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Sample records for 7-d triple therapy

  1. Efficacy of 14-d vs 7-d moxifloxacin-based triple regimens for second-line Helicobacter pylori eradication

    PubMed Central

    Hwang, Jae Jin; Lee, Dong Ho; Lee, Ae-Ra; Yoon, Hyuk; Shin, Cheol Min; Park, Young Soo; Kim, Nayoung

    2015-01-01

    AIM: To evaluate the efficacy of the 14-d moxifloxacin-based triple therapy for the second-line eradication of Helicobacter pylori (H. pylori) infection. METHODS: Between 2011 and 2013, we conducted a retrospective review of the medical records of 160 patients who had experienced failure of their first-line proton pump inhibitor-based eradication therapy and subsequently received the moxifloxacin-based triple therapy as a second-line eradication treatment regimen. The patients who were treated with the moxifloxacin-based triple therapy (oral 20 mg rabeprazole b.i.d., 1000 mg amoxicillin b.i.d., and 400 mg moxifloxacin q.d.) for 7 d were assigned to the RAM-7 group (n = 79) while those who took them for 14 days were assigned to RAM-14 group (n = 81). The eradication rates for both groups were determined by intention-to-treat (ITT) and per-protocol (PP) analyses. ITT analysis compared the treatment groups as originally allocated while the PP analysis including only those patients who had completed the treatment as originally allocated. Successful eradication therapy for H. pylori infection was defined as the documentation of a negative 13C-urea breath test 4 wk after the end of the eradication treatment. RESULTS: The overall ITT eradication rate was 76.2% (122/160). The final ITT eradication rates were 70.8% (56/79; 95%CI: 63.3%-77.1%) in the RAM-7 group and 81.4% (66/81; 95%CI: 74.6%-88.3%) in the RAM-14 group (P = 0.034). The overall PP eradication rate was 84.1% (122/145), and the final PP eradication rates were 77.7% (56/72; 95%CI: 70.2%-85.3%) in the RAM-7 group and 90.4% (66/73; 95%CI: 82.8%-98.1%) in the RAM-14 group (P = 0.017). The H. pylori-eradication rates in the RAM-14 group were significantly higher compared with that of the RAM-7 group according to both the ITT (P = 0.034) and the PP analyses (P = 0.017). Both groups exhibited good treatment compliance (RAM-7/RAM-14 group: 100%/100%). The adverse event rates were 19.4% (14/72) and 20.5% (15/73) in the

  2. Comparison of sequential and 7-, 10-, 14-d triple therapy for Helicobacter pylori infection

    PubMed Central

    Choi, Hyuk Soon; Chun, Hoon Jai; Park, Sang Hoon; Keum, Bora; Seo, Yeon Seok; Kim, Yong Sik; Jeen, Yoon-Tae; Um, Soon Ho; Lee, Hong Sik; Kim, Chang Duck; Ryu, Ho Sang

    2012-01-01

    AIM: To compare the effectiveness of sequential therapy for Helicobacter pylori (H. pylori) infection with that of triple therapy of varying durations. METHODS: The 460 patients enrolled in this study had H. pylori-associated gastritis or a gastric or duodenal ulcer. After screening, H. pylori-infected patients were randomly assigned to receive either conventional triple therapy for 7, 10 or 14 d, or a new 10-d sequential therapy. Each of the 4 treatment groups included 115 patients. The outcomes of eradication therapy were assessed 4 wk after treatment by the urea breath test and histology. RESULTS: The overall eradication rate was 81.0%, and eradication rates were 75.7% for 7-d conventional triple therapy, 81.9% for 10-d conventional triple therapy, 84.4% for 14-d conventional triple therapy, and 82.0% for 10-d sequential therapy. Neither intention-to-treat analysis nor per protocol analysis showed significant differences in eradication rates using sequential therapy or the standard triple therapy (P = 0.416 and P = 0.405, respectively). CONCLUSION: There are no significant differences between 10-d sequential eradication therapy for H. pylori and any duration of standard triple treatment in Korean patients. PMID:22654429

  3. Standard triple therapy for Helicobacter pylori infection in China: A meta-analysis

    PubMed Central

    Wang, Ben; Lv, Zhi-Fa; Wang, You-Hua; Wang, Hui; Liu, Xiao-Qun; Xie, Yong; Zhou, Xiao-Jiang

    2014-01-01

    AIM: To assess the efficacy and safety of standard triple therapy compared with other pre-existing and new therapies in China. METHODS: Literature searches were conducted in the following databases: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, the VIP database, the China National Knowledge Infrastructure database, and the Chinese Biomedical Database. A meta-analysis of all randomized controlled trials (RCTs) comparing standard triple therapy for the eradication of Helicobacter pylori with pre-existing and new therapies in China was performed using Comprehensive Meta-Analysis 2.0. There were 49 studies that met our criteria and the qualities of these studies were assessed using the Jadad scale. The Mantel-Haenszel method was used for pooling dichotomous data. We also conducted subgroup analyses according to age, duration of treatment and drug type. Sensitivity analyses and a cumulative meta-analysis were also performed with CMA 2.0. Publication bias was evaluated using Egger’s test, Begg’s test or a funnel plot. RESULTS: A total of 49 RCTs including 8332 patients were assessed. This meta-analysis showed that standard triple therapy with proton pump inhibitors (PPIs), amoxicillin (AMO) and clarithromycin (CLA) was inferior to sequential therapy [relative risk (RR) = 0.863; 95% confidence interval (CI): 0.824-0.904], but was not superior to quadruple therapy (RR = 1.073; 95%CI: 0.849-1.357) or other triple therapies (RR = 1.01; 95%CI: 0.936-1.089). The meta-analysis also suggested that standard triple therapy is slightly more effective than dual therapy (RR = 1.14; 95%CI: 0.99-1.31). However, the differences were not statistically significant. We removed the only trial with a regimen lasting 14 d by sensitivity analysis and found that 7-d standard triple therapy was superior to 7-d dual therapy (RR = 1.222; 95%CI: 1.021-1.461). Moreover, a sub-analysis based on the duration of quadruple therapy indicated that the 7-d and 10-d standard triple

  4. Randomized control trial: Comparison of Triple Therapy plus Probiotic Yogurt vs. Standard Triple Therapy on Helicobacter Pylori Eradication

    PubMed Central

    Mirzaee, V; Rezahosseini, O

    2012-01-01

    Background Treatment of Helicobacter pylori (H. pylori) as a major cause of gastric diseases is of utmost concern.We aimed to assess efficacy of triple therapy (amoxicillin, clarithromycin and pantoprazole) plus probiotic yogurt (PY) on eradication of H.pylori. Methods Total 102 H. pylori positive patients were divided to 3 groups equally and randomly. For treatment of each group Amoxicillin, clarithromycin and pantoprazole were used. Group A had additional PY, Group B ordinary low fat yogurt and Group C just had triple therapy in their regimen as well. These groups were compared regarding treatment success. Results Total number of 88 patients finished the treatment course. The most common experienced side effects were dysgeusia in groups A and B (25.8% and 32.3%, respectively), and dysgeusia with diarrhea and abdominal pain (30.8%) in group C. Eradication rate was, respectively, 61.3%, 64.5% and 71.3% in group A, B and C of which difference was not statistically significant (P> 0.05). However, the difference between 3 groups in regard to education level was statistically significant (P=0.005). Conclusion PY enriched triple therapy has decreased side effects of antibiotics consumption; however, this has no impact on eradication of Hpylori. PY and triple therapy can be used concomitantly to increase the patient tolerance. PMID:23285418

  5. Triple nucleoside reverse transcriptase inhibitor therapy in children.

    PubMed

    Handforth, Jennifer; Sharland, Mike

    2004-01-01

    Much of the success attributed to HIV therapy in the last few years has resulted from improved ways of using existing drugs in combination therapy regimens. The availability of new, more potent drugs such as protease inhibitors and more accurate viral load tests to aid decisions to start or change treatment has also contributed to the success. Published recommendations for pediatric HIV therapy, generated by a panel of experts and specialists, are readily available and regularly updated. Preferred regimens of 'potent' therapy (referred to as highly active antiretroviral therapy, or HAART) currently consist of two nucleoside reverse transcriptase inhibitors (NRTIs) combined with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor. More intense four-drug regimens using an NNRTI or a second protease inhibitor as a fourth drug are being evaluated. Problems with HAART include: unpalatable drug formulations and adverse effects, coupled with lack of data on the pharmacokinetics, efficacy, and safety of various drug combinations. Adherence is a major factor influencing the efficacy and outcome of antiretroviral therapy. Many children cannot adhere to complex multidrug regimens, which cause virologic failure, despite excellent CD4+ cell count responses. This means a rapid progression through the limited number of treatment regimens available. Simpler regimens such as those containing three NRTIs have been proposed as a method of treatment that will allow suppression of the virus, yet circumvent many of the problems previously mentioned. An additional benefit would be the preservation of antiretroviral drugs from other classes for future treatment options if required. The major advantages of triple NRTI regimens are the simplicity of the regimen, good tolerability, few drug-drug interactions, and infrequent adverse effects coupled with a low pill burden. However, abacavir hypersensitivity remains a major problem. Up to 3% of patients may

  6. Moxifloxacin-containing triple therapy after non-bismuth quadruple therapy failure for Helicobacter pylori infection

    PubMed Central

    Lim, Ji Hyun; Lee, Dong Ho; Lee, Seong Tae; Kim, Nayoung; Park, Young Soo; Shin, Cheol Min; Song, In Sung

    2015-01-01

    AIM: To assess the efficacy of moxifloxacin-containing triple therapy after non-bismuth quadruple therapy failure for Helicobacter pylori (H. pylori) eradication. METHODS: Between January 2010 and December 2012, we screened individuals who were prescribed non-bismuth quadruple therapy for H. pylori eradication. Among them, a total of 98 patients who failed non-bismuth quadruple therapy received 1-wk or 2-wk moxifloxacin-containing triple therapy (400 mg moxifloxacin once daily, and 20 mg of rabeprazole and 1 g of amoxicillin twice daily). H. pylori status was evaluated using the 13C-urea breath test 4 wk later, after treatment completion. The eradication rates were determined by intention-to-treat and per-protocol analyses. RESULTS: In total, 60 and 38 patients received 1-wk and 2-wk moxifloxacin-containing triple therapy, respectively. The intention-to-treat and per-protocol eradication rates were 56.7% (95%CI: 45.0-70.0) and 59.6% (95%CI: 46.6-71.7) in the 1-wk group and 76.3% (95%CI: 63.2-89.5) and 80.6% (95%CI: 66.7-91.9) in the 2-wk group (P = 0.048 and 0.036, respectively). All groups had good compliance (95% vs 94.9%). Neither group showed serious adverse events, and the proportions of patients experiencing mild side effects were not significantly different (21.1% vs 13.9%). Clinical factors such as age, sex, alcohol and smoking habits, comorbidities, and presence of gastric or duodenal ulcer did not influence the eradication therapy efficacy. The efficacy of second-line eradication therapy did not differ significantly according to the first-line regimen. CONCLUSION: Two-week moxifloxacin-containing triple therapy showed better efficacy than a 1-wk regimen after non-bismuth quadruple therapy failure. PMID:26673999

  7. Evaluation of Helicobacter Pylori eradication in pediatric patients by triple therapy plus lactoferrin and probiotics compared to triple therapy alone

    PubMed Central

    2012-01-01

    Background To evaluate whether the addition of a probiotic could improve Helicobacter pylori (H.P.) eradication rates and reduce the side effects of treatment in children. Methods Between July 2008 and July 2011 all patients with a clinical, laboratory and endoscopic diagnosis of H.P. positive gastritis referred to our Unit were included in the study. Patients suffering from allergy to any of drugs used in the study, with previous attempts to eradicate H.P. and those who received antibiotics, PPIs or probiotics within 4 weeks were excluded from the present study. Patients were randomized into two therapy regimens (group A and B): both groups received standard triple treatment (omeprazole, amoxicillin and clarithromycin) while only group B patients were also given a probiotic (Probinul - Cadigroup). Patients compliance was evaluated at the end of the treatment. Successful eradication was defined as a negative 13 C-urea breath test (C13-ubt) result four weeks after therapy discontinuation. Results A total of 68 histopathologically proven H.P.-infection children (32 male and 36 females) were included in the study. All of the patients in both groups used more than 90% of the therapies and no patients were lost at follow up. All side effects were selflimiting and disappeared once the therapy was terminated. Epigastric pain was observed in 6 (17.6%) group A vs 2 (5.8%) group B patients (P<0.05), nausea in 3 (8.8%) group A vs 1 (2.9%) group B patients (P<0.05); vomiting and diarrhea were observed in 2(5.8%) and 8 (23.5%) group A patients, respectively and never in group B (P<0.05). There was no significant difference between the two groups in terms of constipation (5.8% in group A and B). Four weeks after the completion of therapy, 56/68 patients (82.3%) tested negative for H.P. on C13-ubt. H.P. was eradicated in 26 patients (76.4%) in group A and in 30 patients (88.2%) in group B. There was no significantly difference in the rate of H.P. eradication between group A and

  8. Does emerging Clarithromycin resistance signal an obituary to empirical standard triple therapy for Helicobacter pylori infection?

    PubMed

    John, Anil; Al Kaabi, Saad; Doiphode, Sanjay; Chandra, Prem; Sharma, Manik; Babu, Ragesh; Yacoub, Rafie; Derbala, Moutaz

    2015-09-01

    Despite 30 years of its discovery, the ideal therapeutic regimen against Helicobacter pylori is still evasive. Clarithromycin-based standard triple therapy which has been considered the first line empirical therapy has been failing in many parts of the world, due to rising resistance against Clarithromycin, forcing the use of alternate regimens. In this context, we studied the local antibiotic resistance patterns against H. pylori and its impact on standard triple therapy in our region. All patients undergoing diagnostic upper endoscopy during the study period and detected to be positive for rapid urease test (RUT) underwent cultures of gastric mucosal specimens and had their antibiotic resistance patterns mapped out. Standard triple therapy was administered to those tested positive for H. pylori by RUT and eradication rates checked by urea breath test 4 weeks after the completion of treatment. Eradication rates with Clarithromycin-based standard triple therapy were suboptimal with a success of only (71.28%). H. pylori culture and antibiotic susceptibility studies showed high resistance to Clarithromycin (21.2%), Metronidazole (78.1%), and Levofloxacin (15%). However, the resistance to Amoxicillin (2.9%), Tetracycline (0%), and Rifabutin (4.5%) were low. Standard triple therapy is failing in our region due to high Clarithromycin resistance. We need to abandon empirical and blind triple therapy without post-treatment testing and devise alternate effective treatment strategies against H. pylori based on the local resistance patterns observed. PMID:26541342

  9. Triple therapy in type 2 diabetes; a systematic review and network meta-analysis

    PubMed Central

    Bettington, Emilie K.; Gunton, Jenny E.; Turkstra, Erika

    2015-01-01

    Aims. The purpose was to evaluate the evidence for triple therapy regimen using medicines available in Australia for type 2 diabetes. Methods. A systematic literature review was performed to update the relevant evidence from 2002 to 2014 on triple therapy for type 2 diabetes. A multiple-treatments network meta-analysis was undertaken to summarise the comparative efficacy and harms of different triple therapies. Results. Twenty seven trials were identified, most were six months of duration. The following combinations were included in the network meta-analysis: metformin (MET) + sulfonylureas (SU) (used as reference combination); MET + SU+ dipeptidyl peptidase 4 inhibitors (DPP-4-i); MET + SU+ thiazolidinediones (TZD); MET + SU+ glucagon-like peptide-1 receptor agonists (GLP-1-RA); MET + SU+ insulins; MET + TZD + DPP-4-i; and MET + SU+ sodium/glucose cotransporter 2 inhibitors (SGLT2-i). For HbA1c reduction, all triple therapies were statistically superior to MET+SU dual therapy, except for MET + TZD + DPP-4-i. None of the triple therapy combinations demonstrated differences in HbA1c compared with other triple therapies. MET + SU + SGLT2-i and MET + SU + GLP-1-RA resulted in significantly lower body weight than MET + SU + DPP-4-i, MET+SU+insulin and MET + SU + TZDs; MET + SU + DPP-4-i resulted in significantly lower body weight than MET + SU + insulin and MET + SU + TZD. MET + SU + insulin, MET + SU + TZD and MET + SU + DPP-4-i increased the odds of hypoglycaemia when compared to MET + SU. MET + SU + GLP-1-RA reduced the odds of hypoglycaemia compared to MET + SU + insulin. Conclusion. Care when choosing a triple therapy combination is needed as there is often a risk of increased hypoglycaemia events associated with this regimen and there are very limited data surrounding the long-term effectiveness and safety of combined therapies. PMID:26664803

  10. Triple antiplatelet therapy for preventing vascular events: a systematic review and meta-analysis

    PubMed Central

    2010-01-01

    Background Dual antiplatelet therapy is usually superior to mono therapy in preventing recurrent vascular events (VEs). This systematic review assesses the safety and efficacy of triple antiplatelet therapy in comparison with dual therapy in reducing recurrent vascular events. Methods Completed randomized controlled trials investigating the effect of triple versus dual antiplatelet therapy in patients with ischaemic heart disease (IHD), cerebrovascular disease or peripheral vascular disease were identified using electronic bibliographic searches. Data were extracted on composite VEs, myocardial infarction (MI), stroke, death and bleeding and analysed with Cochrane Review Manager software. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using random effects models. Results Twenty-five completed randomized trials (17,383 patients with IHD) were included which involving the use of intravenous (iv) GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban), aspirin, clopidogrel and/or cilostazol. In comparison with aspirin-based therapy, triple therapy using an intravenous GP IIb/IIIa inhibitor significantly reduced composite VEs and MI in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) (VE: OR 0.69, 95% CI 0.55-0.86; MI: OR 0.70, 95% CI 0.56-0.88) and ST elevation myocardial infarction (STEMI) (VE: OR 0.39, 95% CI 0.30-0.51; MI: OR 0.26, 95% CI 0.17-0.38). A significant reduction in death was also noted in STEMI patients treated with GP IIb/IIIa based triple therapy (OR 0.69, 95% CI 0.49-0.99). Increased minor bleeding was noted in STEMI and elective percutaneous coronary intervention (PCI) patients treated with GP IIb/IIIa based triple therapy. Stroke events were too infrequent for us to be able to identify meaningful trends and no data were available for patients recruited into trials on the basis of stroke or peripheral vascular disease. Conclusions Triple antiplatelet therapy based on iv GPIIb/IIIa inhibitors was more

  11. Maximizing Opportunities and Avoiding Mistakes in Triple Therapy for Hepatitis C Virus

    PubMed Central

    Barritt, A. Sidney; Fried, Michael W.

    2013-01-01

    Recently developed drugs and innovative strategies for the treatment of chronic infection with genotype 1 hepatitis C virus (HCV) have become the standard of care. The protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) are the first direct-acting antiviral (DAA) agents approved, and many more are being developed. These drugs substantially increased rates of sustained virologic response in treatment-naïve and -experienced patients, in conjunction with peginterferon and ribavirin (triple therapy), in phase 3 trials. The efficacy of triple therapy depends on appropriate selection of patients, although the population of patients that receive triple therapy could be expanded as the risk/benefit ratio improves. Attention to details that reflect the standard of care, such as appropriate dosing, anticipation of adverse effects, and strict adherence to stopping rules, will insure the success of these drugs and lead the way for new combination therapies. PMID:22537438

  12. Etanercept‐Methotrexate Combination Therapy Initiators Have Greater Adherence and Persistence Than Triple Therapy Initiators With Rheumatoid Arthritis

    PubMed Central

    Johnson, Barbara H.; Tang, Derek H.; Shah, Neel; Harrison, David J.; Collier, David H.

    2015-01-01

    Objective To estimate adherence and persistence with etanercept plus methotrexate (ETN‐MTX) combination therapy and MTX, hydroxychloroquine, and sulfasalazine triple therapy at 1 year following treatment initiation in adults with rheumatoid arthritis (RA). Methods This retrospective analysis used data from the Truven Health MarketScan Commercial and Medicare Supplemental databases from January 2009 to July 2013. Adherence was defined as having percentage of days covered >80% for all drugs within each regimen. Persistence was defined as no treatment gap >45 days for any drug and no addition or switching to other disease‐modifying antirheumatic drugs. Multiple logistic regression models were employed in the analyses to control for potential confounders. Results A total of 3,724 ETN‐MTX patients and 818 triple therapy patients were eligible. At 1 year, 27.9% who were taking ETN‐MTX and 18.2% using triple therapy were adherent to all agents in their regimen (P < 0.0001), and 29.4% who were taking ETN‐MTX and 23.2% using triple therapy were persistent (P < 0.001). After adjusting for confounders, ETN‐MTX patients had significantly greater odds of being adherent (odds ratio [OR] 1.79, 95% confidence interval [95% CI] 1.47–2.17) and persistent (OR 1.45, 95% CI 1.20–1.72) compared with patients using triple therapy. Conclusion Patients with RA initiating treatment with ETN‐MTX combination therapy demonstrated greater adherence and persistence at 1 year than patients initiating triple therapy. PMID:26097194

  13. Role of bismuth in improving Helicobacter pylori eradication with triple therapy.

    PubMed

    Dore, Maria Pina; Lu, Hong; Graham, David Y

    2016-05-01

    In most regions of the world, antimicrobial resistance has increased to the point where empirical standard triple therapy for Helicobacter pylorieradication is no longer recommended. The treatment outcome in a population is calculated as the sum of the treatment success in the subpopulation with susceptible infections plus treatment success in the subpopulation with resistant infections. The addition of bismuth (i.e., 14-day triple therapy plus bismuth) can improve cure rates despite a high prevalence of antimicrobial resistance. The major bismuth effect is to add an additional 30%-40% to the success with resistant infections. The overall result is therefore dependent on the prevalence of resistance and the treatment success in the subpopulation with resistant infections (eg, with proton-pump inhibitor-amoxicillin dual therapy). Here, we explore the contribution of each component and the mechanisms of how bismuth might enhance the effectiveness of triple therapy. We also discuss the limitations of this approach and provide suggestions how triple therapy plus bismuth might be further improved. PMID:26848181

  14. Triple-negative breast cancer: novel therapies and new directions.

    PubMed

    Pal, Sumanta Kumar; Mortimer, Joanne

    2009-08-20

    Triple-negative breast cancer (TNBC) accounts for approximately 15% of breast cancer diagnoses, and exhibits substantial overlap with basal-type and BRCA1-positive breast cancer. In recent years, a greater understanding of the biology of this disease has led to the development of numerous and varied therapeutic approaches. Neoadjuvant trials using conventional cytotoxic agents such as cisplatin have demonstrated TNBC to be a relatively chemo-sensitive disease. In the current review, focus is directed towards novel targeted strategies for TNBC. Recent trials have shown the poly(ADP-ribosyl)ation polymerase (PARP) inhibitors BSI-201 and olaparib to be highly effective in TNBC and BRCA1/2-positive disease, respectively. Efforts to assess the role of antiangiogenic agents such as bevacizumab and sunitinib in TNBC are ongoing. Finally, preclinical studies provide a signal of potential activity with use of heat shock protein 90 (Hsp90) and Src inhibitors in this breast cancer subtype.

  15. Onset of Celiac Disease after Treatment of Chronic Hepatitis C with Interferon Based Triple Therapy

    PubMed Central

    Singh, Amandeep; Zaeri, Nayere; Ho, Immanuel K.

    2015-01-01

    Background. Patients treated with interferon (IFN) based therapies may develop exacerbation of autoimmune disease. We herein present the case of a 53-year-old female patient who developed celiac disease (CD) as a result of triple therapy (interferon, ribavirin, and boceprevir) for chronic HCV. Case. 53-year-old Caucasian female with past medical history of IV drug abuse was referred for abnormal LFTs. Laboratory data showed HCV RNA of 4,515,392 IU/mL, HCV genotype 1a, with normal LFTs. She was treated with 4 weeks of pegylated interferon alfa-2a plus ribavirin, followed by triple therapy using boceprevir for a total of 28 weeks. Approximately 4 weeks after initiation of triple therapy patient developed loose nonbloody bowel movements and was also found to have anemia. Biopsies from first and second portions of the duodenum were consistent with CD. The patient was treated with a gluten-free diet. Her intestinal symptoms improved and the hemoglobin returned to normal. Conclusion. Chronic HCV patients being treated with interferon alfa can develop celiac disease during or after therapy. For patients with positive autoantibodies, all-oral-IFN-free regimens should be considered. Celiac disease should be considered in patients who develop CD-like symptoms while on and shortly after cessation of interferon alfa therapy. PMID:26664772

  16. Telehealth and Occupational Therapy: Integral to the Triple Aim of Health Care Reform.

    PubMed

    Cason, Jana

    2015-01-01

    Programs and concepts included in the Patient Protection and Affordable Care Act of 2010 are expected to transform health care in the United States from a volume-based health system to a value-based health system with increased emphasis on prevention and health promotion. The Triple Aim, a framework set forth by the Institute for Healthcare Improvement, focuses on improving the health care experience, the health of populations, and the affordability of care. This article describes telehealth as an integral component in achieving the Triple Aim of health care and discusses implications for occupational therapy practitioners. PMID:26122676

  17. Long-term atorvastatin-ezetimibe-probucol triple therapy for homozygous familial hypercholesterolaemia from early childhood.

    PubMed

    Lin, Minjie; Dai, Helong; Zhao, Shuiping

    2016-01-01

    In this observational case report, we share our experience of achieving >40% LDL cholesterol reduction in four Chinese homozygous familial hypercholesterolaemia children below 8 years of age with a triple combination of atorvastatin, probucol, and ezetimibe for >6 years. Within a follow-up duration of 6-13 years, this triple therapy achieved significant reduction of LDL cholesterol as well as an impressive regression of xanthomas in all paediatric cases. All the children remained free from treatment-related adverse responses and cardiovascular events throughout follow-up.

  18. A Pilot Randomized Controlled Study of Dexlansoprazole MR-Based Triple Therapy for Helicobacter Pylori Infection

    PubMed Central

    Wu, Deng-Chyang; Kuo, Chao-Hung; Tsay, Feng-Woei; Hsu, Wen-Hung; Chen, Angela; Hsu, Ping-I

    2016-01-01

    Abstract Dexlansoprazole MR is the R-enantiomer of lansoprazole that is delivered by a dual delayed release formulation. It is effective for symptom control of patients with gastroesophageal reflux disease. However, its efficacy in the treatment of Helicobacter pylori infection remains unclear. This pilot, randomized, controlled, head-to-head study was conducted to investigate whether the efficacy of single-dose dexlansoprazole MR-based triple therapy was noninferior to double-dose rabeprazole-based triple therapy in the treatment of H pylori infection. Consecutive H pylori-infected subjects were randomly allocated to either 7-day dexlansoprazole MR-based standard triple therapy (dexlansoprazole MR 60 mg once daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily) or rabeprazole-based triple therapy (rabeprazole 20 mg twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily). H pylori status was assessed 6 weeks after the end of treatment. A total of 177 H pylori-infected patients were randomized to receive dexlansoprazole MR-based (n = 90) or rabeprazole-based (n = 87) triple therapy. Intention-to-treat analysis demonstrated no differences between eradication rates of the 2 study groups (83.3% vs 81.6%; P = 0.736). Per-protocol analysis yielded comparable results (85.1% vs 81.2%; P = 0.497). Both groups exhibited similar frequencies of adverse events (7.8% vs 4.6%; P = 0.536) and drug compliance (98.9% vs 97.7%; P = 0.496). Multivariate analysis disclosed that the presence of clarithromycin resistance was the only independent factors predictive of treatment failure with an odds ratio of 6.8 (95% confidence interval: 1.2–37.6). This work demonstrates that single-dose dexlansoprazole MR-based triple therapy yields a similar eradication rate as double-dose rabeprazole-based therapy. Since the pharmaceutical cost of the single-dose dexlansoprazole MR regime is lower than that of the double

  19. A Pilot Randomized Controlled Study of Dexlansoprazole MR-Based Triple Therapy for Helicobacter Pylori Infection.

    PubMed

    Wu, Deng-Chyang; Kuo, Chao-Hung; Tsay, Feng-Woei; Hsu, Wen-Hung; Chen, Angela; Hsu, Ping-I

    2016-03-01

    Dexlansoprazole MR is the R-enantiomer of lansoprazole that is delivered by a dual delayed release formulation. It is effective for symptom control of patients with gastroesophageal reflux disease. However, its efficacy in the treatment of Helicobacter pylori infection remains unclear. This pilot, randomized, controlled, head-to-head study was conducted to investigate whether the efficacy of single-dose dexlansoprazole MR-based triple therapy was noninferior to double-dose rabeprazole-based triple therapy in the treatment of H pylori infection. Consecutive H pylori-infected subjects were randomly allocated to either 7-day dexlansoprazole MR-based standard triple therapy (dexlansoprazole MR 60 mg once daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily) or rabeprazole-based triple therapy (rabeprazole 20 mg twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily). H pylori status was assessed 6 weeks after the end of treatment. A total of 177 H pylori-infected patients were randomized to receive dexlansoprazole MR-based (n = 90) or rabeprazole-based (n = 87) triple therapy. Intention-to-treat analysis demonstrated no differences between eradication rates of the 2 study groups (83.3% vs 81.6%; P = 0.736). Per-protocol analysis yielded comparable results (85.1% vs 81.2%; P = 0.497). Both groups exhibited similar frequencies of adverse events (7.8% vs 4.6%; P = 0.536) and drug compliance (98.9% vs 97.7%; P = 0.496). Multivariate analysis disclosed that the presence of clarithromycin resistance was the only independent factors predictive of treatment failure with an odds ratio of 6.8 (95% confidence interval: 1.2-37.6). This work demonstrates that single-dose dexlansoprazole MR-based triple therapy yields a similar eradication rate as double-dose rabeprazole-based therapy. Since the pharmaceutical cost of the single-dose dexlansoprazole MR regime is lower than that of the double-dose rabeprazole

  20. Treatment adherence, clinical outcomes, and economics of triple-drug therapy in hypertensive patients.

    PubMed

    Panjabi, Sumeet; Lacey, Michael; Bancroft, Timothy; Cao, Felix

    2013-01-01

    Poor antihypertensive treatment adherence adversely affects blood pressure control. We analyzed US health plan data to assess the impact of fixed- versus loose-dose triple-combination therapy on adherence, clinical, and economic outcomes. Patients initiating triple therapy with an angiotensin receptor blocker, angiotensin-converting enzyme inhibitor, or beta blocker plus amlodipine and hydrochlorothiazide comprised three cohorts. Within-cohort comparisons were made between fixed-dose combinations of two antihypertensives plus a second pill (two pills) or three separate pills. Outcomes included adherence, cardiovascular events, health care resource use, and costs for patients with ≥ 12 months follow-up. A total of 16,290 patients were matched. Patients receiving two pills were more likely to be adherent (P < .001) and less likely to discontinue treatment (P < .001) across all cohorts. Therapy with two versus three pills resulted in significantly lower adjusted risk of cardiovascular events (hazard ratio = 0.76, P = .005) in the beta blocker cohort only. Total adjusted health care costs were significantly lower for two- versus three-pill therapy in the beta blocker cohort only (cost ratio = 0.74 overall, P < .01; 0.71 hypertension-attributable, P < .01). In patients with hypertension requiring triple therapy, fixed-dose combinations that lower pill burden may improve adherence (seen across all cohorts) and clinical outcomes (seen in the beta blocker cohort) without increasing health care costs.

  1. 'Ins' and 'outs' of triple therapy: Optimal antiplatelet therapy in patients on chronic oral anticoagulation who need coronary stenting.

    PubMed

    Dewilde, W; Verheugt, F W A; Breet, N; Koolen, J J; Ten Berg, J M

    2010-09-01

    Chronic oral anticoagulant treatment is obligatory in patients (class I) with mechanical heart valves and in patients with atrial fibrillation with CHADS2 score >1. When these patients undergo percutaneous coronary intervention with placement of a stent, there is also an indication for treatment with aspirin and clopidogrel. Unfortunately, triple therapy is known to increase the bleeding risk. For this group of patients, the bottom line is to find the ideal therapy in patients with indications for both chronic anticoagulation therapy and percutaneous intervention to prevent thromboembolic complications such as stent thrombosis without increasing the risk of bleeding. (Neth Heart J 2010;18:444-50.).

  2. [Triple therapy in cirrhotic patients and those with advanced fibrosis: relevant aspects in clinical practice].

    PubMed

    Albillos, Agustín; Luis Calleja, José; Molina, Esther; Planas, Ramon; Romero-Gómez, Manuel; Turnes, Juan; Hernández-Guerra, Manuel

    2014-07-01

    The first-line option in the treatment of patients with advanced fibrosis and cirrhosis due to genotype 1 hepatitis C virus is currently triple therapy with boceprevir/telaprevir and pegylated interferon-ribavirin. However, certain limitations could constitute a barrier to starting treatment or achieving sustained viral response in these patients. These limitations include the patient's or physician's perception of treatment effectiveness in routine clinical practice-which can weight against the decision to start treatment-, the advanced stage of the disease with portal hypertension and comorbidity, treatment interruption due to poor adherence, and adverse effects, mainly anemia. In addition, it is now possible to identify patients who could benefit from a shorter therapeutic regimen with a similar cure rate. This review discusses these issues and their possible effect on the use of triple therapy. PMID:25907434

  3. Triple Therapy with First Generation Protease Inhibitors for Hepatitis C Markedly Impairs Function of Neutrophil Granulocytes.

    PubMed

    Spindelboeck, Walter; Horvath, Angela; Tawdrous, Monika; Schmerböck, Bianca; Zettel, Gabriele; Posch, Andreas; Streit, Andrea; Jurse, Petra; Lemesch, Sandra; Horn, Martin; Wuensch, Gerit; Stiegler, Philipp; Stauber, Rudolf E; Leber, Bettina; Stadlbauer, Vanessa

    2016-01-01

    First-generation HCV protease inhibitors represent a milestone in antiviral therapy for chronic hepatitis C infection (CHC), but substantially increased rates of viral clearance are offset by increased rates of infection and infection-associated deaths, especially of patients with advanced liver disease. We aimed to assess whether first generation protease inhibitors interfere with neutrophil function. We included 108 consecutive, retrospective CHC patients and 44 consecutive, prospective CHC patients who were treated with peginterferon and ribavirin with or without protease inhibitors according to the guidelines in the period of November 2012 to June 2015. 33 healthy volunteers served as controls. Infection data were evaluated in all patients. Neutrophil phagocytosis, oxidative burst, elastase and diamine oxidase levels during 12 weeks of triple (n = 23) or dual therapy (n = 21) were studied in the prospective part. In the retro- and prospective cohorts patients experiencing clinically relevant infections were significantly more frequent during protease inhibitor therapy (31% and 26%) than during therapy with peginterferon and ribavirin (13% and 0%). Neutrophil phagocytosis decreased to 40% of baseline with addition of protease inhibitors to P/R but recovered 6 months after end of treatment. Protease inhibitors also seemed to reduce serum elastase levels but did not impact on gut permeability. Impaired neutrophil function during triple therapy with first generation HCV protease inhibitors may explain the high infection rate associated to these treatments and be of relevance for treatment success and patient survival. PMID:26938078

  4. Triple Therapy with First Generation Protease Inhibitors for Hepatitis C Markedly Impairs Function of Neutrophil Granulocytes

    PubMed Central

    Tawdrous, Monika; Schmerböck, Bianca; Zettel, Gabriele; Posch, Andreas; Streit, Andrea; Jurse, Petra; Lemesch, Sandra; Horn, Martin; Wuensch, Gerit; Stiegler, Philipp; Stauber, Rudolf E.; Leber, Bettina; Stadlbauer, Vanessa

    2016-01-01

    First-generation HCV protease inhibitors represent a milestone in antiviral therapy for chronic hepatitis C infection (CHC), but substantially increased rates of viral clearance are offset by increased rates of infection and infection-associated deaths, especially of patients with advanced liver disease. We aimed to assess whether first generation protease inhibitors interfere with neutrophil function. We included 108 consecutive, retrospective CHC patients and 44 consecutive, prospective CHC patients who were treated with peginterferon and ribavirin with or without protease inhibitors according to the guidelines in the period of November 2012 to June 2015. 33 healthy volunteers served as controls. Infection data were evaluated in all patients. Neutrophil phagocytosis, oxidative burst, elastase and diamine oxidase levels during 12 weeks of triple (n = 23) or dual therapy (n = 21) were studied in the prospective part. In the retro- and prospective cohorts patients experiencing clinically relevant infections were significantly more frequent during protease inhibitor therapy (31% and 26%) than during therapy with peginterferon and ribavirin (13% and 0%). Neutrophil phagocytosis decreased to 40% of baseline with addition of protease inhibitors to P/R but recovered 6 months after end of treatment. Protease inhibitors also seemed to reduce serum elastase levels but did not impact on gut permeability. Impaired neutrophil function during triple therapy with first generation HCV protease inhibitors may explain the high infection rate associated to these treatments and be of relevance for treatment success and patient survival. Trial Registration ClinicalTrials.gov NCT02545400 ClinicalTrials.gov NCT02545335 PMID:26938078

  5. Helicobacter pylori is not eradicated after triple therapy: a nested PCR based study.

    PubMed

    Patel, Saurabh Kumar; Mishra, Girish Narayan; Pratap, Chandra Bhan; Jain, Ashok Kumar; Nath, Gopal

    2014-01-01

    Detection of Helicobacter pylori after triple therapy is usually carried out by either rapid urease test (RUT), urea breath test (UBT), histology, bacterial isolation, and single round PCR or serological tests. In this study, antral biopsy specimens from 25 patients were tested for H. pylori by RUT, culture, histology, and nested PCR in their antral biopsy specimens before and after treatment. Three genes, namely, heat shock protein (hsp60), phosphoglucosamine mutase (ureC), and flagellar export ATP synthase (fliI) of H. pylori were targeted. Of the 25 antral biopsy specimens, the RUT, culture, histology, and nested PCR positivity dropped from 81.8% to 12%, 31% to 0%, 100 to 84%, and 100% to 92%, respectively, before and after therapy. Further, hsp60 specific amplicons from 23 out of 25 patients gave identical restriction pattern, while 6 fliI and 1 ureC specific amplicon produced different restriction pattern. Furthermore, variations in fliI gene sequences in H. pylori after treatment were also confirmed by sequencing and compared in silico. Nested PCR based detection of H. pylori is more sensitive method to detect H. pylori after therapy than culture, RUT, and histology. Further, this study suggests that H. pylori is not eradicated completely after triple therapy.

  6. Recombinant human lactoferrin enhances the efficacy of triple therapy in mice infected with Helicobacter pylori.

    PubMed

    Yuan, Yuping; Wu, Qinyi; Cheng, Guoxiang; Liu, Xuefang; Liu, Siguo; Luo, Juan; Zhang, Aimin; Bian, Li; Chen, Jianquan; Lv, Jiajun; Dong, Xiangqian; Yang, Gang; Zhu, Yunzhen; Ma, Lanqing

    2015-08-01

    Helicobacter pylori (H. pylori) is a life-threatening pathogen which causes chronic gastritis, gastric ulcers and even stomach cancer. Treatment normally involves bacterial eradication; however, this type of treatment only has a rate of effectiveness of <80%. Thus, it is a matter of some urgency to develop new therapeutic strategies. Lactoferrin, a member of the transferrin family of iron-binding proteins, has been proven to be effective in removing a vast range of pathogens, including H. pylori. In the present study, we examined the effectiveness of recombinant human lactoferrin (rhLf) isolated from transgenic goats as a treatment for H. pylori in vitro and in vivo. For the in vivo experiments, BALB/c mice received an intragastric administration of 0.1 ml of a suspension of H. pylori. The mice were then divided into 4 groups: group A, treated with saline; group B, treated with 1.5 g of rhLF; group C, treated with the standard triple therapy regimen; and group D, treated with the standard triple therapy regimen plus.5 g of rhLF. Following sacrifice, the stomach tissues of the mice were histologically examined for the presence of bacteria. For the in vitro experiments, the bacteria were cultured in BHI broth and RT-qPCR and western blot analysis were carried out to determine the mRNA and protein levels of virulence factors (CagA and VacA) in the cultures. Our results revealed that rhLf not only inhibited the growth of H. pylori, but also suppressed the expression of two major virulence factors. Moreover, rhLf markedly increased bacterial eradication and effectively reduced the inflammatory response when combined with the standard triple therapy regimen. These results provide evidence supporting the use of rhLF as an adjuvant to traditional therapeutic strategies in the treatment of H. pylori.

