups. In both cell lines, AMG641 dose-dependently increased cell proliferation (up to P<0.001). Osteogenic molecular markers expression was differentially regulated by AMG641, with stimulatory (OPN up-regulation) in large or inhibitory (RUNX2 and OPN down-regulation) effects in small cells, respectively. AMG641 significantly increased alkaline phosphatase activity and calcium phosphate deposition in both cell lines. Following treatment with AMG641 during osteogenic differentiation, in both cell lines CaSR expression was inversely related to that of osteogenic markers and inhibition of CaSR by NPS2390 blocked AMG641-dependent responses. Early-stage neurogenic differentiation was promoted/triggered by AMG641 in both cell lines, as Nestin and CaSR mRNA transcription up-regulation were observed. Calcium- and AMG641-induced CaSR stimulation promoted in vitro proliferation and osteogenic and early-stage

  3. Calcium-Sensing Receptor-Mediated Osteogenic and Early-Stage Neurogenic Differentiation in Umbilical Cord Matrix Mesenchymal Stem Cells from a Large Animal Model

    PubMed Central

    Martino, Nicola Antonio; Reshkin, Stephan Joel; Ciani, Elena; Dell'Aquila, Maria Elena

    2014-01-01

    Background Umbilical cord matrix mesenchymal stem cells (UCM-MSCs) present a wide range of potential therapeutical applications. The extracellular calcium-sensing receptor (CaSR) regulates physiological and pathological processes. We investigated, in a large animal model, the involvement of CaSR in triggering osteogenic and neurogenic differentiation of two size-sieved UCM-MSC lines, by using AMG641, a novel potent research calcimimetic acting as CaSR agonist. Methodology/Principal Findings Large (>8µm in diameter) and small (<8µm) equine UCM-MSC lines were cultured in medium with high calcium (Ca2+) concentration ([Ca2+]o; 2.87 mM) and dose-response effects of AMG641 (0.01 to 3µM) on cell proliferation were evaluated. Both cell lines were then cultured in osteogenic or neurogenic differentiation medium containing: 1) low [Ca2+]o (0.37 mM); 2) high [Ca2+]o (2.87 mM); 3) AMG641 (0.05, 0.1 or 1 µM) with high [Ca2+]o and 4) the CaSR antagonist NPS2390 (10 mM for 30 min) followed by incubation with AMG641 in high [Ca2+]o. Expression of osteogenic or neurogenic differentiation biomarkers was compared among groups. In both cell lines, AMG641 dose-dependently increased cell proliferation (up to P<0.001). Osteogenic molecular markers expression was differentially regulated by AMG641, with stimulatory (OPN up-regulation) in large or inhibitory (RUNX2 and OPN down-regulation) effects in small cells, respectively. AMG641 significantly increased alkaline phosphatase activity and calcium phosphate deposition in both cell lines. Following treatment with AMG641 during osteogenic differentiation, in both cell lines CaSR expression was inversely related to that of osteogenic markers and inhibition of CaSR by NPS2390 blocked AMG641-dependent responses. Early-stage neurogenic differentiation was promoted/triggered by AMG641 in both cell lines, as Nestin and CaSR mRNA transcription up-regulation were observed. Conclusions/Significance Calcium- and AMG641-induced CaSR stimulation

  4. Targeting of Cancer Stem Cells and Their Microenvironment in Early-Stage Mutant K-ras Lung Cancer

    DTIC Science & Technology

    2016-12-01

    Scientist Nearest Person Month Worked 1.4 Contribution to Project: Execution of cell biology and mouse experiments 12 Name: Sahba Kasiri Project Role...Postdoctoral Fellow Nearest Person Month Worked: 9.0 Contribution to Project: Execution of cell biology and mouse experiments Funding Support: NIH T32

  5. Th22 cells as well as Th17 cells expand differentially in patients with early-stage and late-stage myelodysplastic syndrome.

    PubMed

    Shao, Lin-lin; Zhang, Lei; Hou, Yu; Yu, Shuang; Liu, Xin-guang; Huang, Xiao-yang; Sun, Yuan-xin; Tian, Tian; He, Na; Ma, Dao-xin; Peng, Jun; Hou, Ming

    2012-01-01

    Immunological mechanisms are increasingly recognized in the progression of myelodysplastic syndrome (MDS). Early-stage MDS (E-MDS) is characterized by autoimmune-mediated myelosuppression whereas late-stage MDS (L-MDS) involves immune evasion, giving dysplastic cells growth potential to progress into acute myeloid leukemia. T-helper (Th) 22 is involved in the pathogenesis of inflammatory autoimmunity and tumorigenesis. The roles of Th22 cells in the pathophysiology of E-MDS and L-MDS remain unsettled. We studied 37 MDS patients (E-MDS, n = 17; L-MDS, n = 20) and 20 healthy controls to characterize their peripheral blood (PB), as well as 25 MDS patients and 10 healthy controls to characterize their bone marrow(BM). The expression of Interleukin-22 (IL-22), IL-17 or interferon gamma (IFN-γ) was examined in E-MDS, L-MDS patients and controls by flow cytometry. The mRNA expression levels of RAR-related orphan receptor C (RORC), IL-6, tumor necrosis factor alpha (TNF-α) and IL-23 in peripheral blood mononuclear cells (PBMCs) were determined by real-time quantitative polymerase chain reaction. The levels of IL-22 and IL-17 both in PB and BM plasma were examined by enzyme-linked immunosorbent assay. In E-MDS, peripheral Th17 cells were significantly elevated and correlated with peripheral Th22 cells compared with healthy controls and L-MDS. Significantly higher levels of peripheral Th22 expansion, mRNA expression of IL-6, TNF-α and lower level of RORC mRNA expression were observed in L-MDS compared with E-MDS. No statistical difference was found in IL-23 mRNA expression or plasma IL-22, IL-17 levels among E-MDS, L-MDS and controls. Our data demonstrated that L-MDS cohort had increased frequencies of peripheral Th22 cells and higher mRNA expression levels of IL-6 and TNF-α, indicating that Th22 cells along with Th17 cells or not are involved in the dynamic immune responses of MDS.

  6. Th22 Cells as Well as Th17 Cells Expand Differentially in Patients with Early-Stage and Late-Stage Myelodysplastic Syndrome

    PubMed Central

    Shao, Lin-lin; Zhang, Lei; Hou, Yu; Yu, Shuang; Liu, Xin-guang; Huang, Xiao-yang; Sun, Yuan-xin; Tian, Tian; He, Na; Ma, Dao-xin; Peng, Jun; Hou, Ming

    2012-01-01

    Background Immunological mechanisms are increasingly recognized in the progression of myelodysplastic syndrome (MDS). Early-stage MDS (E-MDS) is characterized by autoimmune-mediated myelosuppression whereas late-stage MDS (L-MDS) involves immune evasion, giving dysplastic cells growth potential to progress into acute myeloid leukemia. T-helper (Th) 22 is involved in the pathogenesis of inflammatory autoimmunity and tumorigenesis. The roles of Th22 cells in the pathophysiology of E-MDS and L-MDS remain unsettled. Design and Methods We studied 37 MDS patients (E-MDS, n = 17; L-MDS, n = 20) and 20 healthy controls to characterize their peripheral blood (PB), as well as 25 MDS patients and 10 healthy controls to characterize their bone marrow(BM). The expression of Interleukin-22 (IL-22), IL-17 or interferon gamma (IFN-γ) was examined in E-MDS, L-MDS patients and controls by flow cytometry. The mRNA expression levels of RAR-related orphan receptor C (RORC), IL-6, tumor necrosis factor alpha (TNF-α) and IL-23 in peripheral blood mononuclear cells (PBMCs) were determined by real-time quantitative polymerase chain reaction. The levels of IL-22 and IL-17 both in PB and BM plasma were examined by enzyme-linked immunosorbent assay. Results In E-MDS, peripheral Th17 cells were significantly elevated and correlated with peripheral Th22 cells compared with healthy controls and L-MDS. Significantly higher levels of peripheral Th22 expansion, mRNA expression of IL-6, TNF-α and lower level of RORC mRNA expression were observed in L-MDS compared with E-MDS. No statistical difference was found in IL-23 mRNA expression or plasma IL-22, IL-17 levels among E-MDS, L-MDS and controls. Conclusions Our data demonstrated that L-MDS cohort had increased frequencies of peripheral Th22 cells and higher mRNA expression levels of IL-6 and TNF-α, indicating that Th22 cells along with Th17 cells or not are involved in the dynamic immune responses of MDS. PMID:23236476

  7. Radiomics Signature: A Potential Biomarker for the Prediction of Disease-Free Survival in Early-Stage (I or II) Non-Small Cell Lung Cancer.

    PubMed

    Huang, Yanqi; Liu, Zaiyi; He, Lan; Chen, Xin; Pan, Dan; Ma, Zelan; Liang, Cuishan; Tian, Jie; Liang, Changhong

    2016-12-01

    Purpose To develop a radiomics signature to estimate disease-free survival (DFS) in patients with early-stage (stage I-II) non-small cell lung cancer (NSCLC) and assess its incremental value to the traditional staging system and clinical-pathologic risk factors for individual DFS estimation. Materials and Methods Ethical approval by the institutional review board was obtained for this retrospective analysis, and the need to obtain informed consent was waived. This study consisted of 282 consecutive patients with stage IA-IIB NSCLC. A radiomics signature was generated by using the least absolute shrinkage and selection operator, or LASSO, Cox regression model. Association between the radiomics signature and DFS was explored. Further validation of the radiomics signature as an independent biomarker was performed by using multivariate Cox regression. A radiomics nomogram with the radiomics signature incorporated was constructed to demonstrate the incremental value of the radiomics signature to the traditional staging system and other clinical-pathologic risk factors for individualized DFS estimation, which was then assessed with respect to calibration, discrimination, reclassification, and clinical usefulness. Results The radiomics signature was significantly associated with DFS, independent of clinical-pathologic risk factors. Incorporating the radiomics signature into the radiomics-based nomogram resulted in better performance (P < .0001) for the estimation of DFS (C-index: 0.72; 95% confidence interval [CI]: 0.71, 0.73) than with the clinical-pathologic nomogram (C-index: 0.691; 95% CI: 0.68, 0.70), as well as a better calibration and improved accuracy of the classification of survival outcomes (net reclassification improvement: 0.182; 95% CI: 0.02, 0.31; P = .02). Decision curve analysis demonstrated that in terms of clinical usefulness, the radiomics nomogram outperformed the traditional staging system and the clinical-pathologic nomogram. Conclusion The

  8. [Parameters of fibers cell respiration and desmin content in rat soleus muscle at early stages of gravitational unloading].

    PubMed

    Mirzoev, T M; Biriukov, N S; Veselova, O M; Larina, I M; Shenkman, B S; Ogneva, I V

    2012-01-01

    The aim of the work was to study the parameters of fibers cell respiration and desmin content in Wistar rat soleus muscle after 1, 3, 7 and 14 days of gravitational unloading. Gravitational unloading was simulated by antiorthostatic hindlimb suspension. The parameters of cell respiration were determined using the polarography, and desmin content was assessed by means of Western blotting. The results showed that the intensity of cell respiration is reduced after three days of gravitational unloading, reaches a minimum level after seven days and slightly increases by the fourteenth day of hindlimb unloading, as well as the content of desmin, which, however, to the fourteenth day returns to the control level. Taking into account that mitochondrial function depends on the state of cytoskeleton the data allow us to assume that early reduction of the intensity of cell respiration under unloading could be caused by degradation of the protein desmin that determines intracellular localization of mitochondria.

  9. Liquid biopsy in early stage lung cancer

    PubMed Central

    Pérez-Ramírez, Cristina; Robles, Ana I.; Molina, Miguel Ángel; Faus-Dáder, María José; Calleja-Hernández, Miguel Ángel

    2016-01-01

    Lung cancer is the leading cause of cancer-associated deaths worldwide. Surgery is the standard treatment for early-stage non-small cell lung cancer (NSCLC). However, 30% to 80% of these patients will die within 5 yearS of diagnosis. Circulating cell-free DNA (cfDNA) harbors pathologic characteristics of the original tumor, such as gene mutations or epigenetic alterations. Analysis of cfDNA has revolutionized the clinical care of advanced lung cancer patients undergoing targeted therapies. However, the low concentration of cfDNA in the blood of early-stage NSCLC patients has hampered its use for management of early disease. Continuing development of more specific and sensitive techniques for detection and analysis of cfDNA will soon enable its leverage in early stage and, perhaps, even screening settings. Therefore, cfDNA analysis may become a tool used for routine NSCLC diagnosis and for monitoring tumor burden, as well as for identifying hidden residual disease. In this review, we will focus on the current evidence of cfDNA in patients with early-stage NSCLC, new and upcoming approaches to identify circulating-tumor biomarkers, their clinical applications and future directions. PMID:27826533

  10. Altered microRNA expression and pre-mRNA splicing events reveal new mechanisms associated with early stage Mycobacterium avium subspecies paratuberculosis infection.

    PubMed

    Liang, Guanxiang; Malmuthuge, Nilusha; Guan, Yongjuan; Ren, Yuwei; Griebel, Philip J; Guan, Le Luo

    2016-04-22

    The molecular regulatory mechanisms of host responses to Mycobacterium avium subsp. paratuberculosis (MAP) infection during the early subclinical stage are still not clear. In this study, surgically isolated ileal segments in newborn calves (n = 5) were used to establish in vivo MAP infection adjacent to an uninfected control intestinal compartment. RNA-Seq was used to profile the whole transcriptome (mRNAs) and the microRNAome (miRNAs) of ileal tissues collected at one-month post-infection. The most related function of the differentially expressed mRNAs between infected and uninfected tissues was "proliferation of endothelial cells", indicating that MAP infection may lead to the over-proliferation of endothelial cells. In addition, 46.2% of detected mRNAs displayed alternative splicing events. The pre-mRNA of two genes related to macrophage maturation (monocyte to macrophage differentiation-associated) and lysosome function (adenosine deaminase) showed differential alternative splicing events, suggesting that specific changes in the pre-mRNA splicing sites may be a mechanism by which MAP escapes host immune responses. Moreover, 9 miRNAs were differentially expressed after MAP infection. The integrated analysis of microRNAome and transcriptome revealed that these miRNAs might regulate host responses to MAP infection, such as "proliferation of endothelial cells" (bta-miR-196 b), "bacteria recognition" (bta-miR-146 b), and "regulation of the inflammatory response" (bta-miR-146 b).

  11. Outcomes of invasive mediastinal nodal staging versus positron emission tomography staging alone for early-stage non-small cell lung cancer treated with stereotactic body radiation therapy.

    PubMed

    Schonewolf, Caitlin A; Verma, Vivek; Post, Carl M; Berman, Abigail T; Frick, Melissa A; Vachani, Anil; Lin, Chi; Simone, Charles B

    2017-07-14

    The benefit of invasive mediastinal nodal staging (IMNS) in addition to positron emission tomography-computed tomography (PET/CT) is undefined for early stage non-small cell lung cancer (NSCLC). This multi-institutional investigation aimed to evaluate outcomes and patterns of failure in patients staged with PET/CT with or without additional IMNS. Two academic centers assessed all consecutive patients staged with PET/CT for early-stage, primary lung NSCLC (cT1-2aN0M0) treated with SBRT. Local recurrence-free survival (LRFS), nodal recurrence-free survival (NRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were calculated using Kaplan-Meier methodology. Univariate and multivariate Cox proportional hazards modeling addressed factors associated with outcomes. Overall, 180 patients (199 lesions) were staged with PET/CT alone and 56 patients (58 lesions) underwent additional IMNS. Among patients receiving IMNS, 52 (93%) underwent EBUS and 4 (7%) underwent mediastinoscopy. At a median follow-up of 33.5 months (range, 1.9-80.9 months), there was no significant difference in LRFS (37 vs. 47 months, p=0.309), NRFS (34 vs. 42 months p=0.370), DMFS (36 vs. 47 months, p=0.234) or OS (37 vs. 47 months, p=0.236) between patients undergoing PET/CT-only versus PET/CT+IMNS staging, respectively. Receipt of IMNS did not correlate with any outcome on either univariate or multivariate analysis (p>0.05). Patterns of failure in both groups were similar, including crude isolated nodal failure rates (8% PET/CT-only versus 14% PET+IMNS group, p=0.202). Patients undergoing IMNS had similar survival and patterns of recurrence as those receiving PET/CT alone. Further study, ideally prospectively, is needed to determine which subgroups might benefit from IMNS. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. High-Dose and Extended-Field Intensity Modulated Radiation Therapy for Early-Stage NK/T-Cell Lymphoma of Waldeyer's Ring: Dosimetric Analysis and Clinical Outcome

    SciTech Connect

    Bi, Xi-Wen; Li, Ye-Xiong Fang, Hui; Jin, Jing; Wang, Wei-Hu; Wang, Shu-Lian; Liu, Yue-Ping; Song, Yong-Wen; Ren, Hua; Dai, Jian-Rong

    2013-12-01

    Purpose: To assess the dosimetric benefit, treatment outcome, and toxicity of high-dose and extended-field intensity modulated radiation therapy (IMRT) in patients with early-stage NK/T-cell lymphoma of Waldeyer's ring (WR-NKTCL). Methods and Materials: Thirty patients with early-stage WR-NKTCL who received extended-field IMRT were retrospectively reviewed. The prescribed dose was 50 Gy to the primary involved regions and positive cervical lymph nodes (planning target volume requiring radical irradiation [PTV{sub 50}]) and 40 Gy to the negative cervical nodes (PTV{sub 40}). Dosimetric parameters for the target volume and critical normal structures were evaluated. Locoregional control (LRC), overall survival (OS), and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Results: The median mean doses to the PTV{sub 50} and PTV{sub 40} were 53.2 Gy and 43.0 Gy, respectively. Only 1.4% of the PTV{sub 50} and 0.9% of the PTV{sub 40} received less than 95% of the prescribed dose, indicating excellent target coverage. The average mean doses to the left and right parotid glands were 27.7 and 28.4 Gy, respectively. The 2-year OS, PFS, and LRC rates were 71.2%, 57.4%, and 87.8%. Most acute toxicities were grade 1 to 2, except for grade ≥3 dysphagia and mucositis. The most common late toxicity was grade 1-2 xerostomia, and no patient developed any ≥grade 3 late toxicities. A correlation between the mean dose to the parotid glands and the degree of late xerostomia was observed. Conclusions: IMRT achieves excellent target coverage and dose conformity, as well as favorable survival and locoregional control rates with acceptable toxicities in patients with WR-NKTCL.

  13. Sublobar resection versus lobectomy in Surgical Treatment of Elderly Patients with early-stage non-small cell lung cancer (STEPS): study protocol for a randomized controlled trial.

    PubMed

    Yang, Fan; Sui, Xizhao; Chen, Xiuyuan; Zhang, Lixue; Wang, Xun; Wang, Shaodong; Wang, Jun

    2016-04-07

    The appropriateness of lobectomy for all elderly patients is controversial. Meanwhile, sublobar resection is associated with reduced operative risk, better preservation of pulmonary function, and a better quality of life, constituting a potential alternative to standard lobectomy for elderly patients with early-stage non-small cell lung cancer (NSCLC). To date, no randomized trial comparing sublobar resection and lobectomy focusing on elderly patients has been reported. We hypothesized that for patients at least 70 years old with clinical stage T1N0M0 NSCLC, sublobar resection is non-inferior to lobectomy for 3-year disease-free survival (DFS). This is a prospective, randomized, controlled multicenter non-inferiority trial with two study arms: sublobar resection and lobectomy groups. Comprehensive geriatric assessments will be acquired for each patient. A total of 339 subjects will be enrolled on the basis of power calculations, and participants followed up every 6 months post-operation for 3 years. In case of relapse, survival follow-up will be continued until 5 years or death. Pulmonary function testing will be performed at 6, 12, and 36 months post-operation. The primary outcome is 3-year DFS; secondary endpoints include peri-operative complications and mortality, hospitalization time, post-operative ventilator time, overall survival, 3-year recurrence rates, post-operative pulmonary function, quality of life, geriatric assessment data, and 4-year mortality index. The present study is the only prospective, multicenter, randomized controlled trial comparing sublobar resection and lobectomy for elderly patients. The therapeutic outcomes of sublobar resection will be evaluated in comparison with lobectomy for elderly patients (≥70 years) with early-stage NSCLC. NCT02360761 : 01/24/2015 (ClinicalTrials.gov).

  14. Long-term outcome of phase I/II prospective study of dose-escalated proton therapy for early-stage non-small cell lung cancer.

    PubMed

    Chang, Joe Y; Zhang, Wencheng; Komaki, Ritsuko; Choi, Noah C; Chan, Shen; Gomez, Daniel; O'Reilly, Michael; Jeter, Melenda; Gillin, Michael; Zhu, Xiaorong; Zhang, Xiaodong; Mohan, Radhe; Swisher, Stephen; Hahn, Stephen; Cox, James D

    2017-02-01

    The aim of this phase I/II study was to assess the long-term clinical benefits and toxicities of proton beam therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC). From June 2006 to September 2011, 35 patients with medically inoperable T1N0M0 (central or superior location, 12 patients) or T2-3N0M0 (any location, 23 patients) NSCLC were treated with 87.5Gy at 2.5Gy/fraction of proton therapy. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time was 83.1months (95% CI: 69.2-97.1months). For all 35 patients, the 1, 3, and 5-year overall survival rates were 85.7%, 42.9%, and 28.1%, respectively. The 5-year local recurrence-free, regional recurrence-free, and distant metastasis-free survival rates were 85.0%, 89.2%, and 54.4%, respectively. Different T stages had no effect on local and regional recurrence (p=0.499, p=1.00). However, with the increase in T stages, the distant metastasis rate increased significantly (p=0.006). The most common adverse effects were dermatitis (grade 2, 51.4%; grade 3, 2.9%) and radiation pneumonitis (grade 2, 11.4%; grade 3, 2.9%). Other grade 2 toxicities included esophagitis (2.9%), rib fracture (2.9%), heart toxicities (5.7%), and chest wall pain (2.9%). According to our long-term follow-up data, proton therapy with ablative doses is well tolerated and effective in medically inoperable early-stage NSCLC. Systemic therapy should be considered to reduce the rate of distant metastasis in cases of T2 and T3 lesions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Toxicity and Patterns of Failure of Adaptive/Ablative Proton Therapy for Early-Stage, Medically Inoperable Non-Small Cell Lung Cancer

    SciTech Connect

    Chang, Joe Y.; Komaki, Ritsuko; Wen, Hong Y.; De Gracia, Beth; Bluett, Jaques B.; McAleer, Mary F.; Swisher, Stephen G.; Cox, James D.

    2011-08-01

    Purpose: To analyze the toxicity and patterns of failure of proton therapy given in ablative doses for medically inoperable early-stage non-small cell lung cancer (NSCLC). Methods and Materials: Eighteen patients with medically inoperable T1N0M0 (central location) or T2-3N0M0 (any location) NSCLC were treated with proton therapy at 87.5 Gy (relative biological effectiveness) at 2.5 Gy /fraction in this Phase I/II study. All patients underwent treatment simulation with four-dimensional CT; internal gross tumor volumes were delineated on maximal intensity projection images and modified by visual verification of the target volume in 10 breathing phases. The internal gross tumor volumes with maximal intensity projection density was used to design compensators and apertures to account for tumor motion. Therapy consisted of passively scattered protons. All patients underwent repeat four-dimensional CT simulations during treatment to assess the need for adaptive replanning. Results: At a median follow-up time of 16.3 months (range, 4.8-36.3 months), no patient had experienced Grade 4 or 5 toxicity. The most common adverse effect was dermatitis (Grade 2, 67%; Grade 3, 17%), followed by Grade 2 fatigue (44%), Grade 2 pneumonitis (11%), Grade 2 esophagitis (6%), and Grade 2 chest wall pain (6%). Rates of local control were 88.9%, regional lymph node failure 11.1%, and distant metastasis 27.8%. Twelve patients (67%) were still alive at the last follow-up; five had died of metastatic disease and one of preexisting cardiac disease. Conclusions: Proton therapy to ablative doses is well tolerated and produces promising local control rates for medically inoperable early-stage NSCLC.

  16. No Clinically Significant Changes in Pulmonary Function Following Stereotactic Body Radiation Therapy for Early- Stage Peripheral Non-Small Cell Lung Cancer: An Analysis of RTOG 0236

    SciTech Connect

    Stanic, Sinisa; Paulus, Rebecca; Timmerman, Robert D.; Michalski, Jeff M.; Barriger, Robert B.; Bezjak, Andrea; Videtic, Gregory M.M.; Bradley, Jeffrey

    2014-04-01

    Purpose: To investigate pulmonary function test (PFT) results and arterial blood gas changes (complete PFT) following stereotactic body radiation therapy (SBRT) and to see whether baseline PFT correlates with lung toxicity and overall survival in medically inoperable patients receiving SBRT for early stage, peripheral, non-small cell lung cancer (NSCLC). Methods and Materials: During the 2-year follow-up, PFT data were collected for patients with T1-T2N0M0 peripheral NSCLC who received effectively 18 Gy × 3 in a phase 2 North American multicenter study (Radiation Therapy Oncology Group [RTOG] protocol 0236). Pulmonary toxicity was graded by using the RTOG SBRT pulmonary toxicity scale. Paired Wilcoxon signed rank test, logistic regression model, and Kaplan-Meier method were used for statistical analysis. Results: At 2 years, mean percentage predicted forced expiratory volume in the first second and diffusing capacity for carbon monoxide declines were 5.8% and 6.3%, respectively, with minimal changes in arterial blood gases and no significant decline in oxygen saturation. Baseline PFT was not predictive of any pulmonary toxicity following SBRT. Whole-lung V5 (the percentage of normal lung tissue receiving 5 Gy), V10, V20, and mean dose to the whole lung were almost identical between patients who developed pneumonitis and patients who were pneumonitis-free. Poor baseline PFT did not predict decreased overall survival. Patients with poor baseline PFT as the reason for medical inoperability had higher median and overall survival rates than patients with normal baseline PFT values but with cardiac morbidity. Conclusions: Poor baseline PFT did not appear to predict pulmonary toxicity or decreased overall survival after SBRT in this medically inoperable population. Poor baseline PFT alone should not be used to exclude patients with early stage lung cancer from treatment with SBRT.

  17. No Clinically Significant Changes in Pulmonary Function Following Stereotactic Body Radiation Therapy (SBRT) for Early Stage Peripheral Non-small Cell Lung Cancer: An Analysis of RTOG 0236

    PubMed Central

    Stanic, Sinisa; Paulus, Rebecca; Timmerman, Robert D.; Michalski, Jeff M.; Barriger, Robert B.; Bezjak, Andrea; Videtic, Gregory M.M.; Bradley, Jeffrey

    2014-01-01

    Purpose To investigate pulmonary function test (PFT) and arterial blood gas changes (complete PFT) following stereotactic body radiation therapy (SBRT) and to see whether baseline PFT correlates with lung toxicity and overall survival in medically inoperable patients receiving SBRT for early stage, peripheral, non-small cell lung cancer (NSCLC). Methods and materials During the 2-year follow-up, PFT data was collected for patients with T1-T2N0M0 peripheral NSCLC who received effectively 18 Gy × 3 on Phase II North American multicenter study (RTOG 0236). Pulmonary toxicity was graded utilizing the RTOG SBRT pulmonary toxicity scale. Paired Wilcoxon signed rank test, Logistic Regression model, and Kaplan-Meier method were used for the statistical analysis. Results At 2 years, mean % predicted FEV1 and DLCO declines were 5.8% and 6.3%, respectively, with minimal changes of arterial blood gases, and no significant decline of oxygen saturation. Baseline PFT was not predictive of any pulmonary toxicity following SBRT. Whole lung V5, V10, V20 and mean dose to the whole lung were almost identical between patients who developed pneumonitis and patients who were pneumonitis-free. Poor baseline PFT did not predict decreased overall survival. Patients with poor baseline PFT as a reason for medical inoperability had higher median and overall survivals than patients with normal baseline PFT but with cardiac morbidity. Conclusions Poor baseline PFT did not appear to predict toxicity, or decreased overall survival after SBRT in this medically inoperable population. Poor baseline PFT alone should not be used to exclude patients with early stage lung cancer from treatment with SBRT. PMID:24661663

  18. Parenchymal and Stromal Cells Contribute to Pro-Inflammatory Myocardial Environment at Early Stages of Diabetes: Protective Role of Resveratrol.

    PubMed

    Savi, Monia; Bocchi, Leonardo; Sala, Roberto; Frati, Caterina; Lagrasta, Costanza; Madeddu, Denise; Falco, Angela; Pollino, Serena; Bresciani, Letizia; Miragoli, Michele; Zaniboni, Massimiliano; Quaini, Federico; Del Rio, Daniele; Stilli, Donatella

    2016-11-16

    Background: Little information is currently available concerning the relative contribution of cardiac parenchymal and stromal cells in the activation of the pro-inflammatory signal cascade, at the initial stages of diabetes. Similarly, the effects of early resveratrol (RSV) treatment on the negative impact of diabetes on the different myocardial cell compartments remain to be defined. Methods: In vitro challenge of neonatal cardiomyocytes and fibroblasts to high glucose and in vivo/ex vivo experiments on a rat model of Streptozotocin-induced diabetes were used to specifically address these issues. Results: In vitro data indicated that, besides cardiomyocytes, neonatal fibroblasts contribute to generating initial changes in the myocardial environment, in terms of pro-inflammatory cytokine expression. These findings were mostly confirmed at the myocardial tissue level in diabetic rats, after three weeks of hyperglycemia. Specifically, monocyte chemoattractant protein-1 and Fractalkine were up-regulated and initial abnormalities in cardiomyocyte contractility occurred. At later stages of diabetes, a selective enhancement of pro-inflammatory macrophage M1 phenotype and a parallel reduction of anti-inflammatory macrophage M2 phenotype were associated with a marked disorganization of cardiomyocyte ultrastructural properties. RSV treatment inhibited pro-inflammatory cytokine production, leading to a recovery of cardiomyocyte contractile efficiency and a reduced inflammatory cell recruitment. Conclusion: Early RSV administration could inhibit the pro-inflammatory diabetic milieu sustained by different cardiac cell types.

  19. Parenchymal and Stromal Cells Contribute to Pro-Inflammatory Myocardial Environment at Early Stages of Diabetes: Protective Role of Resveratrol

    PubMed Central

    Savi, Monia; Bocchi, Leonardo; Sala, Roberto; Frati, Caterina; Lagrasta, Costanza; Madeddu, Denise; Falco, Angela; Pollino, Serena; Bresciani, Letizia; Miragoli, Michele; Zaniboni, Massimiliano; Quaini, Federico; Del Rio, Daniele; Stilli, Donatella

    2016-01-01

    Background: Little information is currently available concerning the relative contribution of cardiac parenchymal and stromal cells in the activation of the pro-inflammatory signal cascade, at the initial stages of diabetes. Similarly, the effects of early resveratrol (RSV) treatment on the negative impact of diabetes on the different myocardial cell compartments remain to be defined. Methods: In vitro challenge of neonatal cardiomyocytes and fibroblasts to high glucose and in vivo/ex vivo experiments on a rat model of Streptozotocin-induced diabetes were used to specifically address these issues. Results: In vitro data indicated that, besides cardiomyocytes, neonatal fibroblasts contribute to generating initial changes in the myocardial environment, in terms of pro-inflammatory cytokine expression. These findings were mostly confirmed at the myocardial tissue level in diabetic rats, after three weeks of hyperglycemia. Specifically, monocyte chemoattractant protein-1 and Fractalkine were up-regulated and initial abnormalities in cardiomyocyte contractility occurred. At later stages of diabetes, a selective enhancement of pro-inflammatory macrophage M1 phenotype and a parallel reduction of anti-inflammatory macrophage M2 phenotype were associated with a marked disorganization of cardiomyocyte ultrastructural properties. RSV treatment inhibited pro-inflammatory cytokine production, leading to a recovery of cardiomyocyte contractile efficiency and a reduced inflammatory cell recruitment. Conclusion: Early RSV administration could inhibit the pro-inflammatory diabetic milieu sustained by different cardiac cell types. PMID:27854328

  20. Impact of prostate edema on cell survival and tumor control after permanent interstitial brachytherapy for early stage prostate cancers

    PubMed Central

    Chen, Zhe (Jay); Roberts, Kenneth; Decker, Roy; Pathare, Pradip; Rockwell, Sara; Nath, Ravinder

    2011-01-01

    Previous studies have shown that the procedure-induced prostate edema during permanent interstitial brachytherapy (PIB) can cause significant variations in the dose delivered to the prostate gland. Because the clinical impact of edema-induced dose variations depends strongly on the magnitude of the edema, the temporal pattern of its resolution and its interplay with the decay of radioactivity and the underlying biological processes of tumor cells (such as tumor potential doubling time), we investigated the impact of edema-induced dose variations on the tumor cell survival and tumor control probability after PIB with the 131Cs, 125I and 103Pd sources used in current clinical practice. The exponential edema resolution model reported by Waterman et al. (Int. J. Radiat. Oncol. Biol. Phys. 41, 1069–1077–1998) was used to characterize the edema evolutions observed previously during clinical PIB for prostate cancer. The concept of biologically effective dose (BED), taking into account tumor cell proliferation and sublethal damage repair during dose delivery, was used to characterize the effects of prostate edema on cell survival and tumor control probability. Our calculation indicated that prostate edema, if not taken into account appropriately, can increase the cell survival and decrease the probability of local control of PIB. The edema-induced increase in cell survival increased with increasing edema severity, decreasing half-life for radioactive decay and decreasing energy of the photons energy emitted by the source. At the doses currently prescribed for PIB and for prostate cancer cells characterized by nominal radiobiology parameters recommended by AAPM TG-137, PIB using 125I sources was less affected by edema than PIB using 131Cs or 103Pd sources due to the long radioactive decay half-life of 125I. The effect of edema on PIB using 131Cs or 103Pd was similar. The effect of edema on 103Pd PIB was slightly greater, even though the decay half-life of 103Pd (17 days

  1. The impact of prostate edema on cell survival and tumor control after permanent interstitial brachytherapy for early stage prostate cancers

    NASA Astrophysics Data System (ADS)

    (Jay Chen, Zhe; Roberts, Kenneth; Decker, Roy; Pathare, Pradip; Rockwell, Sara; Nath, Ravinder

    2011-08-01

    Previous studies have shown that procedure-induced prostate edema during permanent interstitial brachytherapy (PIB) can cause significant variations in the dose delivered to the prostate gland. Because the clinical impact of edema-induced dose variations strongly depends on the magnitude of the edema, the temporal pattern of its resolution and its interplay with the decay of radioactivity and the underlying biological processes of tumor cells (such as tumor potential doubling time), we investigated the impact of edema-induced dose variations on the tumor cell survival and tumor control probability after PIB with the 131Cs, 125I and 103Pd sources used in current clinical practice. The exponential edema resolution model reported by Waterman et al (1998 Int. J. Radiat. Oncol. Biol. Phys. 41 1069-77) was used to characterize the edema evolutions previously observed during clinical PIB for prostate cancer. The concept of biologically effective dose, taking into account tumor cell proliferation and sublethal damage repair during dose delivery, was used to characterize the effects of prostate edema on cell survival and tumor control probability. Our calculation indicated that prostate edema, if not appropriately taken into account, can increase the cell survival and decrease the probability of local control of PIB. The magnitude of an edema-induced increase in cell survival increased with increasing edema severity, decreasing half-life of radioactive decay and decreasing photon energy emitted by the source. At the doses currently prescribed for PIB and for prostate cancer cells characterized by nominal radiobiology parameters recommended by AAPM TG-137, PIB using 125I sources was less affected by edema than PIB using 131Cs or 103Pd sources due to the long radioactive decay half-life of 125I. The effect of edema on PIB using 131Cs or 103Pd was similar. The effect of edema on 103Pd PIB was slightly greater, even though the decay half-life of 103Pd (17 days) is longer than

  2. In Situ Confocal Raman Microscopy of Hydrated Early Stages of Bacterial Biofilm Formation on Various Surfaces in a Flow Cell.

    PubMed

    Smith-Palmer, Truis; Lin, Sicheng; Oguejiofor, Ikenna; Leng, Tianyang; Pustam, Amanda; Yang, Jin; Graham, Lori L; Wyeth, Russell C; Bishop, Cory D; DeMont, M Edwin; Pink, David

    2016-02-01

    Bacterial biofilms are precursors to biofouling by other microorganisms. Understanding their initiation may allow us to design better ways to inhibit them, and thus to inhibit subsequent biofouling. In this study, the ability of confocal Raman microscopy to follow the initiation of biofouling by a marine bacterium, Pseudoalteromonas sp. NCIMB 2021 (NCIMB 2021), in a flow cell, using optical and confocal Raman microscopy, was investigated. The base of the flow cell comprised a cover glass. The cell was inoculated and the bacteria attached to, and grew on, the cover glass. Bright field images and Raman spectra were collected directly from the hydrated biofilms over several days. Although macroscopically the laser had no effect on the biofilm, within the first 24 h cells migrated away from the position of the laser beam. In the absence of flow, a buildup of extracellular substances occurred at the base of the biofilm. When different coatings were applied to cover glasses before they were assembled into the flow cells, the growth rate, structure, and composition of the resulting biofilm was affected. In particular, the ratio of Resonance Raman peaks from cytochrome c (CC) in the extracellular polymeric substances, to the Raman phenylalanine (Phe) peak from protein in the bacteria, depended on both the nature of the surface and the age of the biofilm. The ratios were highest for 24 h colonies on a hydrophobic surface. Absorption of a surfactant with an ethyleneoxy chain into the hydrophobic coating created a surface similar to that given with a simple PEG coating, where bacteria grew in colonies away from the surface rather than along the surface, and CC:Phe ratios were initially low but increased at least fivefold in the first 48 h.

  3. Bystander Effect Fuels Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells to Quickly Attenuate Early Stage Neurological Deficits After Stroke

    PubMed Central

    Eckert, Auston; Huang, Lei; Gonzalez, Rodolfo; Kim, Hye-Sun; Hamblin, Milton H.

    2015-01-01

    Present therapies for stroke rest with tissue plasminogen activator (tPA), the sole licensed antithrombotic on the market; however, tPA’s effectiveness is limited in that the drug not only must be administered less than 3–5 hours after stroke but often exacerbates blood-brain barrier (BBB) leakage and increases hemorrhagic incidence. A potentially promising therapy for stroke is transplantation of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs). To date, the effects of iPSCs on injuries that take place during early stage ischemic stroke have not been well studied. Consequently, we engrafted iPSC-NSCs into the ipsilesional hippocampus, a natural niche of NSCs, at 24 hours after stroke (prior to secondary BBB opening and when inflammatory signature is abundant). At 48 hours after stroke (24 hours after transplant), hiPSC-NSCs had migrated to the stroke lesion and quickly improved neurological function. Transplanted mice showed reduced expression of proinflammatory factors (tumor necrosis factor-α, interleukin 6 [IL-6], IL-1β, monocyte chemotactic protein 1, macrophage inflammatory protein 1α), microglial activation, and adhesion molecules (intercellular adhesion molecule 1, vascular cell adhesion molecule 1) and attenuated BBB damage. We are the first to report that engrafted hiPSC-NSCs rapidly improved neurological function (less than 24 hours after transplant). Rapid hiPSC-NSC therapeutic activity is mainly due to a bystander effect that elicits reduced inflammation and BBB damage. Significance Clinically, cerebral vessel occlusion is rarely permanent because of spontaneous or thrombolytic therapy-mediated reperfusion. These results have clinical implications indicating a much extended therapeutic window for transplantation of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs; 24 hours after stroke as opposed to the 5-hour window with tissue plasminogen activator [tPA]). In addition, there is potential for a

  4. Bystander Effect Fuels Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells to Quickly Attenuate Early Stage Neurological Deficits After Stroke.

    PubMed

    Eckert, Auston; Huang, Lei; Gonzalez, Rodolfo; Kim, Hye-Sun; Hamblin, Milton H; Lee, Jean-Pyo

    2015-07-01

    : Present therapies for stroke rest with tissue plasminogen activator (tPA), the sole licensed antithrombotic on the market; however, tPA's effectiveness is limited in that the drug not only must be administered less than 3-5 hours after stroke but often exacerbates blood-brain barrier (BBB) leakage and increases hemorrhagic incidence. A potentially promising therapy for stroke is transplantation of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs). To date, the effects of iPSCs on injuries that take place during early stage ischemic stroke have not been well studied. Consequently, we engrafted iPSC-NSCs into the ipsilesional hippocampus, a natural niche of NSCs, at 24 hours after stroke (prior to secondary BBB opening and when inflammatory signature is abundant). At 48 hours after stroke (24 hours after transplant), hiPSC-NSCs had migrated to the stroke lesion and quickly improved neurological function. Transplanted mice showed reduced expression of proinflammatory factors (tumor necrosis factor-α, interleukin 6 [IL-6], IL-1β, monocyte chemotactic protein 1, macrophage inflammatory protein 1α), microglial activation, and adhesion molecules (intercellular adhesion molecule 1, vascular cell adhesion molecule 1) and attenuated BBB damage. We are the first to report that engrafted hiPSC-NSCs rapidly improved neurological function (less than 24 hours after transplant). Rapid hiPSC-NSC therapeutic activity is mainly due to a bystander effect that elicits reduced inflammation and BBB damage. Clinically, cerebral vessel occlusion is rarely permanent because of spontaneous or thrombolytic therapy-mediated reperfusion. These results have clinical implications indicating a much extended therapeutic window for transplantation of human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs; 24 hours after stroke as opposed to the 5-hour window with tissue plasminogen activator [tPA]). In addition, there is potential for a synergistic

  5. Metformin exposure is associated with improved progression-free survival in diabetic patients after resection for early-stage non-small cell lung cancer.

    PubMed

    Medairos, Robert A; Clark, James; Holoubek, Simon; Kubasiak, John C; Pithadia, Ravi; Hamid, Fatima; Chmielewski, Gary W; Warren, William H; Basu, Sanjib; Borgia, Jeffrey A; Liptay, Michael J; Seder, Christopher W

    2016-07-01

    There are little clinical data assessing the antineoplastic effect of metformin in patients with non-small cell lung cancer. We hypothesized that in diabetic patients undergoing pulmonary resection for early-stage non-small cell lung cancer, metformin exposure is associated with improved survival. An institutional database was used to identify patients with stage I or II non-small cell lung cancer who underwent pulmonary resection between 2004 and 2013. Patients were divided into 3 cohorts: type II diabetic patients with metformin exposure (cohort A, n = 81), type II diabetic patients without metformin exposure (cohort B, n = 57), and nondiabetic individuals (cohort C, n = 77). Univariate, multivariate, and propensity-matched analyses were performed to assess progression-free and overall survivals between groups. A total of 215 patients with stage I and II non-small cell lung cancer treated with surgical resection were identified for analysis with a median follow-up of 19.5 months. Patients in cohort A had lower T- and N-stage tumors than those in cohorts B or C. However, on multivariate analysis adjusting for age, gender, and T and N stage, progression-free survival was greater for cohort A than cohort B (hazard ratio [HR], 0.410; 95% confidence interval, 0.199-0.874; P = .022) or cohort C (HR, 0.415; 95% confidence interval, 0.201-0.887; P = .017). Likewise, when propensity-matched analyses were performed, cohort A demonstrated a trend toward improved progression-free survival compared with cohort B (P = .057; HR, 0.44; c-statistic = 0.832) and improved progression-free survival compared with cohort C (P = .02; HR, 0.41; c-statistic = 0.843). No differences were observed in overall survival. Metformin exposure in diabetic patients with early-stage non-small cell lung cancer may be associated with improved progression-free survival, but no effect was seen on overall survival. Further studies are warranted to evaluate if there is a therapeutic

  6. Targeting of Cancer Stem Cells and Their Microenvironment in Early-Stage MutantK-ras Lung Cancer

    DTIC Science & Technology

    2015-10-01

    Smoothened and Patched can be reversed by cyclopamine. Nature. 2000;406(6799):1005-9. Epub 2000/09/13. doi: 10.1038/35023008. PubMed PMID: 10984056. 2...neuron identity. Cell. 1996;87(4):661- 73. Epub 1996/11/15. PubMed PMID: 8929535. 3. Maun HR, Wen X, Lingel A, de Sauvage FJ, Lazarus RA, Scales SJ...M110.112284 [pii]10.1074/jbc.M110.112284. PubMed PMID: 20504762. 4. Sullivan JP, Spinola M, Dodge M, Raso MG, Behrens C, Gao B, Schuster K, Shao C, Larsen JE

  7. The cholesterol-binding protein NPC2 restrains recruitment of stromal macrophage-lineage cells to early-stage lung tumours

    PubMed Central

    Kamata, Tamihiro; Jin, Hong; Giblett, Susan; Patel, Bipin; Patel, Falguni; Foster, Charles; Pritchard, Catrin

    2015-01-01

    The tumour microenvironment is known to play an integral role in facilitating cancer progression at advanced stages, but its function in some pre-cancerous lesions remains elusive. We have used the V600EBRAF-driven mouse lung model that develop premalignant lesions to understand stroma–tumour interactions during pre-cancerous development. In this model, we have found that immature macrophage-lineage cells (IMCs) producing PDGFA, TGFβ and CC chemokines are recruited to the stroma of premalignant lung adenomas through CC chemokine receptor 1 (CCR1)-dependent mechanisms. Stromal IMCs promote proliferation and transcriptional alterations suggestive of epithelial–mesenchymal transition in isolated premalignant lung tumour cells ex vivo, and are required for the maintenance of early-stage lung tumours in vivo. Furthermore, we have found that IMC recruitment to the microenvironment is restrained by the cholesterol-binding protein, Niemann-Pick type C2 (NPC2). Studies on isolated cells ex vivo confirm that NPC2 is secreted from tumour cells and is taken up by IMCs wherein it suppresses secretion of the CCR1 ligand CC chemokine 6 (CCL6), at least in part by facilitating its lysosomal degradation. Together, these findings show that NPC2 secreted by premalignant lung tumours suppresses IMC recruitment to the microenvironment in a paracrine manner, thus identifying a novel target for the development of chemopreventive strategies in lung cancer. PMID:26183450

  8. Development of a cell phone-based video streaming system for persons with early stage Alzheimer's disease.

    PubMed

    Donnelly, Mark P; Nugent, Chris D; Craig, David; Passmore, Peter; Mulvenna, Maurice

    2008-01-01

    The current paper presents details regarding the early developments of a memory prompt solution for persons with early dementia. Using everyday technology, in the form of a cell-phone, video reminders are delivered to assist with daily activities. The proposed CPVS system will permit carers to record and schedule video reminders remotely using a standard personal computer and web cam. It is the aim of the three year project that through the frequent delivery of helpful video reminders that a 'virtual carer' will be present with the person with dementia at all times. The first prototype of the system has been fully implemented with the first field trial scheduled to take place in May 2008. Initially, only three patient carer dyads will be involved, however, the second field trial aims to involve 30 dyads in the study. Details of the first prototype and the methods of evaluation are presented herein.

  9. Stereotactic Body Radiation Therapy for Early-Stage Non-Small-Cell Lung Cancer: The Pattern of Failure Is Distant

    SciTech Connect

    Bradley, Jeffrey D.; El Naqa, Issam; Drzymala, Robert E.; Trovo, Marco; Jones, Griffin; Denning, Mary Dee

    2010-07-15

    Background: Stereotactic body radiation therapy (SBRT) represents a substantial paradigm shift in the treatment of patients with medically inoperable Stage I/II non-small-cell lung cancer. We reviewed our experience using either three- or five-fraction SBRT for peripheral or central tumors, respectively. Methods and Materials: A total of 91 patients signed an institutional review board-approved consent form, were treated with SBRT, and have had {>=}6 months of follow-up. Patients were referred for SBRT because of underlying comorbidities (poor performance status in 31 or poor lung function in 52) or refusal of surgery (8 patients). Of the cancers, 83 were peripheral and eight were central. Peripheral cancers received a mean dose of 18 Gy x three fractions. Cancers within 2 cm of the bronchus, esophagus, or brachial plexus were treated with 9 Gy x five fractions. Results: The median follow-up duration for these patients was 18 months (range, 6-42 months). TNM staging was as follows: 58 patients with T1N0M0, 22 with T2N0M0, 2 with T3N0M0 (chest wall), and 6 with T1N0M1 cancers. The median tumor diameter was 2 cm (range, 1-5 cm). The median forced expiratory volume in 1 s was 46% (range, 17-133%) and the median carbon monoxide diffusing capacity (DLCO) was 49% (range, 15-144%). Two-year local tumor control was achieved in 86% of patients. The predominant pattern of failure was the development of distant metastasis or second lung cancer. The development of distant metastasis was the only significant prognostic factor for overall survival on multivariate analysis. Conclusions: Local tumor control was shown to be high using SBRT for non-small-cell lung cancer. Overall survival is highly coerrelated with the development of distant metastasis.

  10. Impact of Obesity on the Survival of Patients with Early Stage Squamous Cell Carcinoma of the Oral Tongue

    PubMed Central

    Iyengar, Neil M.; Kochhar, Amit; Morris, Patrick G.; Morris, Luc G.; Zhou, Xi K.; Ghossein, Ronald A.; Pino, Alejandro; Fury, Matthew G.; Pfister, David G.; Patel, Snehal G.; Boyle, Jay O.; Hudis, Clifford A.; Dannenberg, Andrew J.