  7. First- and second-line Helicobacter pylori eradication with modified sequential therapy and modified levofloxacin-amoxicillin-based triple therapy

    PubMed Central

    Zullo, Angelo; Ridola, Lorenzo; Efrati, Cesare; Giorgio, Floriana; Nicolini, Giorgia; Cannaviello, Claudio; Alvaro, Domenico; Hassan, Cesare; Gatta, Luigi; Francesco, Vincenzo De

    2014-01-01

    Background Helicobacter pylori (H. pylori) treatment remains a challenge for physicians. Although highly effective, the standard sequential therapy fails in a certain number of patients. Moreover, the cure rate following a levofloxacin-amoxicillin second-line triple therapy seems to be decreasing. We tested the efficacy of modified 10-day sequential therapy, and an intensified levofloxacin-amoxicillin regimen as first- and second-line therapy respectively. Methods In this prospective, open label, multicenter, pilot study H. pylori-infected patients received a first-line modified 10-day sequential therapy regimen including rabeprazole 20 mg, and amoxicillin 1 g for the first 3 days, followed by rabeprazole 20 mg, clarithromycin 250 mg, and metronidazole 250 mg, for the remaining 7 days, all drugs given thrice daily. An 8-day therapy regimen with rabeprazole 20 mg, levofloxacin 250 mg, and amoxicillin 1 g, all thrice daily, was administered a second-line therapy. Results A total of 99 and 15 patients were enrolled for first- and second-line therapy. The eradication rates were 85.9% (95% CI 80-93) and 93.4% (95% CI 88-98) according to ITT and PP analyses following modified sequential therapy, and 60% (95% CI 35-86) and 64.3% (95% CI 39-89) following the intensified second-line therapy. Conclusion A modified sequential 3- plus 7-day regimen with thrice daily drug administration failed to achieve very high eradication rate at ITT analysis. The intensified second-line regimen achieved disappointingly low eradication rate. Novel levofloxacin-free second-line therapies are urged in Italy. PMID:25330819

  8. Helicobacter pylori eradication with either seven-day or 10-day triple therapies, and with a 10-day sequential regimen

    PubMed Central

    Scaccianoce, Giuseppe; Hassan, Cesare; Panarese, Alba; Piglionica, Donato; Morini, Sergio; Zullo, Angelo

    2006-01-01

    BACKGROUND Helicobacter pylori eradication rates achieved by standard seven-day triple therapies are decreasing in several countries, while a novel 10-day sequential regimen has achieved a very high success rate. A longer 10-day triple therapy, similar to the sequential regimen, was tested to see whether it could achieve a better infection cure rate. METHODS Patients with nonulcer dyspepsia and H pylori infection were randomly assigned to one of the following three therapies: esomeprazole 20 mg, clarithromycin 500 mg and amoxycillin 1 g for seven days or 10 days, or a 10-day sequential regimen including esomeprazole 20 mg plus amoxycillin 1 g for five days and esomeprazole 20 mg, clarithromycin 500 mg and tinidazole 500 mg for the remaining five days. All drugs were given twice daily. H pylori eradication was checked four to six weeks after treatment by using a 13C-urea breath test. RESULTS Overall, 213 patients were enrolled. H pylori eradication was achieved in 75.7% and 77.9%, in 81.7% and 84.1%, and in 94.4% and 97.1% of patients following seven-day or 10-day triple therapy and the 10-day sequential regimen, at intention-to-treat and per protocol analyses, respectively. The eradication rate following the sequential regimen was higher than either seven-day (P=0.002) or 10-day triple therapy (P=0.02), while no significant difference emerged between the latter two regimens (P=0.6). CONCLUSIONS The 10-day sequential regimen was significantly more effective than both triple regimens, while 10-day triple therapy failed to significantly increase the H pylori eradication rate achieved by the standard seven-day regimen. PMID:16482238

  9. Rapid Extensive Recurrence of Triple Negative Breast Cancer: Are Both Therapy and Cancer Biology the Culprit?

    PubMed

    Vyas, Dinesh; Deshpande, Kaivalya; Chaturvedi, Lakshmishankar; Gieric, Laput; Ching, Karen

    2016-02-01

    Triple negative breast cancer (TNBC) comprises 17-20% of all breast cancers and is one of the most common breast cancers. The lack of therapy and failure of existing therapy has been a challenge for clinicians. Doxorubicin (DOX) is the first-line therapy, however, it has significant limitations. Rapid extensive recurrence with metastasis in any cancer has been a challenge for surgeons and medical oncologists. The challenge can be due to failure of therapy, drug resistance, or epigenetic changes. Here, we are discussing a stage I breast cancer patient, operated and treated with appropriate chemotherapy with complete response, which recurred in less than 8 months and metastasized to bone, liver and other organs. We are also presenting lab data of the IL-6 secretions on exposure to DOX in one of the most commonly used TNBC cell lines MDA-MB-231. Breast cancer cell line MDA-MB-231 upon exposure to DOX shows an increase in IL-6 levels more than the already elevated IL-6 levels. This might be a reason for early recurrence. We concluded that patients with TNBC might benefit from a standard DOX treatment regimen with an inflammation-blocking agent. PMID:26767086

  10. Rapid Extensive Recurrence of Triple Negative Breast Cancer: Are Both Therapy and Cancer Biology the Culprit?

    PubMed Central

    Vyas, Dinesh; Deshpande, Kaivalya; Chaturvedi, Lakshmishankar; Gieric, Laput; Ching, Karen

    2016-01-01

    Triple negative breast cancer (TNBC) comprises 17-20% of all breast cancers and is one of the most common breast cancers. The lack of therapy and failure of existing therapy has been a challenge for clinicians. Doxorubicin (DOX) is the first-line therapy, however, it has significant limitations. Rapid extensive recurrence with metastasis in any cancer has been a challenge for surgeons and medical oncologists. The challenge can be due to failure of therapy, drug resistance, or epigenetic changes. Here, we are discussing a stage I breast cancer patient, operated and treated with appropriate chemotherapy with complete response, which recurred in less than 8 months and metastasized to bone, liver and other organs. We are also presenting lab data of the IL-6 secretions on exposure to DOX in one of the most commonly used TNBC cell lines MDA-MB-231. Breast cancer cell line MDA-MB-231 upon exposure to DOX shows an increase in IL-6 levels more than the already elevated IL-6 levels. This might be a reason for early recurrence. We concluded that patients with TNBC might benefit from a standard DOX treatment regimen with an inflammation-blocking agent. PMID:26767086

  11. Triple Combination Therapy for Global Cardiovascular Risk: Atorvastatin, Perindopril, and Amlodipine.

    PubMed

    Bertrand, Michel E; Vlachopoulos, Charalambos; Mourad, Jean-Jacques

    2016-08-01

    Statins, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers (CCBs) have markedly changed the clinical progression of patients with coronary artery disease (CAD). The goal of this paper is to review the rationale and evidence for combining these three drug classes in hypertensive patients with hypercholesterolemia or CAD. Data sources include a literature search for publications on the use of a statin combined with various antihypertensive drugs in patients with hypertension and hypercholesterolemia or stable CAD. Hypercholesterolemia and hypertension constitute major physiological risk factors of ischemic heart disease. Current guidelines recommend a global approach to risk management, using agents that address as many risk factors as possible. Dual combination therapies are an important component of guideline-recommended therapy in hypertension. Our review of the literature indicates that triple therapy with a statin, ACE inhibitor, and CCB is associated with a significant reduction in major cardiovascular events. For example, a post hoc analysis in 1056 patients with stable CAD participating in the EUROPA trial indicated that the addition of perindopril to a CCB and a lipid-lowering agent was associated with a 46 % reduction in the composite of cardiovascular death, myocardial infarction, and resuscitated cardiac arrest (p = 0.023). In addition, single pill formulations are known to result in better adherence to the treatment. Single-pill formulations that combine a statin, an ACE inhibitor, and a CCB appear to offer an effective approach to the management of global cardiovascular risk. PMID:27256435

  12. Multifunctional hollow gold nanoparticles designed for triple combination therapy and CT imaging.

    PubMed

    Park, Jaesook; Park, Jin; Ju, Eun Jin; Park, Seok Soon; Choi, Jinhyang; Lee, Jae Hee; Lee, Kyoung Jin; Shin, Seol Hwa; Ko, Eun Jung; Park, Intae; Kim, Chulhee; Hwang, Jung Jin; Lee, Jung Shin; Song, Si Yeol; Jeong, Seong-Yun; Choi, Eun Kyung

    2015-06-10

    Hollow gold nanoparticles (HGNP) are a novel class of hybrid metal nanoparticles whose unique optical and morphological properties have spawned new applications including more effective cancer therapy. The shell thickness of HGNPs can tune the surface plasmon resonance to the near infrared light, resulting in photothermal ablation of tumors with optimal light penetration in tissue. The hollow cavity within a HGNP is able to accommodate a high payload of chemotherapeutic agents. They have also been used for enhancing radiosensitization in tumors during radiotherapy due to the high X-ray absorption capability of gold particles. However, no report has yet been published that utilize HGNPs for the triple combination therapy and CT imaging. In this study, we synthesized HGNPs which exhibit better response to radiation for therapy and imaging and demonstrated the effects of combined chemotherapy, thermal and radiotherapy. This combination strategy presented delayed tumor growth by 4.3-fold and reduced tumor's weight by 6.8-fold compared to control tumors. In addition, we demonstrated the feasibility of HGNP as a CT imaging agent. It is expected that translating these capabilities to human cancer patients could dramatically increase the antitumor effect and potentially overcome resistance to chemotherapeutic agents and radiation. PMID:25863273

  13. Prolactin Pro-Differentiation Pathway in Triple Negative Breast Cancer: Impact on Prognosis and Potential Therapy.

    PubMed

    López-Ozuna, Vanessa M; Hachim, Ibrahim Y; Hachim, Mahmood Y; Lebrun, Jean-Jacques; Ali, Suhad

    2016-01-01

    Triple negative breast cancer (TNBC) is a heterogeneous disease associated with poor clinical outcome and lack of targeted therapy. Here we show that prolactin (PRL) and its signaling pathway serve as a sub-classifier and predictor of pro-differentiation therapy in TNBC. Using immunohistochemistry and various gene expression in silica analyses we observed that prolactin receptor (PRLR) protein and mRNA levels are down regulated in TNBC cases. In addition, examining correlation of PRLR gene expression with metagenes of TNBC subtypes (580 cases), we found that PRLR gene expression sub-classifies TNBC patients into a new subgroup (TNBC-PRLR) characterized by epithelial-luminal differentiation. Importantly, gene expression of PRL signaling pathway components individually (PRL, PRLR, Jak2 and Stat5a), or as a gene signature is able to predict TNBC patients with significantly better survival outcomes. As PRL hormone is a druggable target we determined the biological role of PRL in TNBC biology. Significantly, restoration/activation of PRL pathway in TNBC cells representative of mesenchymal or TNBC-PRLR subgroups led to induction of epithelial phenotype and suppression of tumorigenesis. Altogether, these results offer potential new modalities for TNBC stratification and development of personalized therapy based on PRL pathway activation. PMID:27480353

  14. Prolactin Pro-Differentiation Pathway in Triple Negative Breast Cancer: Impact on Prognosis and Potential Therapy

    PubMed Central

    López-Ozuna, Vanessa M.; Hachim, Ibrahim Y.; Hachim, Mahmood Y.; Lebrun, Jean-Jacques; Ali, Suhad

    2016-01-01

    Triple negative breast cancer (TNBC) is a heterogeneous disease associated with poor clinical outcome and lack of targeted therapy. Here we show that prolactin (PRL) and its signaling pathway serve as a sub-classifier and predictor of pro-differentiation therapy in TNBC. Using immunohistochemistry and various gene expression in silica analyses we observed that prolactin receptor (PRLR) protein and mRNA levels are down regulated in TNBC cases. In addition, examining correlation of PRLR gene expression with metagenes of TNBC subtypes (580 cases), we found that PRLR gene expression sub-classifies TNBC patients into a new subgroup (TNBC-PRLR) characterized by epithelial-luminal differentiation. Importantly, gene expression of PRL signaling pathway components individually (PRL, PRLR, Jak2 and Stat5a), or as a gene signature is able to predict TNBC patients with significantly better survival outcomes. As PRL hormone is a druggable target we determined the biological role of PRL in TNBC biology. Significantly, restoration/activation of PRL pathway in TNBC cells representative of mesenchymal or TNBC-PRLR subgroups led to induction of epithelial phenotype and suppression of tumorigenesis. Altogether, these results offer potential new modalities for TNBC stratification and development of personalized therapy based on PRL pathway activation. PMID:27480353

  15. Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome.

    PubMed

    Coughlin, Curtis R; van Karnebeek, Clara D M; Al-Hertani, Walla; Shuen, Andrew Y; Jaggumantri, Sravan; Jack, Rhona M; Gaughan, Sommer; Burns, Casey; Mirsky, David M; Gallagher, Renata C; Van Hove, Johan L K

    2015-01-01

    Pyridoxine-dependent epilepsy (PDE) is an epileptic encephalopathy characterized by response to pharmacologic doses of pyridoxine. PDE is caused by deficiency of α-aminoadipic semialdehyde dehydrogenase resulting in impaired lysine degradation and subsequent accumulation of α-aminoadipic semialdehyde. Despite adequate seizure control with pyridoxine monotherapy, 75% of individuals with PDE have significant developmental delay and intellectual disability. We describe a new combined therapeutic approach to reduce putative toxic metabolites from impaired lysine metabolism. This approach utilizes pyridoxine, a lysine-restricted diet to limit the substrate that leads to neurotoxic metabolite accumulation and L-arginine to compete for brain lysine influx and liver mitochondrial import. We report the developmental and biochemical outcome of six subjects who were treated with this triple therapy. Triple therapy reduced CSF, plasma, and urine biomarkers associated with neurotoxicity in PDE. The addition of arginine supplementation to children already treated with dietary lysine restriction and pyridoxine further reduced toxic metabolites, and in some subjects appeared to improve neurodevelopmental outcome. Dietary lysine restriction was associated with improved seizure control in one subject, and the addition of arginine supplementation increased the objective motor outcome scale in two twin siblings, illustrating the contribution of each component of this treatment combination. Optimal results were noted in the individual treated with triple therapy early in the course of the disease. Residual disease symptoms could be related to early injury suggested by initial MR imaging prior to initiation of treatment or from severe epilepsy prior to diagnosis. This observational study reports the use of triple therapy, which combines three effective components in this rare condition, and suggests that early diagnosis and treatment with this new triple therapy may ameliorate the

  16. A rare type of ventricular oversensing in ICD therapy--inappropriate ICD shock delivery due to triple counting.

    PubMed

    Guenther, Michael; Rauwolf, Thomas P; Bock, Manja; Strasser, Ruth H; Braun, Martin U

    2010-02-01

    Irregular sensing by triple counting of wide QRS complexes resulted in inappropriate shocks in a patient with a biventricular implantable cardioverter defibrillator (ICD): A 66-year-old male patient with ischemic cardiomyopathy, left bundle branch block, and impaired left ventricular function received a biventricular ICD for optimal therapy of heart failure (CHF). Two years after implantation, the patient experienced recurrent unexpected ICD shocks without clinical symptoms of malignant tachyarrhythmia, or worsened CHF. The patient's condition rapidly worsened, with progressive cardiogenic shock and electrical-mechanical dissociation. After unsuccessful resuscitation of the patient the interrogation of the ICD showed an initial triple counting of extremely wide and fragmented QRS complexes with inappropriate shocks.

  17. Efficacy of the triple therapy: proton pomp inhibitors, amoxicillin and tynidazole in Helicobacter pylori infection treatment.

    PubMed

    Kos, Marek; Zinkiewicz, Krzysztof; Stefanek, Janusz; Dabrowski, Andrzej

    2002-01-01

    The aim of the paper is to present the triple therapy results combined with the application of proton pump inhibitors with amoxicillin and tynidazole in treatment of the contagion caused by Helicobacter pylori. The therapy was carried out among 108 people after realization of endoscopic biopsy and with quick urease test. In the endoscopic investigation 72 people were found to have duodenum ulceration. Inflammation of mucous duodenum was found in 36 patients. Among 108 people under investigation 51.85% were men and 48.15% women. These people were aged between 15-81 (the average age was 44). After the use of eradication 99 out of 108 patients (91.66%) were cured. The lack of improvement was found in 9 people (8.34%). The age of these people varied from 18 to 75, which gives the average age 54.5 (this age is about 10 years and a half higher in relation to the average age of the examined group of patients). The results prove high efficiency of this schema of treatment in relation to comparatively low costs. They also indicate greater efficiency of the treatment of contagious caused by Helicobacter pylori in younger people. PMID:12898919

  18. A perspective on anti-EGFR therapies targeting triple-negative breast cancer.

    PubMed

    Nakai, Katsuya; Hung, Mien-Chie; Yamaguchi, Hirohito

    2016-01-01

    Triple-negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), accounts for about 15-20% of breast cancers and is the most aggressive breast cancer subtype. There are currently no effective therapies against metastatic TNBC. Compared with other breast cancer subtypes, EGFR is frequently overexpressed in TNBC and a potential therapeutic target for this disease. There are two types of EGFR inhibitors, small molecular tyrosine kinase inhibitor (TKI) and monoclonal antibody (mAb), for the treatment of cancers, such as non-small cell lung cancer and colorectal cancer. For breast cancer, however, the clinical trials of EGFR inhibitors have failed due to low response rates. Because a small portion of patients do demonstrate response to EGFR inhibitors, it may be necessary to stratify patients to enhance the efficacy of EGFR inhibitors in TNBC and to develop the effective combination therapy for this patient population. In this review, we describe some of the molecular mechanisms underlying EGFR inhibitor sensitivity and further discuss the possible therapeutic strategies to increase the efficacy of EGFR inhibitors in TNBC. PMID:27648353

  19. A perspective on anti-EGFR therapies targeting triple-negative breast cancer

    PubMed Central

    Nakai, Katsuya; Hung, Mien-Chie; Yamaguchi, Hirohito

    2016-01-01

    Triple-negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), accounts for about 15-20% of breast cancers and is the most aggressive breast cancer subtype. There are currently no effective therapies against metastatic TNBC. Compared with other breast cancer subtypes, EGFR is frequently overexpressed in TNBC and a potential therapeutic target for this disease. There are two types of EGFR inhibitors, small molecular tyrosine kinase inhibitor (TKI) and monoclonal antibody (mAb), for the treatment of cancers, such as non-small cell lung cancer and colorectal cancer. For breast cancer, however, the clinical trials of EGFR inhibitors have failed due to low response rates. Because a small portion of patients do demonstrate response to EGFR inhibitors, it may be necessary to stratify patients to enhance the efficacy of EGFR inhibitors in TNBC and to develop the effective combination therapy for this patient population. In this review, we describe some of the molecular mechanisms underlying EGFR inhibitor sensitivity and further discuss the possible therapeutic strategies to increase the efficacy of EGFR inhibitors in TNBC.

  20. A perspective on anti-EGFR therapies targeting triple-negative breast cancer

    PubMed Central

    Nakai, Katsuya; Hung, Mien-Chie; Yamaguchi, Hirohito

    2016-01-01

    Triple-negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), accounts for about 15-20% of breast cancers and is the most aggressive breast cancer subtype. There are currently no effective therapies against metastatic TNBC. Compared with other breast cancer subtypes, EGFR is frequently overexpressed in TNBC and a potential therapeutic target for this disease. There are two types of EGFR inhibitors, small molecular tyrosine kinase inhibitor (TKI) and monoclonal antibody (mAb), for the treatment of cancers, such as non-small cell lung cancer and colorectal cancer. For breast cancer, however, the clinical trials of EGFR inhibitors have failed due to low response rates. Because a small portion of patients do demonstrate response to EGFR inhibitors, it may be necessary to stratify patients to enhance the efficacy of EGFR inhibitors in TNBC and to develop the effective combination therapy for this patient population. In this review, we describe some of the molecular mechanisms underlying EGFR inhibitor sensitivity and further discuss the possible therapeutic strategies to increase the efficacy of EGFR inhibitors in TNBC. PMID:27648353

  1. Delivery of bortezomib with nanoparticles for basal-like triple-negative breast cancer therapy.

    PubMed

    Shen, Song; Du, Xiao-Jiao; Liu, Jing; Sun, Rong; Zhu, Yan-Hua; Wang, Jun

    2015-06-28

    Basal-like triple negative breast cancer (TNBC) has received particular clinical interest due to its high frequency, poor baseline prognosis and lack of effective clinical therapy. Bortezomib, which was the first proteasome inhibitor approved for the treatment of multiple myeloma, has been proven to be worth investigating for this subtype of breast cancer. In our study, the amphiphilic copolymer poly(ethylene glycol)-block-poly(d,l-lactide) (PEG-b-PLA) was utilized as an excellent delivery carrier of bortezomib (BTZ) to overcome its clinical limitations including low water solubility and unstable properties. Bortezomib encapsulated nanoparticles (NPBTZ) can efficiently deliver the drug into both CSCs (cancer stem cells) and non-CSCs, resulting in proliferation inhibition and apoptosis induction. Remarkably, NPBTZ can more effectively affect the stemness of CSCs compared with free BTZ. Administration of this drug delivery system can markedly prolong the bortezomib circulation half-life and augment the enrichment of drugs in tumor tissue, then enhance the suppression of tumor growth, suggesting the therapeutic promise of NPBTZ delivery in basal-like TNBC therapy.

  2. Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy.

    PubMed

    Lindner, Robert; Sullivan, Catherine; Offor, Onyinye; Lezon-Geyda, Kimberly; Halligan, Kyle; Fischbach, Neal; Shah, Mansi; Bossuyt, Veerle; Schulz, Vincent; Tuck, David P; Harris, Lyndsay N

    2013-01-01

    Triple negative breast cancer (TNBC) is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African American (AA) patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA). It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, gene expression profiling and immunohistochemistry were used to elucidate potential differences between TNBC tumors of EA and AA patients on a molecular level. In a retrospective cohort of 136 TNBC patients, a major transcriptional signature of proliferation was found to be significantly upregulated in samples of AA ethnicity. Furthermore, transcriptional profiles of AA tumors showed differential activation of insulin-like growth factor 1 (IGF1) and a signature of BRCA1 deficiency in this cohort. Using signatures derived from the meta-analysis of TNBC gene expression carried out by Lehmann et al., tumors from AA patients were more likely of basal-like subtypes whereas transcriptional features of many EA samples corresponded to mesenchymal-like or luminal androgen receptor driven subtypes. These results were validated in The Cancer Genome Atlas mRNA and protein expression data, again showing enrichment of a basal-like phenotype in AA tumors and mesenchymal subtypes in EA tumors. In addition, increased expression of VEGF-activated genes together with elevated microvessel area determined by the AQUA method suggest that AA patients exhibit higher tumor vascularization. This study confirms the existence of distinct transcriptional programs in triple negative breast cancer in two separate cohorts and that these programs differ by racial group. Differences in TNBC subtypes and levels of tumor angiogenesis in AA versus EA patients

  3. Clinical pilot study: efficacy of triple antibiotic therapy in Blastocystis positive irritable bowel syndrome patients

    PubMed Central

    2014-01-01

    Background Blastocystis species are common human enteric parasites. Carriage has been linked to Irritable Bowel Syndrome (IBS). Treatment of Blastocystis spp. with antimicrobials is problematic and insensitive diagnostic methods and re-infection complicate assessment of eradication. We investigated whether triple antibiotic therapy comprising diloxanide furoate, trimethoprim/sulfamethoxazole and secnidazole (TAB) given to diarrhoea-predominant IBS (D-IBS) patients positive for Blastocystis would achieve eradication. Methods In a longitudinal, prospective case study 10 D-IBS Blastocystis-positive patients took 14 days of diloxanide furoate 500 mg thrice daily, trimethoprim/sulfamethoxazole 160/80 mg twice daily and secnidazole 400 mg thrice daily. Faecal specimens were collected at baseline, day 15 and 4 weeks after completion of TAB. Specimens were analysed using faecal smear, culture and polymerase chain reaction (PCR) of the 16 SSU rRNA. Patients kept a concurrent clinical diary. Results Six (60%) patients cleared Blastocystis spp. after TAB, including three who had failed previous therapy. Subtypes detected were ST3 (60%), ST4 (40%), ST1 (20%) and ST7, 8 (10%); four patients had mixed ST infections. Serum immunoglobulin A (IgA) levels were low in 40% of patients. Higher rates of Blastocystis clearance were observed in patients symptomatic for less than a year (Mann–Whitney, p = 0.032, 95% confidence) with no associations found with age, previous antibiotic therapy, faecal parasite load, ST, IgA level or clinical improvement. Conclusions Clearance of Blastocystis spp. was achieved with TAB in 60% of D-IBS patients, an improvement over conventional monotherapy. Higher clearance rates are needed to facilitate investigation of the relevance of this parasite in clinically heterogenous IBS. PMID:25349629

  4. A case report: antiviral triple therapy with telaprevir in a haemodialysed HCV patient in Turkey.

    PubMed

    Akhan, S; Sayan, M; Sargin Altunok, E; Aynioglu, A

    2015-12-01

    A 49-year-old woman was diagnosed with chronic hepatitis C 7 years ago. She began haemodialysis at the same time. She was on the waiting list for kidney transplantation (KTx). The real-time PCR technique revealed an HCV RNA viral load of 212,000 IU/ml, genotype 1a, IL28B the rs12979860 minor allele heterozygous CT (rs8099917 TT homozygous). She had a history of first antiviral treatment for 48 weeks of PEG-IFN-alpha 2a, 135 μg/week in 2011, but the HCV infection relapsed. Considering her relatively young age, candidacy for renal transplant, and the heterozygous pattern of IL28B, we decided to proceed with a second (and last) antiviral treatment using triple therapy with telaprevir at the regular dose of 750 mg every 8 hours+PEG-IFN-alpha 2a 135 μg/week sc+200 mg RBV three times a week. At the end of 6-month therapy, HCV RNA was found to be negative at months 3, 5, and 6.The patient has reached the sustained virological response (SVR) and is ready for KTx. All renal transplant candidates (dialysis-dependent, or not) with HCV should be assessed for antiviral treatment given the increased risk of progressive liver disease due to immunosuppressive therapy, increased life expectancy compared to other HCV-positive patients on dialysis, and the inability to receive interferon after transplantation. PMID:26790555

  5. Simultaneous determination of triple therapy for Helicobacter pylori in human plasma by reversed phase chromatography with online wavelength switching

    NASA Astrophysics Data System (ADS)

    Ahmed, Sameh; Atia, Noha N.

    2015-02-01

    The infection of gastric mucosa by Helicobacter pylori (HP) is an essential cofactor in the aetiology of gastroduodenal ulcer and gastric carcinoma. Because of the bacterial resistance, combination therapy containing omeprazole (OME), tinidazole (TNZ) and clarithromycin (CLA) is commonly used for eradication of HP. However, the simultaneous determination of the triple therapy in human plasma was not reported. A simple, reproducible, and selective HPLC method was developed for the simultaneous determination of the triple therapy mixture used for management of HP infections in human plasma. An HPLC procedure based on a liquid-liquid extraction, enrichment of the analytes and subsequent reversed-phase chromatography with UV detection was used. To enable sensitive and selective detection, the method involved the use of online wavelength switching detection, with two different detection wavelengths; 280 nm for detection of OME and TNZ and 210 nm for detection of CLA. Separations were performed on C18 analytical column with acetonitrile-10 mM phosphate buffer of pH = 3.0 at flow rate of 1.0 mL min-1. The linear ranges in human plasma were 0.05-10 μg mL-1 with correlation coefficients >0.9990. The detection limits in human plasma were 0.02-0.07 μg mL-1. Validation parameters were assessed in compliance with US-FDA guidelines. The method proved to be valuable for the therapeutic drug monitoring after oral administration of triple therapy tablets.

  6. Successful Treatment of Chronic Hepatitis C with Triple Therapy in an Opioid Agonist Treatment Program

    PubMed Central

    Litwin, Alain H.; Soloway, Irene J.; Cockerham-Colas, Lauren; Reynoso, Sheila; Heo, Moonseong; Tenore, Christopher; Roose, Robert J.

    2015-01-01

    Background People who inject drugs (PWID) constitute 10 million people globally with hepatitis C virus, including many opioid agonist treatment patients. Little data exist describing clinical outcomes for patients receiving HCV treatment with direct-acting antiviral agents (DAAs) in opioid agonist treatment settings. Methods In this retrospective observational study, we describe clinical outcomes for 50 genotype-1 patients receiving HCV treatment with triple therapy: telaprevir (n = 42) or boceprevir (n = 8) in combination with pegylated interferon and ribavirin on-site in an opioid agonist treatment program. Results Overall, 70% achieved an end of treatment response (ETR) and 62% achieved a sustained virological response (SVR). These treatment outcomes are nearly equivalent to previously published HCV outcomes shown in registration trials, despite high percentages of recent drug use prior to treatment (52%), ongoing drug use during treatment (45%) and psychiatric comorbidity (86%). Only 12% (n=6) discontinued antiviral treatment early for non-virological reasons. Four patients received a blood transfusion, and one discontinued telaprevir due to severe rash. Conclusions These data demonstrate that on-site HCV treatment with direct-acting antiviral agents is effective in opioid agonist treatment patients including patients who are actively using drugs. Future interferon-free regimens will likely be even more effective. Opioid agonist treatment programs represent an opportunity to safely and effectively treat chronic hepatitis C, and PWID should have unrestricted access to DAAs. PMID:26341685

  7. Triple-drug therapy and return to work: results of a Quebec survey.

    PubMed

    Jalbert, Y

    Recent Quebec and Canadian statistics show the death rate declining among people living with HIV/AIDS. Triple-drug therapy has been shown to increase life expectancy and overall health. In the United States, a study of 55 people in Chicago living with HIV/AIDS found that 82 percent of them had considered returning to work. Another U.S. study showed that half the respondents had disclosed their sexual orientation to their employer. A survey questionnaire was prepared and distributed throughout the AIDS service organizations (ASOs) network and in two gay publications to see if the Canadian population has similar figures. The results showed that respondents under 45 years of age were more likely to want to return to work. Other conclusions of the study were that people with HIV/AIDS are not necessarily secure in their jobs, that the state of their health is their major area of concern, and that most people with HIV/AIDS do not want to return to their former jobs because of stress, discrimination, or their employer's attitude. The obligation for employers to make reasonable accommodations is a difficult concept for the employers to understand, and patients have concerns with explaining long or frequent absences from the workforce on their resumes. In 1998, the questionnaire will be distributed throughout the health and social services network. Ordering information is included.

  8. Triple Oral Antithrombotic Therapy in Atrial Fibrillation and Coronary Artery Stenting: Searching for the Best Combination.

    PubMed

    Elewa, Hazem; Ahmed, Dina; Barnes, Geoffrey D

    2016-09-01

    Patients with atrial fibrillation (AF) who are treated with oral anticoagulants often have concurrent coronary artery disease. Triple oral antithrombotic therapy (TOAT) is often necessity to prevent stent thrombosis or myocardial infarction associated with percutaneous coronary intervention or acute coronary syndrome in patients with comorbid coronary artery disease and AF. Although the use of TOAT (aspirin, clopidogrel, and warfarin) has excellent efficacy against thrombotic complications, this comes on the expense of increased bleeding risk. This review discusses potential strategies to improve TOAT benefit-risk ratio evidence from the literature. These strategies include: (1) dropping aspirin; (2) reducing the duration of TOAT; (3) switching warfarin to a direct oral anticoagulant (DOAC); (4) the use of DOAC in combination with a single antiplatelet agent; and (5) switching clopidogrel to a novel antiplatelet agent. Although dropping aspirin and reducing TOAT duration should be considered in selected AF patients at low risk of thrombosis, the role of DOACs and novel antiplatelets in TOAT has not been thoroughly studied, and there is limited evidence to support their use currently. Ongoing studies will provide safety and efficacy data to guide clinicians who frequently face the challenge of determining the best TOAT combination for their patients. PMID:27235831

  9. Enriched transcription factor signatures in triple negative breast cancer indicates possible targeted therapies with existing drugs

    PubMed Central

    Willis, Scooter; De, Pradip; Dey, Nandini; Long, Bradley; Young, Brandon; Sparano, Joseph A.; Wang, Victoria; Davidson, Nancy E.; Leyland-Jones, Brian R.

    2015-01-01

    Purpose Triple negative (TN) breast cancers which lack expression of the estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors convey a poor prognosis due in part to a lack of targeted therapies. Methods To identify viable targets for the treatment of TN disease, we have conducted a gene set enrichment analysis (GSEA) on seven different breast cancer whole genome gene expression cohorts comparing TN vs. ER + HER2 − to identify consistently enriched genes that share a common promoter motif. The seven cohorts were profiled on three different genome expression platforms (Affymetrix, Illumina and RNAseq) consisting in total of 2088 samples with IHC metadata. Results GSEA identified enriched gene expression patterns in TN samples that share common promoter motifs associated with SOX9, E2F1, HIF1A, HMGA1, MYC BACH2, CEBPB, and GCNF/NR6A1. Unexpectedly, NR6A1 an orphan nuclear receptor normally expressed in germ cells of gonads is highly expressed in TN and ER + HER2 − samples making it an ideal drug target. Conclusion With the increasing number of large sample size breast cancer cohorts, an exploratory analysis of genes that are consistently enriched in TN sharing common promoter motifs allows for the identification of possible therapeutic targets with extensive validation in patient derived data sets. PMID:26005638

  10. Current advances in biomarkers for targeted therapy in triple-negative breast cancer

    PubMed Central

    Fleisher, Brett; Clarke, Charlotte; Ait-Oudhia, Sihem

    2016-01-01

    Triple-negative breast cancer (TNBC) is a complex heterogeneous disease characterized by the absence of three hallmark receptors: human epidermal growth factor receptor 2, estrogen receptor, and progesterone receptor. Compared to other breast cancer subtypes, TNBC is more aggressive, has a higher prevalence in African-Americans, and more frequently affects younger patients. Currently, TNBC lacks clinically accepted targets for tailored therapy, warranting the need for candidate biomarkers. BiomarkerBase, an online platform used to find biomarkers reported in clinical trials, was utilized to screen all potential biomarkers for TNBC and select only the ones registered in completed TNBC trials through clinicaltrials.gov. The selected candidate biomarkers were classified as surrogate, prognostic, predictive, or pharmacodynamic (PD) and organized by location in the blood, on the cell surface, in the cytoplasm, or in the nucleus. Blood biomarkers include vascular endothelial growth factor/vascular endothelial growth factor receptor and interleukin-8 (IL-8); cell surface biomarkers include EGFR, insulin-like growth factor binding protein, c-Kit, c-Met, and PD-L1; cytoplasm biomarkers include PIK3CA, pAKT/S6/p4E-BP1, PTEN, ALDH1, and the PIK3CA/AKT/mTOR-related metabolites; and nucleus biomarkers include BRCA1, the gluco-corticoid receptor, TP53, and Ki67. Candidate biomarkers were further organized into a “cellular protein network” that demonstrates potential connectivity. This review provides an inventory and reference point for promising biomarkers for breakthrough targeted therapies in TNBC. PMID:27785100

  11. Analysis of radiation therapy in a model of triple-negative breast cancer brain metastasis.

    PubMed

    Smart, DeeDee; Garcia-Glaessner, Alejandra; Palmieri, Diane; Wong-Goodrich, Sarah J; Kramp, Tamalee; Gril, Brunilde; Shukla, Sudhanshu; Lyle, Tiffany; Hua, Emily; Cameron, Heather A; Camphausen, Kevin; Steeg, Patricia S

    2015-10-01

    Most cancer patients with brain metastases are treated with radiation therapy, yet this modality has not yet been meaningfully incorporated into preclinical experimental brain metastasis models. We applied two forms of whole brain radiation therapy (WBRT) to the brain-tropic 231-BR experimental brain metastasis model of triple-negative breast cancer. When compared to sham controls, WBRT as 3 Gy × 10 fractions (3 × 10) reduced the number of micrometastases and large metastases by 87.7 and 54.5 %, respectively (both p < 0.01); whereas a single radiation dose of 15 Gy × 1 (15 × 1) was less effective, reducing metastases by 58.4 % (p < 0.01) and 47.1 % (p = 0.41), respectively. Neuroinflammation in the adjacent brain parenchyma was due solely to a reaction from metastases, and not radiotherapy, while adult neurogenesis in brains was adversely affected following both radiation regimens. The nature of radiation resistance was investigated by ex vivo culture of tumor cells that survived initial WBRT ("Surviving" cultures). The Surviving cultures surprisingly demonstrated increased radiosensitivity ex vivo. In contrast, re-injection of Surviving cultures and re-treatment with a 3 × 10 WBRT regimen significantly reduced the number of large and micrometastases that developed in vivo, suggesting a role for the microenvironment. Micrometastases derived from tumor cells surviving initial 3 × 10 WBRT demonstrated a trend toward radioresistance upon repeat treatment (p = 0.09). The data confirm the potency of a fractionated 3 × 10 WBRT regimen and identify the brain microenvironment as a potential determinant of radiation efficacy. The data also nominate the Surviving cultures as a potential new translational model for radiotherapy.

  12. Impact of Triple Therapy in Elderly Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

    PubMed Central

    Sambola, Antonia; Mutuberría, Maria; García del Blanco, Bruno; Alonso, Albert; Barrabés, José A.; Bueno, Héctor; Alfonso, Fernando; Cequier, Angel; Zueco, Javier; Rodríguez-Leor, Oriol; Tornos, Pilar; García-Dorado, David

    2016-01-01

    Background and Purpose Selecting an ideal antithrombotic therapy for elderly patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) can be challenging since they have a higher thromboembolic and bleeding risk than younger patients. The current study aimed to assess the efficacy and safety of triple therapy (TT: oral anticoagulation plus dual antiplatelet therapy: aspirin plus clopidogrel) in patients ≥75 years of age with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). Methods A prospective multicenter study was conducted from 2003 to 2012 at 6 Spanish teaching hospitals. A cohort study of consecutive patients with AF undergoing PCI and treated with TT or dual antiplatelet therapy (DAPT) was analyzed. All outcomes were evaluated at 1-year of follow-up. Results Five hundred and eighty-five patients, 289 (49%) of whom were ≥75 years of age (79.6±3.4 years; 33% women) were identified. TT was prescribed in 55.9% of patients at discharge who had a higher thromboembolic risk (CHA2DS2VASc score: 4.23±1.51 vs 3.76±1.40, p = 0.007 and a higher bleeding risk (HAS-BLED ≥3: 88.6% vs 79.2%, p = 0.02) than those on DAPT. Therefore, patients on TT had a lower rate of thromboembolism than those on DAPT (0.6% vs 6.9%, p = 0.004; HR 0.08, 95% CI: 0.01–0.70, p = 0.004). Major bleeding events occurred more frequently in patients on TT than in those on DAPT (11.7% vs 2.4%, p = 0.002; HR 5.2, 95% CI: 1.53–17.57, p = 0.008). The overall mortality rate was similar in both treatment groups (11.9% vs 13.9%, p = 0.38); however, after adjustment for confounding variables, TT was associated with a reduced mortality rate (HR 0.33, 95% CI: 0.12–0.86, p = 0.02). Conclusions In elderly patients with AF undergoing PCI, the use of TT compared to DAPT was associated with reduced thromboembolism and mortality rates, although a higher rate of major bleeding. PMID:26808678

  13. Probiotics improve efficacy and tolerability of triple therapy to eradicate Helicobacter pylori: a meta-analysis of randomized controlled trials

    PubMed Central

    Gong, Yi; Li, Yan; Sun, Qian

    2015-01-01

    Objective: Gastric colonization by Helicobacter pylori is linked to a host of diseases, but eradication rates have declined in recent years. Some experimental studies suggest that probiotics may inhibit growth of H. pylori. This investigation was conducted to assess the impact of probiotics on both efficacy and tolerability of triple therapy to eradicate H. pylori. Methods: PubMed, Web of Science, and the Cochrane Collaboration were searched for relevant articles published through August 31, 2014. All analytics relied on commercially available software (Stata 11). Results: Twenty-three studies (N = 3900) qualified for meta-analysis. Pooled H. pylori eradication rates for triple therapy used alone and with added probiotics were 1464/2026 (72.26%; 95% CI, 67.66%-74.13) and 1513/1874 (80.74%; 95% CI, 74.68%-82.76%), respectively (odds ratio [OR] = 0.58; 95% CI, 0.50-0.68). Loss of appetite was similar in both groups (OR = 0.94; 95% CI, 0.61-1.45), but most adverse events (nausea, diarrhea, epigastric pain, vomiting, taste distortion, and skin rash) were mitigated through addition of probiotics. Publication bias was not evident, as indicated by Begg’s and Egger’s tests. Conclusions: Probiotics may improve the efficacy of triple therapy in eradicating gastric H. pylori and alleviate most treatment-related adverse events. PMID:26131283

  14. Monitoring the Antioxidant Mediated Chemosensitization and ARE-Signaling in Triple Negative Breast Cancer Therapy.

    PubMed

    Foygel, Kira; Sekar, Thillai V; Paulmurugan, Ramasamy

    2015-01-01

    Chemotherapy often fails due to cellular detoxifying mechanisms, including phase-II enzymes. Activation of Nrf2-Keap1 pathway induces phase-II enzymes expression through ARE-signaling and prevents cancer development. Nrf2-overexpression in cancer cells results in chemo- and/or radioresistance. This necessitates understanding of Nrf2-regulation, and identification of Nrf2 activators/inhibitors sensitizing cancer cells to improve chemotherapy. N-terminal 435-amino acids of Nrf2 are crucial for Keap1 binding during ubiquitination. Identification of a minimum Nrf2-domain required for Keap1 binding without altering endogenous ARE-signaling would be a novel tool to study Nrf2-signaling. Current study developed firefly-luciferase reporter fusion with N-terminal Nrf2-domain of different lengths and examined its response to Nrf2-activators in cells. The results identified FLuc2 fusion with N-terminal 100-aa of Nrf2 is sufficient for measuring Nrf2-activation in cancer cells. We used MDA-MB231 cells expressing this particular construct for studying antioxidant induced Nrf2-activation and chemosensitization in triple-negative breast cancer therapy. While antioxidant EGCG showed chemosensitization of MDA-MB231 cells to cisplatin by activating Nrf2-ARE signaling, PTS, another antioxidant showed chemoprotection. Tumor xenograft study in mouse demonstrates that combinational treatment by cisplatin/EGCG resulted in tumor growth reduction, compared to cisplatin alone treatment. The results of this study highlight the importance of identifying selective combination of antioxidants/chemotherapeutic agents for customized treatment strategy. PMID:26536456

  15. Tyrosine triple mutated AAV2-BDNF gene therapy in a rat model of transient IOP elevation

    PubMed Central

    Igarashi, Tsutomu; Kobayashi, Maika; Kameya, Shuhei; Fujimoto, Chiaki; Nakamoto, Kenji; Takahashi, Hisatomo; Igarashi, Toru; Miyake, Noriko; Iijima, Osamu; Hirai, Yukihiko; Shimada, Takashi; Okada, Takashi; Takahashi, Hiroshi

    2016-01-01

    Purpose We examined the neuroprotective effects of exogenous brain-derived neurotrophic factor (BDNF), which provides protection to retinal ganglion cells (RGCs) in rodents, in a model of transient intraocular pressure (IOP) elevation using a mutant (triple Y-F) self-complementary adeno-associated virus type 2 vector encoding BDNF (tm-scAAV2-BDNF). Methods The tm-scAAV2-BDNF or control vector encoding green fluorescent protein (GFP; tm-scAAV2-GFP) was intravitreally administered to rats, which were then divided into four groups: control, ischemia/reperfusion (I/R) injury only, I/R injury with tm-scAAV2-GFP, and tm-scAAV2-BDNF. I/R injury was then induced by transiently increasing IOP, after which the rats were euthanized to measure the inner retinal thickness and cell counts in the RGC layer. Results Intravitreous injection of tm-scAAV2-BDNF resulted in high levels of BDNF expression in the neural retina. Histological analysis showed that the inner retinal thickness and cell numbers in the RGC layer were preserved after transient IOP elevation in eyes treated with tm-scAAV2-BDNF but not in the other I/R groups. Significantly reduced glial fibrillary acidic protein (GFAP) immunostaining after I/R injury in the rats that received tm-scAAV2-BDNF indicated reduced retinal stress, and electroretinogram (ERG) analysis confirmed preservation of retinal function in the tm-scAAV2-BDNF group. Conclusions These results demonstrate the feasibility and effectiveness of neuroprotective gene therapy using tm-scAAV2-BDNF to protect the inner retina from transiently high intraocular pressure. An in vivo gene therapeutic approach to the clinical management of retinal diseases in conditions such as glaucoma, retinal artery occlusion, hypertensive retinopathy, and diabetic retinopathy thus appears feasible. PMID:27440998

  16. Sub-100 nm Gold Nanomatryoshkas Improve Photo-thermal Therapy Efficacy in Large and Highly Aggressive Triple Negative Breast Tumors

    PubMed Central

    Bishnoi, Sandra; Urban, Alexander; Charron, Heather; Mitchell, Tamika; Shea, Martin; Nanda, Sarmistha; Schiff, Rachel; Halas, Naomi; Joshi, Amit

    2014-01-01

    There is an unmet need for efficient near-infrared photothermal transducers for the treatment of highly aggressive cancers and large tumors where the penetration of light can be substantially reduced, and the intra-tumoral nanoparticle transport is restricted due to the presence of hypoxic or nectrotic regions. We report the performance advantages obtained by sub 100 nm gold nanomatryushkas, comprising of concentric gold-silica-gold layers compared to conventional ~150 nm silica core gold nanoshells for photothermal therapy of triple negative breast cancer. We demonstrate that a 33% reduction in silica-core-gold-shell nanoparticle size, while retaining near-infrared plasmon resonance, and keeping the nanoparticle surface charge constant, results in a four to five fold tumor accumulation of nanoparticles following equal dose of injected gold for both sizes. The survival time of mice bearing large (>1000 mm3) and highly aggressive triple negative breast tumors is doubled for the nanomatryushka treatment group under identical photo-thermal therapy conditions. The higher absorption cross-section of a nanomatryoshka results in a higher efficiency of photonic to thermal energy conversion and coupled with 4-5X accumulation within large tumors results in superior therapy efficacy. PMID:25051221

  17. Eradication of H. pylori infection in patients allergic to penicillin using triple therapy with a PPI, metronidazole and sitafloxacin.

    PubMed

    Furuta, Takahisa; Sugimoto, Mitsushige; Yamade, Mihoko; Uotani, Takahiro; Sahara, Shu; Ichikawa, Hitomi; Kagami, Takuma; Yamada, Takanori; Osawa, Satoshi; Sugimoto, Ken; Watanabe, Hiroshi; Umemura, Kazuo

    2014-01-01

    Eradication of H. pylori in patients allergic to penicillin should be performed using regimens without penicillin derivatives. We treated a total of 28 patients allergic to penicillin with a proton pump inhibitor (PPI), metronidazole (250 mg bid) and sitafloxacin (100 mg bid) for one to two weeks. At four to eight weeks after the treatment, the patients underwent the [(13)C]-urea breath test. The overall eradication rate was 100.0%. Mild adverse events were observed. Triple therapy with a PPI, metronidazole and sitafloxacin is well tolerated and effective for the eradication of H. pylori in patients allergic to penicillin. PMID:24633026

  18. Grade 4 febrile neutropenia and Fournier's Syndrome associated with triple therapy for hepatitis C virus: A case report.

    PubMed

    Oliveira, Kelly Cristhian Lima; Cardoso, Emili de Oliveira Bortolon; de Souza, Suzana Carla Pereira; Machado, Flávia Souza; Zangirolami, Carlos Eduardo Alves; Moreira, Alecsandro; Silva, Giovanni Faria; de Oliveira, Cássio Vieira

    2014-06-27

    The use of triple therapy for hepatitis C not only increases the rate of sustained virological responses compared with the use of only interferon and ribavirin (RBV) but also leads to an increased number of side effects. The subject of this study was a 53-year-old male who was cirrhotic with hepatitis C virus genotype 1 A and was a previous null non-responder. We initially attempted retreatment with boceprevir (BOC), Peg-interferon and RBV, and a decrease in viral load was observed in the 8(th) week. In week 12, he presented with disorientation, flapping, fever, tachypnea, arterial hypotension and tachycardia. He also exhibited leucopenia with neutropenia. Cefepime and filgrastim were initiated, and treatment for hepatitis C was suspended. A myelogram revealed hypoplasia, cytotoxicity and maturational retardation. After 48 h, he developed bilateral inguinal erythema that evolved throughout the perineal area to the root of the thighs, with exulcerations and an outflow of seropurulent secretions. Because we hypothesized that he was suffering from Fournier's Syndrome, treatment was replaced with the antibiotics imipenem, linezolid and clindamycin. After this new treatment paradigm was initiated, his lesions regressed without requiring surgical debridement. Triple therapy requires knowledge regarding the management of adverse effects and drug interactions; it also requires an understanding of the importance of respecting the guidelines for the withdrawal of treatment. In this case report, we observed an adverse event that had not been previously reported in the literature with the use of BOC. PMID:25018856

  19. Local triple-combination therapy results in tumour regression and prevents recurrence in a colon cancer model

    NASA Astrophysics Data System (ADS)

    Conde, João; Oliva, Nuria; Zhang, Yi; Artzi, Natalie

    2016-10-01

    Conventional cancer therapies involve the systemic delivery of anticancer agents that neither discriminate between cancer and normal cells nor eliminate the risk of cancer recurrence. Here, we demonstrate that the combination of gene, drug and phototherapy delivered through a prophylactic hydrogel patch leads, in a colon cancer mouse model, to complete tumour remission when applied to non-resected tumours and to the absence of tumour recurrence when applied following tumour resection. The adhesive hydrogel patch enhanced the stability and provided local delivery of embedded nanoparticles. Spherical gold nanoparticles were used as a first wave of treatment to deliver siRNAs against Kras, a key oncogene driver, and rod-shaped gold nanoparticles mediated the conversion of near-infrared radiation into heat, causing the release of a chemotherapeutic as well as thermally induced cell damage. This local, triple-combination therapy can be adapted to other cancer cell types and to molecular targets associated with disease progression.

  20. Polypyrrole-based nanotheranostics for activatable fluorescence imaging and chemo/photothermal dual therapy of triple-negative breast cancer

    NASA Astrophysics Data System (ADS)

    Park, Dongjin; Ahn, Kyung-Ohk; Jeong, Kyung-Chae; Choi, Yongdoo

    2016-05-01

    Here, we fabricated polypyrrole nanoparticles (PPys) (termed HA10-PPy, HA20-PPy, and HA40-PPy) doped with different average molecular weight hyaluronic acids (HAs) (10, 20, and 40 kDa, respectively), and evaluated the effect of molecular weight of doped HA on photothermal induction, fluorescence quenching, and drug loading efficiencies. Doxorubicin-loaded HA-doped PPys (DOX@HA-PPys) could be used for imaging and therapy of triple-negative breast cancer (TNBC). Fluorescence turn-on, stimuli-responsive drug release, and photo-induced heating of DOX@HA-PPys enabled not only activatable fluorescence imaging but also subsequent chemo/photothermal dual therapy for TNBC. In particular, we illustrated the potential usefulness of the photothermal effect of the nanoparticles for overcoming chemoresistance in TNBC.

  1. Evaluation of the prognostic value of liver stiffness in patients with hepatitis C virus treated with triple or dual antiviral therapy: A prospective pilot study

    PubMed Central

    Stasi, Cristina; Piluso, Alessia; Arena, Umberto; Salomoni, Elena; Montalto, Paolo; Monti, Monica; Boldrini, Barbara; Corti, Giampaolo; Marra, Fabio; Laffi, Giacomo; Milani, Stefano; Zignego, Anna Linda

    2015-01-01

    AIM: To evaluate the association between liver stiffness (LS) prior to the initiation of dual/triple therapy and viral response. METHODS: LS was measured in all patients before treatment was administered. The therapeutic approach was based on hepatic, virological, and immunological evaluations and considered the fact that patients with severe fibrosis (F3) or compensated cirrhosis (F4) in Child-Pugh class A are the primary candidates for triple therapy. In total, 65 hepatitis C virus (HCV) patients were treated with Peg-interferon/ribavirin (Peg-IFN/RBV); 24 patients were classified as genotypes 1/4 (36.92%), and 41 patients were classified as genotypes 2/3 (63.08%) (dual therapy). In addition, 20 HCV treatment-experienced genotype 1 patients were treated with PegIFN-RBV and boceprevir (triple therapy). Wilcoxon rank-sum tests were used to compare the groups. RESULTS: LS significantly differed between dual therapy and triple therapy (P = 0.002). The mean LS value before dual therapy treatment was 8.61 ± 5.79 kPa and was significantly different between patients achieving a sustained virologic response (SVR) 24 weeks after therapy and those who did not (7.23 ± 5.18 kPa vs 11.72 ± 5.99 kPa, respectively, P = 0.0003). The relative risk of non-response to therapy was 4.45 (95%CI: 2.32-8.55). The attributable risk of non-response to therapy was 49%. The mean LS value before triple therapy treatment was 13.29 ± 8.57 kPa and was significantly different between patients achieving and not achieving SVR24 (9.41 ± 5.05 vs 19.11 ± 9.74, respectively; P = 0.008). The relative risk of non-response to therapy was 5.57% (95%CI: 1.50-20.65). The attributable risk of non-response to therapy (70%) was increased compared with dual therapy patients. Pre-treatment stiffness > 12 kPa was significantly associated with non-SVR (P < 0.025) in both groups. CONCLUSION: Pre-treatment liver stiffness may be useful for predicting the response to treatment in patients treated with either

  2. Boceprevir or Telaprevir Based Triple Therapy against Chronic Hepatitis C in HIV Coinfection: Real-Life Safety and Efficacy

    PubMed Central

    Neukam, Karin; Munteanu, Daniela I.; Rivero-Juárez, Antonio; Lutz, Thomas; Fehr, Jan; Mandorfer, Mattias; Bhagani, Sanjay; López-Cortés, Luis F.; Haberl, Annette; Stoeckle, Marcel; Márquez, Manuel; Scholten, Stefan; de los Santos-Gil, Ignacio; Mauss, Stefan; Rivero, Antonio; Collado, Antonio; Delgado, Marcial; Rockstroh, Juergen K.; Pineda, Juan A.

    2015-01-01

    Background and Aims Clinical trials of therapy against chronic hepatitis C virus (HCV) infection including boceprevir (BOC) or telaprevir (TVR) plus pegylated interferon and ribavirin (PR) have reported considerably higher response rates than those achieved with PR alone. This study sought to evaluate the efficacy and safety of triple therapy including BOC or TVR in combination with PR in HIV/HCV-coinfected patients under real-life conditions. Methods In a multicentre study conducted in 24 sites throughout five European countries, all HIV/HCV-coinfected patients who initiated a combination of BOC or TVR plus PR and who had at least 60 weeks of follow-up, were analyzed. Sustained virologic response 12 weeks after the scheduled end of therapy date (SVR12) and the rate of discontinuations due to adverse events (AE) were evaluated. Results Of the 159 subjects included, 127 (79.9%) were male, 45 (34.4%) were treatment-naïve for PR and 60 (45.4%) showed cirrhosis. SVR12 was observed in 31/46 (67.4%) patients treated with BOC and 69/113 (61.1%) patients treated with TVR. Overall discontinuations due to AE rates were 8.7% for BOC and 8% for TVR. Grade 3 or 4 hematological abnormalities were frequently observed; anemia 7%, thrombocytopenia 17.2% and neutropenia 16.4%. Conclusion The efficacy and safety of triple therapy including BOC or TVR plus PR under real-life conditions of use in the HIV/HCV-coinfected population was similar to what is observed in clinical trials. Hematological side effects are frequent but manageable. PMID:25923540

  3. Near infrared light-actuated gold nanorods with cisplatin-polypeptide wrapping for targeted therapy of triple negative breast cancer

    NASA Astrophysics Data System (ADS)

    Feng, Bing; Xu, Zhiai; Zhou, Fangyuan; Yu, Haijun; Sun, Qianqian; Wang, Dangge; Tang, Zhaohui; Yu, Haiyang; Yin, Qi; Zhang, Zhiwen; Li, Yaping

    2015-09-01

    Despite considerable progress being made in breast cancer therapy, the complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. We herein report on the fabrication of novel gold nanorods (GNRs) with covalent cisplatin-polypeptide wrapping and folic acid (FA) conjugation (FA-GNR@Pt) for the targeted photothermal (PT) therapy and chemotherapy of TNBC. The FA-GNR@Pt hybrid nanoparticles are designed to integrate the photothermal conversion property of GNRs, the superior biocompatibility of polypeptide poly(l-glutamic acid) (PGA), the chemotoxicity of cisplatin, and the tumor targeting ability of FA into one single nanoplatform. In combination with localized near infrared (NIR) laser illumination, the resulting FA-GNR@Pt hybrid nanoparticles are able to significantly inhibit the growth of the TNBC tumor when administered systemically. In particular, they can extensively suppress the dissemination of TNBC cells from the primary tumor to the lung by eliminating the peripheral tumor blood vessels. Collectively, our studies demonstrate that the combined PT therapy and chemotherapy using cisplatin-loaded GNRs with FA conjugation might imply a promising strategy for targeted treatment of TNBC.Despite considerable progress being made in breast cancer therapy, the complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. We herein report on the fabrication of novel gold nanorods (GNRs) with covalent cisplatin-polypeptide wrapping and folic acid (FA) conjugation (FA-GNR@Pt) for the targeted photothermal (PT) therapy and chemotherapy of TNBC. The FA-GNR@Pt hybrid nanoparticles are designed to integrate the photothermal conversion property of GNRs, the superior biocompatibility of polypeptide poly(l-glutamic acid) (PGA), the chemotoxicity of cisplatin, and the tumor targeting ability of FA into one single nanoplatform. In combination with localized near infrared (NIR

  4. Inefficacy of Triple Therapy and Comparison of Two Different Bismuth-containing Quadruple Regimens as a Firstline Treatment Option for Helicobacter pylori

    PubMed Central

    Kekilli, Murat; Onal, Ibrahim K.; Ocal, Serkan; Dogan, Zeynal; Tanoglu, Alpaslan

    2016-01-01

    Background/Aim: Increasing resistance of Helicobacter pylori to antimicrobials necessitated the development of new regimens and the modification of existing regimens. The present study aimed to compare the efficacy of two bismuth-containing quadruple regimens–one including clarithromycin (C) instead of metronidazole (M) and triple therapy. Patients and Methods: Patients with H. pylori infection given the following regimens were sequentially enrolled in this retrospective study: (1) Triple therapy: Lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., and amoxicillin 1 g b.i.d., (2) bismuth group C: Lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., amoxicillin 1 g b.i.d., and bismuth subsalicylate 524 mg b.i.d., and (3) bismuth group M: Lansoprazole 30 mg b.i.d., amoxicillin 1 g b.i.d., metronidazole 500 mg t.i.d., and bismuth subsalicylate 524 mg b.i.d. for 14 days. Gastroscopy and 14C-urea breath test were performed before enrollment, and urea breath test was repeated four weeks after the treatment. Results: At per-protocol analysis, the eradication rates were 64.7% (95% confidence interval 60.4–68.7) with the triple therapy (n = 504), 95.4% (95% confidence interval 91.5–99.4) with the bismuth group C (n = 501), and 93.9% (95% confidence interval 89.7–98.7) with the bismuth group M (n = 505). The eradication rates were similar between the two bismuth groups (P > 0.05) but significantly greater than that of the triple therapy (P < 0.05). Conclusion: In our study, both of the bismuth-containing quadruple therapies reached high eradication rates, whereas triple therapy was shown to be ineffective. Moreover, clarithromycin may also be a component of bismuth-containing quadruple therapy. PMID:27748322

  5. Telaprevir and Ribavirin Interaction: Higher Ribavirin Levels Are Not Only Due to Renal Dysfunction during Triple Therapy

    PubMed Central

    Gutierrez-Valencia, Alicia; Ruiz-Valderas, Rosa; Ben-Marzouk-Hidalgo, Omar J.; Torres-Cornejo, Almudena; Espinosa, Nuria; Castillo-Ferrando, Juan R.; Viciana, Pompeyo

    2015-01-01

    A higher incidence of anemia has been observed during the treatment of hepatitis C virus genotype 1 (HCV-1) infection with pegylated alpha interferon (pegIFN-α), ribavirin, and telaprevir. We assessed the impacts that concomitant administration of telaprevir and changes in the glomerular filtration rate have on ribavirin plasma levels. The minimum concentrations of ribavirin in plasma (ribavirin Cmin) determined during triple therapy including telaprevir were compared with those observed after telaprevir withdrawal and those observed in the same subjects and in a large cohort during a previous course of pegIFN-α plus ribavirin. Intensive pharmacokinetic sampling for ribavirin was performed at steady state during the triple-therapy phase. Ribavirin levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Twenty-seven HCV-1/HIV-coinfected patients were enrolled. The median ribavirin Cmin for triple therapy (4.08 μg/ml; range, 2.14 to 5.56 μg/ml) was higher than that observed after telaprevir withdrawal (1.96 μg/ml; range, 0.41 to 3.45 μg/ml) (P < 0.001) and that observed for 125 HCV-1/HIV-coinfected patients treated only with pegIFN-α plus ribavirin (1.65 μg/ml; range, 0.41 to 5.56 μg/ml) (P < 0.001). The estimated glomerular filtration rate (eGFR) decreased >20% from the baseline value in 11 of 27 patients and became normal after telaprevir removal in almost all cases. There was a negative correlation between eGFR and ribavirin clearance (r2 = 0.257; P = 0.064) but not the ribavirin area under the concentration-time curve from 0 to 12 h (AUC0–12) (r2 = 0.001; P = 0.455). Thus, there is a significant pharmacokinetic interaction between telaprevir and ribavirin that results in very high ribavirin levels, which explains the excess of toxicity observed with this drug combination. A blockade of the proximal tubular transporters might be implicated in both the increase in plasma creatinine and the high ribavirin levels. (This study has

  6. Ultrasensitive HCV RNA Quantification in Antiviral Triple Therapy: New Insight on Viral Clearance Dynamics and Treatment Outcome Predictors

    PubMed Central

    Garbuglia, Anna Rosa; Visco-Comandini, Ubaldo; Lionetti, Raffaella; Lapa, Daniele; Castiglione, Filippo; D’Offizi, Gianpiero; Taibi, Chiara; Montalbano, Marzia; Capobianchi, Maria Rosaria; Paci, Paola

    2016-01-01

    Objectives Identifying the predictive factors of Sustained Virological Response (SVR) represents an important challenge in new interferon-based DAA therapies. Here, we analyzed the kinetics of antiviral response associated with a triple drug regimen, and the association between negative residual viral load at different time points during treatment. Methods Twenty-three HCV genotype 1 (GT 1a n = 11; GT1b n = 12) infected patients were included in the study. Linear Discriminant Analysis (LDA) was used to establish possible association between HCV RNA values at days 1 and 4 from start of therapy and SVR. Principal component analysis (PCA) was applied to analyze the correlation between HCV RNA slope and SVR. A ultrasensitive (US) method was established to measure the residual HCV viral load in those samples which resulted “detected <12IU/ml” or undetectable with ABBOTT standard assay, and was retrospectively used on samples collected at different time points to establish its predictive power for SVR. Results According to LDA, there was no association between SVR and viral kinetics neither at time points earlier than 1 week (days 1 and 4) after therapy initiation nor later. The slopes were not relevant for classifying patients as SVR or no-SVR. No significant differences were observed in the median HCV RNA values at T0 among SVR and no-SVR patients. HCV RNA values with US protocol (LOD 1.2 IU/ml) after 1 month of therapy were considered; the area under the ROC curve was 0.70. Overall, PPV and NPV of undetectable HCV RNA with the US method for SVR was 100% and 46.7%, respectively; sensitivity and specificity were 38.4% and 100% respectively. Conclusion HCV RNA “not detected” by the US method after 1 month of treatment is predictive of SVR in first generation Protease inhibitor (PI)-based triple therapy. The US method could have clinical utility for advanced monitoring of virological response in new interferon based DAA combination regimens. PMID:27560794

  7. Two-Year Follow-Up Analysis of Telaprevir-Based Antiviral Triple Therapy for HCV Recurrence in Genotype 1 Infected Liver Graft Recipients as a First Step towards Modern HCV Therapy

    PubMed Central

    Neuhaus, Ruth; Eurich, Dennis; Hofmann, Jörg; Bayraktar, Sandra; Pratschke, Johann; Bahra, Marcus

    2016-01-01

    Objective. The introduction of protease inhibitors telaprevir and boceprevir in 2011 had extended the antiviral treatment options especially in genotype 1 infected hepatitis C relapsers and nonresponders to interferon/ribavirin therapy. The aim of this study was to analyze the long-term treatment efficiency of telaprevir-based triple therapy for patients with hepatitis C reinfection after orthotopic liver transplantation. Patients and Methods. We included 12 patients with histologically confirmed graft fibrosis due to hepatitis C reinfection. The treatment duration was scheduled as 12 weeks of telaprevir-based antiviral triple therapy followed by 36 weeks of dual therapy with pegylated interferon/ribavirin. The patients were followed up for two years after the end of triple therapy. Results. Of the 12 patients, 6 (50%) completed the full 48 weeks of antiviral treatment. An end of treatment response and a sustained virological response 52 weeks after the end of the antiviral treatment course were achieved in 8/12 (67%) and 7/12 (58%) patients, respectively. Conclusion. Telaprevir-based triple therapy was shown to be a long-term effective but complex treatment option for individual patients with hepatitis C graft. With the recent improvements in hepatitis C therapy options telaprevir may not be recommended as a standard therapy for this indication anymore. PMID:27195149

  8. Anti-inflammatory and Antitumor Activity of a Triple Therapy for a Colitis-Related Colorectal Cancer

    PubMed Central

    Figueroa-González, Gabriela; García-Castillo, Verónica; Coronel-Hernández, Jossimar; López-Urrutia, Eduardo; León-Cabrera, Sonia; Arias-Romero, Luis E; Terrazas, LI; Rodríguez-Sosa, Miriam; Campos-Parra, Alma Delia; Zúñiga-Calzada, Eduardo; Lopez-Camarillo, Cesar; Morales-González, Fermín; Jacobo-Herrera, Nadia J; Pérez-Plasencia, Carlos

    2016-01-01

    Colorectal cancer (CRC) is an important health issue worldwide, accounting for the third place of cancer incidence. Chronic inflammation, as seen in Crohn's disease and ulcerative colitis, is the most important risk factor for developing CRC, as it favours neoplastic transformation by enhancing epithelial cell turnover in the colonic mucosa. Treatments for CRC need to be improved; currently they are not specific and have several secondary effects in patients. The main objective of this work was to evaluate a new therapeutic strategy against a colitis-related colorectal cancer in vivo and in vitro by targeting mTOR-signaling and lactate dehydrogenase A. Together, these mechanisms directly affect tumor energetics. In this study we evaluated a better and more efficient triple therapy against a chronic inflammation-associated CRC in vivo and in vitro. After the development of tumors, mice were treated intraperitoneally during a forty-day period with single drugs or different combinations of Metformin, Sodium Oxamate and Doxorubicin. Targeted inhibition of the mTOR pathway, lactate dehydrogenase A and the concurrent use of Doxorubicin (called in this work as triple therapy), leaded to a notable reduction in the number and size of tumors in mice, and, a significant pro-inflammatory cytokines reduction Besides, we showed that treated cells were induced to early autophagy, and apoptosis cell death. Our results represent a novel and robust therapeutic strategy for overcoming CRC by means of targeting central molecular pathways in cancer by the combination of Metformin, Oxamate, and Doxorubicin leading to a rapid tumor growth inhibition and a dramatic colorectal crypt restoration. Besides, drug combination resulted in a notable reduction of anti-inflammatory cytokines. PMID:27698900

  9. Anti-inflammatory and Antitumor Activity of a Triple Therapy for a Colitis-Related Colorectal Cancer

    PubMed Central

    Figueroa-González, Gabriela; García-Castillo, Verónica; Coronel-Hernández, Jossimar; López-Urrutia, Eduardo; León-Cabrera, Sonia; Arias-Romero, Luis E; Terrazas, LI; Rodríguez-Sosa, Miriam; Campos-Parra, Alma Delia; Zúñiga-Calzada, Eduardo; Lopez-Camarillo, Cesar; Morales-González, Fermín; Jacobo-Herrera, Nadia J; Pérez-Plasencia, Carlos

    2016-01-01

    Colorectal cancer (CRC) is an important health issue worldwide, accounting for the third place of cancer incidence. Chronic inflammation, as seen in Crohn's disease and ulcerative colitis, is the most important risk factor for developing CRC, as it favours neoplastic transformation by enhancing epithelial cell turnover in the colonic mucosa. Treatments for CRC need to be improved; currently they are not specific and have several secondary effects in patients. The main objective of this work was to evaluate a new therapeutic strategy against a colitis-related colorectal cancer in vivo and in vitro by targeting mTOR-signaling and lactate dehydrogenase A. Together, these mechanisms directly affect tumor energetics. In this study we evaluated a better and more efficient triple therapy against a chronic inflammation-associated CRC in vivo and in vitro. After the development of tumors, mice were treated intraperitoneally during a forty-day period with single drugs or different combinations of Metformin, Sodium Oxamate and Doxorubicin. Targeted inhibition of the mTOR pathway, lactate dehydrogenase A and the concurrent use of Doxorubicin (called in this work as triple therapy), leaded to a notable reduction in the number and size of tumors in mice, and, a significant pro-inflammatory cytokines reduction Besides, we showed that treated cells were induced to early autophagy, and apoptosis cell death. Our results represent a novel and robust therapeutic strategy for overcoming CRC by means of targeting central molecular pathways in cancer by the combination of Metformin, Oxamate, and Doxorubicin leading to a rapid tumor growth inhibition and a dramatic colorectal crypt restoration. Besides, drug combination resulted in a notable reduction of anti-inflammatory cytokines.

  10. Telaprevir-based triple therapy following partial splenic arterial embolization for chronic hepatitis C with thrombocytopenia can reduce carcinogenesis and improve hepatic function reserve

    PubMed Central

    ISHIKAWA, TORU; ABE, SATOSHI; KOJIMA, YUICHI; HORIGOME, RYOKO; SANO, TOMOE; IWANAGA, AKITO; SEKI, KEIICHI; HONMA, TERASU; YOSHIDA, TOSHIAKI

    2015-01-01

    Thrombocytopenia in patients with chronic hepatitis C negatively impacts interferon (IFN)-based treatment. The aim of this study was to evaluate the efficacy and safety of telaprevir (TVR)-based triple therapy including IFN for patients who have undergone partial splenic arterial embolization (PSE). Ten patients with thrombocytopenia who were infected with hepatitis C virus (HCV) genotype 1b received 12 weeks of TVR in combination with 24 weeks of pegylated interferon (PEG-IFN)α2b and ribavirin following PSE. A sustained virological response (SVR) was seen in 9 of the 10 patients who could be assessed. Early relapse was seen in 1 patient who had the IL-28B minor allele and a null response to pretreatment. The α-fetoprotein levels of the patients decreased from 17.94±7.30 ng/ml prior to PSE to 4.33±2.41 ng/ml at 6 months after triple therapy (P=0.08). Furthermore, serum albumin levels improved significantly from 3.68±0.49 g/dl pre-PSE to 4.13±0.34 g/dl at 12 months after triple therapy (P=0.043). PSE contributed to the treatment success of triple therapy, particularly for patients who were either treatment-naïve, had a history of relapse or the IL28B major allele. This strategy can reduce carcinogenesis and improve hepatic function reserve. PMID:26622488

  11. The efficacy of blueberry and grape seed extract combination on triple therapy for Helicobacter pylori eradication: a randomised controlled trial.

    PubMed

    Chua, Chian-Sem; Yang, Kuo-Ching; Chen, Jui-Hao; Liu, Yuh-Hwa; Hsu, Yi-Hsin; Lee, Hsiu-Chuan; Huang, Shih-Yi

    2016-01-01

    Helicobacter pylori is a major risk factor for gastritis, gastric ulcers and gastric cancer. Traditional therapy with proton pump inhibitor and antibiotics is regarded as optimal for H. pylori eradication whereas, the eradication rate is unsatisfactory. Studies have reported that cranberry may inhibit H. pylori adhesion to the human gastric mucus but lack of other berry extracts have been evaluated in clinical study. Thus, a 9-week add-on randomised controlled trial was conducted to explore the impact of blueberry and grape seed extract (BGE) combinations traditional therapy for H. pylori eradication. In results, we found that there was no significant difference of eradication rate between the berry extract group and placebo group in the intention-to-treat analysis and in the per-protocol analysis (94.64% versus 84.62%, p = 0.085). Diarrhoea, constipation and epigastric pain were observed increasing during ingestion of the berry extract in some cases. In conclusion, this study indicated that no significant difference existed between the BGE extract group and placebo group in eradication rate under triple therapy.

  12. Dual Targeted Therapy with p53 siRNA and Epigallocatechingallate in a Triple Negative Breast Cancer Cell Model

    PubMed Central

    Braicu, Cornelia; Pileczki, Valentina; Pop, Laura; Petric, Roxana Cojocneanu; Chira, Sergiu; Pointiere, Eve; Achimas-Cadariu, Patriciu; Berindan-Neagoe, Ioana

    2015-01-01

    Triple-negative breast cancer (TNBC) is a highly aggressive phenotype that is resistant to standard therapy. Thus, the development of alternative therapeutic strategies for TNBC is essential. The purpose of our in vitro study was to evaluate the impact of p53 gene silencing in conjunction with the administration of a natural compound, epigallocatechingallate (EGCG). RT2Profiler PCR Array technology was used to evaluate the impact of dual treatment on the main genes involved in apoptosis in the Hs578T cell culture model of TNBC. Gene expression analysis revealed 28 genes were significantly altered (16 upregulated and 12 downregulated) in response to combined p53 siRNA and EGCG treatment. Further analysis revealed that p53 siRNA and EGCG dual therapy leads to the activation of pro-apoptotic genes and the inhibition of pro-survival genes, autophagy, and cell network formation. These results indicate that this dual therapy targets both the apoptotic and angiogenic pathways, which may improve treatment effectiveness for tumors resistant to conventional treatment. PMID:25849487

  13. Dual targeted therapy with p53 siRNA and Epigallocatechingallate in a triple negative breast cancer cell model.

    PubMed

    Braicu, Cornelia; Pileczki, Valentina; Pop, Laura; Petric, Roxana Cojocneanu; Chira, Sergiu; Pointiere, Eve; Achimas-Cadariu, Patriciu; Berindan-Neagoe, Ioana

    2015-01-01

    Triple-negative breast cancer (TNBC) is a highly aggressive phenotype that is resistant to standard therapy. Thus, the development of alternative therapeutic strategies for TNBC is essential. The purpose of our in vitro study was to evaluate the impact of p53 gene silencing in conjunction with the administration of a natural compound, epigallocatechingallate (EGCG). RT2Profiler PCR Array technology was used to evaluate the impact of dual treatment on the main genes involved in apoptosis in the Hs578T cell culture model of TNBC. Gene expression analysis revealed 28 genes were significantly altered (16 upregulated and 12 downregulated) in response to combined p53 siRNA and EGCG treatment. Further analysis revealed that p53 siRNA and EGCG dual therapy leads to the activation of pro-apoptotic genes and the inhibition of pro-survival genes, autophagy, and cell network formation. These results indicate that this dual therapy targets both the apoptotic and angiogenic pathways, which may improve treatment effectiveness for tumors resistant to conventional treatment. PMID:25849487

  14. The efficacy of blueberry and grape seed extract combination on triple therapy for Helicobacter pylori eradication: a randomised controlled trial.

    PubMed

    Chua, Chian-Sem; Yang, Kuo-Ching; Chen, Jui-Hao; Liu, Yuh-Hwa; Hsu, Yi-Hsin; Lee, Hsiu-Chuan; Huang, Shih-Yi

    2016-01-01

    Helicobacter pylori is a major risk factor for gastritis, gastric ulcers and gastric cancer. Traditional therapy with proton pump inhibitor and antibiotics is regarded as optimal for H. pylori eradication whereas, the eradication rate is unsatisfactory. Studies have reported that cranberry may inhibit H. pylori adhesion to the human gastric mucus but lack of other berry extracts have been evaluated in clinical study. Thus, a 9-week add-on randomised controlled trial was conducted to explore the impact of blueberry and grape seed extract (BGE) combinations traditional therapy for H. pylori eradication. In results, we found that there was no significant difference of eradication rate between the berry extract group and placebo group in the intention-to-treat analysis and in the per-protocol analysis (94.64% versus 84.62%, p = 0.085). Diarrhoea, constipation and epigastric pain were observed increasing during ingestion of the berry extract in some cases. In conclusion, this study indicated that no significant difference existed between the BGE extract group and placebo group in eradication rate under triple therapy. PMID:26883189

  15. Near infrared light-actuated gold nanorods with cisplatin-polypeptide wrapping for targeted therapy of triple negative breast cancer.

    PubMed

    Feng, Bing; Xu, Zhiai; Zhou, Fangyuan; Yu, Haijun; Sun, Qianqian; Wang, Dangge; Tang, Zhaohui; Yu, Haiyang; Yin, Qi; Zhang, Zhiwen; Li, Yaping

    2015-09-28

    Despite considerable progress being made in breast cancer therapy, the complete eradication of highly aggressive triple negative breast cancer (TNBC) remains a notable challenge today. We herein report on the fabrication of novel gold nanorods (GNRs) with covalent cisplatin-polypeptide wrapping and folic acid (FA) conjugation (FA-GNR@Pt) for the targeted photothermal (PT) therapy and chemotherapy of TNBC. The FA-GNR@Pt hybrid nanoparticles are designed to integrate the photothermal conversion property of GNRs, the superior biocompatibility of polypeptide poly(l-glutamic acid) (PGA), the chemotoxicity of cisplatin, and the tumor targeting ability of FA into one single nanoplatform. In combination with localized near infrared (NIR) laser illumination, the resulting FA-GNR@Pt hybrid nanoparticles are able to significantly inhibit the growth of the TNBC tumor when administered systemically. In particular, they can extensively suppress the dissemination of TNBC cells from the primary tumor to the lung by eliminating the peripheral tumor blood vessels. Collectively, our studies demonstrate that the combined PT therapy and chemotherapy using cisplatin-loaded GNRs with FA conjugation might imply a promising strategy for targeted treatment of TNBC. PMID:26222373

  16. Coenzyme Q10 in combination with triple therapy regimens ameliorates oxidative stress and lipid peroxidation in chronic gastritis associated with H. pylori infection.

    PubMed

    Rahmani, Asghar; Abangah, Ghobad; Moradkhani, Atefeh; Hafezi Ahmadi, Mohammad Reza; Asadollahi, Khairollah

    2015-08-01

    Chronic gastritis associated with H. pylori infection causes oxidative stress in the stomach. This study aimed to evaluate the therapeutic effects of coenzyme q10 among gastric patients infected by H. pylori. By a clinical trial, chronic gastric patients infected by H. pylori were randomly divided into 2 groups: intervention and placebo. The placebo group received a standard triple therapy regimen, and the intervention group received the triple regimen + coenzyme Q10 (CoQ10). Mean inflammation score; serum levels of 3 serum markers were then compared. A total of 100 participants of whom 67% were female were evaluated. The mean age of participants was 59.4 ± 11.4 years. The mean inflammation score was considerably decreased at the end of the study, in the intervention group. The mean levels of total antioxidant capacity (TAC) and glutathione peroxidase (GPx) at the end of the study were reduced among the triple therapy group (P < .05, P =.03 respectively). The mean levels of TAC and GPx were significantly higher among the intervention group at the end of the study compared with those at the start of the study. The combination of triple therapy with CoQ10 demonstrated an effective outcome on the mucosal inflammation, and stress oxidative in patients with chronic gastritis.

  17. [Molecular response with triple therapy in patients with chronic myeloid leukemia].

    PubMed

    López-Arroyo, José Luis; Rico-Ramos, Héctor Joel; Portillo-García, Mireya Leticia

    2014-01-01

    INTRODUCCIÓN: la leucemia mieloide crónica es un trastorno mieloproliferativo provocado por la translocación t (9;22)(q34;q11). El mesilato de imatinib es un inhibidor de la tirosina cinasa útil en el tratamiento de la leucemia mieloide crónica. El objetivo de este estudio fue evaluar la respuesta molecular mayor a los 12 meses con esquema terapéutico triple, analizar la evolución de los pacientes, así como la toxicidad general y la hematológica. MÉTODOS: estudio observacional longitudinal en pacientes con leucemia mieloide crónica, tratados con interferón pegilado alfa 2a subcutáneo (90 μg/semana por cuatro semanas) + imatinib oral (800 mg/día por 30 días) + citarabina subcutánea (20 mg/m2 de superficie corporal del día 1 al 10). Se analizaron las respuestas hematológica y molecular a los 12 meses.

  18. Nonbismuth concomitant quadruple therapy for Helicobacter pylori eradication in Chinese regions: A meta-analysis of randomized controlled trials

    PubMed Central

    Lin, Lien-Chieh; Hsu, Tzu-Herng; Huang, Kuang-Wei; Tam, Ka-Wai

    2016-01-01

    AIM: To evaluate the applicability of nonbismuth concomitant quadruple therapy for Helicobacter pylori (H. pylori) eradication in Chinese regions. METHODS: A systematic review and meta-analysis of randomized controlled trials was performed to evaluate the efficacy of nonbismuth concomitant quadruple therapy between sequential therapy or triple therapy for H. pylori eradication in Chinese regions. The defined Chinese regions include China, Hong Kong, Taiwan, and Singapore. The primary outcome was the H. pylori eradication rate; the secondary outcome was the compliance with therapy. The PubMed, Embase, Scopus, and Cochrane databases were searched for studies published in the period up to March 2016 with no language restriction. RESULTS: We reviewed six randomized controlled trials and 1616 patients. In 3 trials comparing concomitant quadruple therapy with triple therapy, the H. pylori eradication rate was significantly higher for 7-d nonbismuth concomitant quadruple therapy than for 7-d triple therapy (91.2% vs 77.9%, risk ratio = 1.17, 95%CI: 1.09-1.25). In 3 trials comparing quadruple therapy with sequential therapy, the eradication rate was not significant between groups (86.9% vs 86.0%). However, higher compliance was achieved with concomitant therapy than with sequential therapy. CONCLUSION: The H. pylori eradication rate was higher for nonbismuth concomitant quadruple therapy than for triple therapy. Moreover, higher compliance was achieved with nonbismuth concomitant quadruple therapy than with sequential therapy. Thus, nonbismuth concomitant quadruple therapy should be the first-line treatment in Chinese regions. PMID:27340362

  19. Association of Triple Therapy with Improvement in Cholesterol Profiles over Two Year Follow-up in the TEAR Trial

    PubMed Central

    Charles-Schoeman, Christina; Wang, Xiaoyan; Lee, Yuen Yin; Shahbazian, Ani; Navarro-Millán, Iris; Yang, Shuo; Chen, Lang; Cofield, Stacey S; Moreland, Larry W; O’Dell, James; Bathon, Joan; Paulus, Harold; Bridges, S. Louis; Curtis, Jeffrey R

    2016-01-01

    Objective To evaluate long term changes in cholesterol levels in early rheumatoid arthritis (RA) patients randomized to initiate methotrexate (MTX) monotherapy, methotrexate + etanercept (MTX+ETA), or triple therapy (TT) [MTX + sulfasalazine (SSZ) + hydroxychloroquine (HCQ)] in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial. Methods Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were analyzed in 416 patients participating in the TEAR trial over 102 weeks of follow-up. Associations of cholesterol changes with disease activity and drug treatment were evaluated using repeated measures analysis with mixed effect linear models to model the within-subject covariance over time. Results Mixed effect models controlling for traditional CV risk factors, TEAR treatment, and baseline prednisone and statin use demonstrated significant inverse associations of RA disease activity with changes in cholesterol over time. Decreases in DAS28, CRP, or ESR were associated with increases in HDL-C, LDL-C, and TC in all treatment groups (p values <0.001–0.035). TT was strongly associated with higher HDL-C and lower LDL-C and TC/HDL-C ratios (p values <0.001) compared to MTX monotherapy and MTX + ETA over two year follow-up. Conclusion Decreases in RA disease activity over long term follow-up was associated with increases in cholesterol in early RA patients treated with either biologic or non-biologic therapies. The use of TT over two year follow-up was associated with higher HDL-C and lower LDL-C and TC/HDL-C ratios compared to MTX monotherapy or MTX + ETA combination therapy. PMID:26606398

  20. Five-day bismuth-free triple therapy for the eradication of Helicobacter pylori and reduction of duodenal ulcer relapse

    SciTech Connect

    Coelho, L.G.; Passos, M.C.; Chausson, Y.; Castro L de, P. )

    1991-08-01

    Previous studies have demonstrated that the eradication of Helicobacter pylori (H. pylori) is associated with a significant reduction of the rate of duodenal ulcer (DU) relapse. The aim of this study was to assess the long-term effect of a bismuth-free triple therapy on the eradication of H. pylori and reduction of DU relapse. After informed consent, 61 patients with endoscopically proven DU and H. pylori infection detected on 14C-urea breath test (BT) were included in the study. All patients received a combination of furazolidone, amoxicillin, and metronidazole, three times a day, for 5 days, in addition to eventual classical antiulcer agents prescribed by their attending physicians. BT was repeated after an interval of at least 60 days to evaluate H. pylori eradication. Endoscopy and another BT were performed again at 6.5 months after therapy to detect possible recurrences. Forty-eight patients completed the trial: 26 (54%) patients were negative for H. pylori at 6.5 months after the end of treatment, and 22 (46%) persisted H. pylori positive. Ninety-two percent of the patients in whom the bacteria were eradicated showed endoscopically healed ulcers and were asymptomatic, and two that were symptomatic presented only occasional pain not requiring therapy. Among the 22 patients who persisted H. pylori positive, six (27%) showed endoscopically active ulcers (p = 0.012) and eight (36%) patients continued to be symptomatic (p less than 0.01), and were still using antiulcer drugs (p = 0.002) 6.5 months after treatment. It is concluded that combined treatment with furazolidone, amoxicillin, and metronidazole for 5 days represents a well-tolerated, inexpensive, and effective therapeutic regime for the eradication of H. pylori and abolition of DU relapse in more than 50% of the patients during a follow-up period of 6.5 months.

  1. Randomised comparison of initial triple DMARD therapy with methotrexate monotherapy in combination with low-dose glucocorticoid bridging therapy; 1-year data of the tREACH trial

    PubMed Central

    de Jong, P H; Hazes, J M; Han, H K; Huisman, M; van Zeben, D; van der Lubbe, P A; Gerards, A H; van Schaeybroeck, B; de Sonnaville, P B; van Krugten, M V; Luime, J J; Weel, A E

    2014-01-01

    Objectives To compare 1-year clinical efficacy of (1) initial triple disease-modifying antirheumatic drug therapy (iTDT) with initial methotrexate (MTX) monotherapy (iMM) and (2) different glucocorticoid (GC) bridging therapies: oral versus a single intramuscular injection in early rheumatoid arthritis. Methods In a single-blinded randomised clinical trial patients were randomised into three arms: (A) iTDT (methotrexate+sulfasalazine+hydroxychloroquine) with GCs intramuscularly; (B) iTDT with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. Primary outcomes were (1) area under the curve (AUC) of Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS) and (2) the proportion of patients with radiographic progression. Results 281 patients were randomly assigned to arms A (n=91), B (n=93) or C (n=97). The AUC DAS and HAQ were respectively −2.39 (95% CI −4.77 to −0.00) and −1.67 (95% CI −3.35 to 0.02) lower in patients receiving iTDT than in those receiving iMM. After 3 months, treatment failure occurred less often in the iTDT group, resulting in 40% fewer treatment intensifications. The difference in treatment intensifications between the arms required to maintain the predefined treatment goal remained over time. No differences were seen between the two GC bridging therapies. Respectively 21%, 24% and 23% of patients in arms A, B and C had radiographic progression after 1 year. Patients receiving iTDT had more adjustments of their medication owing to adverse events than those receiving iMM. Conclusions Treatment goals are attained more quickly and maintained with fewer treatment intensifications with iTDT than with iMM. However, no difference in radiographic progression is seen. Both GC bridging therapies are equally effective and, therefore, both can be used. Trial registration number ISRCTN26791028. PMID:24788619

  2. Vonoprazan, a novel potassium-competitive acid blocker, as a component of first-line and second-line triple therapy for Helicobacter pylori eradication: a phase III, randomised, double-blind study

    PubMed Central

    Murakami, Kazunari; Sakurai, Yuuichi; Shiino, Madoka; Funao, Nobuo; Nishimura, Akira; Asaka, Masahiro

    2016-01-01

    Objective The objective of this study was to assess the efficacy, safety and tolerability of vonoprazan, a novel potassium-competitive acid blocker, as a component of Helicobacter pylori eradication therapy. Design A randomised, double-blind, multicentre, parallel-group study was conducted to verify the non-inferiority of vonoprazan 20 mg to lansoprazole 30 mg as part of first-line triple therapy (with amoxicillin 750 mg and clarithromycin 200 or 400 mg) in H pylori-positive patients with gastric or duodenal ulcer history. The first 50 patients failing first-line therapy with good compliance also received second-line vonoprazan-based triple therapy (with amoxicillin 750 mg and metronidazole 250 mg) as an open-label treatment. Results Of the 650 subjects randomly allocated to either first-line triple therapy, 641 subjects completed first-line therapy and 50 subjects completed second-line therapy. The first-line eradication rate (primary end point) was 92.6% (95% CI 89.2% to 95.2%) with vonoprazan versus 75.9% (95% CI 70.9% to 80.5%) with lansoprazole, with the difference being 16.7% (95% CI 11.2% to 22.1%) in favour of vonoprazan, thus confirming the non-inferiority of vonoprazan (p<0.0001). The second-line eradication rate (secondary end point) was also high (98.0%; 95% CI 89.4% to 99.9%) in those who received second-line therapy (n=50). Both first-line triple therapies were well tolerated with no notable differences. Second-line triple therapy was also well tolerated. Conclusion Vonoprazan is effective as part of first-line triple therapy and as part of second-line triple therapy in H pylori-positive patients with a history of gastric or duodenal ulcer. Trial registration number NCT01505127. PMID:26935876

  3. Down-regulating HIF-1α by lentivirus-mediated shRNA for therapy of triple negative breast cancer.

    PubMed

    Li, Shuang; Wei, Qingzhu; Li, Qin; Zhang, Bin; Xiao, Qiang

    2015-01-01

    Hypoxia is associated with poor response to treatment in various cancers. Hypoxia inducible factor 1 (HIF-1) is a major transcription factor that mediates adaptation of cancer cells to a hypoxic environment and regulates many genes that are involved in key cellular functions, including cell immortalization, stem cell maintenance, autocrine growth/survival, angiogenesis, invasion/metastasis, and resistance to chemotherapy. HIF-1α has been considered as an attractive therapeutic target for cancer treatment, but there is limited success in this research field. In the present study, we designed a recombinant lentivirus containing HIF-1α siRNA, developed stably transfected cell lines, and tested the anticancer effects of the siRNA on cancer cells in vitro and in vivo. Our results indicated that the stable downregulation of HIF-1α reversed chemoresistance, inhibited proliferation, migration and invasion of cancer cells, and slowed down the tumor growth in breast cancer xenograft models. In conclusion, the recombinant lentivirus containing HIF-1α siRNA provides a new avenue for developing novel therapy for triple negative breast cancer.