    2014-01-01

    Background While obesity increases risk and negatively impacts survival for many malignancies, the prognostic implications in squamous cell carcinoma (SCC) of the oral tongue, a disease often associated with pre-diagnosis weight loss, are unknown. Methods Patients with T1–T2 oral tongue SCC underwent curative-intent resection in this single-institution study. All patients underwent nutritional assessment prior to surgery. Body mass index (BMI) was calculated from measured height and weight and categorized as obese (≥30 kg/m2), overweight (25 to 29.9 kg/m2), or normal (18.5 to 24.9 kg/m2). Clinical outcomes including disease specific survival (DSS), recurrence free survival (RFS), and overall survival (OS), were compared by BMI group using Cox regression. Results From 2000–2009, 155 patients (90 men, 65 women) of median age 57 (range 18 to 86) were included. Baseline characteristics were similar by BMI group. Obesity was significantly associated with adverse DSS compared with normal weight in univariable (hazard ratio [HR] = 2.65, 95% confidence interval [CI], 1.07 to 6.59; P = .04) and multivariable analyses (HR = 5.01; 95% CI, 1.69 to 14.81; P = .004). A consistent association was seen between obesity and worse RFS (HR =1.87; 95% CI, .90 to 3.88) and between obesity and worse OS (HR=2.03; 95% CI, .88 to 4.65) though without reaching statistical significance (P = .09 and P = .10 respectively) in multivariable analyses. Conclusions In this retrospective study, obesity was an adverse independent prognostic variable. This association may not have been previously appreciated due to confounding by multiple factors including pre-diagnosis weight loss. PMID:24449483

  11. Impact of obesity on the survival of patients with early-stage squamous cell carcinoma of the oral tongue.

    PubMed

    Iyengar, Neil M; Kochhar, Amit; Morris, Patrick G; Morris, Luc G; Zhou, Xi K; Ghossein, Ronald A; Pino, Alejandro; Fury, Matthew G; Pfister, David G; Patel, Snehal G; Boyle, Jay O; Hudis, Clifford A; Dannenberg, Andrew J

    2014-04-01

    Although obesity increases risk and negatively affects survival for many malignancies, the prognostic implications in squamous cell carcinoma (SCC) of the oral tongue, a disease often associated with prediagnosis weight loss, are unknown. Patients with T1-T2 oral tongue SCC underwent curative-intent resection in this single-institution study. All patients underwent nutritional assessment prior to surgery. Body mass index (BMI) was calculated from measured height and weight and categorized as obese (≥ 30 kg/m(2) ), overweight (25-29.9 kg/m(2) ), or normal (18.5-24.9 kg/m(2) ). Clinical outcomes, including disease-specific survival, recurrence-free survival, and overall survival, were compared by BMI group using Cox regression. From 2000 to 2009, 155 patients (90 men, 65 women) of median age 57 years (range, 18-86 years) were included. Baseline characteristics were similar by BMI group. Obesity was significantly associated with adverse disease-specific survival compared with normal weight in univariable (hazard ratio [HR] = 2.65, 95% confidence interval [CI] = 1.07-6.59; P = .04) and multivariable analyses (HR = 5.01; 95% CI = 1.69-14.81; P = .004). A consistent association was seen between obesity and worse recurrence-free survival (HR = 1.87; 95% CI = 0.90-3.88) and between obesity and worse overall survival (HR = 2.03; 95% CI = 0.88-4.65) though without reaching statistical significance (P = .09 and P = .10, respectively) in multivariable analyses. In this retrospective study, obesity was an adverse independent prognostic variable. This association may not have been previously appreciated due to confounding by multiple factors including prediagnosis weight loss. © 2013 American Cancer Society.

  12. A novel clinicopathological analysis of early stage ovarian Sertoli-Leydig cell tumors at a single institution

    PubMed Central

    Nam, Seon Mi; Kim, Jee Whan; Eoh, Kyung Jin; Kim, Hye Min; Lee, Jung Yun; Nam, Eun Ji; Kim, Sunghoon; Kim, Sang Wun

    2017-01-01

    Objective To evaluate the clinical and pathologic characteristics of patients who were diagnosed with ovarian Sertoli-Leydig cell tumors (SLCTs) in a single institution. Methods The medical records of 11 patients who were pathologically diagnosed with SLCTs beginning in 1995 in a single institute was reviewed. Results The median patient age was 31 years (range, 16 to 70 years). Patient International Federation of Gynecology and Obstetrics stages were IA, IC, and IIB in 3 (27.3%), 6 (54.5%), and 2 (18.2%) patients, respectively. Six patients (54.5%) had grade 3 tumors, 3 patients (27.3%) had grade 2 tumors, and 1 patient (9.1%) had a grade 1 tumor. Four patients without children underwent fertility-sparing surgery, and 7 patients had full staging surgery, including a hysterectomy and bilateral salpingo-oophorectomy, with a laparoscopic approach used in 3. Eight patients underwent pelvic lymph node dissection, and 8 patients were administered adjuvant chemotherapy consisting of bleomycin, etoposide, and cisplatin in 6 cases, a modified bleomycin, etoposide, and cisplatin regimen in 1 case, and a combined paclitaxel and cisplatin regimen in 1 case. Two patients died of disease and were re-diagnosed with Sertoli form endometrioid carcinoma. The other patients remain alive without recurrence at the time of reporting. Conclusion Our findings suggest that regardless of tumor stage or grade, ovarian SLCT patients have a good prognosis. Close observation and unilateral salpingo-oophorectomy would be beneficial for women who still wish to have children, while hysterectomy and bilateral salpingo-oophorectomy with adjuvant chemotherapy would be the optimal treatment in other cases. Furthermore, meticulous pathologic diagnosis is needed to develop a precise treatment strategy. PMID:28217670

  13. Baseline and post-surgery endothelial progenitor cell levels in patients with early-stage non-small-cell lung carcinoma: impact on cancer recurrence and survival.

    PubMed

    Pirro, Matteo; Cagini, Lucio; Paciullo, Francesco; Pecoriello, Roberta; Mannarino, Massimo R; Bagaglia, Francesco; Capozzi, Rosanna; Puma, Francesco; Mannarino, Elmo

    2013-10-01

    Endothelial progenitor cells (EPCs) are believed to play a role in promoting abnormal vascularization in neoplastic sites. We measured the number of circulating EPCs in treatment-naïve patients with early non-small-cell lung cancer (NSCLC) and healthy controls. The prospective influence of baseline and post-surgery EPC levels on cancer recurrence and survival was investigated. Circulating EPCs were quantified by FACS analysis in 34 patients with Stage I-II NSCLC and 68 healthy age- and sex-matched controls. Measurement of EPCs was repeated 48 h after thoracic surgery and at the hospital discharge. Cancer recurrence and survival was evaluated after 446 ± 106 days of follow-up (range 182-580 days). The base 10 logarithmic [log] number of circulating EPCs was comparable between patients with NSCLC and controls [mean ± standard deviation (SD): 2.3 ± 0.32 vs 2.3 ± 0.26 n/ml, P = 0.776]. In regression analysis, smoking status [standardized coefficient beta (β) = -0.26, 95% confidence interval (CI) for B -0.29/-0.03, P = 0.014] and systolic blood pressure [β = -0.23, 95% CI for B -0.011/-0.001, P = 0.018] were independent predictors of the number of EPCs, irrespective of the NSCLC status. The mean number of EPCs did not change after surgical treatment. However, a post-surgery EPC increase was observed in 44% patients. Patients with a 48 h post-surgery EPC increase had a higher rate of cancer recurrence/death than patients with either stable or decreased post-surgery EPC levels [hazard ratio (HR) 4.4, 95% CI 1.1-17.3; P = 0.032], irrespective of confounders. Circulating EPC levels are comparable between patients with early-stage NSCLC and healthy controls. Overall, surgical cancer resection was not associated with a significant early EPC change. However, an early post-surgery EPC increase is able to predict an increased risk of cancer recurrence and death.

  14. Stereotactic Body Radiotherapy for Early-stage Non-small-cell Lung Cancer in Patients 80 Years and Older: A Multi-center Analysis.

    PubMed

    Cassidy, Richard J; Patel, Pretesh R; Zhang, Xinyan; Press, Robert H; Switchenko, Jeffrey M; Pillai, Rathi N; Owonikoko, Taofeek K; Ramalingam, Suresh S; Fernandez, Felix G; Force, Seth D; Curran, Walter J; Higgins, Kristin A

    2017-09-01

    Stereotactic body radiotherapy (SBRT) is the standard of care for medically inoperable early-stage non-small-cell lung cancer. Despite the limited number of octogenarians and nonagenarians on trials of SBRT, its use is increasingly being offered in these patients, given the aging cancer population, medical fragility, or patient preference. Our purpose was to investigate the efficacy, safety, and survival of patients ≥ 80 years old treated with definitive lung SBRT. Patients who underwent SBRT were reviewed from 2009 to 2015 at 4 academic centers. Patients diagnosed at ≥ 80 years old were included. Kaplan-Meier and multivariate logistic regression and Cox proportional hazard regression analyses were performed. Recursive partitioning analysis was done to determine a subgroup of patients most likely to benefit from therapy. A total of 58 patients were included, with a median age of 84.9 years (range, 80.1-95.2 years), a median follow-up time of 19.9 months (range, 6.9-64.9 months), a median fraction size of 10.0 Gy (range, 7.0-20.0 Gy), and a median number of fractions of 5.0 (range, 3.0-8.0 fractions). On multivariate analysis, higher Karnofsky performance status (KPS) was associated with higher local recurrence-free survival (hazard ratio [HR], 0.92; P < .01), regional recurrence-free survival (HR, 0.94; P < .01), and overall survival (HR, 0.91; P < .01). On recursive partitioning analysis, patients with KPS ≥ 75 had improved 3-year cancer-specific and overall survival (99.4% and 91.9%, respectively) compared with patients with KPS < 75 (47.8% and 23.6%, respectively; P < .01). Definitive lung SBRT for early-stage non-small-cell lung cancer was efficacious and safe in patients ≥ 80 years old. Patients with a KPS of ≥ 75 derived the most benefit from therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Lack of a Dose-Effect Relationship for Pulmonary Function Changes After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer

    SciTech Connect

    Guckenberger, Matthias; Klement, Rainer J.; Kestin, Larry L.; Hope, Andrew J.; Belderbos, Jose; Werner-Wasik, Maria; Yan, Di; Sonke, Jan-Jakob; Bissonnette, Jean-Pierre; Xiao, Ying; Grills, Inga S.

    2013-03-15

    Purpose: To evaluate the influence of tumor size, prescription dose, and dose to the lungs on posttreatment pulmonary function test (PFT) changes after stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC). Methods and Materials: The analysis is based on 191 patients treated at 5 international institutions: inclusion criteria were availability of pre- and post-SBRT PFTs and dose-volume histograms of the lung and planning target volume (PTV); patients treated with more than 1 SBRT course were excluded. Correlation between early (1-6 months, median 3 months) and late (7-24 months, median 12 months) PFT changes and tumor size, planning target volume (PTV) dose, and lung doses was assessed using linear regression analysis, receiver operating characteristics analysis, and Lyman's normal tissue complication probability model. The PTV doses were converted to biologically effective doses and lung doses to 2 Gy equivalent doses before correlation analyses. Results: Up to 6 months after SBRT, forced expiratory volume in 1 second and carbon monoxide diffusion capacity changed by −1.4% (95% confidence interval [CI], −3.4% to 0) and −7.6% (95% CI, −10.2% to −3.4%) compared with pretreatment values, respectively. A modest decrease in PFTs was observed 7-24 months after SBRT, with changes of −8.1% (95% CI, −13.3% to −5.3%) and −12.4% (95% CI, −15.5% to −6.9%), respectively. Using linear regression analysis, receiver operating characteristic analysis, and normal tissue complication probability modeling, all evaluated parameters of tumor size, PTV dose, mean lung dose, and absolute and relative volumes of the lung exposed to minimum doses of 5-70 Gy were not correlated with early and late PFT changes. Subgroup analysis based on pre-SBRT PFTs (greater or equal and less than median) did not identify any dose-effect relationship. Conclusions: This study failed to demonstrate a significant dose-effect relationship for

  16. Altered microRNA expression and pre-mRNA splicing events reveal new mechanisms associated with early stage Mycobacterium avium subspecies paratuberculosis infection

    PubMed Central

    Liang, Guanxiang; Malmuthuge, Nilusha; Guan, Yongjuan; Ren, Yuwei; Griebel, Philip J.; Guan, Le Luo

    2016-01-01

    The molecular regulatory mechanisms of host responses to Mycobacterium avium subsp. paratuberculosis (MAP) infection during the early subclinical stage are still not clear. In this study, surgically isolated ileal segments in newborn calves (n = 5) were used to establish in vivo MAP infection adjacent to an uninfected control intestinal compartment. RNA-Seq was used to profile the whole transcriptome (mRNAs) and the microRNAome (miRNAs) of ileal tissues collected at one-month post-infection. The most related function of the differentially expressed mRNAs between infected and uninfected tissues was “proliferation of endothelial cells”, indicating that MAP infection may lead to the over-proliferation of endothelial cells. In addition, 46.2% of detected mRNAs displayed alternative splicing events. The pre-mRNA of two genes related to macrophage maturation (monocyte to macrophage differentiation-associated) and lysosome function (adenosine deaminase) showed differential alternative splicing events, suggesting that specific changes in the pre-mRNA splicing sites may be a mechanism by which MAP escapes host immune responses. Moreover, 9 miRNAs were differentially expressed after MAP infection. The integrated analysis of microRNAome and transcriptome revealed that these miRNAs might regulate host responses to MAP infection, such as “proliferation of endothelial cells” (bta-miR-196 b), “bacteria recognition” (bta-miR-146 b), and “regulation of the inflammatory response” (bta-miR-146 b). PMID:27102525

  17. Cell-based fluorescence assay for evaluation of new-drugs potential for phospholipidosis in an early stage of drug development.

    PubMed

    Fujimura, Hisako; Dekura, Eriha; Kurabe, Michie; Shimazu, Noriko; Koitabashi, Mieko; Toriumi, Wataru

    2007-08-01

    To evaluate new-drugs potential for phospholipidosis (PL), we developed a cell-based fluorescence assay using a fluorescent-labeled phospholipid analogue (NBD-PE). CHL/IU cells derived from newborn hamster lung were exposed to positive reference compounds (amiodarone, imipramine, chloroquine, propranolol, chlorpromazine and amantadine) in the presence of NBD-PE, and the level of PL, as indicated by accumulation of fluorescent inclusions in the cytoplasm, was evaluated using fluorescence microscopy and fluorometry. All positive reference compounds induced accumulation of fluorescent inclusions in a concentration-dependent manner with an increase in fluorescence intensity. Fluorescence microscopically, the positive dose of test compound was determined as the concentration with a grade equivalent to or above that of 3.13 microM of amiodarone. Based on this criterion, 8 of 20 test compounds including PL-positive or -negative compounds were judged positive that were concurrent with the pathological results from rat toxicity studies. Furthermore, a positive criterion for fluorometry was decided as equivalent to or above 25% of maximum intensity induced by 1.56-25.0 microM amiodarone. In comparison of fluorometry methods with fluorescence microscopy method, 19 of 20 compounds were judged same. From these findings, we concluded that the assay developed in this study is a rapid and reliable method to predict new-drugs potential for PL at an early stage of drug development.

  18. Telomere length and recurrence risk after curative resection in patients with early-stage non-small-cell lung cancer: a prospective cohort study.

    PubMed

    Kim, Eric S; Ye, Yuanqing; Vaporciyan, Ara A; Xing, Jinliang; Huang, Maosheng; Gu, Jian; Roth, Jack A; Lippman, Scott M; Wu, Xifeng

    2015-02-01

    We hypothesized that telomere length in peripheral blood would have significant predictive value for risk of recurrence after curative resection in non-small-cell lung cancer (NSCLC). This prospective study included 473 patients with histologically confirmed early stage NSCLC who underwent curative therapy at MD Anderson Cancer Center between 1995 and 2008. Relative telomere length (RTL) of peripheral leukocytes was measured by real-time polymerase chain reaction. The risk of recurrence was estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) using a multivariable Cox proportional hazard regression model. Median duration of follow-up was 61 months, and 151 patients (32%) had developed recurrence at time of analysis. Patients who developed recurrence had significantly longer mean RTL compared with those without recurrence (1.13 versus 1.07, p = 0.046). A subgroup analysis indicates that women had longer RTL compared with men (1.12 versus 1.06, p = 0.025), and the patients with adenocarcinoma demonstrated longer RTL compared with those with other histologic types (1.11 versus 1.05, p = 0.042). To determine whether longer RTL in women and adenocarcinoma subgroup would predict risk of recurrence, multivariate Cox analysis adjusting for age, sex, stage, pack year and treatment regimens was performed. Longer telomeres were significantly associated with higher risk of developing recurrence in women (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.02-4.96, p = 0.044) and adenocarcinoma subgroups (HR, 2.19; 95% CI, 1.05-4.55, p = 0.036). The increased risk of recurrence due to long RTL was more apparent in women with adenocarcinoma (HR, 2.67; 95% CI, 1.19-6.03, p = 0.018). This is the first prospective study to suggest that long RTL is associated with recurrence in early stage NSCLC after curative resection. Women and adenocarcinoma seem to be special subgroups in which telomere biology may play an important role.

  19. What Would Be the Most Appropriate α/β Ratio in the Setting of Stereotactic Body Radiation Therapy for Early Stage Non-Small Cell Lung Cancer

    PubMed Central

    Chi, Alexander; Wen, Sijin; Liao, Zhongxing; Fowler, Jack; Xu, Jiahong; Nguyen, Nam P.; Welsh, James S.; Komaki, Ritsuko

    2013-01-01

    We hypothesize that the correlation between the radiation dose expressed as the biologically effective dose (BED) and the clinical endpoints will correlate better as the value of the α/β ratio is increased to >10 Gy, which theoretically minimizes the overestimation of the dose potency associated with the linear quadratic (LQ) formula in the setting of stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC). A search was conducted in the PubMed electronic databases in August 2011. In the studies analyzed, increasing the α/β ratio is associated with an increase in the strength of the correlation between isocenter BED and local control, especially in the studies with median followup of ≥24 months, for which Spearman's correlation coefficients of 0.74–0.76 were achieved for α/β of 20 Gy, 30 Gy, and 50 Gy (P =  0.007–0.008). A trend toward statistical significance was observed for the correlation of isocenter BED and the 2-year overall survival when an α/β of 20 Gy was used approached statistical significance (P = 0.073). Our results suggest that an α/β > 10 Gy may be more appropriate for the prediction of dose response in the setting of lung SBRT. PMID:24350266

  20. Improved survival with stereotactic ablative radiotherapy (SABR) over lobectomy for early stage non-small cell lung cancer (NSCLC): addressing the fallout of disruptive randomized data

    PubMed Central

    Kavanagh, Brian D.; Karam, Sana D.

    2015-01-01

    The gold-standard therapy for early stage non-small cell lung cancer (esNSCLC) has historically been lobectomy with mediastinal lymph node dissection. However, up to one-third of patients with esNSCLC are considered medically-inoperable due to factors such as advanced age and comorbid illnesses. The past decade has witnessed a dramatic increase in the use of high-dose conformal radiotherapy delivered over 1-5 fractions, synonymously termed stereotactic ablative radiotherapy (SABR) or stereotactic body radiation therapy (SBRT). High rates of tumor control and favorable toxicity profiles have led to the adoption of SABR as the treatment of choice for medically-inoperable patients. Limited but growing data exist using SABR for medically-operable patients who are also candidates for lobectomy. A recent pooled analysis of two multicenter prospective randomized trials, the STARS (NCT00840749) and ROSEL (NCT00687986) protocols, published by Chang and colleagues (PMID 25981812) reported improved overall survival (OS) and reduced toxicity with SABR over lobectomy for medically-operable patients with esNSCLC. In this article we review the outcomes of this analysis in the context of existing radiotherapy and surgical data for NSCLC. Further, we discuss the potential causes and implications of these provocative results, including the shifting balance between oncologic control and treatment-related mortality in comparisons of SABR and surgical resection, termed the Head Start Effect. PMID:26244136

  1. A study of the early-stage evolution of relativistic electron-ion shock using three-dimensional particle-in-cell simulations

    SciTech Connect

    Choi, E. J.; Min, K.; Choi, C. R.; Nishikawa, K.-I.

    2014-07-15

    We report the results of a 3D particle-in-cell simulation carried out to study the early-stage evolution of the shock formed when an unmagnetized relativistic jet interacts with an ambient electron-ion plasma. Full-shock structures associated with the interaction are observed in the ambient frame. When open boundaries are employed in the direction of the jet, the forward shock is seen as a hybrid structure consisting of an electrostatic shock combined with a double layer, while the reverse shock is seen as a double layer. The ambient ions show two distinct features across the forward shock: a population penetrating into the shocked region from the precursor region and an accelerated population escaping from the shocked region into the precursor region. This behavior is a signature of a combination of an electrostatic shock and a double layer. Jet electrons are seen to be electrostatically trapped between the forward and reverse shock structures showing a ring-like distribution in a phase-space plot, while ambient electrons are thermalized and become essentially isotropic in the shocked region. The magnetic energy density grows to a few percent of the jet kinetic energy density at both the forward and the reverse shock transition layers in a rather short time scale. We see little disturbance of the jet ions over this time scale.

  2. Prognostic value of isolated tumor cells and micrometastases of lymph nodes in early-stage breast cancer: a French sentinel node multicenter cohort study.

    PubMed

    Houvenaeghel, Gilles; Classe, Jean-Marc; Garbay, Jean-Rémy; Giard, Sylvia; Cohen, Monique; Faure, Christelle; Hélène, Charytensky; Belichard, Catherine; Uzan, Serge; Hudry, Delphine; Azuar, Pierre; Villet, Richard; Penault Llorca, Frédérique; Tunon de Lara, Christine; Goncalves, Anthony; Esterni, Benjamin

    2014-10-01

    To define the prognostic value of isolated tumor cells (ITC), micrometastases (pN1mi) and macrometastases in early stage breast cancer (ESBC). We conducted a retrospective multicenter cohort study at 13 French sites. All the eligible patients who underwent SLNB from January 1999 to December 2008 were identified, and appropriate data were extracted from medical records and analyzed. Among 8001 patients, including 70% node-negative (n = 5588), 4% ITC (n = 305), 10% pN1mi (n = 794) and 16% macrometastases (n = 1314) with a median follow-up of 61.3 months, overall survival (OS) and recurrence-free survival (RFS) rates at 84 months were not statistically different in ITC or pN1mi compared to tumor-free nodes. Axillary recurrence (AR) was significantly more frequent in ITC (1.7%) and pN1mi (1.5%) compared to negative nodes (0.6%). Survival and AR rates of single macrometastases were not different from those of ITC or pN1mi. In case of 2 macrometastases or more, survival rates decreased and recurrence rates increased significantly. Micrometastases and ITC do not have a negative prognostic value. Single macrometastases might have an intermediate prognostic value while 2 macrometastases or more are associated with poorer prognosis.

  3. CaaX-prenyltransferases are essential for expression of genes involvedin the early stages of monoterpenoid biosynthetic pathway in Catharanthus roseus cells.

    PubMed

    Courdavault, Vincent; Thiersault, Martine; Courtois, Martine; Gantet, Pascal; Oudin, Audrey; Doireau, Pierre; St-Pierre, Benoit; Giglioli-Guivarc'h, Nathalie

    2005-04-01

    CaaX-prenyltransferases (CaaX-PTases) catalyse the covalent attachment of isoprenyl groups to conserved cysteine residues located at the C-terminal CaaX motif of a protein substrate. This post-translational modification is required for the function and/or subcellular localization of some transcription factors and components of signal transduction and membrane trafficking machinery. CaaX-PTases, including protein farnesyltransferase (PFT) and type-I protein geranylgeranyltransferase (PGGT-I), are heterodimeric enzymes composed of a common alpha subunit and a specific beta subunit. We have established RNA interference cell lines targeting the beta subunits of PFT and PGGT-I, respectively, in the Catharanthus roseus C20D cell line, which synthesizes monoterpenoid indole alkaloids in response to auxin depletion from the culture medium. In both types of RNAi cell lines, expression of a subset of genes involved in the early stage of monoterpenoid biosynthetic pathway (ESMB genes), including the MEP pathway, is strongly decreased. The role of CaaX-PTases in ESMB gene regulation was confirmed by using the general prenyltransferase inhibitor s-perillyl alcohol (SP) and the specific PFT inhibitor Manumycin A on the wild type line. Furthermore, supplementation of SP inhibited cells with monoterpenoid intermediates downstream of the steps encoded by the ESMB genes restores monoterpenoid indole alkaloids biosynthesis. We conclude that protein targets for both PFT and PGGT-I are required for the expression of ESMB genes and monoterpenoid biosynthesis in C. roseus, this represents a non previously described role for protein prenyltransferase in plants.

  4. Inhibitory effects of vitamin E on osteocyte apoptosis and DNA oxidative damage in bone marrow hemopoietic cells at early stage of steroid-induced femoral head necrosis.

    PubMed

    Jia, Yan-Bo; Jiang, Dian-Ming; Ren, Yi-Zhong; Liang, Zi-Hong; Zhao, Zhen-Qun; Wang, Yu-Xin

    2017-04-01

    Apoptosis and DNA oxidative damage serve significant roles in the pathogenesis of steroid‑induced femoral head necrosis. Vitamin E demonstrates anti‑apoptotic and anti‑oxidant properties. Therefore, the present study investigated the effects of vitamin E on osteocyte apoptosis and DNA oxidative damage in bone marrow hemopoietic cells at an early stage of steroid‑induced femoral head osteonecrosis. Japanese white rabbits were randomly divided into three groups (steroid, vitamin E‑treated, and control groups), each comprising 12 rabbits. Those in the steroid group (group S) were initially injected twice with an intravenous dose of 100 µg/kg Escherichia coli endotoxin, with a 24 h interval between the two injections, and then with an intramuscular dose of 20 mg/kg methylprednisolone, three times at intervals of 24 h in order to establish a rabbit model of osteonecrosis. The vitamin E treated group (group E) received the same treatment as group S, and were administered 0.6 g/kg/d vitamin E daily from the beginning of modeling. The control group (group C) was injected with normal saline at the equivalent dosage and times as the aforementioned two groups. Two time points, weeks 4 and 6 following the completion of modeling, were selected. Osteonecrosis was verified by histopathology with hematoxylin-eosin staining. The apoptosis rate of osteonecrosis was analyzed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The apoptosis expression levels of caspase‑3 and B‑cell lymphoma 2 (Bcl‑2), and DNA oxidative damage of bone marrow hematopoietic cells were analyzed by immunohistochemistry. At weeks 4 and 6 following the completion of modeling, the vacant bone lacunae rates of group E were 15.87±1.97 and 25.09±2.67%, respectively, lower than the results of 20.02±2.21 and 27.79±1.39% for group S; and the osteocyte apoptosis indexes of group E were 20.99±2.95 and 33.93±1.62%, respectively, lower than the results

  5. Early stage of nanocrystal growth

    SciTech Connect

    2012-01-01

    Berkeley Lab researchers at the Molecular Foundry have elucidated important mechanisms behind oriented attachment, the phenomenon that drives biomineralization and the growth of nanocrystals. This electron microscopy movie shows the early stage of nanocrystal growth. Nanoparticles make transient contact at many points and orientations until their lattices are perfectly matched. The particles then make a sudden jump-to-contact to form attached aggregates. (Movie courtesy of Jim DeYoreo)

  6. Strong expression of polypeptide N-acetylgalactosaminyltransferase 3 independently predicts shortened disease-free survival in patients with early stage oral squamous cell carcinoma.

    PubMed

    Harada, Yoshikazu; Izumi, Hiroto; Noguchi, Hirotsugu; Kuma, Akihiro; Kawatsu, Yuichiro; Kimura, Tomoko; Kitada, Shohei; Uramoto, Hidetaka; Wang, Ke-Yong; Sasaguri, Yasuyuki; Hijioka, Hiroshi; Miyawaki, Akihiko; Oya, Ryoichi; Nakayama, Toshiyuki; Kohno, Kimitoshi; Yamada, Sohsuke

    2016-01-01

    The polypeptide N-acetylgalactosaminyltransferase (GalNAc-Ts) family of enzymes regulates the critical initial steps of mucin-type O-glycosylation. Among GalNAc-Ts that may significantly influence cancer biology, thus affecting cell differentiation, adhesion, invasion, and/or metastasis, GalNAc-T3 exhibits a high expression in several human cancers, closely associated with tumor progression and a poor prognosis. However, the expression pattern of GalNAc-T3 in oral squamous cell carcinoma (OSCC) remains obscure. Since postoperative recurrence of even early stage OSCC (ESOSCC) occurs at an early phase, significantly affecting their clinical course and worse outcome, the identification of clinically significant accurate biomarkers is needed. Therefore, we investigated the correlation between the immunohistochemical GalNAc-T3 expression and various clinicopathological characteristics and recurrence using 110 paraffin-embedded tumor samples obtained from patients with surgically resected ESOSCC (T1-2N0). Recurrence was recognized in 37 of 110 (33.6 %) patients. The GalNAc-T3 expression was considered to be strongly positive when 20 % or more of the cancer cells showed positive cytoplasmic staining. Consequently, a strong expression of GalNAc-T3 was observed in 40 patients (36.4 %), showing a close relationship to poor differentiation, the presence of lymphatic and vascular invasion, and recurrence. Univariate and multivariate analyses further demonstrated that the patients with a strong GalNAc-T3+ status had markedly lower disease-free survival (DFS) rates, especially within the first 2 years postoperatively. Therefore, GalNAc-T3 might play a role in the pathogenesis of ESOSCC recurrence, and its immunohistochemical detection potentially predicts a shorter DFS and may be a useful parameter for providing clinical management against ESOSCC in the early postoperative phase.

  7. Phagosomal Acidification Prevents Macrophage Inflammatory Cytokine Production to Malaria, and Dendritic Cells Are the Major Source at the Early Stages of Infection

    PubMed Central

    Wu, Xianzhu; Gowda, Nagaraj M.; Gowda, D. Channe

    2015-01-01

    Inflammatory cytokines produced at the early stages of malaria infection contribute to shaping protective immunity and pathophysiology. To gain mechanistic insight into these processes, it is important to understand the cellular origin of cytokines because both cytokine input and cytokine-producing cells play key roles. Here, we determined cytokine responses by monocytes, macrophages, and dendritic cells (DCs) to purified Plasmodium falciparum and Plasmodium berghei ANKA, and by spleen macrophages and DCs from Plasmodium yoelii 17NXL-infected and P. berghei ANKA-infected mice. The results demonstrate that monocytes and macrophages do not produce inflammatory cytokines to malaria parasites and that DCs are the primary source early in infection, and DC subsets differentially produce cytokines. Importantly, blocking of phagosomal acidification by inhibiting vacuolar-type H+-ATPase enabled macrophages to elicit cytokine responses. Because cytokine responses to malaria parasites are mediated primarily through endosomal Toll-like receptors, our data indicate that the inability of macrophages to produce cytokines is due to the phagosomal acidification that disrupts endosomal ligand-receptor engagement. Macrophages efficiently produced cytokines to LPS upon simultaneously internalizing parasites and to heat-killed Escherichia coli, demonstrating that phagosomal acidification affects endosomal receptor-mediated, but not cell surface receptor-mediated, recognition of Toll-like receptor agonists. Enabling monocytes/macrophages to elicit immune responses to parasites by blocking endosomal acidification can be a novel strategy for the effective development of protective immunity to malaria. The results have important implications for enhancing the efficacy of a whole parasite-based malaria vaccine and for designing strategies for the development of protective immunity to pathogens that induce immune responses primarily through endosomal receptors. PMID:26240140

  8. Phagosomal Acidification Prevents Macrophage Inflammatory Cytokine Production to Malaria, and Dendritic Cells Are the Major Source at the Early Stages of Infection: IMPLICATION FOR MALARIA PROTECTIVE IMMUNITY DEVELOPMENT.

    PubMed

    Wu, Xianzhu; Gowda, Nagaraj M; Gowda, D Channe

    2015-09-18

    Inflammatory cytokines produced at the early stages of malaria infection contribute to shaping protective immunity and pathophysiology. To gain mechanistic insight into these processes, it is important to understand the cellular origin of cytokines because both cytokine input and cytokine-producing cells play key roles. Here, we determined cytokine responses by monocytes, macrophages, and dendritic cells (DCs) to purified Plasmodium falciparum and Plasmodium berghei ANKA, and by spleen macrophages and DCs from Plasmodium yoelii 17NXL-infected and P. berghei ANKA-infected mice. The results demonstrate that monocytes and macrophages do not produce inflammatory cytokines to malaria parasites and that DCs are the primary source early in infection, and DC subsets differentially produce cytokines. Importantly, blocking of phagosomal acidification by inhibiting vacuolar-type H(+)-ATPase enabled macrophages to elicit cytokine responses. Because cytokine responses to malaria parasites are mediated primarily through endosomal Toll-like receptors, our data indicate that the inability of macrophages to produce cytokines is due to the phagosomal acidification that disrupts endosomal ligand-receptor engagement. Macrophages efficiently produced cytokines to LPS upon simultaneously internalizing parasites and to heat-killed Escherichia coli, demonstrating that phagosomal acidification affects endosomal receptor-mediated, but not cell surface receptor-mediated, recognition of Toll-like receptor agonists. Enabling monocytes/macrophages to elicit immune responses to parasites by blocking endosomal acidification can be a novel strategy for the effective development of protective immunity to malaria. The results have important implications for enhancing the efficacy of a whole parasite-based malaria vaccine and for designing strategies for the development of protective immunity to pathogens that induce immune responses primarily through endosomal receptors.

  9. Virtual exploration of early stage atherosclerosis.

    PubMed

    Olivares, Andy L; González Ballester, Miguel A; Noailly, Jérôme

    2016-12-15

    Biological mechanisms contributing to atherogenesis are multiple and complex. The early stage of atherosclerosis (AS) is characterized by the accumulation of low-density lipoprotein (LDL) droplets, leading to the creation of foam cells (FC). To address the difficulty to explore the dynamics of interactions that controls this process, this study aimed to develop a model of agents and infer on the most influential cell- and molecule-related parameters. FC started to accumulate after six to eight months of simulated hypercholesterolemia. A sensitivity analysis revealed the strong influence of LDL oxidation rate on the risk of FC creation, which was exploited to model the antioxidant effect of statins. Combined with an empirical simulation of the drug ability to decrease the level of LDL, the virtual statins treatment led to reductions of oxidized LDL levels similar to reductions measured in vivo. An Open source software was used to develop the agent-based model of early AS. Two different concentrations of LDL agents were imposed in the intima layer to simulate healthy and hypercholesterolemia groups of 'virtual patients'. The interactions programmed between molecules and cells were based on experiments and models reported in the literature. A factorial sensitivity analysis explored the respective effects of the less documented model parameters as (i) agent migration speed, (ii) LDL oxidation rate and (iii) concentration of autoantibody agents. Finally, the response of the model to known perturbations was assessed by introducing statins agents, able to reduce the oxidation rate of LDL agents and the LDL boundary concentrations. jerome.noailly@upf.eduSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. Tumour budding evaluated in biopsy specimens is a useful predictor of prognosis in patients with cN0 early stage oral squamous cell carcinoma.

    PubMed

    Seki, Mai; Sano, Takaaki; Yokoo, Satoshi; Oyama, Tetsunari

    2017-05-01

    Oral squamous cell carcinoma (OSCC) prognosis depends upon lymph node metastasis (LNM). We have reported recently that tumour budding is a good predictive factor for LNM in squamous cell carcinoma (SCC) of the tongue and floor of the mouth (FOM). Our aim was to evaluate whether tumour budding is a good prognostic factor in OSCC. We examined conventional histopathological assessment and a new factor, tumour budding, in 209 cases of OSCC in incisional biopsy specimens. The relationship of tumour budding with LNM and prognosis was studied. The budding score was evaluated using immunostaining for pan-cytokeratin in all biopsies specimens; the number of budding foci was counted using a ×20 objective lens. Significant factors using univariate analysis (P < 0.05) in association with LNM were the budding score (intermediate or high score ≥3; high score ≥5), tumour grade (2 and 3), tumour depth (≥5 mm), infiltrative pattern (INF), lymphatic invasion and vessel invasion. In multivariate analysis, the budding score, INF and lymphatic invasion were found to be independent risk factors for LNM; in particular, budding score concerning relapse-free survival was statistically significant among patients with T1/2 stage and cN0 cancer using the Kaplan-Meier method and the log-rank test. The assessment of tumour budding is effective in predicting prognosis in cN0 early stage OSCC. In T1/2 stage and cN0 cancer, prophylactic neck dissection to prevent LNM should be considered when the tumour budding score regarding pre-operative biopsy specimens is intermediate or high. © 2016 John Wiley & Sons Ltd.

  11. Long-term survival of early-stage non-small cell lung cancer patients who underwent robotic procedure: a propensity score-matched study.

    PubMed

    Yang, Hao-Xian

    2016-07-07

    In the past decade, many researchers focused on to robot-assisted surgery. However, on long-term outcomes for patients with early-stage non-small cell lung cancer (NSCLC), whether the robotic procedure is superior to video-assisted thoracic surgery (VATS) and thoracotomy is unclear. Nonetheless, in the article titled "Long-term survival based on the surgical approach to lobectomy for clinical stage I non-small cell lung cancer: comparison of robotic, video assisted thoracic surgery, and thoracotomy lobectomy" by Yang et al. that was recently published in Annals of Surgery, the authors provided convincing evidence that the robotic procedure results in similar long-term survival as compared with VATS and thoracotomy. Minimally invasive procedures typically result in shorter lengths of hospital stay, and the robotic procedure in particular results in superior lymph node assessment. Our propensity score-matched study generated high-quality data. Based on our findings, we see promise in expanding patient access to robotic lung resections. In this study, propensity score matching minimized the bias involved between groups. Nevertheless, due to its retrospective nature, bias may still exist. Currently, the concept of rapid rehabilitation is widely accepted, and it is very difficult to set up a randomized controlled trial to compare robotic, VATS, and thoracotomy procedures for the treatment of NSCLC. Therefore, to overcome this limitation and to minimize bias, the best approach is to use a registry and prospectively collected, propensity score-matched data. Robotic lung resections result in similar long-term survival as compared with VATS and thoracotomy. Robot-assisted and VATS procedures are associated with short lengths of hospital stay, and the robotic procedure in particular results in superior lymph node assessment. Considering the alarming increase in the incidence of lung cancer in China, a nationwide database of prospectively collected data available for clinical

  12. Kaposi’s Sarcoma-Associated Herpesvirus Genome Programming during the Early Stages of Primary Infection of Peripheral Blood Mononuclear Cells

    PubMed Central

    Jha, Hem C.; Lu, Jie; Verma, Subhash C.; Banerjee, Shuvomoy; Mehta, Devan

    2014-01-01

    ABSTRACT The early period of Kaposi’s sarcoma-associated herpesvirus (KSHV) infection involves the dynamic expression of viral genes, which are temporally and epigenetically regulated. KSHV can effectively infect and persist in endothelial as well as human B cells with different gene expression patterns. To understand the temporal epigenetic changes which occur when KSHV infects the lymphocytic compartment, we infected human peripheral blood mononuclear cells (PBMCs) and comprehensively analyzed the changes which occurred at the binding sites of virally encoded lytic as well as latent proteins along with epigenetic modifications across the KSHV genome during early primary infection. Using chromatin immunoprecipitation (ChIP) assays, we showed that the KSHV genome acquires a uniquely distinct histone modification pattern of methylation (H3K4me3, H3K9me3, and H3K27me3) and acetylation (H3Ac) during de novo infection of human PBMCs. This pattern showed that the epigenetic changes were temporally controlled. The binding profiles of KSHV latent protein LANA and the immediate early proteins RTA and K8 showed specific patterns at different times postinfection, which reflects the gene expression program. Further analysis demonstrated that KSHV can concurrently express lytic and latent genes which were associated with histone modifications at these specific regions on the viral genome. We identified three KSHV genes, K3, ORF49, and ORF64, which exhibited different profiles of histone modifications during the early stages of PBMC infection. These studies established a distinct pattern of epigenetic modification which correlates with viral gene expression temporally regulated during the first 7 days of PBMC infection and provides clues to the regulatory program required for successful infection by KSHV of human PBMCs. PMID:25516617

  13. Use of laser capture microdissection for the assessment of equine lamellar basal epithelial cell signalling in the early stages of laminitis

    PubMed Central

    Leise, B. S.; Watts, M.; Roy, S.; Yilmaz, S.; Alder, H.; Belknap, J. K.

    2016-01-01

    Summary Reason for performing study Dysadhesion of the laminar basal epithelial cells (LBEC) from the underlying dermis is the central event leading to structural failure in equine laminitis. Although many studies of sepsis-related laminitis have reported multiple events occurring throughout the lamellar tissue, there is minimal information regarding signalling events occurring specifically in the LBEC. Objectives To determine the signalling events in the LBECs during the early stages of carbohydrate induced laminitis. Study Design Experimental study. Methods Eight horses were given an overload of carbohydrate (corn starch mixture, CHO) via nasogastric tube. Prior to administration of CHO, lamellar biopsies were taken from the left fore foot (CON). Biopsies were taken from the left hind foot at the onset of fever (DEV) and from the right fore foot at the onset of lameness (OG1). Laminar basal epithelial cells (LBECs) were isolated from cryosections using a LCM microscope. Next generation sequencing (RNA-Seq) was used to identify transcripts expressed in the LBECs for each time point and bioinformatic analysis was performed with thresholds for between group comparisons set at a greater than 2-fold change and p-value ≤0.05. Results Forty genes (22 increased/18 decreased) were significantly different from DEV time vs. CON and 107 genes (57 increased/50 decreased) were significantly different from OG1 time vs. CON. Significant increases in inflammatory genes were present in addition to significantly altered expression of genes related to extracellular matrix composition, stability and turnover. Conclusions Inflammatory response and extracellular matrix regulation signalling was strongly represented at the DEV and OG1 times. These results indicate that the LBEC is not only a casualty but also an active participant in lamellar events leading to structural failure of the digital lamellae in equine laminitis. PMID:24750316

  14. Altered MARCH1 ubiquination-regulated dendritic cell immune functions during the early stage of zymosan-induced multiple organ dysfunction syndrome (MODS) in mice.

    PubMed

    Li, Fei; Lu, Jiang-yang; Liu, Qian; Wang, Hong-wei; Guo, Huiqin

    2013-02-01

    Using a zymosan-induced mouse model of multiple organ dysfunction syndrome (MODS), we previously found profound increases in spleen immune cells' expressions of ubiquitin and MHC-II molecules and increased CD11c+ dendritic cells (DCs) within 24h of zymosan injection. We postulated that the early stage of MODS altered DCs function via an ubiquitination-associated mechanism. We intraperitoneally injected zymosan into 100 male C57BL/6 mice (0.8mg/g) and randomly divided them into 5 groups based on the days after injection (20mice/group): 1d, 3d, 5d, 7d, and 10d. Mice were examined for spleen CD11c+ DC functions at the indicated days. Untreated mice were used for normal spleen tissue and T cell samples. By qPCR, IL-12 and TNF-α mRNA expressions in spleen CD11c+ DCs were significantly increased in MODS 1d mice; on subsequent days post-injection, these mRNA levels gradually returned to control levels. The same patterns were found for MODS mice DCs induction of untreated mouse T cells proliferation and IL-2 and IFN-γ mRNA expressions. When T cell functions were examined using MODS 1d DCs with and without MG132 treatment, an inhibitor of ubiquitinated protein degradation, T cell functional activities were enhanced by DCs treated with MG132. MODS 1d DCs also had significantly reduced MARCH1 mRNA expression, a key ubiquitin ligase that regulates DCs MHC-II expression. Silencing DCs MARCH1 expression with siRNA resulted in enhancing their induction of T cell functional activities. Using co-immunoprecipitation, Western blot, and flow cytometry assays, we deduced that MARCH1 ubiquitinated DC surface MHC-II molecules to regulate DC's immune functions in MODS mice. Our results suggest that aberrant degradation of spleen DCs MARCH1-mediated ubiquitinated proteins is involved during the earliest stage of MODS development. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. RNA-Seq analysis of Citrus reticulata in the early stages of Xylella fastidiosa infection reveals auxin-related genes as a defense response.

    PubMed

    Rodrigues, Carolina M; de Souza, Alessandra A; Takita, Marco A; Kishi, Luciano T; Machado, Marcos A

    2013-10-03

    Citrus variegated chlorosis (CVC), caused by Xylella fastidiosa, is one the most important citrus diseases, and affects all varieties of sweet orange (Citrus sinensis L. Osb). On the other hand, among the Citrus genus there are different sources of resistance against X. fastidiosa. For these species identifying these defense genes could be an important step towards obtaining sweet orange resistant varieties through breeding or genetic engineering. To assess these genes we made use of mandarin (C. reticulata Blanco) that is known to be resistant to CVC and shares agronomical characteristics with sweet orange. Thus, we investigated the gene expression in Ponkan mandarin at one day after infection with X. fastidiosa, using RNA-seq. A set of genes considered key elements in the resistance was used to confirm its regulation in mandarin compared with the susceptible sweet orange. Gene expression analysis of mock inoculated and infected tissues of Ponkan mandarin identified 667 transcripts repressed and 724 significantly induced in the later. Among the induced transcripts, we identified genes encoding proteins similar to Pattern Recognition Receptors. Furthermore, many genes involved in secondary metabolism, biosynthesis and cell wall modification were upregulated as well as in synthesis of abscisic acid, jasmonic acid and auxin. This work demonstrated that the defense response to the perception of bacteria involves cell wall modification and activation of hormone pathways, which probably lead to the induction of other defense-related genes. We also hypothesized the induction of auxin-related genes indicates that resistant plants initially recognize X. fastidiosa as a necrotrophic pathogen.

  16. RNA-Seq analysis of Citrus reticulata in the early stages of Xylella fastidiosa infection reveals auxin-related genes as a defense response

    PubMed Central

    2013-01-01

    Background Citrus variegated chlorosis (CVC), caused by Xylella fastidiosa, is one the most important citrus diseases, and affects all varieties of sweet orange (Citrus sinensis L. Osb). On the other hand, among the Citrus genus there are different sources of resistance against X. fastidiosa. For these species identifying these defense genes could be an important step towards obtaining sweet orange resistant varieties through breeding or genetic engineering. To assess these genes we made use of mandarin (C. reticulata Blanco) that is known to be resistant to CVC and shares agronomical characteristics with sweet orange. Thus, we investigated the gene expression in Ponkan mandarin at one day after infection with X. fastidiosa, using RNA-seq. A set of genes considered key elements in the resistance was used to confirm its regulation in mandarin compared with the susceptible sweet orange. Results Gene expression analysis of mock inoculated and infected tissues of Ponkan mandarin identified 667 transcripts repressed and 724 significantly induced in the later. Among the induced transcripts, we identified genes encoding proteins similar to Pattern Recognition Receptors. Furthermore, many genes involved in secondary metabolism, biosynthesis and cell wall modification were upregulated as well as in synthesis of abscisic acid, jasmonic acid and auxin. Conclusions This work demonstrated that the defense response to the perception of bacteria involves cell wall modification and activation of hormone pathways, which probably lead to the induction of other defense-related genes. We also hypothesized the induction of auxin-related genes indicates that resistant plants initially recognize X. fastidiosa as a necrotrophic pathogen. PMID:24090429

  17. Assessing the usefulness of 18F-fluorodeoxyglucose PET-CT scan after stereotactic body radiotherapy for early-stage non-small cell lung cancer.

    PubMed

    Pastis, Nicholas J; Greer, Travis J; Tanner, Nichole T; Wahlquist, Amy E; Gordon, Leonie L; Sharma, Anand K; Koch, Nicholas C; Silvestri, Gerard A

    2014-08-01

    Although stereotactic body radiation therapy (SBRT) is an established treatment option for early-stage lung cancer, there are no guidelines for reassessing patients for local treatment failure or intrathoracic recurrence after treatment. This study reports the sensitivity, specificity, and positive and negative predictive values for 18F-fluorodeoxyglucose (FDG) PET-CT scanning when used to evaluate patients after SBRT. Charts were reviewed of all patients who received SBRT and a subsequent FDG PET-CT scan at a university hospital over a 5-year period. Pretreatment and 3-month posttreatment tumor characteristics on PET-CT scan and outcome data (adverse events from SBRT, need for repeat biopsy, rate of local treatment failure and recurrent disease, and all-cause mortality) were recorded. Eighty-eight patients were included in the study. Fourteen percent of patients (12 of 88) had positive 3-month PET scans. Of the positive results, 67% (eight of 12) were true positives. Eighty-six percent (76 of 88 patients) had negative 3-month FDG PET-CT scans, with 89% (68 of 76) true negatives. FDG PET-CT scan performed 3 months after SBRT for non-small cell lung cancer (NSCLC) had a sensitivity of 50% (95% CI, 0.26-0.75), a specificity of 94% (95% CI, 0.89-1.0), a positive predictive value of 67% (95% CI, 0.4-0.93), and a negative predictive value of 89% (95% CI, 0.83- 0.96). FDG PET-CT scan 3 months after treatment of NSCLC with SBRT was a specific but insensitive test for the detection of recurrence or treatment failure. Serial CT scans should be used for early surveillance following SBRT, whereas FDG PET-CT scans should be reserved to define suspected metastatic disease or to evaluate new abnormalities on CT scan, or for possible reassessment later in the follow-up period after radiation-related inflammation subsides.

  18. Definitive Treatment of Early-Stage Non-Small Cell Lung Cancer with Stereotactic Ablative Body Radiotherapy in a Community Cancer Center Setting.