  4. Dual antiplatelet compared to triple antithrombotic therapy in anterior wall acute myocardial infarction complicated by depressed left ventricular ejection fraction

    PubMed Central

    Oyetayo, Ola O.; Slicker, Kipp; De La Rosa, Lisa; Lane, Wesley; Langsjoen, Dane; Patel, Chhaya; Brough, Kevin; Chiles, Christopher

    2015-01-01

    Current guidelines recommend triple antithrombotic therapy (TT) consisting of warfarin, aspirin, and a P2Y12 inhibitor following an anterior ST elevation myocardial infarction (STEMI) complicated by extensive wall motion abnormalities. This recommendation, however, is based on data collected before percutaneous coronary intervention (PCI) became the standard of care for the treatment of STEMI. We designed a retrospective study of patients who received PCI for anterior STEMI over an 8-year period to compare rates of thromboembolic and bleeding events between patients receiving dual antiplatelet therapy (DAPT) and those receiving TT, including warfarin. Patients were included if the predischarge echocardiogram showed extensive wall motion abnormality and an ejection fraction ≤35%. Patients with known left ventricular thrombus were excluded. A total of 124 patients met the criteria, with 80 patients in the DAPT group and 44 in the TT group. The median age was 58 years in the TT group and 64 years in the DAPT group (P < 0.04), with an average ejection fraction of 31%. Thromboembolic events occurred in 4 patients (5%) in the DAPT group compared with 3 patients (6.8%) in the TT group (P = 0.70). Bleeding occurred in 2 patients in the DAPT group and 4 patients in the TT group (2.5% in DAPT vs. 9.1% in TT group, P = 0.18). No differences in rates of clinical embolism or left ventricular thrombus were found. Our data support recent findings that warfarin may not be indicated for patients following PCI for anterior STEMI, even when significant wall motion abnormalities and reduced ejection fraction ≤35% are present. PMID:26424937

  5. Theranostic nanoparticles for enzyme-activatable fluorescence imaging and photodynamic/chemo dual therapy of triple-negative breast cancer

    PubMed Central

    Choi, Jaehee; Kim, Hyunjin

    2015-01-01

    Background Triple-negative breast cancer (TNBC) is a highly diverse group of cancers characterized by tumors that does not express estrogen and progesterone receptors, as well as human epidermal growth factor receptor 2 (HER2) gene expression. TNBC is associated with poor prognosis due to high rate of recurrence and distance metastasis, lack of response to hormonal or HER2-targeted therapies, and partial response to chemotherapy. Hence, development of new therapeutic strategies to overcome such limitations is of great importance. Here we describe the application of photosensitizer-conjugated and camptothecin (CPT)-encapsulated hyaluronic acid (HA) nanoparticles as enzyme-activatable theranostic nanoparticles (EATNP) for near-infrared (NIR) fluorescence imaging and photodynamic/chemo dual therapy of TNBC. Methods For the preparation of EATNPs, chlorin e6 (Ce6), a second generation photosensitizer, was covalently conjugated to a monomethoxy poly(ethylene glycol)-grafted HA backbone. Ce6-conjugated HA (Ce6-HA) formed self-assembled nanoparticles (i.e., Ce6-HA NPs) in an aqueous solution. Subsequently, CPT, a topoisomerase 1 inhibitor with remarkable anticancer efficacy but with low water solubility, was encapsulated inside the hydrophobic core of Ce6-HA NPs thereby forming EATNPs. Results Fluorescence and singlet oxygen generation (SOG) of EATNPs are quenched in its native state. Treatment of EATNPs with hyaluronidase (HAdase) induces enzyme concentration-dependent activation of NIR fluorescence and SOG. Moreover, HAdase-mediated degradation of the nanoparticles also triggers the release of CPT from the EATNPs. In vitro confocal microscopy and cytotoxicity tests confirmed that EATNPs were efficiently introduced into MDA-MB-231 TNBC cell line, thereby inducing better cytotoxicity than that by free CPT. Additional light irradiation onto the EATNP-treated cells significantly increased therapeutic efficacy in TNBC, which indicates that EATNP plays an important role in

  6. The CUPIC algorithm: an accurate model for the prediction of sustained viral response under telaprevir or boceprevir triple therapy in cirrhotic patients.

    PubMed

    Boursier, J; Ducancelle, A; Vergniol, J; Veillon, P; Moal, V; Dufour, C; Bronowicki, J-P; Larrey, D; Hézode, C; Zoulim, F; Fontaine, H; Canva, V; Poynard, T; Allam, S; De Lédinghen, V

    2015-12-01

    Triple therapy using boceprevir or telaprevir remains the reference treatment for genotype 1 chronic hepatitis C in countries where new interferon-free regimens have not yet become available. Antiviral treatment is highly required in cirrhotic patients, but they represent a difficult-to-treat population. We aimed to develop a simple algorithm for the prediction of sustained viral response (SVR) in cirrhotic patients treated with triple therapy. A total of 484 cirrhotic patients from the ANRS CO20 CUPIC cohort treated with triple therapy were randomly distributed into derivation and validation sets. A total of 52.1% of patients achieved SVR. In the derivation set, a D0 score for the prediction of SVR before treatment initiation included the following independent predictors collected at day 0: prior treatment response, gamma-GT, platelets, telaprevir treatment, viral load. To refine the prediction at the early phase of the treatment, a W4 score included as additional parameter the viral load collected at week 4. The D0 and W4 scores were combined in the CUPIC algorithm defining three subgroups: 'no treatment initiation or early stop at week 4', 'undetermined' and 'SVR highly probable'. In the validation set, the rates of SVR in these three subgroups were, respectively, 11.1%, 50.0% and 82.2% (P < 0.001). By replacing the variable 'prior treatment response' with 'IL28B genotype', another algorithm was derived for treatment-naïve patients with similar results. The CUPIC algorithm is an easy-to-use tool that helps physicians weigh their decision between immediately treating cirrhotic patients using boceprevir/telaprevir triple therapy or waiting for new drugs to become available in their country. PMID:26216230

  7. Optimal antagonism of the Renin-Angiotensin-aldosterone system: do we need dual or triple therapy?

    PubMed

    Werner, Christian; Pöss, Janine; Böhm, Michael

    2010-07-01

    HeFT and CHARM-ADDED have shown that combined RAAS inhibition with an ACE inhibitor and ARB significantly reduced the morbidity endpoint in certain patient subgroups compared with standard therapy. However, in clinical practice, dual RAAS blockade is rarely employed, as seen, for instance, in the CORONA trial. The RALES and EPHESUS trials, investigating the effects of aldosterone blockade on cardiovascular outcomes in CHF patients, revealed that the addition of an aldosterone antagonist to standard heart failure therapy conferred powerful relative risk reductions for both morbidity and mortality. Future studies will elucidate whether this also holds true for patients who are asymptomatic or who have heart failure with preserved ejection fraction. In selected patients with renal disease, several studies have suggested that combined RAAS blockade brings about additional renoprotective antiproteinuric effects independent of blood pressure reduction, and large trials with robust endpoints are underway. In summary, combined therapy with several RAAS inhibitors is not recommended for all patients along the cardiorenovascular continuum. Patients with CHF with incomplete neuroendocrine blockade, as indicated, for example, by repetitive cardiac decompensation or refractory symptoms, might benefit from dual therapy as long as safety issues are well controlled. Finally, novel pharmacological agents such as the direct renin inhibitor aliskiren may provide additional therapeutic tools, but their role has yet to be established. PMID:20568830

  8. [Effect of triple antiretroviral therapy on Tunisian AIDS profile: study of 139 cases].

    PubMed

    Zouiten, Fayçal; Ammari, Lamia; Goubantini, Ahmed; Tiouiri, Hanène; Slim, Amine; Maamouri, Ahmed; Kilani, Badreddine; Kanoun, Fakher; Marrakchi, Chekib; Neifer, Nahed; Mihoub, Leila; Jenhani, Faouzi; Garbouj, Mounira; Ben Chaabane, Taoufik

    2003-12-01

    We report a retrospective study to estimate highly active antiretroviral therapy (HAART) effect in 139 HIV infected patients. Four criteria are studied: prevalence of opportunistic infections, CD4 cell count evolution, viral load progression and mortality. Gastrointestinal side effects are the most common clinical adverse reaction (61.1 percent), and hematological side effects are the most common biological adverse reaction (61.2 percent). During the 22.8 months (3 months to 6 years) follow-up average period, CD4 cell counts remained above 500 per cubic millimeter in only 25.8 percent of cases, while 63.5 percent of patients had a viral load below 400 copies per milliliter. During the study on patients receiving HAART, opportunistic infections appeared in 17.3 percent of cases (24 cases) and mortality in 6.4 percent of cases.

  9. Use of PCR and culture to detect Helicobacter pylori in naturally infected cats following triple antimicrobial therapy.

    PubMed

    Perkins, S E; Yan, L L; Shen, Z; Hayward, A; Murphy, J C; Fox, J G

    1996-06-01

    Helicobacter pylori causes gastritis and peptic ulcers and is linked to gastric cancer. Domestic cats from a commercial source were found to be naturally infected with H. pylori, and studies were undertaken to eradicate H. pylori from infected cats by using triple antimicrobial therapy. Eight cats infected with H. pylori were used in the study. Six cats received a 21-day course of oral amoxicillin, metronidazole, and omeprazole, and two cats served as controls. Two weeks and 4 weeks posttreatment (p.t.), all six treated cats were negative at several sites (saliva, gastric juice, and gastric mucosa) for H. pylori by culture. However, as determined by PCR with primers specific for the 26-kDa product, the majority of cats at 2 and 4 weeks p.t. had gastric fluid samples which were positive for H. pylori and three of three cats at 2 weeks p.t. had dental plaque which was positive for H. pylori. At 6 weeks p.t., all six cats had H. pylori-negative cultures for samples from several gastric sites taken at necropsy, and only one cat had H. pylori cultured from gastric juice. PCR analysis revealed that five of six cats had H. pylori DNA amplification products from plaque, saliva, and/or gastric fluid samples. Negative bacterial cultures for cats for which there was demonstrable PCR amplification of H. pylori DNA may reflect the inability of in vitro culture techniques to isolate small numbers of H. pylori organisms, focal colonization at sites not cultured, or a failure of the antibiotics to successfully eradicate H. pylori from extragastric sites which allowed subsequent recolonization of the stomach after cessation of therapy. Alternatively, the treatment strategy may have induced in vivo viable but nonculturable coccoid forms of H. pylori. The H. pylori cat model should allow further studies to test these hypotheses as well as the efficacies of other combined therapeutic regimens. Also, because 100% of these cats were naturally infected with H.pylori, this model should

  10. One-week triple therapy with lansoprazole, clarithromycin, and metronidazole to cure Helicobacter pylori infection in peptic ulcer disease in Korea.

    PubMed

    Perng, C L; Kim, J G; El-Zimaity, H M; Osato, M S; Graham, D Y

    1998-03-01

    The efficacy and acceptability of classical bismuth triple therapy may be limited by poor patient compliance and adverse effects. It is widely agreed that improved, simpler, and reliable therapies are needed to cure Helicobacter pylori infection and foster patient compliance. We evaluated the efficacy and side effects of a Bazzoli triple therapy substituting lansoprazole for omeprazole for H. pylori infection in active peptic ulcer in Korea (30 mg of lansoprazole, 250 mg of clarithromycin, and 400 mg of metronidazole, all twice daily). H. pylori status was evaluated by rapid urease test, histology, and culture at entry and four or more weeks after ending antimicrobial therapy. Fifty-eight patients (mean age: 43 years) with gastric (N = 30) or duodenal ulcer (N = 28) and H. pylori infection were studied. H. pylori was cured in 47 (81%, 95% CI = 69-90%). Mild side effects, including vomiting, diarrhea, and itching, were observed in four patients (7%). Compliance averaged 95%. Fifty-five ulcers (95%) were healed. Pretreatment pylorobulbar deformity was observed in 49 patients (85%), and in 43 (88%) the deformity disappeared after treatment. Pretreatment metronidazole and clarithromycin resistance was observed in 87% and 2% of patients, respectively. The cure rate of H. pylori infection was significantly higher in patients >50 years of age than those <50. Treatment with low-dose one-week lansoprazole, clarithromycin, and metronidazole resulted in a relatively low cure rate, but was well tolerated. Studies to define the optimal duration, dose, and dosing interval of this combination therapy in Korea are needed.

  11. Changes in lipid levels after 48 weeks of dual versus triple therapy observed in the GARDEL study

    PubMed Central

    Cahn, Pedro; Andrade Villanueva, Jaime; Arribas, Jose; Gatell, Jose; Lama, Javier; Norton, Michel; Patterson, Patricia; Sierra Madero, Juan; Sued, Omar; Ines Figueroa, Maria; Jose Rolón, Maria

    2014-01-01

    Introduction Treatment with ritonavir-boosted protease inhibitors and nucleoside analogues frequently leads to rises in lipids, which might increase the cardiovascular risk. The aim of this study was to describe changes in lipid levels among HIV positive patients participating in the GARDEL study. Materials and Methods The GARDEL study compared the efficacy and safety of a dual therapy (DT) combination of LPV/r 400/100 mg BID+3TC 150 mg BID to a triple therapy (TT) with LPV/r 400/100 mg BID+3TC or FTC and a third investigator-selected NRTI in fixed-dose combination among HIV+ treatment naïve patients. We compared changes in lipid levels from baseline to week 48 in both arms. Results Patient's characteristics were well balanced regarding mean baseline total cholesterol (157 mg/dL DT, 154 mg/dL TT), triglycerides (142 mg/dL DT, 139 mg/Dl TT), LDL-C (94 mg/dL DT, 91 mg/dL TT) and HDL-C (36 mg/dL DT, 35 mg/dL TT). Changes in total cholesterol, LDL-C and HDL-C were higher in DT arm, compared to TT (32% DT vs 26% TT for cholesterol; 25% DT vs 16% TT for LDL and 33% DT vs 28% TT for HDL). Increase in triglycerides was higher in TT compared to DT (55% DT vs 92% TT) (Table 1). In TT arm LDL-C and total cholesterol elevations were lower among patients receiving TDF compared to those treated with ZDV or ABC. Conclusion Changes in lipid parameters were observed in both arms. Albeit the increase was numerically higher for cholesterol (total and LDL-C) in DT arm while TT arm had higher increases in TG; no difference was observed when week 48 values were compared with the NCEP ATP III goals for cardiovascular risk reduction [1]. So, the DT strategy, even missing the lipid-lowering effect observed with tenofovir, does not seem to add significant risk to patients treated with this novel strategy. PMID:25394061

  12. Cisplatin/Tegafur/Uracil/Irinotecan Triple Combination Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma: A Phase I/II Clinical Study

    PubMed Central

    Chen, San-Chi; Chang, Peter Mu-Hsin

    2016-01-01

    Lessons Learned Cisplatin/tegafur/uracil/irinotecan triple combination therapy shows moderate response, especially in patients without previous chemoradiotherapy within the 6 months before this combination therapy. Toxicity is tolerable, and quality of life is improved in responders. Background. The prognosis is poor in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Triple combination therapy may increase tumor response. Methods. This phase I/II prospective trial first determined the dose-limiting toxicity and recommended dose of irinotecan with cisplatin and tegafur/uracil (UFUR) in phase I. Irinotecan was supplied at doses of 40, 50, 60, and 70 mg/m2 by using a standard 3+3 design. Doses of cisplatin and UFUR were held stable. In phase II, the recommended dose of irinotecan was administered intravenously (i.v.) over 90 min on day 1, with cisplatin 50 mg/m2 i.v. over 60 min also on day 1, and oral UFUR 200 mg twice a day for 5 days every 2 weeks a cycle. Results. In the phase I portion, 14 patients were enrolled, and the dose level of irinotecan at 60 mg/m2 was defined as the recommended dose for the phase II portion of the study. Among 43 patients enrolled in the phase II portion, complete response was seen in 2 patients (4.7%) and partial response in 10 patients (23.3%), and the disease control rate was 39.5%. In a subgroup analysis of patients whose prior chemoradiotherapy was more than 6 months earlier, a response rate of 40.7% and disease control rate of 59.3% were observed. Conclusion. Cisplatin/UFUR/irinotecan triple combination therapy is tolerated and effective for selected patients. Individualized choice of treatment will influence prognosis and quality of life in R/M HNSCC patients. PMID:27091418

  13. Randomized trial of radiation-free central nervous system prophylaxis comparing intrathecal triple therapy with liposomal cytarabine in acute lymphoblastic leukemia

    PubMed Central

    Bassan, Renato; Masciulli, Arianna; Intermesoli, Tamara; Audisio, Ernesta; Rossi, Giuseppe; Pogliani, Enrico Maria; Cassibba, Vincenzo; Mattei, Daniele; Romani, Claudio; Cortelezzi, Agostino; Corti, Consuelo; Scattolin, Anna Maria; Spinelli, Orietta; Tosi, Manuela; Parolini, Margherita; Marmont, Filippo; Borlenghi, Erika; Fumagalli, Monica; Cortelazzo, Sergio; Gallamini, Andrea; Marfisi, Rosa Maria; Oldani, Elena; Rambaldi, Alessandro

    2015-01-01

    Developing optimal radiation-free central nervous system prophylaxis is a desirable goal in acute lymphoblastic leukemia, to avoid the long-term toxicity associated with cranial irradiation. In a randomized, phase II trial enrolling 145 adult patients, we compared intrathecal liposomal cytarabine (50 mg: 6/8 injections in B-/T-cell subsets, respectively) with intrathecal triple therapy (methotrexate/cytarabine/prednisone: 12 injections). Systemic therapy included methotrexate plus cytarabine or L-asparaginase courses, with methotrexate augmented to 2.5 and 5 g/m2 in Philadelphia-negative B- and T-cell disease, respectively. The primary study objective was the comparative assessment of the risk/benefit ratio, combining the analysis of feasibility, toxicity and efficacy. In the liposomal cytarabine arm 17/71 patients (24%) developed grade 3–4 neurotoxicity compared to 2/74 (3%) in the triple therapy arm (P=0.0002), the median number of episodes of neurotoxicity of any grade was one per patient compared to zero, respectively (P=0.0001), and even though no permanent disabilities or deaths were registered, four patients (6%) discontinued intrathecal prophylaxis on account of these toxic side effects (P=0.06). Neurotoxicity worsened with liposomal cytarabine every 14 days (T-cell disease), and was improved by the adjunct of intrathecal dexamethasone. Two patients in the liposomal cytarabine arm suffered from a meningeal relapse (none with T-cell disease, only one after high-dose chemotherapy) compared to four in the triple therapy arm (1 with T-cell disease). While intrathecal liposomal cytarabine could contribute to improved, radiation-free central nervous system prophylaxis, the toxicity reported in this trial does not support its use at 50 mg and prompts the investigation of a lower dosage. (clinicaltrials.gov identifier: NCT-00795756). PMID:25749825

  14. Telaprevir- and Boceprevir-Based Triple Therapy for Hepatitis C in Liver Transplant Recipients with Advanced Recurrent Disease: A Multicenter Study

    PubMed Central

    Verna, Elizabeth C.; Saxena, Varun; Burton, James R.; O’Leary, Jacqueline G.; Dodge, Jennifer L.; Stravitz, Richard T.; Levitsky, Joshua; Trotter, James F.; Everson, Gregory T.; Brown, Robert S.; Terrault, Norah A.

    2016-01-01

    Background Antiviral treatment with sustained virologic response (SVR) improves survival in liver transplant (LT) recipients, and is especially relevant to patients with advanced recurrent hepatitis C virus (HCV). We assessed the safety and efficacy of protease inhibitor (PI)-based triple therapy in patients with recurrent advanced fibrosis and cholestatic hepatitis. Methods LT recipients with genotype 1 HCV and advanced fibrosis (F3-4/4) or cholestatic hepatitis treated with telaprevir or boceprevir-based triple therapy at 6 centers (CRUSH-C consortium) were retrospectively assessed. The primary endpoints were sustained virologic response at 12 weeks (SVR12) and safety. Results 45 patients with advanced fibrosis and 9 with cholestatic hepatitis (74% male, 57% with genotype 1a, and 63% prior non-responders) were included. SVR12 occurred in 51% of those with advanced fibrosis and 44% with cholestatic hepatitis, and eRVR was highly predictive of SVR12. Previous null/partial response (OR 0.09, p=0.003), low platelet count (OR 1.02, p=0.004), and steroid use (OR 0.16, p=0.03) were negatively associated with SVR12 in multivariable models. Six (11%) patients died during or after treatment, and hepatic decompensation during treatment occurred in 22% of patients with advanced fibrosis and 33% of patients with cholestatic hepatitis. Hispanic ethnicity (OR 9.37, p=0.03) and low albumin at treatment start (OR 0.01, p=0.001) were predictive of death or decompensation in multivariable models. Conclusions For LT recipients with recurrent advanced HCV and at highest need of effective treatment, PI-based triple therapy achieved sustained viral clearance in ~50% of patients. However, there is significant risk of serious adverse events including hepatic decompensation, arguing for earlier therapeutic intervention. The availability of antiviral drug combinations with higher efficacy and improved safety are of particular importance for post-transplant patients with advanced disease

  15. Investigation of NS3 Protease Resistance-Associated Variants and Phenotypes for the Prediction of Treatment Response to HCV Triple Therapy

    PubMed Central

    Susser, Simone; Vermehren, Johannes; Peiffer, Kai-Henrik; Filmann, Natalie; Bon, Dimitra; Kuntzen, Thomas; Mauss, Stefan; Grammatikos, Georgios; Perner, Dany; Berkowski, Caterina; Herrmann, Eva; Zeuzem, Stefan; Bartenschlager, Ralf; Sarrazin, Christoph

    2016-01-01

    Triple therapy of chronic hepatitis C virus (HCV) infection with boceprevir (BOC) or telaprevir (TVR) leads to virologic failure in many patients which is often associated with the selection of resistance-associated variants (RAVs). These resistance profiles are of importance for the selection of potential rescue treatment options. In this study, we sequenced baseline NS3 RAVs population-based and investigated the sensitivity of NS3 phenotypes in an HCV replicon assay together with clinical factors for a prediction of treatment response in a cohort of 165 German and Swiss patients treated with a BOC or TVR-based triple therapy. Overall, the prevalence of baseline RAVs was low, although the frequency of RAVs was higher in patients with virologic failure compared to those who achieved a sustained virologic response (SVR) (7% versus 1%, P = 0.06). The occurrence of RAVs was associated with a resistant NS3 quasispecies phenotype (P<0.001), but the sensitivity of phenotypes was not associated with treatment outcome (P = 0.2). The majority of single viral and host predictors of SVR was only weakly associated with treatment response. In multivariate analyses, low AST levels, female sex and an IFNL4 CC genotype were independently associated with SVR. However, a combined analysis of negative predictors revealed a significantly lower overall number of negative predictors in patients with SVR in comparison to individuals with virologic failure (P<0.0001) and the presence of 2 or less negative predictors was indicative for SVR. These results demonstrate that most single baseline viral and host parameters have a weak influence on the response to triple therapy, whereas the overall number of negative predictors has a high predictive value for SVR. PMID:27281344

  16. Adjunctive Triple Chronotherapy (Combined Total Sleep Deprivation, Sleep Phase Advance, and Bright Light Therapy) Rapidly Improves Mood and Suicidality in Suicidal Depressed Inpatients: An Open Label Pilot Study

    PubMed Central

    Sahlem, Gregory L.; Kalivas, Benjamin; Fox, James B.; Lamb, Kayla; Roper, Amanda; Williams, Emily N.; Williams, Nolan R.; Korte, Jeffrey E.; Zuschlag, Zachary D.; El Sabbagh, Salim; Guille, Constance; Barth, Kelly S.; Uhde, Thomas W.; George, Mark S.; Short, E.Baron

    2014-01-01

    Previous studies have demonstrated that combined total sleep deprivation (Wake therapy), sleep phase advance, and bright light therapy (Triple Chronotherapy) produce a rapid and sustained antidepressant effect in acutely depressed individuals. To date no studies have explored the impact of the intervention on unipolar depressed individuals with acute concurrent suicidality. Participants were suicidal inpatients (N=10, Mean age=44±16.4SD, 6F) with unipolar depression. In addition to standard of care, they received open label Triple Chronotherapy. Participants underwent one night of total sleep deprivation (33–36 hours), followed by a three-night sleep phase advance along with four 30-minute sessions of bright light therapy (10,000 lux) each morning. Primary outcome measures included the 17 item Hamilton depression scale (HAM17), and the Columbia Suicide Severity Rating Scale (CSSRS), which were recorded at baseline prior to total sleep deprivation, and at protocol completion on day five. Both HAM17, and CSSRS scores were greatly reduced at the conclusion of the protocol. HAM17 scores dropped from a mean of 24.7±4.2SD at baseline to a mean of 9.4±7.3SD on day five (p=.002) with six of the ten individuals meeting criteria for remission. CSSRS scores dropped from a mean of 19.5±8.5SD at baseline to a mean of 7.2±5.5SD on day five (p=.01). The results of this small pilot trial demonstrate that adjunctive Triple Chronotherapy is feasible and tolerable in acutely suicidal and depressed inpatients. Limitations include a small number of participants, an open label design, and the lack of a comparison group. Randomized controlled studies are needed. PMID:25231629

  17. Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: an open label pilot study.

    PubMed

    Sahlem, Gregory L; Kalivas, Benjamin; Fox, James B; Lamb, Kayla; Roper, Amanda; Williams, Emily N; Williams, Nolan R; Korte, Jeffrey E; Zuschlag, Zachary D; El Sabbagh, Salim; Guille, Constance; Barth, Kelly S; Uhde, Thomas W; George, Mark S; Short, E Baron

    2014-12-01

    Previous studies have demonstrated that combined total sleep deprivation (Wake therapy), sleep phase advance, and bright light therapy (Triple Chronotherapy) produce a rapid and sustained antidepressant effect in acutely depressed individuals. To date no studies have explored the impact of the intervention on unipolar depressed individuals with acute concurrent suicidality. Participants were suicidal inpatients (N = 10, Mean age = 44 ± 16.4 SD, 6F) with unipolar depression. In addition to standard of care, they received open label Triple Chronotherapy. Participants underwent one night of total sleep deprivation (33-36 h), followed by a three-night sleep phase advance along with four 30-min sessions of bright light therapy (10,000 lux) each morning. Primary outcome measures included the 17 item Hamilton depression scale (HAM17), and the Columbia Suicide Severity Rating Scale (CSSRS), which were recorded at baseline prior to total sleep deprivation, and at protocol completion on day five. Both HAM17, and CSSRS scores were greatly reduced at the conclusion of the protocol. HAM17 scores dropped from a mean of 24.7 ± 4.2 SD at baseline to a mean of 9.4 ± 7.3 SD on day five (p = .002) with six of the ten individuals meeting criteria for remission. CSSRS scores dropped from a mean of 19.5 ± 8.5 SD at baseline to a mean of 7.2 ± 5.5 SD on day five (p = .01). The results of this small pilot trial demonstrate that adjunctive Triple Chronotherapy is feasible and tolerable in acutely suicidal and depressed inpatients. Limitations include a small number of participants, an open label design, and the lack of a comparison group. Randomized controlled studies are needed.

  18. Integration of photothermal therapy and synergistic chemotherapy by a porphyrin self-assembled micelle confers chemosensitivity in triple-negative breast cancer.

    PubMed

    Su, Shishuai; Ding, Yanping; Li, Yiye; Wu, Yan; Nie, Guangjun

    2016-02-01

    Triple-negative breast cancer is a malignant cancer type with a high risk of early recurrence and distant metastasis. Unlike other breast cancers, triple-negative breast cancer is lack of targetable receptors and, therefore, patients largely receive systemic chemotherapy. However, inevitable adverse effects and acquired drug resistance severely constrain the therapeutic outcome. Here we tailor-designed a porphyrin-based micelle that was self-assembled from a hybrid amphiphilic polymer comprising polyethylene glycol, poly (d, l-lactide-co-glycolide) and porphyrin. The bilayer micelles can be simultaneously loaded with two chemotherapeutic drugs with synergistic cytotoxicity and distinct physiochemical properties, forming a uniform and spherical nanostructure. The drug-loaded micelles showed a tendency to accumulate in the tumor and can be internalized by tumor cells for drug release in acidic organelles. Under near-infrared laser irradiation, high density of self-quenched porphyrins in the hydrophobic layer absorbed light efficiently and converted into an excited state, leading to the release of sufficient heat for photothermal therapy. The integration of localized photothermal effect and synergistic chemotherapy conferred great chemosensitivity to cancer cells and achieved tumor regression using about 1/10 of traditional drug dosage. As a result, chemotherapy-associated adverse effects were successfully avoided. Our present study established a novel porphyrin-based nanoplatform with photothermal activity and expanded drug loading capacity, providing new opportunities for challenging conventional chemotherapy and fighting against stubborn triple-negative breast cancer.

  19. [A successful case of hybrid therapy for the left main trunk and triple coronary vessel lesions with acute myocardial infarction and cardiogenic shock].

    PubMed

    Ohkado, A; Nakano, K; Nakatani, H; Gomi, A; Sugiyama, N; Itoh, A; Ohnishi, S; Itai, T; Namiki, S; Hayashi, H; Nirei, T; Hirata, N

    2000-02-01

    A 86-year-patient who had acute myocardial infarction and critical cardiogenic shock was diagnosed to have the left main trunk (LMT) and triple vessel disease. Emergent coronary artery bypass grafting to the left anterior descending artery was performed using saphenous vein graft without cardiopulmonary bypass through median sternotomy. On the 41st postoperative day, catheter intervention was performed to the remaining lesions by stenting of LMT and percutaneous transluminal coronary angioplasty to the right coronary artery lesions. Tl scintigraphy showed remarkable reduction of myocardial ischemia. Hybrid therapy is the effective new strategy for critical cases which cannot be successfully and securely treated by medical or surgical approach alone.

  20. No correspondence between resistance mutations in the HCV-NS3 protease at baseline and early telaprevir-based triple therapy.

    PubMed

    Hoffmann, Luísa; Faffe, Débora Souza; Lima, Jennifer Fróes Cruz; Capitanio, Thayanna Araujo; Cabral, Bianca Catarina Azeredo; Ürményi, Turán Péter; Coelho, Henrique Sergio Moraes; Rondinelli, Edson; Villela-Nogueira, Cristiane Alves; Silva, Rosane

    2015-06-01

    Direct-acting antiviral (DAA)-based therapy is the new standard treatment for chronic hepatitis C virus (HCV) infection. However, protease inhibitor (PI)-resistant viral variants have been often described. This study aimed to examine HCV-NS3 protease variants at baseline and at 4 weeks under triple therapy. To this end, we analyzed the presence of variants in HCV-NS3 protease region from peripheral blood samples of 16 patients infected with HCV-1 at baseline and at 4 weeks of combined therapy with telaprevir, pegylated interferon, and ribavirin, using next-generation sequencing. Several variants with synonymous and non-synonymous amino acid substitutions were detected at both time points. Variants detected at low frequency corresponded to 74% (HCV-1a) and 35% (HCV-1b) of non-synonymous substitutions. We found nine PI-resistance-associated variants (V36A, T54S, V55I, Q80K, Q80R, V107I, I132V, D168E, M175L) in HCV-NS3 of 10 patients. There was no correspondence of resistance-associated variant profile between baseline and at 4 weeks. Moreover, these resistance variants at baseline and short-term treatment are not good predictors of outcome under triple therapy. Our study also shows a large number of others minor and major non-synonymous variants in HCV-NS3 early in telaprevir-based therapy that can be important for further drug resistance association studies with newly developed PI agents. PMID:26674563

  1. [Analysis of the causes leading to withdrawal of the treatment with triple antiviral therapy for hepatitis C patients].

    PubMed

    Ruiz Ramos, J; Lorente Fernández, L; Gil Gómez, I; Cueto Sola, M; Monte Boquet, E; Poveda Andrés, J L

    2014-05-01

    Objetivo: Evaluar las causas de suspensión de tratamientofrente a Hepatitis C que reciben triple terapia antiviral (peginterferon+ ribavirina + inhibidor de proteasa).Métodos: Estudio observacional retrospectivo de pacientes queiniciaron triple terapia antiviral entre enero 2012 - marzo 2013y suspendieron el tratamiento antes de completar el mismo.Resultados: De 156 pacientes que iniciaron triple terapia, 41interrumpieron el tratamiento: Diecinueve por toxicidad, siendodermatológica en siete pacientes (36,8%), intolerancia en seis(31,6%) y hematológica en cuatro (15,8%). Dieciséis pacientessuspendieron todo el tratamiento por ineficacia. El grupo depacientes con mayor porcentaje de fracasos por ineficacia fueronlos “no respondedores” (32,3%) mientras que el grupo depacientes “recidivantes” fueron el grupo con mayor porcentajede suspensiones por toxicidad (15,6%). Dos pacientes fallecierondurante el tratamiento por neumonía.Conclusiones: La triple terapia frente a VHC está asociada a unnúmero importante de fracasos terapéuticos tanto por toxicidadcomo por ineficacia.

  2. Effects of 2'-deoxycoformycin, 9-beta-D-arabinofuranosyladenine 5'-phosphate, and 1-beta-D-arabinofuranosylcytosine triple combination therapy on intracerebral leukemia 1210.

    PubMed

    Caron, N; Lee, S H; Kimball, A P

    1977-09-01

    The triple combination of 2'-deoxycoformycin (2'-dCF), 9-beta-D-arabinofuranosyladenine 5'-phosphate, and 9-beta-D-arabinofuranosylcytosine was found to be very effective in the therapy of C57BL X DBA/2 F1 mice with intracerebral L1210. At the dosages and dosage scheduling used, the double combination of 2'-dCF and 9-beta-D-arabinofuranosyladenine 5'-phosphate gave minimal but significant increases in life-span. When 9-beta-D-arabinofuranosylcytosine was given at suboptimal dosage to mice with intracerebral L1210, the host toxicity caused by 2'-dCF and 9-beta-D-arabinofuranosyladenine 5'-phosphate in combination was decreased by a factor of 2, allowing a more prolonged therapy. "Cures" were obtained with the triple combination at dosages of 9-beta-D-arabinofuranosylcytosine that did not "cure". The supernatant adenosine deaminase from C57BL X DBA/2 F1 mouse brains was purified and the Ki for 2'-dCF using 9-beta-D-arabinofuranosyladenine as substrate was determined to be not more than 2 X 10(-11) M.

  3. Relationship between the early boceprevir-S isomer plasma concentrations and the onset of breakthrough during HCV genotype 1 triple therapy.

    PubMed

    Boglione, L; De Nicolò, A; Cardellino, C S; Ruggiero, T; Ghisetti, V; Cariti, G; Di Perri, G; D'Avolio, A

    2015-02-01

    In a prospective cohort of 18 patients treated with boceprevir, we examined the role of boceprevir plasma concentration at the onset of breakthrough during the treatment. Nine patients experienced breakthrough during therapy. The resistance patterns were as follows: S122S/R, I132V, T54A/I132V, V156S/I170A, V36M/T54S/R155K, V36M/R155K and T54/R155K. Boceprevir-S isomer (SCH 534128) median concentration in patients with breakthrough was 48.3 ng/mL (interquartile range 43-58 ng/mL); in others, it was significantly (p 0.019) higher: 151 ng/mL. Low boceprevir plasma concentration can lead to virologic resistance; therapeutic drug monitoring should be used to prevent the onset of viral breakthrough during triple-regimen therapy with boceprevir. PMID:25658567

  4. A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient

    PubMed Central

    Ali, Siraj M.; Watson, Jessica; Wang, Kai; Chung, Jon H.; McMahon, Caitlin; Ross, Jeffrey S.; Dicke, Karel A.

    2016-01-01

    After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC). We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%). A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients. PMID:27293397

  5. A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient.

    PubMed

    Ali, Siraj M; Watson, Jessica; Wang, Kai; Chung, Jon H; McMahon, Caitlin; Ross, Jeffrey S; Dicke, Karel A

    2016-01-01

    After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC). We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%). A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients. PMID:27293397

  6. Esomeprazole- or rabeprazole-based triple therapy eradicated Helicobacter pylori comparably regardless of clarithromycin susceptibility and CYP2C19 genotypes

    PubMed Central

    Okimoto, Tadayoshi; Mizukami, Kazuhiro; Ogawa, Ryo; Okamoto, Kazuhisa; Shuto, Mitsutaka; Fukuda, Kensuke; Kodama, Masaaki; Murakami, Kazunari

    2016-01-01

    The aim of this study was to assess the efficacy of esomeprazole-based triple therapy compared with rabeprazole-based triple therapy according to CYP2C19 genotype and clarithromycin susceptibility status for first-line eradication therapy of Helicobacter pylori (H. pylori) in Japan. We enrolled 219 H. pylori-infected patients, and randomly allocated patients to the EAC group (esomeprazole 20 mg, clarithromycin 200 mg, amoxicillin 750 mg for one week, with all drugs given twice daily) or RAC group (rabeprazole 10 mg, clarithromycin 200 mg, amoxicillin 750 mg for one week, with all drugs given twice daily). The H. pylori eradication rate according to the PP analyses was 75.0% (95% CI: 65.2–82.8%) in the EAC group and 71.4% (95% CI: 61.4–79.1%) in the RAC group. There were no statistically significant differences. The eradication rates of the clarithromycin-resistant/-sensitive strains were, respectively, 45.0% (95% CI: 30.7–60.2%)/98.0% (95% CI: 88.7–100%) in the EAC group and 39.5% (95% CI: 25.6–55.3%)/93.5% (95% CI: 81.9–98.4%) in the RAC group. The eradication rate of the clarithromycin-sensitive strains was significantly higher than that of the resistant strains in both groups. In conclusion, EAC and RAC therapies show a comparable efficacy regardless of the CYP2C19 genotype and clarithromycin susceptibility status in Japan.

  7. Triple antithrombotic therapy in patients with atrial fibrillation undergoing coronary artery stenting: hovering among bleeding risk, thromboembolic events, and stent thrombosis

    PubMed Central

    2012-01-01

    Dual antiplatelet treatment with aspirin and clopidogrel is the antithrombotic treatment recommended after an acute coronary syndrome and/or coronary artery stenting. The evidence for optimal antiplatelet therapy for patients, in whom long-term treatment oral anticoagulation is mandatory, is however scarce. To evaluate the safety and efficacy of the various antithrombotic strategies adopted in this population, we reviewed the available evidence on the management of patients receiving oral anticoagulation, such as a vitamin-k-antagonists, referred for coronary artery stenting. Atrial fibrillation is the most frequent indication for oral anticoagulation. The need of starting antiplatelet therapy in this clinical scenario raises concerns about the combination to choose: triple therapy with warfarin, aspirin, and a thienopyridine being the most frequent and advised. The safety of this regimen appeared suboptimal because of an increased risk in hemorrhagic complications. On the other hand, the combination of oral anticoagulation and an antiplatelet agent is suboptimal in preventing thromboembolic events and stent thrombosis; dual antiplatelet therapy may be considered only when a high hemorrhagic risk and low thromboembolic risk are perceived. Indeed, the need for prolonged multiple-drug antithrombotic therapy increases the bleeding risks when drug eluting stents are used. Since current evidence derives mainly from small, single-center and retrospective studies, large-scale prospective multicenter studies are urgently needed. PMID:23075316

  8. Rationale for triple fixed-dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic

    PubMed Central

    Volpe, Massimo; Tocci, Giuliano

    2012-01-01

    Hypertension is a growing global health problem, and is predicted to affect 1.56 billion people by 2025. Treatment remains suboptimal, with control of blood pressure achieved in only 20%–35% of patients, and the majority requiring two or more antihypertensive drugs to achieve recommended blood pressure goals. To improve blood pressure control, the European hypertension guidelines recommend that angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) are combined with calcium channel blockers (CCBs) and/or thiazide diuretics. The rationale for this strategy is based, in part, on their different effects on the renin-angiotensin system, which improves antihypertensive efficacy. Data from a large number of trials support the efficacy of ACEIs or ARBs in combination with CCBs and/or hydrochlorothiazide (HCTZ). Combining two different classes of antihypertensive drugs has an additive effect on lowering of blood pressure, and does not increase adverse events, with the ARBs showing a tolerability advantage over the ACEIs. Among the different ARBs, olmesartan medoxomil is available as a dual fixed-dose combination with either amlodipine or HCTZ, and the increased blood pressure-lowering efficacy of these two combinations is proven. Triple therapy is required in 15%–20% of treated uncontrolled hypertensive patients, with a renin-angiotensin system blocker, CCB, and thiazide diuretic considered to be a rational combination according to the European guidelines. Olmesartan, amlodipine, and HCTZ are available as a triple fixed-dose combination, and significant blood pressure reductions have been observed with this regimen compared with the possible dual combinations. The availability of these fixed-dose combinations should lead to improvement in blood pressure control and aid compliance with long-term therapy, optimizing the management of this chronic condition. PMID:22745561

  9. ITPA and SLC29A1 Genotyping for the Prediction of Ribavirin Dose Reduction in Anti-HCV Triple Therapy with Protease Inhibitors.

    PubMed

    Lombardi, Andrea; Landonio, Simona; Magni, Carlo; Cheli, Stefania; Mazzali, Cristina; Mondelli, Mario U; Rizzardini, Giuliano; Clementi, Emilio; Falvella, Felicia Stefania

    2015-01-01

    Chronic hepatitis C is one of the most important causes of liver disease, leading to cirrhosis, hepatic decompensation and hepatocellular carcinoma. Recently some important advances in therapy have been achieved with the introduction of first wave, first generation direct acting antiviral agents (DAAs) such as boceprevir (BOC), in combination with pegylated interferon (Peg-IFN) and ribavirin (RBV). The superior rate of sustained virological response with this treatment is accompanied by an elevated frequency of anaemia. Several studies have evidenced the importance of single nucleotide polymorphisms (SNPs) in inosine triphosphatase (ITPA) and solute carrier family 29, member 1 (SLC29A1) genes in the development of this adverse event. Here, we investigated haemoglobin levels and the best-known functional SNPs in ITPA and SLC29A1 genes in 22 patients treated with triple therapy with BOC/Peg-IFN/RBV. The identification of ITPA protective and SLC29A1 risk genotypes still appears to be a current methodology in RBV dosing during hepatitis C virus therapy with DAAs. PMID:26279293

  10. Efficacy of Low-Level Laser Therapy in Relieving Nipple Pain in Breastfeeding Women: A Triple-Blind, Randomized, Controlled Trial.

    PubMed

    Coca, Kelly Pereira; Marcacine, Karla Oliveira; Gamba, Mônica Antar; Corrêa, Luciana; Aranha, Ana Cecília Corrêa; Abrão, Ana Cristina Freitas de Vilhena

    2016-08-01

    Pain accruing from nipple lesions caused by inadequate latching by the baby is a common complaint among breastfeeding women and an important obstacle to successful breastfeeding. Nipple pain occurs during the first days after delivery and is considered one of the main causes for early weaning. To investigate the efficacy of low-level laser therapy as a treatment for nipple pain due to breastfeeding. A triple-blind, randomized, clinical study. A university-affiliated hospital in São Paulo, Brazil. Fifty-nine women with nipple lesions at the time of their admission. Thirty women (intervention group) received three sessions of laser therapy (InGaAIP laser, 660 nanometer, 40 milliwatts of power, 5 Joules per square centimeter of energy density for 5 seconds each, total energy = 0.6 Joules) in the region of the nipples at three different points in time (0 hour, 24 hours, and 48 hours after diagnosis of nipple lesion). Twenty-nine women with similar clinical conditions were randomly assigned to the control group. Self-reported pain was recorded before and after laser therapy using a visual analogue scale. The intervention group experienced a decrease of 2.0 centimeters in intensity of pain (p = .016) 24 hours after the first intervention and also presented lower levels of pain compared with the control group. Low-level laser therapy was considered effective for treating nipple lesions in breastfeeding women with pain, providing relief and prolonging exclusive breastfeeding. More clinical trials with different laser dosimetry and parameters are necessary to optimize laser therapy protocols for breastfeeding women. PMID:27363734

  11. Current data of targeted therapies for the treatment of triple-negative advanced breast cancer: empiricism or evidence-based?

    PubMed

    Petrelli, Fausto; Cabiddu, Mary; Ghilardi, Mara; Barni, Sandro

    2009-10-01

    Approximately 10 - 15% of breast carcinomas (BCs) are known to be 'triple-negative (TN) receptor' (i.e., not expressing ER or PR and not exhibiting overexpression and/or gene amplification of HER2-neu). Triple-negative BCs comprise approximately 85% of all basal-type tumours. Classically, basal-like BCs have been characterised by low expression of ER, PR, and HER2 neu and high expression of CK5, CK14, caveolin-1, CAIX, p63, and EGFR (HER1), which reflects the mammary gland basal/myoepithelial cell component. Although there is no standard first-line chemotherapy regimen for metastatic TN BCs, anthracycline- and taxane-containing regimens are acceptable treatments. A large number of agents, including DNA-damaging agents, EGFR inhibitors, antiangiogenic agents and novel taxane formulations are currently being tested in clinical trials for first-line and pretreated patients. Limited experiences with platinum salts, poly(ADP-ribose) polymerase (PARP) inhibitors, cetuximab, bevacizumab and ixabepilone have been published in recent years and will be reported. Novel immunohistochemistry analysis for identification of basal like/TN phenotype are awaited to correctly select this population. The clinical trials investigating new agents have to be designed for a specific (and possibly large) subset of patients with BC. In the future, a gene array platform with greater sensitivity for distinguishing the various BC subtypes, as well as having the power to predict the molecular biology of the disease, will be an indispensible tool for treatment selection. Currently, treatment of TN BC is more empirical than evidence-based. The cornerstone of treatment is chemotherapy, but in the near future, novel target agents will emerge as possible partners.

  12. Novel cell-penetrating peptide-loaded nanobubbles synergized with ultrasound irradiation enhance EGFR siRNA delivery for triple negative Breast cancer therapy.

    PubMed

    Jing, Hui; Cheng, Wen; Li, Shouqiang; Wu, Bolin; Leng, Xiaoping; Xu, Shouping; Tian, Jiawei

    2016-10-01

    The lack of safe and effective gene delivery strategies remains a bottleneck for cancer gene therapy. Here, we describe the synthesis, characterization, and application of cell-penetrating peptide (CPP)-loaded nanobubbles (NBs), which are characterized by their safety, strong penetrating power and high gene loading capability for gene delivery. An epidermal growth factor receptor (EGFR)-targeted small interfering RNA (siEGFR) was transfected into triple negative breast cancer (TNBC) cells via prepared CPP-NBs synergized with ultrasound-targeted microbubble destruction (UTMD) technology. Fluorescence microscopy showed that siEGFR and CPP were loaded on the shells of the NBs. The transfection efficiency and cell proliferation levels were evaluated by FACS and MTT assays, respectively. In addition, in vivo experiments showed that the expression of EGFR mRNA and protein could be efficiently downregulated and that the growth of a xenograft tumor derived from TNBC cells could be inhibited. Our results indicate that CPP-NBs carrying siEGFR could potentially be used as a promising non-viral gene vector that can be synergized with UTMD technology for efficient TNBC therapy. PMID:27388967

  13. Highly porous PEGylated Bi2S3 nano-urchins as a versatile platform for in vivo triple-modal imaging, photothermal therapy and drug delivery.

    PubMed

    Li, Zhenglin; Hu, Ying; Chang, Manli; Howard, Kenneth A; Fan, Xuelei; Sun, Ye; Besenbacher, Flemming; Yu, Miao

    2016-09-21

    Biocompatible single-component nanoplatforms simultaneously integrating multiple therapeutic functions with multiple imaging modes are desirable for anticancer treatments. Herein, elaborately-designed highly porous PEGylated bismuth sulfide nano-urchins (Bi2S3-PEG NUs) have been successfully synthesized by using Bi2O3 nanospheres as the sacrificial template via the hydrothermal process. It is demonstrated that the Bi2S3-PEG NUs possess high compatibility, stability, X-ray attenuation ability, near-infrared (NIR) absorbance and photothermal conversion capability, without noticeable toxicity. Based on both in vitro and in vivo results, the product shows excellent performance in highly effective photothermal therapy (PTT) guided by triple-modal imaging, including X-ray computed tomography (CT), and photoacoustic (PA) and infrared thermal (IRT) imaging, without noticeable toxicity in vivo. Importantly, the NUs are highly porous with a high specific surface area and copious mesopores, providing high loading capacity to accommodate drugs (or guest biomolecules) for further applications in chemotherapy and other additional functions. Doxorubicin is loaded as an example, showing a rather high loading capacity (∼37.9%) together with a bimodal on-demand pH/photothermal-sensitive drug release property. Such fascinating multifunctional nanoagents may have considerable applications in antitumor diagnosis and therapy in the clinic. PMID:27545304

  14. Androgen deprivation therapy sensitizes triple negative breast cancer cells to immune-mediated lysis through androgen receptor independent modulation of osteoprotegerin

    PubMed Central

    Gameiro, Sofia R.; Richards, Jacob; Hall, Ashley B.; Hodge, James W.

    2016-01-01

    Among breast cancer types, triple-negative breast cancer (TNBC) has the fewest treatment options and the lowest 5-year survival rate. Androgen receptor (AR) inhibition has displayed efficacy against breast cancer preclinically and is currently being examined clinically in AR positive TNBC patients. Androgen deprivation has been shown to induce immunogenic modulation; the alteration of tumor cell phenotype resulting in increased sensitivity to immune-mediated killing. We evaluated the ability of AR inhibition to reduce the growth and improve the immune-mediated killing of breast cancer cells with differing expression of the estrogen receptor and AR. While AR expression was required for the growth inhibitory effects of enzalutamide on breast cancer cells, both enzalutamide and abiraterone improved the sensitivity of breast cancer cells to immune-mediated lysis independent of detectable AR expression. This increase in sensitivity was linked to an increase in cell surface tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression as well as a significant reduction in the expression of osteoprotegerin (OPG). The reduction in OPG was further examined and found to be critical for the increase in sensitivity of AR- TNBC cells to immune-mediated killing. The data presented herein further support the use of AR inhibition therapy in the AR+ TNBC setting. These data, however, also support the consideration of AR inhibition therapy for the treatment of AR- TNBC, especially in combination with cancer immunotherapy, providing a potential novel therapeutic option for select patients. PMID:27015557

  15. A Network-Based Data Integration Approach to Support Drug Repurposing and Multi-Target Therapies in Triple Negative Breast Cancer.

    PubMed

    Vitali, Francesca; Cohen, Laurie D; Demartini, Andrea; Amato, Angela; Eterno, Vincenzo; Zambelli, Alberto; Bellazzi, Riccardo

    2016-01-01

    The integration of data and knowledge from heterogeneous sources can be a key success factor in drug design, drug repurposing and multi-target therapies. In this context, biological networks provide a useful instrument to highlight the relationships and to model the phenomena underlying therapeutic action in cancer. In our work, we applied network-based modeling within a novel bioinformatics pipeline to identify promising multi-target drugs. Given a certain tumor type/subtype, we derive a disease-specific Protein-Protein Interaction (PPI) network by combining different data-bases and knowledge repositories. Next, the application of suitable graph-based algorithms allows selecting a set of potentially interesting combinations of drug targets. A list of drug candidates is then extracted by applying a recent data fusion approach based on matrix tri-factorization. Available knowledge about selected drugs mechanisms of action is finally exploited to identify the most promising candidates for planning in vitro studies. We applied this approach to the case of Triple Negative Breast Cancer (TNBC), a subtype of breast cancer whose biology is poorly understood and that lacks of specific molecular targets. Our "in-silico" findings have been confirmed by a number of in vitro experiments, whose results demonstrated the ability of the method to select candidates for drug repurposing. PMID:27632168

  16. A Network-Based Data Integration Approach to Support Drug Repurposing and Multi-Target Therapies in Triple Negative Breast Cancer

    PubMed Central

    Cohen, Laurie D.; Demartini, Andrea; Amato, Angela; Eterno, Vincenzo; Zambelli, Alberto; Bellazzi, Riccardo

    2016-01-01

    The integration of data and knowledge from heterogeneous sources can be a key success factor in drug design, drug repurposing and multi-target therapies. In this context, biological networks provide a useful instrument to highlight the relationships and to model the phenomena underlying therapeutic action in cancer. In our work, we applied network-based modeling within a novel bioinformatics pipeline to identify promising multi-target drugs. Given a certain tumor type/subtype, we derive a disease-specific Protein-Protein Interaction (PPI) network by combining different data-bases and knowledge repositories. Next, the application of suitable graph-based algorithms allows selecting a set of potentially interesting combinations of drug targets. A list of drug candidates is then extracted by applying a recent data fusion approach based on matrix tri-factorization. Available knowledge about selected drugs mechanisms of action is finally exploited to identify the most promising candidates for planning in vitro studies. We applied this approach to the case of Triple Negative Breast Cancer (TNBC), a subtype of breast cancer whose biology is poorly understood and that lacks of specific molecular targets. Our “in-silico” findings have been confirmed by a number of in vitro experiments, whose results demonstrated the ability of the method to select candidates for drug repurposing. PMID:27632168

  17. Improved Helicobacter pylori Eradication Rate of Tailored Triple Therapy by Adding Lactobacillus delbrueckii and Streptococcus thermophilus in Northeast Region of Thailand: A Prospective Randomized Controlled Clinical Trial

    PubMed Central

    Tongtawee, Taweesak; Dechsukhum, Chavaboon; Leeanansaksiri, Wilairat; Kaewpitoon, Soraya; Kaewpitoon, Natthawut; Loyd, Ryan A.; Matrakool, Likit; Panpimanmas, Sukij

    2015-01-01

    Background and Aim. To evaluate the effect of Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus to Helicobacter pylori eradication in different periods of therapeutic protocol. Methods. Infected patients were randomized to one-week tailored triple therapy (esomeprazole 20 mg bid, clarithromycin 500 mg bid/metronidazole 400 mg tid if clarithromycin resistant, and amoxicillin 1000 mg bid) with placebo (group 1, n=100); one week of pretreatment with probiotics (group 2, n=100); and one week of pretreatment with probiotic followed by one week of the same probiotics after treatment (group 3, n=100). Result. PP analysis involved 292 patients, 98 in group 1, 97 in group 2, and 97 in group 3. Successful eradication was observed in 229 patients; by PP analysis, the eradication rates were significantly higher (P<0.01, 95% CI; 0.71–0.97) in group 2 and group 3 than group 1. ITT analysis eradication rates were significantly higher in group 2 and group 3 than group 1 (P<0.01 95% CI; 0.72–0.87), and there is no significant difference between the three groups (P=0.32) in terms of adverse events. Conclusion. Adding probiotics before or before and after tailored treatment can improve Helicobacter pylori eradication rates. This trial is registered with Thai Clinical Trials Registry number: TCTR20141209001. PMID:26167176

  18. One-week triple regime therapy consisting of pantoprazole, amoxicillin and clarithromycin for cure of Helicobacter pylori-associated upper gastrointestinal diseases.

    PubMed

    Dajani, A I; Awad, S; Ukabam, S; Nounou, M A; Abdul Rasheed, Z; Gautam, S; Abdul Aal, G; Nayal, S

    1999-01-01

    This study was designed to determine the efficacy and safety of 1-week triple therapy regime consisting of pantoprazole, amoxicillin and clarithromycin in the cure of Helicobacter pylori infection leading to duodenal ulcer disease and/or gastritis. Sixty-one patients (47 males, 14 females with a mean age of 34 years) belonging to different ethnic groups suffering from H. pylori-associated duodenal ulcer and/or gastritis for an average of 2.46 years were recruited. Having satisfied primary selection criteria, patients received pantoprazole 40 mg b.i.d., clarithromycin 500 mg b.i.d. and amoxicillin 1,000 mg b.i.d. for 7 days. All medications were stopped there after H. pylori eradication was determined 4-6 weeks after treatment by a repeat endoscopy, a rapid urease test, H. pylori culture and histology assessment as indicators of cure. All three tests must be negative to consider the infection to have been successfully eradicated. Fifty-seven patients completed the efficacy analysis per protocol. Dramatic symptomatic improvement was noted in most patients immediately after stopping treatment and it was sustained at 6 weeks. At the end of the study, the healing rate of duodenal ulcers (complete re-epithelialization) following 1-week treatment only, as indicated above, and without any maintenance therapy was 66.7%, that of gastritis was 55.7%, and that of erosions was 64.3%. The overall eradication rate for H. pylori, however, was 93% (95% CI 83.0-98.1%). Furthermore, histologic evaluation revealed a remarkable resolution in the activity of gastritis in all the patients who had successful eradication of the infection.

  19. The efficacy and safety of adding the probiotic Saccharomyces boulardiito standard triple therapy for eradication of H.pylori: a randomized controlled trial

    PubMed Central

    Ghobakhlou, Mehdi; Rajabalinia, Hassan; Ataei, Elnaz; Jahani Sherafat, Somayeh; Moghimi-Dehkordi, Bijan; Bahreiny, Rasoul

    2013-01-01

    Aim Evaluating the efficacy and safety of adding the probiotic Saccharomyces boulardiito standard triple therapy for eradication of Helicobacter pylori. Background Several probiotics such as Saccharomyces boulardii have been investigated for their clinical efficacy. This probiotic, inhibit H. pylori urease by lowering the gastric pH, adhesion of H. pylori to gastric epithelial cells, stabilize the gastric barrier function and reduce the side effects of antibiotics. Patients and methods In this randomized controlled trial we evaluated 160 adult patients with biopsy confirmed H. Pylori infection referred to gastroenterology ward of Taleghani hospital. The patients were randomized into two treatment regimens: patients in group A (n = 80) were given amoxicillin (1000 mg, b.i.d), clarithromycin (500 mg, b.i.d), omeprazole (20 mg, b.i.d) and probiotic of saccaromyces boularidi (Yomogi) (250 mg, b.i.d) for 14 days, moreover patients in group B (n = 80) were given amoxicillin (1000 mg, b.i.d), clarithromycin (500 mg b.i.d) and omeprazole (20 mg,b.i.d) for 14 days. Results 160 patients (66 male 41.25%, 94female 58.75%) with the mean age of 47.1±11.4 years were evaluated. The success rate for H. pylori eradication in group A was higher 75(87.5%) than group B 65 (81.2%), but the difference between two groups was not significant (p = 0.350). Moreover, in case group side effects as nausea, diarrhea, abdominal discomfort and bloating were significantly lower than control group in first and second weeks. Conclusion This study showed that saccaromyces boularidi decreased the adverse effects associated with H.pylori therapy but did not significantly decrease the eradication rate of H.pylori. PMID:24834296

  20. Belgian experience with triple therapy with boceprevir and telaprevir in genotype 1 infected patients who inject drugs.

    PubMed

    Arain, A; Bourgeois, S; de Galocsy, C; Henrion, J; Deltenre, P; d'Heygere, F; George, C; Bastens, B; Van Overbeke, L; Verrando, R; Bruckers, L; Mathei, C; Buntinx, F; Van Vlierberghe, H; Francque, S; Laleman, W; Moreno, C; Janssens, F; Nevens, F; Robaeys, G

    2016-01-01

    No data have been reported yet on treatment outcome in persons who inject drugs (PWID) infected with hepatitis C virus treated with boceprevir or telaprevir in combination with peginterferon (Peg IFN) and ribavirin (RBV). Additionally, there are concerns about the safety of boceprevir and telaprevir in some subgroups of patients with hepatitis C (HCV). In a cohort of HCV patients infected with genotype 1 in Belgium, treatment outcome of patients infected due to IV drug use was analyzed and compared with patients who have no history of substance use. The study population consisted of 179 patients: 78 PWID and 101 controls treated with boceprevir (n = 79) or telaprevir (n = 100) additional to Peg IFN and RBV; 53 (30%) had advanced disease (F3, F4) and 79 (44%) had an antiviral therapy previously. There were no significant differences in the baseline characteristics between both groups, except that PWID patients were more frequently infected with genotype 1a (67% vs 21%), were younger and were predominantly male. Psychiatric complaints during follow-up occurred more frequently in the PWID patients: 24% versus 11% (P = .02). Treatment failure for other reasons than absence of viral response was 70% and 64% in PWID and non-PWID respectively. The sustained viral response (SVR) rates were similar in both groups (71% in PWID vs 72% in non-PWID); with a non-inferiority test with -5% margin there is a difference of -1% (95% CI [-15%, 13%]) and P = 0.30. There are no reasons to exclude PWID from treatment with boceprevir, telaprevir and novel antiviral therapies. PMID:26121975

  1. Classical Cyclophosphamide, Methotrexate, and Fluorouracil Chemotherapy Is More Effective in Triple-Negative, Node-Negative Breast Cancer: Results From Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer

    PubMed Central

    Colleoni, Marco; Cole, Bernard F.; Viale, Giuseppe; Regan, Meredith M.; Price, Karen N.; Maiorano, Eugenio; Mastropasqua, Mauro G.; Crivellari, Diana; Gelber, Richard D.; Goldhirsch, Aron; Coates, Alan S.; Gusterson, Barry A.

    2010-01-01

    Purpose Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents. Patients and Methods Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present. Results Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor–absent, and endocrine receptor–present subtypes. No clear chemotherapy benefit was observed in endocrine receptor–present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor–present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor–absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor–present disease). Conclusion The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer. PMID:20458051

  2. A phase III randomised controlled trial of single-dose triple therapy in COPD: the IMPACT protocol.

    PubMed

    Pascoe, Steven J; Lipson, David A; Locantore, Nicholas; Barnacle, Helen; Brealey, Noushin; Mohindra, Rajat; Dransfield, Mark T; Pavord, Ian; Barnes, Neil

    2016-08-01

    Patients with symptomatic advanced chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations are particularly at risk of poor outcomes and present a significant burden on healthcare systems. The relative merits of treating with different inhaled combination therapies e.g. inhaled corticosteroids (ICS)/long-acting β2-agonist (LABA), LABA/long-acting muscarinic antagonists (LAMA), ICS/LABA/LAMA, in this patient group are poorly understood, as is reflected in current guidelines. The InforMing the PAthway of COPD Treatment (IMPACT) study will evaluate the efficacy and safety of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus FF/VI or UMEC/VI over a 52-week treatment period. The study has been designed with a focus on understanding the comparative merits of each treatment modality in different phenotypes/endotypes.This is a phase III, randomised, double-blind, three-arm, parallel-group, global multicentre study comparing the rate of moderate and severe exacerbations between FF/UMEC/VI and FF/VI or UMEC/VI over a 52-week treatment period. The study aims to recruit 10 000 patients from approximately 1070 centres. Eligible patients are aged ≥40 years, with symptomatic advanced COPD (Global initiative for chronic Obstructive Lung Disease (GOLD) group D) and an exacerbation in the previous 12 months.The first patients were recruited to the IMPACT study (ClinicalTrials.gov: NCT02164513) in June 2014 and the anticipated completion date is July 2017. PMID:27418551

  3. Replacement of clarithromycin with azithromycin in triple therapy regimens for the eradication of helicobacter pylori: A randomized clinical trial

    PubMed Central

    Khoshnood, A; Hakimi, P; Salman-Roghani, H; Reza Mirjalili, M

    2014-01-01

    Abstract Background: Eradication of helicobacter pylori is important for treatment of GU but an ideal regimen is not available. HP is resistant to metronidazole and clarithromycin. Clarithromycin is expensive and is not available in under developing countries. This study aimed to compare two regimens containing clarithromycin or azithromycin. Methods: Totally, seventy-eight patients with GU (confirmed with endoscopy) and infection of HP (Confirmed by Rapid Urease Test (RUT)) were allocated to one of the groups of study (35 participants in each group). Two weeks regimen of Clarithromycin (2×500 mg) + Amoxicillin (2×1 gr) + omeprazole (2×20 mg) was administered for group A of patients while group B got a 10 days regimen of Azithromycin (1×250 mg) + 14 days Amoxicillin (2×1 gr) + omeprazole (2×20 mg). At the end of the treatment course, the patients were evaluated according to the side effects of the drugs. In addition, two months after the end of therapy, patients underwent endoscopy and biopsy to evaluate HP eradication. Results: After two weeks, the side effects of the drug were: Nausea 8 patients in group A and 7 patients in group B, Diarrhea 2 patients in group A, 3 patients in group B and vomiting 2 patients in group A, 3 patients in group B. There were no serious side effects in any group. Eradication rate in group A was 82.9% (based on per protocol analysis (PPA)) and 84.6 % (intention to treat (ITT)). In group B, eradication rate was 77.1 % (PPA) and 79.5 % (ITT) (P=0.55). Conclusion: Based on our study results, azithromycin can be used in HP eradication regimen because of its similar efficacy to clarithromycin but also have lower cost, side effects and resistance. PMID:25408735

  4. Triple gastric peptic ulcer perforation.

    PubMed

    Radojkovic, Milan; Mihajlovic, Suncica; Stojanovic, Miroslav; Stanojevic, Goran; Damnjanovic, Zoran

    2016-03-01

    Patients with advanced or metastatic cancer have compromised nutritional, metabolic, and immune conditions. Nevertheless, little is known about gastroduodenal perforation in cancer patients. Described in the present report is the case of a 41-year old woman with stage IV recurrent laryngeal cancer, who used homeopathic anticancer therapy and who had triple peptic ulcer perforation (PUP) that required surgical repair. Triple gastric PUP is a rare complication. Self-administration of homeopathic anticancer medication should be strongly discouraged when evidence-based data regarding efficacy and toxicity is lacking.

  5. Comparisons of Oncologic Outcomes between Triple-Negative Breast Cancer (TNBC) and Non-TNBC among Patients Treated with Breast-Conserving Therapy

    PubMed Central

    Kim, Sanghwa; Park, Hyung Seok; Kim, Jee Ye; Ryu, Jegyu; Park, Seho

    2016-01-01

    Purpose The optimum local surgical strategy regarding breast-conserving therapy (BCT) for triple-negative breast cancer (TNBC) is controversial. To investigate whether BCT is appropriate for patients with TNBC, we evaluated the clinical outcomes of BCT in women with TNBC compared to those of women without TNBC, using a large, single-center cohort. Materials and Methods We performed a retrospective analysis of 1533 women (TNBC n=321; non-TNBC n=1212) who underwent BCT for primary breast cancer between 2000 and 2010. Clinicopathological characteristics, locoregional recurrence-free survival (LRFS), and overall survival (OS) were analyzed. Results Tumors from the TNBC group had a higher T stage (T2 37.4% vs. 21.0%, p<0.001), a lower N stage (N0 86.9% vs. 75.5%, p<0.001), and a higher histologic grade (Grade III 66.8% vs. 15.4%, p<0.001) than the non-TNBC group. There were no differences in 5-year LRFS rates between the TNBC and non-TNBC groups (98.7% vs. 97.8%, p=0.63). The non-TNBC group showed a slightly better 5-year OS than the TNBC group; however, the difference was not significant (96.2% vs. 97.3%, p=0.72). In multivariate analyses, TNBC was not associated with poor clinical outcomes in terms of LRFS and OS [hazard ratio (HR) for LRFS=0.37, 95% confidence interval (CI): 0.10–1.31; HR for OS=1.03, 95% CI: 0.31–3.39]. Conclusion TNBC patients who underwent BCT showed non-inferior locoregional recurrence compared to non-TNBC patients with BCT. Thus, BCT is an acceptable surgical approach in patients with TNBC. PMID:27401651

  6. The risk of bleeding of triple therapy with vitamin K-antagonists, aspirin and clopidogrel after coronary stent implantation: Facts and questions

    PubMed Central

    Rubboli, Andrea

    2011-01-01

    Background Triple therapy (TT) with vitamin K-antagonists (VKA), aspirin and clopidogrel is the recommended antithrombotic treatment following percutaneous coronary intervention with stent implantation (PCI-S) in patients with an indication for oral anticoagulation. TT is associated with an increased risk of bleeding, but available evidence is flawed by important limitations, including the limited size and the retrospective design of most of the studies, as well as the rare reporting of the incidence of in-hospital bleeding and the treatment which was actually ongoing at the time of bleeding. Since the perceived high bleeding risk of TT may deny patients effective strategies, the determination of the true safety profile of TT is of paramount importance. Methods All the 27 published studies where the incidence of bleeding at various time points during follow-up has been reported separately for patients on TT were reviewed, and the weakness of the data was analyzed. Results The absolute incidence of major bleeding upon discharge at in-hospital, ≤ 1 month, 6 months, 12 months and ≥ 12 months was: 3.3% ± 1.9%, 5.1% ± 6.7%, 8.0% ± 5.2%, 9.0% ± 8.0, and 6.2% ± 7.8%, respectively, and not substantially different from that observed in previous studies with prolonged dual antiplatelet treatment with aspirin and clopidogrel. Conclusions While waiting for the ongoing, large-scale, registries and clinical trials to clarify the few facts and to answer the many questions regarding the risk of bleeding of TT, this treatment should not be denied to patients with an indication for VKA undergoing PCI-S provided that the proper measures and cautions are implemented. PMID:22783307

  7. Increased Risk of Locoregional Recurrence for Women With T1-2N0 Triple-Negative Breast Cancer Treated With Modified Radical Mastectomy Without Adjuvant Radiation Therapy Compared With Breast-Conserving Therapy

    PubMed Central

    Abdulkarim, Bassam S.; Cuartero, Julie; Hanson, John; Deschênes, Jean; Lesniak, David; Sabri, Siham

    2011-01-01

    Purpose To evaluate the risk of locoregional recurrence (LRR) associated with locoregional treatment of women with primary breast cancer tumors negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (triple-negative breast cancer [TNBC]). Patients and Methods Patients diagnosed with TNBC were identified from a cancer registry in a single institution (n=768). LRR-free survival was estimated using Kaplan-Meier analysis. The Cox proportional hazards regression model was used to determine risk of LRR on the basis of locoregional management: breast-conserving therapy (BCT; ie, lumpectomy and adjuvant radiation therapy [RT]) and modified radical mastectomy (MRM) in the TNBC population and T1-2N0 subgroup. Results At a median follow-up of 7.2 years, 77 patients (10%) with TNBC developed LRR. Five-year LRR-free survival was 94%, 85%, and 87% in the BCT, MRM, and MRM + RT groups, respectively (P < .001). In multivariate analysis, MRM (compared with BCT), lymphovascular invasion and lymph node positivity were associated with increased LRR. Conversely, adjuvant chemotherapy was associated with decreased risk of LRR. For patients with T1-2N0 tumors, 5-year LRR-free survival was 96% and 90% in the BCT and MRM groups, respectively (P =.027), and MRM was the only independent prognostic factor associated with increased LRR compared with BCT (hazard ratio, 2.53; 95% CI, 1.12 to 5.75; P= .0264). Conclusion Women with T1-2N0 TNBC treated with MRM without RT have a significant increased risk of LRR compared with those treated with BCT. Prospective studies are warranted to investigate the benefit of adjuvant RT after MRM in TNBC. PMID:21670451

  8. Targeted Cancer Therapy: Correlative Light-Electron Microscopy Shows RGD-Targeted ZnO Nanoparticles Dissolve in the Intracellular Environment of Triple Negative Breast Cancer Cells and Cause Apoptosis with Intratumor Heterogeneity (Adv. Healthcare Mater. 11/2016).

    PubMed

    Othman, Basmah A; Greenwood, Christina; Abuelela, Ayman F; Bharath, Anil A; Chen, Shu; Theodorou, Ioannis; Douglas, Trevor; Uchida, Maskai; Ryan, Mary; Merzaban, Jasmeen S; Porter, Alexandra E

    2016-06-01

    On page 1310 J. S. Merzaban, A. E. Porter, and co-workers present fluorescently labeled RGD-targeted ZnO nanoparticles (NPs; green) for the targeted delivery of cytotoxic ZnO to integrin αvβ3 receptors expressed on triple negative breast cancer cells. Correlative light-electron microscopy shows that NPs dissolve into ionic Zn(2+) (blue) upon uptake and cause apoptosis (red) with intra-tumor heterogeneity, thereby providing a possible strategy for targeted breast cancer therapy. Cover design by Ivan Gromicho. PMID:27275627

  9. Role of concomitant therapy for Helicobacter pylori eradication: A technical note

    PubMed Central

    Losurdo, Giuseppe; Giorgio, Floriana; Iannone, Andrea; Principi, Mariabeatrice; Barone, Michele; Di Leo, Alfredo; Ierardi, Enzo

    2016-01-01

    We read with interest the recent meta-analysis by Lin et al who evaluated the effectiveness of concomitant regimen for Helicobacter pylori (H. pylori) in Chinese regions. They found that 7-d concomitant regimen is undoubtedly superior to 7-d triple therapy (91.2% vs 77.9%, P < 0.0001). However, it is a common belief that a triple therapy lasting 7 d should be definitively removed from the clinical practice for its ineffectiveness. Only its prolongation to 14 d may give satisfactory success rate. Thus, the assessment of an old and outdated treatment versus a more recent and successful one does not seem to bring novel and useful information. Moreover, a 7-d duration has not been ascertained for concomitant regimen, as main guidelines recommend a 10-d schedule for this scheme. Therefore, only studies comparing 10-d concomitant versus 14-d triple seem to be appropriate according to current Guidelines and would clarify which regimen is the most suitable worldwide. Additionally, in this meta-analysis concomitant and sequential therapy showed similar performances, despite it is common opinion that sequential is more prone than concomitant therapy to fail when metronidazole resistance occurs, and China is characterized by high rate of resistance to this antibiotic. None of the included studies evaluated a priori antibiotic resistances, and the lack of this detail hampers the unveiling of this apparent contradiction. In conclusion, the lack of the evaluation of the quality of included trials as well as their high heterogeneity constitute a burdensome limit to draw solid conclusions in this meta-analysis. On the bases of these considerations and the low number of examined trials, we believe that further studies and the knowledge of antibiotic resistances will support with high quality evidence which is the best regimen and its optimal duration. PMID:27784977

  10. Triple Collision and Close Triple Encounters

    NASA Astrophysics Data System (ADS)

    Waldvogel, Joerg

    In gravitational systems of point masses binary collisions are mathematically simple and well understood. Collisions of three or more particles are much more complicated, i.e. a dramatic increase of complexity occurs when the number N of particles involved in a collision increases from 2 to 3. Collisions of more than three particles seem to be of the same complexity as triple collisions. However, there are still unanswered questions concerning general N-body collisions.The reason for the complexity of triple collision is the inherent sensitivity to initial conditions for solutions passing near triple collision, even after a short time. Specifically, a solution passing near triple collision may change dramatically if the initial conditions prior to the close encounter are modified infinitesimally. In contrast, this is not the case for a binary collision.We use the planar three-body problem as a model in order to discuss the main features of triple collision of point masses and of its realistic counterpart, the close triple encounter. This comparatively simple model allows us to study all important aspects of close encounters of N > 2 gravitationally interacting point masses.In Chapters 1 and 2 we discuss classical results, beginning with the equations of motion, then studying relationships between the total angular momentum and triple collision. C. L. Siegel's famous series for triple collision solutions, one time considered the highlight of the theory of triple collision, conclude the traditional part of these lectures.Chapter 3 is devoted to studying the relationship between solutions engaging in a sharp triple collision and neighbouring solutions. The variational equation gives a rough idea of what is happening. A complete understanding can be achieved by means of R. McGehee's concept of the collision manifold, which arises by introducing special coordinates blowing up all possible states close to triple collision. In this context, possibilities of regularizing

  11. Impact of IL28B, APOH and ITPA Polymorphisms on Efficacy and Safety of TVR- or BOC-Based Triple Therapy in Treatment-Experienced HCV-1 Patients with Compensated Cirrhosis from the ANRS CO20-CUPIC Study

    PubMed Central

    About, Frédégonde; Oudot-Mellakh, Tiphaine; Niay, Jonathan; Rabiéga, Pascaline; Pedergnana, Vincent; Duffy, Darragh; Sultanik, Philippe; Cagnot, Carole; Carrat, Fabrice; Marcellin, Patrick; Zoulim, Fabien; Larrey, Dominique; Hézode, Christophe; Fontaine, Hélène; Bronowicki, Jean-Pierre; Pol, Stanislas; Albert, Matthew L.; Theodorou, Ioannis

    2015-01-01

    Background Human genetic factors influence the outcome of pegylated interferon and ribavirin hepatitis C therapy. We explored the role of IL28B, APOH and ITPA SNPs on the outcomes of triple therapy including telaprevir or boceprevir in patients with compensated cirrhosis chronically infected with HCV-1. Patients and Methods A total of 256 HCV-1 Caucasian treatment-experienced patients with compensated cirrhosis from the ANRS CO20-CUPIC cohort were genotyped for a total of 10 candidate SNPs in IL28B (rs12979860 and rs368234815), APOH (rs8178822, rs12944940, rs10048158, rs52797880, rs1801689 and rs1801690) and ITPA (rs1127354 and rs7270101). We tested the association of IL28B and APOH SNPs with sustained virological response and of ITPA SNPs with anemia related phenotypes by means of logistic regression assuming an additive genetic model. Results None of the six APOH SNPs were associated with sustained virological response. The favorable alleles of the IL28B SNPs rs12979860 and rs368234815 were associated with sustained virological response (rs12979860: OR = 2.35[1.50–3.70], P = 2x10-4). Refined analysis showed that the effect of IL28B SNPs on sustained virological response was restricted to prior PegIFN/RBV relapse (OR = 3.80[1.82–8.92], P = 8x10-4). We also confirmed the association between ITPA low activity alleles and protection against early hemoglobin decline in triple therapy (P = 2x10-5). Conclusion Our results suggest that the screening of rs12979860 may remain interesting for decision making in prior relapse HCV-1 Caucasian patients with compensated cirrhosis eligible for a telaprevir- or boceprevir-based therapy. PMID:26670100

  12. Noninvasive theranostic imaging of HSV1-sr39TK-NTR/GCV-CB1954 dual-prodrug therapy in metastatic lung lesions of MDA-MB-231 triple negative breast cancer in mice.

    PubMed

    Sekar, Thillai V; Foygel, Kira; Ilovich, Ohad; Paulmurugan, Ramasamy

    2014-01-01

    Metastatic breast cancer is an obdurate cancer type that is not amenable to chemotherapy regimens currently used in clinic. There is a desperate need for alternative therapies to treat this resistant cancer type. Gene-Directed Enzyme Prodrug Therapy (GDEPT) is a superior gene therapy method when compared to chemotherapy and radiotherapy procedures, proven to be effective against many types of cancer in pre-clinical evaluations and clinical trials. Gene therapy that utilizes a single enzyme/prodrug combination targeting a single cellular mechanism needs significant overexpression of delivered therapeutic gene in order to achieve therapy response. Hence, to overcome this obstacle we recently developed a dual therapeutic reporter gene fusion that uses two different prodrugs, targeting two distinct cellular mechanisms in order to achieve effective therapy with a limited expression of delivered transgenes. In addition, imaging therapeutic reporter genes offers additional information that indirectly correlates gene delivery, expression, and functional effectiveness as a theranostic approach. In the present study, we evaluate the therapeutic potential of HSV1-sr39TK-NTR fusion dual suicide gene therapy system that we recently developed, in MDA-MB-231 triple negative breast cancer lung-metastatic lesions in a mouse model. We compared the therapeutic potential of HSV1-sr39TK-NTR fusion with respective dual prodrugs GCV-CB1954 with HSV1-sr39TK/GCV and NTR/CB1954 single enzyme prodrug system in this highly resistant metastatic lesion of the lungs. In vitro optimization of dose and duration of exposure to GCV and CB1954 was performed in MDA-MB-231 cells. Drug combinations of 1 μg/ml GCV and 10 μM CB1954 for 3 days was found to be optimal regimen for induction of significant cell death, as assessed by FACS analysis. In vivo therapeutic evaluation in animal models showed a complete ablation of lung metastatic nodules of MDA-MB-231 triple negative breast cancer cells following

  13. Sustained virological response after ten days of triple anti-hepatitis C virus (HCV) therapy with telaprevir plus pegylated interferon and ribavirin in an HIV/HCV co-infected cirrhotic woman.

    PubMed

    Hasson, Hamid; Messina, Emanuela; Merli, Marco; Della Torre, Liviana; Morsica, Giulia; Bagaglio, Sabrina; Lazzarin, Adriano; Uberti-Foppa, Caterina

    2014-12-01

    The introduction of first-generation protease inhibitors for the treatment of chronic hepatitis C in subjects infected with hepatitis C virus (HCV) genotype 1 has significantly improved the sustained virological response (SVR) rate. As liver cirrhosis reduces the probability of achieving SVR, current guidelines discourage response-guided therapy in cirrhotic patients. We report the first case of a cirrhotic woman with chronic HCV and HIV co-infection achieving virological response after an ultra-short course of therapy. A 40-year-old HIV/HCV co-infected woman with compensated liver cirrhosis was treated with anti-HCV triple therapy containing telaprevir plus pegylated interferon and ribavirin. Baseline plasma HCV RNA was 3.6 log IU/ml and transaminases were within the normal range. She harboured IL28B rs12979860C/C alleles. Ten days after starting therapy, the patient stopped treatment because of mild anorexia and nausea. Virological response was detected at treatment discontinuation and was maintained up to 24 weeks. This case describes an unexpected SVR after a 10-day course of antiviral therapy in a cirrhotic HIV/HCV co-infected woman presenting positive predictive factors for a response (low viral load, IL28B genotype). Nonetheless, there is no evidence to suggest a shorter duration of treatment in this subset of patients.

  14. Potent efficacy of metronomic topotecan and pazopanib combination therapy in preclinical models of primary or late stage metastatic triple-negative breast cancer

    PubMed Central

    Man, Shan; Bocci, Guido; Kerbel, Robert S.

    2015-01-01

    Metronomic chemotherapy has shown promising activity in numerous preclinical studies and also some phase II clinical studies involving various tumor types, and is currently undergoing phase III trial evaluation. Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis following progression after standard chemotherapeutic regimens. Herein, we evaluated the potential therapeutic impact and molecular mechanisms of topotecan administered in a continuous low-dose metronomic (LDM) manner, alone or in concurrent combination with pazopanib, an antiangiogenic tyrosine kinase inhibitor (TKI), in a triple-negative, primary and metastatic breast cancer orthotopic model; potential molecular mechanisms of efficacy were also studied, especially the impact of hypoxic conditions. The combination of metronomic topotecan and pazopanib significantly enhanced antitumor activity compared to monotherapy with either drug and prolonged survival, even in the advanced metastatic survival setting, with a marked decrease in tumor vascularity, proliferative index, and the induction of apoptosis. Significant changes in tumor angiogenesis, cancer cell proliferation, apoptosis, HIF1α levels, HIF-1 target genes and ABCG2 were found both in vitro and in tumor tissue. Notably, the pazopanib and metronomic topotecan combination treatment inhibited expression of HIF1α and ABCG2 genes in cells grown under hypoxic conditions, and this was associated with an increased intracellular concentration of the active form of topotecan. Our results suggest a potential novel therapeutic option for the treatment of metastatic triple-negative breast cancer patients. PMID:26623560

  15. Triple Starr Valve Replacement

    PubMed Central

    Braimbridge, M. V.; Clement, A. J.; Brown, A. Hedley; Sabar, E.; Mendel, D.

    1969-01-01

    Of nine patients who have had triple valve replacements for organic rheumatic triple valve disease two died in the postoperative period from inadequate myocardial reserve, and a third died four months later from cerebral embolism originating from clot on the left atrial wall. The remainder are well and, except for one, leading normal lives. Though cardiac transplantation has been recommended and used successfully for triple valve disease by Cooley, it is suggested that the long-term outlook today of triple valve replacement is likely to be better than that of transplantation. ImagesFig. 1Fig. 2Fig. 3 PMID:5809243

  16. Taking Triple Aim at the Triple Aim.

    PubMed

    Bryan, Stirling; Donaldson, Cam

    2016-01-01

    Since its introduction to the USA, the Triple Aim is now being adopted in the healthcare systems of other advanced economies. Verma and Bhatia (2016) (V&B) argue that provincial governments in Canada now need to step up to the plate and lead on the implementation of a Triple Aim reform program here. Their proposals are wide ranging and ambitious, looking for governments to act as the "integrators" within the healthcare system, and lead the reforms. Our view is that, as a vision and set of goals for the healthcare system, the Triple Aim is all well and good, but as a pathway for system reform, as articulated by V&B, it misses the mark in at least three important respects. First, the emphasis on improvement driven by performance measurement and pay-for-performance is troubling and flies in the face of emerging evidence. Second, we know that scarcity can be recognized and managed, even in politically complex systems, and so we urge the Triple Aim proponents to embrace more fully notions of resource stewardship. Third, if we want to take seriously "population health" goals, we need to think very differently and consider broader health determinants; Triple Aim innovation targeted at healthcare systems will not deliver the goals. PMID:27009583

  17. Optical frequency tripling with improved suppression and sideband selection.

    PubMed

    Thakur, Manoj P; Medeiros, Maria C R; Laurêncio, Paula; Mitchell, John E

    2011-12-12

    A novel optical dispersion tolerant millimetre-wave radio-over-fibre system using optical frequency tripling technique with enhanced and selectable sideband suppression is demonstrated. The implementation utilises cascaded optical modulators to achieve either an optical single sideband (OSSB) or double sideband-suppressed carrier (DSB-SC) signal with high sideband suppression. Our analysis and simulation results indicate that the achievable suppression ratio of this configuration is only limited by other system factors such as optical noise and drifting of the operational conditions. The OSSB transmission system performance is assessed experimentally by the transport of 4 WiMax channels modulating a 10 GHz optical upconverted RF carrier as well as for optical frequency doubling and tripling. The 10 GHz and tripled carrier at 30 GHz are dispersion tolerant resulting both in an average relative constellation error (RCE) of -28.7 dB after 40 km of fibre. PMID:22274056

  18. Optical frequency tripling with improved suppression and sideband selection.

    PubMed

    Thakur, Manoj P; Medeiros, Maria C R; Laurêncio, Paula; Mitchell, John E

    2011-12-12

    A novel optical dispersion tolerant millimetre-wave radio-over-fibre system using optical frequency tripling technique with enhanced and selectable sideband suppression is demonstrated. The implementation utilises cascaded optical modulators to achieve either an optical single sideband (OSSB) or double sideband-suppressed carrier (DSB-SC) signal with high sideband suppression. Our analysis and simulation results indicate that the achievable suppression ratio of this configuration is only limited by other system factors such as optical noise and drifting of the operational conditions. The OSSB transmission system performance is assessed experimentally by the transport of 4 WiMax channels modulating a 10 GHz optical upconverted RF carrier as well as for optical frequency doubling and tripling. The 10 GHz and tripled carrier at 30 GHz are dispersion tolerant resulting both in an average relative constellation error (RCE) of -28.7 dB after 40 km of fibre.

  19. Polymer Nanoparticles Mediated Codelivery of AntimiR-10b and AntimiR-21 for Achieving Triple Negative Breast Cancer Therapy

    PubMed Central

    2015-01-01

    The current study shows the therapeutic outcome achieved in triple negative breast cancer (TNBC) by simultaneously antagonizing miR-21-induced antiapoptosis and miR-10b-induced metastasis, using antisense-miR-21-PS and antisense-miR-10b-PS delivered by polymer nanoparticles (NPs). We synthesized the antisense-miR-21 and antisense-miR-10b loaded PLGA-b-PEG polymer NPs and evaluated their cellular uptake, serum stability, release profile, and the subsequent synchronous blocking of endogenous miR-21 and miR-10b function in TNBC cells in culture, and tumor xenografts in living animals using molecular imaging. Results show that multitarget antagonization of endogenous miRNAs could be an efficient strategy for targeting metastasis and antiapoptosis in the treatment of metastatic cancer. Targeted delivery of antisense-miR-21 and antisense-miR-10b coloaded urokinase plasminogen activator receptor (uPAR) targeted polymer NPs treated mice showed substantial reduction in tumor growth at very low dose of 0.15 mg/kg, compared to the control NPs treated mice and 40% reduction in tumor growth compared to scramble peptide conjugated NPs treated mice, thus demonstrating a potential new therapeutic option for TNBC. PMID:25652012

  20. The effects of symbiotic therapy on anthropometric measures, body composition and blood pressure in patient with metabolic syndrome: a triple blind RCT

    PubMed Central

    Rabiei, Samira; Shakerhosseini, Rahebeh; Saadat, Navid

    2015-01-01

    Background: Increase in prevalence of obesity and type 2 diabetes which are of the main risk factors of metabolic syndrome, is not only the result of changes in genetic, diet or physical activity, but also an imbalance of micro flora may play an important role. Therefore, alteration of micro flora using pre/probiotic is considered as a new strategy for treatment of metabolic disorders. Methods: The current study is a triple blind randomized controlled trial. 46 patients from both sexes, who fulfilled inclusion criteria, randomly categorized into intervention or placebo group. The intervention and placebo groups consumed 2 probiotic capsules or 2 placebo capsules during 3 months, respectively. Both groups received a weight loss diet, according to their adjusted ideal body weight. Anthropometric, body composition, blood pressure and nutritional measurements were done in the beginning, at 6th week, and at the end of the study. T-test and paired-t test were used for statistical analysis. Results: 40 patients completed the study. BMI, WC, HC, fat mass, lean mass and blood pressure were reduced in all participants (p< 0.05). Systolic blood pressure in symbiotic group was less than placebo group, significantly (p< 0.05). The trend of weight loss in symbiotic group continued at least for 12 weeks while it was stopped at week 6 in placebo group. Conclusion: Symbiotic supplement with the weight loss diet had synergistic effects on improvement in systolic blood pressure and anthropometric measurements. Based on our findings, symbiotic can postpone plateau phase of weight loss and it may prevent resistance to further weight loss. PMID:26478871

  1. Hepatitis C virus NS3 protease genotyping and drug concentration determination during triple therapy with telaprevir or boceprevir for chronic infection with genotype 1 viruses, southeastern France.