    PubMed

    Heal, Cory; Ding, William; Lamond, John; Wong, Michael; Lanciano, Rachelle; Su, Stacy; Yang, Jun; Feng, Jing; Arrigo, Stephen; Markiewicz, Deborah; Hanlon, Alexandra; Brady, Luther

    2015-01-01

    Stereotactic ablative body radiotherapy (SABR) provides a superior non-small cell lung cancer (NSCLC) treatment option when compared to conventional radiotherapy for patients deemed inoperable or refusing surgery. This study retrospectively analyzed the rates of tumor control and toxicity following SABR treatment (Cyberknife system) of primary early-stage NSCLC in a community setting. One hundred patients were treated between 2007 and 2011. Patients with T3-4 or N1-3 disease, metastasis, recurrent local disease, or a non-lung primary were excluded from analysis. All patients had biopsy proven disease. Staging included CT or fluorodeoxyglucose-positron emission tomography scan. Median dose was 54 Gy (45-60); 18 Gy (10-20) per fraction. Median planned target volume expansion was 8 mm (2-10). Median BED was 151.2. Tumors were tracked via Synchrony, X-Sight Lung, or X-Sight Spine. Patients were evaluated for local control, overall survival (OS), and toxicity. All local failures were determined by evaluating post treatment PET/CT. With a median follow up of 27.5 months, the 1-, 2-, and 3-year local control rates were 100, 93.55, and 84.33%, respectively. Median survival was 2.29 years; actuarial 3-year survival was 37.20%. Grade-3 toxicity was observed in 2% of patients (pneumonia within 2 months of treatment, n = 1; chronic pneumonitis requiring hospital admission, n = 1). No patients demonstrated toxicity above Grade-3. Multivariate analysis did not show T-stage as an independent predictor of OS, though it did trend toward significance. In a community-center setting, definitive treatment of NSCLC with SABR for non-surgical candidates and those who choose to forego surgery result in excellent and comparable rates of local control and toxicity compared to published series from large academic centers.

  19. Biomarkers p16, Human Papillomavirus and p53 Predict Recurrence and Survival in Early Stage Squamous Cell Carcinoma of the Vulva.

    PubMed

    Hay, Casey M; Lachance, Jason A; Lucas, F L; Smith, Kahsi A; Jones, Michael A

    2016-07-01

    Vulvar squamous cell carcinoma (VSCC) develops through 2 distinct molecular pathways, one involving high-risk human papillomavirus (HPV) infection and the other through early p53 suppressor gene mutation. We sought to evaluate the influence of p53 mutation, HPV status, and p16 expression on local recurrence and disease-specific mortality in early stage VSCC. We performed a retrospective chart review of all patients with stage I VSCC at the Maine Medical Center from 1998 to 2007 (n = 92). Tumor size, depth of invasion, lymphatic/vascular space invasion, and growth pattern were recorded. Paraffin-embedded tissue blocks were stained by immunohistochemistry for p16 and p53; high-risk HPV was detected by polymerase chain reaction assay. Margin distance was determined by a gynecologic pathologist. Survival analyses were conducted to examine predictors of VSCC recurrence and disease-specific mortality. Age, depth of invasion, lymphatic/vascular space invasion, growth pattern, and margin status were not significant predictors of recurrence or disease-specific mortality. Tumor size of greater than 4.0 cm indicated a 4-fold increase in disease-specific mortality but did not significantly increase recurrence. p16-Positive patients were less likely to recur and had no VSCC-related deaths. Human papillomavirus-positive patients were less likely to recur and had no VSCC-related deaths. p53-positive patients were 3 times more likely to recur and nearly 7 times more likely to die from vulvar cancer. Our findings suggest that HPV and the surrogate biomarker p16 indicate a less aggressive type of vulvar cancer. p53 positivity was associated with poor prognosis and significantly increased both recurrence and disease-specific mortality.

  20. Are we ready to use biomarkers for staging, prognosis and treatment selection in early-stage non-small-cell lung cancer?

    PubMed Central

    Massuti, Bartomeu; Sanchez, Jose Miguel; Hernando-Trancho, Florentino; Rosell, Rafael

    2013-01-01

    Lung cancer accounts for the majority of cancer-related deaths worldwide. At present, platinum-based therapy represents the standard of care in fit stage II and IIIA non-small cell lung cancer (NSCLC) patients following surgical resection. In advanced disease, personalized chemotherapy and targeted biologic therapy based on histological and molecular tumor profiling have already shown promise in terms of optimizing treatment efficacy. While disease stage is associated with outcome and is commonly used to determine adjuvant treatment eligibility, it is known that a subset of patients with early stage disease experience shorter survival than others with the same clinicopathological characteristics. Improved methods for identifying these individuals, at or near the time of initial diagnosis, may inform the decision to pursue adjuvant therapy options. Among the numerous candidate molecular biomarkers, only few gene-expression profiling signatures provide clinically relevant information, while real-time quantitative polymerase-chain reaction (RT-qPCR) strategy involving relatively small numbers of genes offers a practical alternative with high cross-platform performance. mRNA and/or protein expression levels of excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase M subunit 1 (RRM1) and breast cancer susceptibility gene 1 (BRCA1) are among the most promising potential biomarkers for early disease and their clinical utility is currently being evaluated in randomized phase II and III clinical trials. This review describes the most promising clinicopathological and molecular biomarkers with predictive and prognostic significance in lung cancer that have been identified through advanced research and which could influence adjuvant and neoadjuvant chemotherapy decisions for operable NSCLC in routine clinical practice. PMID:25806234

  1. [Mortality in early-stage, surgically resected non-small cell lung cancer less than 3 cm of size: Competing risk analysis].

    PubMed

    Jordá Aragón, Carlos; Peñalver Cuesta, Juan Carlos; Mancheño Franch, Nuria; de Aguiar Quevedo, Karol; Vera Sempere, Francisco; Padilla Alarcón, José

    2015-09-07

    Survival studies of non-small cell lung cancer (NSCLC) are usually based on the Kaplan-Meier method. However, other factors not covered by this method may modify the observation of the event of interest. There are models of cumulative incidence (CI), that take into account these competing risks, enabling more accurate survival estimates and evaluation of the risk of death from other causes. We aimed to evaluate these models in resected early-stage NSCLC patients. This study included 263 patients with resected NSCLC whose diameter was ≤ 3 cm without node involvement (N0). Demographic, clinical, morphopathological and surgical variables, TNM classification and long-term evolution were analysed. To analyse CI, death by another cause was considered to be competitive event. For the univariate analysis, Gray's method was used, while Fine and Gray's method was employed for the multivariate analysis. Mortality by NSCLC was 19.4% at 5 years and 14.3% by another cause. Both curves crossed at 6.3 years, and probability of death by another cause became greater from this point. In multivariate analysis, cancer mortality was conditioned by visceral pleural invasion (VPI) (P=.001) and vascular invasion (P=.020), with age>50 years (P=.034), smoking (P=.009) and the Charlson index ≥ 2 (P=.000) being by no cancer. By the method of CI, VPI and vascular invasion conditioned cancer death in NSCLC >3 cm, while non-tumor causes of long-term death were determined. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  2. Morphogenesis of early stage melanoma

    NASA Astrophysics Data System (ADS)

    Chatelain, Clément; Amar, Martine Ben

    2015-08-01

    Melanoma early detection is possible by simple skin examination and can insure a high survival probability when successful. However it requires efficient methods for identifying malignant lesions from common moles. This paper provides an overview first of the biological and physical mechanisms controlling melanoma early evolution, and then of the clinical tools available today for detecting melanoma in vivo at an early stage. It highlights the lack of diagnosis methods rationally linking macroscopic observables to the microscopic properties of the tissue, which define the malignancy of the tumor. The possible inputs of multiscale models for improving these methods are shortly discussed.

  3. A propensity-matched analysis of surgery and stereotactic body radiotherapy for early stage non-small cell lung cancer in the elderly

    PubMed Central

    Wang, Peng; Zhang, Dong; Guo, Xue-Guang; Li, Xiao-Mei; Du, Le-Hui; Sun, Bao-Jun; Fang, Xiang-Qun; Guo, Ying-Hua; Guo, Jun; An, Li; Qu, Ge-Ping; Liu, Chang-Ting

    2016-01-01

    Abstract Elderly patients with early stage non-small cell lung cancer (NSCLC) who undergo surgical resection are at a high risk of treatment-related complications. Stereotactic body radiation therapy (SBRT) is considered an alternative treatment option with a favorable safety profile. Given that prospective comparative data on SBRT and surgical treatments are limited, we compared the 2 treatments for early stage NSCLC in the elderly. We retrospectively collected information from the database at our geriatric institution on patients with clinical stage IA/B NSCLC who were treated with surgery or SBRT. The patients were matched using a propensity score based on gender, age, T stage, tumor location, pulmonary function (forced expiratory volume in 1 second [FEV1]% and FEV1), Charlson comorbidity score, and World Health Organization performance score. We compared locoregional control rate, recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) between the 2 treatment cohorts before and after propensity score matching. A total of 106 patients underwent surgery, and 74 received SBRT. Surgical patients were significantly younger (72.6 ± 7.9 vs 82.6 ± 4.1 years, P = 0.000), with a significantly higher rate of adenocarcinoma (P = 0.000), better Eastern Cooperative Oncology Group performance scores (P = 0.039), and better pulmonary function test results (P = 0.034 for predicted FEV1 and P = 0.032 for FEV1). In an unmatched comparison, there were significant differences in locoregional control (P = 0.0012) and RFS (P < 0.001). The 5-year OS was 69% in patients who underwent surgery and 44.6% in patients who underwent SBRT (P = 0.0007). The 5-year CSS was 73.9% in the surgery group and 57.5% in the SBRT group (P = 0.0029). Thirty-five inoperable or marginally operable surgical patients and 35 patients who underwent SBRT were matched to their outcomes in a blinded manner (1:1 ratio, caliper

  4. [Influences of exendin-4 on the secretion function of islet beta cells from rats in the early stage of severe scald].

    PubMed

    Zhao, D X; Ma, L; Shen, Z A; Li, D W; Shang, Y R; Yin, K; Cheng, W F; Wang, X; Liu, Z X

    2016-12-20

    Objective: To observe the secretion function changes of islet beta cells isolated from rats in the early stage of severe scald, and to explore the influence of them. Methods: Thirty-six Wistar rats were divided into sham injury (SI) group, sham injury+ exendin-4 (SIE) group, scald (S) group, and scald+ exendin-4 (SE) group according to the random number table, with 9 rats in each group. Rats in groups S and SE were inflicted with 50% total body surface area full-thickness scald by a 12-s immersion of back and a 6-s immersion of abdomen in 94 ℃ hot water. Rats in groups SI and SIE were sham injured through immersion of back and abdomen in 37 ℃ warm water. Rats in groups S and SE were subcutaneously injected with exendin-4 (4 μg/kg) twice a day post injury, while rats in groups SI and SIE were subcutaneously injected with sterile water in the same volume. At post injury hour (PIH) 72, the following detections were performed. Eight rats of each group were respectively selected to measure level of fasting blood glucose with cutting-tail method, and to detect plasma level of glucagon-like peptide 1 (GLP-1) and serum level of insulin by enzyme-linked immunosorbent assay (ELISA). The insulin resistant index (HOMA-IR) was calculated. Six rats of each group were respectively selected for islet isolation. The isolated rat islets were stimulated with RPMI 1640 medium containing 2.8 or 16.7 mmol/L glucose, respectively. Insulin content in supernatant was detected by ELISA, and insulin secretion index was calculated with 6 samples in each group. The isolated islets from 3 rats of each group were selected for the observation of the super-structure of islet beta cells under transmission electron microscope. The number of docked granules in per 10 μm membrane of islet beta cells and the ratio of insulin vesicles to the total insulin granules were calculated with 3 samples in each group. Data were processed with one-way analysis of variance and LSD test. Results: (1) Compared

  5. Evaluation of Tumor-Derived Exosomal miRNA as Potential Diagnostic Biomarkers for Early-Stage Non-Small Cell Lung Cancer Using Next-Generation Sequencing.

    PubMed

    Jin, Xiance; Chen, Yanfan; Chen, Hanbin; Fei, Shaoran; Chen, Didi; Cai, Xiaona; Liu, Linger; Lin, Baochai; Su, Huafang; Zhao, Lihao; Su, Meng; Pan, Huanle; Shen, Lanxiao; Xie, Deyao; Xie, Congying

    2017-09-01

    Purpose: To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma and squamous cell carcinoma (SCC) as a noninvasive method in the early diagnosis of non-small cell lung cancer (NSCLC).Experimental Design: Tumor-derived exosomes from the plasma of early-stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate adenocarcinoma- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals.Results: There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in adenocarcinoma and SCC patients, respectively, compared with healthy volunteers. Distinct adenocarcinoma- and SCC-specific exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24, and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p, and miR-361-5p were adenocarcinoma-specific, and miR-10b-5p, miR-15b-5p, and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, adenocarcinoma, and SCC, respectively.Conclusions: Tumor-derived exosomal miRNAs, adenocarcinoma-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p, and miR-320b were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for early NSCLC diagnosis. Clin Cancer Res; 23(17); 5311-9. ©2017 AACR. ©2017 American Association for Cancer Research.

  6. No differences in radiological changes after 3D conformal vs VMAT-based stereotactic radiotherapy for early stage non-small cell lung cancer.

    PubMed

    Badellino, Serena; Muzio, Jacopo Di; Schivazappa, Giulia; Guarneri, Alessia; Ragona, Riccardo; Bartoncini, Sara; Trino, Elisabetta; Filippi, Andrea Riccardo; Fonio, Paolo; Ricardi, Umberto

    2017-10-01

    To compare patterns of acute and late radiological lung injury following either 3D conformal or image-guided volumetric modulated arc therapy stereotactic radiotherapy for Stage I non-small-cell lung cancer. We included 148 patients from a prospective mono-institutional stereotactic body radiation therapy (SBRT) series (time interval 2004-2014), treated with prescription BED10 Gy (at 80%) in the range 100-120 Gy. The first 95 patients (2004-2010) were planned with 3D-CRT, with a stereotactic body frame. The second cohort (2010-2014) included 53 patients, planned with volumetric IMRT on a smaller planning target volume generated from a patient's specific internal target volume, with a frameless approach through cone-beam CT guidance. Acute and late radiological modifications were scored based on modified Kimura's and Koenig's classifications, respectively. Median follow-up time was 20.5 months. The incidence of acute radiological changes was superimposable between the groups: increased density was observed in 68.4 and 64.2% of patients for 3D-CRT and VMAT, respectively, and patchy ground glass opacity in 23.7 and 24.5%, respectively; diffuse ground glass opacity was 2.6 vs 9.4%, respectively, and patchy consolidation 2.6 vs 1.9%, respectively. Late changes occurred in approximately 60% of patients: modified conventional pattern was the most frequent modification (25 vs 32.6%, respectively); other patterns were less common (mass-like 19.6 vs 17.4%, and scar-like 13 vs 10.9%, respectively). Results of the present study indicate that the pattern of radiological lung changes following SBRT for peripheral early stage non-small-cell lung cancer is not influenced by the different techniques used for planning and delivery. Advances in knowledge: This comparative observational study shows that smaller margins, image guidance and most importantly dose distribution do not change the pattern of radiological injury after lung SBRT; the same scoring system can be used, and

  7. The Impact of Tumor Size on Outcomes After Stereotactic Body Radiation Therapy for Medically Inoperable Early-Stage Non-Small Cell Lung Cancer

    SciTech Connect

    Allibhai, Zishan; Taremi, Mojgan; Bezjak, Andrea; Brade, Anthony; Hope, Andrew J.; Sun, Alexander; Cho, B.C. John

    2013-12-01

    Purpose: Stereotactic body radiation therapy for medically inoperable early-stage non-small cell lung cancer (NSCLC) offers excellent control rates. Most published series deal mainly with small (usually <4 cm), peripheral, solitary tumors. Larger tumors are associated with poorer outcomes (ie, lower control rates, higher toxicity) when treated with conventional RT. It is unclear whether SBRT is sufficiently potent to control these larger tumors. We therefore evaluated and examined the influence of tumor size on treatment outcomes after SBRT. Methods and Materials: Between October 2004 and October 2010, 185 medically inoperable patients with early (T1-T2N0M0) NSCLC were treated on a prospective research ethics board-approved single-institution protocol. Prescription doses were risk-adapted based on tumor size and location. Follow-up included prospective assessment of toxicity (as per Common Terminology Criteria for Adverse Events, version 3.0) and serial computed tomography scans. Patterns of failure, toxicity, and survival outcomes were calculated using Kaplan-Meier method, and the significance of tumor size (diameter, volume) with respect to patient, treatment, and tumor factors was tested. Results: Median follow-up was 15.2 months. Tumor size was not associated with local failure but was associated with regional failure (P=.011) and distant failure (P=.021). Poorer overall survival (P=.001), disease-free survival (P=.001), and cause-specific survival (P=.005) were also significantly associated with tumor size (with tumor volume more significant than diameter). Gross tumor volume and planning target volume were significantly associated with grade 2 or worse radiation pneumonitis. However, overall rates of grade ≥3 pneumonitis were low and not significantly affected by tumor or target size. Conclusions: Currently employed stereotactic body radiation therapy dose regimens can provide safe effective local therapy even for larger solitary NSCLC tumors (up to 5.7 cm

  8. Variations of target volume definition and daily target volume localization in stereotactic body radiotherapy for early-stage non-small cell lung cancer patients under abdominal compression.

    PubMed

    Han, Chunhui; Sampath, Sagus; Schultheisss, Timothy E; Wong, Jeffrey Y C

    2017-01-01

    We aimed to compare gross tumor volumes (GTV) in 3-dimensional computed tomography (3DCT) simulation and daily cone beam CT (CBCT) with the internal target volume (ITV) in 4-dimensional CT (4DCT) simulation in stereotactic body radiotherapy (SBRT) treatment of patients with early-stage non-small cell lung cancer (NSCLC) under abdominal compression. We retrospectively selected 10 patients with NSCLC who received image-guided SBRT treatments under abdominal compression with daily CBCT imaging. GTVs were contoured as visible gross tumor on the planning 3DCT and daily CBCT, and ITVs were contoured using maximum intensity projection (MIP) images of the planning 4DCT. Daily CBCTs were registered with 3DCT and MIP images by matching of bony landmarks in the thoracic region to evaluate interfractional GTV position variations. Relative to MIP-based ITVs, the average 3DCT-based GTV volume was 66.3 ± 17.1% (range: 37.5% to 92.0%) (p < 0.01 in paired t-test), and the average CBCT-based GTV volume was 90.0 ± 6.7% (daily range: 75.7% to 107.1%) (p = 0.02). Based on bony anatomy matching, the center-of-mass coordinates for CBCT-based GTVs had maximum absolute shift of 2.4 mm (left-right), 7.0 mm (anterior-posterior [AP]), and 5.2 mm (superior-inferior [SI]) relative to the MIP-based ITV. CBCT-based GTVs had average overlapping ratio of 81.3 ± 11.2% (range: 45.1% to 98.9%) with the MIP-based ITV, and 57.7 ± 13.7% (range: 35.1% to 83.2%) with the 3DCT-based GTV. Even with abdominal compression, both 3DCT simulations and daily CBCT scans significantly underestimated the full range of tumor motion. In daily image-guided patient setup corrections, automatic bony anatomy-based image registration could lead to target misalignment. Soft tissue-based image registration should be performed for accurate treatment delivery. Copyright © 2017 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

  9. Support vector machine-based prediction of local tumor control after stereotactic body radiation therapy for early-stage non-small cell lung cancer.

    PubMed

    Klement, Rainer J; Allgäuer, Michael; Appold, Steffen; Dieckmann, Karin; Ernst, Iris; Ganswindt, Ute; Holy, Richard; Nestle, Ursula; Nevinny-Stickel, Meinhard; Semrau, Sabine; Sterzing, Florian; Wittig, Andrea; Andratschke, Nicolaus; Guckenberger, Matthias

    2014-03-01

    Several prognostic factors for local tumor control probability (TCP) after stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) have been described, but no attempts have been undertaken to explore whether a nonlinear combination of potential factors might synergistically improve the prediction of local control. We investigated a support vector machine (SVM) for predicting TCP in a cohort of 399 patients treated at 13 German and Austrian institutions. Among 7 potential input features for the SVM we selected those most important on the basis of forward feature selection, thereby evaluating classifier performance by using 10-fold cross-validation and computing the area under the ROC curve (AUC). The final SVM classifier was built by repeating the feature selection 10 times with different splitting of the data for cross-validation and finally choosing only those features that were selected at least 5 out of 10 times. It was compared with a multivariate logistic model that was built by forward feature selection. Local failure occurred in 12% of patients. Biologically effective dose (BED) at the isocenter (BED(ISO)) was the strongest predictor of TCP in the logistic model and also the most frequently selected input feature for the SVM. A bivariate logistic function of BED(ISO) and the pulmonary function indicator forced expiratory volume in 1 second (FEV1) yielded the best description of the data but resulted in a significantly smaller AUC than the final SVM classifier with the input features BED(ISO), age, baseline Karnofsky index, and FEV1 (0.696 ± 0.040 vs 0.789 ± 0.001, P<.03). The final SVM resulted in sensitivity and specificity of 67.0% ± 0.5% and 78.7% ± 0.3%, respectively. These results confirm that machine learning techniques like SVMs can be successfully applied to predict treatment outcome after SBRT. Improvements over traditional TCP modeling are expected through a nonlinear combination of multiple features

  10. Support Vector Machine-Based Prediction of Local Tumor Control After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer

    SciTech Connect

    Klement, Rainer J.; Allgäuer, Michael; Appold, Steffen; Dieckmann, Karin; Ernst, Iris; Ganswindt, Ute; Holy, Richard; Nestle, Ursula; Nevinny-Stickel, Meinhard; Semrau, Sabine; Sterzing, Florian; Wittig, Andrea; Andratschke, Nicolaus; Guckenberger, Matthias

    2014-03-01

    Background: Several prognostic factors for local tumor control probability (TCP) after stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) have been described, but no attempts have been undertaken to explore whether a nonlinear combination of potential factors might synergistically improve the prediction of local control. Methods and Materials: We investigated a support vector machine (SVM) for predicting TCP in a cohort of 399 patients treated at 13 German and Austrian institutions. Among 7 potential input features for the SVM we selected those most important on the basis of forward feature selection, thereby evaluating classifier performance by using 10-fold cross-validation and computing the area under the ROC curve (AUC). The final SVM classifier was built by repeating the feature selection 10 times with different splitting of the data for cross-validation and finally choosing only those features that were selected at least 5 out of 10 times. It was compared with a multivariate logistic model that was built by forward feature selection. Results: Local failure occurred in 12% of patients. Biologically effective dose (BED) at the isocenter (BED{sub ISO}) was the strongest predictor of TCP in the logistic model and also the most frequently selected input feature for the SVM. A bivariate logistic function of BED{sub ISO} and the pulmonary function indicator forced expiratory volume in 1 second (FEV1) yielded the best description of the data but resulted in a significantly smaller AUC than the final SVM classifier with the input features BED{sub ISO}, age, baseline Karnofsky index, and FEV1 (0.696 ± 0.040 vs 0.789 ± 0.001, P<.03). The final SVM resulted in sensitivity and specificity of 67.0% ± 0.5% and 78.7% ± 0.3%, respectively. Conclusions: These results confirm that machine learning techniques like SVMs can be successfully applied to predict treatment outcome after SBRT. Improvements over traditional TCP

  11. Stereotactic Ablative Radiation Therapy is Highly Safe and Effective for Elderly Patients With Early-stage Non-Small Cell Lung Cancer.

    PubMed

    Brooks, Eric D; Sun, Bing; Zhao, Lina; Komaki, Ritsuko; Liao, Zhonxing; Jeter, Melenda; Welsh, James W; O'Reilly, Michael S; Gomez, Daniel R; Hahn, Stephen M; Heymach, John V; Rice, David C; Chang, Joe Y

    2017-07-15

    To discern the effectiveness and toxicity of stereotactic ablative radiation therapy (SABR) in the elderly population (aged ≥75 years) and to consider how SABR outcomes compare with surgical outcomes historically reported in the elderly. A total of 772 patients with clinical early-stage I-II non-small cell lung cancer (NSCLC; stage T1-T3N0M0) underwent SABR (50 Gy in 4 fractions or 70 Gy in 10 fractions) from 2004 to 2014 at our center (n=442, aged <75 years; n=330, aged ≥75 years). The primary endpoints included overall survival (OS), time-to-progression, and grade ≥3 toxicity. The median follow-up time was approximately 55 months. Compared with patients aged <75 years, those aged ≥75 years had no difference in the time-to-progression (P=.419), lung cancer-specific survival (P=.275), or toxicity (P=.536). OS was the same between both age groups at 2 years of follow-up but diverged thereafter, with patients aged <75 years when treatment began having greater OS rates at 5 years. The median OS rates for patients aged ≥75 years were 86% at 1 year, 57.5% at 3 years, and 39.5% at 5 years. The median OS rates for patients aged <75 years were 87.3% at 1 year, 67.6% at 3 years, and 51.5% at 5 years. No patient aged ≥75 years experienced any grade 4 or 5 toxicity. The effectiveness of SABR was the same for the elderly as for the average-age population according to lung cancer-specific survival and time-to-progression. It also poses no increased toxicity. Compared with the historical outcomes with surgery in the elderly, SABR outcomes can be considered comparable for stage I-II disease but with less morbidity. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 in early stage of non-small cell lung cancer.

    PubMed

    Lafuente-Sanchis, A; Zúñiga, Á; Galbis, J M; Cremades, A; Estors, M; Martínez-Hernández, N J; Carretero, J

    2016-08-01

    Nowadays, 40 % of early-stage NSCLC patients relapse in the 2 years following resection, suggesting a mis-staging in this group of patients who are not receiving adjuvant chemotherapy. Although different biomarkers, such as ERCC1, RRM1 and BRCA1 have been found to present prognostic value in advanced NSCLC patients, in early-stage NSCLC patients its relevance remains unclear. Moreover, SETDB1 has been recently proposed as a bona fide oncogene in lung tumourigenesis and related with metastasis. The aim of the present study was to analyze the prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 expression levels in NSCLC patients at stage I. ERCC1, RRM1, BRCA1 and SETDB1 expression at mRNA level was analyzed by real-time quantitative RT-PCR in fresh-frozen tumor and normal adjacent lung tissue samples from 64 stage I NSCLC patients. Later, significant association between gene expression levels, clinicopathological characteristics and patient's disease-free survival was assessed. We did not find any statistically significant correlation between gene expression and gender, age, histological type or smoking status. Univariate followed by multivariate Cox analysis showed that higher levels of BRCA1 and SETDB1 expression were significantly associated with shorter disease-free survival in stage I NSCLC patients. Our study finds that ERCC1 and RRM1 are not independent prognostic factors of recurrence in stage I NSCLC patients. By contrast, BRCA1 and SETDB1 stand out as the most significant prognostic markers in this group of patients, appearing as promising tools to predict tumor recurrence in early-stage NSCLC patients.

  13. A matched cohort comparison of mTHPC-mediated photodynamic therapy and trans-oral surgery of early stage oral cavity squamous cell cancer.

    PubMed

    Karakullukcu, Baris; Stoker, Sharon D; Wildeman, Anne P E; Copper, Marcel P; Wildeman, Maarten A; Tan, I Bing

    2013-03-01

    Photodynamic therapy (PDT) of early stage oral cavity tumors have been thoroughly reported. However, statistical comparison of PDT to the surgical treatment is not available in published literature. We have identified and matched cohorts of patients with early stage oral cavity cancers undergoing surgery (n = 43) and PDT (n = 55) from a single institute experience. The groups are matched demographically and had the same pre-treatment screening and follow-up schedule. Both groups consisted only of tumors thinner than 5 mm to ensure comparability. The endpoints were local disease free survival, disease free survival, overall survival and response to initial treatment. Local disease free survival at 5 years were 67 and 74 % for PDT and surgery groups, respectively [univariate HR = 1.9 (p = 0.26), multivariable HR = 2.7 (p = 0.13)]. Disease free survival at 5 years are 47 and 53 % for PDT and surgery groups, respectively [univariate HR = 0.8 (p = 0.52), multivariable HR = 0.75 (p = 0.45)]. Overall survival was 83 and 75 % for PDT and surgery groups, respectively [(univariate HR = 0.5 (p = 0.19), multivariable HR = 0.5 (p = 0.17)]. In the PDT group, six patients (11 %) and in the surgery group 11 patients (26 %) had to receive additional treatments after the initial. All of the tested parameters did not have statistical significant difference. Although there is probably a selection bias due to the non-randomized design, this study shows that PDT of early stage oral cavity cancer is comparable in terms of disease control and survival to trans-oral resection and can be offered as an alternative to surgical treatment.

  14. Prostate cancer cells preferentially home to osteoblast-rich areas in the early stages of bone metastasis: evidence from in vivo models.

    PubMed

    Wang, Ning; Docherty, Freyja E; Brown, Hannah K; Reeves, Kimberley J; Fowles, Anne C M; Ottewell, Penelope D; Dear, T Neil; Holen, Ingunn; Croucher, Peter I; Eaton, Colby L

    2014-12-01

    It has been suggested that metastasis-initiating cells gain a foothold in bone by homing to a metastastatic microenvironment (or "niche"). Whereas the precise nature of this niche remains to be established, it is likely to contain bone cell populations including osteoblasts and osteoclasts. In the mouse tibia, the distribution of osteoblasts on endocortical bone surfaces is non-uniform, and we hypothesize that studying co-localization of individual tumor cells with resident cell populations will reveal the identity of critical cellular components of the niche. In this study, we have mapped the distribution of three human prostate cancer cell lines (PC3-NW1, LN-CaP, and C4 2B4) colonizing the tibiae of athymic mice following intracardiac injection and evaluated their interaction with potential metastatic niches. Prostate cancer cells labeled with the fluorescent cell membrane dye (Vybrant DiD) were found by two-photon microscopy to be engrafted in the tibiae in close proximity (∼40 µm) to bone surfaces and 70% more cancer cells were detected in the lateral compared to the medial endocortical bone regions. This was associated with a 5-fold higher number of osteoblasts and 7-fold higher bone formation rate on the lateral endocortical bone surface compared to the medial side. By disrupting cellular interactions mediated by the chemokine (C-X-C motif) receptor 4 (CXCR4)/chemokine ligand 12 (CXCL12) axis with the CXCR4 inhibitor AMD3100, the preferential homing pattern of prostate cancer cells to osteoblast-rich bone surfaces was disrupted. In this study, we map the location of prostate cancer cells that home to endocortical regions in bone and our data demonstrate that homing of prostate cancer cells is associated with the presence and activity of osteoblast lineage cells, and suggest that therapies targeting osteoblast niches should be considered to prevent development of incurable prostate cancer bone metastases.

  15. Src homology 2-containing 5-inositol phosphatase (SHIP) suppresses an early stage of lymphoid cell development through elevated interleukin-6 production by myeloid cells in bone marrow.

    PubMed

    Nakamura, Koji; Kouro, Taku; Kincade, Paul W; Malykhin, Alexander; Maeda, Kazuhiko; Coggeshall, K Mark

    2004-01-19

    The Src homology (SH)2-containing inositol 5-phosphatase (SHIP) negatively regulates a variety of immune responses through inhibitory immune receptors. In SHIP(-/-) animals, we found that the number of early lymphoid progenitors in the bone marrow was significantly reduced and accompanied by expansion of myeloid cells. We exploited an in vitro system using hematopoietic progenitors that reproduced the in vivo phenotype of SHIP(-/-) mice. Lineage-negative marrow (Lin(-)) cells isolated from wild-type mice failed to differentiate into B cells when cocultured with those of SHIP(-/-) mice. Furthermore, culture supernatants of SHIP(-/-) Lin(-) cells suppressed the B lineage expansion of wild-type lineage-negative cells, suggesting the presence of a suppressive cytokine. SHIP(-/-) Lin(-) cells contained more IL-6 transcripts than wild-type Lin(-) cells, and neutralizing anti-IL-6 antibody rescued the B lineage expansion suppressed by the supernatants of SHIP(-/-) Lin(-) cells. Finally, we found that addition of recombinant IL-6 to cultures of wild-type Lin(-) bone marrow cells reproduced the phenotype of SHIP(-/-) bone marrow cultures: suppression of B cell development and expansion of myeloid cells. The results identify IL-6 as an important regulatory cytokine that can suppress B lineage differentiation and drive excessive myeloid development in bone marrow.

  16. Dislocation generation during early stage sintering.

    NASA Technical Reports Server (NTRS)

    Sheehan, J. E.; Lenel, F. V.; Ansell, G. S.

    1973-01-01

    Discussion of the effects of capillarity-induced stresses on dislocations during early stage sintering. A special version of Hirth's (1963) theoretical calculation procedures modified to describe dislocation nucleation on planes meeting the sintering body's neck surface obliquely is shown to predict plastic flow at stress levels know to exist between micron size metal particles in the early stages of sintering.

  17. Mild Toxicity and Favorable Prognosis of High-Dose and Extended Involved-Field Intensity-Modulated Radiotherapy for Patients With Early-Stage Nasal NK/T-Cell Lymphoma

    SciTech Connect

    Wang Hua; Li Yexiong; Wang Weihu; Jin Jing; Dai Jianrong; Wang Shulian; Liu Yueping; Song Yongwen; Wang Zhaoyang; Liu Qingfeng; Fang Hui; Qi Shunan; Liu Xinfan; Yu Zihao

    2012-03-01

    Purpose: The value of intensity-modulated radiotherapy (IMRT) for early-stage nasal NK/T-cell lymphoma has not been previously reported. The aim of the present study was to assess the dosimetric parameters, toxicity, and treatment outcomes of patients with nasal NK/T-cell lymphoma. Methods and Materials: Between 2003 and 2008, 42 patients with early-stage nasal NK/T-cell lymphoma underwent definitive high-dose and extended involved-field IMRT with or without combination chemotherapy. The median radiation dose to the primary tumor was 50 Gy. The dose-volume histograms of the target volume and critical normal structures were evaluated in all patients. The locoregional control, overall survival, and progression-free survival were calculated using the Kaplan-Meier method. Results: The average mean dose delivered to the planning target volume was 55.5 Gy. Only 1.3% and 2.5% of the planning target volume received <90% and 95% of the prescribed dose, respectively, indicating excellent planning target volume coverage. The mean dose and average dose to the parotid glands was 15 Gy and 14 Gy, respectively. With a median follow-up time of 27 months, the 2-year locoregional control, overall survival, and progression-free survivalrate was 93%, 78%, and 74%, respectively. No Grade 4 or 5 acute or late toxicity was reported. Conclusions: High-dose and extended involved-field IMRT for patients with early-stage nasal NK/T-cell lymphoma showed favorable locoregional control, overall survival, and progression-free survival, with mild toxicity. The dose constraints of IMRT for the parotid glands can be limited to <20 Gy in these patients.

  18. Tumor suppressor SET9 guides the epigenetic plasticity of breast cancer cells and serves as an early-stage biomarker for predicting metastasis.

    PubMed

    Montenegro, M F; Sánchez-Del-Campo, L; González-Guerrero, R; Martínez-Barba, E; Piñero-Madrona, A; Cabezas-Herrera, J; Rodríguez-López, J N

    2016-11-24

    During the course of cancer progression, neoplastic cells undergo dynamic and reversible transitions between multiple phenotypic states, and this plasticity is enabled by underlying shifts in epigenetic regulation. Our results identified a negative feedback loop in which SET9 controls DNA methyltransferase-1 protein stability, which represses the transcriptional activity of the SET9 promoter in coordination with Snail. The modulation of SET9 expression in breast cancer cells revealed a connection with E2F1 and the silencing of SET9 was sufficient to complete an epigenetic program that favored epithelial-mesenchymal transition and the generation of cancer stem cells, indicating that SET9 plays a role in modulating breast cancer metastasis. SET9 expression levels were significantly higher in samples from patients with pathological complete remission than in samples from patients with disease recurrence, which indicates that SET9 acts as a tumor suppressor in breast cancer and that its expression may serve as a prognostic marker for malignancy.

  19. Delayed Accumulation of H3K27me3 on Nascent DNA Is Essential for Recruitment of Transcription Factors at Early Stages of Stem Cell Differentiation.

    PubMed

    Petruk, Svetlana; Cai, Jingli; Sussman, Robyn; Sun, Guizhi; Kovermann, Sina K; Mariani, Samanta A; Calabretta, Bruno; McMahon, Steven B; Brock, Hugh W; Iacovitti, Lorraine; Mazo, Alexander

    2017-04-20

    Recruitment of transcription factors (TFs) to repressed genes in euchromatin is essential to activate new transcriptional programs during cell differentiation. However, recruitment of all TFs, including pioneer factors, is impeded by condensed H3K27me3-containing chromatin. Single-cell and gene-specific analyses revealed that, during the first hours of induction of differentiation of mammalian embryonic stem cells (ESCs), accumulation of the repressive histone mark H3K27me3 is delayed after DNA replication, indicative of a decondensed chromatin structure in all regions of the replicating genome. This delay provides a critical "window of opportunity" for recruitment of lineage-specific TFs to DNA. Increasing the levels of post-replicative H3K27me3 or preventing S phase entry inhibited recruitment of new TFs to DNA and significantly blocked cell differentiation. These findings suggest that recruitment of lineage-specifying TFs occurs soon after replication and is facilitated by a decondensed chromatin structure. This insight may explain the developmental plasticity of stem cells and facilitate their exploitation for therapeutic purposes. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Eugenia jambolana (Java Plum) Fruit Extract Exhibits Anti-Cancer Activity against Early Stage Human HCT-116 Colon Cancer Cells and Colon Cancer Stem Cells

    PubMed Central

    Charepalli, Venkata; Reddivari, Lavanya; Vadde, Ramakrishna; Walia, Suresh; Radhakrishnan, Sridhar; Vanamala, Jairam K. P

    2016-01-01

    The World Health Organization predicts over a 70% increase in cancer incidents in developing nations over the next decade. Although these nations have limited access to novel therapeutics, they do have access to foods that contain chemopreventive bioactive compounds such as anthocyanins, and as such, consumption of these foods can be encouraged to combat cancer. We and others have previously characterized the anti-colon cancer properties of dietary anthocyanins from different sources. Eugenia jambolana (Java plum) is a tropical medicinal fruit rich in anthocyanins, however, its anti-colon cancer properties are not well characterized. Furthermore, recent evidence suggests that colon cancer stem cells (colon CSCs) promote resistance to chemotherapy, relapse of tumors and contribute to poor prognosis. The objectives of this study were to 1) characterize the anthocyanin profile of Java plum using HPLC-MS; and 2) determine the anti-proliferative (cell counting and MTT) and pro-apoptotic (TUNEL and caspase 3/7 glo assay) properties of Java plum fruit extract (JPE) using HCT-116 colon cancer cell line and colon CSCs (positive for CD 44, CD 133 and ALDH1b1 markers). HPLC-MS analysis showed that JPE contains a variety of anthocyanins including glucosides of delphinidin, cyanidin, petunidin, peonidin and malvidin. JPE anthocyanins suppressed (p < 0.05) proliferation in HCT-116 cells and elevated (p < 0.05) apoptosis in both HCT-116 cells and colon CSCs. JPE also suppressed the stemness in colon CSCs as evaluated using colony formation assay. These results warrant further assessment of the anti-cancer activity of JPE, and its molecular mechanisms using pre-clinical models of colon cancer. PMID:26927179

  1. Mitochondria-targeted DsRed2 protein expression during the early stage of bovine somatic cell nuclear transfer embryo development.

    PubMed

    Park, Hyo-Jin; Min, Sung-Hun; Choi, Hoonsung; Park, Junghyung; Kim, Sun-Uk; Lee, Seunghoon; Lee, Sang-Rae; Kong, Il-Keun; Chang, Kyu-Tae; Koo, Deog-Bon; Lee, Dong-Seok

    2016-09-01

    Somatic cell nuclear transfer (SCNT) has been widely used as an efficient tool in biomedical research for the generation of transgenic animals from somatic cells with genetic modifications. Although remarkable advances in SCNT techniques have been reported in a variety of mammals, the cloning efficiency in domestic animals is still low due to the developmental defects of SCNT embryos. In particular, recent evidence has revealed that mitochondrial dysfunction is detected during the early development of SCNT embryos. However, there have been relatively few or no studies regarding the development of a system for evaluating mitochondrial behavior or dynamics. For the first time, in mitochondria of bovine SCNT embryos, we developed a method for the visualization of mitochondria and expression of fluorescence proteins. To express red fluorescence in mitochondria of cloned embryos, bovine ear skin fibroblasts, nuclear donor, were stably transfected with a vector carrying mitochondria-targeting DsRed2 gene tagged with V5 epitope (mito-DsRed2-V5 tag) using lentivirus-mediated gene transfer because of its ability to integrate in the cell genome and the potential for long-term transgene expression in the transduced cells and their dividing cells. From western blotting analysis of V5 tag protein using mitochondrial fraction and confocal microscopy of red fluorescence using SCNT embryos, we found that the mitochondrial expression of the mito-DsRed2 protein was detected until the blastocyst stage. In addition, according to image analysis, it may be suggested possible use of the system for visualization of mitochondrial localization and evaluation of mitochondrial behaviors or dynamics in early development of bovine SCNT embryos.

  2. Low B and T lymphocyte attenuator expression on CD4+ T cells in the early stage of sepsis is associated with the severity and mortality of septic patients: a prospective cohort study.

    PubMed

    Shao, Rui; Li, Chun-Sheng; Fang, Yingying; Zhao, Lianxing; Hang, Chenchen

    2015-08-28

    B and T lymphocyte attenuator (BTLA) is an inhibitory receptor, whose primary role in CD4(+) T cell is thought to inhibit cytokine production. We explore BTLA expression on CD4(+) T cells in healthy controls and septic patients, and assess the correlation of BTLA expression on CD4(+) T cells in the early stage of sepsis with the severity and mortality of septic patients in the emergency department (ED). 336 consecutive patients were included in this study. BTLA expression on CD4(+) T cells was measured by flow cytometry within 24h of ED admission. Our results showed that the percentage of BTLA(+)/CD4(+) T cells was high expression in healthy volunteers and it was statistically reduced in severe sepsis and septic shock compared with healthy controls(all P<0.01). The area under the receiver operating characteristic (AUC) curves of BTLA expression on CD4(+) T cells was slightly lower than that of procalcitonin (PCT) and Mortality in Emergency Department Sepsis (MEDS) score. The percentage of BTLA(+)/CD4(+)T cells was lower in non-survivors than in survivors (P<0.01), and similar results were obtained when expressed as mean of fluorescence intensities (MFI) (P<0.01). Adjusted logistic regression analysis suggested that the percentage of BTLA(+)/CD4(+) T cells was associated with 28-day mortality in septic patients (odds ratio (OR) = 0.394). Our study shows that the percentage of BTLA(+)/CD4(+) T cells was high in healthy volunteers. Furthermore, lower percentage of BTLA(+)/CD4(+) T cells during the early stage of sepsis is associated with the severity and the mortality of septic patients.

  3. On the role of extracellular polymeric substances during early stages of Xylella fastidiosa biofilm formation.

    PubMed

    Lorite, Gabriela S; de Souza, Alessandra A; Neubauer, Daniel; Mizaikoff, Boris; Kranz, Christine; Cotta, Mônica A

    2013-02-01

    The structural integrity and protection of bacterial biofilms are intrinsically associated with a matrix of extracellular polymeric substances (EPS) produced by the bacteria cells. However, the role of these substances during biofilm adhesion to a surface remains largely unclear. In this study, the influence of EPS on Xylella fastidiosa biofilm formation was investigated. This bacterium is associated with economically important plant diseases; it presents a slow growth rate and thus allows us to pinpoint more precisely the early stages of cell-surface adhesion. Scanning electron microscopy and atomic force microscopy show evidence of EPS production in such early stages and around individual bacteria cells attached to the substrate surface even a few hours after inoculation. In addition, EPS formation was investigated via attenuated total reflectance (ATR) Fourier transform infrared spectroscopy (FTIR). To this end, X. fastidiosa cells were inoculated within an ATR liquid cell assembly. IR-ATR spectra clearly reveal EPS formation already during the early stages of X. fastidiosa biofilm formation, thereby providing supporting evidence for the hypothesis of the relevance of the EPS contribution to the adhesion process.

  4. Comparison of treatment outcomes between single-port video-assisted thoracoscopic anatomic segmentectomy and lobectomy for non-small cell lung cancer of early-stage: a retrospective observational study

    PubMed Central

    Lin, Yuxing; Zheng, Wei; Zhu, Yong; Guo, Zhaohui; Zheng, Bin

    2016-01-01

    Background There are few reports of single-port video-assisted thoracoscopic surgery (S-VATS) anatomic segmentectomy and S-VATS lobectomy for early-stage non-small cell lung cancer (NSCLC) and no comparisons between them have yet been reported. Therefore, the aim of this study was to compare the safety and efficacy of S-VATS anatomic segmentectomy and S-VATS lobectomy for early-stage NSCLC. Methods In this retrospective observational study, the outcomes of 79 consecutive patients who had undergone S-VATS anatomic segmentectomy (32 patients) or S-VATS lobectomy (47 patients) for early-stage NSCLC from April 2014 to June 2015 were examined. The operation time, intraoperative blood loss, numbers of dissected lymph nodes and mediastinal nodal stations, numbers of staples used, postoperative drainage volume and duration, duration of hospital stay, costs, postoperative complications, local recurrence, and survival were compared between these two groups. Results The postoperative drainage volume was smaller and the postoperative drainage duration shorter in the S-VATS segmentectomy than the lobectomy group (P<0.05). There were no significant differences in operation time, intraoperative blood loss, number of staples used, number and stations of dissected mediastinal lymph nodes, duration of hospital stay, costs, or postoperative complications. At the time of writing, no deaths or local recurrences had occurred in either group. Conclusions S-VATS segmentectomy is as safe and effective as S-VATS lobectomy. Patients who undergo S-VATS segmentectomy seem to recover faster. PMID:27293849

  5. TGFβ1 overexpression is associated with improved survival and low tumor cell proliferation in patients with early-stage pancreatic ductal adenocarcinoma

    PubMed Central

    Glazer, Evan S.; Welsh, Eric; Pimiento, Jose M.; Teer, Jamie K.; Malafa, Mokenge P.

    2017-01-01

    The role of transforming growth factor beta-type-1 (TGFβ1) in pancreatic ductal adenocarcinoma (PDAC) progression is stage-dependent. We hypothesized that TGFβ1 expression is associated with survival and proliferation markers in patients with early-stage PDAC. We acquired clinicopathologic, treatment, and mRNA expression data from The Cancer Genome Atlas data set for 106 patients identified with stage I/II PDAC who underwent pancreaticoduodenectomy. Patients were categorized as high expression when mRNA expression was ≥75th percentile for each gene. Average log2 mRNA expression of TGFβ1 in patients with high expression was 11.6 ± 0.2 and 10.5 ± 0.6 in patients with low expression (P<0.001). Low TGFβ1 expression is associated with shorter median survival compared with high TGFβ1 expression (17 versus at least 60 months; P=0.005). Patients with tumors demonstrating high MKI67 (the gene encoding Ki-67) expression have shorter median survival versus those with lowerMKI67 expression (16 versus 20 months; P=0.026). TGFβ1 and MKI67 are inversely associated (P=0.009). On multivariate analysis, improved survival is associated with TGFβ1 overexpression (P=0.017), adjuvant chemotherapy (P=0.001), and adjuvant radiotherapy (P=0.017), whereas positive surgical margins are associated with worse survival (P=0.002). In patients who undergo pancreaticoduodenectomy for PDAC, high TGFβ1 expression may counteract the worse survival associated with high proliferation. PMID:27895310

  6. Lymph node micrometastases are associated with disease recurrence and poor survival for early-stage non-small cell lung cancer patients: a meta-analysis.

    PubMed

    Deng, Xu Feng; Jiang, Li; Liu, Quan Xing; Zhou, Dong; Hou, Bing; Cui, Kefan; Min, Jia Xin; Dai, Ji Gang

    2016-02-16

    We performed a meta-analysis to clarify whether the molecular detection of tumor cells or micrometastases in the lymph node (LN) indicates a high risk of disease recurrence and poor survival in negative pathologic lymph node status non-small cell lung cancer (NSCLC). A literature search was performed using relevant keywords. We searched relevant studies from PubMed, Embase, and the Cochrane Library. Direct and indirect meta-estimates were generated using Review Manager software with fixed effects for the study. Study-to-study heterogeneity was summarized using I (2) statistics and predictive intervals (PIs). Our analysis of eight eligible studies revealed that patients with lymph node micrometastases (LNMM) were associated with poor overall survival (OS) (HR, 1.98; 95 % CI, 1.50 to 2.62; p < 0.00001) and disease-free survival (DFS) (HR, 2.34; 95 % CI, 1.67-3.27; p < 0.00001). LNMM is associated with an increased risk of disease recurrence and poor survival in patients with negative pathologic node negative NSCLC. Thus, these patients need to be carefully followed up after the initial pulmonary resection.

  7. Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients.

    PubMed

    Scrima, Marianna; Zito Marino, Federica; Oliveira, Duarte Mendes; Marinaro, Cinzia; La Mantia, Elvira; Rocco, Gaetano; De Marco, Carmela; Malanga, Donatella; De Rosa, Nicla; Rizzuto, Antonia; Botti, Gerardo; Franco, Renato; Zoppoli, Pietro; Viglietto, Giuseppe

    2017-01-01

    Background: Purpose of this study was to evaluate the contribution of the Extracellular-regulated protein kinase (ERK)-1/2 pathway to oncogenic signaling elicited by the tyrosine kinase receptor HER2 in Non-Small Cell Lung Cancer (NSCLC) and to assess the prognostic value of these oncoproteins in NSCLC patients. Methods: Immunohistochemistry was performed to determine expression and activation of HER2 and ERK1/2 (detected by phosphorylation of Y1248 and T202/Y204, respectively) using Tissue Micro Arrays (TMA) containing matched normal and neoplastic tissues from 132 NSCLC patients. Survival analysis was carried out using the Kaplan-Meier method. Univariate and multivariate analysis were used to evaluate the prognostic value of pERK1/2, pHER2 and a combination thereof with clinical-pathological parameters such as age, lymph node status (N), size (T), stage (TNM) and grade. Results: We found that HER2 was overexpressed in 33/120 (27%) and activated in 41/114 (36%) cases; ERK1/2 was activated in 44/102 (43%) cases. A direct association was found between pERK1/2 and pHER2 (23/41; p=0.038). In addition, patients positive for pERK1/2 and for both pHER2 and pERK1/2 showed significantly worse overall survival (OS) and disease-free survival (DFS) compared with negative patients. Univariate and multivariate analysis of patients' survival revealed that positivity for pHER2-pERK1/2 and for pERK1/2 alone were independent prognostic factors of poor survival in NSCLC patients. In particular, this association was significantly important for DFS in stage I+II patients. Conclusion: This study provides evidence that activated ERK1/2 and/or the combined activation of HER2 and ERK1/2 are good indicators of poor prognosis in NSCLC patients, not only in unselected patients but also in early stage disease.

  8. Aberrant Signaling through the HER2-ERK1/2 Pathway is Predictive of Reduced Disease-Free and Overall Survival in Early Stage Non-Small Cell Lung Cancer (NSCLC) Patients

    PubMed Central

    Scrima, Marianna; Zito Marino, Federica; Oliveira, Duarte Mendes; Marinaro, Cinzia; La Mantia, Elvira; Rocco, Gaetano; De Marco, Carmela; Malanga, Donatella; De Rosa, Nicla; Rizzuto, Antonia; Botti, Gerardo; Franco, Renato; Zoppoli, Pietro; Viglietto, Giuseppe

    2017-01-01

    Background: Purpose of this study was to evaluate the contribution of the Extracellular-regulated protein kinase (ERK)-1/2 pathway to oncogenic signaling elicited by the tyrosine kinase receptor HER2 in Non-Small Cell Lung Cancer (NSCLC) and to assess the prognostic value of these oncoproteins in NSCLC patients. Methods: Immunohistochemistry was performed to determine expression and activation of HER2 and ERK1/2 (detected by phosphorylation of Y1248 and T202/Y204, respectively) using Tissue Micro Arrays (TMA) containing matched normal and neoplastic tissues from 132 NSCLC patients. Survival analysis was carried out using the Kaplan-Meier method. Univariate and multivariate analysis were used to evaluate the prognostic value of pERK1/2, pHER2 and a combination thereof with clinical-pathological parameters such as age, lymph node status (N), size (T), stage (TNM) and grade. Results: We found that HER2 was overexpressed in 33/120 (27%) and activated in 41/114 (36%) cases; ERK1/2 was activated in 44/102 (43%) cases. A direct association was found between pERK1/2 and pHER2 (23/41; p=0.038). In addition, patients positive for pERK1/2 and for both pHER2 and pERK1/2 showed significantly worse overall survival (OS) and disease-free survival (DFS) compared with negative patients. Univariate and multivariate analysis of patients' survival revealed that positivity for pHER2-pERK1/2 and for pERK1/2 alone were independent prognostic factors of poor survival in NSCLC patients. In particular, this association was significantly important for DFS in stage I+II patients. Conclusion: This study provides evidence that activated ERK1/2 and/or the combined activation of HER2 and ERK1/2 are good indicators of poor prognosis in NSCLC patients, not only in unselected patients but also in early stage disease. PMID:28243327

  9. Polyfunctional T Cell Responses in Children in Early Stages of Chronic Trypanosoma cruzi Infection Contrast with Monofunctional Responses of Long-term Infected Adults

    PubMed Central

    Albareda, María C.; De Rissio, Ana M.; Tomas, Gonzalo; Serjan, Alicia; Alvarez, María G.; Viotti, Rodolfo; Fichera, Laura E.; Esteva, Mónica I.; Potente, Daniel; Armenti, Alejandro; Tarleton, Rick L.; Laucella, Susana A.

    2013-01-01

    Background Adults with chronic Trypanosoma cruzi exhibit a poorly functional T cell compartment, characterized by monofunctional (IFN-γ-only secreting) parasite-specific T cells and increased levels of terminally differentiated T cells. It is possible that persistent infection and/or sustained exposure to parasites antigens may lead to a progressive loss of function of the immune T cells. Methodology/Principal Findings To test this hypothesis, the quality and magnitude of T. cruzi-specific T cell responses were evaluated in T. cruzi-infected children and compared with long-term T. cruzi-infected adults with no evidence of heart failure. The phenotype of CD4+ T cells was also assessed in T. cruzi-infected children and uninfected controls. Simultaneous secretion of IFN-γ and IL-2 measured by ELISPOT assays in response to T. cruzi antigens was prevalent among T. cruzi-infected children. Flow cytometric analysis of co-expression profiles of CD4+ T cells with the ability to produce IFN-γ, TNF-α, or to express the co-stimulatory molecule CD154 in response to T. cruzi showed polyfunctional T cell responses in most T. cruzi-infected children. Monofunctional T cell responses and an absence of CD4+TNF-α+-secreting T cells were observed in T. cruzi-infected adults. A relatively high degree of activation and differentiation of CD4+ T cells was evident in T. cruzi-infected children. Conclusions/Significance Our observations are compatible with our initial hypothesis that persistent T. cruzi infection promotes eventual exhaustion of immune system, which might contribute to disease progression in long-term infected subjects. PMID:24349591

  10. Improved polymerase chain reaction-based method to detect early-stage epitheliotropic T-cell lymphoma (mycosis fungoides) in formalin-fixed, paraffin-embedded skin biopsy specimens of the dog.

    PubMed

    Chaubert, Pascal; Baur Chaubert, Audrey S; Sattler, Ursula; Forster, Ursula; Bornand, Valérie; Suter, Maja; Welle, Monika

    2010-01-01

    In the dog, early-stage epitheliotropic T-cell lymphoma (ETCL) can clinically and histologically mimic a large range of inflammatory dermatoses and often progresses rapidly to a more aggressive tumor stage. Early diagnosis of ETCL is essential to proceed with a specific oncologic therapy that is favorable for the prognosis. In the present study, an improved method for the detection of T-cell receptor gamma (TCRgamma) rearrangement was developed by designing a new set of consensus primers to amplify the different forms of rearranged canine TCRgamma gene sequences by polymerase chain reaction. The amplicons were analyzed by conventional polyacrylamide gel electrophoresis, which requires minimal specific equipment and may be performed in almost every pathology laboratory at low costs. The method proved to be highly specific and sensitive to detect early ETCL in formalin-fixed, paraffin-embedded biopsy specimens, providing an efficient tool for veterinary pathologists to distinguish early neoplastic from reactive cutaneous T-cell infiltrates (tumor-specific marker) or to discriminate T-cell lymphoma from B-cell lymphomas or nonlymphoid neoplasms (T-cell lineage marker). By direct sequencing analysis of amplified TCRgamma gene sequences, ETCL was found to rearrange exclusively the joining (J) 4 region, which suggests specific biology for primary cutaneous T-cell lymphomas. Also, a novel (seventh) functional J region in the TCRgamma gene, localized approximately 2.3 kb upstream of J5, was identified.

  11. Intestinal Cell Tight Junctions Limit Invasion of Candida albicans through Active Penetration and Endocytosis in the Early Stages of the Interaction of the Fungus with the Intestinal Barrier.

    PubMed

    Goyer, Marianne; Loiselet, Alicia; Bon, Fabienne; L'Ollivier, Coralie; Laue, Michael; Holland, Gudrun; Bonnin, Alain; Dalle, Frederic

    2016-01-01

    C. albicans is a commensal yeast of the mucous membranes in healthy humans that can also cause disseminated candidiasis, mainly originating from the digestive tract, in vulnerable patients. It is necessary to understand the cellular and molecular mechanisms of the interaction of C. albicans with enterocytes to better understand the basis of commensalism and pathogenicity of the yeast and to improve the management of disseminated candidiasis. In this study, we investigated the kinetics of tight junction (TJ) formation in parallel with the invasion of C. albicans into the Caco-2 intestinal cell line. Using invasiveness assays on Caco-2 cells displaying pharmacologically altered TJ (i.e. differentiated epithelial cells treated with EGTA or patulin), we were able to demonstrate that TJ protect enterocytes against invasion of C. albicans. Moreover, treatment with a pharmacological inhibitor of endocytosis decreased invasion of the fungus into Caco-2 cells displaying altered TJ, suggesting that facilitating access of the yeast to the basolateral side of intestinal cells promotes endocytosis of C. albicans in its hyphal form. These data were supported by SEM observations of differentiated Caco-2 cells displaying altered TJ, which highlighted membrane protrusions engulfing C. albicans hyphae. We furthermore demonstrated that Als3, a hypha-specific C. albicans invasin, facilitates internalization of the fungus by active penetration and induced endocytosis by differentiated Caco-2 cells displaying altered TJ. However, our observations failed to demonstrate binding of Als3 to E-cadherin as the trigger mechanism of endocytosis of C. albicans into differentiated Caco-2 cells displaying altered TJ.

  12. Intestinal Cell Tight Junctions Limit Invasion of Candida albicans through Active Penetration and Endocytosis in the Early Stages of the Interaction of the Fungus with the Intestinal Barrier

    PubMed Central

    Bon, Fabienne; L’Ollivier, Coralie; Laue, Michael; Holland, Gudrun; Bonnin, Alain; Dalle, Frederic

    2016-01-01

    C. albicans is a commensal yeast of the mucous membranes in healthy humans that can also cause disseminated candidiasis, mainly originating from the digestive tract, in vulnerable patients. It is necessary to understand the cellular and molecular mechanisms of the interaction of C. albicans with enterocytes to better understand the basis of commensalism and pathogenicity of the yeast and to improve the management of disseminated candidiasis. In this study, we investigated the kinetics of tight junction (TJ) formation in parallel with the invasion of C. albicans into the Caco-2 intestinal cell line. Using invasiveness assays on Caco-2 cells displaying pharmacologically altered TJ (i.e. differentiated epithelial cells treated with EGTA or patulin), we were able to demonstrate that TJ protect enterocytes against invasion of C. albicans. Moreover, treatment with a pharmacological inhibitor of endocytosis decreased invasion of the fungus into Caco-2 cells displaying altered TJ, suggesting that facilitating access of the yeast to the basolateral side of intestinal cells promotes endocytosis of C. albicans in its hyphal form. These data were supported by SEM observations of differentiated Caco-2 cells displaying altered TJ, which highlighted membrane protrusions engulfing C. albicans hyphae. We furthermore demonstrated that Als3, a hypha-specific C. albicans invasin, facilitates internalization of the fungus by active penetration and induced endocytosis by differentiated Caco-2 cells displaying altered TJ. However, our observations failed to demonstrate binding of Als3 to E-cadherin as the trigger mechanism of endocytosis of C. albicans into differentiated Caco-2 cells displaying altered TJ. PMID:26933885

  13. PrPc does not mediate internalization of PrPSc but is required at an early stage for de novo prion infection of Rov cells.

    PubMed

    Paquet, Sophie; Daude, Nathalie; Courageot, Marie-Pierre; Chapuis, Jérôme; Laude, Hubert; Vilette, Didier

    2007-10-01

    We have studied the interactions of exogenous prions with an epithelial cell line inducibly expressing PrPc protein and permissive to infection by a sheep scrapie agent. We demonstrate that abnormal PrP (PrPSc) and prion infectivity are efficiently internalized in Rov cells, whether or not PrPc is expressed. At odds with earlier studies implicating cellular heparan sulfates in PrPSc internalization, we failed to find any involvement of such molecules in Rov cells, indicating that prions can enter target cells by several routes. We further show that PrPSc taken up in the absence of PrPc was unable to promote efficient prion multiplication once PrPc expression was restored in the cells. This observation argues that interaction of PrPSc with PrPc has to occur early, in a specific subcellular compartment(s), and is consistent with the view that the first prion multiplication events may occur at the cell surface.

  14. Neurons Derived from Induced Pluripotent Stem Cells of Patients with Down Syndrome Reproduce Early Stages of Alzheimer's Disease Type Pathology in vitro.

    PubMed

    Dashinimaev, Erdem B; Artyuhov, Alexander S; Bolshakov, Alexey P; Vorotelyak, Ekaterina A; Vasiliev, Andrey V

    2017-01-01

    People with Down syndrome (DS) are at high risk of developing pathology similar to Alzheimer's disease (AD). Modeling of this pathology in vitro may be useful for studying this phenomenon. In this study, we analyzed three different cultures of neural cells carrying trisomy of chromosome 21, which were generated by directed differentiation from induced pluripotent stem cells (iPS cells). We report here that in vitro generated DS neural cells have abnormal metabolism of amyloid-β (Aβ) manifested by increased secretion and accumulation of Aβ granules of Aβ42 pathological isoform with upregulated expression of the APP gene. Additionally, we found increased expression levels of genes that are considered to be associated with AD (BACE2, RCAN1, ETS2, TMED10), as compared to healthy controls. Thus, the neural cells generated from induced pluripotent stem cells with DS reproduce initial cellular signs of AD-type pathology and can be useful tools for modeling and studying this variant of AD in vitro.

  15. Disruptive cell cycle regulation involving epigenetic downregulation of Cdkn2a (p16(Ink4a)) in early-stage liver tumor-promotion facilitating liver cell regeneration in rats.

    PubMed

    Tsuchiya, Takuma; Wang, Liyun; Yafune, Atsunori; Kimura, Masayuki; Ohishi, Takumi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2012-09-28

    Cell cycle aberration was immunohistochemically examined in relation to preneoplastic liver cell foci expressing glutathione S-transferase placental form (GST-P) at early stages of tumor-promotion in rats with thioacetamide (TAA), a hepatocarcinogen facilitating liver cell regeneration. Immunoexpression of p16(Ink4a) following exposure to other hepatocarcinogens/promoters and its DNA methylation status were also analyzed during early and late tumor-promotion stages. GST-P(+) liver cell foci increased cell proliferation and decreased apoptosis when compared with surrounding liver cells. In concordance with GST-P(+) foci, checkpoint proteins at G(1)/S (p21(Cip1), p27(Kip1) and p16(Ink4a)) and G(2)/M (phospho-checkpoint kinase 1, Cdc25c and phospho-Wee1) were either up- or downregulated. Cellular distribution within GST-P(+) foci was either increased or decreased with proteins related to G(2)-M phase or DNA damage (topoisomerase IIα, phospho-histone H2AX, phospho-histone H3 and Cdc2). In particular, p16(Ink4a) typically downregulated in GST-P(+) foci and regenerative nodules at early tumor-promotion stage with hepatocarcinogens facilitating liver cell regeneration and in neoplastic lesions at late tumor-promotion stage with hepatocarcinogens/promoters irrespective of regenerating potential. Hypermethylation at exon 2 of Cdkn2a was detected at both early- and late-stages. Thus, diverse disruptive expression of G(1)/S and G(2)/M proteins, which allows for clonal selection of GST-P(+) foci, results in the acquisition of multiple aberrant phenotypes to disrupt checkpoint function. Moreover, increased DNA-damage responses within GST-P(+) foci may be the signature of genetic alterations. Intraexonic hypermethylation may be responsible for p16(Ink4a)-downregulation, which facilitates cell cycle progression in early preneoplastic lesions produced by repeated cell regeneration and late-stage neoplastic lesions irrespective of the carcinogenic mechanism. Copyright © 2012

  16. Proteomic analysis of nipple aspirate fluid from women with early-stage breast cancer using isotope-coded affinity tags and tandem mass spectrometry reveals differential expression of vitamin D binding protein

    PubMed Central

    Pawlik, Timothy M; Hawke, David H; Liu, Yanna; Krishnamurthy, Savitri; Fritsche, Herbert; Hunt, Kelly K; Kuerer, Henry M

    2006-01-01

    Background Isotope-coded affinity tag (ICAT) tandem mass spectrometry (MS) allows for qualitative and quantitative analysis of paired protein samples. We sought to determine whether ICAT technology could quantify and identify differential expression of tumor-specific proteins in nipple aspirate fluid (NAF) from the tumor-bearing and contralateral disease-free breasts of patients with unilateral early-stage breast cancer. Methods Paired NAF samples from 18 women with stage I or II unilateral invasive breast carcinoma and 4 healthy volunteers were analyzed using ICAT labeling, sodium dodecyl sulfate-polyacrylamide gel (SDS-PAGE), liquid chromatography, and MS. Proteins were identified by sequence database analysis. Western blot analysis of NAF from an independent sample set from 12 women (8 with early-stage breast cancer and 4 healthy volunteers) was also performed. Results 353 peptides were identified from tandem mass spectra and matched to peptide sequences in the National Center for Biotechnology Information database. Equal numbers of peptides were up- versus down-regulated. Alpha2HS-glycoprotein [Heavy:Light (H:L) ratio 0.63] was underexpressed in NAF from tumor-bearing breasts, while lipophilin B (H:L ratio 1.42), beta-globin (H:L ratio 1.98), hemopexin (H:L ratio 1.73), and vitamin D-binding protein precursor (H:L ratio 1.82) were overexpressed. Western blot analysis of pooled samples of NAF from healthy volunteers versus NAF from women with breast cancer confirmed the overexpression of vitamin D-binding protein in tumor-bearing breasts. Conclusion ICAT tandem MS was able to identify and quantify differences in specific protein expression between NAF samples from tumor-bearing and disease-free breasts. Proteomic screening techniques using ICAT and NAF may be used to find markers for diagnosis of breast cancer. PMID:16542425

  17. Treatment of early stage vocal cord carcinoma

    SciTech Connect

    Ayers, G.

    1989-03-01

    The cure rates for early stage vocal cord cancer are excellent with primary radiotherapy. Voice quality remains as good or becomes better than prior to treatment. For the local failures that do occur, surgical salvage will yield ultimate cure rates of about 95% for T1 and 90% for T2 tumors.

  18. Consistently lower narcotics consumption after video-assisted thoracoscopic surgery for early stage non-small cell lung cancer when compared to open surgery: a one-year follow-up study.

    PubMed

    Fang, Hsin-Yuan; Chen, Chih-Yi; Wang, Yao-Ching; Wang, Pin-Hui; Shieh, Shwn-Huey; Chien, Chun-Ru

    2013-04-01

    Video-assisted thoracoscopic surgery (VATS) is possibly associated with reduced acute pain and narcotics consumption when compared to open surgery, but little is known about the long-term effect. The goal of our study was to evaluate whether narcotics consumption is consistently lower after VATS for early stage non-small cell lung cancer (NSCLC), as compared to open surgery, during one-year follow-up. This nationwide retrospective cohort study was conducted using data relating to cancer registry and national compulsory comprehensive claims in Taiwan. Our study cases were those newly diagnosed with clinical Stage I NSCLC, who underwent primary lung resection in the year 2007. The date of the admission during which index surgery was performed was used as the index date. We compared the use of narcotics, between the VATS and open surgery groups, over a period of one year following the index date. We defined narcotics as either Level 1 or 2 drugs as regulated in Taiwan. We also used an equiananalgesic dose chart to convert drug consumption into a uniform narcotics equivalent dose. Chi-square and t-tests were used for statistical analysis. We identified 329 cases (114 for VATS and 215 for open surgery). These two groups were balanced for most clinical variables. VATS was associated with lower narcotics consumption during the index admission (mean equivalent dose of intravenous morphine: 54.6 vs 71.4 mg) and this trend extended to the period covering the 2nd to 12th month after index date (73.8 vs 149.5mg). Narcotics consumption is consistently lower after VATS for early stage NSCLC, as compared to open surgery. Further prospective studies would be of great value in validating this finding.

  19. A comparative study of the target volume definition in radiotherapy with «Slow CT Scan» vs. 4D PET/CT Scan in early stages non-small cell lung cancer.

    PubMed

    Molla, M; Anducas, N; Simó, M; Seoane, A; Ramos, M; Cuberas-Borros, G; Beltran, M; Castell, J; Giralt, J

    To evaluate the use of 4D PET/CT to quantify tumor respiratory motion compared to the «Slow»-CT (CTs) in the radiotherapy planning process. A total of 25 patients with inoperable early stage non small cell lung cancer (NSCLC) were included in the study. Each patient was imaged with a CTs (4s/slice) and 4D PET/CT. The adequacy of each technique for respiratory motion capture was evaluated using the volume definition for each of the following: Internal target volume (ITV) 4D and ITVslow in relation with the volume defined by the encompassing volume of 4D PET/CT and CTs (ITVtotal). The maximum distance between the edges of the volume defined by each technique to that of the total volume was measured in orthogonal beam's eye view. The ITV4D showed less differences in relation with the ITVtotal in both the cranio-caudal and the antero-posterior axis compared to the ITVslow. The maximum differences were 0.36mm in 4D PET/CTand 0.57mm in CTs in the antero-posterior axis. 4D PET/CT resulted in the definition of more accurate (ITV4D/ITVtotal 0.78 vs. ITVs/ITVtotal 0.63), and larger ITVs (19.9 cc vs. 16.3 cc) than those obtained with CTs. Planning with 4D PET/CT in comparison with CTs, allows incorporating tumor respiratory motion and improving planning radiotherapy of patients in early stages of lung cancer. Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  20. Chalcone synthase localization in early stages of plant development. I. Immunohistochemical use of plasmolysis for localizing the enzyme in epidermal cell cytoplasm of illuminated buckwheat hypocotyls.

    PubMed

    Zobel, A M; Hrazdina, G

    1995-01-01

    Immunohistochemical methods combined with progressive plasmolysis were used to localize chalcone synthase (CHS), an important enzyme for plant metabolism of aromatics in hypocotyls of illuminated buckwheat (Fagopyrum esculentum M.) seedlings. Illumination of etiolated seedlings with white light results in anthocyanin synthesis in the epidermal layer of the hypocotyl. Anthocyanin-containing epidermal peels, after fixation for 30 min in 4% paraformaldehyde, 2.5% glutaraldehyde, 0.1% caffeine, were treated with a specific rabbit anti-buckwheat CHS antibody and a 20 nm goat anti-rabbit IgG gold conjugate. CHS is specifically shown in epidermal cells as pink to dark red deposits. Progressive plasmolysis combined with our immunohistochemical method showed that CHS was located exclusively in the cytoplasm of the epidermal cells of buckwheat hypocotyls except for the guard cells, which contained no detectable CHS.

  1. The Effect of Exercise on the Early Stages of Mesenchymal Stromal Cell-Induced Cartilage Repair in a Rat Osteochondral Defect Model

    PubMed Central

    Yamaguchi, Shoki; Aoyama, Tomoki; Ito, Akira; Nagai, Momoko; Iijima, Hirotaka; Tajino, Junichi; Zhang, Xiangkai; Kiyan, Wataru; Kuroki, Hiroshi

    2016-01-01

    The repair of articular cartilage is challenging owing to the restriction in the ability of articular cartilage to repair itself. Therefore, cell supplementation therapy is possible cartilage repair method. However, few studies have verified the efficacy and safety of cell supplementation therapy. The current study assessed the effect of exercise on early the phase of cartilage repair following cell supplementation utilizing mesenchymal stromal cell (MSC) intra-articular injection. An osteochondral defect was created on the femoral grooves bilaterally of Wistar rats. Mesenchymal stromal cells that were obtained from male Wistar rats were cultured in monolayer. After 4 weeks, MSCs were injected into the right knee joint and the rats were randomized into an exercise or no-exercise intervention group. The femurs were divided as follows: C group (no exercise without MSC injection); E group (exercise without MSC injection); M group (no exercise with MSC injection); and ME group (exercise with MSC injection). At 2, 4, and 8 weeks after the injection, the femurs were sectioned and histologically graded using the Wakitani cartilage repair scoring system. At 2 weeks after the injection, the total histological scores of the M and ME groups improved significantly compared with those of the C group. Four weeks after the injection, the scores of both the M and ME groups improved significantly. Additionally, the scores in the ME group showed a significant improvement compared to those in the M group. The improvement in the scores of the E, M, and ME groups at 8 weeks were not significantly different. The findings indicate that exercise may enhance cartilage repair after an MSC intra-articular injection. This study highlights the importance of exercise following cell transplantation therapy. PMID:26968036

  2. Proteomic Analysis on the Alteration of Protein Expression in the Early-Stage Placental Villous Tissue of Electromagnetic Fields Associated With Cell Phone Exposure

    PubMed Central

    Luo, Qiong; Jiang, Ying; Jin, Min

    2013-01-01

    Background: To explore the possible adverse effects and search for cell phone electromagnetic field (EMF)-responsive proteins in human early reproduction, a proteomics approach was employed to investigate the changes in protein expression profile induced by cell phone EMF in human chorionic tissues of early pregnancy in vivo. Methods: Volunteer women about 50 days pregnant were exposed to EMF at the average absorption rate of 1.6 to 8.8 W/kg for 1 hour with the irradiation device placed 10 cm away from the umbilicus at the midline of the abdomen. The changes in protein profile were examined using 2-dimensional electrophoresis (2-DE). Results: Up to 15 spots have yielded significant change at least 2- to 2.5-folds up or down compared to sham-exposed group. Twelve proteins were identified— procollagen–proline, eukaryotic translation elongation factor 1 delta, chain D crystal structure of human vitamin D-binding protein, thioredoxin-like 3, capping protein, isocitrate dehydrogenase 3 alpha, calumenin, Catechol-O-methyltransferase protein, proteinase inhibitor 6 (PI-6; SerpinB6) protein, 3,2-trans-enoyl-CoA isomerase protein, chain B human erythrocyte 2,3-bisphosphoglycerate mutase, and nucleoprotein. Conclusion: Cell phone EMF might alter the protein profile of chorionic tissue of early pregnancy, during the most sensitive stage of the embryos. The exposure to EMF may cause adverse effects on cell proliferation and development of nervous system in early embryos. Furthermore, 2-DE coupled with mass spectrometry is a promising approach to elucidate the effects and search for new biomarkers for environmental toxic effects. PMID:23420827

  3. Surgical Management of Early-Stage Non-small Cell Lung Carcinoma and the Present and Future Roles of Adjuvant Therapy: A Review for the Radiation Oncologist

    SciTech Connect

    Medford-Davis, Laura; DeCamp, Malcom; Recht, Abram; Flickinger, John; Belani, Chandra P.; Varlotto, John

    2012-12-01

    We review the evidence for optimal surgical management and adjuvant therapy for patients with stages I and II non-small cell lung cancer (NSCLC) along with factors associated with increased risks of recurrence. Based on the current evidence, we recommend optimal use of mediastinal lymph node dissection, adjuvant chemotherapy, and post-operative radiation therapy, and make suggestions for areas to explore in future prospective randomized clinical trials.

  4. Proteomic analysis on the alteration of protein expression in the early-stage placental villous tissue of electromagnetic fields associated with cell phone exposure.

    PubMed

    Luo, Qiong; Jiang, Ying; Jin, Min; Xu, Jian; Huang, He-Feng

    2013-09-01

    To explore the possible adverse effects and search for cell phone electromagnetic field (EMF)-responsive proteins in human early reproduction, a proteomics approach was employed to investigate the changes in protein expression profile induced by cell phone EMF in human chorionic tissues of early pregnancy in vivo. Volunteer women about 50 days pregnant were exposed to EMF at the average absorption rate of 1.6 to 8.8 W/kg for 1 hour with the irradiation device placed 10 cm away from the umbilicus at the midline of the abdomen. The changes in protein profile were examined using 2-dimensional electrophoresis (2-DE). Up to 15 spots have yielded significant change at least 2- to 2.5-folds up or down compared to sham-exposed group. Twelve proteins were identified- procollagen-proline, eukaryotic translation elongation factor 1 delta, chain D crystal structure of human vitamin D-binding protein, thioredoxin-like 3, capping protein, isocitrate dehydrogenase 3 alpha, calumenin, Catechol-O-methyltransferase protein, proteinase inhibitor 6 (PI-6; SerpinB6) protein, 3,2-trans-enoyl-CoA isomerase protein, chain B human erythrocyte 2,3-bisphosphoglycerate mutase, and nucleoprotein. Cell phone EMF might alter the protein profile of chorionic tissue of early pregnancy, during the most sensitive stage of the embryos. The exposure to EMF may cause adverse effects on cell proliferation and development of nervous system in early embryos. Furthermore, 2-DE coupled with mass spectrometry is a promising approach to elucidate the effects and search for new biomarkers for environmental toxic effects.

  5. SipA Activation of Caspase-3 Is a Decisive Mediator of Host Cell Survival at Early Stages of Salmonella enterica Serovar Typhimurium Infection

    PubMed Central

    McIntosh, Anne; Meikle, Lynsey M.; Ormsby, Michael J.; McCormick, Beth A.; Christie, John M.; Brewer, James M.; Roberts, Mark

    2017-01-01

    ABSTRACT Salmonella invasion protein A (SipA) is a dual-function effector protein that plays roles in both actin polymerization and caspase-3 activation in intestinal epithelial cells. To date its function in other cell types has remained largely unknown despite its expression in multiple cell types and its extracellular secretion during infection. Here we show that in macrophages SipA induces increased caspase-3 activation early in infection. This activation required a threshold level of SipA linked to multiplicity of infection and may be a limiting factor controlling bacterial numbers in infected macrophages. In polymorphonuclear leukocytes, SipA or other Salmonella pathogenicity island 1 effectors had no effect on induction of caspase-3 activation either alone or in the presence of whole bacteria. Tagging of SipA with the small fluorescent phiLOV tag, which can pass through the type three secretion system, allowed visualization and quantification of caspase-3 activation by SipA-phiLOV in macrophages. Additionally, SipA-phiLOV activation of caspase-3 could be tracked in the intestine through multiphoton laser scanning microscopy in an ex vivo intestinal model. This allowed visualization of areas where the intestinal epithelium had been compromised and demonstrated the potential use of this fluorescent tag for in vivo tracking of individual effectors. PMID:28630067

  6. Impact of gefitinib in early stage treatment on circulating cytokines and lymphocytes for patients with advanced non-small cell lung cancer

    PubMed Central

    Sheng, Jin; Fang, Wenfeng; Liu, Xia; Xing, Shan; Zhan, Jianhua; Ma, Yuxiang; Huang, Yan; Zhou, Ningning; Zhao, Hongyun; Zhang, Li

    2017-01-01

    Objectives The impact of epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) on the human immune system remains undefined. This study illustrates the immunomodulatory effect of gefitinib in patients with advanced non-small cell lung cancer (NSCLC) and its relevant prognostic significance. Patients and methods Peripheral blood samples were collected from 54 patients at baseline and after 4 weeks of gefitinib treatment. Circulating lymphocyte populations and cytokine levels were measured. Pilot investigation of the impact of gefitinib on programmed cell death ligand-1 (PD-L1) expression was conducted by immunohistochemistry (IHC). Results and conclusion A significant increase of peripheral natural killer cells and interferon-gamma (INF-γ) after 4 weeks of gefitinib treatment (P=0.005 and 0.02, respectively). In addition, circulating interleukin (IL)-6 was significantly decreased, especially in patients sensitive to gefitinib (P<0.001). Higher levels of IL-6 at baseline independently correlated with poorer progression-free survival. Experiments with NSCLC specimens illustrated that PD-L1 expression were downregulated after 4 weeks of gefitinib treatment. In summary, it was found that gefitinib treatment can alter circulating cytokines and lymphocytes. Dynamic changes of circulating lymphocytes, cytokines, and even PD-L1 IHC expression around gefitinib treatment support the specific immunomodulatory effect of this agent for advanced NSCLC. PMID:28260924

  7. Differentiating Early Stage Cystic Keratoacanthoma, Nodular Basal Cell Carcinoma, and Excoriated Acne Vulgaris by Clinical Exam, Dermoscopy, and Optical Coherence Tomography: A Report of 3 Cases.

    PubMed

    Markowitz, Orit; Utz, Sarah

    2015-04-01

    Making accurate diagnoses when certain lesions are in a relatively young stage can prove challenging, as their "textbook descriptions" are often not fully apparent, and may in fact be markedly different. The authors present three interesting cases of early lesions that were clinically difficult to differentiate from one another: a cystic variation of a keratoacanthoma squamous cell carcinoma, a basal cell carcinoma, and an excoriated facial acne vulgaris. The subtle clinical nuances found in each of these cases demonstrated the importance of a careful clinical evaluation; however, this was not sufficient for adequate assessment of whether or not to biopsy. With early lesions such as these, the use of the noninvasive imaging modalities of dermoscopy and optical coherence tomography becomes critical in order to avoid unnecessary biopsy. The discussion of the clinically and dermoscopically challenging features is both instructive and enlightening. Oftentimes, "textbook descriptions" of lesions focus on the description of an already mature stage of growth, despite the fact that we continue to strive toward earlier detection of potential malignancies. With this in mind, the features found with optical coherence tomography proved essential to the elucidation of these difficult lesions. These three interesting cases illustrated the challenges encountered when dealing with early lesions specifically. The authors bring to light features in each of these cases that are often not thought of as being the "typical" presentation in each lesion category and demonstrate the clinical utility of noninvasive devices in difficult-to-diagnose cases such as these.

  8. Differentiating Early Stage Cystic Keratoacanthoma, Nodular Basal Cell Carcinoma, and Excoriated Acne Vulgaris by Clinical Exam, Dermoscopy, and Optical Coherence Tomography: A Report of 3 Cases

    PubMed Central

    Utz, Sarah

    2015-01-01

    Making accurate diagnoses when certain lesions are in a relatively young stage can prove challenging, as their “textbook descriptions” are often not fully apparent, and may in fact be markedly different. The authors present three interesting cases of early lesions that were clinically difficult to differentiate from one another: a cystic variation of a keratoacanthoma squamous cell carcinoma, a basal cell carcinoma, and an excoriated facial acne vulgaris. The subtle clinical nuances found in each of these cases demonstrated the importance of a careful clinical evaluation; however, this was not sufficient for adequate assessment of whether or not to biopsy. With early lesions such as these, the use of the noninvasive imaging modalities of dermoscopy and optical coherence tomography becomes critical in order to avoid unnecessary biopsy. The discussion of the clinically and dermoscopically challenging features is both instructive and enlightening. Oftentimes, “textbook descriptions” of lesions focus on the description of an already mature stage of growth, despite the fact that we continue to strive toward earlier detection of potential malignancies. With this in mind, the features found with optical coherence tomography proved essential to the elucidation of these difficult lesions. These three interesting cases illustrated the challenges encountered when dealing with early lesions specifically. The authors bring to light features in each of these cases that are often not thought of as being the “typical” presentation in each lesion category and demonstrate the clinical utility of noninvasive devices in difficult-to-diagnose cases such as these. PMID:26060518

  9. Actin-dependent deposition of putative endosomes and of endoplasmic reticulum during early stages of wound healing in characean internodal cells

    PubMed Central

    Klima, A.; Foissner, I.

    2012-01-01

    We investigated the behaviour of organelles stained by FM1-43 (putative endosomes) and/or LysoTracker Red (LTred; acidic compartments) and that of the endoplasmic reticulum (ER) during healing of puncture and UV-induced wounds in internodal cells of Nitella flexilis and Chara corallina. Immediately after puncturing, wounds were passively sealed by a plug of solid vacuolar inclusions onto which a bipartite wound wall was actively deposited. The outer, callose-containing amorphous layer consisted of remnants of FM1-43- and LTred-labelled organelles, of ER cisternae and of polysaccharide-containing secretory vesicles which became deposited in the absence of membrane retrieval (compound exocytosis). During formation of the inner, cellulosic layer exocytosis of secretory vesicles with the newly formed plasma membrane is coupled to endocytosis via coated vesicles. Migration of FM1-43- and LTred-stained organelles, of ER and of secretory vesicles towards the cell cortex and the deposition of a bipartite wound wall could also be induced by spot-like irradiation with ultraviolet light. Cytochalasin D reversibly inhibited the accumulation and deposition of organelles. Our study indicates that active, actin-dependent deposition of putative recycling endosomes is required for wound healing (plasma membrane repair) and supports the hypothesis that deposition of ER cisternae helps to restore wounding-disturbed Ca2+ metabolism. PMID:21668600

  10. A modified hypoxia-based TCP model to investigate the clinical outcome of stereotactic hypofractionated regimes for early stage non-small-cell lung cancer (NSCLC)

    SciTech Connect

    Strigari, L.; Benassi, M.; Sarnelli, A.; Polico, R.; D'Andrea, M.

    2012-07-15

    Purpose: Stereotactic body radiotherapy (SBRT) has been applied to lung tumors at different stages and sizes with good local tumor control (LC) rates. The linear quadratic model (LQM), in its basic formulation, does not seem to be appropriate to describe the response to radiotherapy for clinical trials, based on a few fractions. Thus, the main aim of this work was to develop a model, which takes into account the hypoxic cells and their reoxygenation. Methods: A parameter named B has been introduced in a modified tumor control probability (TCP) from LQM and linear-quadratic-linear model (LQLM), and represents the fraction of hypoxic cells that survive and become oxygenated after each irradiation. Based on published trials evaluating LC at 3 yr (LC3), values of B were obtained by maximum likelihood minimization between predicted TCP and clinical LC3. Two oxygen enhancement ratio (OER) parameter sets (1 and 2) from literature have been adopted to calculate the B-factors. Initial hypoxic cell fractions ({eta}{sub h}) from 0.05 to 0.50 were assumed. Log-likelihood (L) and Akaike information criterion (AIC) were determined in an independent clinical validation dataset. Results: The B-values of modified TCPs spanned the whole interval from 0 to 1, depending on the fractionation scheme (number of fractions and dose/fraction), showing a maximum (close to 1) at doses/fraction of 8-12 Gy. The B-values calculated using the OER parameter set 1 exhibited a smoother falloff than set 2. An analytical expression was derived to describe the B-value's dependence on the fractionation scheme. The R{sup 2}-adjusted values varied from 0.63 to 0.67 for LQ models and OER set 1 and from 0.75 to 0.78 for LQ model and OER set 2. Lower values of R{sup 2}-adjusted were found for LQLM and both OER sets. L and AIC, calculated using a fraction of {eta}{sub h} = 0.15 and the B-value from the authors analytical expression were higher than for other {eta}{sub h}-values, irrespective of model or OER

  11. Treatment Patterns and Health Resource Utilization Among Patients Diagnosed With Early Stage Resected Non-Small Cell Lung Cancer at US Community Oncology Practices.

    PubMed

    Buck, Philip O; Saverno, Kimberly R; Miller, Paul J E; Arondekar, Bhakti; Walker, Mark S

    2015-11-01

    Data on adjuvant therapy in resected non-small cell lung cancer (NSCLC) in routine practice are lacking in the United States. This retrospective observational database study included 609 community oncology patients with resected stage IB to IIIA NSCLC. Use of adjuvant therapy was 39.1% at disease stage IB and 64.9% to 68.2% at stage II to IIIA. The most common regimen at all stages was carboplatin and paclitaxel. Platin-based adjuvant chemotherapy has extended survival in clinical trials in patients with completely resected non-small cell lung cancer (NSCLC). There are few data on the use of adjuvant therapy in community-based clinical practice in the United States. This was a retrospective observational study using electronic medical record and billing data collected during routine care at US community oncology sites in the Vector Oncology Data Warehouse between January 2007 and January 2014. Patients aged ≥ 18 years with a primary diagnosis of stage IB to IIIA NSCLC were eligible if they had undergone surgical resection. Treatment patterns, health care resource use, and cost were recorded, stratified by stage at diagnosis. The study included 609 patients (mean age, 64.8 years, 52.9% male), of whom 215 had stage IB disease, 130 stage IIA/II, 110 stage IIB, and 154 stage IIIA. Adjuvant systemic therapy after resection was provided to 345 (56.7%) of 609 patients, with lower use in patients with stage IB disease (39.1%) than stage II to IIIA disease (64.9-68.2%) (P < .0001). The most common adjuvant regimen at all stages was the combination of carboplatin and paclitaxel. There were no statistically significant differences in office visits or incidence of hospitalization by disease stage. During adjuvant treatment, the total monthly median cost per patient was $17,389.75 (interquartile range, $8,815.61 to $23,360.85). Adjuvant systemic therapy was used in some patients with stage IB NSCLC and in the majority of patients with stage IIA to IIIA disease. There were few

  12. Characterization of intracellular dynamics of inoculated PrP-res and newly generated PrPSc during early stage prion infection in Neuro2a cells

    PubMed Central

    Yamasaki, Takeshi; Baron, Gerald S; Suzuki, Akio; Hasebe, Rie; Horiuchi, Motohiro

    2014-01-01

    Summary To clarify the cellular mechanisms for the establishment of prion infection, we analyzed the intracellular dynamics of inoculated and newly generated abnormal isoform of prion protein (PrPSc) in Neuro2a cells. Within 24 h after inoculation, the newly generated PrPSc was evident at the plasma membrane, in early endosomes, and in late endosomes, but this PrPSc was barely evident in lysosomes; in contrast, the majority of the inoculated PrPSc was evident in late endosomes and lysosomes. However, during the subsequent 48 h, the newly generated PrPSc increased remarkably in early endosomes and recycling endosomes. Overexpression of wild-type and mutant Rab proteins showed that membrane trafficking along not only the endocytic-recycling pathway but also the endo-lysosomal pathway is involved in de novo PrPSc generation. These results suggest that the trafficking of exogenously introduced PrPSc from the endo-lysosomal pathway to the endocytic-recycling pathway is important for the establishment of prion infection. PMID:24503096

  13. Pretreatment Modified Glasgow Prognostic Score Predicts Clinical Outcomes After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer

    SciTech Connect

    Kishi, Takahiro; Matsuo, Yukinori Ueki, Nami; Iizuka, Yusuke; Nakamura, Akira; Sakanaka, Katsuyuki; Mizowaki, Takashi; Hiraoka, Masahiro

    2015-07-01

    Purpose: This study aimed to evaluate the prognostic significance of the modified Glasgow Prognostic Score (mGPS) in patients with non-small cell lung cancer (NSCLC) who received stereotactic body radiation therapy (SBRT). Methods and Materials: Data from 165 patients who underwent SBRT for stage I NSCLC with histologic confirmation from January 1999 to September 2010 were collected retrospectively. Factors, including age, performance status, histology, Charlson comorbidity index, mGPS, and recursive partitioning analysis (RPA) class based on sex and T stage, were evaluated with regard to overall survival (OS) using the Cox proportional hazards model. The impact of the mGPS on cause of death and failure patterns was also analyzed. Results: The 3-year OS was 57.9%, with a median follow-up time of 3.5 years. A higher mGPS correlated significantly with poor OS (P<.001). The 3-year OS of lower mGPS patients was 66.4%, whereas that of higher mGPS patients was 44.5%. On multivariate analysis, mGPS and RPA class were significant factors for OS. A higher mGPS correlated significantly with lung cancer death (P=.019) and distant metastasis (P=.013). Conclusions: The mGPS was a significant predictor of clinical outcomes for SBRT in NSCLC patients.

  14. Expression Levels of Some Antioxidant and Epidermal Growth Factor Receptor Genes in Patients with Early-Stage Non-Small Cell Lung Cancer

    PubMed Central

    De Palma, Giuseppe; Mozzoni, Paola; Acampa, Olga; Internullo, Eveline; Carbognani, Paolo; Rusca, Michele; Goldoni, Matteo; Corradi, Massimo; Tiseo, Marcello; Apostoli, Pietro; Mutti, Antonio

    2010-01-01

    This study was aimed at: (i) investigating the expression profiles of some antioxidant and epidermal growth factor receptor genes in cancerous and unaffected tissues of patients undergoing lung resection for non-small cell lung cancer (NSCLC) (cross-sectional phase), (ii) evaluating if gene expression levels at the time of surgery may be associated to patients' survival (prospective phase). Antioxidant genes included heme oxygenase 1 (HO-1), superoxide dismutase-1 (SOD-1), and -2 (SOD-2), whereas epidermal growth factor receptor genes consisted of epidermal growth factor receptor (EGFR) and v-erb-b2 erythroblastic leukaemia viral oncogene homolog 2 (HER-2). Twenty-eight couples of lung biopsies were obtained and gene transcripts were quantified by Real Time RT-PCR. The average follow-up of patients lasted about 60 months. In the cancerous tissues, antioxidant genes were significantly hypo-expressed than in unaffected tissues. The HER-2 transcript levels prevailed in adenocarcinomas, whereas EGFR in squamocellular carcinomas. Patients overexpressing HER-2 in the cancerous tissues showed significantly lower 5-year survival than the others. PMID:20700416

  15. Identification of prognostic genes and gene sets for early-stage non-small cell lung cancer using bi-level selection methods

    PubMed Central

    Tian, Suyan; Wang, Chi; Chang, Howard H.; Sun, Jianguo

    2017-01-01

    In contrast to feature selection and gene set analysis, bi-level selection is a process of selecting not only important gene sets but also important genes within those gene sets. Depending on the order of selections, a bi-level selection method can be classified into three categories – forward selection, which first selects relevant gene sets followed by the selection of relevant individual genes; backward selection which takes the reversed order; and simultaneous selection, which performs the two tasks simultaneously usually with the aids of a penalized regression model. To test the existence of subtype-specific prognostic genes for non-small cell lung cancer (NSCLC), we had previously proposed the Cox-filter method that examines the association between patients’ survival time after diagnosis with one specific gene, the disease subtypes, and their interaction terms. In this study, we further extend it to carry out forward and backward bi-level selection. Using simulations and a NSCLC application, we demonstrate that the forward selection outperforms the backward selection and other relevant algorithms in our setting. Both proposed methods are readily understandable and interpretable. Therefore, they represent useful tools for the researchers who are interested in exploring the prognostic value of gene expression data for specific subtypes or stages of a disease. PMID:28387364

  16. High Radiation Dose May Reduce the Negative Effect of Large Gross Tumor Volume in Patients With Medically Inoperable Early-Stage Non-Small Cell Lung Cancer

    SciTech Connect

    Zhao Lujun; West, Brady T.; Hayman, James A.; Lyons, Susan; Cease, Kemp; Kong, F.-M. . E-mail: Fengkong@med.umich.edu

    2007-05-01

    Purpose: To determine whether the effect of radiation dose varies with gross tumor volume (GTV) in patients with stage I/II non-small cell lung cancer (NSCLC). Methods and Materials: Included in the study were 114 consecutive patients with medically inoperable stage I/II NSCLC treated with three-dimensional conformal radiotherapy between 1992 and 2004. The median biologic equivalent dose (BED) was 79.2 Gy (range, 58.2-124.5 Gy). The median GTV was 51.8 cm{sup 3} (range, 2.1-727.8 cm{sup 3}). The primary endpoint was overall survival (OS). Kaplan-Meier estimation and Cox regression models were used for survival analyses. Results: Multivariate analysis showed that there was a significant interaction between radiation dose and GTV (p < 0.001). In patients with BED {<=}79.2 Gy (n = 68), the OS medians for patients with GTV >51.8 cm{sup 3} and {<=}51.8 cm{sup 3} were 18.2 and 23.9 months, respectively (p 0.015). If BED was >79.2 Gy (n = 46), no significant difference was found between GTV groups (p = 0.681). For patients with GTV >51.8 cm{sup 3} (n = 45), the OS medians in those with BED >79.2 Gy and {<=}79.2 Gy were 30.4 and 18.2 months, respectively (p < 0.001). If GTV was {<=}51.8 cm{sup 3} (n = 45), the difference was no longer significant (p = 0.577). Conclusion: High-dose radiation is more important for patients with larger tumors and may be effective in reducing the adverse outcome associated with large GTV. Further prospective studies are needed to confirm this finding.

  17. Cost-Effectiveness Analysis of Stereotactic Body Radiotherapy and Radiofrequency Ablation for Medically Inoperable, Early-Stage Non-Small Cell Lung Cancer

    SciTech Connect

    Sher, David J.

    2011-12-01

    Purpose: The standard management of medically inoperable Stage I non-small-cell lung cancer (NSCLC) conventionally has been fractionated three-dimensional conformal radiation therapy (3D-CRT). The relatively poor local control rate and inconvenience associated with this therapy have prompted the development of stereotactic body radiotherapy (SBRT), a technique that delivers very high doses of irradiation typically over 3 to 5 sessions. Radiofrequency ablation (RFA) has also been investigated as a less costly, single-day therapy that thermally ablates small, peripheral tumors. The cost-effectiveness of these three techniques has never been compared. Methods and Materials: We developed a Markov model to describe health states of 65-year-old men with medically inoperable NSCLC after treatment with 3D-CRT, SBRT, and RFA. Given their frail state, patients were assumed to receive supportive care after recurrence. Utility values, recurrence risks, and costs were adapted from the literature. Sensitivity analyses were performed to model uncertainty in these parameters. Results: The incremental cost-effectiveness ratio for SBRT over 3D-CRT was $6,000/quality-adjusted life-year, and the incremental cost-effectiveness ratio for SBRT over RFA was $14,100/quality-adjusted life-year. One-way sensitivity analysis showed that the results were robust across a range of tumor sizes, patient utility values, and costs. This result was confirmed with probabilistic sensitivity analyses that varied local control rates and utilities. Conclusion: In comparison to 3D-CRT and RFA, SBRT was the most cost-effective treatment for medically inoperable NSCLC over a wide range of treatment and disease assumptions. On the basis of efficacy and cost, SBRT should be the primary treatment approach for this disease.