    PubMed

    Aherfi, Sarah; Solas, Caroline; Motte, Anne; Moreau, Jacques; Borentain, Patrick; Mokhtari, Saadia; Botta-Fridlund, Danielle; Dhiver, Catherine; Portal, Isabelle; Ruiz, Jean-Marie; Ravaux, Isabelle; Bregigeon, Sylvie; Poizot-Martin, Isabelle; Stein, Andreas; Gérolami, René; Brouqui, Philippe; Tamalet, Catherine; Colson, Philippe

    2014-11-01

    Telaprevir and boceprevir, the two first hepatitis C virus (HCV) NS3 protease inhibitors (PIs), considerably increase rates of sustained virologic response in association with pegylated interferon and ribavirin in chronic HCV genotype 1 infections. The 30 first patients treated by telaprevir or boceprevir including anti-HCV therapies since 2011 in Marseille University hospitals, France, were monitored. HCV loads and plasmatic concentrations of telaprevir and boceprevir were determined on sequential blood samples. HCV NS3 protease gene population sequencing was performed at baseline of treatment and in case of treatment failure. Fifteen patients (including 7 co-infected with HIV) received telaprevir and the other 15 patients (including 4 co-infected with HIV) received boceprevir. At baseline, HCV NS3 protease from six patients harbored amino acid substitutions associated with PI-resistance. Treatment failure occurred at week 12 for 7 patients. Amino acid substitutions associated with PI-resistance were observed in six of these cases. HCV NS3 R155K and T54A/S mutants, all of genotype 1a, were found from four patients. Median (interquartile range) plasma concentrations were 3,092 ng/ml (2,320-3,525) for telaprevir and 486 ng/ml (265-619) for boceprevir. For HIV-HCV co-infected patients, median concentrations were 3,162 ng/ml (2,270-4,232) for telaprevir and 374 ng/ml (229-519) for boceprevir. Plasma drug concentration monitoring revealed undetectable concentrations for two patients at week 4, and probable non-adherence to therapy for another patient. These findings indicate that routine HCV NS3 protease sequencing and plasma PI concentration monitoring might be helpful to characterize cases of therapy failure, at a cost dramatically low compared to that of anti-HCV therapy.

  2. Feasibility, endocrine and anti-tumour effects of a triple endocrine therapy with tamoxifen, a somatostatin analogue and an antiprolactin in post-menopausal metastatic breast cancer: a randomized study with long-term follow-up.

    PubMed Central

    Bontenbal, M.; Foekens, J. A.; Lamberts, S. W.; de Jong, F. H.; van Putten, W. L.; Braun, H. J.; Burghouts, J. T.; van der Linden, G. H.; Klijn, J. G.

    1998-01-01

    Suppression of the secretion of prolactin, growth hormone and insulin-like growth factor 1 (IGF-1) might be important in the growth regulation and treatment of breast cancer. Because oestrogens may counteract the anti-tumour effects of such treatment, the combination of an anti-oestrogen (tamoxifen), a somatostatin analogue (octreotide) and a potent anti-prolactin (CV 205-502) might be attractive. In this respect, we performed a first exploratory long-term study on the feasibility of combined treatment and possible clear differences in endocrine and anti-tumour effects during such combined treatment vs standard treatment with tamoxifen alone. Twenty-two post-menopausal patients with metastatic breast cancer (ER and/or PR positive or unknown) were randomized to receive either 40 mg of tamoxifen per day or the combination of 40 mg of tamoxifen plus 75 microg of CV 205-502 orally plus 3 x 0.2 mg of octreotide s.c. as first-line endocrine therapy. An objective response was found in 36% of the patients treated with tamoxifen alone and in 55% of the patients treated with combination therapy. Median time to progression was 33 weeks for patients treated with tamoxifen and 84 weeks for patients treated with combination therapy, but the numbers are too small for hard conclusions. There was no difference in overall post-relapse survival between the two treatment arms. With respect to the endocrine parameters, there was a significant decrease of plasma IGF-1 levels in both treatment arms, whereas during combined treatment plasma growth hormone tended to decrease and plasma prolactin levels were strongly suppressed; in some patients insulin and transforming growth factor alpha (TGF-alpha) decreased during the triple therapy. Although there was no significant difference in mean decrease of plasma IGF-1 levels between the two treatment arms, combined treatment resulted in a more uniform suppression of IGF-1. Therefore, the addition of a somatostatin analogue and an anti

  3. Triple Point Topological Metals

    NASA Astrophysics Data System (ADS)

    Zhu, Ziming; Winkler, Georg W.; Wu, QuanSheng; Li, Ju; Soluyanov, Alexey A.

    2016-07-01

    Topologically protected fermionic quasiparticles appear in metals, where band degeneracies occur at the Fermi level, dictated by the band structure topology. While in some metals these quasiparticles are direct analogues of elementary fermionic particles of the relativistic quantum field theory, other metals can have symmetries that give rise to quasiparticles, fundamentally different from those known in high-energy physics. Here, we report on a new type of topological quasiparticles—triple point fermions—realized in metals with symmorphic crystal structure, which host crossings of three bands in the vicinity of the Fermi level protected by point group symmetries. We find two topologically different types of triple point fermions, both distinct from any other topological quasiparticles reported to date. We provide examples of existing materials that host triple point fermions of both types and discuss a variety of physical phenomena associated with these quasiparticles, such as the occurrence of topological surface Fermi arcs, transport anomalies, and topological Lifshitz transitions.

  4. Nematostatics of triple lines.

    PubMed

    Rey, Alejandro D

    2003-01-01

    The Landau-de Gennes model for nematic liquid crystal bulk and interfaces has been extended to nematic triple lines involving the intersection of two isotropic fluids and one nematic liquid crystalline phase. A complete set of bulk, interface, and triple line force and torque balance equations has been formulated. The triple line force and torque balance equations have linear, interfacial, and bulk contributions. The bulk contributions appear as junction integrals, the surface contributions as junctions sums, and the line contributions as gradients of stresses. Reduction of dimensionality from three to one dimensional creates the following effects: (a) bulk terms enter interfacial balances as surface jumps and line balances as junction integrals, and (b) surface terms enter linear balances as junction sums. Line stress and torque equations are derived using classical liquid crystal models. The correspondence between line stress and line torque and their surface and bulk analogs is established. The triple line force and torque balance equations are use to analyze the contact angle in a nematic lens lying at the interface between two isotropic fluids, when the preferred surface orientation is tangential. The effect of anisotropy and long range elasticity on triple line phases is established. Under weak anchoring the contact angle is shown to be a function of the anchoring energy at the nematic-isotropic interface, while under strong anchoring conditions the contact angle is a function of the Peach-Koehler force that originates from bulk long range elasticity and acts on the triple line. The use of the complete set of balance equations removes the classical inconsistency in force balances at a contact line by properly taking into account long range (bulk gradient elasticity) and anisotropic (interfacial anchoring elasticity) effects.

  5. Determination of HER2 and p53 Mutations by Sequence Analysis Method and EGFR/Chromosome 7 Gene Status by Fluorescence in Situ Hybridization for the Predilection of Targeted Therapy Modalities in Immunohistochemically Triple Negative Breast Carcinomas in Turkish Population.

    PubMed

    Pala, Emel Ebru; Bayol, Umit; Keskin, Elif Usturali; Ozguzer, Alp; Kucuk, Ulku; Ozer, Ozge; Koc, Altug

    2015-09-01

    Triple negative breast cancer (TNBC), an agressive subtype accounts nearly 15 % of all breast carcinomas. Conventional chemotherapy is the only treatment modality thus new, effective targeted therapy methods have been investigated. Epidermal growth factor receptor (EGFR) inhibitors give hope according to the recent studies results. Also therapeutic agents have been tried against aberrant p53 signal activity as TNBC show high p53 mutation rates. Our aim was to detect the incidence of mutations/amplifications identified in TNBC in our population. Here we used sequence analysis to detect HER2 (exon 18-23), p53 (exon 5-8) mutations; fluorescence in situ hybridization (FISH) method to analyse EGFR/chromosome 7 centromere gene status in 82 immunohistochemically TNBC. Basaloid phenotype was identified in 49 (59.8 %) patients. EGFR amplification was noted in 5 cases (6.1 %). All EGFR amplified cases showed EGFR overexpression by immunohistochemistry (IHC). p53 mutations were identified in 33 (40.2 %) cases. Almost 60 % of the basal like breast cancer cases showed p53 mutation. Only one case showed HER2 mutation (exon 20:g.36830_3). Our results showed that gene amplification is not the unique mechanism in EGFR overexpression. IHC might be used in the decision of anti-EGFR therapy in routine practice. p53 mutation rate was lower than the rates reported in the literature probably due to ethnic differences and low sensitivity of sanger sequences in general mutation screening. We also established the rarity of HER2 mutation in TNBC. In conclusion EGFR and p53 are the major targets in TNBC also for our population.

  6. Directly Acting Triple Drug Anti-HCV Therapy Induces Sustained Virologic Response with a Six Week Regimen: A Proof of Concept Phase 2a Cohort Study

    PubMed Central

    Kohli, Anita; Osinusi, Anuoluwapo; Sims, Zayani; Nelson, Amy; Meissner, Eric G.; Barrett, Lisa L.; Bon, Dimitra; Marti, Miriam M; Silk, Rachel; Kotb, Colleen; Gross, Chloe; Jolley, Tim A; Sidharthan, Sreetha; Petersen, Tess; Townsend, Kerry; Egerson, D’Andrea; Kapoor, Rama; Spurlin, Emily; Sneller, Michael; Proschan, Michael; Herrmann, Eva; Kwan, Richard; Teferi, Gebeyehu; Talwani, Rohit; Diaz, Gabbie; Kleiner, David E.; Wood, Brad J.; Chavez, Jose; Abbott, Stephen; Symonds, William T.; Subramanian, G. Mani; Pang, Phillip S.; McHutchison, John; Polis, Michael A.; Fauci, Anthony S; Masur, Henry; Kottilil, Shyam

    2015-01-01

    Background Direct acting anti-HCV drugs have demonstrated a high cure rate and favorable tolerability. The development of shorter courses of therapy may improve affordability and adherence. Sofosbuvir and ledipasvir together with ribavirin have yielded high efficacy when administered for 8, but not for 6 weeks. We hypothesized that addition of a third potent directly acting antiviral to sofosbuvir and ledipasvir would allow for shortened durations of therapy. Methods In this single center, open-label cohort, phase 2 atrial, sixty HCV GT-1 treatment naïve patients were sequentially enrolled onto three arms and treated with 12 weeks of sofosbuvir and ledipasvir (an NS5B nucleotide polymerase inhibitor and an NS5A inhibitor, respectively) (n=20); or 6 weeks with sofosbuvir, ledipasvir, and GS-9669 (a non-nucleoside NS5B inhibitor) (n=20) or 6 weeks with sofosbuvir, ledipasvir and GS-9451 (an NS3/4A protease inhibitor) (n=20). Patients and investigators were unmasked to treatment assignment. The primary efficacy analysis was SVR12 (HCV RNA less than the level of quantitation 12 weeks after treatment completion). Findings All subjects treated with sofosbuvir and ledipasvir for 12 weeks achieved SVR12 (95%CI: 83–100%). Nineteen of 20 patients (95% CI: 75–100%) treated with sofosbuvir, ledipasvir and GS-9669 achieved SVR12, with 1 patient relapsing 2 weeks after completion of therapy. Nineteen of 20 patients (95% CI: 75–100%) treated with sofosbuvir, ledipasvir, and GS-9451 for 6 weeks achieved SVR12, one patient was lost to follow up after achieving SVR4. There were no discontinuations of treatment due to adverse events. Interpretation In this small proof of concept study, two different three drug regimens administered for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Funding NIAID, National Cancer Institute and Clinical Center Intramural Program. Clinical Trials.gov number NCT01805882. The study was also supported in part by

  7. Nearly Isosceles Pythagorean Triples.

    ERIC Educational Resources Information Center

    Ryden, Robert

    1983-01-01

    The nature of an investigation into numbers termed Nearly Isosceles Pythagorean Triples (NIPTs) is detailed. The exploration, even though it is stated to have no practical value, is defended as helping pupils see the beauty of patterns in mathematics. Two questions regarding the pattern of generating NIPTs are noted. (MP)

  8. A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy.

    PubMed

    Murata, Masayuki; Furusyo, Norihiro; Ogawa, Eiichi; Mitsumoto, Fujiko; Hiramine, Satoshi; Ikezaki, Hiroaki; Takayama, Koji; Shimizu, Motohiro; Toyoda, Kazuhiro; Kainuma, Mosaburo; Hayashi, Jun

    2014-05-01

    In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir, emtricitabine and

  9. Triple-functional core-shell structured upconversion luminescent nanoparticles covalently grafted with photosensitizer for luminescent, magnetic resonance imaging and photodynamic therapy in vitro

    NASA Astrophysics Data System (ADS)

    Qiao, Xiao-Fei; Zhou, Jia-Cai; Xiao, Jia-Wen; Wang, Ye-Fu; Sun, Ling-Dong; Yan, Chun-Hua

    2012-07-01

    Upconversion luminescent nanoparticles (UCNPs) have been widely used in many biochemical fields, due to their characteristic large anti-Stokes shifts, narrow emission bands, deep tissue penetration and minimal background interference. UCNPs-derived multifunctional materials that integrate the merits of UCNPs and other functional entities have also attracted extensive attention. Here in this paper we present a core-shell structured nanomaterial, namely, NaGdF4:Yb,Er@CaF2@SiO2-PS, which is multifunctional in the fields of photodynamic therapy (PDT), magnetic resonance imaging (MRI) and fluorescence/luminescence imaging. The NaGdF4:Yb,Er@CaF2 nanophosphors (10 nm in diameter) were prepared via sequential thermolysis, and mesoporous silica was coated as shell layer, in which photosensitizer (PS, hematoporphyrin and silicon phthalocyanine dihydroxide) was covalently grafted. The silica shell improved the dispersibility of hydrophobic PS molecules in aqueous environments, and the covalent linkage stably anchored the PS molecules in the silica shell. Under excitation at 980 nm, the as-fabricated nanomaterial gave luminescence bands at 550 nm and 660 nm. One luminescent peak could be used for fluorescence imaging and the other was suitable for the absorption of PS to generate singlet oxygen for killing cancer cells. The PDT performance was investigated using a singlet oxygen indicator, and was investigated in vitro in HeLa cells using a fluorescent probe. Meanwhile, the nanomaterial displayed low dark cytotoxicity and near-infrared (NIR) image in HeLa cells. Further, benefiting from the paramagnetic Gd3+ ions in the core, the nanomaterial could be used as a contrast agent for magnetic resonance imaging (MRI). Compared with the clinical commercial contrast agent Gd-DTPA, the as-fabricated nanomaterial showed a comparable longitudinal relaxivities value (r1) and similar imaging effect.Upconversion luminescent nanoparticles (UCNPs) have been widely used in many biochemical

  10. Impact of HCV kinetics on treatment outcome differs by the type of real-time HCV assay in NS3/4A protease inhibitor-based triple therapy.

    PubMed

    Ogawa, Eiichi; Furusyo, Norihiro; Murata, Masayuki; Hayashi, Takeo; Shimizu, Motohiro; Mukae, Haru; Toyoda, Kazuhiro; Hotta, Taeko; Uchiumi, Takeshi; Hayashi, Jun

    2016-02-01

    Repeated measurement of the HCV RNA level is essential for properly monitoring treatment efficacy. The aim of this study was to determine the utility of two HCV real-time assays in the evaluation of the impact of hepatitis C virus (HCV) kinetics on the outcome of triple therapy with NS3/4A protease inhibitors (PIs), telaprevir or simeprevir. This study consisted of 171 Japanese patients infected with HCV genotype 1. All 3266 serum samples taken during and post treatment were tested with both the COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) HCV Test v2.0 and the Abbott RealTime (ART) HCV Test. Of the 2597 samples undetectable (lower limit of detection [

  11. Impact of HCV kinetics on treatment outcome differs by the type of real-time HCV assay in NS3/4A protease inhibitor-based triple therapy.

    PubMed

    Ogawa, Eiichi; Furusyo, Norihiro; Murata, Masayuki; Hayashi, Takeo; Shimizu, Motohiro; Mukae, Haru; Toyoda, Kazuhiro; Hotta, Taeko; Uchiumi, Takeshi; Hayashi, Jun

    2016-02-01

    Repeated measurement of the HCV RNA level is essential for properly monitoring treatment efficacy. The aim of this study was to determine the utility of two HCV real-time assays in the evaluation of the impact of hepatitis C virus (HCV) kinetics on the outcome of triple therapy with NS3/4A protease inhibitors (PIs), telaprevir or simeprevir. This study consisted of 171 Japanese patients infected with HCV genotype 1. All 3266 serum samples taken during and post treatment were tested with both the COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) HCV Test v2.0 and the Abbott RealTime (ART) HCV Test. Of the 2597 samples undetectable (lower limit of detection [

  12. The clinical outcomes of triple antiplatelet therapy versus dual antiplatelet therapy for high-risk patients after coronary stent implantation: a meta-analysis of 11 clinical trials and 9,553 patients

    PubMed Central

    Fan, Zhong-Guo; Ding, Guo-Bin; Li, Xiao-Bo; Gao, Xiao-Fei; Gao, Ya-Li; Tian, Nai-Liang

    2016-01-01

    Background The optimal antiplatelet regimen after in-coronary intervention among patients presenting with complex coronary artery lesions or acute coronary syndrome (ACS) has remained unclear. This study sought to evaluate the clinical outcomes of triple antiplatelet treatment (TAPT) (cilostazol added to aspirin plus clopidogrel) in these patients. Methods The PubMed, EMBASE, MEDLINE, and other Internet sources were searched for relevant articles. The primary end point was major adverse cardiac events (MACE), including all-cause mortality, myocardial infarction, and target vessel revascularization. The incidence of definite/probable stent thrombosis and bleeding were analyzed as the safety end points. Results Eleven clinical trials involving 9,553 patients were analyzed. The risk of MACE was significantly decreased following TAPT after stent implantation in the ACS subgroup (odds ratio [OR]: 0.72; 95% confidence interval [CI]: 0.61–0.85; P<0.001), which might mainly result from the lower risk of all-cause mortality in this subset (OR: 0.62; 95% CI: 0.48–0.80; P<0.001). The risk of bleeding was not increased with respect to TAPT. Conclusion TAPT after stent implantation was associated with feasible benefits on reducing the risk of MACE, especially on reducing the incidence of all-cause mortality among patients suffering from ACS, without higher incidence of bleeding. Larger and more powerful randomized trials are still warranted to prove the superiority of TAPT for such patients. PMID:27799743

  13. 17 CFR 270.7d-2 - Definition of “public offering” as used in section 7(d) of the Act with respect to certain...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Definition of âpublic offeringâ as used in section 7(d) of the Act with respect to certain Canadian tax-deferred retirement... COMMISSION (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.7d-2 Definition of...

  14. Let-7d miRNA Shows Both Antioncogenic and Oncogenic Functions in Osteosarcoma-Derived 3AB-OS Cancer Stem Cells.

    PubMed

    Di Fiore, Riccardo; Drago-Ferrante, Rosa; Pentimalli, Francesca; Di Marzo, Domenico; Forte, Iris Maria; Carlisi, Daniela; De Blasio, Anna; Tesoriere, Giovanni; Giordano, Antonio; Vento, Renza

    2016-08-01

    Osteosarcoma (OS), an aggressive highly invasive and metastatic bone-malignancy, shows therapy resistance and recurrence, two features that likely depend on cancer stem cells (CSCs), which hold both self-renewing and malignant potential. So, effective anticancer therapies against OS should specifically target and destroy CSCs. We previously found that the let-7d microRNA was downregulated in the 3AB-OS-CSCs, derived from the human OS-MG63 cells. Here, we aimed to assess whether let-7d modulation affected tumorigenic and stemness properties of these OS-CSCs. We found that let-7d-overexpression reduced cell proliferation by decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also decreased sarcosphere-and-colony forming ability, two features associated with self-renewing, and it reduced the expression of stemness genes, including Oct3/4, Sox2, Nanog, Lin28B, and HMGA2. Moreover, let-7d induced mesenchymal-to-epithelial-transition, as shown by both N-Cadherin-E-cadherin-switch and decrease in vimentin. Surprisingly, such switch was accompanied by enhanced migratory/invasive capacities, with a strong increase in MMP9, CXCR4 and VersicanV1. Let-7d- overexpression also reduced cell sensitivity to apoptosis induced by both serum-starvation and various chemotherapy drugs, concomitant with decrease in caspase-3 and increase in BCL2 expression. Our data suggest that let-7d in 3AB-OS-CSCs could induce plastic-transitions from CSCs-to-non-CSCs and vice-versa. To our knowledge this is the first study to comprehensively examine the expression and functions of let-7d in OS-CSCs. By showing that let-7d has both tumor suppressor and oncogenic functions in this context, our findings suggest that, before prospecting new therapeutic strategies based on let-7d modulation, it is urgent to better define its multiple functions. J. Cell. Physiol. 231: 1832-1841, 2016. © 2015 Wiley Periodicals, Inc.

  15. Let-7d miRNA Shows Both Antioncogenic and Oncogenic Functions in Osteosarcoma-Derived 3AB-OS Cancer Stem Cells.

    PubMed

    Di Fiore, Riccardo; Drago-Ferrante, Rosa; Pentimalli, Francesca; Di Marzo, Domenico; Forte, Iris Maria; Carlisi, Daniela; De Blasio, Anna; Tesoriere, Giovanni; Giordano, Antonio; Vento, Renza

    2016-08-01

    Osteosarcoma (OS), an aggressive highly invasive and metastatic bone-malignancy, shows therapy resistance and recurrence, two features that likely depend on cancer stem cells (CSCs), which hold both self-renewing and malignant potential. So, effective anticancer therapies against OS should specifically target and destroy CSCs. We previously found that the let-7d microRNA was downregulated in the 3AB-OS-CSCs, derived from the human OS-MG63 cells. Here, we aimed to assess whether let-7d modulation affected tumorigenic and stemness properties of these OS-CSCs. We found that let-7d-overexpression reduced cell proliferation by decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also decreased sarcosphere-and-colony forming ability, two features associated with self-renewing, and it reduced the expression of stemness genes, including Oct3/4, Sox2, Nanog, Lin28B, and HMGA2. Moreover, let-7d induced mesenchymal-to-epithelial-transition, as shown by both N-Cadherin-E-cadherin-switch and decrease in vimentin. Surprisingly, such switch was accompanied by enhanced migratory/invasive capacities, with a strong increase in MMP9, CXCR4 and VersicanV1. Let-7d- overexpression also reduced cell sensitivity to apoptosis induced by both serum-starvation and various chemotherapy drugs, concomitant with decrease in caspase-3 and increase in BCL2 expression. Our data suggest that let-7d in 3AB-OS-CSCs could induce plastic-transitions from CSCs-to-non-CSCs and vice-versa. To our knowledge this is the first study to comprehensively examine the expression and functions of let-7d in OS-CSCs. By showing that let-7d has both tumor suppressor and oncogenic functions in this context, our findings suggest that, before prospecting new therapeutic strategies based on let-7d modulation, it is urgent to better define its multiple functions. J. Cell. Physiol. 231: 1832-1841, 2016. © 2015 Wiley Periodicals, Inc. PMID:26679758

  16. Expression of HIF-1α and Markers of Angiogenesis Are Not Significantly Different in Triple Negative Breast Cancer Compared to Other Breast Cancer Molecular Subtypes: Implications for Future Therapy

    PubMed Central

    Yehia, Lamis; Boulos, Fouad; Jabbour, Mark; Mahfoud, Ziyad; Fakhruddin, Najla; El-Sabban, Marwan

    2015-01-01

    Introduction Triple negative breast cancer lacks estrogen, progesterone and epidermal growth factor receptors rendering it refractory to available targetedtherapies. TNBC is associated with central fibrosis and necrosis, both indicators of tumor hypoxia. Hypoxia inducible factor 1α is up-regulated under hypoxia and its expression is associated with induction of angiogenesis resulting in proliferation, aggressive tumor phenotype and metastasis. In this study we evaluate the potential use of HIF-1α as aTNBC-specific marker. Methods 62 TNBC, 64 HER2+, and 64 hormone-receptors positive breast cancer cases were evaluated for central fibrosis and necrosis, HIF-1α, HIF-1β, VEGFR3, CD31 expression and microvessel density. RNA extraction from paraffin-embedded samples, followed by quantitative real-time polymerase chain reaction (qRT-PCR) evaluation of HIF-1α and VEGF transcripts was performed on 54 cases (18 from each subtype). Results HIF-1α protein was expressed in 35.5% TNBC, 45.3% HER2+and 25.0% ER+/PR+ (p = 0.055; χ2 test). PCRanalysis of subgroup of breast cancers, 84.2% expressed HIF-1α protein and its transcripts, while only 66.7% expressed VEGF transcripts simultaneously with the HIF-1α protein and its transcripts. Central fibrosis and necrosis was highest in TNBC (p = 0.015; χ2 test), while MVD was comparable among all groups (p = 0.928; χ2 test). VEGFR3 was highest in TNBC expressing HIF-1α. HIF-1β protein was expressed in 32.0% of HIF-1α(+), and in (44.3%) of HIF-1α(-) breast cancer cases (p = 0.033; χ2 test). Moreover, HIF-1α expression in cases with central fibrosis and necrosis was highest in the HER2+ followed by the TNBC (p = 0.156; χ2 test). Conclusions A proportion of TNBC express HIF-1α but not in a significantly different manner from other breast cancer subtypes. The potential of anti-HIF-1α targeted therapy is therefore not a candidate for exclusive use in TNBC, but should be considered in all breast cancers, especially in the

  17. Teaching Triple Science: GCSE Chemistry

    ERIC Educational Resources Information Center

    Learning and Skills Network (NJ3), 2007

    2007-01-01

    The Department for Children, Schools and Families (DCSF) has contracted with the Learning and Skills Network to support awareness and take-up of Triple Science GCSEs through the Triple Science Support Programme. This publication provides an introduction to teaching and learning approaches for the extension topics within GCSE Chemistry. It…

  18. Density of Primitive Pythagorean Triples

    ERIC Educational Resources Information Center

    Killen, Duncan A.

    2004-01-01

    Based on the properties of a Primitive Pythagorean Triple (PPT), a computer program was written to generate, print, and count all PPTs greater than or equal to I[subscript x], where I[subscript x] is an arbitrarily chosen integer. The Density of Primitive Pythagorean Triples may be defined as the ratio of the number of PPTs whose hypotenuse is…

  19. Teaching Triple Science: GCSE Biology

    ERIC Educational Resources Information Center

    Learning and Skills Network (NJ3), 2007

    2007-01-01

    The Department for Children, Schools and Families (DCSF) has contracted with the Learning and Skills Network to support awareness and take-up of Triple Science GCSEs through the Triple Science Support Programme. This publication provides an introduction to teaching and learning approaches for the extension topics within GCSE Biology. It highlights…

  20. Triple acting radial seal

    DOEpatents

    Ebert, Todd A; Carella, John A

    2012-03-13

    A triple acting radial seal used as an interstage seal assembly in a gas turbine engine, where the seal assembly includes an interstage seal support extending from a stationary inner shroud of a vane ring, the interstage seal support includes a larger annular radial inward facing groove in which an outer annular floating seal assembly is secured for radial displacement, and the outer annular floating seal assembly includes a smaller annular radial inward facing groove in which an inner annular floating seal assembly is secured also for radial displacement. A compliant seal is secured to the inner annular floating seal assembly. The outer annular floating seal assembly encapsulates the inner annular floating seal assembly which is made from a very low alpha material in order to reduce thermal stress.

  1. Overexpression of PRL7D1 in Leydig Cells Causes Male Reproductive Dysfunction in Mice.

    PubMed

    Liu, Yaping; Su, Xingyu; Hao, Jie; Chen, Maoxin; Liu, Weijia; Liao, Xiaogang; Li, Gang

    2016-01-01

    Prolactin family 7, subfamily d, member 1 (PRL7D1) is found in mouse placenta. Our recent work showed that PRL7D1 is also present in mouse testis Leydig cells, and the expression of PRL7D1 in the testis exhibits an age-related increase. In the present study, we generated transgenic mice with Leydig cell-specific PRL7D1 overexpression to explore its function during male reproduction. Prl7d1 male mice exhibited subfertility as reflected by reduced sperm counts and litter sizes. The testes from Prl7d1 transgenic mice appeared histologically normal, but the frequency of apoptotic germ cells was increased. Prl7d1 transgenic mice also had lower testosterone concentrations than wild-type mice. Mechanistic studies revealed that Prl7d1 transgenic mice have defects in the testicular expression of steroidogenic acute regulatory protein (STAR) and hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase cluster (HSD3B). Further studies revealed that PRL7D1 overexpression affected the expression of transferrin (TF) in Sertoli cells. These results suggest that PRL7D1 overexpression could lead to increased germ cell apoptosis and exert an inhibitory effect on testosterone production in Leydig cells by reducing the expression of certain steroidogenic-related genes. In addition, PRL7D1 appears to have important roles in the function of Sertoli cells, which, in turn, affects male fertility. We conclude that the expression level of PRL7D1 is associated with the reproductive function of male mice. PMID:26771609

  2. Overexpression of PRL7D1 in Leydig Cells Causes Male Reproductive Dysfunction in Mice.

    PubMed

    Liu, Yaping; Su, Xingyu; Hao, Jie; Chen, Maoxin; Liu, Weijia; Liao, Xiaogang; Li, Gang

    2016-01-13

    Prolactin family 7, subfamily d, member 1 (PRL7D1) is found in mouse placenta. Our recent work showed that PRL7D1 is also present in mouse testis Leydig cells, and the expression of PRL7D1 in the testis exhibits an age-related increase. In the present study, we generated transgenic mice with Leydig cell-specific PRL7D1 overexpression to explore its function during male reproduction. Prl7d1 male mice exhibited subfertility as reflected by reduced sperm counts and litter sizes. The testes from Prl7d1 transgenic mice appeared histologically normal, but the frequency of apoptotic germ cells was increased. Prl7d1 transgenic mice also had lower testosterone concentrations than wild-type mice. Mechanistic studies revealed that Prl7d1 transgenic mice have defects in the testicular expression of steroidogenic acute regulatory protein (STAR) and hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase cluster (HSD3B). Further studies revealed that PRL7D1 overexpression affected the expression of transferrin (TF) in Sertoli cells. These results suggest that PRL7D1 overexpression could lead to increased germ cell apoptosis and exert an inhibitory effect on testosterone production in Leydig cells by reducing the expression of certain steroidogenic-related genes. In addition, PRL7D1 appears to have important roles in the function of Sertoli cells, which, in turn, affects male fertility. We conclude that the expression level of PRL7D1 is associated with the reproductive function of male mice.

  3. Triple flames and flame stabilization

    NASA Technical Reports Server (NTRS)

    Broadwell, James E.

    1994-01-01

    It is now well established that when turbulent jet flames are lifted, combustion begins, i.e., the flame is stabilized, at an axial station where the fuel and air are partially premixed. One might expect, therefore, that the beginning of the combustion zone would be a triple flame. Such flames have been described; however, other experiments provide data that are difficult to reconcile with the presence of triple flames. In particular, laser images of CH and OH, marking combustion zones, do not exhibit shapes typical of triple flames, and, more significantly, the lifted flame appears to have a propagation speed that is an order of magnitude higher than the laminar flame speed. The speed of triple flames studied thus far exceeds the laminar value by a factor less than two. The objective of the present task is the resolution of the apparent conflict between the experiments and the triple flame characteristics, and the clarification of the mechanisms controlling flame stability. Being investigated are the resolution achieved in the experiments, the flow field in the neighborhood of the stabilization point, propagation speeds of triple flames, laboratory flame unsteadiness, and the importance of flame ignition limits in the calculation of triple flames that resemble lifted flames.

  4. Third-line rescue therapy for Helicobacter pylori infection

    PubMed Central

    Cianci, Rossella; Montalto, Massimo; Pandolfi, Franco; Gasbarrini, Giovan Battista; Cammarota, Giovanni

    2006-01-01

    H pylori gastric infection is one of the most prevalent infectious diseases worldwide. The discovery that most upper gastrointestinal diseases are related to H pylori infection and therefore can be treated with antibiotics is an important medical advance. Currently, a first-line triple therapy based on proton pump inhibitor (PPI) or ranitidine bismuth citrate (RBC) plus two antibiotics (clarithromycin and amo-xicillin or nitroimidazole) is recommended by all consensus conferences and guidelines. Even with the correct use of this drug combination, infection can not be eradicated in up to 23% of patients. Therefore, several second line therapies have been recommended. A 7 d quadruple therapy based on PPI, bismuth, tetracycline and metronidazole is the more frequently accepted. However, with second-line therapy, bacterial eradication may fail in up to 40% of cases. When H pylori eradication is strictly indicated the choice of further treatment is controversial. Currently, a standard third-line therapy is lacking and various protocols have been proposed. Even after two consecutive failures, the most recent literature data have demonstrated that H pylori eradication can be achieved in almost all patients, even when antibiotic susceptibility is not tested. Different possibilities of empirical treatment exist and the available third-line strategies are herein reviewed. PMID:16688818

  5. Clinical Implications of iNOS Levels in Triple-Negative Breast Cancer Responding to Neoadjuvant Chemotherapy

    PubMed Central

    Jiang, Nan; Zhang, Lei; Li, Yiming; Xu, Xiaoyin; Cai, Shouliang; Wei, Liang; Liu, Xuhong; Chen, Guanglei; Zhou, Yizhen; Liu, Cheng; Li, Zhan; Jin, Feng; Chen, Bo

    2015-01-01

    Triple-negative breast cancer is a high-risk breast cancer with poor survival rate. To date, there is a lack of targeted therapy for this type of cancer. One unique phenomenon is that inflammatory breast cancer is frequently triple negative. However, it is still ambiguous how inflammation influences triple-negative breast cancer growth and responding to chemotherapy. Herein, we investigated the levels of inflammation-associated enzyme, iNOS, in 20 triple-negative breast cancer patients’ tumors, and examined its correlation with patients’ responses to platinum-based neoadjuvant chemotherapy. Our studies showed that triple-negative breast cancer patients with attenuated iNOS levels in tumor cells after treatment showed better responses to platinum-based neoadjuvant chemotherapy than other triple-negative breast cancer patients. Our further in vitro studies confirmed that induction of proper levels of NO increased the resistance to cisplatin in triple-negative MDA-MB-231 cells. Our data suggest that aberrant high level of iNOS/NO are associated with less effectiveness of platinum-based neoadjuvant chemotherapy in triple-negative breast cancer. Therefore, we propose to monitor iNOS levels as a new predictor for triple-negative breast cancer patient’s response to platinum-based neoadjuvant chemotherapy. Moreover, iNOS/NO is considered as a potential target for combination therapy with platinum drugs for triple-negative breast cancer. PMID:26196284

  6. Incorporation of the factor IX Padua mutation into FIX-Triple improves clotting activity in vitro and in vivo.

    PubMed

    Kao, Chung-Yang; Yang, Shu-Jhu; Tao, Mi-Hua; Jeng, Yung-Ming; Yu, I-Shing; Lin, Shu-Wha

    2013-08-01

    Using gain-of-function factor IX (FIX) for replacement therapy for haemophilia B (HB) is an attractive strategy. We previously reported a high-activity FIX, FIX-Triple (FIX-V86A/E277A/R338A) as a good substitute for FIX-WT (wild-type) in protein replacement therapy, gene therapy, and cell therapy. Here we generated a new recombinant FIX-TripleL (FIX-V86A/E277A/R338L) by replacing the alanine at residue 338 of FIX-Triple with leucine as in FIX-Padua (FIX-R338L). Purified FIX-TripleL exhibited 22-fold higher specific clotting activity and 15-fold increased binding affinity to activated FVIII compared to FIX-WT. FIX-TripleL increased the therapeutic potential of FIX-Triple by nearly 100% as demonstrated with calibrated automated thrombogram and thromboelastography. FIX-TripleL demonstrated a normal clearance rate in HB mice. The clotting activity of FIX-TripleL was consistently 2- to 3-fold higher in these mice than that of FIX-Triple or FIX-R338L. Gene delivery of adeno-associated virus (AAV) in HB mice showed that FIX-TripleL had 15-fold higher specific clotting activity than FIX-WT, and this activity was significantly better than FIX-Triple (10-fold) or FIX-R338L (6-fold). At a lower viral dose, FIX-TripleL improved FIX activity from sub-therapeutic to therapeutic levels. Under physiological conditions, no signs of adverse thrombotic events were observed in long-term AAV-FIX-treated C57Bl/6 mice. Hepatocellular adenomas were observed in the high- but not the medium- or the low-dose AAV-treated mice expressing FIX-WT or FIX-Triple, indicating the advantages of using hyperfunctional FIX variants to reduce viral doses while maintaining therapeutic clotting activity. Thus, incorporation of the FIX Padua mutation significantly improves the clotting function of FIX-Triple so as to optimise protein replacement therapy and gene therapy. PMID:23676890

  7. Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation–Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105

    PubMed Central

    Telli, Melinda L.; Jensen, Kristin C.; Vinayak, Shaveta; Kurian, Allison W.; Lipson, Jafi A.; Flaherty, Patrick J.; Timms, Kirsten; Abkevich, Victor; Schackmann, Elizabeth A.; Wapnir, Irene L.; Carlson, Robert W.; Chang, Pei-Jen; Sparano, Joseph A.; Head, Bobbie; Goldstein, Lori J.; Haley, Barbara; Dakhil, Shaker R.; Reid, Julia E.; Hartman, Anne-Renee; Manola, Judith; Ford, James M.

    2015-01-01

    Purpose This study was designed to assess efficacy, safety, and predictors of response to iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation–associated breast cancer. Patients and Methods This single-arm phase II study enrolled patients with stage I to IIIA (T ≥ 1 cm) estrogen receptor–negative (≤ 5%), progesterone receptor–negative (≤ 5%), and human epidermal growth factor receptor 2–negative or BRCA1/2 mutation–associated breast cancer. Neoadjuvant gemcitabine (1,000 mg/m2 intravenously [IV] on days 1 and 8), carboplatin (area under curve of 2 IV on days 1 and 8), and iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) were administered every 21 days for four cycles, until the protocol was amended to six cycles. The primary end point was pathologic complete response (no invasive carcinoma in breast or axilla). All patients underwent comprehensive BRCA1/2 genotyping, and homologous recombination deficiency was assessed by loss of heterozygosity (HRD-LOH) in pretreatment core breast biopsies. Results Among 80 patients, median age was 48 years; 19 patients (24%) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13%), IIA (36%), IIB (36%), and IIIA (15%). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36% (90% CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021). Conclusion Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation–associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted. PMID:25847929

  8. Solution Patterns Predicting Pythagorean Triples

    ERIC Educational Resources Information Center

    Ezenweani, Ugwunna Louis

    2013-01-01

    Pythagoras Theorem is an old mathematical treatise that has traversed the school curricula from secondary to tertiary levels. The patterns it produced are quite interesting that many researchers have tried to generate a kind of predictive approach to identifying triples. Two attempts, namely Diophantine equation and Brahmagupta trapezium presented…

  9. Triple products of Eisenstein series

    NASA Astrophysics Data System (ADS)

    Venkatesh, Anil

    In this thesis, we construct a Massey triple product on the Deligne cohomology of the modular curve with coefficients in symmetric powers of the standard representation of the modular group. This result is obtained by constructing a Massey triple product on the extension groups in the category of admissible variations of mixed Hodge structure over the modular curve, which induces the desired construction on Deligne cohomology. The result extends Brown's construction of the cup product on Deligne cohomology to a higher cohomological product. Massey triple products on Deligne cohomology have been previously investigated by Deninger, who considered Deligne cohomology with trivial real coefficients. By working over the reals, Deninger was able to compute cohomology exclusively with differential forms. In this work, Deligne cohomology is studied over the rationals, which introduces an obstruction to applying Deninger's results. The obstruction arises from the fact that the integration map from the de Rham complex to the Eilenberg-MacLane complex of the modular group is not an algebra homomorphism. We compute the correction terms of the integration map as regularized iterated integrals of Eisenstein series, and show that these integrals arise in the cup product and Massey triple product on Deligne cohomology.

  10. Triple junction distributions in polycrystals

    SciTech Connect

    King, W.E.; Kumar, M.; Schwartz, A.J.

    1999-07-01

    Recently, it has been demonstrated that some material properties can be enhanced by grain boundary engineering, i.e., the systematic modifications in the topology of the microstructure through thermomechanical processing. Experimental observations have shown that the microstructural parameter likely responsible for improved properties is the grain boundary character distribution (GBCD). It has been suggested that improvements in the fractions of special boundaries as defined by the coincident site lattice model (1) are necessary, but not fully sufficient to cause property improvements. For example, it has been observed that cracks propagating along interconnected networks of random grain boundaries can be arrested (2) when intersecting a triple junction where the remaining two pathways are special boundaries. Therefore, it is of interest to characterize microstructures in terms of the distributions of triple junction types. A simple method to describe a triple junction is by the types of grain boundaries intersecting at that junction [special vs. random, as described by the coincident site lattice (CSL) model]. The distribution of 0-CSL, 1-CSL, 2-CSL and 3-CSL triple junctions in the microstructure can then be plotted as a function of the fraction of special boundaries. Such data has been collected using orientation-imaging microscopy (OIM) (3--5) for oxygen-free-electronic (ofe)-Cu and Inconel 600 over a range of special fraction of grain boundaries. These results have been compared with theoretical models considering isolated triple junctions and invoking the {Sigma}-product rule (6) where {Sigma} is the inverse density of coincident lattice sites (7).

  11. Triple negative breast cancer: the role of metabolic pathways.

    PubMed

    Dean, S J R; Rhodes, A

    2014-12-01

    The incidence of breast cancer in Malaysia and other Asian countries is on the increase, reflecting lifestyle changes some of which are known risk factors for the development of breast cancer. Most breast cancers are amenable to adjuvant therapies that target hormone receptors or HER2 receptors on the surface of the cancer cells and bring about significant improvement in survival. However, approximately 17% of Malaysian women with breast cancer, present with tumours that are devoid of these receptors and are consequently termed 'triple negative' breast cancers. These triple negative breast cancers typically occur in women of a younger age than receptor positive cancers, are predominantly of high grade tumours and the prognosis is usually poor. There is therefore a pressing need to understand the biological pathways that drive these tumours, in order that effective strategies are developed to treat these aggressive tumours. With the increasing affluence of developing countries, obesity and Type II Diabetes are also on the rise. These diseases are associated with an increased risk of developing a range of cancers including those of the breast. In particular, the metabolic syndrome has been shown to be associated with triple negative breast cancer. This article reviews some of the metabolic pathways and biomarkers which have been shown to be aberrantly expressed in triple negative breast cancer and highlights some of the ongoing work in this area. PMID:25500513

  12. Evolution from double to triple-antimalarial drug combinations.

    PubMed

    Shanks, G Dennis; Edstein, Michael D; Jacobus, David

    2015-03-01

    Drug combinations are used to treat multiple-drug resistant malaria parasites and to attempt to further delay the evolution of drug resistance. Most current antimalarial combinations are binary but it is likely that new triple drug combinations will be required in the future. A review of previous triple combinations of antimalarial drugs was done to focus attention on past problems and possible future combinations. The advantages of such triple drug combinations include greater efficacy against multiple-drug resistant strains, synergistic action between the different medications and simplification of the regimen so that it could be administered under direct observation and possibly as single-dose therapy. The disadvantages of poly-pharmacy include increased cost of medication, difficulty preparing robust regulatory packages and problems constructing combined formulations due to drug-drug interactions. Given the arrival of artemisinin tolerance/resistance in Southeast Asia, it is likely that new drugs introduced for malaria treatment will be in triple drug combinations. PMID:25549631

  13. Triple helix purification and sequencing

    DOEpatents

    Wang, R.; Smith, L.M.; Tong, X.E.