  18. T cell reactivity against antigen 85 but not against the 18- and 65-kD heat shock proteins in the early stages of acquired immunity against Mycobacterium leprae.

    PubMed Central

    Launois, P; Niang N'Diaye, M; Sarthou, J L; Drowart, A; Van Vooren, J P; Cartel, J L; Huygen, K

    1994-01-01

    T cell proliferation and interferon-gamma (IFN-gamma) production of peripheral blood mononuclear cells (PBMC) from 20 household contacts were tested against the 18- and 65-kD heat shock proteins from Mycobacterium leprae (ML18 and ML65 respectively) and antigen 85 from Myco. bovis bacille Calmette-Guérin (BCG) (Ag 85) during a 12-months follow-up study. Among the eight contacts that became positive, eight showed positive reactivity against Ag 85, 5/8 against ML65 and 4/8 against ML18 at the end of the study. Of the 16 contacts who were lepromin-positive either at first or second testing, all responded to Ag 85, 11 to ML 65, but only eight reacted to ML18 antigen. Contacts who were lepromin-positive at first testing developed responses to ML18 only at second testing. In contrast, among the four contacts that remained lepromin-negative during the follow up, three proliferated to Ag 85 either at first or second testing, but only one produced IFN-gamma against Ag 85 at the end of the study. These results demonstrated that T cell reactivity and particularly IFN-gamma secretion against Ag 85, but not against ML18 and ML65, might be a predominant mechanism in the early stages of acquired protective immunity against Myco. leprae. PMID:8149672

  19. Simultaneous detection of circulating immunological parameters and tumor biomarkers in early stage breast cancer patients during adjuvant chemotherapy.

    PubMed

    Rovati, B; Mariucci, S; Delfanti, S; Grasso, D; Tinelli, C; Torre, C; De Amici, M; Pedrazzoli, P

    2016-06-01

    Chemotherapy-induced immune suppression has mainly been studied in patients with advanced cancer, but the influence of chemotherapy on the immune system in early stage cancer patients has so far not been studied systematically. The aim of the present study was to monitor the immune system during anthracycline- and taxane-based adjuvant chemotherapy in early stage breast cancer patients, to assess the impact of circulating tumor cells on selected immune parameters and to reveal putative angiogenic effects of circulating endothelial cells. Peripheral blood samples from 20 early stage breast cancer patients were analyzed using a flow cytometric multi-color of antibodies to enumerate lymphocyte and dendritic cell subsets, as well as endothelial and tumor cells. An enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of various serological factors. During chemotherapy, all immunological parameters and angiogenesis surrogate biomarkers showed significant decreases. The numbers of circulating tumor cells showed significant inverse correlations with the numbers of T helper cells, a lymphocyte subset directly related to effective anti-tumor responses. Reduced T helper cell numbers may contribute to systemic immunosuppression and, as such, the activation of dormant tumor cells. From our results we conclude that adjuvant chemotherapy suppresses immune function in early stage breast cancer patients. In addition, we conclude that the presence of circulating tumor cells, defined as pan-cytokeratin(+), CD326(+), CD45(-) cells, may serve as an important indicator of a patient's immune status. Further investigations are needed to firmly define circulating tumor cells as a predictor for the success of breast cancer adjuvant chemotherapy.

  20. Stereotactic Body Radiation Therapy for Early-Stage Non-Small-Cell Lung Carcinoma: Four-Year Results of a Prospective Phase II Study

    SciTech Connect

    Fakiris, Achilles J.; McGarry, Ronald C.; Yiannoutsos, Constantin T.; Papiez, Lech; Williams, Mark; Henderson, Mark A.; Timmerman, Robert

    2009-11-01

    Purpose: The 50-month results of a prospective Phase II trial of stereotactic body radiation therapy (SBRT) in medically inoperable patients are reported. Methods and Materials: A total of 70 medically inoperable patients had clinically staged T1 (34 patients) or T2 (36 patients) (<=7 cm), N0, M0, biopsy-confirmed non-small-cell lung carcinoma (NSCLC) and received SBRT as per our previously published reports. The SBRT treatment dose of 60-66 Gy was prescribed to the 80% isodose volume in three fractions. Results: Median follow-up was 50.2 months (range, 1.4-64.8 months). Kaplan-Meier local control at 3 years was 88.1%. Regional (nodal) and distant recurrence occurred in 6 (8.6%) and 9 (12.9%) patients, respectively. Median survival (MS) was 32.4 months and 3-year overall survival (OS) was 42.7% (95% confidence interval [95% CI], 31.1-54.3%). Cancer-specific survival at 3 years was 81.7% (95% CI, 70.0-93.4%). For patients with T1 tumors, MS was 38.7 months (95% CI, 25.3-50.2) and for T2 tumors MS was 24.5 months (95% CI, 18.5-37.4) (p = 0.194). Tumor volume (<=5 cc, 5-10 cc, 10-20 cc, >20 cc) did not significantly impact survival: MS was 36.9 months (95% CI, 18.1-42.9), 34.0 (95% CI, 16.9-57.1), 32.8 (95% CI, 21.3-57.8), and 21.4 months (95% CI, 17.8-41.6), respectively (p = 0.712). There was no significant survival difference between patients with peripheral vs. central tumors (MS 33.2 vs. 24.4 months, p = 0.697). Grade 3 to 5 toxicity occurred in 5 of 48 patients with peripheral lung tumors (10.4%) and in 6 of 22 patients (27.3%) with central tumors (Fisher's exact test, p = 0.088). Conclusion: Based on our study results, use of SBRT results in high rates of local control in medically inoperable patients with Stage I NSCLC.

  1. Stereotactic body radiotherapy for centrally located early-stage non-small cell lung cancer or lung metastases from the RSSearch(®) patient registry.

    PubMed

    Davis, Joanne N; Medbery, Clinton; Sharma, Sanjeev; Pablo, John; Kimsey, Frank; Perry, David; Muacevic, Alexander; Mahadevan, Anand

    2015-05-15

    The purpose of this study was to evaluate treatment patterns and outcomes of stereotactic body radiotherapy (SBRT) for centrally located primary non-small cell lung cancer (NSCLC) or lung metastases from the RSSearch(®) Patient Registry, an international, multi-center patient registry dedicated to radiosurgery and SBRT. Eligible patients included those with centrally located lung tumors clinically staged T1-T2 N0, M0, biopsy-confirmed NSCLC or lung metastases treated with SBRT between November 2004 and January 2014. Descriptive analysis was used to report patient demographics and treatment patterns. Overall survival (OS) and local control (LC) were determined using Kaplan-Meier method. Toxicity was reported using the Common Terminology Criteria for Adverse Events version 3.0. In total, 111 patients with 114 centrally located lung tumors (48 T1-T2,N0,M0 NSCLC and 66 lung metastases) were treated with SBRT at 19 academic and community-based radiotherapy centers in the US and Germany. Median follow-up was 17 months (range, 1-72). Median age was 74 years for primary NSCLC patients and 65 years for lung metastases patients (p < 0.001). SBRT dose varied from 16 - 60 Gy (median 48 Gy) delivered in 1-5 fractions (median 4 fractions). Median dose to centrally located primary NSCLC was 48 Gy compared to 37.5 Gy for lung metastases (p = 0.0001) and median BED10 was 105.6 Gy for primary NSCLC and 93.6 Gy for lung metastases (p = 0.0005). Two-year OS for T1N0M0 and T2N0M0 NSCLC was 79 and 32.1 %, respectively (p = 0.009) and 2-year OS for lung metastases was 49.6 %. Two-year LC was 76.4 and 69.8 % for primary NSCLC and lung metastases, respectively. Toxicity was low with no Grade 3 or higher acute or late toxicities. Overall, patients with centrally located primary NSCLC were older and received higher doses of SBRT than those with lung metastases. Despite these differences, LC and OS was favorable for patients with central lung tumors treated with SBRT

  2. Early-stage squamous cell carcinoma of the oropharynx: Radiotherapy vs. Trans-Oral Robotic Surgery (ORATOR) – study protocol for a randomized phase II trial

    PubMed Central

    2013-01-01

    Background The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has markedly increased over the last three decades due to newly found associations with human papillomavirus (HPV) infection. Primary radiotherapy (RT) is the treatment of choice for OPSCC at most centers, and over the last decade, the addition of concurrent chemotherapy has led to a significant improvement in survival, but at the cost of increased acute and late toxicity. Transoral robotic surgery (TORS) has emerged as a promising alternative treatment, with preliminary case series demonstrating encouraging oncologic, functional, and quality of life (QOL) outcomes. However, comparisons of TORS and RT in a non-randomized fashion are susceptible to bias. The goal of this randomized phase II study is to compare QOL, functional outcomes, toxicity profiles, and survival following primary RT (± chemotherapy) vs. TORS (± adjuvant [chemo] RT) in patients with OPSCC. Methods/Design The target patient population comprises OPSCC patients who would be unlikely to require chemotherapy post-resection: Tumor stage T1-T2 with likely negative margins at surgery; Nodal stage N0-2, ≤3 cm in size, with no evidence of extranodal extension on imaging. Participants will be randomized in a 1:1 ratio between Arm 1 (RT ± chemotherapy) and Arm 2 (TORS ± adjuvant [chemo] RT). In Arm 1, patients with N0 disease will receive RT alone, whereas N1-2 patients will receive concurrent chemoradiation. In Arm 2, patients will undergo TORS along with selective neck dissections, which may be staged. Pathologic high-risk features will be used to determine the requirement for adjuvant radiotherapy +/- chemotherapy. The primary endpoint is QOL score using the M.D. Anderson Dysphagia Inventory (MDADI), with secondary endpoints including survival, toxicity, other QOL outcomes, and swallowing function. A sample of 68 patients is required. Discussion This study, if successful, will provide a much-needed randomized

  3. An association between preoperative anemia and decreased survival in early-stage non-small-cell lung cancer patients treated with surgery alone

    SciTech Connect

    Yovino, Susannah; Kwok, Young; Krasna, Mark; Bangalore, Madan; Suntharalingam, Mohan . E-mail: msuntha@umm.edu

    2005-08-01

    Purpose: Surgical resection is the mainstay of therapy for patients presenting with Stage I and II non-small-cell lung cancer (NSCLC). Despite optimal staging and surgery, these patients are still at significant risk for failure. The purpose of this study is to report a retrospective analysis of the outcome of patients treated with surgery alone, as well as to analyze prognostic factors associated with survival. Materials and Methods: From May 2000 to November 2002, there was a total of 125 patients who were treated with surgery for NSCLC at University of Maryland Medical Center. Of these, 82 Stage I and II patients who received surgery alone as the definitive therapy were identified. The median age of the entire cohort was 68 years (range, 43-88 years). There were 48 males and 34 females. Sixty-three patients (76.8%) underwent lobectomies whereas 19 patients (23.2%) underwent nonlobectomy (wedge resection or segmentectomy) procedures. Patients who received neoadjuvant or adjuvant radiation therapy or chemotherapy were excluded from the study. Factors included in univariate and multivariate analyses were age, sex, tumor histology, pathologic stage, p53 status, preoperative hemoglobin (Hgb), and type of surgery performed. Endpoints of the study were relapse-free survival (RFS) and overall survival (OS). Results: Median follow-up was 20.8 months (range, 0.4-43.2 months). For the entire cohort, the 2-year RFS was 66.0% and 2-year OS was 76.3%. Median survival for the entire cohort has not been achieved. In univariate analysis, the only factor that achieved statistical significance was preoperative Hgb level. Patients who had preoperative Hgb <12 mg/dL experienced significantly worse RFS (mean RFS: 26.6 months vs. 34.9 months, p = 0.043) and OS (median OS: 27 months vs. 42.5 months, p = 0.011). For Stage I patients (n = 72), the 2-year RFS and OS were 66.4% and 77.1%, respectively. In the subgroup of stage IA patients (n = 37), there was a trend toward decreased

  4. Discovery of piRNAs Pathway Associated with Early-Stage Spermatogenesis in Chicken.

    PubMed

    Xu, Lu; Qiu, Lingling; Chang, Guobin; Guo, Qixin; Liu, Xiangping; Bi, Yulin; Zhang, Yu; Wang, Hongzhi; Li, Zhiteng; Guo, Xiaoming; Wan, Fang; Zhang, Yang; Xu, Qi; Chen, Guohong

    2016-01-01

    Piwi-interacting RNAs (piRNAs) play a key role in spermatogenesis. Here, we describe the piRNAs profiling of primordial germ cells (PGCs), spermatogonial stem cells (SSCs), and the spermatogonium (Sp) during early-stage spermatogenesis in chicken. We obtained 31,361,989 reads from PGCs, 31,757,666 reads from SSCs, and 46,448,327 reads from Sp cells. The length distribution of piRNAs in the three samples showed peaks at 33 nt. The resulting genes were subsequently annotated against the Gene Ontology (GO) database. Five genes (RPL7A, HSPA8, Pum1, CPXM2, and PRKCA) were found to be involved in cellular processes. Interactive pathway analysis (IPA) further revealed three important pathways in early-stage spermatogenesis including the FGF, Wnt, and EGF receptor signaling pathways. The gene Pum1 was found to promote germline stem cell proliferation, but it also plays a role in spermatogenesis. In conclusion, we revealed characteristics of piRNAs during early spermatogonial development in chicken and provided the basis for future research.

  5. Discovery of piRNAs Pathway Associated with Early-Stage Spermatogenesis in Chicken

    PubMed Central

    Chang, Guobin; Guo, Qixin; Liu, Xiangping; Bi, Yulin; Zhang, Yu; Wang, Hongzhi; Li, Zhiteng; Guo, Xiaoming; Wan, Fang; Zhang, Yang; Xu, Qi; Chen, Guohong

    2016-01-01

    Piwi-interacting RNAs (piRNAs) play a key role in spermatogenesis. Here, we describe the piRNAs profiling of primordial germ cells (PGCs), spermatogonial stem cells (SSCs), and the spermatogonium (Sp) during early-stage spermatogenesis in chicken. We obtained 31,361,989 reads from PGCs, 31,757,666 reads from SSCs, and 46,448,327 reads from Sp cells. The length distribution of piRNAs in the three samples showed peaks at 33 nt. The resulting genes were subsequently annotated against the Gene Ontology (GO) database. Five genes (RPL7A, HSPA8, Pum1, CPXM2, and PRKCA) were found to be involved in cellular processes. Interactive pathway analysis (IPA) further revealed three important pathways in early-stage spermatogenesis including the FGF, Wnt, and EGF receptor signaling pathways. The gene Pum1 was found to promote germline stem cell proliferation, but it also plays a role in spermatogenesis. In conclusion, we revealed characteristics of piRNAs during early spermatogonial development in chicken and provided the basis for future research. PMID:27045806

  6. Acoustic determination of early stages of intravascular blood coagulation.

    PubMed

    Uzlova, Svetlana G; Guria, Konstantin G; Guria, Georgy Th

    2008-10-13

    The blood coagulation system (BCS) is a complex biological system playing a principal role in the maintenance of haemostasis. Insufficient activity of the BCS may lead to bleeding and blood loss (e.g. in the case of haemophilia). On the other hand, excessive activity may cause intravascular blood coagulation, thromboses and embolization. Most of the methods currently used for BCS monitoring suffer from the major disadvantage of being invasive. The purpose of the present work is to demonstrate the feasibility of using ultrasonic methods for non-invasive registration of the early stages of blood coagulation processes in intensive flows. With this purpose, a special experimental set-up was designed, facilitating the simultaneous detection of optical and acoustic signals during the clotting process. It was shown that (i) as microemboli appear in the flow during the early stage of blood coagulation, the intensity of the Doppler signal increases twofold, and (ii) microemboli formation in the early stages of blood clotting always reveals itself through an acoustic contrast. Both of these effects are well defined, so we hope that they may be used for non-invasive BCS monitoring in clinical practice.

  7. A treatment planning comparison between modulated tri-cobalt-60 teletherapy and linear accelerator-based stereotactic body radiotherapy for central early-stage non-small cell lung cancer.

    PubMed

    Merna, Catherine; Rwigema, Jean-Claude M; Cao, Minsong; Wang, Pin-Chieh; Kishan, Amar U; Michailian, Argin; Lamb, James; Sheng, Ke; Agazaryan, Nzhde; Low, Daniel A; Kupelian, Patrick; Steinberg, Michael L; Lee, Percy

    2016-01-01

    We evaluated the feasibility of planning stereotactic body radiotherapy (SBRT) for large central early-stage non-small cell lung cancer with a tri-cobalt-60 (tri-(60)Co) system equipped with real-time magnetic resonance imaging (MRI) guidance, as compared to linear accelerator (LINAC)-based SBRT. In all, 20 patients with large central early-stage non-small cell lung cancer who were treated between 2010 and 2015 with LINAC-based SBRT were replanned using a tri-(60)Co system for a prescription dose of 50Gy in 4 fractions. Doses to organs at risk were evaluated based on established MD Anderson constraints for central lung SBRT. R100 values were calculated as the total tissue volume receiving 100% of the dose (V100) divided by the planning target volume and compared to assess dose conformity. Dosimetric comparisons between LINAC-based and tri-(60)Co SBRT plans were performed using Student׳s t-test and Wilcoxon Ranks test. Blinded reviews by radiation oncologists were performed to assess the suitability of both plans for clinical delivery. The mean planning target volume was 48.3cc (range: 12.1 to 139.4cc). Of the tri-(60)Co SBRT plans, a mean 97.4% of dosimetric parameters per patient met MD Anderson dose constraints, whereas a mean 98.8% of dosimetric parameters per patient were met with LINAC-based SBRT planning (p = 0.056). R100 values were similar between both plans (1.20 vs 1.21, p = 0.79). Upon blinded review by 4 radiation oncologists, an average of 90% of the tri-(60)Co SBRT plans were considered acceptable for clinical delivery compared with 100% of the corresponding LINAC-based SBRT plans (p = 0.17). SBRT planning using the tri-(60)Co system with built-in MRI is feasible and achieves clinically acceptable plans for most central lung patients, with similar target dose conformity and organ at risk dosimetry. The added benefit of real-time MRI-guided therapy may further optimize tumor targeting while improving normal tissue sparing, which warrants further

  8. Keratin 34betaE12/keratin7 expression is a prognostic factor of cancer-specific and overall survival in patients with early stage non-small cell lung cancer.

    PubMed

    Pøhl, Mette; Olsen, Karen Ege; Holst, Rene; Donnem, Tom; Busund, Lill-Tove; Bremnes, Roy M; Al-Saad, Samer; Andersen, Sigve; Richardsen, Elin; Ditzel, Henrik J; Hansen, Olfred

    2016-01-01

    Carcinomas and their metastases often retain the keratin patterns of their epithelial origin, and are therefore useful as lineage-specific markers in diagnostic pathology. Recently, it has become clear that intermediate filaments composed by keratins play a role in modulation of cell proliferation, migration, and possibly cancer invasion, factors impacting prognosis in early stage non-small cell lung cancer (NSCLC). Tumor tissue from a retrospective Danish cohort of 177 patients with completely resected NSCLC, stage I-IIIA tumors, were analyzed for keratin 7 (K7) and keratin 34βE12 expression by immunohistochemistry and validated in a comparable independent Norwegian cohort of 276 stage I-IIIA NSCLC patients. Based on keratin 34βE12/K7 expression, three subgroups with significantly different median cancer-specific survival rates were identified (34βE12+/K7+, 168 months vs. 34βE12+/K7+, 73 months vs. 34βE12-/K7+, 30 months; p = 0.0004). In multivariate analysis, stage II-IIIA (HR 2.9), 34βE12+/K7+ (HR 1.90) and 34βE12-/K7+ (HR 3.7), were prognostic factors of poor cancer-specific survival (CSS) (p < 0.001). Validation in the Norwegian cohort confirmed that stage II-IIIA (HR 2.3), 34βE12+/K7+ (HR 1.6), and 34βE12-/K7+ (HR 2.0) were prognostic factors of poor CSS (p < 0.05). Multivariate Cox proportional-hazard analysis demonstrated that 34βE12+/K7 + and 34βE12+/K7 + status was significantly associated with poor overall survival (p < 0.05). Keratin 34βE12/K7 expression is a prognostic parameter in resected early stage NSCLC that allows identification of high-risk NSCLC patients with poor cancer-specific and overall survival.

  9. A treatment planning comparison between modulated tri-cobalt-60 teletherapy and linear accelerator–based stereotactic body radiotherapy for central early-stage non−small cell lung cancer

    SciTech Connect

    Merna, Catherine; Rwigema, Jean-Claude M.; Cao, Minsong; Wang, Pin-Chieh; Kishan, Amar U.; Michailian, Argin; Lamb, James; Sheng, Ke; Agazaryan, Nzhde; Low, Daniel A.; Kupelian, Patrick; Steinberg, Michael L.; Lee, Percy

    2016-04-01

    We evaluated the feasibility of planning stereotactic body radiotherapy (SBRT) for large central early-stage non−small cell lung cancer with a tri-cobalt-60 (tri-{sup 60}Co) system equipped with real-time magnetic resonance imaging (MRI) guidance, as compared to linear accelerator (LINAC)–based SBRT. In all, 20 patients with large central early-stage non−small cell lung cancer who were treated between 2010 and 2015 with LINAC-based SBRT were replanned using a tri-{sup 60}Co system for a prescription dose of 50 Gy in 4 fractions. Doses to organs at risk were evaluated based on established MD Anderson constraints for central lung SBRT. R{sub 100} values were calculated as the total tissue volume receiving 100% of the dose (V{sub 100}) divided by the planning target volume and compared to assess dose conformity. Dosimetric comparisons between LINAC-based and tri-{sup 60}Co SBRT plans were performed using Student's t-test and Wilcoxon Ranks test. Blinded reviews by radiation oncologists were performed to assess the suitability of both plans for clinical delivery. The mean planning target volume was 48.3 cc (range: 12.1 to 139.4 cc). Of the tri-{sup 60}Co SBRT plans, a mean 97.4% of dosimetric parameters per patient met MD Anderson dose constraints, whereas a mean 98.8% of dosimetric parameters per patient were met with LINAC-based SBRT planning (p = 0.056). R{sub 100} values were similar between both plans (1.20 vs 1.21, p = 0.79). Upon blinded review by 4 radiation oncologists, an average of 90% of the tri-{sup 60}Co SBRT plans were considered acceptable for clinical delivery compared with 100% of the corresponding LINAC-based SBRT plans (p = 0.17). SBRT planning using the tri-{sup 60}Co system with built-in MRI is feasible and achieves clinically acceptable plans for most central lung patients, with similar target dose conformity and organ at risk dosimetry. The added benefit of real-time MRI-guided therapy may further optimize tumor targeting while improving

  10. RNA-seq liver transcriptome analysis reveals an activated MHC-I pathway and an inhibited MHC-II pathway at the early stage of vaccine immunization in zebrafish

    PubMed Central

    2012-01-01

    Background Zebrafish (Danio rerio) is a prominent vertebrate model of human development and pathogenic disease and has recently been utilized to study teleost immune responses to infectious agents threatening the aquaculture industry. In this work, to clarify the host immune mechanisms underlying the protective effects of a putative vaccine and improve its immunogenicity in the future efforts, high-throughput RNA sequencing technology was used to investigate the immunization-related gene expression patterns of zebrafish immunized with Edwardsiella tarda live attenuated vaccine. Results Average reads of 18.13 million and 14.27 million were obtained from livers of zebrafish immunized with phosphate buffered saline (mock) and E. tarda vaccine (WED), respectively. The reads were annotated with the Ensembl zebrafish database before differential expressed genes sequencing (DESeq) comparative analysis, which identified 4565 significantly differentially expressed genes (2186 up-regulated and 2379 down-regulated in WED; p<0.05). Among those, functional classifications were found in the Gene Ontology database for 3891 and in the Kyoto Encyclopedia of Genes and Genomes database for 3467. Several pathways involved in acute phase response, complement activation, immune/defense response, and antigen processing and presentation were remarkably affected at the early stage of WED immunization. Further qPCR analysis confirmed that the genes encoding the factors involved in major histocompatibility complex (MHC)-I processing pathway were up-regulated, while those involved in MHC-II pathway were down-regulated. Conclusion These data provided insights into the molecular mechanisms underlying zebrafish immune response to WED immunization and might aid future studies to develop a highly immunogenic vaccine against gram-negative bacteria in teleosts. PMID:22805612

  11. RNA-seq liver transcriptome analysis reveals an activated MHC-I pathway and an inhibited MHC-II pathway at the early stage of vaccine immunization in zebrafish.

    PubMed

    Yang, Dahai; Liu, Qin; Yang, Minjun; Wu, Haizhen; Wang, Qiyao; Xiao, Jingfan; Zhang, Yuanxing

    2012-07-17

    Zebrafish (Danio rerio) is a prominent vertebrate model of human development and pathogenic disease and has recently been utilized to study teleost immune responses to infectious agents threatening the aquaculture industry. In this work, to clarify the host immune mechanisms underlying the protective effects of a putative vaccine and improve its immunogenicity in the future efforts, high-throughput RNA sequencing technology was used to investigate the immunization-related gene expression patterns of zebrafish immunized with Edwardsiella tarda live attenuated vaccine. Average reads of 18.13 million and 14.27 million were obtained from livers of zebrafish immunized with phosphate buffered saline (mock) and E. tarda vaccine (WED), respectively. The reads were annotated with the Ensembl zebrafish database before differential expressed genes sequencing (DESeq) comparative analysis, which identified 4565 significantly differentially expressed genes (2186 up-regulated and 2379 down-regulated in WED; p<0.05). Among those, functional classifications were found in the Gene Ontology database for 3891 and in the Kyoto Encyclopedia of Genes and Genomes database for 3467. Several pathways involved in acute phase response, complement activation, immune/defense response, and antigen processing and presentation were remarkably affected at the early stage of WED immunization. Further qPCR analysis confirmed that the genes encoding the factors involved in major histocompatibility complex (MHC)-I processing pathway were up-regulated, while those involved in MHC-II pathway were down-regulated. These data provided insights into the molecular mechanisms underlying zebrafish immune response to WED immunization and might aid future studies to develop a highly immunogenic vaccine against gram-negative bacteria in teleosts.

  12. Effects of genistein on early-stage cutaneous wound healing

    SciTech Connect

    Park, Eunkyo; Lee, Seung Min; Jung, In-Kyung; Lim, Yunsook; Kim, Jung-Hyun

    2011-07-08

    Highlights: {yields} We examine the effect of genistein on cutaneous wound healing. {yields} Genistein enhanced wound closure during the early stage of wound healing. {yields} These genistein effects on wound closure were induced by reduction of oxidative stress through increasing antioxidant capacity and modulation of pro-inflammatory cytokine expression. -- Abstract: Wound healing occurs in three sequential phases: hemostasis and inflammation, proliferation, and remodeling. Inflammation, the earliest phase, is considered a critical period for wound healing because immune cells remove damaged tissues, foreign debris, and remaining dead tissue. Wound healing would be delayed without inflammation, and this phase is affected by antioxidation capacity. Therefore, we hypothesized that genistein, which has an antioxidant effect, might modulate the wound healing process by altering the inflammatory response. After three days of acclimation, mice were divided into three groups: control, 0.025% genistein, and 0.1% genistein. After two weeks of an experimental diet, skin wounds were induced. Wounded skin areas were imaged, and the healing rate calculated. To measure lipid peroxidation, antioxidant enzyme expression and activity, and pro-inflammatory cytokine expression, skin and liver tissues were harvested at 12, 24, 48, and 72 h. Genistein did not affect body weight. The rate of wound closure in mice fed genistein was significantly faster than in the control group during the early stage of wound healing, especially in first three days. Cu, Zn-SOD and Mn-SOD expression in wound skin tissue in the 0.1% genistein group was lower than in the control group. However, CAT expression did not differ among groups. We also found that genistein modulated NF-{kappa}B and TNF-{alpha} expression during the early stage of wound healing. The genistein group had significantly lower hepatic lipid peroxidation and higher SOD, CAT, and GPx activities than the control group. These results

  13. Protective Role of Naturally Occurring Interleukin-17A-Producing γδ T Cells in the Lung at the Early Stage of Systemic Candidiasis in Mice ▿ †

    PubMed Central

    Dejima, Takashi; Shibata, Kensuke; Yamada, Hisakata; Hara, Hiromitsu; Iwakura, Yoichiro; Naito, Seiji; Yoshikai, Yasunobu

    2011-01-01

    Interleukin-17A (IL-17A)-producing γδ T cells differentiate in the fetal thymus and reside in the peripheral tissues, such as the lungs of naïve adult mice. We show here that naturally occurring γδ T cells play a protective role in the lung at a very early stage after systemic infection with Candida albicans. Selective depletion of neutrophils by in vivo administration of anti-Ly6G monoclonal antibody (MAb) impaired fungal clearance more prominently in the lung than in the kidney 24 h after intravenous infection with C. albicans. Rapid and transient production of IL-23 was detected in the lung at 12 h, preceding IL-17A production and the influx of neutrophils, which reached a peak at 24 h after infection. IL-17A knockout (KO) mice showed reduced infiltration of neutrophils concurrently with impaired fungal clearance in the lung after infection. The major source of IL-17A was the γδ T cell population in the lung, and Cδ KO mice showed little IL-17A production and reduced neutrophil infiltration after infection. Early IL-23 production in a TLR2/MyD88-dependent manner and IL-23-triggered tyrosine kinase 2 (Tyk2) signaling were essential for IL-17A production by γδ T cells. Thus, our study demonstrated a novel role of naturally occurring IL-17A-producing γδ T cells in the first line of host defense against C. albicans infection. PMID:21875963

  14. Maximum Standardized Uptake Value From Staging FDG-PET/CT Does not Predict Treatment Outcome for Early-Stage Non-Small-Cell Lung Cancer Treated With Stereotactic Body Radiotherapy

    SciTech Connect

    Burdick, Michael J.; Stephans, Kevin L.; Reddy, Chandana A.; Djemil, Toufik; Srinivas, Shyam M.; Videtic, Gregory M.M.

    2010-11-15

    Purpose: To perform a retrospective review to determine whether maximum standardized uptake values (SUV{sub max}) from staging 2-deoxy-2- [{sup 18}F] fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) studies are associated with outcomes for early-stage non-small-cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). Methods and Materials: Seventy-two medically inoperable patients were treated between October 17, 2003 and August 17, 2007 with SBRT for T1-2N0M0 NSCLC. SBRT was administered as 60 Gy in 3 fractions, 50 Gy in 5 fractions, or 50 Gy in 10 fractions using abdominal compression and image-guided SBRT. Cox proportional hazards regression was performed to determine whether PET SUV{sub max} and other variables influenced outcomes: mediastinal failure (MF), distant metastases (DM), and overall survival (OS). Results: Biopsy was feasible in 49 patients (68.1%). Forty-nine patients had T1N0 disease, and 23 had T2N0 disease. Median SUV{sub max} was 6.55 (range, 1.5-21). Median follow-up was 16.9 months (range, 0.1-37.9 months). There were 3 local failures, 8 MF, 19 DM, and 30 deaths. Two-year local control, MF, DM, and OS rates were 94.0%, 10.4%, 30.1%, and 61.3%, respectively. In univariate analysis, PET/CT SUV{sub max}, defined either as a continuous or dichotomous variable, did not predict for MF, DM, or OS. On multivariable analysis, the only predictors for overall survival were T1 stage (hazard ratio = 0.331 [95% confidence interval, 0.156-0.701], p = 0.0039) and smoking pack-year history (hazard ratio = 1.015 [95% confidence interval, 1.004-1.026], p = 0.0084). Conclusions: Pretreatment PET SUV{sub max} did not predict for MF, DM, or OS in patients treated with SBRT for early-stage NSCLC.

  15. Transcriptome profile of the early stages of breast cancer tumoral spheroids.

    PubMed

    Pacheco-Marín, Rosario; Melendez-Zajgla, Jorge; Castillo-Rojas, Gonzalo; Mandujano-Tinoco, Edna; Garcia-Venzor, Alfredo; Uribe-Carvajal, Salvador; Cabrera-Orefice, Alfredo; Gonzalez-Torres, Carolina; Gaytan-Cervantes, Javier; Mitre-Aguilar, Irma B; Maldonado, Vilma

    2016-03-29

    Oxygen or nutrient deprivation of early stage tumoral spheroids can be used to reliably mimic the initial growth of primary and metastatic cancer cells. However, cancer cell growth during the initial stages has not been fully explored using a genome-wide approach. Thus, in the present study, we investigated the transcriptome of breast cancer cells during the initial stages of tumoral growth using RNAseq in a model of Multicellular Tumor Spheroids (MTS). Network analyses showed that a metastatic signature was enriched as several adhesion molecules were deregulated, including EPCAM, E-cadherin, integrins and syndecans, which were further supported by an increase in cell migration. Interestingly, we also found that the cancer cells at this stage of growth exhibited a paradoxical hyperactivation of oxidative mitochondrial metabolism. In addition, we found a large number of regulated (long non coding RNA) lncRNAs, several of which were co-regulated with neighboring genes. The regulatory role of some of these lncRNAs on mRNA expression was demonstrated with gain of function assays. This is the first report of an early-stage MTS transcriptome, which not only reveals a complex expression landscape, but points toward an important contribution of long non-coding RNAs in the final phenotype of three-dimensional cellular models.

  16. Transcriptome profile of the early stages of breast cancer tumoral spheroids

    PubMed Central

    Pacheco-Marín, Rosario; Melendez-Zajgla, Jorge; Castillo-Rojas, Gonzalo; Mandujano-Tinoco, Edna; Garcia-Venzor, Alfredo; Uribe-Carvajal, Salvador; Cabrera-Orefice, Alfredo; Gonzalez-Torres, Carolina; Gaytan-Cervantes, Javier; Mitre-Aguilar, Irma B.; Maldonado, Vilma

    2016-01-01

    Oxygen or nutrient deprivation of early stage tumoral spheroids can be used to reliably mimic the initial growth of primary and metastatic cancer cells. However, cancer cell growth during the initial stages has not been fully explored using a genome-wide approach. Thus, in the present study, we investigated the transcriptome of breast cancer cells during the initial stages of tumoral growth using RNAseq in a model of Multicellular Tumor Spheroids (MTS). Network analyses showed that a metastatic signature was enriched as several adhesion molecules were deregulated, including EPCAM, E-cadherin, integrins and syndecans, which were further supported by an increase in cell migration. Interestingly, we also found that the cancer cells at this stage of growth exhibited a paradoxical hyperactivation of oxidative mitochondrial metabolism. In addition, we found a large number of regulated (long non coding RNA) lncRNAs, several of which were co-regulated with neighboring genes. The regulatory role of some of these lncRNAs on mRNA expression was demonstrated with gain of function assays. This is the first report of an early-stage MTS transcriptome, which not only reveals a complex expression landscape, but points toward an important contribution of long non-coding RNAs in the final phenotype of three-dimensional cellular models. PMID:27021602

  17. The Potential Role of Respiratory Motion Management and Image Guidance in the Reduction of Severe Toxicities Following Stereotactic Ablative Radiation Therapy for Patients with Centrally Located Early Stage Non-Small Cell Lung Cancer or Lung Metastases

    PubMed Central

    Chi, Alexander; Nguyen, Nam Phong; Komaki, Ritsuko

    2014-01-01

    Image guidance allows delivery of very high doses of radiation over a few fractions, known as stereotactic ablative radiotherapy (SABR). This treatment is associated with excellent outcome for early stage non-small cell lung cancer and metastases to the lungs. In the delivery of SABR, central location constantly poses a challenge due to the difficulty of adequately sparing critical thoracic structures that are immediately adjacent to the tumor if an ablative dose of radiation is to be delivered to the tumor target. As of current, various respiratory motion management and image guidance strategies can be used to ensure accurate tumor target localization prior and/or during daily treatment, which allows for maximal and safe reduction of set up margins. The incorporation of both may lead to the most optimal normal tissue sparing and the most accurate SABR delivery. Here, the clinical outcome, treatment related toxicities, and the pertinent respiratory motion management/image guidance strategies reported in the current literature on SABR for central lung tumors are reviewed. PMID:25009800

  18. Construction of a pathological risk model of occult lymph node metastases for prognostication by semi-automated image analysis of tumor budding in early-stage oral squamous cell carcinoma.

    PubMed

    Pedersen, Nicklas Juel; Jensen, David Hebbelstrup; Lelkaitis, Giedrius; Kiss, Katalin; Charabi, Birgitte; Specht, Lena; von Buchwald, Christian

    2017-02-14

    It is challenging to identify at diagnosis those patients with early oral squamous cell carcinoma (OSCC), who have a poor prognosis and those that have a high risk of harboring occult lymph node metastases. The aim of this study was to develop a standardized and objective digital scoring method to evaluate the predictive value of tumor budding. We developed a semi-automated image-analysis algorithm, Digital Tumor Bud Count (DTBC), to evaluate tumor budding. The algorithm was tested in 222 consecutive patients with early-stage OSCC and major endpoints were overall (OS) and progression free survival (PFS). We subsequently constructed and cross-validated a binary logistic regression model and evaluated its clinical utility by decision curve analysis. A high DTBC was an independent predictor of both poor OS and PFS in a multivariate Cox regression model. The logistic regression model was able to identify patients with occult lymph node metastases with an area under the curve (AUC) of 0.83 (95% CI: 0.78-0.89, P <0.001) and a 10-fold cross-validated AUC of 0.79. Compared to other known histopathological risk factors, the DTBC had a higher diagnostic accuracy. The proposed, novel risk model could be used as a guide to identify patients who would benefit from an up-front neck dissection.

  19. Novel application of stereotactic ablative radiotherapy using CyberKnife(®) for early-stage renal cell carcinoma in patients with pre-existing chronic kidney disease: Initial clinical experiences.

    PubMed

    Lo, Cheng-Hsiang; Huang, Wen-Yen; Chao, Hsing-Lung; Lin, Kuen-Tze; Jen, Yee-Min

    2014-07-01

    The treatment of renal cell carcinoma (RCC) in patients diagnosed with chronic kidney disease (CKD) requires particular care in order to preserve the remaining renal function. The present study aimed to investigate the potential of a novel nephron-sparing treatment, which is capable of targeting tumors embedded deep within tissues. The present study analyzed three patients, with pre-existing CKD and multiple comorbidities, who were successfully treated for stage I RCC using the CyberKnife(®) stereotactic ablative radiotherapy (SABR) system. The total prescribed dose was 40 Gy in five fractions administered over five consecutive days. Treatment efficiency was determined using computed tomography scans of the tumors and periodic measurements of the glomerular filtration rate over a period of 12-40 months. Local control, defined as a radiologically stable condition, was achieved in all patients. Lung metastasis was observed in one patient nine months after SABR; however, the side-effects were generally mild and self-limiting. One patient developed renal failure 26 months after SABR, while the severity of CKD was only marginally altered in the other two patients and renal failure did not occur. In conclusion, in the present study, SABR with CyberKnife(®) was observed to be well tolerated in the patients, with an acceptable acute toxicity effect. Therefore, it may represent a potential therapeutic option for patients with early-stage RCC who have previously been diagnosed with CKD, but for whom other nephron-sparing treatments are contraindicated.

  20. Suicide in the Early Stage of Schizophrenia.

    PubMed

    Ventriglio, Antonio; Gentile, Alessandro; Bonfitto, Iris; Stella, Eleonora; Mari, Massimo; Steardo, Luca; Bellomo, Antonello

    2016-01-01

    Suicide is a relevant leading cause of death among patients affected by schizophrenia. Even if suicidal ideation may be present in different stages of disease, some differences have been described between the risk of suicide in patients experiencing first episode of psychosis and those with long-term schizophrenia. It is particularly higher during the first year of illness and reaches a steady decline over the following years. Suicidal ideation and attempts may also be common among subjects with subthreshold psychotic experiences. Factors associated with the risk of suicide in the early phase of schizophrenia are previous suicidal attempts and social aspects: the lack of social support and stable relationships, social drift after the first episode, and social impairment. Also, several psychotic symptoms (suspiciousness, paranoid delusions, mental disintegration and agitation, negative symptoms, depression and hopelessness, and command hallucinations) and substance abuse are associated with higher risk of suicide. It has been described that perfectionism and good levels of insight among individuals who have recently developed psychotic symptoms are significantly associated with higher numbers of suicidal attempts. Moreover, recent evidences show that prefrontal cortex-based circuit dysfunction may be related to suicide in the early stage of schizophrenia. This narrative review summarizes available evidences on suicide in the early stage of schizophrenia and deals with issues to be further studied and discussed.

  1. Suicide in the Early Stage of Schizophrenia

    PubMed Central

    Ventriglio, Antonio; Gentile, Alessandro; Bonfitto, Iris; Stella, Eleonora; Mari, Massimo; Steardo, Luca; Bellomo, Antonello

    2016-01-01

    Suicide is a relevant leading cause of death among patients affected by schizophrenia. Even if suicidal ideation may be present in different stages of disease, some differences have been described between the risk of suicide in patients experiencing first episode of psychosis and those with long-term schizophrenia. It is particularly higher during the first year of illness and reaches a steady decline over the following years. Suicidal ideation and attempts may also be common among subjects with subthreshold psychotic experiences. Factors associated with the risk of suicide in the early phase of schizophrenia are previous suicidal attempts and social aspects: the lack of social support and stable relationships, social drift after the first episode, and social impairment. Also, several psychotic symptoms (suspiciousness, paranoid delusions, mental disintegration and agitation, negative symptoms, depression and hopelessness, and command hallucinations) and substance abuse are associated with higher risk of suicide. It has been described that perfectionism and good levels of insight among individuals who have recently developed psychotic symptoms are significantly associated with higher numbers of suicidal attempts. Moreover, recent evidences show that prefrontal cortex-based circuit dysfunction may be related to suicide in the early stage of schizophrenia. This narrative review summarizes available evidences on suicide in the early stage of schizophrenia and deals with issues to be further studied and discussed. PMID:27445872

  2. Arterial endothelial function in a porcine model of early stage atherosclerotic vascular disease

    PubMed Central

    Turk, James R; Henderson, Kyle K; Vanvickle, Gregory D; Watkins, Justin; Laughlin, M Harold

    2005-01-01

    Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States and is projected to become the leading cause of mortality in the world. Atherosclerosis is the most important single factor contributing to this disease burden. In this study, we characterize relationships between endothelial dysfunction and vascular disease in an animal model of diet-induced, early-stage atherosclerotic vascular disease. We tested the hypothesis that hypercholesterolaemia induces vascular disease and impairs endothelium-dependent relaxation (EDR) in conduit arteries of adult male Yucatan pigs. Pigs were fed a normal fat (NF) or high fat cholesterol (HFC) diet for 20–24 weeks. Results indicate that, while the HFC diet did not alter EDR in femoral or brachial arteries, EDR was significantly decreased in both carotid and coronary arteries. Sudanophilic fatty streaks were significantly present in the abdominal aorta and common carotid artery. Histopathology revealed increased intima-media thickness (IMT) and foam cell accumulation in Stary Stage I–III lesions in the abdominal aorta, common carotid artery and femoral arteries. In the coronary arteries, the accumulation of foam cells in Stary Stage I and II lesions resulted in a trend for increased IMT. There was no evidence of vascular disease in the brachial arteries. These results indicate that early stages of CVD (Stary Stage I–III) precede decreases in EDR induced by HFC diet, because femoral arteries exhibited foam cell accumulation and an increased IMT but no change in endothelial function. PMID:16191105

  3. High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center

    SciTech Connect

    Bush, David A.; Cheek, Gregory; Zaheer, Salman; Wallen, Jason; Mirshahidi, Hamid; Katerelos, Ari; Grove, Roger; Slater, Jerry D.

    2013-08-01

    Purpose: We update our previous reports on the use of hypofractionated proton beam radiation therapy for early-stage lung cancer patients. Methods and Materials: Eligible subjects had biopsy-proven non-small cell carcinoma of the lung and were medically inoperable or refused surgery. Clinical workup required staging of T1 or T2, N0, M0. Subjects received hypofractionated proton beam therapy to the primary tumor only. The dose delivered was sequentially escalated from 51 to 60 Gy, then to 70 Gy in 10 fractions over 2 weeks. Endpoints included toxicity, pulmonary function, overall survival (OS), disease-specific survival (DSS), and local control (LC). Results: One hundred eleven subjects were analyzed for treatment outcomes. The patient population had the following average characteristics; age 73.2 years, tumor size 3.6 cm, and 1.33 L forced expiratory volume in 1 second. The entire group showed improved OS with increasing dose level (51, 60, and 70 Gy) with a 4-year OS of 18%, 32%, and 51%, respectively (P=.006). Peripheral T1 tumors exhibited LC of 96%, DSS of 88%, and OS of 60% at 4 years. Patients with T2 tumors showed a trend toward improved LC and survival with the 70-Gy dose level. On multivariate analysis, larger tumor size was strongly associated with increased local recurrence and decreased survival. Central versus peripheral location did not correlate with any outcome measures. Clinical radiation pneumonitis was not found to be a significant complication, and no patient required steroid therapy after treatment for radiation pneumonitis. Pulmonary function was well maintained 1 year after treatment. Conclusions: High-dose hypofractionated proton therapy achieves excellent outcomes for lung carcinomas that are peripherally or centrally located. The 70-Gy regimen has been adopted as standard therapy for T1 tumors at our institution. Larger T2 tumors show a trend toward improved outcomes with higher doses, suggesting that better results could be seen with

  4. High-dose hypofractionated proton beam radiation therapy is safe and effective for central and peripheral early-stage non-small cell lung cancer: results of a 12-year experience at Loma Linda University Medical Center.

    PubMed

    Bush, David A; Cheek, Gregory; Zaheer, Salman; Wallen, Jason; Mirshahidi, Hamid; Katerelos, Ari; Grove, Roger; Slater, Jerry D

    2013-08-01

    We update our previous reports on the use of hypofractionated proton beam radiation therapy for early-stage lung cancer patients. Eligible subjects had biopsy-proven non-small cell carcinoma of the lung and were medically inoperable or refused surgery. Clinical workup required staging of T1 or T2, N0, M0. Subjects received hypofractionated proton beam therapy to the primary tumor only. The dose delivered was sequentially escalated from 51 to 60 Gy, then to 70 Gy in 10 fractions over 2 weeks. Endpoints included toxicity, pulmonary function, overall survival (OS), disease-specific survival (DSS), and local control (LC). One hundred eleven subjects were analyzed for treatment outcomes. The patient population had the following average characteristics; age 73.2 years, tumor size 3.6 cm, and 1.33 L forced expiratory volume in 1 second. The entire group showed improved OS with increasing dose level (51, 60, and 70 Gy) with a 4-year OS of 18%, 32%, and 51%, respectively (P=.006). Peripheral T1 tumors exhibited LC of 96%, DSS of 88%, and OS of 60% at 4 years. Patients with T2 tumors showed a trend toward improved LC and survival with the 70-Gy dose level. On multivariate analysis, larger tumor size was strongly associated with increased local recurrence and decreased survival. Central versus peripheral location did not correlate with any outcome measures. Clinical radiation pneumonitis was not found to be a significant complication, and no patient required steroid therapy after treatment for radiation pneumonitis. Pulmonary function was well maintained 1 year after treatment. High-dose hypofractionated proton therapy achieves excellent outcomes for lung carcinomas that are peripherally or centrally located. The 70-Gy regimen has been adopted as standard therapy for T1 tumors at our institution. Larger T2 tumors show a trend toward improved outcomes with higher doses, suggesting that better results could be seen with intensified treatment. Copyright © 2013 Elsevier Inc. All

  5. Raman spectrum reveals Mesenchymal stem cells inhibiting HL60 cells growth

    NASA Astrophysics Data System (ADS)

    Su, Xin; Fang, Shaoyin; Zhang, Daosen; Zhang, Qinnan; Lu, Xiaoxu; Tian, Jindong; Fan, Jinping; Zhong, Liyun

    2017-04-01

    Though some research results reveals that Mesenchymal stem cells (MSCs) have the ability of inhibiting tumor cells proliferation, it remains controversial about the precise interaction mechanism during MSCs and tumor cells co-culture. In this study, combing Raman spectroscopic data and principle component analysis (PCA), the biochemical changes of MSCs or Human promyelocytic leukemia (HL60) cells during their co-culture were presented. The obtained results showed that some main Raman peaks of HL60 assigned to nucleic acids or proteins were greatly higher in intensity in the late stage of co-culture than those in the early stage of co-culture while they were still lower relative to the control group, implicating that the effect of MSCs inhibiting HL60 proliferation appeared in the early stage but gradually lost the inhibiting ability in the late stage of co-culture. Moreover, some other peaks of HL60 assigned to proteins were decreased in intensity in the early stage of co-culture relative to the control group but rebounded to the level similar to the control group in the late stage, showing that the content and structure changes of these proteins might be generated in the early stage but returned to the original state in the late stage of co-culture. As a result, in the early stage of MSCs-HL60 co-culture, along with the level of Akt phosphorylation of HL60 was lowered relative to its control group, the proliferation rate of HL60 cells was decreased. And in the late stage of co-culture, along with the level of Akt phosphorylation was rebounded, the reverse transfer of Raman peaks within 875-880 cm- 1 appeared, thus MSCs lost the ability to inhibit HL60 growth and HL60 proliferation was increased. In addition, it was observed that the peak at 811 cm- 1, which is a marker of RNA, was higher in intensity in the late stage than that in the control group, indicating that MSCs might be differentiated into myofibroblast-like MSCs. In addition, PCA results also exhibited

  6. Effects of genistein on early-stage cutaneous wound healing.

    PubMed

    Park, Eunkyo; Lee, Seung Min; Jung, In-Kyung; Lim, Yunsook; Kim, Jung-Hyun

    2011-07-08

    Wound healing occurs in three sequential phases: hemostasis and inflammation, proliferation, and remodeling. Inflammation, the earliest phase, is considered a critical period for wound healing because immune cells remove damaged tissues, foreign debris, and remaining dead tissue. Wound healing would be delayed without inflammation, and this phase is affected by antioxidation capacity. Therefore, we hypothesized that genistein, which has an antioxidant effect, might modulate the wound healing process by altering the inflammatory response. After three days of acclimation, mice were divided into three groups: control, 0.025% genistein, and 0.1% genistein. After two weeks of an experimental diet, skin wounds were induced. Wounded skin areas were imaged, and the healing rate calculated. To measure lipid peroxidation, antioxidant enzyme expression and activity, and pro-inflammatory cytokine expression, skin and liver tissues were harvested at 12, 24, 48, and 72 h. Genistein did not affect body weight. The rate of wound closure in mice fed genistein was significantly faster than in the control group during the early stage of wound healing, especially in first three days. Cu, Zn-SOD and Mn-SOD expression in wound skin tissue in the 0.1% genistein group was lower than in the control group. However, CAT expression did not differ among groups. We also found that genistein modulated NF-κB and TNF-α expression during the early stage of wound healing. The genistein group had significantly lower hepatic lipid peroxidation and higher SOD, CAT, and GPx activities than the control group. These results suggest that genistein supplementation reduces oxidative stress by increasing antioxidant capacity and modulating proinflammatory cytokine expression during the early stage of wound healing. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer

    PubMed Central

    Diab, Nabih; Trevino, Richard; Villanueva, Geri; Rains, Steven; Sanchez, Luis A.; Badri, Nabeel; Otoukesh, Salman; Khammanivong, Ali; Liss, Danielle; Baca, Sarah T.; Aguilera, Renato J.; Dickerson, Erin B.; Torabi, Alireza; Dwivedi, Alok K.; Abbas, Aamer; Chambers, Karinn; Bryan, Brad A.; Nahleh, Zeina

    2017-01-01

    Previous studies suggest beta-adrenergic receptor (β-AR) antagonists (β-blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of β1-AR and β3-AR in breast cancer. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor proliferation. Our analysis revealed that non-selective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% (p < 0.0001) in early stage breast cancer compared to non-users. We tested the efficacy of propranolol on an early stage breast cancer patient, and quantified the tumor proliferative index before and after treatment, revealing a propranolol-mediated 23% reduction (p = 0.02) in Ki67 positive tumor cells over a three-week period. The anti-proliferative effects of β-blockers were measured in a panel of breast cancer lines, demonstrating that mammary epithelial cells were resistant to propranolol, and that most breast cancer cell lines displayed dose dependent viability decreases following treatment. Selective β-blockers alone or in combination were not as effective as propranolol at reducing breast cancer cell proliferation. Molecular analysis revealed that propranolol treatment of the SK-BR-3 breast cancer line, which showed high sensitivity to beta blockade, led to a reduction in Ki67 protein expression, decreased phosphorylation of the mitogenic signaling regulators p44/42 MAPK, p38 MAPK, JNK, and CREB, increased phosphorylation of the cell survival/apoptosis regulators AKT, p53, and GSK3β. In conclusion, use of non-selective β-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation. PMID:28031536

  8. Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer.

    PubMed

    Montoya, Alexa; Amaya, Clarissa N; Belmont, Andres; Diab, Nabih; Trevino, Richard; Villanueva, Geri; Rains, Steven; Sanchez, Luis A; Badri, Nabeel; Otoukesh, Salman; Khammanivong, Ali; Liss, Danielle; Baca, Sarah T; Aguilera, Renato J; Dickerson, Erin B; Torabi, Alireza; Dwivedi, Alok K; Abbas, Aamer; Chambers, Karinn; Bryan, Brad A; Nahleh, Zeina

    2017-01-24

    Previous studies suggest beta-adrenergic receptor (β-AR) antagonists (β-blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of β1-AR and β3-AR in breast cancer. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor proliferation. Our analysis revealed that non-selective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% (p < 0.0001) in early stage breast cancer compared to non-users. We tested the efficacy of propranolol on an early stage breast cancer patient, and quantified the tumor proliferative index before and after treatment, revealing a propranolol-mediated 23% reduction (p = 0.02) in Ki67 positive tumor cells over a three-week period. The anti-proliferative effects of β-blockers were measured in a panel of breast cancer lines, demonstrating that mammary epithelial cells were resistant to propranolol, and that most breast cancer cell lines displayed dose dependent viability decreases following treatment. Selective β-blockers alone or in combination were not as effective as propranolol at reducing breast cancer cell proliferation. Molecular analysis revealed that propranolol treatment of the SK-BR-3 breast cancer line, which showed high sensitivity to beta blockade, led to a reduction in Ki67 protein expression, decreased phosphorylation of the mitogenic signaling regulators p44/42 MAPK, p38 MAPK, JNK, and CREB, increased phosphorylation of the cell survival/apoptosis regulators AKT, p53, and GSK3β. In conclusion, use of non-selective β-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation.

  9. Understanding early-stage dune development: morphodynamics of aeolian protodunes

    NASA Astrophysics Data System (ADS)

    Baddock, Matthew; Wiggs, Giles; Nield, Joanna

    2016-04-01

    For such a fundamental aspect of bedform development, the initiation and early-stage growth of sand dunes remain poorly understood. Protodunes are bedforms within the continuum of early-stage depositional aeolian features that exist between flat sand patches and small dunes. As transitory bedforms with the potential to develop into dunes, the detailed study of protodune morphodynamics can provide significant insights into nascent dune development. As part of a multi-annual study investigating bedform change through repeat morphological surveys of bedforms with differing maturity, measurements of near-surface airflow and sand transport were conducted over a protodune in a small Namibian barchan dune field. The protodune was approximately 85 m in length and 1 m high, and was without a slipface. Data show that over the course of a week, patterns of airflow and transport flux variation were linked with accretion at the crest, and erosion of the leeside edge showing an increase in protodune height, and providing evidence of the dune's vertical development. Surveys reveal the longer term evolution of the protodune, in the context of changes exhibited by nearby, fully developed barchan dunes, and long term monitoring of wind regime at the site.

  10. Unusual Presentation of Recurrent Early Stage Endometrial Carcinoma 28 Years after Primary Surgery

    PubMed Central

    Franchello, Alessandro; Fronda, Gianruggero; Deiro, Giacomo; Fiore, Alessia; Cassine, Davide; Molinaro, Luca; Chiusa, Luigi; Galati, Sara; Resegotti, Andrea; Silvestri, Stefano

    2015-01-01

    Endometrial carcinoma is the most common neoplasia of female genital tract. The prognosis of early stage disease (FIGO I and FIGO II) is excellent: recurrence after surgery is less than 15%, most of which are reported within 3 years after primary treatment. Herein we report a case of late rectal recurrence from FIGO Ib endometrial adenocarcinoma. Patient had also familiar and personal history of colonic adenocarcinoma and previous findings of microsatellite instability (MSI); molecular analysis evidenced heterozygotic somatic mutation in MLH1 gene. Twenty-eight years after hysterectomy and bilateral salpingoovariectomy, a rectal wall mass was detected during routine colonoscopy. Patients underwent CT scan, pelvic MRI, and rectal EUS with FNA: histopathological and immunohistochemical analysis revealed differentiated carcinoma cells of endometrial origin. No neoadjuvant treatment was planned and low rectal anterior resection with protective colostomy was performed; histology confirmed rectal lesion as metastasis from endometrial carcinoma. Recurrence of early stage endometrial carcinoma after a long period from primary surgery is possible. It is important to keep in mind this possibility in order to set a correct diagnostic and therapeutic algorithm, including preoperative immunohistochemical staining, and to plan a prolonged follow-up program. PMID:26783488

  11. Inflammation-nutrition scope predicts prognosis of early-stage hepatocellular carcinoma after curative resection.

    PubMed

    Zhu, Ying; Li, Jian-Hua; Yang, Jing; Gao, Xiao-Mei; Jia, Hu-Liang; Yang, Xin

    2017-09-01

    We developed a novel inflammation-nutrition scope (INS) based on systemic inflammatory response and nutritional status, and explored its prognostic value in hepatocellular carcinoma (HCC), especially for those with early-stage disease.The INS was developed based on a retrospective study of 185 patients with HCC undergoing hepatectomy between 2006 and 2007, and validated in a prospective study of 131 patients enrolled from 2009 to 2010. Prediction accuracy was evaluated with area under the receiver operating characteristic curve (AUCs).The INS was constructed as follows: patients with both an elevated red blood cell distribution width (RDW, ≥13.25%) and platelet-lymphocyte ratio (PLR, ≥1.1) were allocated a score of 2. Patients in whom only 1 or none of these biochemical abnormalities was present were allocated a score of 1 or 0, respectively. An elevated INS was associated with larger tumor size, tumor thrombus, and high tumor lymph nodes metastasis (TNM) stage. Univariate and multivariate analyses revealed the INS was an independent predictor for overall survival, and a prognostic factor for patients with TNM I stage. The AUCs of the INS for survival were higher than other conventional clinical indices.The INS is a promising predictor of poor outcome in patients with HCC, especially for those with early-stage disease, and is a promising tool for HCC treatment strategy decisions for future clinical trials targeting nutritional decline.

  12. Early stages of arthrospore maturation in Streptomyces.

    PubMed Central

    Manzanal, M B; Hardisson, C

    1978-01-01

    In the sporogenesis of Streptomyces, two basic stages can be considered: sporulation septum synthesis and arthrospore maturation. Most of the information about the ultrastructural changes accompanying the sporogenesis refer to the first stage of the process, but nothing has been published about the evolution of the sporulation septum during maturation. In a previous paper, proposed three basic types of sporulation septum formation in Streptomyces. Our ultrastructural study on the evolution of the sporulation septum during the early stages of arthrospore maturation in seven species of Streptomyces indicates correlation between the sporulation septum type and its evolution during the arthrospore maturation. In types I and II the material of the annuli was incorporated into the lateral walls of the arthrospore, whereas in types II and III the deposits were lysed during the maturation. Only in type III was the arthrospore wall synthesized de novo. In type I there was total integration and in type II there was partial integration of the septum into the arthrospore wall. Images PMID:618842

  13. Computed Tomography-Based Anatomic Assessment Overestimates Local Tumor Recurrence in Patients With Mass-like Consolidation After Stereotactic Body Radiotherapy for Early-Stage Non-Small Cell Lung Cancer

    SciTech Connect

    Dunlap, Neal E.; Yang Wensha; McIntosh, Alyson; Sheng, Ke; Benedict, Stanley H.; Read, Paul W.; Larner, James M.

    2012-12-01

    Purpose: To investigate pulmonary radiologic changes after lung stereotactic body radiotherapy (SBRT), to distinguish between mass-like fibrosis and tumor recurrence. Methods and Materials: Eighty consecutive patients treated with 3- to 5-fraction SBRT for early-stage peripheral non-small cell lung cancer with a minimum follow-up of 12 months were reviewed. The mean biologic equivalent dose received was 150 Gy (range, 78-180 Gy). Patients were followed with serial CT imaging every 3 months. The CT appearance of consolidation was defined as diffuse or mass-like. Progressive disease on CT was defined according to Response Evaluation Criteria in Solid Tumors 1.1. Positron emission tomography (PET) CT was used as an adjunct test. Tumor recurrence was defined as a standardized uptake value equal to or greater than the pretreatment value. Biopsy was used to further assess consolidation in select patients. Results: Median follow-up was 24 months (range, 12.0-36.0 months). Abnormal mass-like consolidation was identified in 44 patients (55%), whereas diffuse consolidation was identified in 12 patients (15%), at a median time from end of treatment of 10.3 months and 11.5 months, respectively. Tumor recurrence was found in 35 of 44 patients with mass-like consolidation using CT alone. Combined with PET, 10 of the 44 patients had tumor recurrence. Tumor size (hazard ratio 1.12, P=.05) and time to consolidation (hazard ratio 0.622, P=.03) were predictors for tumor recurrence. Three consecutive increases in volume and increasing volume at 12 months after treatment in mass-like consolidation were highly specific for tumor recurrence (100% and 80%, respectively). Patients with diffuse consolidation were more likely to develop grade {>=}2 pneumonitis (odds ratio 26.5, P=.02) than those with mass-like consolidation (odds ratio 0.42, P=.07). Conclusion: Incorporating the kinetics of mass-like consolidation and PET to the current criteria for evaluating posttreatment response will

  14. A collaborative analysis of stereotactic lung radiotherapy outcomes for early-stage non-small-cell lung cancer using daily online cone-beam computed tomography image-guided radiotherapy.

    PubMed

    Grills, Inga Siiner; Hope, Andrew J; Guckenberger, Matthias; Kestin, Larry L; Werner-Wasik, Maria; Yan, Di; Sonke, Jan-Jakob; Bissonnette, Jean-Pierre; Wilbert, Juergen; Xiao, Ying; Belderbos, Jose

    2012-09-01

    We report lung stereotactic-body radiotherapy (SBRT) outcomes for a large pooled cohort treated using daily online cone-beam computed tomography. Five hundred and five stage I-IIB (T1-3N0M0) non-small-cell lung cancer (NSCLC) cases underwent SBRT using cone-beam computed tomography image guidance at five international institutions from 1998 to 2010. Median age was 74 years (range, 42-92) whereas median forced expiratory volume in 1 second/diffusing lung capacity for carbon monoxide were 1.4 liter (65%) and 10.8 ml/min/mmHg (53%). Of the 505 cases, 64% were biopsy proven and 87% medically inoperable. Staging was: IA 63%, IB 33%, IIA 2%, and recurrent 1%. Median max tumor dimension was 2.6 cm (range, 0.9-8.5). Median heterogeneously calculated volumetric prescription dose (PD) was 54 Gy (range, 20-64 Gy) in three fractions (range, 1-15) over 8 days (range, 1-27). Median biologically equivalent PD biological equivalent doses (BED10) was 132 Gy (range, 60-180). With a median follow-up of 1.6 years (range, 0.1-7.3), the 2-year Kaplan-Meier local control (LC), regional control, and distant metastasis (DM) rates were 94%, 89%, and 20%, respectively, whereas cause-specific and overall survival were 87% and 60% (78% operable, 58% inoperable, p = 0.01), respectively. Stage, gross-tumor volume size (≥ 2.7 cm) and PD(BED10) predicted local relapse (LR) and DM. LR was 15% for BED10 less than 105 Gy versus 4% for BED10 of 105 Gy or more (p < 0.001); DM was 31% versus 18% for BED10 less than 105 versus 105 Gy or more (p = 0.01). On multivariate analysis, PD(BED10) and elapsed days during radiotherapy predicted LR; gross-tumor volume size predicted DM. Grade 2 or higher pneumonitis, rib fracture, myositis, and dermatitis were 7%, 3%, 1%, and 2%, respectively. In the largest early-stage NSCLC SBRT data set to date, a high rate of local control was achieved, which was correlated with a PD(BED10) of 105 Gy or more. Failures were primarily distant, severe toxicities were rare, and

  15. Computed tomography-based anatomic assessment overestimates local tumor recurrence in patients with mass-like consolidation after stereotactic body radiotherapy for early-stage non-small cell lung cancer.

    PubMed

    Dunlap, Neal E; Yang, Wensha; McIntosh, Alyson; Sheng, Ke; Benedict, Stanley H; Read, Paul W; Larner, James M

    2012-12-01

    To investigate pulmonary radiologic changes after lung stereotactic body radiotherapy (SBRT), to distinguish between mass-like fibrosis and tumor recurrence. Eighty consecutive patients treated with 3- to 5-fraction SBRT for early-stage peripheral non-small cell lung cancer with a minimum follow-up of 12 months were reviewed. The mean biologic equivalent dose received was 150 Gy (range, 78-180 Gy). Patients were followed with serial CT imaging every 3 months. The CT appearance of consolidation was defined as diffuse or mass-like. Progressive disease on CT was defined according to Response Evaluation Criteria in Solid Tumors 1.1. Positron emission tomography (PET) CT was used as an adjunct test. Tumor recurrence was defined as a standardized uptake value equal to or greater than the pretreatment value. Biopsy was used to further assess consolidation in select patients. Median follow-up was 24 months (range, 12.0-36.0 months). Abnormal mass-like consolidation was identified in 44 patients (55%), whereas diffuse consolidation was identified in 12 patients (15%), at a median time from end of treatment of 10.3 months and 11.5 months, respectively. Tumor recurrence was found in 35 of 44 patients with mass-like consolidation using CT alone. Combined with PET, 10 of the 44 patients had tumor recurrence. Tumor size (hazard ratio 1.12, P=.05) and time to consolidation (hazard ratio 0.622, P=.03) were predictors for tumor recurrence. Three consecutive increases in volume and increasing volume at 12 months after treatment in mass-like consolidation were highly specific for tumor recurrence (100% and 80%, respectively). Patients with diffuse consolidation were more likely to develop grade ≥ 2 pneumonitis (odds ratio 26.5, P=.02) than those with mass-like consolidation (odds ratio 0.42, P=.07). Incorporating the kinetics of mass-like consolidation and PET to the current criteria for evaluating posttreatment response will increase the likelihood of correctly identifying

  16. Whole transcriptome sequencing reveals genes involved in plastid/chloroplast division and development are regulated by the HP1/DDB1 at an early stage of tomato fruit development.

    PubMed

    Tang, Xiaofeng; Tang, Zizhi; Huang, Shengxiong; Liu, Jikai; Liu, Jia; Shi, Wei; Tian, Xuefen; Li, Yuxiang; Zhang, Danfeng; Yang, Jian; Gao, Yongfeng; Zeng, Deer; Hou, Pei; Niu, Xiangli; Cao, Ying; Li, Guangwei; Li, Xiao; Xiao, Fangming; Liu, Yongsheng

    2013-11-01

    The phenotype of tomato high pigment-1 (hp1) mutant is characterized by overproduction of pigments including chlorophyll and carotenoids during fruit development and ripening. Although the increased plastid compartment size has been thought to largely attribute to the enhanced pigmentation, the molecular aspects of how the HP1/DDB1 gene manipulates plastid biogenesis and development are largely unknown. In the present study, we compared transcriptome profiles of immature fruit pericarp tissue between tomato cv. Ailsa Craig (WT) and its isogenic hp1 mutant. Over 20 million sequence reads, representing > 1.6 Gb sequence data per sample, were generated and assembled into 21,972 and 22,167 gene models in WT and hp1, respectively, accounting for over 60 % official gene models in both samples. Subsequent analyses revealed that 8,322 and 7,989 alternative splicing events, 8833 or 8510 extended 5'-UTRs, 8,263 or 8,939 extended 3'-UTRs, and 1,136 and 1,133 novel transcripts, exist in WT and hp1, respectively. Significant differences in expression level of 880 genes were detected between the WT and hp1, many of which are involved in signaling transduction, transcription regulation and biotic and abiotic stresses response. Distinctly, RNA-seq datasets, quantitative RT-PCR analyses demonstrate that, in hp1 mutant pericarp tissue at early developmental stage, an apparent expression alteration was found in several regulators directly involved in plastid division and development. These results provide a useful reference for a more accurate and more detailed characterization of the molecular process in the development and pigmentation of tomato fruits.

  17. SBRT in operable early stage lung cancer patients.

    PubMed

    Roesch, Johannes; Andratschke, Nicolaus; Guckenberger, Matthias

    2014-08-01

    Since decades the gold standard for treatment of early stage non-small cell lung cancer (NSCLC) is surgical lobectomy plus mediastinal lymph node dissection. Patients in worse health status are treated with sublobar resection or radiation treatment. With development of stereotactic-body-radiotherapy (SBRT), outcome of patients treated with radiation was substantially improved. Comparison of SBRT and surgical techniques is difficult due to the lack of randomized trials. However, all available evidence in form of case control studies of population based studies show equivalence between sublobar resection and SBRT indicating that SBRT-when performed by a trained and experienced team-should be offered to all high-risk surgical patients. For patients not willing to take the risk of lobectomy and therefore refusing surgery, SBRT is an excellent treatment option.

  18. SBRT in operable early stage lung cancer patients

    PubMed Central

    Andratschke, Nicolaus; Guckenberger, Matthias

    2014-01-01

    Since decades the gold standard for treatment of early stage non-small cell lung cancer (NSCLC) is surgical lobectomy plus mediastinal lymph node dissection. Patients in worse health status are treated with sublobar resection or radiation treatment. With development of stereotactic-body-radiotherapy (SBRT), outcome of patients treated with radiation was substantially improved. Comparison of SBRT and surgical techniques is difficult due to the lack of randomized trials. However, all available evidence in form of case control studies of population based studies show equivalence between sublobar resection and SBRT indicating that SBRT—when performed by a trained and experienced team—should be offered to all high-risk surgical patients. For patients not willing to take the risk of lobectomy and therefore refusing surgery, SBRT is an excellent treatment option. PMID:25806303

  19. Exercise maintains blood-brain barrier integrity during early stages of brain metastasis formation.

    PubMed

    Wolff, Gretchen; Davidson, Sarah J; Wrobel, Jagoda K; Toborek, Michal

    2015-08-07

    Tumor cell extravasation into the brain requires passage through the blood-brain barrier, which is a highly protected microvascular environment fortified with tight junction (TJ) proteins. TJ integrity can be regulated under physiological and pathophysiological conditions. There is evidence that exercise can modulate oxidation status within the brain microvasculature and protect against tumor cell extravasation and metastasis formation. In order to study these events, mature male mice were given access to voluntary exercise on a running wheel (exercise) or access to a locked wheel (sedentary) for five weeks. The average running distance was 9.0 ± 0.2 km/day. Highly metastatic tumor cells (murine Lewis lung carcinoma) were then infused into the brain microvasculature through the internal carotid artery. Analyses were performed at early stage (48 h) and late stage (3 weeks) post tumor cell infusion. Immunohistochemical analysis revealed fewer isolated tumor cells extravasating into the brain at both 48 h and 3 weeks post surgery in exercised mice. Occludin protein levels were reduced in the sedentary tumor group, but maintained in the exercised tumor group at 48 h post tumor cell infusion. These results indicate that voluntary exercise may participate in modulating blood-brain barrier integrity thereby protecting the brain during metastatic progression.

  20. CCR study: evidence for benefit of TARP vaccine for men with early stage prostate cancer | Center for Cancer Research

    Cancer.gov

    Results from a pilot clinical trial found that TARP, or T-cell receptor gamma chain alternate reading frame protein, vaccination slowed prostate-specific antigen (PSA) rise in the majority of patients with early stage prostate cancer.

  1. Plasma of argon accelerates murine fibroblast adhesion in early stages of titanium disk colonization.

    PubMed

    Canullo, Luigi; Cassinelli, Clara; Götz, Werner; Tarnow, Dennis

    2013-01-01

    This study was conducted to analyze how a cleaning treatment using plasma of argon would affect fibroblast growth on titanium disks at different time points to determine whether this treatment could enhance soft tissue healing around titanium dental implant abutments. Sixty sterile disks made of machined grade 5 titanium were divided into two groups; 30 disks were left untreated (control) and 30 were cleaned using plasma of argon (test). To simulate clinical conditions during soft tissue healing around titanium abutments, both groups were immersed in a culture of murine fibroblasts (L929) for 2, 8, or 48 hours. After preparation, they were stained using 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) to label the cellular nuclei and fluorescent phalloidin to label the cellular bodies. The nuclei were counted, and cellular bodies were analyzed with fluorescent microscopy and imaging analysis software. Analysis was performed at the three different time points. Fibroblast adhesion for the test group was statistically significantly greater versus the control group at 2 and 8 hours but not at 48 hours. At 2 and 8 hours, the cellular bodies in the test group appeared flatter and more spread out, revealing more advanced cellular adhesion, compared to the cells observed in the control group. At 48 hours, the test and control specimens were nearly indistinguishable. The removal of organic and inorganic contaminants from the surfaces of titanium disks using plasma of argon accelerated fibroblast adhesion in the early stages of colonization (2 to 8 hours). This effect disappeared after 48 hours as a result of saturation. Clinically, abutment cleaning using plasma of argon might positively affect soft tissue healing in early stages.

  2. A Candida albicans early stage biofilm detachment event in rich medium

    PubMed Central

    2009-01-01

    Background Dispersal from Candida albicans biofilms that colonize catheters is implicated as a primary factor in the link between contaminated catheters and life threatening blood stream infections (BSI). Appropriate in vitro C. albicans biofilm models are needed to probe factors that induce detachment events. Results Using a flow through system to culture C. albicans biofilms we characterized a detachment process which culminates in dissociation of an entire early stage biofilm from a silicone elastomer surface. We analyzed the transcriptome response at time points that bracketed an abrupt transition in which a strong adhesive association with the surface is weakened in the initial stages of the process, and also compared batch and biofilm cultures at relevant time points. K means analysis of the time course array data revealed categories of genes with similar patterns of expression that were associated with adhesion, biofilm formation and glycoprotein biosynthesis. Compared to batch cultures the biofilm showed a pattern of expression of metabolic genes that was similar to the C. albicans response to hypoxia. However, the loss of strong adhesion was not obviously influenced by either the availability of oxygen in the medium or at the silicone elastomer surface. The detachment phenotype of mutant strains in which selected genes were either deleted or overexpressed was characterized. The microarray data indicated that changes associated with the detachment process were complex and, consistent with this assessment, we were unable to demonstrate that transcriptional regulation of any single gene was essential for loss of the strong adhesive association. Conclusion The massive dispersal of the early stage biofilm from a biomaterial surface that we observed is not orchestrated at the level of transcriptional regulation in an obvious manner, or is only regulated at this level by a small subpopulation of cells that mediate adhesion to the surface. PMID:19187560

  3. Comparing stochastic differential equations and agent-based modelling and simulation for early-stage cancer.

    PubMed

    Figueredo, Grazziela P; Siebers, Peer-Olaf; Owen, Markus R; Reps, Jenna; Aickelin, Uwe

    2014-01-01

    There is great potential to be explored regarding the use of agent-based modelling and simulation as an alternative paradigm to investigate early-stage cancer interactions with the immune system. It does not suffer from some limitations of ordinary differential equation models, such as the lack of stochasticity, representation of individual behaviours rather than aggregates and individual memory. In this paper we investigate the potential contribution of agent-based modelling and simulation when contrasted with stochastic versions of ODE models using early-stage cancer examples. We seek answers to the following questions: (1) Does this new stochastic formulation produce similar results to the agent-based version? (2) Can these methods be used interchangeably? (3) Do agent-based models outcomes reveal any benefit when compared to the Gillespie results? To answer these research questions we investigate three well-established mathematical models describing interactions between tumour cells and immune elements. These case studies were re-conceptualised under an agent-based perspective and also converted to the Gillespie algorithm formulation. Our interest in this work, therefore, is to establish a methodological discussion regarding the usability of different simulation approaches, rather than provide further biological insights into the investigated case studies. Our results show that it is possible to obtain equivalent models that implement the same mechanisms; however, the incapacity of the Gillespie algorithm to retain individual memory of past events affects the similarity of some results. Furthermore, the emergent behaviour of ABMS produces extra patters of behaviour in the system, which was not obtained by the Gillespie algorithm.

  4. Association Between Increased Vascular Density and Loss of Protective RAS in Early-stage NPDR

    NASA Technical Reports Server (NTRS)

    Radhakrishnan, Krishnan; Raghunandan, Sneha; Vyas, Ruchi J.; Vu, Amanda C.; Bryant, Douglas; Yaqian, Duan; Knecht, Brenda E.; Grant, Maria B.; Chalam, K. V.; Parsons-Wingerter, Patricia

    2016-01-01

    Our hypothesis predicts that retinal blood vessels increase in density during early-stage progression to moderate nonproliferative diabetic retinopathy (NPDR). The renin-angiotensin system (RAS) is implicated in the pathogenesis of DR and in the function of circulating angiogenic cells (CACs), a critical bone marrow-derived population that is instrumental in vascular repair.

  5. Src Homology 2–containing 5-Inositol Phosphatase (SHIP) Suppresses an Early Stage of Lymphoid Cell Development through Elevated Interleukin-6 Production by Myeloid Cells in Bone Marrow

    PubMed Central

    Nakamura, Koji; Kouro, Taku; Kincade, Paul W.; Malykhin, Alexander; Maeda, Kazuhiko; Coggeshall, K. Mark

    2004-01-01

    The Src homology (SH)2–containing inositol 5-phosphatase (SHIP) negatively regulates a variety of immune responses through inhibitory immune receptors. In SHIP−/− animals, we found that the number of early lymphoid progenitors in the bone marrow was significantly reduced and accompanied by expansion of myeloid cells. We exploited an in vitro system using hematopoietic progenitors that reproduced the in vivo phenotype of SHIP−/− mice. Lineage-negative marrow (Lin−) cells isolated from wild-type mice failed to differentiate into B cells when cocultured with those of SHIP−/− mice. Furthermore, culture supernatants of SHIP−/− Lin− cells suppressed the B lineage expansion of wild-type lineage-negative cells, suggesting the presence of a suppressive cytokine. SHIP−/− Lin− cells contained more IL-6 transcripts than wild-type Lin− cells, and neutralizing anti–IL-6 antibody rescued the B lineage expansion suppressed by the supernatants of SHIP−/− Lin− cells. Finally, we found that addition of recombinant IL-6 to cultures of wild-type Lin− bone marrow cells reproduced the phenotype of SHIP−/− bone marrow cultures: suppression of B cell development and expansion of myeloid cells. The results identify IL-6 as an important regulatory cytokine that can suppress B lineage differentiation and drive excessive myeloid development in bone marrow. PMID:14718513

  6. High-throughput quantification of early stages of phagocytosis.

    PubMed

    Yeo, Jeremy Changyu; Wall, Adam Alexander; Stow, Jennifer Lea; Hamilton, Nicholas Ahti

    2013-09-01

    Phagocytosis--the engulfment of cells and foreign bodies--is an important cellular process in innate immunity, development, and disease. Quantification of various stages of phagocytosis, especially in a rapid screening fashion, is an invaluable tool for elucidating protein function during this process. However, current methods for assessing phagocytosis are largely limited to flow cytometry and manual image-based assays, providing limited information. Here, we present an image-based, semi-automated phagocytosis assay to rapidly quantitate three distinct stages during the early engulfment of opsonized beads. Captured images are analyzed using the image-processing software ImageJ and quantified using a macro. Modifications to this method allowed quantification of phagocytosis only in fluorescently labeled transfected cells. Additionally, the time course of bead internalization could be measured using this approach. The assay could discriminate perturbations to stages of phagocytosis induced by known pharmacological inhibitors of filamentous actin and phosphoinositol-3-kinase. Our methodology offers the ability to automatically categorize large amounts of image data into the three early stages of phagocytosis within minutes, clearly demonstrating its potential value in investigating aberrant phagocytosis when manipulating proteins of interest in drug screens and disease.

  7. Endoscopic mucosal resection of early stage colon neuroendocrine carcinoma

    PubMed Central

    Yamasaki, Yasushi; Uedo, Noriya; Ishihara, Ryu; Tomita, Yasuhiko

    2015-01-01

    Early stage colorectal neuroendocrine carcinoma is rare. A small colon tumour was found in a 56-year-old man during diagnostic colonoscopy performed after a positive faecal occult blood test, and he was referred for treatment. A slightly reddish superficial elevated lesion with a shallow depression 10 mm in size was found in the transverse colon. Magnifying narrow-band imaging revealed disrupted irregular microvessels and the absence of a surface pattern in the depressed area. En bloc endoscopic mucosal resection (EMR) of the tumour was undertaken. The tumour was positive for chromogranin A and synaptophysin, and had a mitotic rate of >20/10 high-power fields and a Ki-67 proliferative index of >50%; it was diagnosed as a neuroendocrine carcinoma. The tumour minimally invaded the submucosa (300 μm) without lymphovascular involvement. The patient was followed up carefully, and at 1 year after EMR, no recurrence was found using colonoscopy and CT scans. PMID:25737221

  8. The Early Stages of Groundwater-fed River Bifurcation

    NASA Astrophysics Data System (ADS)

    Yi, R.; Seybold, H. F.; Gibbins, G.; Rothman, D.

    2014-12-01

    Recent work shows, both theoretically and empirically, that river networks fed by subsurface flow bifurcate on average at an angle of 2π/5 [1]. However, the network's existence within a complex natural framework obscures the emergence of this pattern. Fortunately, this ambiguity betrays the presence of processes that have had some effect on the channels during the network's long history. In particular, we concern ourselves with the signature of the third dimension - the topographic relief - on the early stages of channel bifurcation. While, on average, channels grow in a direction dictated by the shape of the groundwater table, we hypothesize that the valley relief plays a crucial role in determining the opening angle and its relaxation to 2π/5 in this regime. A network-wide averaging of several thousand channel bifurcations driven by subsurface flow on the Florida Panhandle reveals that rivers on average branch initially at an angle wider than 2π/5, yet quickly relax to 2π/5 after a few meters. We hypothesize that this initial wide growth direction is governed by the shape of the topography. As these channels form independent valleys, the Laplacian field prevails, yielding an emergent 2π/5 branching angle. Our results therefore suggest that the path-selection of incipient channels fed by subsurface flow is coupled both to the local topography and the surrounding groundwater field. 1. Devauchelle, Olivier, et al. "Ramification of stream networks." Proceedings of the National Academy of Sciences 109.51 (2012): 20832-20836.

  9. Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer.

    PubMed

    Han, Jun; Meng, Qingyang; Xi, Qiulei; Zhang, Yongxian; Zhuang, Qiulin; Han, Yusong; Jiang, Yi; Ding, Qiurong; Wu, Guohao

    2016-01-01

    Chronic inflammation is a well-known etiological factor for colorectal cancer (CRC) and cancer cells are known to preferentially metabolize glucose through aerobic glycolysis. However, the connection between chronic inflammation and aerobic glycolysis in the development of CRC is largely unexplored. The present study investigated whether interleukin-6 (IL-6), a pro-inflammatory cytokine, promotes the development of CRC by regulating the aerobic glycolysis and the underlying molecular mechanisms. In colitis-associated CRC mouse, anti-IL-6 receptor antibody treatment reduced the incidence of CRC and decreased the expression of key genes in aerobic glycolysis, whereas the plasma concentrations of glucose and lactate were not affected. Consistently, IL-6 treatment stimulated aerobic glycolysis, upregulated key genes in aerobic glycolysis and promoted cell proliferation and migration in SW480 and SW1116 CRC cells. 6-phoshofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) was the most downregulated gene by anti-IL-6 receptor antibody in colorectal adenoma tissues. Further analysis in human samples revealed overexpression of PFKFB3 in colorectal adenoma and adenocarcinoma tissues, which was also associated with lymph node metastasis, intravascular cancer embolus and TNM stage. In addition, the effect of IL-6 on CRC cells can be abolished by knocking down PRKFB3 through siRNA transfection. Our data suggest that chronic inflammation promotes the development of CRC by stimulating aerobic glycolysis and IL-6 is functioning, at least partly, through regulating PFKFB3 at early stage of CRC.

  10. Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy.

    PubMed

    Reyes-Avilés, Elane; Kostadinova, Lenche; Rusterholtz, Anne; Cruz-Lebrón, Angelica; Falck-Ytter, Yngve; Anthony, Donald D

    2015-01-01

    Approximately half of those with chronic hepatitis C virus (HCV) infection have circulating rheumatoid factor (RF), and a portion of these individuals develop cryoglobulinemic vasculitis. B cell phenotype/function in relation to RF in serum has been unclear. We examined B cell subset distribution, activation state (CD86), cell cycle state (Ki67), and ex-vivo response to BCR, TLR9 and TLR7/8 stimulation, in chronic HCV-infected donors with or without RF, and uninfected donors. Mature-activated B-cells of HCV-infected donors had lower CD86 expression compared to uninfected donors, and in the presence of RF they also showed reduced CD86 expression in response to BCR and TLR9 stimulation. Additionally, mature activated memory B cells of HCV RF+ donors less commonly expressed Ki67+ than HCV RF- donors, and did not proliferate as well in response to BCR stimulation. Proportions of mature-activated B cells were enhanced, while naïve B-cells were lower in the peripheral blood of HCV-RF+ compared to RF- and uninfected donors. None of these parameters normalize by week 8 of IFN free direct acting antiviral (DAA) therapy in HCV RF+ donors, while in RF- donors, mature activated B cell proportions did normalize. These data indicate that while chronic HCV infection alone results in a lower state of activation in mature activated memory B cells, the presence of RF in serum is associated with a more pronounced state of unresponsiveness and an overrepresentation of these B cells in the blood. This phenotype persists at least during the early time window after removal of HCV from the host.

  11. Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy

    PubMed Central

    Reyes-Avilés, Elane; Kostadinova, Lenche; Rusterholtz, Anne; Cruz-Lebrón, Angelica; Falck-Ytter, Yngve; Anthony, Donald D.

    2015-01-01

    Approximately half of those with chronic hepatitis C virus (HCV) infection have circulating rheumatoid factor (RF), and a portion of these individuals develop cryoglobulinemic vasculitis. B cell phenotype/function in relation to RF in serum has been unclear. We examined B cell subset distribution, activation state (CD86), cell cycle state (Ki67), and ex-vivo response to BCR, TLR9 and TLR7/8 stimulation, in chronic HCV-infected donors with or without RF, and uninfected donors. Mature-activated B-cells of HCV-infected donors had lower CD86 expression compared to uninfected donors, and in the presence of RF they also showed reduced CD86 expression in response to BCR and TLR9 stimulation. Additionally, mature activated memory B cells of HCV RF+ donors less commonly expressed Ki67+ than HCV RF- donors, and did not proliferate as well in response to BCR stimulation. Proportions of mature-activated B cells were enhanced, while naïve B-cells were lower in the peripheral blood of HCV-RF+ compared to RF- and uninfected donors. None of these parameters normalize by week 8 of IFN free direct acting antiviral (DAA) therapy in HCV RF+ donors, while in RF- donors, mature activated B cell proportions did normalize. These data indicate that while chronic HCV infection alone results in a lower state of activation in mature activated memory B cells, the presence of RF in serum is associated with a more pronounced state of unresponsiveness and an overrepresentation of these B cells in the blood. This phenotype persists at least during the early time window after removal of HCV from the host. PMID:26649443

  12. Nanoparticles target early-stage breast cancer metastasis in vivo.

    PubMed

    Goldman, Evgeniya; Zinger, Assaf; da Silva, Dana; Yaari, Zvi; Kajal, Ashima; Vardi-Oknin, Dikla; Goldfeder, Mor; Schroeder, Josh E; Shainsky-Roitman, Janna; Hershkovitz, Dov; Schroeder, Avi

    2017-10-27

    Despite advances in cancer therapy, treating cancer after it has metastasized remains an unmet clinical challenge. In this study we demonstrate that 100 nm liposomes target triple-negative murine breast-cancer metastases post intravenous administration. Metastatic breast cancer was induced in BALB/c mice either experimentally, by a tail vein injection of 4T1 cells, or spontaneously, after implanting a primary tumor xenograft. To track their biodistribution in vivo the liposomes were labeled with multi-modal diagnostic agents, including indocyanine green and rhodamine for whole-animal fluorescent imaging, gadolinium for magnetic resonance imaging (MRI), and europium for a quantitative biodistribution analysis. The accumulation of liposomes in the metastases peaked at 24 h post the intravenous administration, similar to the time they peaked in the primary tumor. The efficiency of liposomal targeting to the metastatic tissue exceeded that of a non-liposomal agent by 4.5-fold. Liposomes were detected at very early stages in the metastatic progression, including metastatic lesions smaller than 2 mm in diameter. Surprisingly, while nanoparticles target breast cancer metastasis, they may also be found in elevated levels in the pre-metastatic niche, several days before metastases are visualized by MRI or histologically in the tissue. This study highlights the promise of diagnostic and therapeutic nanoparticles for treating metastatic cancer, possibly even for preventing the onset of the metastatic dissemination by targeting the pre-metastatic niche.

  13. Patients with Old Age or Proximal Tumors Benefit from Metabolic Syndrome in Early Stage Gastric Cancer

    PubMed Central

    Zhang, Ying; Liu, Jian-xin; Yu, Hong-mei; Liang, Wei-ping; Jin, Ying; Ren, Chao; He, Ming-ming; Chen, Wei-wei; Luo, Hui-yan; Wang, Zhi-qiang; Zhang, Dong-sheng; Wang, Feng-hua; Li, Yu-hong; Xu, Rui-hua

    2014-01-01

    Background Metabolic syndrome and/or its components have been demonstrated to be risk factors for several cancers. They are also found to influence survival in breast, colon and prostate cancer, but the prognostic value of metabolic syndrome in gastric cancer has not been investigated. Methods Clinical data and pre-treatment information of metabolic syndrome of 587 patients diagnosed with early stage gastric cancer were retrospectively collected. The associations of metabolic syndrome and/or its components with clinical characteristics and overall survival in early stage gastric cancer were analyzed. Results Metabolic syndrome was identified to be associated with a higher tumor cell differentiation (P = 0.036). Metabolic syndrome was also demonstrated to be a significant and independent predictor for better survival in patients aged >50 years old (P = 0.009 in multivariate analysis) or patients with proximal gastric cancer (P = 0.047 in multivariate analysis). No association was found between single metabolic syndrome component and overall survival in early stage gastric cancer. In addition, patients with hypertension might have a trend of better survival through a good control of blood pressure (P = 0.052 in univariate analysis). Conclusions Metabolic syndrome was associated with a better tumor cell differentiation in patients with early stage gastric cancer. Moreover, metabolic syndrome was a significant and independent predictor for better survival in patients with old age or proximal tumors. PMID:24599168

  14. Patients with old age or proximal tumors benefit from metabolic syndrome in early stage gastric cancer.

    PubMed

    Wei, Xiao-li; Qiu, Miao-zhen; Lin, Huan-xin; Zhang, Ying; Liu, Jian-xin; Yu, Hong-mei; Liang, Wei-ping; Jin, Ying; Ren, Chao; He, Ming-ming; Chen, Wei-wei; Luo, Hui-yan; Wang, Zhi-qiang; Zhang, Dong-sheng; Wang, Feng-hua; Li, Yu-hong; Xu, Rui-hua

    2014-01-01

    Metabolic syndrome and/or its components have been demonstrated to be risk factors for several cancers. They are also found to influence survival in breast, colon and prostate cancer, but the prognostic value of metabolic syndrome in gastric cancer has not been investigated. Clinical data and pre-treatment information of metabolic syndrome of 587 patients diagnosed with early stage gastric cancer were retrospectively collected. The associations of metabolic syndrome and/or its components with clinical characteristics and overall survival in early stage gastric cancer were analyzed. Metabolic syndrome was identified to be associated with a higher tumor cell differentiation (P=0.036). Metabolic syndrome was also demonstrated to be a significant and independent predictor for better survival in patients aged >50 years old (P=0.009 in multivariate analysis) or patients with proximal gastric cancer (P=0.047 in multivariate analysis). No association was found between single metabolic syndrome component and overall survival in early stage gastric cancer. In addition, patients with hypertension might have a trend of better survival through a good control of blood pressure (P=0.052 in univariate analysis). Metabolic syndrome was associated with a better tumor cell differentiation in patients with early stage gastric cancer. Moreover, metabolic syndrome was a significant and independent predictor for better survival in patients with old age or proximal tumors.

  15. Time-Varying Pattern of Postoperative Recurrence Risk of Early-Stage (T1a-T2bN0M0) Non-Small Cell Lung Cancer (NSCLC): Results of a Single-Center Study of 994 Chinese Patients

    PubMed Central

    Zhu, Jian-fei; Feng, Xing-yu; Zhang, Xue-wen; Wen, Ying-sheng; Lin, Peng; Rong, Tie-hua

    2014-01-01

    Background The aim of this study was to analyze the time-varying pattern of recurrence risk of early-stage (T1a-T2bN0M0) non-small cell lung cancer (NSCLC) after surgery using the hazard function and identify patients who might benefit from adjuvant chemotherapy. Patients and Methods This retrospective study enrolled 994 patients with early-stage NSCLC who underwent radical surgical resection between January 1999 and October 2009. Survival curves were generated using the Kaplan-Meier method, and the annual recurrence hazard was estimated using the hazard function. Results The median recurrence-free survival (RFS) was 8.8 years. The life table survival analysis showed that the 1-year, 3-year, 5-year and 10-year recurrence rates were 82.0%, 67.0%, 59.0% and 48.0%, respectively. Approximately 256 (25.7%) patients experienced relapse [locoregional: 32 (3.2%) and distant: 224 (22.5%)], and 162 patients died from cancer. The annual recurrence hazard curve for the entire population showed that the first major recurrence surge reached a maximum 1.6 years after surgery. The curve subsequently declined until reaching a nadir at 7.2 years. A second peak occurred at 8.8 years. An analysis of clinical-pathological factors demonstrated that this double-peaked pattern was present in several subgroups. Conclusions The presence of a double-peaked pattern indicates that there is a predictable temporal distribution of the recurrence hazard of early-stage NSCLC. The annual recurrence hazard may be an effective method of selecting patients at high risk of recurrence, who may benefit from adjuvant therapy. PMID:25203402

  16. Time-varying pattern of postoperative recurrence risk of early-stage (T1a-T2bN0M0) non-small cell lung cancer (NSCLC): results of a single-center study of 994 Chinese patients.

    PubMed

    Zhu, Jian-fei; Feng, Xing-yu; Zhang, Xue-wen; Wen, Ying-sheng; Lin, Peng; Rong, Tie-hua; Cai, Ling; Zhang, Lan-jun

    2014-01-01

    The aim of this study was to analyze the time-varying pattern of recurrence risk of early-stage (T1a-T2bN0M0) non-small cell lung cancer (NSCLC) after surgery using the hazard function and identify patients who might benefit from adjuvant chemotherapy. This retrospective study enrolled 994 patients with early-stage NSCLC who underwent radical surgical resection between January 1999 and October 2009. Survival curves were generated using the Kaplan-Meier method, and the annual recurrence hazard was estimated using the hazard function. The median recurrence-free survival (RFS) was 8.8 years. The life table survival analysis showed that the 1-year, 3-year, 5-year and 10-year recurrence rates were 82.0%, 67.0%, 59.0% and 48.0%, respectively. Approximately 256 (25.7%) patients experienced relapse [locoregional: 32 (3.2%) and distant: 224 (22.5%)], and 162 patients died from cancer. The annual recurrence hazard curve for the entire population showed that the first major recurrence surge reached a maximum 1.6 years after surgery. The curve subsequently declined until reaching a nadir at 7.2 years. A second peak occurred at 8.8 years. An analysis of clinical-pathological factors demonstrated that this double-peaked pattern was present in several subgroups. The presence of a double-peaked pattern indicates that there is a predictable temporal distribution of the recurrence hazard of early-stage NSCLC. The annual recurrence hazard may be an effective method of selecting patients at high risk of recurrence, who may benefit from adjuvant therapy.