    1995-03-28

    Disclosed herein are methods, kits, and equipment for purifying single stranded circular DNA and then using the DNA for DNA sequencing purposes. Templates are provided with an insert having a hybridization region. An elongated oligonucleotide has two regions that are complementary to the insert and the oligo is bound to a magnetic anchor. The oligo hybridizes to the insert on two sides to form a stable triple helix complex. The anchor can then be used to drag the template out of solution using a magnet. The system can purify sequencing templates, and if desired the triple helix complex can be opened up to a double helix so that the oligonucleotide will act as a primer for further DNA synthesis. 4 figures.

  14. Triple helix purification and sequencing

    DOEpatents

    Wang, Renfeng; Smith, Lloyd M.; Tong, Xinchun E.

    1995-01-01

    Disclosed herein are methods, kits, and equipment for purifying single stranded circular DNA and then using the DNA for DNA sequencing purposes. Templates are provided with an insert having a hybridization region. An elongated oligonucleotide has two regions that are complementary to the insert and the oligo is bound to a magnetic anchor. The oligo hybridizes to the insert on two sides to form a stable triple helix complex. The anchor can then be used to drag the template out of solution using a magnet. The system can purify sequencing templates, and if desired the triple helix complex can be opened up to a double helix so that the oligonucleotide will act as a primer for further DNA synthesis.

  15. Severe Infections with Human Adenovirus 7d in 2 Adults in Family, Illinois, USA, 2014

    PubMed Central

    Ison, Michael G.

    2016-01-01

    Human adenovirus 7d, a genomic variant with no reported circulation in the United States, was isolated from 2 adults with severe respiratory infections in Illinois. Molecular typing identified a close relationship with strains of the same genome type isolated from cases of respiratory disease in several provinces of China since 2009. PMID:26982199

  16. Levofloxacin/amoxicillin-based schemes vs quadruple therapy for Helicobacter pylori eradication in second-line.

    PubMed

    Di Caro, Simona; Fini, Lucia; Daoud, Yayha; Grizzi, Fabio; Gasbarrini, Antonio; De Lorenzo, Antonino; Di Renzo, Laura; McCartney, Sara; Bloom, Stuart

    2012-10-28

    Worldwide prevalence of Helicobacter pylori (H. pylori) infection is approximately 50%, with the highest being in developing countries. We compared cure rates and tolerability (SE) of second-line anti-H. pylori levofloxacin/amoxicillin (LA)-based triple regimens vs standard quadruple therapy (QT). An English language literature search was performed up to October 2010. A meta-analysis was performed including randomized clinical trials comparing 7- or 10-d LA with 7-d QT. In total, 10 articles and four abstracts were identified. Overall eradication rate in LA was 76.5% (95% CI: 64.4%-97.6%). When only 7-d regimens were included, cure rate was 70.6% (95% CI: 40.2%-99.1%), whereas for 10-d combinations, cure rate was significantly higher (88.7%; 95% CI: 56.1%-109.9%; P < 0.05). Main eradication rate for QT was 67.4% (95% CI: 49.7%-67.9%). The 7-d LA and QT showed comparable efficacy [odds ratio (OR): 1.09; 95% CI: 0.63-1.87], whereas the 10-d LA regimen was significantly more effective than QT (OR: 5.05; 95% CI: 2.74-9.31; P < 0.001; I(2) = 75%). No differences were reported in QT eradication rates among Asian and European studies, whereas LA regimens were more effective in European populations (78.3% vs 67.7%; P = 0.05). Incidence of SE was lower in LA therapy than QT (OR: 0.39; 95% CI: 0.18-0.85; P = 0.02). A higher rate of side effects was reported in Asian patients who received QT. Our findings support the use of 10-d LA as a simple second-line treatment for H. pylori eradication with an excellent eradication rate and tolerability. The optimal second-line alternative scheme might differ among countries depending on quinolone resistance.

  17. Energy Efficient Triple IG Automation EEE (Triple-E)

    SciTech Connect

    McGlinchy, Timothy B

    2013-02-28

    GED Integrated Solutions collaborated with US window and door manufactures to investigate, design and verify technical and cost feasibility for producing high performance, high volume, low material and labor cost window, utilizing a modified window design containing a triple insulating glass unit (IGU). This window design approach when combined with a high volume IGU manufacturing system, can produce R5 rated windows for an approximate additional consumer cost of only $4 per square foot when compared to conventional Low-E argon dual pane IG windows, resulting in a verify practical, reliable and affordable high performance window for public use.

  18. Lymphatic and blood vessels in basal and triple-negative breast cancers: characteristics and prognostic significance.

    PubMed

    Mohammed, Rabab A A; Ellis, Ian O; Mahmmod, Ali M; Hawkes, E Claire; Green, Andrew R; Rakha, Emad A; Martin, Stewart G

    2011-06-01

    -negative tumours have similar vascular characteristics in terms of lymphatic vessel density and vascular invasion but higher microvessel density, suggesting that such groups may preferentially benefit from anti-angiogenic therapy. Vascular invasion was, in all phenotypes, almost entirely lymphatic vessel invasion and could stratify basal-like and triple-negative phenotypes into distinct prognostic groups.

  19. Triple Therapy with Prednisolone, Pegylated Interferon and Sodium Valproate Improves Clinical Outcome and Reduces Human T-Cell Leukemia Virus Type 1 (HTLV-1) Proviral Load, Tax and HBZ mRNA Expression in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

    PubMed

    Boostani, Reza; Vakili, Rosita; Hosseiny, Samane Sadat; Shoeibi, Ali; Fazeli, Bahare; Etemadi, Mohammad Mehdi; Sabet, Faeze; Valizade, Narges; Rezaee, Seyed Abdolrahim

    2015-10-01

    Considering that there is no effective treatment for human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis, this study aimed to assess the impact of triple combination therapy-interferon-α, valproic acid, and prednisolone-on clinical outcomes, main HTLV-1 viral factors, and host anti-HTLV-1 antibody response. HTLV-1 proviral load (PVL), and HBZ and Tax mRNA expression levels were measured in peripheral blood mononuclear cells of 13 patients with HTLV-1-associated myelopathy/tropical spastic paraparesis before and after treatment with 180 μg pegylated interferon once a week, 10-20 mg/kg/day sodium valproate, and 5 mg/day prednisolone for 25 weeks using a TaqMan real-time polymerase chain reaction assay. Furthermore, anti-HTLV-1 titer, Osame Motor Disability Score, Ashworth spasticity scale, and urinary symptoms (through standard questionnaire and clinical monitoring) were assessed in patients before and after the treatment. HTLV-1 PVL and HBZ expression significantly decreased after the treatment [PVL from 1443 ± 282 to 660 ± 137 copies/10(4) peripheral blood mononuclear cells (p = 0.01); and HBZ from 8.0 ± 1.5 to 3.0 ± 0.66 (p < 0.01)]. Tax mRNA expression decreased after the treatment from 2.26 ± 0.45 to 1.44 ± 0.64, but this reduction was not statistically significant (p = 0.10). Furthermore, anti-HTLV-1 titer reduced dramatically after the treatment, from 3123 ± 395 to 815 ± 239 (p < 0.01). Clinical signs and symptoms, according to Osame Motor Disability Score and Ashworth score, improved significantly (both p < 0.01). Urinary symptoms and sensory disturbances with lower back pain were reduced, though not to a statistically significant degree. Although signs and symptoms of spasticity were improved, frequent urination and urinary incontinence were not significantly affected by the triple therapy. The results provide new insight into the complicated conditions

  20. Triple Therapy with Prednisolone, Pegylated Interferon and Sodium Valproate Improves Clinical Outcome and Reduces Human T-Cell Leukemia Virus Type 1 (HTLV-1) Proviral Load, Tax and HBZ mRNA Expression in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

    PubMed

    Boostani, Reza; Vakili, Rosita; Hosseiny, Samane Sadat; Shoeibi, Ali; Fazeli, Bahare; Etemadi, Mohammad Mehdi; Sabet, Faeze; Valizade, Narges; Rezaee, Seyed Abdolrahim

    2015-10-01

    Considering that there is no effective treatment for human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis, this study aimed to assess the impact of triple combination therapy-interferon-α, valproic acid, and prednisolone-on clinical outcomes, main HTLV-1 viral factors, and host anti-HTLV-1 antibody response. HTLV-1 proviral load (PVL), and HBZ and Tax mRNA expression levels were measured in peripheral blood mononuclear cells of 13 patients with HTLV-1-associated myelopathy/tropical spastic paraparesis before and after treatment with 180 μg pegylated interferon once a week, 10-20 mg/kg/day sodium valproate, and 5 mg/day prednisolone for 25 weeks using a TaqMan real-time polymerase chain reaction assay. Furthermore, anti-HTLV-1 titer, Osame Motor Disability Score, Ashworth spasticity scale, and urinary symptoms (through standard questionnaire and clinical monitoring) were assessed in patients before and after the treatment. HTLV-1 PVL and HBZ expression significantly decreased after the treatment [PVL from 1443 ± 282 to 660 ± 137 copies/10(4) peripheral blood mononuclear cells (p = 0.01); and HBZ from 8.0 ± 1.5 to 3.0 ± 0.66 (p < 0.01)]. Tax mRNA expression decreased after the treatment from 2.26 ± 0.45 to 1.44 ± 0.64, but this reduction was not statistically significant (p = 0.10). Furthermore, anti-HTLV-1 titer reduced dramatically after the treatment, from 3123 ± 395 to 815 ± 239 (p < 0.01). Clinical signs and symptoms, according to Osame Motor Disability Score and Ashworth score, improved significantly (both p < 0.01). Urinary symptoms and sensory disturbances with lower back pain were reduced, though not to a statistically significant degree. Although signs and symptoms of spasticity were improved, frequent urination and urinary incontinence were not significantly affected by the triple therapy. The results provide new insight into the complicated conditions

  1. Aliskiren, amlodipine and hydrochlorothiazide triple combination for hypertension

    PubMed Central

    Judd, Eric; Jaimes, Edgar A

    2013-01-01

    Cardiovascular-related morbidity and mortality is linked to hypertension with proportional gains in cardiovascular risk factor reduction with the lowering of blood pressure. Clinical trial data has shown that attaining goal blood pressure requires, for most patients, at least two antihypertensive medications, with a significant proportion requiring regimens of three or more medications. Single-pill triple combinations have returned to the market following results of increased efficacy and adherence over dual- and mono-therapy. The combination of aliskiren, amlodipine and hydrochlorothiazide is a rational choice for combination therapy and recent studies suggest that it is safe and effective in lowering blood pressure in patients who fail dual combination therapy. PMID:22390800

  2. Guided search for triple conjunctions.

    PubMed

    Nordfang, Maria; Wolfe, Jeremy M

    2014-08-01

    A key tenet of feature integration theory and of related theories such as guided search (GS) is that the binding of basic features requires attention. This would seem to predict that conjunctions of features of objects that have not been attended should not influence search. However, Found (1998) reported that an irrelevant feature (size) improved the efficiency of search for a Color × Orientation conjunction if it was correlated with the other two features across the display, as compared to the case in which size was not correlated with color and orientation features. We examined this issue with somewhat different stimuli. We used triple conjunctions of color, orientation, and shape (e.g., search for a red, vertical, oval-shaped item). This allowed us to manipulate the number of features that each distractor shared with the target (sharing) and it allowed us to vary the total number of distractor types (and, thus, the number of groups of identical items: grouping). We found that these triple conjunction searches were generally very efficient--producing very shallow Reaction Time × Set Size slopes, consistent with strong guidance by basic features. Nevertheless, both of the variables, sharing and grouping, modulated performance. These influences were not predicted by previous accounts of GS; however, both can be accommodated in a GS framework. Alternatively, it is possible, though not necessary, to see these effects as evidence for "preattentive binding" of conjunctions. PMID:25005070

  3. The Sinai triple junction revisited

    NASA Astrophysics Data System (ADS)

    Courtillot, Vincent; Armijo, Rolando; Tapponnier, Paul

    1987-09-01

    This paper is a summary of a more detailed analysis of the kinematics of the Sinai triple junction (Courtillot et al., 1987). Accurate kinematic data are lacking along the Red Sea and they can be supplemented by bathymetric, topographic and geological data pertaining to the three arms of the entirely continental Sinai triple junction. Motions across the northern Red Sea and along the Gulf of Elat are an order of magnitude larger than across the Gulf of Suez. The direction of motion there remains a major uncertainty. A possible kinematic model is highlighted, in which right-lateral strike-slip motion and small pull-apart basins occur along the Gulf of Suez, in agreement with recent field observations in Egypt. Early Miocene is marked by major geodynamical changes all along the northern boundaries of the African and Indian plates. We suggest that rifting in the Arabian Sea, Gulf of Aden, Red Sea and Gulf of Suez was initiated at the end of the first phase of continental extrusion of Indochina, when the Tibetan plateau began to rise and spreading in the South China Sea came to a halt.

  4. Complete genome sequence of a giant Vibrio bacteriophage VH7D.

    PubMed

    Luo, Zhu-Hua; Yu, Yan-Ping; Jost, Günter; Xu, Wei; Huang, Xiang-Ling

    2015-12-01

    A Vibrio sp. lytic phage VH7D was isolated from seawater of an abalone farm in Xiamen, China. The phage was capable of lysing Vibrio rotiferianus DSM 17186(T) and Vibrio harveyi DSM 19623(T). The complete genome of this phage consists of 246,964 nucleotides with a GC content of 41.31%, which characterized it as a giant vibriophage. Here we report the complete genome sequence and major findings from the genomic annotation. PMID:26476690

  5. Combination therapy of murine mucormycosis or aspergillosis with iron chelation, polyenes, and echinocandins.

    PubMed

    Ibrahim, Ashraf S; Gebremariam, Teclegiorgis; Luo, Guanpingsheng; Fu, Yue; French, Samuel W; Edwards, John E; Spellberg, Brad

    2011-04-01

    Liposomal amphotericin B (LAmB) combined wither either micafungin or deferasirox was synergistic in previous murine studies with mucormycosis or aspergillosis. We hypothesized that triple therapy using LAmB, micafungin, and deferasirox could further improve outcomes of mucormycosis or aspergillosis. Triple therapy improved survival and reduced tissue fungal burden of mice with mucormycosis and to a lesser extent with aspergillosis. Continued investigation into the use of triple therapy against mucormycosis and aspergillosis is warranted.

  6. Existence Regions of Shock Wave Triple Configurations

    ERIC Educational Resources Information Center

    Bulat, Pavel V.; Chernyshev, Mikhail V.

    2016-01-01

    The aim of the research is to create the classification for shock wave triple configurations and their existence regions of various types: type 1, type 2, type 3. Analytical solutions for limit Mach numbers and passing shock intensity that define existence region of every type of triple configuration have been acquired. The ratios that conjugate…

  7. 49 CFR 380.205 - LCV Triples.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS SPECIAL TRAINING REQUIREMENTS LCV Driver-Training Program § 380.205 LCV Triples. (a) To qualify for the training necessary to... training, have: (1) A valid Class A CDL with a double/triple trailer endorsement; (2) Experience...

  8. 49 CFR 380.205 - LCV Triples.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS SPECIAL TRAINING REQUIREMENTS LCV Driver-Training Program § 380.205 LCV Triples. (a) To qualify for the training necessary to... training, have: (1) A valid Class A CDL with a double/triple trailer endorsement; (2) Experience...

  9. Identification of prognostic genes for recurrent risk prediction in triple negative breast cancer patients in Taiwan.

    PubMed

    Chen, Lee H; Kuo, Wen-Hung; Tsai, Mong-Hsun; Chen, Pei-Chun; Hsiao, Chuhsing K; Chuang, Eric Y; Chang, Li-Yun; Hsieh, Fon-Jou; Lai, Liang-Chuan; Chang, King-Jen

    2011-01-01

    Discrepancies in the prognosis of triple negative breast cancer exist between Caucasian and Asian populations. Yet, the gene signature of triple negative breast cancer specifically for Asians has not become available. Therefore, the purpose of this study is to construct a prediction model for recurrence of triple negative breast cancer in Taiwanese patients. Whole genome expression profiling of breast cancers from 185 patients in Taiwan from 1995 to 2008 was performed, and the results were compared to the previously published literature to detect differences between Asian and Western patients. Pathway analysis and Cox proportional hazard models were applied to construct a prediction model for the recurrence of triple negative breast cancer. Hierarchical cluster analysis showed that triple negative breast cancers from different races were in separate sub-clusters but grouped in a bigger cluster. Two pathways, cAMP-mediated signaling and ephrin receptor signaling, were significantly associated with the recurrence of triple negative breast cancer. After using stepwise model selection from the combination of the initial filtered genes, we developed a prediction model based on the genes SLC22A23, PRKAG3, DPEP3, MORC2, GRB7, and FAM43A. The model had 91.7% accuracy, 81.8% sensitivity, and 94.6% specificity under leave-one-out support vector regression. In this study, we identified pathways related to triple negative breast cancer and developed a model to predict its recurrence. These results could be used for assisting with clinical prognosis and warrant further investigation into the possibility of targeted therapy of triple negative breast cancer in Taiwanese patients.

  10. Triple flame structure and diffusion flame stabilization

    NASA Technical Reports Server (NTRS)

    Veynante, D.; Vervisch, L.; Poinsot, T.; Linan, A.; Ruetsch, G.

    1994-01-01

    The stabilization of diffusion flames is studied using asymptotic techniques and numerical tools. The configuration studied corresponds to parallel streams of cold oxidizer and fuel initially separated by a splitter plate. It is shown that stabilization of a diffusion flame may only occur in this situation by two processes. First, the flame may be stabilized behind the flame holder in the wake of the splitter plate. For this case, numerical simulations confirm scalings previously predicted by asymptotic analysis. Second, the flame may be lifted. In this case a triple flame is found at longer distances downstream of the flame holder. The structure and propagation speed of this flame are studied by using an actively controlled numerical technique in which the triple flame is tracked in its own reference frame. It is then possible to investigate the triple flame structure and velocity. It is shown, as suggested from asymptotic analysis, that heat release may induce displacement speeds of the triple flame larger than the laminar flame speed corresponding to the stoichiometric conditions prevailing in the mixture approaching the triple flame. In addition to studying the characteristics of triple flames in a uniform flow, their resistance to turbulence is investigated by subjecting triple flames to different vortical configurations.

  11. The wheat calcium-dependent protein kinase TaCPK7-D positively regulates host resistance to sharp eyespot disease.

    PubMed

    Wei, Xuening; Shen, Fangdi; Hong, Yantao; Rong, Wei; Du, Lipu; Liu, Xin; Xu, Huijun; Ma, Lingjian; Zhang, Zengyan

    2016-10-01

    Sharp eyespot, caused mainly by the necrotrophic fungus Rhizoctonia cerealis, limits wheat production worldwide. Here, TaCPK7-D, encoding a subgroup III member of the calcium-dependent protein kinase (CPK) family, was identified from the sharp eyespot-resistant wheat line CI12633 through comparative transcriptomic analysis. Subsequently, the defence role of TaCPK7-D against R. cerealis infection was studied by the generation and characterization of TaCPK7-D-silenced and TaCPK7-D-overexpressing wheat plants. Rhizoctonia cerealis inoculation induced a higher transcriptional level of TaCPK7-D in the resistant wheat line CI12633 than in the susceptible cultivar Wenmai 6. The expression of TaCPK7-D was significantly induced after exogenous application of 1-aminocyclopropane-1-carboxylic acid (an ethylene biosynthesis precursor). The green fluorescent protein signal distribution assays indicated that TaCPK7-D localizes to the plasma membrane in both onion epidermal cells and wheat protoplasts. Following R. cerealis inoculation, TaCPK7-D-silenced wheat CI12633 plants displayed more severe sharp eyespot symptoms than control CI12633 plants. Four defence-associated genes (β-1,3-glucanase, chitinase 1, defensin and TaPIE1) and an ethylene biosynthesis key gene, ACO2, were significantly suppressed in the TaCPK7-D-silenced wheat plants compared with control plants. Conversely, TaCPK7-D-overexpressing wheat lines showed increased resistance to sharp eyespot compared with untransformed recipient wheat Yangmai 16. Furthermore, the transcriptional levels of these four defence-related genes and ACO2 gene were significantly elevated in TaCPK7-D-overexpressing plants compared with untransformed recipient wheat plants. These results suggest that TaCPK7-D positively regulates the wheat resistance response to R. cerealis infection through the modulation of the expression of these defence-associated genes, and that TaCPK7-D is a candidate to improve sharp eyespot resistance in wheat.

  12. The acid-induced folded state of Sac7d is the native state.

    PubMed Central

    Bedell, J. L.; McCrary, B. S.; Edmondson, S. P.; Shriver, J. W.

    2000-01-01

    Sac7d unfolds at low pH in the absence of salt, with the greatest extent of unfolding obtained at pH 2. We have previously shown that the acid unfolded protein is induced to refold by decreasing the pH to 0 or by addition of salt (McCrary BS, Bedell J. Edmondson SP, Shriver JW, 1998, J Mol Biol 276:203-224). Both near-ultraviolet circular dichroism spectra and ANS fluorescence enhancements indicate that the acid- and salt-induced folded states have a native fold and are not molten globular. 1H,15N heteronuclear single quantum coherence NMR spectra confirm that the native, acid-, and salt-induced folded states are essentially identical. The most significant differences in amide 1H and 15N chemical shifts are attributed to hydrogen bonding to titrating carboxyl side chains and through-bond inductive effects. The 1H NMR chemical shifts of protons affected by ring currents in the hydrophobic core of the acid- and salt-induced folded states are identical to those observed in the native. The radius of gyration of the acid-induced folded state at pH 0 is shown to be identical to that of the native state at pH 7 by small angle X-ray scattering. We conclude that acid-induced collapse of Sac7d does not lead to a molten globule but proceeds directly to the native state. The folding of Sac7d as a function of pH and anion concentration is summarized with a phase diagram that is similar to those observed for other proteins that undergo acid-induced folding except that the A-state is encompassed by the native state. These results demonstrate that formation of a molten globule is not a general property of proteins that are refolded by acid. PMID:11106160

  13. Reliability and Validity of a Domain-Specific Last 7-d Sedentary Time Questionnaire

    PubMed Central

    WIJNDAELE, KATRIEN; DE BOURDEAUDHUIJ, ILSE; GODINO, JOB G.; LYNCH, BRIGID M.; GRIFFIN, SIMON J.; WESTGATE, KATE; BRAGE, SØREN

    2014-01-01

    ABSTRACT Purpose The objective of this study is to examine test–retest reliability, criterion validity, and absolute agreement of a self-report, last 7-d sedentary behavior questionnaire (SIT-Q-7d), which assesses total daily sedentary time as an aggregate of sitting/lying down in five domains (meals, transportation, occupation, nonoccupational screen time, and other sedentary time). Dutch (DQ) and English (EQ) versions of the questionnaire were examined. Methods Fifty-one Flemish adults (ages 39.4 ± 11.1 yr) wore a thigh accelerometer (activPAL3™) and simultaneously kept a domain log for 7 d. The DQ was subsequently completed twice (median test–retest interval: 3.3 wk). Thigh-acceleration sedentary time was log annotated to create comparable domain-specific and total sedentary time variables. Four hundred two English adults (ages 49.6 ± 7.3 yr) wore a combined accelerometer and HR monitor (Actiheart®) for 6 d to objectively measure total sedentary time. The EQ was subsequently completed twice (median test–retest interval: 3.4 wk). In both samples, the questionnaire reference frame overlapped with the criterion measure administration period. All participants had five or more valid days of criterion data, including one or more weekend day. Results Test–retest reliability (intraclass correlation coefficient (95% CI)) was fair to good for total sedentary time (DQ: 0.68 (0.50–0.81); EQ: 0.53 (0.44–0.62)) and poor to excellent for domain-specific sedentary time (DQ: from 0.36 (0.10–0.57) (meals) to 0.66 (0.46–0.79) (occupation); EQ: from 0.45 (0.35–0.54) (other sedentary time) to 0.76 (0.71–0.81) (meals)). For criterion validity (Spearman rho), significant correlations were found for total sedentary time (DQ: 0.52; EQ: 0.22; all P <0.001). Compared with domain-specific criterion variables (DQ), modest-to-strong correlations were found for domain-specific sedentary time (from 0.21 (meals) to 0.76 (P < 0.001) (screen time)). The questionnaire

  14. Establishing a threshold for the number of missing days using 7 d pedometer data.

    PubMed

    Kang, Minsoo; Hart, Peter D; Kim, Youngdeok

    2012-11-01

    The purpose of this study was to examine the threshold of the number of missing days of recovery using the individual information (II)-centered approach. Data for this study came from 86 participants, aged from 17 to 79 years old, who had 7 consecutive days of complete pedometer (Yamax SW 200) wear. Missing datasets (1 d through 5 d missing) were created by a SAS random process 10,000 times each. All missing values were replaced using the II-centered approach. A 7 d average was calculated for each dataset, including the complete dataset. Repeated measure ANOVA was used to determine the differences between 1 d through 5 d missing datasets and the complete dataset. Mean absolute percentage error (MAPE) was also computed. Mean (SD) daily step count for the complete 7 d dataset was 7979 (3084). Mean (SD) values for the 1 d through 5 d missing datasets were 8072 (3218), 8066 (3109), 7968 (3273), 7741 (3050) and 8314 (3529), respectively (p > 0.05). The lower MAPEs were estimated for 1 d missing (5.2%, 95% confidence interval (CI) 4.4-6.0) and 2 d missing (8.4%, 95% CI 7.0-9.8), while all others were greater than 10%. The results of this study show that the 1 d through 5 d missing datasets, with replaced values, were not significantly different from the complete dataset. Based on the MAPE results, it is not recommended to replace more than two days of missing step counts.

  15. Metastability in the evolution of triple systems

    NASA Astrophysics Data System (ADS)

    Martynova, A. I.; Orlov, V. V.; Rubinov, A. V.

    2003-10-01

    The dynamical evolution of 15000 equal-mass triple systems with zero initial velocities (the free-fall three-body problem) is considered. The equations of motion are numerically integrated using regularization of binary and triple encounters. We find 170 triple systems which reach a state where the motions take place within a limited region of phase space during a long time. These regions are concentrated in the zones of regular motions in the vicinities of stable periodic orbits: the von Schubart orbit in the rectilinear problem, the Broucke orbit in the isosceles problem, and the `Eight' orbit. The classification of such metastable orbits is suggested. A change of the types is found during the dynamical evolution of some metastable systems. The triple system leaves the metastable regime after some time, and its evolution is finished by the escape of one body.

  16. Coloring RDF Triples to Capture Provenance

    NASA Astrophysics Data System (ADS)

    Flouris, Giorgos; Fundulaki, Irini; Pediaditis, Panagiotis; Theoharis, Yannis; Christophides, Vassilis

    Recently, the W3C Linking Open Data effort has boosted the publication and inter-linkage of large amounts of RDF datasets on the Semantic Web. Various ontologies and knowledge bases with millions of RDF triples from Wikipedia and other sources, mostly in e-science, have been created and are publicly available. Recording provenance information of RDF triples aggregated from different heterogeneous sources is crucial in order to effectively support trust mechanisms, digital rights and privacy policies. Managing provenance becomes even more important when we consider not only explicitly stated but also implicit triples (through RDFS inference rules) in conjunction with declarative languages for querying and updating RDF graphs. In this paper we rely on colored RDF triples represented as quadruples to capture and manipulate explicit provenance information.

  17. Triple ion beam irradiation facility

    SciTech Connect

    Lewis, M.B.; Allen, W.R.; Buhl, R.A.; Packan, N.H.; Cook, S.W.; Mansur, L.K.

    1988-12-01

    A unique ion irradiation facility consisting of three accelerators is described. The accelerators can be operated simultaneously to deliver three ion beams on one target sample. The energy ranges of the ions are 50 to 400 keV, 200 keV to 2.5 MeV, and 1.0 to 5.0 MeV. Three different ions in the appropriate mass range can be simultaneously implanted to the same depth in a target specimen as large as 100 mm/sup 2/ in area. Typical depth ranges are 0.1 to 1.0 ..mu..m. The X-Y profiles of all three ion beams are measured by a system of miniature Faraday cups. The low-voltage accelerator can periodically ramp the ion beam energy during the implantation. Three different types of target chambers are in use at this facility. The triple-beam high-vacuum chamber can hold nine transmission electron microscopy specimens at elevated temperature during a irradiation by the three simultaneous beams. A second high-vacuum chamber on the medium-voltage accelerator beamline houses a low- and high-temperature translator and a two-axis goniometer for ion channeling measurements. The third chamber on the high-energy beamline can be gas-filled for special stressed specimen irradiations. Special applications for the surface modification of materials with this facility are described. Appendixes containing operating procedures are also included. 18 refs., 27 figs., 1 tab.

  18. Arthroscopic Subtalar, Double, and Triple Fusion.

    PubMed

    Walter, Richard; Parsons, Stephen; Winson, Ian

    2016-09-01

    Arthroscopic approaches to subtalar, double, and triple arthrodesis allow relative preservation of the soft tissue envelope compared with traditional open approaches. The surgical technique involving the use of a 4.5-mm 30° arthroscope via sinus tarsi portals is described. All 3 joints of the triple joint can be prepared for fusion with motorized burrs. Rigid fixation is achieved with cannulated screws. High union rates and low complication rates have been reported. PMID:27524712

  19. Triple junction motion and grain microstructure evolution

    SciTech Connect

    Gottstein, G. . E-mail: gottstein@imm.rwth-aachen.de; Ma, Y.; Shvindlerman, L.S.

    2005-03-01

    The classical concepts of grain growth in polycrystals are based on the dominant role of grain boundaries. This is reflected by the well known von Neumann-Mullins relation. According to this approach triple junctions do not affect grain boundary motion, and their role in grain growth is reduced to maintaining the thermodynamically prescribed equilibrium angles at the lines where boundaries meet. In the current study the experimental data of triple junction mobility are considered with respect to the process of grain growth in 2D systems, in particular with regard to the controlling kinetics. When boundary kinetics prevails grain growth in a polycrystal complies with the von Neumann-Mullins relation. When grain growth is governed by the mobility of triple junctions the kinetics change, and the von Neumann-Mullins relation does not hold anymore. This is the more pronounced the smaller the triple junction mobility. We present a generalized theory of 2D grain growth including a limited triple junction mobility. In this concept the criterion {lambda} plays a central role. It reflects the ratio of boundary to triple junction mobility but is proportional to the grain size as well. The generalized von Neumann-Mullins relation can be expressed in terms of {lambda}. For small values of {lambda}, conspicuous changes of microstructure evolution during grain growth and of microstructural stability are predicted. The theoretical predictions are compared to results of computer simulations by a virtual vertex model.

  20. The von Neumann Triple Point Paradox

    NASA Astrophysics Data System (ADS)

    Sanders, Richard; Tesdall, Allen M.

    We describe the problem of weak shock reflection off a wedge and discuss the triple point paradox that arises. When the shock is sufficiently weak and the wedge is thin, Mach reflection appears to be observed but is impossible according to what von Neumann originally showed in 1943. We summarize some recent numerical results for weak shock reflection problems for the unsteady transonic small disturbance equations, the nonlinear wave system, and the Euler equations. Rather than finding a standard but mathematically inadmissible Mach reflection with a shock triple point, the solutions contain a complex structure: there is a sequence of triple points and supersonic patches in a tiny region behind the leading triple point, with an expansion fan originating at each triple point. The sequence of patches may be infinite, and we refer to this structure as Guderley Mach reflection. The presence of the expansion fans at the triple points resolves the paradox. We describe some recent experimental evidence which is consistent with these numerical findings.

  1. On the auxiliary lattices and dislocation reactions at triple junctions.

    PubMed

    Gertsman, V Y

    2002-03-01

    Coincidence site and displacement shift complete lattices of triple junctions are analysed. Dislocation reactions at triple junctions are considered. It is shown that in alpha=1 junctions no trapped residual triple-junction dislocation is geometrically necessary for dislocation transmission between adjoining grain boundaries. However, the situation is different for alpha (unequal) 1 triple junctions, where in some cases the residual dislocation cannot leave the triple junction for a grain boundary without generating a stacking-fault-like defect.

  2. Strong Enrichment of Aromatic Residues in Binding Sites from a Charge-neutralized Hyperthermostable Sso7d Scaffold Library*

    PubMed Central

    Kiefer, Jonathan D.; Srinivas, Raja R.; Lobner, Elisabeth; Tisdale, Alison W.; Mehta, Naveen K.; Yang, Nicole J.; Tidor, Bruce; Wittrup, K. Dane

    2016-01-01

    The Sso7d protein from the hyperthermophilic archaeon Sulfolobus solfataricus is an attractive binding scaffold because of its small size (7 kDa), high thermal stability (Tm of 98 °C), and absence of cysteines and glycosylation sites. However, as a DNA-binding protein, Sso7d is highly positively charged, introducing a strong specificity constraint for binding epitopes and leading to nonspecific interaction with mammalian cell membranes. In the present study, we report charge-neutralized variants of Sso7d that maintain high thermal stability. Yeast-displayed libraries that were based on this reduced charge Sso7d (rcSso7d) scaffold yielded binders with low nanomolar affinities against mouse serum albumin and several epitopes on human epidermal growth factor receptor. Importantly, starting from a charge-neutralized scaffold facilitated evolutionary adaptation of binders to differentially charged epitopes on mouse serum albumin and human epidermal growth factor receptor, respectively. Interestingly, the distribution of amino acids in the small and rigid binding surface of enriched rcSso7d-based binders is very different from that generally found in more flexible antibody complementarity-determining region loops but resembles the composition of antibody-binding energetic hot spots. Particularly striking was a strong enrichment of the aromatic residues Trp, Tyr, and Phe in rcSso7d-based binders. This suggests that the rigidity and small size of this scaffold determines the unusual amino acid composition of its binding sites, mimicking the energetic core of antibody paratopes. Despite the high frequency of aromatic residues, these rcSso7d-based binders are highly expressed, thermostable, and monomeric, suggesting that the hyperstability of the starting scaffold and the rigidness of the binding surface confer a high tolerance to mutation. PMID:27582495

  3. Concepts and targets in triple-negative breast cancer: recent results and clinical implications

    PubMed Central

    Saha, Poornima; Nanda, Rita

    2016-01-01

    Triple-negative breast cancer (TNBC) is a heterogeneous disease in which tumors are defined by lack of expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) receptor. No targeted therapies are available for the treatment of TNBC, and chemotherapy remains the standard of care. Gene expression profiling has identified six distinct molecular subtypes of TNBC. The identification of novel targets, coupled with the development of therapies for different subsets of TNBC, holds great promise for the future treatment of this aggressive form of breast cancer. This review focuses on novel therapies in development for the treatment of TNBC. PMID:27583027

  4. Concepts and targets in triple-negative breast cancer: recent results and clinical implications.

    PubMed

    Saha, Poornima; Nanda, Rita

    2016-09-01

    Triple-negative breast cancer (TNBC) is a heterogeneous disease in which tumors are defined by lack of expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) receptor. No targeted therapies are available for the treatment of TNBC, and chemotherapy remains the standard of care. Gene expression profiling has identified six distinct molecular subtypes of TNBC. The identification of novel targets, coupled with the development of therapies for different subsets of TNBC, holds great promise for the future treatment of this aggressive form of breast cancer. This review focuses on novel therapies in development for the treatment of TNBC.

  5. Concepts and targets in triple-negative breast cancer: recent results and clinical implications.

    PubMed

    Saha, Poornima; Nanda, Rita

    2016-09-01

    Triple-negative breast cancer (TNBC) is a heterogeneous disease in which tumors are defined by lack of expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) receptor. No targeted therapies are available for the treatment of TNBC, and chemotherapy remains the standard of care. Gene expression profiling has identified six distinct molecular subtypes of TNBC. The identification of novel targets, coupled with the development of therapies for different subsets of TNBC, holds great promise for the future treatment of this aggressive form of breast cancer. This review focuses on novel therapies in development for the treatment of TNBC. PMID:27583027

  6. N =2 SO(4) 7D gauged supergravity with topological mass term from 11 dimensions

    NASA Astrophysics Data System (ADS)

    Karndumri, Parinya

    2014-11-01

    We construct a consistent reduction ansatz of eleven-dimensional supergravity to N =2 SO(4) seven-dimensional gauged supergravity with topological mass term for the three-form field. The ansatz is obtained from a truncation of the S 4 reduction giving rise to the maximal N =4 SO(5) gauged supergravity. Therefore, the consistency is guaranteed by the consistency of the S 4 reduction. Unlike the gauged supergravity without topological mass having a half-supersymmetric domain wall vacuum, the resulting 7D gauged supergravity theory admits a maximally supersymmetric AdS 7 critical point. This corresponds to N = (1 , 0) superconformal field theory in six dimensions. We also study RG flows from this N = (1 , 0) SCFT to non-conformal N = (1 , 0) Super Yang-Mills theories in the seven-dimensional framework and use the reduction ansatz to uplift this RG flow to eleven dimensions.

  7. Triple-negative breast cancer: role of antiangiogenic agents.

    PubMed

    Greenberg, Sally; Rugo, Hope S

    2010-01-01

    New blood vessel formation plays an important role in breast cancer growth, invasion, and metastasis. Tumor growth is preceded by the development of new blood vessels, which provide a pathway for metastases and nutrients essential for growth. Vascular endothelial growth factor (VEGF) is a key angiogenic mediator that stimulates endothelial cell proliferation and regulates vascular permeability. Highly proliferative tumors, such as those that are negative for the estrogen, progesterone, and HER2/neu receptors have enhanced angiogenesis that supports rapid growth and early metastases and have been found to have high levels of VEGF. Drugs developed to inhibit the angiogenic process may be particularly effective in triple-negative breast cancer. Subset analyses have demonstrated efficacy with combinations of the VEGF antibody bevacizumab in combination with chemotherapy and, to a limited degree, with other antiangiogenic agents. Many targeted biologic agents in development inhibit angiogenesis including those that inhibit the mammalian target of rapamycin, fibroblast growth factor, Notch, hypoxic inducible factor, 2-methoxyestradiol, insulin like growth factor, matrix metalloproteinase, and others. Ongoing studies are focusing on the effects of these agents in triple-negative disease, and there is an urgent need to identify markers that can predict response to specific targeted therapy. PMID:20164688

  8. MicroRNA let-7d is a target of cannabinoid CB1 receptor and controls cannabinoid signaling.

    PubMed

    Chiarlone, Anna; Börner, Christine; Martín-Gómez, Laura; Jiménez-González, Ada; García-Concejo, Adrián; García-Bermejo, María L; Lorente, Mar; Blázquez, Cristina; García-Taboada, Elena; de Haro, Amador; Martella, Elisa; Höllt, Volker; Rodríguez, Raquel; Galve-Roperh, Ismael; Kraus, Jürgen; Guzmán, Manuel

    2016-09-01

    Cannabinoid CB1 receptor, the molecular target of endocannabinoids and cannabis active components, is one of the most abundant metabotropic receptors in the brain. Cannabis is widely used for both recreational and medicinal purposes. Despite the ever-growing fundamental roles of microRNAs in the brain, the possible molecular connections between the CB1 receptor and microRNAs are surprisingly unknown. Here, by using reporter gene constructs that express interaction sequences for microRNAs in human SH-SY5Y neuroblastoma cells, we show that CB1 receptor activation enhances the expression of several microRNAs, including let-7d. This was confirmed by measuring hsa-let-7d expression levels. Accordingly, knocking-down CB1 receptor in zebrafish reduced dre-let-7d levels, and knocking-out CB1 receptor in mice decreased mmu-let-7d levels in the cortex, striatum and hippocampus. Conversely, knocking-down let-7d increased CB1 receptor mRNA expression in zebrafish, SH-SY5Y cells and primary striatal neurons. Likewise, in primary striatal neurons chronically exposed to a cannabinoid or opioid agonist, a let-7d-inhibiting sequence facilitated not only cannabinoid or opioid signaling but also cannabinoid/opioid cross-signaling. Taken together, these findings provide the first evidence for a bidirectional link between the CB1 receptor and a microRNA, namely let-7d, and thus unveil a new player in the complex process of cannabinoid action. PMID:27179908

  9. MicroRNA let-7d is a target of cannabinoid CB1 receptor and controls cannabinoid signaling.

    PubMed

    Chiarlone, Anna; Börner, Christine; Martín-Gómez, Laura; Jiménez-González, Ada; García-Concejo, Adrián; García-Bermejo, María L; Lorente, Mar; Blázquez, Cristina; García-Taboada, Elena; de Haro, Amador; Martella, Elisa; Höllt, Volker; Rodríguez, Raquel; Galve-Roperh, Ismael; Kraus, Jürgen; Guzmán, Manuel

    2016-09-01

    Cannabinoid CB1 receptor, the molecular target of endocannabinoids and cannabis active components, is one of the most abundant metabotropic receptors in the brain. Cannabis is widely used for both recreational and medicinal purposes. Despite the ever-growing fundamental roles of microRNAs in the brain, the possible molecular connections between the CB1 receptor and microRNAs are surprisingly unknown. Here, by using reporter gene constructs that express interaction sequences for microRNAs in human SH-SY5Y neuroblastoma cells, we show that CB1 receptor activation enhances the expression of several microRNAs, including let-7d. This was confirmed by measuring hsa-let-7d expression levels. Accordingly, knocking-down CB1 receptor in zebrafish reduced dre-let-7d levels, and knocking-out CB1 receptor in mice decreased mmu-let-7d levels in the cortex, striatum and hippocampus. Conversely, knocking-down let-7d increased CB1 receptor mRNA expression in zebrafish, SH-SY5Y cells and primary striatal neurons. Likewise, in primary striatal neurons chronically exposed to a cannabinoid or opioid agonist, a let-7d-inhibiting sequence facilitated not only cannabinoid or opioid signaling but also cannabinoid/opioid cross-signaling. Taken together, these findings provide the first evidence for a bidirectional link between the CB1 receptor and a microRNA, namely let-7d, and thus unveil a new player in the complex process of cannabinoid action.

  10. Phage display selection of tight specific binding variants from a hyperthermostable Sso7d scaffold protein library.

    PubMed

    Zhao, Ning; Schmitt, Margaret A; Fisk, John D

    2016-04-01

    Antibodies, the quintessential biological recognition molecules, are not ideal for many applications because of their large size, complex modifications, and thermal and chemical instability. Identifying alternative scaffolds that may be evolved into tight, specific binding molecules with improved physical properties is of increasing interest, particularly for biomedical applications in resource-limited environments. Hyperthermophilic organisms, such as Sulfolobus solfataricus, are an attractive source of highly stable proteins that may serve as starting points for alternative molecular recognition scaffolds. We describe the first application of phage display to identify binding proteins based on the S. solfataricus protein Sso7d scaffold. Sso7d is a small cysteine-free DNA-binding protein (approximately 7 kDa, 63 amino acids), with a melting temperature of nearly 100 °C. Tight-binding Sso7d variants were selected for a diverse set of protein targets from a 10(10) member library, demonstrating the versatility of the scaffold. These Sso7d variants are able to discriminate among closely related human, bovine and rabbit serum albumins. Equilibrium dissociation constants in the nanomolar to low micromolar range were measured via competitive ELISA. Importantly, the Sso7d variants continue to bind their targets in the absence of the phage context. Furthermore, phage-displayed Sso7d variants retain their binding affinity after exposure to temperatures up to 70 °C. Taken together, our results suggest that the Sso7d scaffold will be a complementary addition to the range of non-antibody scaffold proteins that may be utilized in phage display. Variants of hyperthermostable binding proteins have potential applications in diagnostics and therapeutics for environments with extreme conditions of storage and deployment. PMID:26835881

  11. Phage display selection of tight specific binding variants from a hyperthermostable Sso7d scaffold protein library.

    PubMed

    Zhao, Ning; Schmitt, Margaret A; Fisk, John D

    2016-04-01

    Antibodies, the quintessential biological recognition molecules, are not ideal for many applications because of their large size, complex modifications, and thermal and chemical instability. Identifying alternative scaffolds that may be evolved into tight, specific binding molecules with improved physical properties is of increasing interest, particularly for biomedical applications in resource-limited environments. Hyperthermophilic organisms, such as Sulfolobus solfataricus, are an attractive source of highly stable proteins that may serve as starting points for alternative molecular recognition scaffolds. We describe the first application of phage display to identify binding proteins based on the S. solfataricus protein Sso7d scaffold. Sso7d is a small cysteine-free DNA-binding protein (approximately 7 kDa, 63 amino acids), with a melting temperature of nearly 100 °C. Tight-binding Sso7d variants were selected for a diverse set of protein targets from a 10(10) member library, demonstrating the versatility of the scaffold. These Sso7d variants are able to discriminate among closely related human, bovine and rabbit serum albumins. Equilibrium dissociation constants in the nanomolar to low micromolar range were measured via competitive ELISA. Importantly, the Sso7d variants continue to bind their targets in the absence of the phage context. Furthermore, phage-displayed Sso7d variants retain their binding affinity after exposure to temperatures up to 70 °C. Taken together, our results suggest that the Sso7d scaffold will be a complementary addition to the range of non-antibody scaffold proteins that may be utilized in phage display. Variants of hyperthermostable binding proteins have potential applications in diagnostics and therapeutics for environments with extreme conditions of storage and deployment.