  17. Patterns of CT lung injury and toxicity after stereotactic radiotherapy delivered with helical tomotherapy in early stage medically inoperable NSCLC

    PubMed Central

    Agolli, L; Portalone, L; Migliorino, M R; Lopergolo, M G; Monaco, A; Dognini, J; Pressello, M C; Bracci, S; Donato, V

    2015-01-01

    Objective: To evaluate toxicity and patterns of radiologic lung injury on CT images after hypofractionated image-guided stereotactic body radiotherapy (SBRT) delivered with helical tomotherapy (HT) in medically early stage inoperable non-small-cell lung cancer (NSCLC). Methods: 28 elderly patients (31 lesions) with compromised pulmonary reserve were deemed inoperable and enrolled to undergo SBRT. Patterns of lung injury based on CT appearance were assessed at baseline and during follow up. Acute (6 months or less) and late (more than 6 months) events were classified as radiation pneumonitis and radiation fibrosis (RF), respectively. Results: After a median follow-up of 12 months (range, 4–20 months), 31 and 25 lesions were examined for acute and late injuries, respectively. Among the former group, 25 (80.6%) patients showed no radiological changes. The CT appearance of RF revealed modified conventional, mass-like and scar-like patterns in three, four and three lesions, respectively. No evidence of late lung injury was demonstrated in 15 lesions. Five patients developed clinical pneumonitis (four patients, grade 2 and one patient, grade 3, respectively), and none of whom had CT findings at 3 months post-treatment. No instance of symptomatic RF was detected. The tumour response rate was 84% (complete response + partial response). Local control was 83% at 1 year. Conclusion: Our findings show that HT-SBRT can be considered an effective treatment with a mild toxicity profile in medically inoperable patients with early stage NSCLC. No specific pattern of lung injury was demonstrated. Advances in knowledge: Our study is among the few showing that HT-SBRT represents a safe and effective option in patients with early stage medically inoperable NSCLC, and that it is not associated with a specific pattern of lung injury. PMID:25645106

  18. Speech acoustic markers of early stage and prodromal Huntington's disease: a marker of disease onset?

    PubMed

    Vogel, Adam P; Shirbin, Christopher; Churchyard, Andrew J; Stout, Julie C

    2012-12-01

    Speech disturbances (e.g., altered prosody) have been described in symptomatic Huntington's Disease (HD) individuals, however, the extent to which speech changes in gene positive pre-manifest (PreHD) individuals is largely unknown. The speech of individuals carrying the mutant HTT gene is a behavioural/motor/cognitive marker demonstrating some potential as an objective indicator of early HD onset and disease progression. Speech samples were acquired from 30 individuals carrying the mutant HTT gene (13 PreHD, 17 early stage HD) and 15 matched controls. Participants read a passage, produced a monologue and said the days of the week. Data were analysed acoustically for measures of timing, frequency and intensity. There was a clear effect of group across most acoustic measures, so that speech performance differed in-line with disease progression. Comparisons across groups revealed significant differences between the control and the early stage HD group on measures of timing (e.g., speech rate). Participants carrying the mutant HTT gene presented with slower rates of speech, took longer to say words and produced greater silences between and within words compared to healthy controls. Importantly, speech rate showed a significant correlation to burden of disease scores. The speech of early stage HD differed significantly from controls. The speech of PreHD, although not reaching significance, tended to lie between the performance of controls and early stage HD. This suggests that changes in speech production appear to be developing prior to diagnosis. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. ECT2 amplification and overexpression as a new prognostic biomarker for early-stage lung adenocarcinoma

    PubMed Central

    Murata, Yoshihiko; Minami, Yuko; Iwakawa, Reika; Yokota, Jun; Usui, Shingo; Tsuta, Koji; Shiraishi, Kouya; Sakashita, Shingo; Satomi, Kaishi; Iijima, Tatsuo; Noguchi, Masayuki

    2014-01-01

    Genetic abnormality in early-stage lung adenocarcinoma was examined to search for new prognostic biomarkers. Six in situ lung adenocarcinomas and nine small but invasive adenocarcinomas were examined by array-comparative genomic hybridization, and candidate genes of interest were screened. To examine gene abnormalities, 83 cases of various types of lung carcinoma were examined by quantitative real-time genomic PCR and immunohistochemistry. The results were then verified using another set of early-stage adenocarcinomas. Array-comparative genomic hybridization indicated frequent amplification at chromosome 3q26. Of the seven genes located in this region, we focused on the epithelial cell transforming sequence 2 (ECT2) oncogene, as ECT2 amplification was detected only in invasive adenocarcinoma, and not in in situ carcinoma. Quantitative PCR and immunohistochemistry analyses also detected overexpression of ECT2 in invasive adenocarcinoma, and this was correlated with both the Ki-67 labeling index and mitotic index. In addition, it was associated with disease-free survival and overall survival of patients with lung adenocarcinoma. These results were verified using another set of early-stage adenocarcinomas resected at another hospital. Abnormality of the ECT2 gene occurs at a relatively early stage of lung adenocarcinogenesis and would be applicable as a new biomarker for prognostication of patients with lung adenocarcinoma. PMID:24484057

  20. Weight loss in the early stage of progressive supranuclear palsy.

    PubMed

    Tsuge, Ayako; Kaneko, Satoshi; Wate, Reika; Oki, Mitsuaki; Nagashima, Masato; Asayama, Shinya; Nakamura, Masataka; Fujita, Kengo; Saito, Akemi; Takenouchi, Norihiro; Kusaka, Hirofumi

    2017-02-01

    To clarify whether weight change in patients with Parkinson's disease (PD) or progressive supranuclear palsy (PSP) is caused by the disease itself or secondarily by other factors. We conducted a retrospective analysis of 51 patients with PD and 14 patients with PSP, especially during the early stage of their diseases. All patients were independent in terms of their activities of daily living and did not have any feeding difficulty. The body mass index measured within 3 years after the disease onset did not show a significant difference between the two diseases. However, the subsequent weight was stable in patients with PD and significantly decreased in patients with PSP. Weight loss begins in the early stage of PSP, whereas dopaminergic treatment may contribute to keep weight in the early stage of PD through reduction of energy expenditure and/or improvement in appetite.

  1. Unraveling Mixed Hydrate Formation: Microscopic Insights into Early Stage Behavior.

    PubMed

    Hall, Kyle Wm; Zhang, Zhengcai; Kusalik, Peter G

    2016-12-29

    The molecular-level details of mixed hydrate nucleation remain unclear despite the broad implications of this process for a variety of scientific domains. Through analysis of mixed hydrate nucleation in a prototypical CH4/H2S/H2O system, we demonstrate that high-level kinetic similarities between mixed hydrate systems and corresponding pure hydrate systems are not a reliable basis for estimating the composition of early stage mixed hydrate nuclei. Moreover, we show that solution compositions prior to and during nucleation are not necessarily effective proxies for the composition of early stage mixed hydrate nuclei. Rather, microscopic details, (e.g., guest-host interactions and previously neglected cage types) apparently play key roles in determining early stage behavior of mixed hydrates. This work thus provides key foundational concepts and insights for understanding mixed hydrate nucleation.

  2. The mobilization, recruitment and contribution of bone marrow-derived endothelial progenitor cells to the tumor neovascularization occur at an early stage and throughout the entire process of hepatocellular carcinoma growth.

    PubMed

    Zhu, Haitao; Shao, Qianwen; Sun, Xitai; Deng, Zhengming; Yuan, Xianwen; Yu, Decai; Zhou, Xiang; Ding, Yitao

    2012-10-01

    Obvious neovascularization is a key feature of hepatocellular carcinoma (HCC) and the status of neovascularization in HCC is closely correlated with the tumor growth and patient prognosis. The actual effect of current antivascular treatment including embolization to HCC is not satisfactory. Compensatory angiogenesis is one of the primary causes responsible for failure of antiangiogenic therapy. Bone marrow-derived endothelial progenitor cells (BM-EPCs) are considered as important building blocks for adult neovascularization. However, the role of mobilized BM-EPCs in HCC remains unknown. In this study, GFP+-BM orthotropic HCC mice were established to investigate whether BM-EPCs are involved in HCC-induced neovascularization. We found that a large number of BM-EPCs were mobilized into the circulation with the development of HCC, recruited into the HCC region and incorporated into the vascular endothelium directly by differentiation into vascular endothelial cells, including sinus, capillary vessels and great vessels. Dynamic observation revealed that the mobilization and the incorporation of BM-EPCs into different types of vessels were present in early phases and throughout the whole process of HCC growth. The proportion of BM-EPCs in vessels increased gradually, from 17 to 21% with tumor growth. Moreover, injected GFP+-EPCs also specifically homed to tumor tissue and incorporated into tumor vessels directly. In this initial study, we demonstrated that BM-EPCs play a prominent role in HCC neovascularization. Blockade of BM-EPC-mediated vasculogenesis may improve the efficacy of current anti-vascularization therapy for patients with HCC.

  3. Native language change during early stages of second language learning

    PubMed Central

    Bice, Kinsey; Kroll, Judith F.

    2015-01-01

    Research on proficient bilinguals has demonstrated that both languages are always active, even when only one is required. The co-activation of the two languages creates both competition and convergence, facilitating the processing of cognate words, but slowing lexical access when there is a requirement to engage control mechanisms to select the target language. Critically, these consequences are evident in the native language (L1) as well as the second language (L2). The present study asked whether L1 change can be detected at early stages of L2 learning and how it is modulated by L2 proficiency. Native English speakers learning Spanish performed an English (L1) lexical decision task that included cognates while event-related potentials (ERPs) were recorded. They also performed verbal fluency, working memory, and inhibitory control tasks. A group of matched monolinguals performed the same tasks in English only. The results revealed that intermediate learners demonstrate a reduced N400 for cognates compared to noncognates in English (L1), and an emerging effect is visually present in beginning learners as well; however, no behavioral cognate effect was present for either group. Additionally, slower reaction times in English (L1) are related to a larger cognate N400 magnitude in English (L1) and Spanish (L2), and to better inhibitory control for learners but not for monolinguals. The results suggest that contrary to the claim that the L2 affects the L1 only when L2 speakers are highly proficient, L2 learning begins to impact the L1 early in the development of L2 skill. PMID:26351964

  4. Native language change during early stages of second language learning.

    PubMed

    Bice, Kinsey; Kroll, Judith F

    2015-11-11

    Research on proficient bilinguals has demonstrated that both languages are always active, even when only one is required. The coactivation of the two languages creates both competition and convergence, facilitating the processing of cognate words, but slowing lexical access when there is a requirement to engage control mechanisms to select the target language. Critically, these consequences are evident in the native language (L1) as well as in the second language (L2). The present study questioned whether L1 changes can be detected at early stages of L2 learning and how they are modulated by L2 proficiency. Native English speakers learning Spanish performed an English (L1) lexical decision task that included cognates while event-related potentials were recorded. They also performed verbal fluency, working memory, and inhibitory control tasks. A group of matched monolinguals performed the same tasks in English only. The results revealed that intermediate learners demonstrate a reduced N400 for cognates compared with noncognates in English (L1), and an emerging effect is visually present in beginning learners as well; however, no behavioral cognate effect was present for either group. In addition, slower reaction times in English (L1) are related to a larger cognate N400 magnitude in English (L1) and Spanish (L2), and to better inhibitory control for learners but not for monolinguals. The results suggest that contrary to the claim that L2 affects L1 only when L2 speakers are highly proficient, L2 learning begins to impact L1 early in the development of the L2 skill.

  5. Locomotor function in the early stage of Parkinson's disease.

    PubMed

    Carpinella, Ilaria; Crenna, Paolo; Calabrese, Elena; Rabuffetti, Marco; Mazzoleni, Paolo; Nemni, Raffaello; Ferrarin, Maurizio

    2007-12-01

    The cardinal motor symptoms of Parkinson's disease (PD) have been widely investigated with particular reference to abnormalities of steady-state walking. The great majority of studies, however are related to severe forms of PD patients (phases > = 3 of Hoehn and Yahr scale), where locomotor abnormalities are clearly manifested. Goal of the present study was to quantitatively describe locomotor symptoms in subjects with mild PD. Accordingly, a multitask protocol involving instrumental analysis of steady-state linear walking, initiation of gait, and turning while walking was applied to a group of patients with idiopathic PD in their early clinical stage (phases 1 and 2 of Hoehn and Yahr scale), as well as in age-matched elderly controls. Kinematic, kinetic, and myoelectric measures were obtained by optoelectronic motion analysis, force platform, and telemetric electromyography. Results in PD patients showed a tendency to bradykinetic gait, with reduction of walking speed and cadence. Impairments of gait initiation consisted in reduction of the backward shift of the center of pressure (CoP) and prolongation of the stepping phase. Alterations of the turning task were more consistent and included delayed reorientation of the head toward the new direction, altered head-upper trunk rotational strategy, and adoption of a greater number of steps to complete the turning. It is concluded that patients in the early stage of PD reveal mild alterations of steady-state linear walking and more significant anomalies in the transitional conditions, especially during changes in the travel direction. Quantitative analysis of nonstationary locomotor tasks might be a potentially useful starting point for further studies on the pathophysiology of PD.

  6. Light- and electron-microscopic autoradiographic analysis of proliferating cells during the early stages of chemical hepatocarcinogenesis in the rat induced by feeding N-2-fluorenylacetamide in a choline-deficient diet.

    PubMed

    Sell, S; Salman, J

    1984-02-01

    Proliferating cells that appear after feeding the hepatocarcinogen N-2-fluorenylacetamide in a choline-deficient diet were identified by autoradiographic electron and light microscopy. Labeled cells are first seen as nondescript periductular cells 1 day after feeding carcinogen. Proliferation of duct lining cells begins at 2-3 days. For the next three weeks there is proliferation and extension of a mixture of nondescript cells and cells with a duct like appearance from the portal zone into the adjacent liver. By 3-4 weeks the entire liver lobule contains this new cell population. At 3 weeks more differentiated duct like structures are seen at the edge of the advancing new cell population. Newly appearing duct like cells differ from normal duct cells in that they contain AFP and albumin. It is concluded that the new cell population may arise from duct cells or periportal "stem" cells, or both.

  7. Stereotactic body radiation therapy for inoperable early stage lung cancer.

    PubMed

    Timmerman, Robert; Paulus, Rebecca; Galvin, James; Michalski, Jeffrey; Straube, William; Bradley, Jeffrey; Fakiris, Achilles; Bezjak, Andrea; Videtic, Gregory; Johnstone, David; Fowler, Jack; Gore, Elizabeth; Choy, Hak

    2010-03-17

    Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management. To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer. Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non-small cell tumors (measuring <5 cm in diameter) and medical conditions precluding surgical treatment. The prescription dose was 18 Gy per fraction x 3 fractions (54 Gy total) with entire treatment lasting between 1(1/2) and 2 weeks. The study opened May 26, 2004, and closed October 13, 2006; data were analyzed through August 31, 2009. The primary end point was 2-year actuarial primary tumor control; secondary end points were disease-free survival (ie, primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity, and overall survival. A total of 59 patients accrued, of which 55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a primary tumor failure; the estimated 3-year primary tumor control rate was 97.6% (95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within the involved lobe; the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure; the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients experienced disseminated recurrence; the 3-year rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%). The rates for disease-free survival and overall survival at 3 years were 48.3% (95% CI, 34.4%-60.8%) and 55.8% (95% CI, 41.6%-67.9%), respectively. The median overall survival was 48.1 months (95% CI, 29.6 months to not

  8. Prognostic factors in early-stage ovarian cancer

    PubMed Central

    Tognon, Germana; Carnazza, Mario; Ragnoli, Monica; Calza, Stefano; Ferrari, Federico; Gambino, Angela; Zizioli, Valentina; Notaro, Sara; Sostegni, Benedetta; Sartori, Enrico

    2013-01-01

    The purpose of this study was to identify the main prognostic factors in patients with early-stage epithelial ovarian cancer. Data were extracted from 222 patients with initial stage (I–IIA) invasive epithelial ovarian cancer treated with primary surgery followed or not followed by adjuvant therapy, from 1 January 1980 to 31 December 2008, at the Division of Obstetrics and Gynecology, Spedali Civili, Brescia, Italy; the median follow-up was 79 months (SD ± 35,945, range 20–250 months). The negative prognostic factors that were statistically significant (p<0.050) in univariate analysis were grade 2, 3, and X (clear cell in our study); stage IB, IC, IIA; positive peritoneal cytology, age equal to/greater than 54; dense adhesions; capsule rupture (pre-operative or intra-operative) and endometrioid histotype (only for disease-free survival (DFS)). Positive cytology was strongly associated with peritoneal relapses, while adhesions were associated with pelvic relapses. A positive prognosis was associated with the mucinous histotype. Conservative treatment had been carried out in 52% of patients under 40 years of age, and we detected only two relapses and three completions of surgery after a few weeks among 31 women in total. Our study indicated a possible execution in patients with patients with cancer stage IA G1–G2 (p=0.030) or IC G1 (p=0.050), provided well staged. Adjuvant chemotherapy improved the survival of cancers that were not IA G1. The positive prognostic role of taxanes must be emphasised, when used in combination with platino. PMID:23781280

  9. Early Stages of the Evolution of Life: a Cybernetic Approach

    NASA Astrophysics Data System (ADS)

    Melkikh, Alexey V.; Seleznev, Vladimir D.

    2008-08-01

    Early stages of the evolution of life are considered in terms of control theory. A model is proposed for the transport of substances in a protocell possessing the property of robustness with regard to changes in the environmental concentration of a substance.

  10. Radiation Plus Chemotherapy in Early-Stage Hodgkin Lymphoma

    Cancer.gov

    Adding radiation therapy to chemotherapy may improve outcomes in patients with early-stage Hodgkin lymphoma, according to a paper published in the Cochrane Database of Systematic Reviews in February 2011, but the long-term effects of this regimen are not

  11. Radiation Plus Chemotherapy in Early-Stage Hodgkin Lymphoma

    Cancer.gov

    Adding radiation therapy to chemotherapy may improve outcomes in patients with early-stage Hodgkin lymphoma, according to a paper published in the Cochrane Database of Systematic Reviews in February 2011, but the long-term effects of this regimen are not

  12. [The conservative treatment of early-stage benign prostatic hypertrophy].

    PubMed

    Kumanov, Kh; Stoianova, V; Lilov, A; Kaloianov, D

    1993-01-01

    After outlining the methods currently used in benign prostate hyperplasia (BPH) treatment, data defining some etiological aspects of the disease are briefly analyzed. Initial experience had with the treatment of early stage BPH using Permixon--a drug exerting effect on alpha-2 reductase--is described. The results in a series of twenty-seven patients presenting BPH are encouraging.

  13. Management of Early-stage Hodgkin Lymphoma: A Practice Guideline.

    PubMed

    Herst, J; Crump, M; Baldassarre, F G; MacEachern, J; Sussman, J; Hodgson, D; Cheung, M C

    2017-01-01

    In the past, treatment for patients with early-stage Hodgkin lymphoma consisted mainly of radiotherapy. Now, chemotherapy alone and chemoradiotherapy are treatment options. These guidelines aim to provide recommendations on the optimal management of early-stage Hodgkin lymphoma. We conducted a systematic review searching MEDLINE, EMBASE, the Cochrane Library and other literature sources from 2003 to 2015, and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Two authors independently reviewed and selected studies, and appraised the evidence quality. The document underwent internal and external review by content, methodology experts, a patient representative and clinicians in Ontario. We have issued recommendations for patients with classical Hodgkin lymphoma and with nodular lymphocyte predominant Hodgkin lymphoma; with favourable and unfavourable prognosis; and for the use of positron emission tomography to direct treatment. We have provided our interpretation of the evidence and considerations for implementation. Examples of recommendations are: 'Patients with early-stage classical Hodgkin lymphoma should not be treated with radiotherapy alone'; 'chemotherapy plus radiotherapy or chemotherapy alone are recommended treatment options for patients with early-stage non-bulky Hodgkin lymphoma'; 'The Working Group does not recommend the use of a negative interim positron emission tomography scan alone to identify patients with early-stage Hodgkin lymphoma for whom radiotherapy can be omitted without a reduction in progression-free survival'. Through the use of GRADE, recommendations were geared towards patient important outcomes and their strength reflected the available evidence and its interpretation from the patients' point of view. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

  14. Regulation of immune responses aginst the syngeneic ADJ-PC-5 plasmacytoma in BALB-c mice. III. Induction of specific T suppressor cells to the BALB/c plasmacytoma ADJ-PC-5 during early stages of tumorigenesis.

    PubMed Central

    Haubeck, H D; Kölsch, E

    1982-01-01

    Initial stages of tumour growth are not easily accessible to investigation. Therefore an experimental procedure was developed to mimic tumorigenesis as closely as possible. BALB/c mice received intraperitoneally exponentially increasing numbers of irradiated syngeneic ADJ-PC-5 plasmacytoma cells. The initial injection began with two cells per mouse and according to the generation time of this tumour, subsequent doses were doubled until mice had received up to 10(5) tumour cells. At various stages of treatment, peritoneal exudate cells (PEC) and spleen cells (SC) were tested for either cytotoxicity or specific suppression of induction of a primary in vitro T-cell cytotoxic response (CTL) of BALB/c spleen cells against ADJ-PC-5 plasmacytoma cells. No cytotoxic PEC were found. Instead, PEC from mice in which the final tumour cells number had reached or exceeded 10(3) irradiated ADJ-PC-5 cells, induced complete suppression of this primary in vitro CTL. Specificity was found both in the induction and effector phase of suppression. Specific suppression was mediated by Thy-1.2+ cells and amplified by non-specific suppression through adherent cells. The data arae discussed in context with previous findings on the in vivo immunogenicity and tolerogenicity of the ADJ-PC-5 plasmacytoma. They suggest that induction of T suppressor (Ts) cells might be an early event in tumorigenesis. PMID:6215340

  15. Nerve growth factor regulates axial rotation during early stages of chick embryo development.

    PubMed

    Manca, Annalisa; Capsoni, Simona; Di Luzio, Anna; Vignone, Domenico; Malerba, Francesca; Paoletti, Francesca; Brandi, Rossella; Arisi, Ivan; Cattaneo, Antonino; Levi-Montalcini, Rita

    2012-02-07

    Nerve growth factor (NGF) was discovered because of its neurotrophic actions on sympathetic and sensory neurons in the developing chicken embryo. NGF was subsequently found to influence and regulate the function of many neuronal and non neuronal cells in adult organisms. Little is known, however, about the possible actions of NGF during early embryonic stages. However, mRNAs encoding for NGF and its receptors TrkA and p75(NTR) are expressed at very early stages of avian embryo development, before the nervous system is formed. The question, therefore, arises as to what might be the functions of NGF in early chicken embryo development, before its well-established actions on the developing sympathetic and sensory neurons. To investigate possible roles of NGF in the earliest stages of development, stage HH 11-12 chicken embryos were injected with an anti-NGF antibody (mAb αD11) that binds mature NGF with high affinity. Treatment with anti-NGF, but not with a control antibody, led to a dose-dependent inversion of the direction of axial rotation. This effect of altered rotation after anti NGF injection was associated with an increased cell death in somites. Concurrently, a microarray mRNA expression analysis revealed that NGF neutralization affects the expression of genes linked to the regulation of development or cell proliferation. These results reveal a role for NGF in early chicken embryo development and, in particular, in the regulation of somite survival and axial rotation, a crucial developmental process linked to left-right asymmetry specification.

  16. The δ-cyclin expression at early stages of embryogenesis of Brassica rapa L. under clinorotation

    NASA Astrophysics Data System (ADS)

    Artemenko, O. A.; Popova, A. F.

    We present some results of comparison studying of Brassica embryo development and the δ-cyclin genes expression under slow horizontal clinorotation and in the laboratory control. Some backlog of the δ1-cyclin genes expression at early stages of embryogenesis under clinorotation was revealed in comparison with the laboratory control. The similar level of the δ3-cyclin expression at all stages of embryo formation (from one to nine days) in both variants is shown. Some delays in the rate of Brassica rapa embryo development under clinorotation in comparison with the laboratory control can be a result of decrease of a level and some backlog of the δ1-cyclin expression at early stages of embryogenesis.

  17. Analysis on Gene Expression Profile in Oncospheres and Early Stage Metacestodes from Echinococcus multilocularis

    PubMed Central

    Dang, Zhisheng; Suzuki, Yutaka; Horiuchi, Terumi; Yagi, Kinpei; Kouguchi, Hirokazu; Irie, Takao; Kim, Kyeongsoon; Oku, Yuzaburo

    2016-01-01

    Alveolar echinococcosis is a worldwide zoonosis of great public health concern. Analysis of genome data for Echinococcus multilocularis has identified antigen families that can be used in diagnostic assays and vaccine development. However, little gene expression data is available for antigens of the egg and early larval stages. To address this information gap, we used a Next-Generation Sequencing approach to investigate three different stages (non-activated and activated oncospheres, and early stage metacestodes) of E. multilocularis (Nemuro strain). Transcriptome data analysis revealed that some diagnostic antigen gp50 isoforms and the antigen Eg95 family dominated in activated oncospheres, and the antigen B family dominated in early stage metacestodes. Furthermore, heat shock proteins and antigen II/3 are constantly expressed in the three stages. The expression pattern of various known antigens in E. multilocularis may give fundamental information for choosing candidate genes used in diagnosis and vaccine development. PMID:27092774

  18. Implementation of the TMS in the early stages of Parkinson's disease.

    PubMed

    Guekht, A; Selikhova, M; Serkin, G; Gusev, E

    2005-01-01

    47 PD patients were investigated with the single-pulse TMS to find out changes in motor evoked potential and motor conduction related to the stage of minimal motor symptoms and its further deterioration in groups with the different clinical types of the disease. The investigation revealed a markedly longer MEP duration along with the increased number of phases, than in controls, which were bilateral and advanced despite the minimal unilateral motor symptoms. There was also increased MEP amplitude in facilitation, with a higher degree of asymmetry, compared to controls. Patients with predominant rigid clinical forms had the further MEP duration and amplitude increase proportionally to bradikinesia and rigidity in the early stages of the disease. Patients with tremor predominant forms had no further changes in the MEP duration and amplitude, but had their motor CCT decreased in the early stages. Patients with the akinetic form were characterized by the asymmetric increase in the MEP Amplitude in relaxation and motor CCT shortening. Thus, TMS allows us to diagnose early the possible central motor changes secondary to Parkinson's disease, reveals the difference in compensational capacity according to the clinical type of the disease and helps in monitoring of the severity of motor changes in early stages.

  19. Folding of Polymer Chains in Early Stage of Crystallization

    NASA Astrophysics Data System (ADS)

    Yuan, Shichen; Miyoshi, Toshikazu

    Understanding the structural formation of long polymer chains in the early stage of crystallization is one of the long-standing problems in polymer science. Using solid state NMR, we investigated chain trajectory of isotactic polypropylene in the mesomorphic nano-domains formed via rapid and deep quenching. Comparison of experimental and simulated 13C-13C Double Quantum (DQ) buildup curves demonstrated that instead of random re-entry models and solidification models, individual chains in the mesomorphic form iPP adopt adjacent reentry sequences with an average folding number of = 3-4 (assuming an adjacent re-entry fraction of of 100%) during mesomorphic formation process via nucleation and growth in the early stage. This work was financially supported by the National Science Foundation (Grant DMR-1105829 and 1408855) and startup funds from the UA.

  20. Signatures of unfolding in the early stages of protein denaturation

    NASA Astrophysics Data System (ADS)

    Gray, Harry B.; Winkler, Jay R.; Kozak, John J.

    2012-04-01

    A comparative study of the early stages of unfolding of five proteins: cyt c, c-b 562, cyt c‧, azurin, and lysozyme is reported. From crystallographic data, helical regions and intervening non-helical (or 'turning') regions are identified in each. Exploiting a previously introduced geometrical model, the paper describes quantitatively the stepwise extension of a polypeptide chain subject to the geometrical constraint that the spatial relationship among the residues of each triplet is fixed by native-state crystallographic data. Despite differences among the above-cited proteins, remarkable universality of behavior is found in the early stages of unfolding. At the very earliest stages, internal residues in each helical region have a common unfolding history; the terminal residues, however, are extraordinarily sensitive to structural perturbations. Residues in non-helical sections of the polypeptide unfold after residues in the internal helical regions, but with increasing steric perturbation playing a dominant role in advancing denaturation.

  1. Adjuvant chemotherapy for early-stage cervical cancer.

    PubMed

    Asano, Hiroshi; Todo, Yukiharu; Watari, Hidemichi

    2016-04-01

    The aim of this review is to address the current status of adjuvant chemotherapy alone in early-stage cervical cancer treatments in the literature. At present, the therapeutic effect of adjuvant chemotherapy alone after radical surgery (RS) has not yet been established, and radiation therapy (RT) or concurrent chemoradiotherapy (CCRT) is recommended as the standard adjuvant therapy after RS for early-stage cervical cancer in various guidelines. The main purpose of adjuvant therapy after RS, however, should be to reduce extrapelvic recurrence rather than local recurrence, although adjuvant RT or CCRT has survival benefits for patients with intermediate- or high-risk factors for recurrence. Moreover, several studies reported that adjuvant therapies including RT were associated with a higher incidence of complications, such as lymphedema, bowel obstruction and urinary disturbance, and a lower grade of long-term quality of life (QOL) or sexual functioning than adjuvant chemotherapy alone. The effect of adjuvant chemotherapy alone for early-stage cervical cancer with intermediate- or high-risk factors for recurrence were not fully investigated in prospective studies, but several retrospective studies suggest that the adjuvant effects of chemotherapy alone are at least similar to that of RT or CCRT in terms of recurrence rate, disease-free survival, or overall survival (OS) with lower incidence of complications. Whereas cisplatin based combination regimens were used in these studies, paclitaxel/cisplatin (TP) regimen, which is currently recognized as a standard chemotherapy regimen for patients with metastatic, recurrent or persistent cervical cancer by Gynecologic Oncology Group (GOG), had also survival benefit as an adjuvant therapy. Therefore, it may be worth considering a prospective randomized controlled trial (RCT) of adjuvant chemotherapy alone using TP regimen versus adjuvant RT as an alternative adjuvant therapy. Because early-stage cervical cancer is a curable

  2. Adjuvant chemotherapy for early-stage cervical cancer

    PubMed Central

    Asano, Hiroshi; Todo, Yukiharu; Watari, Hidemichi

    2016-01-01

    The aim of this review is to address the current status of adjuvant chemotherapy alone in early-stage cervical cancer treatments in the literature. At present, the therapeutic effect of adjuvant chemotherapy alone after radical surgery (RS) has not yet been established, and radiation therapy (RT) or concurrent chemoradiotherapy (CCRT) is recommended as the standard adjuvant therapy after RS for early-stage cervical cancer in various guidelines. The main purpose of adjuvant therapy after RS, however, should be to reduce extrapelvic recurrence rather than local recurrence, although adjuvant RT or CCRT has survival benefits for patients with intermediate- or high-risk factors for recurrence. Moreover, several studies reported that adjuvant therapies including RT were associated with a higher incidence of complications, such as lymphedema, bowel obstruction and urinary disturbance, and a lower grade of long-term quality of life (QOL) or sexual functioning than adjuvant chemotherapy alone. The effect of adjuvant chemotherapy alone for early-stage cervical cancer with intermediate- or high-risk factors for recurrence were not fully investigated in prospective studies, but several retrospective studies suggest that the adjuvant effects of chemotherapy alone are at least similar to that of RT or CCRT in terms of recurrence rate, disease-free survival, or overall survival (OS) with lower incidence of complications. Whereas cisplatin based combination regimens were used in these studies, paclitaxel/cisplatin (TP) regimen, which is currently recognized as a standard chemotherapy regimen for patients with metastatic, recurrent or persistent cervical cancer by Gynecologic Oncology Group (GOG), had also survival benefit as an adjuvant therapy. Therefore, it may be worth considering a prospective randomized controlled trial (RCT) of adjuvant chemotherapy alone using TP regimen versus adjuvant RT as an alternative adjuvant therapy. Because early-stage cervical cancer is a curable

  3. Biomarkers of early stage osteoarthritis, rheumatoid arthritis and musculoskeletal health

    PubMed Central

    Ahmed, Usman; Anwar, Attia; Savage, Richard S.; Costa, Matthew L.; Mackay, Nicola; Filer, Andrew; Raza, Karim; Watts, Richard A.; Winyard, Paul G.; Tarr, Joanna; Haigh, Richard C.; Thornalley, Paul J.; Rabbani, Naila

    2015-01-01

    There is currently no biochemical test for detection of early-stage osteoarthritis (eOA). Tests for early-stage rheumatoid arthritis (eRA) such as rheumatoid factor (RF) and anti–cyclic citrullinated peptide (CCP) antibodies require refinement to improve clinical utility. We developed robust mass spectrometric methods to quantify citrullinated protein (CP) and free hydroxyproline in body fluids. We detected CP in the plasma of healthy subjects and surprisingly found that CP was increased in both patients with eOA and eRA whereas anti–CCP antibodies were predominantly present in eRA. A 4-class diagnostic algorithm combining plasma/serum CP, anti-CCP antibody and hydroxyproline applied to a cohort gave specific and sensitive detection and discrimination of eOA, eRA, other non-RA inflammatory joint diseases and good skeletal health. This provides a first-in-class plasma/serum-based biochemical assay for diagnosis and type discrimination of early-stage arthritis to facilitate improved treatment and patient outcomes, exploiting citrullinated protein and related differential autoimmunity. PMID:25788417

  4. Biomarkers of early stage osteoarthritis, rheumatoid arthritis and musculoskeletal health.

    PubMed

    Ahmed, Usman; Anwar, Attia; Savage, Richard S; Costa, Matthew L; Mackay, Nicola; Filer, Andrew; Raza, Karim; Watts, Richard A; Winyard, Paul G; Tarr, Joanna; Haigh, Richard C; Thornalley, Paul J; Rabbani, Naila

    2015-03-19

    There is currently no biochemical test for detection of early-stage osteoarthritis (eOA). Tests for early-stage rheumatoid arthritis (eRA) such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies require refinement to improve clinical utility. We developed robust mass spectrometric methods to quantify citrullinated protein (CP) and free hydroxyproline in body fluids. We detected CP in the plasma of healthy subjects and surprisingly found that CP was increased in both patients with eOA and eRA whereas anti-CCP antibodies were predominantly present in eRA. A 4-class diagnostic algorithm combining plasma/serum CP, anti-CCP antibody and hydroxyproline applied to a cohort gave specific and sensitive detection and discrimination of eOA, eRA, other non-RA inflammatory joint diseases and good skeletal health. This provides a first-in-class plasma/serum-based biochemical assay for diagnosis and type discrimination of early-stage arthritis to facilitate improved treatment and patient outcomes, exploiting citrullinated protein and related differential autoimmunity.

  5. Interleukin-1 (IL-1) signaling in intestinal stromal cells controls KC/ CXCL1 secretion, which correlates with recruitment of IL-22- secreting neutrophils at early stages of Citrobacter rodentium infection.

    PubMed

    Lee, Yong-Soo; Yang, Hyungjun; Yang, Jin-Young; Kim, Yeji; Lee, Su-Hyun; Kim, Ji Heui; Jang, Yong Ju; Vallance, Bruce A; Kweon, Mi-Na

    2015-08-01

    Attaching and effacing pathogens, including enterohemorrhagic Escherichia coli in humans and Citrobacter rodentium in mice, raise serious public health concerns. Here we demonstrate that interleukin-1 receptor (IL-1R) signaling is indispensable for protection against C. rodentium infection in mice. Four days after infection with C. rodentium, there were significantly fewer neutrophils (CD11b+ Ly6C+ Ly6G+) in the colons of IL-1R−/− mice than in wild-type mice. Levels of mRNA and protein of KC/CXCL1 were also significantly reduced in colon homogenates of infected IL-1R−/− mice relative to wild-type mice. Of note, infiltrated CD11b+ Ly6C+ Ly6G+ neutrophils were the main source of IL-22 secretion after C. rodentium infection. Interestingly, intestinal stromal cells isolated from IL-1R−/− mice secreted lower levels of KC/CXCL1 than stromal cells from wild-type mice during C. rodentium infection. Similar effects were found when mouse intestinal stromal cells and human nasal polyp stromal cells were treated with IL-1R antagonists (i.e., anakinra) in vitro. These results suggest that IL-1 signaling plays a pivotal role in activating mucosal stromal cells to secrete KC/CXCL1, which is essential for infiltration of IL-22-secreting neutrophils upon bacterial infection.

  6. Reduced fractional anisotropy in early-stage cerebellar variant of multiple system atrophy.

    PubMed

    Oishi, Kenichi; Konishi, Junya; Mori, Susumu; Ishihara, Hiroyuki; Kawamitsu, Hideaki; Fujii, Masahiko; Kanda, Fumio

    2009-04-01

    In patients with the cerebellar variant of multiple system atrophy (MSA-C), reduced fractional anisotropy (FA) has been reported in several brain areas. However, since previous studies have employed predetermined regions of interest (ROI), the brain areas showing the earliest alterations in FA are unknown. The sensitivity of detecting early-stage MSA-C and the time course of the FA reduction are also unknown. The purpose was to address these issues to determine the diagnostic value of FA for early diagnosis. Twenty-one patients with MSA-C were investigated. Voxel-based FA analysis and morphometry were used to detect the differences between early-stage MSA-C and normal controls. An ROI-based FA analysis was also used to clarify the temporal profile. From the early-stage, MSA-C patients exhibited reduced FA and white matter atrophy in the middle cerebellar peduncle, the inferior cerebellar peduncle, and the ventral pons. The FA of these areas decreased rapidly during the first few years after onset, after which a rather gradual reduction occurred. The receiver operating characteristics analysis revealed a high sensitivity and specificity for discriminating early MSA-C from normal controls. FA measurement could potentially be used to make an early diagnosis and monitor progression in MSA-C patients.

  7. Varying postresection lactate dehydrogenase with overall survival of early stage pancreatic cancer patients

    PubMed Central

    Xiao, Yuanyuan; Xie, Zhihui; Shao, Zhenyi; Chen, Wen; Xie, Hua; Qin, Guoyou; Zhao, Naiqing

    2017-01-01

    Abstract Several previously published studies revealed a hazardous role of pretreatment lactate dehydrogenase (LDH) in survival of advanced or metastatic pancreatic cancer (PC) patients. Nevertheless, in early stage PC patients who are eligible for curative resection, the prognostic role of postresection LDH has never been discussed. In this study, we aimed to explore the prognostic significance of varying postresection LDH among early stage PC patients. In total, 80 PC patients who received curative resection were retrospectively selected from a population-based electronic inpatients database which originated from Shanghai, China. A dynamic survival analysis method, counting process approach in combination with the multiple failure-time Cox model, was applied to evaluate the association between postresection LDH and OS. The multiple failure-time Cox model found that age, resection modality, and postresection LDH were significantly associated with OS: an elevated LDH (defined as > 250 U/L) was related to 2.93 (95% CI: 1.26–6.79) folds of death hazard. Further analysis disclosed an identifiable dose–response association between LDH and OS: compared with LDH≤155 U/L, the HRs for 155 U/L < LDH < 196 U/L, and LDH≥196 U/L were 2.07 (95% CI: 0.88–4.88) and 3.15 (95% CI: 1.30–7.59), respectively. Our study results suggest that postresection LDH is a prominent prognostic factor in this group of early stage PC patients. Maintaining normally ranged LDH after resection might bring about survival benefit in early stage PC patients. PMID:28328834

  8. Varying postresection lactate dehydrogenase with overall survival of early stage pancreatic cancer patients: A retrospective study.

    PubMed

    Xiao, Yuanyuan; Xie, Zhihui; Shao, Zhenyi; Chen, Wen; Xie, Hua; Qin, Guoyou; Zhao, Naiqing

    2017-03-01

    Several previously published studies revealed a hazardous role of pretreatment lactate dehydrogenase (LDH) in survival of advanced or metastatic pancreatic cancer (PC) patients. Nevertheless, in early stage PC patients who are eligible for curative resection, the prognostic role of postresection LDH has never been discussed. In this study, we aimed to explore the prognostic significance of varying postresection LDH among early stage PC patients. In total, 80 PC patients who received curative resection were retrospectively selected from a population-based electronic inpatients database which originated from Shanghai, China. A dynamic survival analysis method, counting process approach in combination with the multiple failure-time Cox model, was applied to evaluate the association between postresection LDH and OS. The multiple failure-time Cox model found that age, resection modality, and postresection LDH were significantly associated with OS: an elevated LDH (defined as > 250 U/L) was related to 2.93 (95% CI: 1.26-6.79) folds of death hazard. Further analysis disclosed an identifiable dose-response association between LDH and OS: compared with LDH≤155 U/L, the HRs for 155 U/L < LDH < 196 U/L, and LDH≥196 U/L were 2.07 (95% CI: 0.88-4.88) and 3.15 (95% CI: 1.30-7.59), respectively. Our study results suggest that postresection LDH is a prominent prognostic factor in this group of early stage PC patients. Maintaining normally ranged LDH after resection might bring about survival benefit in early stage PC patients.

  9. TCM tongue diagnosis index of early-stage breast cancer.

    PubMed

    Lo, Lun-Chien; Cheng, Tsung-Lin; Chen, Yi-Jing; Natsagdorj, Sainbuyan; Chiang, John Y

    2015-10-01

    This paper investigates discriminating tongue features to distinguish between early stage breast cancer (BC) patients and non-breast cancer individuals through non-invasive traditional Chinese medicine (TCM) tongue diagnosis. The tongue features for 67 patients with 0 and 1 stages of BC, and 70 non-breast cancer individuals are extracted by the automatic tongue diagnosis system (ATDS). A total of nine tongue features, namely, tongue color, tongue quality, tongue fissure, tongue fur, red dot, ecchymosis, tooth mark, saliva, and tongue shape are identified for each tongue. Features extracted are further sub-divided according to the areas located, i.e., spleen-stomach, liver-gall-left, liver-gall-right, kidney, and heart-lung areas. This study focuses on deriving significant tongue features (p<0.05) to discriminate early-stage BC patients from non-breast cancer individuals. The Mann-Whitney test shows that the amount of tongue fur (p=0.024), maximum covering area of tongue fur (p=0.009), thin tongue fur (p=0.009), the average area of red dot (p=0.049), the maximum area of red dot (p=0.009), red dot in the spleen-stomach area (p=0.000), and red dot in the heart-lung area (p=0.000) demonstrate significant differences. The data collected are further classified into two groups. The training group consists of 57 early-stage BC patients and 60 non-breast cancer individuals, while the testing group is composed of 10 early-stage BC patients and 10 non-breast cancer individuals. The logistic regression by utilizing these 7 tongue features with significant differences in Mann-Whitney test as factors is performed. In order to reduce the number of tongue features employed in prediction, tongue features with the least amount of significant difference, namely, maximum area of red dot and average area of red dot, are removed progressively. The tongue features of the testing group are employed in the aforementioned three models to test the power of significant tongue features

  10. Stereotactic body radiotherapy for early stage lung cancer: History and updated role.

    PubMed

    Ricardi, Umberto; Badellino, Serena; Filippi, Andrea Riccardo

    2015-12-01

    Stereotactic Body Radiotherapy (SBRT) represents a consolidated treatment option for patients with medically inoperable early stage non-small cell lung cancer (NSCLC). The clinical evidence accumulated over the past decade supports its use as an alternative to surgery with comparable survival outcomes. Due to its limited toxicity, SBRT is also applicable to elderly patients with very poor baseline pulmonary function or other severe comorbidities. Recent comparative studies in operable patients raised the issue of the possible use of SBRT also for this subgroup, with quite promising results that still should be fully confirmed by prospective trials with long-term follow up. In early stage lung cancer, clinicians are now faced with a decision-making process that should take into account different factors. The need of pathological diagnosis and accurate nodal staging still represents a challenge, as well as the interpretation of radiological findings after SBRT, often confusing du to the difficulties in distinguishing between radiation-induced changes and local relapse. Aim of this review is to summarize and discuss the major studies on SBRT for early stage lung cancer, providing data on its efficacy and toxicity and discussing the still open issues on its role. Quality of life, pulmonary function and risk of secondary cancers are also discussed, as well as future perspectives and current research topics. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. Bridging the gap: facilities and technologies for development of early stage therapeutic mAb candidates.

    PubMed

    Munro, Trent P; Mahler, Stephen M; Huang, Edwin P; Chin, David Y; Gray, Peter P

    2011-01-01

    Therapeutic monoclonal antibodies (mAbs) currently dominate the biologics marketplace. Development of a new therapeutic mAb candidate is a complex, multistep process and early stages of development typically begin in an academic research environment. Recently, a number of facilities and initiatives have been launched to aid researchers along this difficult path and facilitate progression of the next mAb blockbuster. Complementing this, there has been a renewed interest from the pharmaceutical industry to reconnect with academia in order to boost dwindling pipelines and encourage innovation. In this review, we examine the steps required to take a therapeutic mAb from discovery through early stage preclinical development and toward becoming a feasible clinical candidate. Discussion of the technologies used for mAb discovery, production in mammalian cells and innovations in single-use bioprocessing is included. We also examine regulatory requirements for product quality and characterization that should be considered at the earliest stages of mAb development. We provide details on the facilities available to help researchers and small-biotech build value into early stage product development, and include examples from within our own facility of how technologies are utilized and an analysis of our client base.

  12. The Neuroprotective Effects of Carnosine in Early Stage of Focal Ischemia Rodent Model

    PubMed Central

    Park, Hui-Seung; Han, Kyung-Hoon; Shin, Jeoung-A; Park, Joo-Hyun; Song, Kwan-Young

    2014-01-01

    Objective This study was conducted to elucidate neuroprotective effect of carnosine in early stage of stroke. Methods Early stage of rodent stroke model and neuroblastoma chemical hypoxia model was established by middle cerebral artery occlusion and antimycin A. Neuroprotective effect of carnosine was investigated with 100, 250, and 500 mg of carnosine treatment. And antioxidant expression was analyzed by enzyme linked immunosorbent assay (ELISA) and western blot in brain and blood. Results Intraperitoneal injection of 500 mg carnosine induced significant decrease of infarct volume and expansion of penumbra (p<0.05). The expression of superoxide dismutase (SOD) showed significant increase than in saline group in blood and brain (p<0.05). In the analysis of chemical hypoxia, carnosine induced increase of neuronal cell viability and decrease of reactive oxygen species (ROS) production. Conclusion Carnosine has neuroprotective property which was related to antioxidant capacity in early stage of stroke. And, the oxidative stress should be considered one of major factor in early ischemic stroke. PMID:24851146

  13. Outcomes of laparoscopic fertility-sparing surgery in clinically early-stage epithelial ovarian cancer

    PubMed Central

    Park, Jin-Young; Lee, Yoo-Young; Kim, Tae-Joong; Kim, Byoung-Gie; Bae, Duk-Soo

    2016-01-01

    Objective Fertility-sparing surgery (FSS) is becoming an important technique in the surgical management of young women with early-stage epithelial ovarian cancer (EOC). We retrospectively evaluated the outcome of laparoscopic FSS in presumed clinically early-stage EOC. Methods We retrospectively searched databases of patients who received laparoscopic FSS for EOC between January 1999 and December 2012 at Samsung Medical Center. Women aged ≤40 years were included. The perioperative, oncological, and obstetric outcomes of these patients were evaluated. Results A total of 18 patients was evaluated. The median age of the patients was 33.5 years (range, 14 to 40 years). The number of patients with clinically stage IA and IC was 6 (33.3%) and 12 (66.7%), respectively. There were 7 (38.9%), 5 (27.8%), 3 (16.7%), and 3 patients (16.7%) with mucinous, endometrioid, clear cell, and serous tumor types, respectively. Complete surgical staging to preserve the uterus and one ovary with adnexa was performed in 4 patients (22.2%). Two out of them were upstaged to The International Federation of Gynecology and Obstetrics stage IIIA1. During the median follow-up of 47.3 months (range, 11.5 to 195.3 months), there were no perioperative or long term surgical complications. Four women (22.2%) conceived after their respective ovarian cancer treatments. Three (16.7%) of them completed full-term delivery and one is expecting a baby. One patient had disease recurrence. No patient died of the disease. Conclusion FSS in young patients with presumed clinically early-stage EOC is a challenging and cautious procedure. Further studies are urgent to determine the safety and feasibility of laparoscopic FSS in young patients with presumed clinically early-stage EOC. PMID:26768783

  14. Factors that influence 12 or more harvested lymph nodes in early-stage colorectal cancer.

    PubMed

    Hsu, Chao-Wen; Lin, Chieh-Hsin; Wang, Jui-Ho; Wang, Hsin-Tai; Ou, Wen-Chieh; King, Tai-Ming

    2009-02-01

    The number of lymph nodes required for accurate staging is a critical component in early-stage (stage A and B) colorectal cancer (CRC). Current guidelines demand at least 12 lymph nodes to be retrieved. Results of previous studies were contradictory in factors, which influenced the number of harvested lymph nodes. This study was designed to determine the factors that influence the number of harvested lymph nodes (> or =12) in early-stage CRC in a single institution. Between 2003 and 2007, data on patients who underwent surgery for early-stage CRC were analyzed retrospectively. Data for a total of 470 patients were collected and all the tumor-bearing specimens were fixed with node identification performed. Several possible factors that influence 12 or more harvested lymph nodes were investigated and classified into four aspects: (1) operating surgeon, (2) examining pathologist, (3) patient (age, sex, and body mass index), and (4) disease (maximal length of tumor, length of specimen, tumor localization, tumor cell differentiation, Dukes stage, type of resection, and type of tumor). A total of 289 patients (61.5%) with 12 or more harvested lymph nodes and 181 patients (38.5%) with < 12 lymph nodes were analyzed. The results demonstrate that within a single institution the maximal length of tumor, tumor localization, and depth of tumor invasion according to Dukes stage were independent influencing factors of 12 or more harvested lymph nodes. Maximal length of tumor was associated with more harvested lymph nodes (P < 0.001). Neither the operating surgeon nor the examining pathologist had significant influence on the number of harvested lymph nodes. The number of harvested lymph nodes was highly variable in patients who underwent resection of early-stage CRC. Neither the operating surgeon nor the examining pathologist had significant influence on the number of harvested lymph nodes. Therefore, from the viewpoint of the surgeons, disease itself is the most important

  15. NR2F6 Expression Correlates with Pelvic Lymph Node Metastasis and Poor Prognosis in Early-Stage Cervical Cancer.

    PubMed

    Niu, Chunhao; Sun, Xiaoying; Zhang, Weijing; Li, Han; Xu, Liqun; Li, Jun; Xu, Benke; Zhang, Yanna

    2016-10-20

    There is an abnormal expression of nuclear receptor subfamily 2 group F member 6 (NR2F6) in human cancers such as breast cancer, colon cancer, and acute myelogenous leukemia. However, its clinical significance in cervical cancer has not been established. We explored NR2F6 expression and its clinicopathological significance in early-stage cervical cancer. NR2F6 expression in cervical cancer cell lines and cervical cancer tissues was determined by Western blotting, real-time PCR, and immunochemistry (IHC). NR2F6 expression in 189 human early-stage cervical cancer tissue samples was evaluated using IHC. The relevance between NR2F6 expression and early-stage cervical cancer prognosis and clinicopathological features was determined. There was marked NR2F6 mRNA and protein overexpression in the cervical cancer cells and clinical tissues compared with an immortalized squamous cell line and adjacent noncancerous cervical tissues, respectively. In the 189 cervical cancer samples, NR2F6 expression was positively related to International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.006), squamous cell carcinoma antigen (p = 0.006), vital status (p < 0.001), tumor recurrence (p = 0.001), chemotherapy (p = 0.039), and lymph node metastasis (p < 0.001). Overall and disease-free survival was shorter in patients with early-stage cervical cancer and higher NR2F6 levels than in patients with lower levels of NR2F6. Univariate and multivariate analysis determined that NR2F6 was an independent prognostic factor of survival in early-stage cervical cancer. Taken together, our findings suggest that high NR2F6 expression predicts pelvic lymph node metastasis, tumor recurrence and poor prognosis in early-stage cervical cancer. NR2F6 might be a novel prognostic biomarker and potential therapeutic target of cervical cancer.

  16. NR2F6 Expression Correlates with Pelvic Lymph Node Metastasis and Poor Prognosis in Early-Stage Cervical Cancer

    PubMed Central

    Niu, Chunhao; Sun, Xiaoying; Zhang, Weijing; Li, Han; Xu, Liqun; Li, Jun; Xu, Benke; Zhang, Yanna

    2016-01-01

    Background: There is an abnormal expression of nuclear receptor subfamily 2 group F member 6 (NR2F6) in human cancers such as breast cancer, colon cancer, and acute myelogenous leukemia. However, its clinical significance in cervical cancer has not been established. We explored NR2F6 expression and its clinicopathological significance in early-stage cervical cancer. Methods: NR2F6 expression in cervical cancer cell lines and cervical cancer tissues was determined by Western blotting, real-time PCR, and immunochemistry (IHC). NR2F6 expression in 189 human early-stage cervical cancer tissue samples was evaluated using IHC. The relevance between NR2F6 expression and early-stage cervical cancer prognosis and clinicopathological features was determined. Results: There was marked NR2F6 mRNA and protein overexpression in the cervical cancer cells and clinical tissues compared with an immortalized squamous cell line and adjacent noncancerous cervical tissues, respectively. In the 189 cervical cancer samples, NR2F6 expression was positively related to International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.006), squamous cell carcinoma antigen (p = 0.006), vital status (p < 0.001), tumor recurrence (p = 0.001), chemotherapy (p = 0.039), and lymph node metastasis (p < 0.001). Overall and disease-free survival was shorter in patients with early-stage cervical cancer and higher NR2F6 levels than in patients with lower levels of NR2F6. Univariate and multivariate analysis determined that NR2F6 was an independent prognostic factor of survival in early-stage cervical cancer. Conclusions: Taken together, our findings suggest that high NR2F6 expression predicts pelvic lymph node metastasis, tumor recurrence and poor prognosis in early-stage cervical cancer. NR2F6 might be a novel prognostic biomarker and potential therapeutic target of cervical cancer. PMID:27775588

  17. Investigations into Retinal Pathology in the Early Stages of a Mouse Model of Alzheimer’s Disease

    PubMed Central

    Chidlow, Glyn; Wood, John P.M.; Manavis, Jim; Finnie, John; Casson, Robert J.

    2016-01-01

    There is increasing recognition that visual performance is impaired in early stages of Alzheimer’s disease (AD); however, no consensus exists as to the mechanisms underlying this visual dysfunction, in particular regarding the timing, nature, and extent of retinal versus cortical pathology. If retinal pathology presents sufficiently early, it offers great potential as a source of novel biomarkers for disease diagnosis. The current project utilized an array of immunochemical and molecular tools to perform a characterization of retinal pathology in the early stages of disease progression using a well-validated mouse model of AD (APPSWE/PS1ΔE9). Analytical endpoints included examination of aberrant amyloid and tau in the retina, quantification of any neuronal degeneration, delineation of cellular stress responses of neurons and particularly glial cells, and investigation of oxidative stress. Brain, eyes, and optic nerves were taken from transgenic and wild-type mice of 3 to 12 months of age and processed for immunohistochemistry, qPCR, or western immunoblotting. The results revealed robust expression of the human APP transgene in the retinas of transgenic mice, but a lack of identifiable retinal pathology during the period when amyloid deposits were dramatically escalating in the brain. We were unable to demonstrate the presence of amyloid plaques, dystrophic neurites, neuronal loss, macro- or micro-gliosis, aberrant cell cycle re-entry, oxidative stress, tau hyperphosphorylation, or upregulations of proinflammatory cytokines or stress signaling molecules in the retina. The overall results do not support the hypothesis that detectable retinal pathology occurs concurrently with escalating amyloid deposition in the brains of APPSWE/PS1ΔE9 mice. PMID:28035930

  18. Dynamic migration and cell-cell interactions of early reprogramming revealed by high resolution time-lapse imaging

    PubMed Central

    Megyola, Cynthia M.; Gao, Yuan; Teixeira, Alexandra M.; Cheng, Jijun; Heydari, Kartoosh; Cheng, Ee-chun; Nottoli, Timothy; Krause, Diane S.; Lu, Jun; Guo, Shangqin

    2014-01-01

    Discovery of the cellular and molecular mechanisms of induced pluripotency has been hampered by its low efficiency and slow kinetics. Here, we report an experimental system with multi-color time-lapse microscopy that permits direct observation of pluripotency induction at single cell resolution, with temporal intervals as short as five minutes. Using granulocyte-monocyte progenitors as source cells, we visualized nascent pluripotent cells emerge from a hematopoietic state. We engineered a suite of image processing and analysis software to annotate the behaviors of the reprogramming cells, which revealed the highly dynamic cell-cell interactions associated with early reprogramming. We observed frequent cell migration, which can lead to sister colonies, satellite colonies and colonies of mixed genetic makeup. In addition, we discovered a previously unknown morphologically distinct 2-cell intermediate of reprogramming, which occurs prior to other reprogramming landmarks. By directly visualizing the reprogramming process with E-cadherin inhibition, we demonstrate the requirement of E-cadherin for proper cellular interactions from an early stage of reprogramming, including the 2-cell intermediate. The detailed cell-cell interactions revealed by this imaging platform shed light on previously unappreciated early reprogramming dynamics. This experimental system could serve as a powerful tool to dissect the complex mechanisms of early reprogramming by focusing on the relevant but rare cells with superb temporal and spatial resolution. PMID:23335078

  19. Development of a New Outcome Prediction Model in Early-stage Squamous Cell Carcinoma of the Oral Cavity Based on Histopathologic Parameters With Multivariate Analysis: The Aditi-Nuzhat Lymph-node Prediction Score (ANLPS) System.

    PubMed

    Arora, Aditi; Husain, Nuzhat; Bansal, Ankur; Neyaz, Azfar; Jaiswal, Ritika; Jain, Kavitha; Chaturvedi, Arun; Anand, Nidhi; Malhotra, Kiranpreet; Shukla, Saumya

    2017-07-01

    The aim of this study was to evaluate the histopathologic parameters that predict lymph node metastasis in patients with oral squamous cell carcinoma (OSCC) and to design a new assessment score on the basis of these parameters that could ultimately allow for changes in treatment decisions or aid clinicians in deciding whether there is a need for close follow-up or to perform early lymph node dissection. Histopathologic parameters of 336 cases of OSCC with stage cT1/T2 N0M0 disease were analyzed. The location of the tumor and the type of surgery used for the management of the tumor were recorded for all patients. The parameters, including T stage, grading of tumor, tumor budding, tumor thickness, depth of invasion, shape of tumor nest, lymphoid response at tumor-host interface and pattern of invasion, eosinophilic reaction, foreign-body giant cell reaction, lymphovascular invasion, and perineural invasion, were examined. Ninety-two patients had metastasis in lymph nodes. On univariate and multivariate analysis, independent variables for predicting lymph node metastasis in descending order were depth of invasion (P=0.003), pattern of invasion (P=0.007), perineural invasion (P=0.014), grade (P=0.028), lymphovascular invasion (P=0.038), lymphoid response (P=0.037), and tumor budding (P=0.039). We designed a scoring system on the basis of these statistical results and tested it. Cases with scores ranging from 7 to 11, 12 to 16, and ≥17 points showed LN metastasis in 6.4%, 22.8%, and 77.1% of cases, respectively. The difference between these 3 groups in relation to nodal metastasis was very significant (P<0.0001). A patient at low risk for lymph node metastasis (score, 7 to 11) had a 5-year survival of 93%, moderate-risk patients (score, 12 to 16) had a 5-year survival of 67%, and high-risk patients (score, 17 to 21) had a 5-year survival of 39%. The risk of lymph node metastasis in OSCC is influenced by many histologic parameters that are not routinely analyzed in

  20. The influence of TP53 mutations on the prognosis of patients with early stage non-small cell lung cancer may depend on the intratumor heterogeneity of the mutations.

    PubMed

    Lee, Shin Yup; Jeon, Hyo-Sung; Hwangbo, Yup; Jeong, Ji Yun; Park, Ji Young; Lee, Eun Jin; Jin, Guang; Shin, Kyung Min; Yoo, Seung Soo; Lee, Jaehee; Lee, Eung Bae; Cha, Seung Ick; Kim, Chang Ho; Park, Jae Yong

    2015-02-01

    A large number of studies have evaluated the impact of TP53 mutations on the prognosis of patients with non-small cell lung cancer (NSCLC); however, the results of these studies are still controversial. Recently, considerable intratumor heterogeneity for genetic alterations has been demonstrated in various human cancers, including lung cancer. In the present study, we evaluated TP53 mutations in NSCLCs by direct sequencing and observed remarkable variation in the values of relative intensity (RI, the height of the peak of mutated allele/the height of the peak of non-mutated allele) of the mutations. We also examined whether the RI values were associated with intratumor heterogeneity of TP53 mutations. In addition, we evaluated the relationship between TP53 mutations and survival outcome. The patients with a TP53 mutation did not have significantly worse survival compared to those without the mutation. However, when tumors with a TP53 mutation were categorized into two groups, those with a low and those with a high RI, the latter group had significantly worse survival compared to those with wild-type TP53 (adjusted hazard ratio = 2.58, 95% confidence interval = 1.21-5.48, P = 0.01), whereas the former group did not. These results suggest that intratumor genetic heterogeneity may be an important factor in determining the role of TP53 mutations on the prognosis of NSCLC patients.

  1. Pooled Analysis of the Prognostic and Predictive Effects of TP53 Comutation Status Combined With KRAS or EGFR Mutation in Early-Stage Resected Non-Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy.

    PubMed

    Shepherd, Frances A; Lacas, Benjamin; Le Teuff, Gwénaël; Hainaut, Pierre; Jänne, Pasi A; Pignon, Jean-Pierre; Le Chevalier, Thierry; Seymour, Lesley; Douillard, Jean-Yves; Graziano, Stephen; Brambilla, Elizabeth; Pirker, Robert; Filipits, Martin; Kratzke, Robert; Soria, Jean-Charles; Tsao, Ming-Sound

    2017-06-20

    Purpose Our previous work evaluated individual prognostic and predictive roles of TP53, KRAS, and EGFR in non-small-cell lung cancer (NSCLC). In this analysis, we explore the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations in randomized trials of adjuvant chemotherapy versus observation. Patients and Methods Mutation analyses (wild-type [WT] and mutant) for TP53, KRAS, and EGFR were determined in blinded fashion in multiple laboratories. Primary and secondary end points of pooled analysis were overall survival and disease-free survival. We evaluated the role of TP53/KRAS comutation in all patients and in the adenocarcinoma subgroup as well as the TP53/EGFR comutation in adenocarcinoma only through a multivariable Cox proportional hazards model stratified by trial. Results Of 3,533 patients with NSCLC, 1,181 (557 deaths) and 404 (170 deaths) were used for TP53/KRAS and TP53/EGFR analyses. For TP53/KRAS mutation status, no prognostic effect was observed ( P = .61), whereas a borderline predictive effect ( P = .04) was observed with a deleterious effect of chemotherapy with TP53/KRAS comutations versus WT/WT (hazard ratio, 2.49 [95% CI, 1.10 to 5.64]; P = .03). TP53/EGFR comutation in adenocarcinoma was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival. Conclusion We could identify no prognostic effect of the KRAS or EGFR driver and TP53 tumor suppressor comutation. Our observation of a potential negative predictive effect of TP53/KRAS comutation requires validation.

  2. Robot-assisted Supraomohyoid neck dissection via a modified face-lift or retroauricular approach in early-stage cN0 squamous cell carcinoma of the oral cavity: a comparative study with conventional technique.

    PubMed

    Lee, Hyoung Shin; Kim, Won Shik; Hong, Hyun Jun; Ban, Myung Jin; Lee, Dongwon; Koh, Yoon Woo; Choi, Eun Chang

    2012-11-01

    Supraomohyoid neck dissection (SOND) in clinical N0 (cN0) neck of oral cavity squamous cell carcinoma (SCC) is performed by many head and neck surgeons showing improved regional control and disease-specific survival. However, disfiguring neck scars have been accepted to be unavoidable. In this study, we sought to introduce and evaluate the feasibility of our surgical technique to hide the external scar of neck dissection using the robotic system via a modified face-lift or retroauricular approach. Twenty-six patients with cN0 oral cavity SCC were divided into two groups of robot-assisted neck dissection and conventional neck dissection via external cervical incision. The operation time, amount and duration of drainage, length of hospital stay, complications, number of retrieved lymph nodes, and satisfaction scores were compared. Mean operation time was longer in the robot-assisted group (157 ± 22 min) than the conventional group (78 ± 16 min) (P < 0.001). However, the amount and duration of drainage, hospital stay, retrieved lymph nodes, and complications were comparable. Because the postoperative scar was hidden by the auricle and hair, the satisfaction score was significantly higher in the robot-assisted group (P < 0.001). Robot-assisted SOND via a modified face-lift or retroauricular approach in cN0 oral cavity SCC was feasible compared to conventional technique and showed a clear cosmetic benefit. Longer operation time remains the drawback of this procedure. However, it could be considered for patients who require SOND and prefer to avoid external neck scar.

  3. Short report: interim safety results for a phase II trial measuring the integration of stereotactic ablative radiotherapy (SABR) plus surgery for early stage non-small cell lung cancer (MISSILE-NSCLC).

    PubMed

    Palma, David A; Nguyen, Timothy K; Kwan, Keith; Gaede, Stewart; Landis, Mark; Malthaner, Richard; Fortin, Dalilah; Louie, Alexander V; Frechette, Eric; Rodrigues, George B; Yaremko, Brian; Yu, Edward; Dar, A Rashid; Lee, Ting-Yim; Gratton, Al; Warner, Andrew; Ward, Aaron; Inculet, Richard

    2017-01-27

    A phase II trial was launched to evaluate if neoadjuvant stereotactic ablative radiotherapy (SABR) before surgery improves oncologic outcomes in patients with stage I non-small cell lung cancer (NSCLC). We report a mandated interim safety analysis for the first 10 patients who completed protocol treatment. Operable patients with biopsy-proven T1-2 N0 NSCLC were eligible. SABR was delivered using a risk-adapted fractionation (54Gy/3 fractions, 55/5 or 60/8). Surgical resection was planned 10 weeks later at a high-volume center (>200 lung cancer resections annually). Patients were imaged with dynamic positron emission tomography-computed tomography scans using (18)F-fludeoxyglucose ((18)F-FDG-PET CT) and dynamic contrast-enhanced CT before SABR and again before surgery. Toxicity was recorded using CTCAE version 4.0. Twelve patients were enrolled between 09/2014 and 09/2015. Two did not undergo surgery, due to patient or surgeon preference; neither patient has developed toxicity or recurrence. For the 10 patients completing both treatments, median age was 70 (range: 54-76), 60% had T1 disease, and 60% had adenocarcinoma. Median FEV1 was 73% predicted (range: 54-87%). Median time to surgery post-SABR was 10.1 weeks (range: 9.3-15.6 weeks). Surgery consisted of lobectomy (n = 8) or wedge resection (n = 2). Median follow-up post-SABR was 6.3 months. After combined treatment, the rate of acute grade 3-4 toxicity was 10%. There was no post-operative mortality at 90 days. The small sample size included herein precludes any definitive conclusions regarding overall toxicity rates until larger datasets are available. However, these data may inform others who are designing or conducting similar trials. NCT02136355 . Registered 8 May 2014.

  4. Inflammation in the early stages of neurodegenerative pathology

    PubMed Central

    Khandelwal, Preeti J.; Herman, Alexander M.; Moussa, Charbel E-H

    2011-01-01

    Inflammation is secondary to protein accumulation in neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Amyotrophic Lateral Sclerosis. Emerging evidence indicate sustained inflammatory responses, involving microglia and astrocytes in animal models of neurodegeneration. It is unknown whether inflammation is beneficial or detrimental to disease progression and how inflammatory responses are induced within the CNS. Persistence of an inflammatory stimulus or failure to resolve sustained inflammation can result in pathology, thus, mechanisms that counteract inflammation are indispensable. Here we review studies on inflammation mediated by innate and adaptive immunity in the early stages of neurodegeneration and highlight important areas for future investigation. PMID:21820744

  5. Pooled Analysis of the Prognostic and Predictive Effects of KRAS Mutation Status and KRAS Mutation Subtype in Early-Stage Resected Non–Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy

    PubMed Central

    Shepherd, Frances A.; Domerg, Caroline; Hainaut, Pierre; Jänne, Pasi A.; Pignon, Jean-Pierre; Graziano, Stephen; Douillard, Jean-Yves; Brambilla, Elizabeth; Le Chevalier, Thierry; Seymour, Lesley; Bourredjem, Abderrahmane; Teuff, Gwénaël Le; Pirker, Robert; Filipits, Martin; Rosell, Rafael; Kratzke, Robert; Bandarchi, Bizhan; Ma, Xiaoli; Capelletti, Marzia; Soria, Jean-Charles; Tsao, Ming-Sound

    2013-01-01

    Purpose We undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non–small-cell lung cancer (NSCLC). Methods KRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model. Results Among 1,543 patients (763 OBS, 780 ACT), 300 had KRAS mutations (codon 12, n = 275; codon 13, n = 24; codon 14, n = 1). In OBS patients, there was no prognostic difference for overall survival for codon-12 (mutation v wild type [WT] hazard ratio [HR] = 1.04; 95% CI, 0.77 to 1.40) or codon-13 (HR = 1.01; 95% CI, 0.47 to 2.17) mutations. No significant benefit from ACT was observed for WT-KRAS (ACT v OBS HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) or codon-12 mutations (HR = 0.95; 95% CI, 0.67 to 1.35; P = .77); with codon-13 mutations, ACT was deleterious (HR = 5.78; 95% CI, 2.06 to 16.2; P < .001; interaction P = .002). There was no prognostic effect for specific codon-12 amino acid substitution. The effect of ACT was variable among patients with codon-12 mutations: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02). Conclusion KRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT. PMID:23630215

  6. Stereotactic Ablative Radiation Therapy for Centrally Located Early Stage or Isolated Parenchymal Recurrences of Non-Small Cell Lung Cancer: How to Fly in a “No Fly Zone”

    SciTech Connect

    Chang, Joe Y.; Li, Qiao-Qiao; Xu, Qing-Yong; Allen, Pamela K.; Rebueno, Neal; Gomez, Daniel R.; Balter, Peter; Komaki, Ritsuko; Mehran, Reza; Swisher, Stephen G.; Roth, Jack A.

    2014-04-01

    Purpose: We extended our previous experience with stereotactic ablative radiation therapy (SABR; 50 Gy in 4 fractions) for centrally located non-small cell lung cancer (NSCLC); explored the use of 70 Gy in 10 fractions for cases in which dose-volume constraints could not be met with the previous regimen; and suggested modified dose-volume constraints. Methods and Materials: Four-dimensional computed tomography (4DCT)-based volumetric image-guided SABR was used for 100 patients with biopsy-proven, central T1-T2N0M0 (n=81) or isolated parenchymal recurrence of NSCLC (n=19). All disease was staged with positron emission tomography/CT; all tumors were within 2 cm of the bronchial tree, trachea, major vessels, esophagus, heart, pericardium, brachial plexus, or vertebral body. Endpoints were toxicity, overall survival (OS), local and regional control, and distant metastasis. Results: At a median follow-up time of 30.6 months, median OS time was 55.6 months, and the 3-year OS rate was 70.5%. Three-year cumulative actuarial local, regional, and distant control rates were 96.5%, 87.9%, and 77.2%, respectively. The most common toxicities were chest-wall pain (18% grade 1, 13% grade 2) and radiation pneumonitis (11% grade 2 and 1% grade 3). No patient experienced grade 4 or 5 toxicity. Among the 82 patients receiving 50 Gy in 4 fractions, multivariate analyses showed mean total lung dose >6 Gy, V{sub 20} >12%, or ipsilateral lung V{sub 30} >15% to independently predict radiation pneumonitis; and 3 of 9 patients with brachial plexus D{sub max} >35 Gy experienced brachial neuropathy versus none of 73 patients with brachial D{sub max} <35 Gy (P=.001). Other toxicities were analyzed and new dose-volume constraints are proposed. Conclusions: SABR for centrally located lesions produces clinical outcomes similar to those for peripheral lesions when normal tissue constraints are respected.

  7. WE-G-BRD-06: Variation in Dynamic Positron Emission Tomography Imaging of Tumor Hypoxia in Early Stage Non-Small Cell Lung Cancer Patients Undergoing Stereotactic Body Radiotherapy

    SciTech Connect

    Kelada, O; Decker, R; Rockwell, S; Carlson, D; Zheng, M; Huang, Y; Xia, Y; Gallezot, J; Liu, C; Carson, R; Oelfke, U

    2014-06-15

    Purpose: Tumor hypoxia is correlated with treatment failure. To date, there are no published studies investigating hypoxia in non-small cell lung cancer (NSCLC) patients undergoing SBRT. We aim to use 18F-fluoromisonidazole (18F-FMISO) positron emission tomography (PET) imaging to non-invasively quantify the tumor hypoxic volume (HV), to elucidate potential roles of reoxygenation and tumor vascular response at high doses, and to identify an optimal prognostic imaging time-point. Methods: SBRT-eligible patients with NSCLC tumors >1cm were prospectively enrolled in an IRB-approved study. Computed Tomography and dynamic PET images (0–120min, 150–180min, and 210–240min post-injection) were acquired using a Siemens BiographmCT PET/CT scanner. 18F-FMISO PET was performed on a single patient at 3 different time points around a single SBRT delivery of 18 Gy and HVs were compared using a tumor-to-blood ratio (TBR)>1.2 and rate of influx (Ki)>0.0015 (Patlak). Results: Results from our first patient showed substantial temporal changes in HV following SBRT. Using a TBR threshold >1.2 and summed images 210–240min, the HVs were 19%, 31% and 13% of total tumor volume on day 0, 2 (48 hours post-SBRT), and 4 (96 hours post-SBRT). The absolute volume of hypoxia increased by nearly a factor of 2 after 18 Gy and then decreased almost to baseline 96 hours later. Selected imaging timepoints resulted in temporal changes in HV quantification obtained with TBR. Ki, calculated using 4-hour dynamic data, evaluated HVs as 22%, 75% and 21%, respectively. Conclusions: ith the results of only one patient, this novel pilot study highlights the potential benefit of 18F-FMISO PET imaging as results indicate substantial temporal changes in tumor HV post-SBRT. Analysis suggests that TBR is not a robust parameter for accurate HV quantification and heavily influenced by imaging timepoint selection. Kinetic modeling parameters are more sensitive and may aid in future treatment individualization

  8. Mapping Thalamocortical Functional Connectivity in Chronic and Early Stages of Psychotic Disorders.

    PubMed

    Woodward, Neil D; Heckers, Stephan

    2016-06-15

    There is considerable evidence that the thalamus is abnormal in psychotic disorders. Resting-state functional magnetic resonance imaging has revealed an intriguing pattern of thalamic dysconnectivity in psychosis characterized by reduced prefrontal cortex (PFC) connectivity and increased somatomotor-thalamic connectivity. However, critical knowledge gaps remain with respect to the onset, anatomical specificity, and clinical correlates of thalamic dysconnectivity in psychosis. Resting-state functional magnetic resonance imaging was collected on 105 healthy subjects and 148 individuals with psychosis, including 53 early-stage psychosis patients. Using all 253 subjects, the thalamus was parceled into functional regions of interest (ROIs) on the basis of connectivity with six a priori defined cortical ROIs covering most of the cortical mantle. Functional connectivity between each cortical ROI and its corresponding thalamic ROI was quantified and compared across groups. Significant differences in the ROI-to-ROI analysis were followed up with voxelwise seed-based analyses to further localize thalamic dysconnectivity. ROI analysis revealed reduced PFC-thalamic connectivity and increased somatomotor-thalamic connectivity in both chronic and early-stage psychosis patients. PFC hypoconnectivity and motor cortex hyperconnectivity correlated in patients, suggesting that they result from a common pathophysiological mechanism. Seed-based analyses revealed thalamic hypoconnectivity in psychosis localized to dorsolateral PFC, medial PFC, and cerebellar areas of the well-described executive control network. Across all subjects, thalamic connectivity with areas of the fronto-parietal network correlated with cognitive functioning, including verbal learning and memory. Thalamocortical dysconnectivity is present in both chronic and early stages of psychosis, includes reduced thalamic connectivity with the executive control network, and is related to cognitive impairment. Copyright

  9. Circulating ECV-Associated miRNAs as Potential Clinical Biomarkers in Early Stage HBV and HCV Induced Liver Fibrosis

    PubMed Central

    Lambrecht, Joeri; Jan Poortmans, Pieter; Verhulst, Stefaan; Reynaert, Hendrik; Mannaerts, Inge; van Grunsven, Leo A.

    2017-01-01

    Introduction: Chronic hepatitis B (HBV) and C (HCV) virus infection is associated with the activation of hepatic stellate cells (HSCs) toward a myofibroblastic phenotype, resulting in excessive deposition of extracellular matrix, the development of liver fibrosis, and its progression toward cirrhosis. The gold standard for the detection and staging of liver fibrosis remains the liver biopsy, which is, however, associated with some mild and severe drawbacks. Other non-invasive techniques evade these drawbacks, but lack inter-stage specificity and are unable to detect early stages of fibrosis. We investigated whether circulating vesicle-associated miRNAs can be used in the diagnosis and staging of liver fibrosis in HBV and HCV patients. Methods: Plasma samples were obtained from 14 healthy individuals and 39 early stage fibrotic patients (F0–F2) with chronic HBV or HCV infection who underwent transient elastography (Fibroscan). Extracellular vesicles were extracted from the plasma and the level of miRNA-122, -150, -192, -21, -200b, and -92a was analyzed by qRT-PCR in total plasma and circulating vesicles. Finally, these same miRNAs were also quantified in vesicles extracted from in vitro activating primary HSCs. Results: In total plasma samples, only miRNA-200b (HBV: p = 0.0384; HCV: p = 0.0069) and miRNA-122 (HBV: p < 0.0001; HCV: p = 0.0007) were significantly up-regulated during early fibrosis. In circulating vesicles, miRNA-192 (HBV: p < 0.0001; HCV: p < 0.0001), -200b (HBV: p < 0.0001; HCV: p < 0.0001), -92a (HBV: p < 0.0001; HCV: p < 0.0001), and -150 (HBV: p = 0.0016; HCV: p = 0.004) displayed a significant down-regulation in both HBV and HCV patients. MiRNA expression profiles in vesicles isolated from in vitro activating primary mouse HSCs resembled the miRNA expression profile in circulating vesicles. Conclusion: Our analysis revealed a distinct miRNA expression pattern in total plasma and its circulating vesicles. The expression profile of miRNAs in

  10. Circulating ECV-Associated miRNAs as Potential Clinical Biomarkers in Early Stage HBV and HCV Induced Liver Fibrosis.

    PubMed

    Lambrecht, Joeri; Jan Poortmans, Pieter; Verhulst, Stefaan; Reynaert, Hendrik; Mannaerts, Inge; van Grunsven, Leo A

    2017-01-01

    Introduction: Chronic hepatitis B (HBV) and C (HCV) virus infection is associated with the activation of hepatic stellate cells (HSCs) toward a myofibroblastic phenotype, resulting in excessive deposition of extracellular matrix, the development of liver fibrosis, and its progression toward cirrhosis. The gold standard for the detection and staging of liver fibrosis remains the liver biopsy, which is, however, associated with some mild and severe drawbacks. Other non-invasive techniques evade these drawbacks, but lack inter-stage specificity and are unable to detect early stages of fibrosis. We investigated whether circulating vesicle-associated miRNAs can be used in the diagnosis and staging of liver fibrosis in HBV and HCV patients. Methods: Plasma samples were obtained from 14 healthy individuals and 39 early stage fibrotic patients (F0-F2) with chronic HBV or HCV infection who underwent transient elastography (Fibroscan). Extracellular vesicles were extracted from the plasma and the level of miRNA-122, -150, -192, -21, -200b, and -92a was analyzed by qRT-PCR in total plasma and circulating vesicles. Finally, these same miRNAs were also quantified in vesicles extracted from in vitro activating primary HSCs. Results: In total plasma samples, only miRNA-200b (HBV: p = 0.0384; HCV: p = 0.0069) and miRNA-122 (HBV: p < 0.0001; HCV: p = 0.0007) were significantly up-regulated during early fibrosis. In circulating vesicles, miRNA-192 (HBV: p < 0.0001; HCV: p < 0.0001), -200b (HBV: p < 0.0001; HCV: p < 0.0001), -92a (HBV: p < 0.0001; HCV: p < 0.0001), and -150 (HBV: p = 0.0016; HCV: p = 0.004) displayed a significant down-regulation in both HBV and HCV patients. MiRNA expression profiles in vesicles isolated from in vitro activating primary mouse HSCs resembled the miRNA expression profile in circulating vesicles. Conclusion: Our analysis revealed a distinct miRNA expression pattern in total plasma and its circulating vesicles. The expression profile of miRNAs in

  11. A case of painless thyroiditis in a very early stage of pregnancy.

    PubMed

    Sato, Shiori; Endo, Kei; Iizaka, Toru; Saiki, Ryo; Iwaku, Kenji; Sato, Shotaro; Takahashi, Yasuyoshi; Otsuka, Fumiko; Taniyama, Matsuo

    2012-01-01

    We report a case of painless thyroiditis detected during the first trimester of pregnancy. A 29-year-old Japanese woman was hospitalized because of thyrotoxicosis and she was confirmed to be pregnant. The gestational age was 4 weeks. Blood examinations revealed negative TSH receptor antibodies, however, we started potassium iodide because we were unable to rule out Graves' disease. Thyroid hormone levels were normalized in 3 weeks and remained low even after discontinuation of medication. She received replacement therapy with levothyroxine sodium hydrate till 3 months after delivery. Painless thyroiditis can be one of the differential diagnoses of thyrotoxicosis in a very early stage of pregnancy.

  12. Early stages during plasma nitriding of pure iron

    SciTech Connect

    Palacios, M.D.; Martinez, O.; Oseguera, J.

    1995-12-31

    The sequence of nitride formation during the early stages of plasma nitriding of pure iron was studied by optical microscopy, SEM, TEM and x-ray diffraction. Plasma nitriding at {approximately}490 C in a 25 vol.%H{sub 2} + 75 vol.%N{sub 2} mixture starts with the formation of {gamma}{prime}-Fe{sub 4}N after 40s. Once {gamma}{prime} nucleates, it mainly spreads laterally due to diffusion shortcuts in the discontinuous surface nitride layer. Before {gamma}{prime} is continuous on the surface, {epsilon} nucleates on top of it shortly after 40S. Epsilon is then observed to grow, both inwardly and laterally along with {gamma}{prime}. A compact {gamma}{prime}/{epsilon} bilayer forms on the surface at around 100s. The kinetics of nucleation, growth and compactation of the nitrides observed in the present work was significantly more rapid than in any of the nitriding process reported in the literature, including plasma nitriding. The acceleration of the nitriding kinetics in the early stages of plasma nitriding may be attributed to enhanced diffusion resulting from a high nitrogen flux from the plasma atmosphere. The results presented are consistent with the findings of a companion work on modeling the kinetics of nitride layer growth.

  13. Oral propranolol in early stages of retinopathy of prematurity.

    PubMed

    Bancalari, Aldo; Schade, Ricardo; Muñoz, Tomás; Lazcano, Carolina; Parada, Rodrigo; Peña, Rubén

    2016-07-01

    To assess the effect of oral propranolol on the progression of early stages of retinopathy of prematurity (ROP) in very low birth weight (VLBW) infants. We analyzed VLBW infants with ROP (stages 2-3, zones II-III). Newborns received oral propranolol (0.5 mg/kg/dose q8h), and were monitored throughout the treatment period for possible side effects. Propranolol was administered until regression of ROP. A historic control group of patients with equivalent ROP was used. We compared characteristics of both groups and the progression of retinopathy. Forty-seven newborns were included, 20 in the propranolol group and 27 in the control group. There were no significant differences in gestational age, birthweight or gender. The mean duration of treatment with propranolol was 58.2±17.6 days. Most patients started treatment with stage 2 disease (65.0%), and had zone III involvement (55.0%). In the treated group, 90.0% (18/20) of patients did not require intervention with laser or bevacizumab, compared to 51.8% in the control group (P<0.005). No cases of bradycardia, hypotension or hypoglycemia were observed. Oral propranolol in early stages of ROP could prevent disease progression and reduce the need for invasive rescue therapy with laser or bevacizumab. No significant side effects were reported.

  14. Radical Hysterectomy for Early Stage Cervical Cancer: Laparoscopy Versus Laparotomy

    PubMed Central

    McBee, William C.; Richard, Scott D.; Edwards, Robert P.

    2011-01-01

    Objectives: Gynecologic oncologists have recently begun using laparoscopic techniques to treat early stage cervical cancer. We evaluated a single institution's experience of laparoscopic radical hysterectomy and staging compared with laparotomy. Methods: A retrospective chart review identified stage IA2 and IB1 cervical cancer patients who underwent laparoscopic radical hysterectomy and pelvic lymph node dissection from July 2003 to April 2009. A 2:1 cohort of patients treated with laparotomy were matched by stage. Results: Nine laparoscopic patients (3 stage IA2, 6 stage IB1) with 18 matched controls (6 and 12) were identified. Demographics for each group were similar. None had positive margins or lymph nodes. An average of 11.2 vs.13.9 pelvic lymph nodes (P=0.237) were removed. Average operating time was 231.7 vs. 207.2 minutes (P=0.434), and average estimated blood loss was 161.1 vs. 394.4mL (P=0.059). Average length of stay was 2.9 vs. 5.5 days (P=0.012). No transfusions or operative complications were noted in the laparoscopic group vs. 3 each in the open group (P=0.194). No laparoscopic patients and 5 open patients had a postoperative wound infection (P=0.079). No recurrences were noted. Conclusions: Laparoscopic radical hysterectomy is a feasible alternative to laparotomy for early stage cervical cancer. Similar surgical outcomes are achieved with significantly less morbidity. PMID:21902978

  15. Early stage of nanodroplet impact on solid wall

    NASA Astrophysics Data System (ADS)

    Kobayashi, Kazumichi; Konno, Kazuki; Yaguchi, Hisao; Fujii, Hiroyuki; Sanada, Toshiyuki; Watanabe, Masao

    2016-03-01

    In this study, we investigated nanodroplet spreading at the early stage after the impact using molecular dynamics simulations by changing the magnitude of the intermolecular force between the liquid and wall molecules. We showed that the droplet deformation after the impact greatly depends on the intermolecular force. The temporal evolution of the spreading diameters was measured by the cylindrical control volume for several molecular layers in the vicinity of the wall. At the early stage of the nanodroplet impact, the normalized spreading radius of the droplet is proportional to the square root of the normalized time, t ˆ . This result is understood by the geometrical consideration presented by Rioboo et al. ["Time evolution of liquid drop impact onto solid, dry surfaces," Exp. Fluids 33, 112-124 (2002)]. In addition, we found that as the intermolecular force between the liquid and wall becomes stronger, the normalized spreading diameter of the first molecular layer on the wall remains less dependent on the impact velocity. Furthermore, the time evolution of the droplet spreading changes from √{ t ˆ } to log t ˆ with time.

  16. Neural changes underlying early stages of L2 vocabulary acquisition.

    PubMed

    Pu, He; Holcomb, Phillip J; Midgley, Katherine J

    2016-11-01

    Research has shown neural changes following second language (L2) acquisition after weeks or months of instruction. But are such changes detectable even earlier than previously shown? The present study examines the electrophysiological changes underlying the earliest stages of second language vocabulary acquisition by recording event-related potentials (ERPs) within the first week of learning. Adult native English speakers with no previous Spanish experience completed less than four hours of Spanish vocabulary training, with pre- and post-training ERPs recorded to a backward translation task. Results indicate that beginning L2 learners show rapid neural changes following learning, manifested in changes to the N400 - an ERP component sensitive to lexicosemantic processing and degree of L2 proficiency. Specifically, learners in early stages of L2 acquisition show growth in N400 amplitude to L2 words following learning as well as a backward translation N400 priming effect that was absent pre-training. These results were shown within days of minimal L2 training, suggesting that the neural changes captured during adult second language acquisition are more rapid than previously shown. Such findings are consistent with models of early stages of bilingualism in adult learners of L2 (e.g. Kroll and Stewart's RHM) and reinforce the use of ERP measures to assess L2 learning.

  17. Early stage of Superradiance from Bose-Einstein condensates

    NASA Astrophysics Data System (ADS)

    Buchmann, Lukas

    2011-05-01

    We investigate the dynamics of matter and optical waves at the early stage of superradiant Rayleigh scattering from Bose-Einstein condensates, an instance of four-wave-mixing of matter and optical waves. Our analysis is within a spatially dependent model which treats the matter-waves as well as the optical end-fire modes quantum mechanically and is capable of providing analytic solutions for the operators of interest. In particular, we study the statistical properties of the outgoing scattered light which provide insight into the rich internal dynamics of the system at this early stage. Furthermore, we investigate coherence properties of pairs of counter propagating atomic sidemodes produced during the process. It is shown that these clouds exhibit long-range spatial coherence and strong nonclassical density cross-correlations due to entanglement between the clouds. These findings make this scheme a promising candidate for the production of highly directional nonclassically correlated atomic pulses. Our prediction of number difference squeezing between the clouds was observed in another instance of a four-wave mixing process using metastable helium. Work performed at IESL-FORTH in Crete, Greece

  18. Sensorimotor Cortical Neuroplasticity in the Early Stage of Bell's Palsy

    PubMed Central

    Dai, Minhui; Xuan, Lihua; Cao, Zhijian; Zhou, Sisi; Lang, Courtney; Lv, Kun

    2017-01-01

    Neuroplasticity is a common phenomenon in the human brain following nerve injury. It is defined as the brain's ability to reorganize by creating new neural pathways in order to adapt to change. Here, we use task-related and resting-state fMRI to investigate neuroplasticity in the primary sensory (S1) and motor cortex (M1) in patients with acute Bell's palsy (BP). We found that the period directly following the onset of BP (less than 14 days) is associated with significant decreases in regional homogeneity (ReHo), fractional amplitude of low frequency fluctuations (fALFF), and intrinsic connectivity contrast (ICC) values in the contralateral S1/M1 and in ReHo and ICC values in the ipsilateral S1/M1, compared to healthy controls. The regions with decreased ReHo, fALFF, and ICC values were in both the face and hand region of S1/M1 as indicated by resting-state fMRI but not task-related fMRI. Our results suggest that the early stages of BP are associated with functional neuroplasticity in both the face and hand regions of S1/M1 and that resting-state functional fMRI may be a sensitive tool to detect these early stages of plasticity in patient populations. PMID:28299208

  19. miRNAs in Urine Extracellular Vesicles as Predictors of Early-Stage Diabetic Nephropathy

    PubMed Central

    Jia, Yijie; Guan, Meiping; Zheng, Zongji; Zhang, Qian; Tang, Chuan; Xu, Wenwei; Xiao, Zhizhou; Wang, Ling; Xue, Yaoming

    2016-01-01

    Background. miR-192, miR-194, and miR-215 are enriched in the kidney and play roles in the pathogenesis of diabetic nephropathy (DN). Extracellular vesicles (EVs) can be detected in body fluids and may serve as disease biomarkers. Methods. Eighty type 2 diabetes patients with normoalbuminuria (n = 30), microalbuminuria (n = 30), or macroalbuminuria (n = 20), as well as 10 healthy controls, were enrolled in this study. Real-time PCR was used to evaluate urinary EV miRNAs expression. Results. The miR-192 levels were significantly higher than the miR-194 and miR-215 levels in urine EVs and all three miRNAs were significantly increased in the microalbuminuric group compared with the normoalbuminuric and control subjects but were decreased in the macroalbuminuric group. In patients with normoalbuminuria and microalbuminuria, miR-192 was positively correlated with albuminuria (r = 0.357, P = 0.005) levels and transforming growth factor- (TGF-) β1 (r = 0.356, P = 0.005) expression. Receiver operating characteristic (ROC) curve analysis revealed that miR-192 was better than miR-194 and miR-215 in discriminating the normoalbuminuric group from the microalbuminuric group. Exposure of human renal tubular epithelial cells to high glucose increased the expression of both miRNAs in cellular supernatant EVs, indicating a potential source. Conclusion. These results suggest the potential use of urinary EV miR-192 as a biomarker of the early stage of DN. PMID:26942205

  20. Early Stage Biomineralization in the Periostracum of the ‘Living Fossil’ Bivalve Neotrigonia

    PubMed Central

    Checa, Antonio G.; Salas, Carmen; Harper, Elizabeth M.; Bueno-Pérez, Juan de Dios

    2014-01-01

    A detailed investigation of the shell formation of the palaeoheterodont ‘living fossil’ Neotrigonia concentrated on the timing and manufacture of the calcified ‘bosses’ which stud the outside of all trigonioid bivalves (extant and fossil) has been conducted. Electron microscopy and optical microscopy revealed that Neotrigonia spp. have a spiral-shaped periostracal groove. The periostracum itself is secreted by the basal cell, as a thin dark pellicle, becoming progressively transformed into a thin dark layer by additions of secretions from the internal outer mantle fold. Later, intense secretion of the internal surface of the outer mantle fold forms a translucent layer, which becomes transformed by tanning into a dark layer. The initiation of calcified bosses occurred at a very early stage of periostracum formation, deep within the periostracal groove immediately below the initialmost dark layer. At this stage, they consist of a series of polycyclically twinned crystals. The bosses grow as the periostracum traverse through the periostracal groove, in coordination with the thickening of the dark periostracal layer and until, upon reaching the mantle edge, they impinge upon each other and become transformed into large prisms separated by dark periostracal walls. In conclusion, the initial bosses and the external part of the prismatic layer are fully intraperiostracal. With later growth, the prisms transform into fibrous aggregates, although the details of the process are unknown. This reinforces the relationships with other groups that have the ability to form intraperiostracal calcifications, for example the unionoids with which the trigonioids form the clade Paleoheterodonta. The presence of similar structures in anomalodesmatans and other euheterodonts raises the question of whether this indicates a relationship or represents a convergence. The identification of very early calcification within an organic sheet has interesting implications for our

  1. Early stage biomineralization in the periostracum of the 'living fossil' bivalve Neotrigonia.

    PubMed

    Checa, Antonio G; Salas, Carmen; Harper, Elizabeth M; Bueno-Pérez, Juan de Dios

    2014-01-01

    A detailed investigation of the shell formation of the palaeoheterodont 'living fossil' Neotrigonia concentrated on the timing and manufacture of the calcified 'bosses' which stud the outside of all trigonioid bivalves (extant and fossil) has been conducted. Electron microscopy and optical microscopy revealed that Neotrigonia spp. have a spiral-shaped periostracal groove. The periostracum itself is secreted by the basal cell, as a thin dark pellicle, becoming progressively transformed into a thin dark layer by additions of secretions from the internal outer mantle fold. Later, intense secretion of the internal surface of the outer mantle fold forms a translucent layer, which becomes transformed by tanning into a dark layer. The initiation of calcified bosses occurred at a very early stage of periostracum formation, deep within the periostracal groove immediately below the initialmost dark layer. At this stage, they consist of a series of polycyclically twinned crystals. The bosses grow as the periostracum traverse through the periostracal groove, in coordination with the thickening of the dark periostracal layer and until, upon reaching the mantle edge, they impinge upon each other and become transformed into large prisms separated by dark periostracal walls. In conclusion, the initial bosses and the external part of the prismatic layer are fully intraperiostracal. With later growth, the prisms transform into fibrous aggregates, although the details of the process are unknown. This reinforces the relationships with other groups that have the ability to form intraperiostracal calcifications, for example the unionoids with which the trigonioids form the clade Paleoheterodonta. The presence of similar structures in anomalodesmatans and other euheterodonts raises the question of whether this indicates a relationship or represents a convergence. The identification of very early calcification within an organic sheet has interesting implications for our understanding of

  2. Evaluation of the enhanced permeability and retention effect in the early stages of lymph node metastasis.

    PubMed

    Mikada, Mamoru; Sukhbaatar, Ariunbuyan; Miura, Yoshinobu; Horie, Sachiko; Sakamoto, Maya; Mori, Shiro; Kodama, Tetsuya

    2017-02-17

    Most solid cancers spread to new sites via the lymphatics before hematogenous dissemination. However, only a small fraction of an intravenously administered anti-cancer drug enters the lymphatic system to reach metastatic lymph nodes (LNs). Here, we show that the enhanced permeability and retention (EPR) effect is not induced during the early stages of LN metastasis. Luciferase-expressing tumor cells were injected into the subiliac LN of the MXH10/Mo-lpr/lpr mouse to induce metastasis to the proper axillary LN (PALN). In vivo biofluorescence imaging was used to confirm metastasis induction and to quantify the EPR effect, measured as PALN accumulation of intravenously injected indocyanine green (ICG) liposomes. PALN blood vessel volume changes were measured by contrast-enhanced high-frequency ultrasound imaging. The volume and density of blood vessels in the PALN increased until day 29 after inoculation whereas the LN volume remained constant. ICG retention was first detected on day 29 post-inoculation. While CD31-positive cells increased up to day 29 post-inoculation, α-smooth muscle actin-positive cells were detected on day 29 post-inoculation for the first time. These results suggest that the EPR effect was not induced in the early stages of LN metastasis; therefore, systemic chemotherapy would likely not be beneficial during the early stages of LN metastasis. The development of an alternative drug delivery system, independent of the EPR effect, is required for the treatment of LN metastasis. This article is protected by copyright. All rights reserved.

  3. Bacterial community dynamics during the early stages of biofilm formation in a chlorinated experimental drinking water distribution system: implications for drinking water discolouration

    PubMed Central

    Douterelo, I; Sharpe, R; Boxall, J

    2014-01-01

    Aims To characterize bacterial communities during the early stages of biofilm formation and their role in water discolouration in a fully representative, chlorinated, experimental drinking water distribution systems (DWDS). Methods and Results Biofilm development was monitored in an experimental DWDS over 28 days; subsequently the system was disturbed by raising hydraulic conditions to simulate pipe burst, cleaning or other system conditions. Biofilm cell cover was monitored by fluorescent microscopy and a fingerprinting technique used to assess changes in bacterial community. Selected samples were analysed by cloning and sequencing of the 16S rRNA gene. Fingerprinting analysis revealed significant changes in the bacterial community structure over time (P < 0·05). Cell coverage increased over time accompanied by an increase in bacterial richness and diversity. Conclusions Shifts in the bacterial community structure were observed along with an increase in cell coverage, bacterial richness and diversity. Species related to Pseudomonas spp. and Janthinobacterium spp. dominated the process of initial attachment. Based on fingerprinting results, the hydraulic regimes did not affect the bacteriological composition of biofilms, but they did influence their mechanical stability. Significance and Importance of the Study This study gives a better insight into the early stages of biofilm formation in DWDS and will contribute to the improvement of management strategies to control the formation of biofilms and the risk of discolouration. PMID:24712449

  4. Bacterial community dynamics during the early stages of biofilm formation in a chlorinated experimental drinking water distribution system: implications for drinking water discolouration.

    PubMed

    Douterelo, I; Sharpe, R; Boxall, J

    2014-07-01

    To characterize bacterial communities during the early stages of biofilm formation and their role in water discolouration in a fully representative, chlorinated, experimental drinking water distribution systems (DWDS). Biofilm development was monitored in an experimental DWDS over 28 days; subsequently the system was disturbed by raising hydraulic conditions to simulate pipe burst, cleaning or other system conditions. Biofilm cell cover was monitored by fluorescent microscopy and a fingerprinting technique used to assess changes in bacterial community. Selected samples were analysed by cloning and sequencing of the 16S rRNA gene. Fingerprinting analysis revealed significant changes in the bacterial community structure over time (P < 0·05). Cell coverage increased over time accompanied by an increase in bacterial richness and diversity. Shifts in the bacterial community structure were observed along with an increase in cell coverage, bacterial richness and diversity. Species related to Pseudomonas spp. and Janthinobacterium spp. dominated the process of initial attachment. Based on fingerprinting results, the hydraulic regimes did not affect the bacteriological composition of biofilms, but they did influence their mechanical stability. This study gives a better insight into the early stages of biofilm formation in DWDS and will contribute to the improvement of management strategies to control the formation of biofilms and the risk of discolouration. © 2014 The Authors. published by John Wiley & Sons Ltd on behalf of Society for Applied Microbiology.

  5. 13 CFR 107.1181 - Interest reserve requirements for Early Stage SBICs.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... ADMINISTRATION SMALL BUSINESS INVESTMENT COMPANIES SBA Financial Assistance for Licensees (Leverage) Special Rules for Leverage Issued by An Early Stage Sbic § 107.1181 Interest reserve requirements for Early Stage SBICs. (a) Reserve requirement. If you are an Early Stage SBIC with outstanding Leverage, for...

  6. 13 CFR 107.1180 - Required distributions to SBA by Early Stage SBICs.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... ADMINISTRATION SMALL BUSINESS INVESTMENT COMPANIES SBA Financial Assistance for Licensees (Leverage) Special Rules for Leverage Issued by An Early Stage Sbic § 107.1180 Required distributions to SBA by Early Stage SBICs. (a) Distribution requirement. If you are an Early Stage SBIC with outstanding Leverage, you...

  7. 13 CFR 107.1181 - Interest reserve requirements for Early Stage SBICs.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... ADMINISTRATION SMALL BUSINESS INVESTMENT COMPANIES SBA Financial Assistance for Licensees (Leverage) Special Rules for Leverage Issued by An Early Stage Sbic § 107.1181 Interest reserve requirements for Early Stage SBICs. (a) Reserve requirement. If you are an Early Stage SBIC with outstanding Leverage, for...

  8. 13 CFR 107.1180 - Required distributions to SBA by Early Stage SBICs.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... ADMINISTRATION SMALL BUSINESS INVESTMENT COMPANIES SBA Fi