  12. Electrostatic Modeling of Vacuum Insulator Triple Junctions

    SciTech Connect

    Tully, L K; Goerz, D A; Houck, T L; Javedani, J B

    2006-10-25

    Triple junctions are often initiation points for insulator flashover in pulsed power devices. The two-dimensional finite-element TriComp [1] modeling software suite was utilized for its electrostatic field modeling package to investigate electric field behavior in the anode and cathode triple junctions of a high voltage vacuum-insulator interface. TriComp enables simple extraction of values from a macroscopic solution for use as boundary conditions in a subset solution. Electric fields computed with this zoom capability correlate with theoretical analysis of the anode and cathode triple junctions within submicron distances for nominal electrode spacing of 1.0 cm. This paper will discuss the iterative zoom process with TriComp finite-element software and the corresponding theoretical verification of the results.

  13. Structure and morphology of a triple point

    NASA Astrophysics Data System (ADS)

    Hekiri, H.; Emanuel, G.

    2015-05-01

    A comprehensive analytical/numerical treatment of triple points is based on over 5 × 103 parametric solutions. The approach is applicable to triple points in steady or unsteady, three-dimensional flow with a variable freestream. The analysis is for a perfect gas with three different ratios of specific heat values and an upstream Mach number that ranges from an onset value to 10. The structure and morphology of the solution manifold is extensively discussed. This includes solution type, solution overlap, double, triple, and split solutions, shock wave and slipstream angular orientations, the strength of the shocks, etc. Both the reflected and Mach stem shocks can be normal shocks. The occurrence, conditions, and parametric results for these normal shocks are provided.

  14. A pseudoneoplastic finding of deep endometriosis: laparoscopic triple segmental bowel resection.

    PubMed

    Cosma, Stefano; Ceccaroni, Marcello; Benedetto, Chiara

    2014-09-01

    Bowel endometriosis affects 3-37% of patients with endometriosis, involving more frequently the rectum and the rectosigmoid junction. Severe endometriosis with bowel involvement is often refractory to standard medical therapy. For these reasons, surgery for bowel treatment is frequently needed. We report the case of a 36-year-old woman with deep endometriosis of the pelvis, triple segmental bowel involvement (recto-sigma, ileum-cecum, transverse colon) and massive endometriotic ascites with secondary Glisson's capsule inflammation, refractory to medical therapy. A laparoscopic triple segmental bowel resection and complete fertility sparing excision of pelvic endometriotic lesions was performed. At 48 months of follow-up, the woman was asymptomatic, with no evidence of recurrence of disease or ascites. Laparoscopic segmental bowel resection, including multiple section, is feasible in selected symptomatic patients with consequent improved quality of life, morbidity rates similar to those achieved by laparotomy and with a less detrimental effect on fertility.

  15. Therapeutic targets of triple-negative breast cancer: a review

    PubMed Central

    Jamdade, Vinayak S; Sethi, Nikunj; Mundhe, Nitin A; Kumar, Parveen; Lahkar, Mangala; Sinha, Neeraj

    2015-01-01

    Breast cancer (BC) is the second most common cause of cancer deaths. Triple-negative breast cancer (TNBC) does not show immunohistochemical expression of oestrogen receptors, progesterone receptors or HER2. At present, no suitable treatment option is available for patients with TNBC. This dearth of effective conventional therapies for the treatment of advanced stage breast cancer has provoked the development of novel strategies for the management of patients with TNBC. This review presents recent information associated with different therapeutic options for the treatment of TNBC focusing on promising targets such as the Notch signalling, Wnt/β-catenin and Hedgehog pathways, in addition to EGFR, PARP1, mTOR, TGF-β and angiogenesis inhibitors. PMID:26040571

  16. The triple point of sulfur hexafluoride

    NASA Astrophysics Data System (ADS)

    Rourke, P. M. C.

    2016-04-01

    A cryogenic fixed point cell has been filled with high purity (99.999%) sulfur hexafluoride (SF6) and measured in an adiabatic closed-cycle cryostat system. Temperature measurements of the SF6 melting curve were performed using a capsule-type standard platinum resistance thermometer (CSPRT) calibrated over the International Temperature Scale of 1990 (ITS-90) subrange from the triple point of equilibrium hydrogen to the triple point of water. The measured temperatures were corrected by 0.37 mK for the effects of thermometer self-heating, and the liquidus-point temperature estimated by extrapolation to melted fraction F  =  1 of a simple linear regression versus melted fraction F in the range F  =  0.53 to 0.84. Based on this measurement, the temperature of the triple point of sulfur hexafluoride is shown to be 223.555 23(49) K (k  =  1) on the ITS-90. This value is in excellent agreement with the best prior measurements reported in the literature, but with considerably smaller uncertainty. An analysis of the detailed uncertainty budget of this measurement suggests that if the triple point of sulfur hexafluoride were to be included as a defining fixed point of the next revision of the International Temperature Scale, it could do so with a total realization uncertainty of approximately 0.43 mK, slightly larger than the realization uncertainties of the defining fixed points of the ITS-90. Since the combined standard uncertainty of this SF6 triple point temperature determination is dominated by chemical impurity effects, further research exploring gas purification techniques and the influence of specific impurity species on the SF6 triple point temperature may bring the realization uncertainty of SF6 as a fixed point material into the range of the defining fixed points of the ITS-90.

  17. Triple arthrodesis for adult acquired flatfoot.

    PubMed

    Catanzariti, Alan R; Dix, Brian T; Richardson, Phillip E; Mendicino, Robert W

    2014-07-01

    The primary goal of triple arthrodesis for stage III and IV adult acquired flatfoot is to obtain a well-aligned plantigrade foot that will support the ankle in optimal alignment. Ancillary procedures including posterior muscle group lengthening, medial displacement calcaneal osteotomy, medial column stabilization, peroneus brevis tenotomy, or transfer and harvest of regional bone graft are often necessary to achieve adequate realignment. Image intensification is helpful in confirming optimal realignment before fixation. Results of triple arthrodesis are enhanced with adequate preparation of joint surfaces, bone graft/orthobiologics, 2-point fixation of all 3 tritarsal joints, and a vertical heel position.

  18. Biomarkers in triple negative breast cancer: A review

    PubMed Central

    Yadav, Budhi S; Chanana, Priyanka; Jhamb, Swaty

    2015-01-01

    Breast cancer is an intrinsically heterogeneous disease. In the world about 1 million cases of breast cancer are diagnosed annually and more than 170000 are triple-negative. Characteristic feature of triple negative breast cancer (TNBC) is that it lacks expression of oestrogen, progesterone and human epidermal growth factor receptor-2/neu receptors. They comprise 15%-20% of all breast cancers. We did a systematic review of PubMed and conference databases to identify studies published on biomarkers in TNBC. We included studies with biomarkers including: Epidermal growth factor receptor, vascular endothelial growth factor, c-Myc, C-kit and basal cytokeratins, Poly(ADP-ribose) polymerase-1, p53, tyrosinase kinases, m-TOR, heat and shock proteins and TOP-2A in TNBC. We also looked for studies published on synthetic lethality and inhibition of angiogenesis, growth, and survival pathways. TNBC is a complex disease subtype with many subclasses. Majority TNBC have a basal-like molecular phenotype by gene expression profiling. Their clinical and pathologic features overlap with hereditary BRCA1 related breast cancers. Management of these tumours is a challenge to the clinician because of its aggressive behaviour, poor outcome, and absence of targeted therapies. As the complexity of this disease is being simplified over time new targets are also being discovered for the treatment of this disease. There are many biomarkers in TNBC being used in clinical practice. Biomarkers may be useful as prognostic or predictive indicators as well as suggest possible targets for novel therapies. Many targeted agents are being studied for treatment of TNBC. PMID:26677438

  19. Biomarkers in triple negative breast cancer: A review.

    PubMed

    Yadav, Budhi S; Chanana, Priyanka; Jhamb, Swaty

    2015-12-10

    Breast cancer is an intrinsically heterogeneous disease. In the world about 1 million cases of breast cancer are diagnosed annually and more than 170000 are triple-negative. Characteristic feature of triple negative breast cancer (TNBC) is that it lacks expression of oestrogen, progesterone and human epidermal growth factor receptor-2/neu receptors. They comprise 15%-20% of all breast cancers. We did a systematic review of PubMed and conference databases to identify studies published on biomarkers in TNBC. We included studies with biomarkers including: Epidermal growth factor receptor, vascular endothelial growth factor, c-Myc, C-kit and basal cytokeratins, Poly(ADP-ribose) polymerase-1, p53, tyrosinase kinases, m-TOR, heat and shock proteins and TOP-2A in TNBC. We also looked for studies published on synthetic lethality and inhibition of angiogenesis, growth, and survival pathways. TNBC is a complex disease subtype with many subclasses. Majority TNBC have a basal-like molecular phenotype by gene expression profiling. Their clinical and pathologic features overlap with hereditary BRCA1 related breast cancers. Management of these tumours is a challenge to the clinician because of its aggressive behaviour, poor outcome, and absence of targeted therapies. As the complexity of this disease is being simplified over time new targets are also being discovered for the treatment of this disease. There are many biomarkers in TNBC being used in clinical practice. Biomarkers may be useful as prognostic or predictive indicators as well as suggest possible targets for novel therapies. Many targeted agents are being studied for treatment of TNBC.

  20. Triple-negative breast cancer: treatment challenges and solutions

    PubMed Central

    Collignon, Joëlle; Lousberg, Laurence; Schroeder, Hélène; Jerusalem, Guy

    2016-01-01

    Triple-negative breast cancers (TNBCs) are defined by the absence of estrogen and progesterone receptors and the absence of HER2 overexpression. These cancers represent a heterogeneous breast cancer subtype with a poor prognosis. Few systemic treatment options exist besides the use of chemotherapy (CT). The heterogeneity of the disease has limited the successful development of targeted therapy in unselected patient populations. Currently, there are no approved targeted therapies for TNBC. However, intense research is ongoing to identify specific targets and develop additional and better systemic treatment options. Standard adjuvant and neoadjuvant regimens include anthracyclines, cyclophosphamide, and taxanes. Platinum-based CT has been proposed as another CT option of interest in TNBC. We review the role of this therapy in general, and particularly in patients carrying BRCA germ-line mutations. Available data concerning the role of platinum-based CT in TNBC were acquired primarily in the neoadjuvant setting. The routine use of platinum-based CT is not yet recommended by available guidelines. Many studies have reported the molecular characterization of TNBCs. Several actionable targets have been identified. Novel therapeutic strategies are currently being tested in clinical trials based on promising results observed in preclinical studies. These targets include androgen receptor, EGFR, PARP, FGFR, and the angiogenic pathway. We review the recent data on experimental drugs in this field. We also discuss the recent data concerning immunologic checkpoint inhibitors. PMID:27284266

  1. 12. TRIPLE WINDOW, FIRST FLOOR, SOUTH SIDE. Typical for all ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    12. TRIPLE WINDOW, FIRST FLOOR, SOUTH SIDE. Typical for all triple windows on first and second floors. Note single swing jib door - John Joyner Smith House, 400 Wilmington Street, Beaufort, Beaufort County, SC

  2. Fixed Point Problems for Linear Transformations on Pythagorean Triples

    ERIC Educational Resources Information Center

    Zhan, M.-Q.; Tong, J.-C.; Braza, P.

    2006-01-01

    In this article, an attempt is made to find all linear transformations that map a standard Pythagorean triple (a Pythagorean triple [x y z][superscript T] with y being even) into a standard Pythagorean triple, which have [3 4 5][superscript T] as their fixed point. All such transformations form a monoid S* under matrix product. It is found that S*…

  3. 17 CFR 270.7d-1 - Specification of conditions and arrangements for Canadian management investment companies...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.7d-1 Specification of conditions and... management investment company organized under the laws of Canada or any province thereof may obtain an order... company, or its directors, officers or employees, the Charter or By Laws shall state that the applicant...

  4. 17 CFR 270.7d-1 - Specification of conditions and arrangements for Canadian management investment companies...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.7d-1 Specification of conditions and... management investment company organized under the laws of Canada or any province thereof may obtain an order... company, or its directors, officers or employees, the Charter or By Laws shall state that the applicant...

  5. 17 CFR 270.7d-1 - Specification of conditions and arrangements for Canadian management investment companies...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.7d-1 Specification of conditions and... management investment company organized under the laws of Canada or any province thereof may obtain an order... company, or its directors, officers or employees, the Charter or By Laws shall state that the applicant...

  6. 17 CFR 270.7d-1 - Specification of conditions and arrangements for Canadian management investment companies...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.7d-1 Specification of conditions and... management investment company organized under the laws of Canada or any province thereof may obtain an order... company, or its directors, officers or employees, the Charter or By Laws shall state that the applicant...

  7. 17 CFR 259.404 - Certificate to be filed pursuant to § 250.7(d) of this chapter.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... List of CFR Sections Affected, which appears in the Finding Aids section of the printed volume and on... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Certificate to be filed pursuant to § 250.7(d) of this chapter. 259.404 Section 259.404 Commodity and Securities...

  8. Gauging triple stores with actual biological data

    PubMed Central

    2012-01-01

    Background Semantic Web technologies have been developed to overcome the limitations of the current Web and conventional data integration solutions. The Semantic Web is expected to link all the data present on the Internet instead of linking just documents. One of the foundations of the Semantic Web technologies is the knowledge representation language Resource Description Framework (RDF). Knowledge expressed in RDF is typically stored in so-called triple stores (also known as RDF stores), from which it can be retrieved with SPARQL, a language designed for querying RDF-based models. The Semantic Web technologies should allow federated queries over multiple triple stores. In this paper we compare the efficiency of a set of biologically relevant queries as applied to a number of different triple store implementations. Results Previously we developed a library of queries to guide the use of our knowledge base Cell Cycle Ontology implemented as a triple store. We have now compared the performance of these queries on five non-commercial triple stores: OpenLink Virtuoso (Open-Source Edition), Jena SDB, Jena TDB, SwiftOWLIM and 4Store. We examined three performance aspects: the data uploading time, the query execution time and the scalability. The queries we had chosen addressed diverse ontological or biological questions, and we found that individual store performance was quite query-specific. We identified three groups of queries displaying similar behaviour across the different stores: 1) relatively short response time queries, 2) moderate response time queries and 3) relatively long response time queries. SwiftOWLIM proved to be a winner in the first group, 4Store in the second one and Virtuoso in the third one. Conclusions Our analysis showed that some queries behaved idiosyncratically, in a triple store specific manner, mainly with SwiftOWLIM and 4Store. Virtuoso, as expected, displayed a very balanced performance - its load time and its response time for all the

  9. Double Planet Meets Triple Star

    NASA Astrophysics Data System (ADS)

    2002-08-01

    atmosphere, a large campaign involving more than twenty scientists and engineers from the Paris Observatory and associated institutions [1] was organized to observe the July 20, 2002, event involving an occultation of a star of visual magnitude 11 (i.e., about 100 times fainter than what can be perceived with then unaided eye), referred to as "P126" in McDonald and Elliot's catalogue. In May 2002, preparatory observations showed that star to be double, with the brighter component of the system ( "P126 A" ) being likely to be occulted by Pluto, as seen from South America. However, because of the duplicity, the predictions of exactly where the shadow of Pluto would sweep the ground were uncertain by about 0.1 arcsec in the sky, corresponding to more than 2000 km on the ground. The NACO images ESO PR Photo 21b/02 ESO PR Photo 21b/02 [Preview - JPEG: 400 x 469 pix - 47k] [Normal - JPEG: 800 x 937 pix - 208k] ESO PR Photo 21c/02 ESO PR Photo 21c/02 [Preview - JPEG: 400 x 467 pix - 53k] [Normal - JPEG: 800 x 933 pix - 232k] Caption : PR Photo 21b/02 shows one of the images obtained with the NAOS-CONICA (NACO) adaptive optics (AO) camera mounted on the ESO VLT 8.2-m YEPUN telescope at the Paranal Observatory in connection with a stellar occultation by Pluto on July 20, 2002. The star was found to be triple - the three components (A, B and C), as well as Pluto and its moon, Charon, are indicated in PR Photo 21c/02 for easy orientation. The images are based on data available from the NACO data webpage. See the text for details. In the end, the close approach (an "appulse" in astronomical terminology) of Pluto and P126 A was indeed observed from various sites in South America, with several mobile telescopes and also including major facilities at the ESO La Silla and Paranal Observatories. In particular, unique and very sharp images were obtained with the NAOS-CONICA (NACO) adaptive optics (AO) camera mounted on the ESO VLT 8.2-m YEPUN telescope . One of the NACO images is shown in PR

  10. Locoregional treatments for triple-negative breast cancer.

    PubMed

    Eiermann, W; Vallis, K A

    2012-08-01

    The absence of drug-targetable receptors in triple-negative breast cancer (TNBC) makes the use of targeted systemic therapy inappropriate for this breast cancer subgroup. Although patients with TNBC show sensitivity to some chemotherapy regimens, in early-stage disease greater emphasis is placed on locoregional treatments, based on surgery and radiation therapy (RT). Ongoing improvements in both screening and surgical techniques have reduced the need for radical surgical intervention in all breast cancers, and breast-conserving surgery (BCS) followed by RT is now increasingly common for all tumour types. However, while evidence has clearly established the importance of post-surgical RT for favourable long-term outcomes in breast cancer, it is less well-established as to where and under which conditions more radical surgeries than BCS, such as modified radical mastectomy (MRM), may be indicated for TNBC. A high proportion of TNBC tumours are BRCA1-mutated and therefore patients with this type of tumour are at a potentially elevated risk of ipsilateral or contralateral recurrence. In addition, while some studies indicate that post-BCS locoregional TNBC relapse rates generally appear similar to other tumour types, some evidence suggests that distant relapse rates may be higher. There is evidence that some subtypes of TNBC may require MRM rather than BCS for optimal long-term outcomes. More research is needed to establish whether TNBC-specific approaches to locoregional treatment may be required.

  11. Analysis of circulating tumor cells in patients with triple negative breast cancer during preoperative chemotherapy.

    PubMed

    Lavrov, A V; Zubtsova, Zh I; Zubtsov, D A; Frolova, M A; Ignatova, E O; Skrypnikova, M A; Malysheva, E V; Legchenko, E V; Petrovskii, A V; Utyashev, I A; Tyulyandin, S A; Gol'dshtein, D V

    2014-05-01

    The presence of circulating tumor cells in the blood of patients with triple negative breast cancer (early and locally advanced cancer) before and after preoperative chemotherapy was assessed using expression markers. Before therapy, circulating tumor cells were detected in 5 of 13 (38%) patients with early cancer and in 7 of 17 (41.2%) patients with locally advanced cancer. After therapy, the circulating immune cells were detected in one patient with locally advanced cancer, who had no circulating cells before therapy. The tumor was resistant to chemotherapy and the disease progressed. The detected circulating tumor cells were HER-2-positive, while the primary tumor was HER-2-negative. It was concluded that the circulating immune cells can be a potential marker of the efficiency of therapy and predictors of the disease course, while their phenotype can differ from the phenotype of the primary tumor.

  12. Triple orbital metastases from prostate cancer.

    PubMed

    Tun, Kagan; Bulut, Turgay

    2016-01-01

    Prostate carcinoma, when metastatic, typically involves bone and produces both osteoblastic and osteolytic changes. A 73-year-old man was admitted to our department because of unilateral progressive proptosis and visual blurriness for 3 months. The patient had a history of prostate adenocarcinoma diagnosis 5 years ago. We report a case of orbital involvement presented that intraorbital mass (including periocular structures), temporal bone and temporal muscle from prostate cancer. The mass was removed with total excision. Despite the frequency of bone metastasis in prostatic carcinoma, triple orbital metastases are extremely rare. The best of our knowledge, prostate adenocarcinoma and its triple (temporal bone, temporal muscle and intraorbital mass) orbital metastases have not been published previously. Metastatic orbital tumor secondary to prostate cancer should be considered in patients who have varying degrees of eye symptoms. PMID:27591068

  13. Isotopically enhanced triple-quantum-dot qubit.

    PubMed

    Eng, Kevin; Ladd, Thaddeus D; Smith, Aaron; Borselli, Matthew G; Kiselev, Andrey A; Fong, Bryan H; Holabird, Kevin S; Hazard, Thomas M; Huang, Biqin; Deelman, Peter W; Milosavljevic, Ivan; Schmitz, Adele E; Ross, Richard S; Gyure, Mark F; Hunter, Andrew T

    2015-05-01

    Like modern microprocessors today, future processors of quantum information may be implemented using all-electrical control of silicon-based devices. A semiconductor spin qubit may be controlled without the use of magnetic fields by using three electrons in three tunnel-coupled quantum dots. Triple dots have previously been implemented in GaAs, but this material suffers from intrinsic nuclear magnetic noise. Reduction of this noise is possible by fabricating devices using isotopically purified silicon. We demonstrate universal coherent control of a triple-quantum-dot qubit implemented in an isotopically enhanced Si/SiGe heterostructure. Composite pulses are used to implement spin-echo type sequences, and differential charge sensing enables single-shot state readout. These experiments demonstrate sufficient control with sufficiently low noise to enable the long pulse sequences required for exchange-only two-qubit logic and randomized benchmarking. PMID:26601186

  14. Development of a triple beam irradiation facility

    NASA Astrophysics Data System (ADS)

    Hamada, S.; Miwa, Y.; Yamaki, D.; Katano, Y.; Nakazawa, T.; Noda, K.

    1998-10-01

    A triple beam ion irradiation facility has been developed to study the synergistic effects of displacement damage, helium and hydrogen atoms on microstructural changes of materials under irradiation environments simulating a fusion reactor. The system consists of a vacuum chamber and three beamlines, which are connected with each electrostatic accelerator. Samples can be irradiated in the wide temperature range from liquid nitrogen to 1273 K in the chamber by replacing two kinds of sample stages alternatively. An austenitic stainless steel was simultaneously irradiated with triple beam of nickel, helium and hydrogen ions at 573-673 K using this facility and TEM observations were carried out from a cross sectional view normal to the incident surface. It was shown that the number density of dislocation loops decreased in the region where hydrogen and helium were deposited in comparison with ones in the region where only displacement damage was induced to a similar damage level.

  15. Isotopically enhanced triple-quantum-dot qubit

    PubMed Central

    Eng, Kevin; Ladd, Thaddeus D.; Smith, Aaron; Borselli, Matthew G.; Kiselev, Andrey A.; Fong, Bryan H.; Holabird, Kevin S.; Hazard, Thomas M.; Huang, Biqin; Deelman, Peter W.; Milosavljevic, Ivan; Schmitz, Adele E.; Ross, Richard S.; Gyure, Mark F.; Hunter, Andrew T.

    2015-01-01

    Like modern microprocessors today, future processors of quantum information may be implemented using all-electrical control of silicon-based devices. A semiconductor spin qubit may be controlled without the use of magnetic fields by using three electrons in three tunnel-coupled quantum dots. Triple dots have previously been implemented in GaAs, but this material suffers from intrinsic nuclear magnetic noise. Reduction of this noise is possible by fabricating devices using isotopically purified silicon. We demonstrate universal coherent control of a triple-quantum-dot qubit implemented in an isotopically enhanced Si/SiGe heterostructure. Composite pulses are used to implement spin-echo type sequences, and differential charge sensing enables single-shot state readout. These experiments demonstrate sufficient control with sufficiently low noise to enable the long pulse sequences required for exchange-only two-qubit logic and randomized benchmarking. PMID:26601186

  16. [Principles of reorientation in triple arthrodesis].

    PubMed

    Döderlein, L

    2006-04-01

    Triple arthrodesis can be used for a three-dimensional correction of all types of hindfoot deformities. Prerequisites are a functional integrity of the ankle joint and an adequate bone stock. The procedure blocks the cardanic mechanism of the hindfoot and therefore reduces the shock-absorbing and mobile-adaptive functions of the foot. This results in increased stresses with the risk of long-term degenerative changes. In addition to triple arthrodesis, procedures to the forefoot are often necessary. Especially in neurogenic deformities, muscle lengthening and balancing procedures may be needed. In the evaluation of the results, different etiologies (e.g. posttraumatic, degenerative, neurogenic, congenital) and different deformities (varus, valgus, cavovarus, equinus) should not be mixed up. The results in congenital and neurogenic deformities in the literature are inferior to those of degenerative and posttraumatic origin. A standardization of indications, techniques, and evaluation criteria is still needed in order to exactly estimate the value of this procedure for different pathologies.

  17. Lignin-Based Triple Shape Memory Polymers.

    PubMed

    Sivasankarapillai, Gopakumar; Li, Hui; McDonald, Armando G

    2015-09-14

    Lignin-based triple shape memory polymers comprised of both permanent covalent cross-links and physical cross-links have been synthesized. A mixing phase with poly(ester-amine) and poly(ester-amide) network having two distinct glass transitions was hot mixed with more structurally homogenized methanol soluble lignin fraction by one-pot, two-step method. Triple shape properties arise from the combined effect of the glass transition of polyester copolymers and lignin and the dissociation of self-complementary hydrogen bonding and cross-link density. The percentage of recovery in each stage was investigated and it was proved that the first recovery is related with lignin-poly(ester-amine) rich network and the second recovery stage is related with lignin-poly(ester-amide) rich network. The thermal and mechanical properties of the lignin-copolymer networks were also investigated using differential scanning calorimetry and dynamic mechanical analysis.

  18. Asteroid Systems: Binaries, Triples, and Pairs

    NASA Astrophysics Data System (ADS)

    Margot, J.-L.; Pravec, P.; Taylor, P.; Carry, B.; Jacobson, S.

    In the past decade, the number of known binary near-Earth asteroids has more than quadrupled and the number of known large main-belt asteroids with satellites has doubled. Half a dozen triple asteroids have been discovered, and the previously unrecognized populations of asteroid pairs and small main-belt binaries have been identified. The current observational evidence confirms that small (≲20 km) binaries form by rotational fission and establishes that the Yarkovsky-O'Keefe-Radzievskii-Paddack (YORP) effect powers the spin-up process. A unifying paradigm based on rotational fission and post-fission dynamics can explain the formation of small binaries, triples, and pairs. Large (>~20 km) binaries with small satellites are most likely created during large collisions.

  19. Triple plasmon resonance of bimetal nanoshell

    SciTech Connect

    Shirzaditabar, Farzad; Saliminasab, Maryam; Arghavani Nia, Borhan

    2014-07-15

    In this paper, light absorption spectra properties of a bimetal multilayer nanoshell based on quasi-static approach are investigated. Comparing with silver-dielectric-silver and silver-dielectric-gold nanoshells, gold-dielectric-silver nanoshells have three intense and separated plasmon peaks which are more suitable for multiplex biosensing. Calculations show that relatively small thickness of outer silver shell and large dielectric constant of middle dielectric layer of gold-dielectric-silver nanoshell are suitable to obtain the triple plasmon resonance.

  20. Device Maintains Water At The Triple Point

    NASA Technical Reports Server (NTRS)

    West, J. W.; Burkett, C. G.

    1988-01-01

    Inexpensive device maintains water at 0.01 degree C for 10 weeks or longer. New device consists of four basic assemblies; small, commercial chest freezer containing insulated water tank; insulated copper cell holder; "ice switch" for cycling freezer compressor and externally-mounted air pump for circulation. Access hole in freezer lid allows triple point measurements without opening lid. Modified freezer used to calibrate standard platinum resistance thermomenters.

  1. [Synchronous tumors of the female genital tract: triple malignant and one benign tumor].

    PubMed

    Dudnyikova, Anna; Vereczkey, Ildikó; Pete, Imre

    2012-03-01

    Synchronous tumors of the female genital tract are rare, accounting for 0.7-1.8% of all cases. Double synchronous tumors are most often mentioned in the literature. Reviewing the English literature on this topic, we have found only one case report of a triple synchronous tumor. The 55-year-old patient mentioned in our case has had advanced diabetes mellitus, and has been treated with corticosteroid therapy for a long time because of chronic obstructive pulmonary disease (COPD). She was examined because of her vulvar tumor. During the diagnostic procedure, cervical and endometrial malignant tumors and a benign ovarian cyst have also been found. This event brings to our attention the fact that we should be prepared to manage synchronous even triple malignant gynecological tumors.

  2. [Non-metastatic triple-negative breast cancer in 2016: Definitions and management].

    PubMed

    Portha, H; Jankowski, C; Cortet, M; Desmoulins, I; Martin, E; Lorgis, V; Arnould, L; Coutant, C

    2016-09-01

    Triple-negative breast cancer (TN), as defined by the triple negativity in immunohistochemistry: the absence of estrogen receptor, progesterone receptor and the absence of overexpression or amplification of HER2, corresponds to 15 % of invasive breast cancers. This is a very heterogeneous group of tumors both at the genomic and transcriptomic level and at morphological, clinical and prognostic level. Although there are some good prognosis forms, the majority of TN tumors is characterized by a poor prognosis with a greater frequency of visceral metastases and a maximum risk of relapse in the first two years after diagnosis. Systemic adjuvant treatment with chemotherapy is almost always indicated. The surgical treatment and radiotherapy treatment should be comparable to the other subtypes and obey the same rules of oncologic surgery. TN tumors are not associated with a higher risk of locoregional relapse after conservative treatment and adjuvant radiotherapy. Optimization of systemic therapies is currently and for the last decade a challenge. A number of targeted therapies and efficiency biomarkers identification of these targeted therapies is essential to allow significant progress in optimizing systemic therapy for these tumors.

  3. Structural basis for the binding of the neutralizing antibody, 7D11, to the poxvirus L1 protein

    SciTech Connect

    Su, Hua-Poo; Golden, Joseph W.; Gittis, Apostolos G.; Hooper, Jay W.; Garboczi, David N.

    2007-11-25

    Medical countermeasures to prevent or treat smallpox are needed due to the potential use of poxviruses as biological weapons. Safety concerns with the currently available smallpox vaccine indicate a need for research on alternative poxvirus vaccine strategies. Molecular vaccines involving the use of proteins and/or genes and recombinant antibodies are among the strategies under current investigation. The poxvirus L1 protein, encoded by the L1R open reading frame, is the target of neutralizing antibodies and has been successfully used as a component of both protein subunit and DNA vaccines. L1-specific monoclonal antibodies (e.g., mouse monoclonal antibody mAb-7D11, mAb-10F5) with potent neutralizing activity bind L1 in a conformation-specific manner. This suggests that proper folding of the L1 protein used in molecular vaccines will affect the production of neutralizing antibodies and protection. Here, we co-crystallized the Fab fragment of mAb-7D11 with the L1 protein. The crystal structure of the complex between Fab-7D11 and L1 reveals the basis for the conformation-specific binding as recognition of a discontinuous epitope containing two loops that are held together by a disulfide bond. The structure of this important conformational epitope of L1 will contribute to the development of molecular poxvirus vaccines and also provides a novel target for anti-poxvirus drugs. In addition, the sequence and structure of Fab-7D11 will contribute to the development of L1-targeted immunotherapeutics.

  4. A 7-d toxicity test for marine pollutants using the Pacific mysid Mysidopsis intii. 2: Protocol evaluation

    SciTech Connect

    Harmon, V.L.; Langdon, C.J.

    1996-10-01

    The sensitivity of the Pacific coast mysid Mysidopsis intii to pollutants was compared in 7-d toxicity tests with that of the Gulf coast mysid M. bahia and the Pacific coast mysid Holmesimysis costata. Survival and growth responses of M. intii to zinc (maximum acceptable toxicant concentration [MATC] survival and growth, 152 {micro}g/L) were as sensitive as survival of both M. bahia (MATC survival, 152 {micro}g/L) and H. costata (MATC survival, 152 {micro}g/L). In contrast, the 7-d test for M. intii was less sensitive (MATC growth and survival, 4.99 mg/L) than the test for H. costata (MATC survival, 1.99 mg/L) when sodium dodecyl sulfate (SDS) was used as the toxicant. Interlaboratory evaluation of the 7-d test for M. intii exposed to SDS indicated that the test was reliable. The mean test results for the group of participating laboratories were not significantly different from those of a group of three in-house tests, indicating that shipping and handling did not affect mysid sensitivity to SDS. Mysid growth was not as sensitive to SDS as survival in the interlaboratory tests. Although there were significant differences in median lethal concentration (LC50) values among participating laboratories, coefficients of variation of LC50 and MATC survival values among laboratories were 10.3 and 37%, respectively. These coefficients were comparable to those reported for interlaboratory tests with H. costata.

  5. Grain boundary hardening and triple junction hardening in polycrystalline molybdenum

    SciTech Connect

    Kobayashi, Shigeaki . E-mail: skoba@ashitech.ac.jp; Tsurekawa, Sadahiro; Watanabe, Tadao

    2005-02-01

    The grain boundary and triple junction hardenings in molybdenum with different carbon content were studied in connection with the character and the connectivity of grain boundaries at triple junctions by the micro-indentation test. The triple junction hardening is smaller at the junctions composed of low-angle and {sigma} boundaries than at the junctions composed of random boundaries. This difference in the hardening depending on the grain boundary connectivity becomes more significant with a decrease in carbon content in molybdenum.

  6. Geometrical theory of triple junctions of CSL boundaries.

    PubMed

    Gertsman, V Y

    2001-07-01

    When three grain boundaries having misorientations generating coincidence site lattices (CSLs) meet at a triple junction, a common (triple-junction) CSL is formed. A theory is developed as a set of theorems establishing the relationships between the geometrical parameters of the grain-boundary and triple-junction CSLs. Application of the theory is demonstrated in detail for the case of the cubic crystal system. It is also shown how the theory can be extended to an arbitrary crystal lattice.

  7. Triple-energy contrast enhanced digital mammography

    NASA Astrophysics Data System (ADS)

    Puong, Sylvie; Milioni de Carvalho, Pablo; Muller, Serge

    2010-04-01

    With the injection of iodine, Contrast Enhanced Digital Mammography (CEDM) provides functional information about breast tumour angiogenesis that can potentially help in cancer diagnosis. In order to generate iodine images in which the gray level is proportional to the iodine thickness, temporal and dual-energy approaches have already been considered. The dual-energy method offers the advantage of less patient motion artifacts and better comfort during the exam. However, this approach requires knowledge of the breast thickness at each pixel. Generally, as compression is applied, the breast thickness at each pixel is taken as the compression thickness. Nevertheless, in the breast border region, this assumption is not correct anymore and this causes inaccuracies in the iodine image. Triple-Energy CEDM could overcome these limitations by providing supplemental information in the form of a third image acquired with a different spectrum than the other two. This precludes the need of a priori knowledge of the breast thickness. Moreover, with Triple-Energy CEDM, breast thickness and glandularity maps could potentially be derived. In this study, we first focused on the method to recombine the three images in order to generate the iodine image, analyzing the performance of either quadratic, cubic or conic recombination functions. Then, we studied the optimal acquisition spectra in order to maximize the iodine SDNR in the recombined image for a given target total glandular dose. The concept of Triple-Energy CEDM was validated on simulated textured images and poly-energetic images acquired with a conventional X-ray mammography tube.

  8. Determination of the Latent Heats and Triple Point of Perfluorocyclobutane

    ERIC Educational Resources Information Center

    Briggs, A. G.; Strachan, A. N.

    1977-01-01

    Proposes the use of Perfluorocyclobutane in physical chemistry courses to conduct experiments on latent heat, triple point temperatures and pressures, boiling points, and entropy of vaporization. (SL)

  9. Gleason's Theorem for Rectangular JBW-Triples

    NASA Astrophysics Data System (ADS)

    Edwards, C. Martin; Rüttimann, Gottfried T.

    A JBW*-triple B is said to be rectangular if there exists a W*-algebra A and a pair (p,q) of centrally equivalent elements of the complete orthomodular lattice of projections in A such that B is isomorphic to the JBW*-triple pAq. Any weak*-closed injective operator space provides an example of a rectangular JBW*-triple. The principal order ideal of the complete *-lattice of centrally equivalent pairs of projections in a W*-algebra A, generated by (p,q), forms a complete lattice that is order isomorphic to the complete lattice of weak*-closed inner ideals in B and to the complete lattice of structural projections on B. Although not itself, in general, orthomodular, possesses a complementation that allows for definitions of orthogonality, centre, and central orthogonality to be given. A less familiar notion in lattice theory, that is well-known in the theory of Jordan algebras and Jordan triple systems, is that of rigid collinearity of a pair (e2,f2) and (e2,f2) of elements of . This is defined and characterized in terms of properties of . A W*-algebra A is sometimes thought of as providing a model for a statistical physical system. In this case B, or, equivalently, pAq, may be thought of as providing a model for a fixed sub-system of that represented by A. Therefore, may be considered to represent the set consisting of a particular kind of sub-system of that represented by pAq. Central orthogonality and rigid collinearity of pairs of elements of may be regarded as representing two different types of disjointness, the former, classical disjointness, and the latter, decoherence, of the two sub-systems. It is therefore natural to consider bounded measures m on that are additive on centrally orthogonal and rigidly collinear pairs of elements. Using results of J.D.M. Wright, it is shown that, provided that neither of the two hereditary sub-W*-algebras pAp and qAq of A has a weak*-closed ideal of Type I2, such measures are precisely those that are the restrictions of

  10. Binaries and triples among asteroid pairs

    NASA Astrophysics Data System (ADS)

    Pravec, Petr; Scheirich, Peter; Kušnirák, Peter; Hornoch, Kamil; Galád, Adrián

    2015-08-01

    Despite major achievements obtained during the past two decades, our knowledge of the population and properties of small binary and multiple asteroid systems is still far from advanced. There is a numerous indirect evidence for that most small asteroid systems were formed by rotational fission of cohesionless parent asteroids that were spun up to the critical frequency presumably by YORP, but details of the process are lacking. Furthermore, as we proceed with observations of more and more binary and paired asteroids, we reveal new facts that substantially refine and sometimes change our understanding of the asteroid systems. One significant new finding we have recently obtained is that primaries of many asteroid pairs are actually binary or triple systems. The first such case found is (3749) Balam (Vokrouhlický, ApJL 706, L37, 2009). We have found 9 more binary systems among asteroid pairs within our ongoing NEOSource photometric project since October 2012. They are (6369) 1983 UC, (8306) Shoko, (9783) Tensho-kan, (10123) Fideoja, (21436) Chaoyichi, (43008) 1999 UD31, (44620) 1999 RS43, (46829) 1998 OS14 and (80218) 1999 VO123. We will review their characteristics. These paired binaries as we call them are mostly similar to binaries in the general ("background") population (of unpaired asteroids), but there are a few trends. The paired binaries tend to have larger secondaries with D_2/D_1 = 0.3 to 0.5 and they also tend to be wider systems with 8 of the 10 having orbital periods between 30 and 81 hours, than average among binaries in the general population. There may be also a larger fraction of triples; (3749) Balam is a confirmed triple, having a larger close and a smaller distant satellite, and (8306) Shoko and (10123) Fideoja are suspect triples as they show additional rotational lightcurve components with periods of 61 and 38.8 h that differ from the orbital period of 36.2 and 56.5 h, respectively. The unbound secondaries tend to be of the same size or

  11. The fate of chemoresistance in triple negative breast cancer (TNBC)

    PubMed Central

    O’Reilly, Elma A.; Gubbins, Luke; Sharma, Shiva; Tully, Riona; Guang, Matthew Ho Zhing; Weiner-Gorzel, Karolina; McCaffrey, John; Harrison, Michele; Furlong, Fiona; Kell, Malcolm; McCann, Amanda

    2015-01-01

    Background Treatment options for women presenting with triple negative breast cancer (TNBC) are limited due to the lack of a therapeutic target and as a result, are managed with standard chemotherapy such as paclitaxel (Taxol®). Following chemotherapy, the ideal tumour response is apoptotic cell death. Post-chemotherapy, cells can maintain viability by undergoing viable cellular responses such as cellular senescence, generating secretomes which can directly enhance the malignant phenotype. Scope of Review How tumour cells retain viability in response to chemotherapeutic engagement is discussed. In addition we discuss the implications of this retained tumour cell viability in the context of the development of recurrent and metastatic TNBC disease. Current adjuvant and neo-adjuvant treatments available and the novel potential therapies that are being researched are also reviewed. Major conclusions Cellular senescence and cytoprotective autophagy are potential mechanisms of chemoresistance in TNBC. These two non-apoptotic outcomes in response to chemotherapy are inextricably linked and are neglected outcomes of investigation in the chemotherapeutic arena. Cellular fate assessments may therefore have the potential to predict TNBC patient outcome. General Significance Focusing on the fact that cancer cells can bypass the desired cellular apoptotic response to chemotherapy through cellular senescence and cytoprotective autophagy will highlight the importance of targeting non-apoptotic survival pathways to enhance chemotherapeutic efficacy. PMID:26676166

  12. The triple threat of HIV-1 protease inhibitors.

    PubMed

    Potempa, Marc; Lee, Sook-Kyung; Wolfenden, Richard; Swanstrom, Ronald

    2015-01-01

    Newly released human immunodeficiency virus type 1 (HIV-1) particles obligatorily undergo a maturation process to become infectious. The HIV-1 protease (PR) initiates this step, catalyzing the cleavage of the Gag and Gag-Pro-Pol structural polyproteins. Proper organization of the mature virus core requires that cleavage of these polyprotein substrates proceeds in a highly regulated, specific series of events. The vital role the HIV-1 PR plays in the viral life cycle has made it an extremely attractive target for inhibition and has accordingly fostered the development of a number of highly potent substrate-analog inhibitors. Though the PR inhibitors (PIs) inhibit only the HIV-1 PR, their effects manifest at multiple different stages in the life cycle due to the critical importance of the PR in preparing the virus for these subsequent events. Effectively, PIs masquerade as entry inhibitors, reverse transcription inhibitors, and potentially even inhibitors of post-reverse transcription steps. In this chapter, we review the triple threat of PIs: the intermolecular cooperativity in the form of a cooperative dose-response for inhibition in which the apparent potency increases with increasing inhibition; the pleiotropic effects of HIV-1 PR inhibition on entry, reverse transcription, and post-reverse transcription steps; and their potency as transition state analogs that have the potential for further improvement that could lead to an inability of the virus to evolve resistance in the context of single drug therapy. PMID:25778681

  13. IMMUNOHISTOCHEMICAL DIFFERENTIATION OF TRIPLE NEGATIVE BREAST CANCER.

    PubMed

    Lesar, Miroslav; Stanec, Mladen; Lesar, Nikola; Vrdoljak, Danko Velimir; Zore, Zvonimir; Banović, Marija; Brozović, Gordana

    2016-03-01

    Based on immunohistochemical staining for the basal markers cytokeratin 5/6 (CK 5/6), cytokeratin 14 (CK 14) and P-cadherin, triple negative tumors (TNT) are divided into two groups: 1) basal-like (BL) positive for one or all three markers; and 2) non basal-like (NBL) negative for all three markers. Even though the different origin of the cells of these two types of tumors implies different biological properties, they had been treated as one entity until recently. This paper analyzes TNT collected from 150 patients and distributed into two groups according to the results of immunohistochemical analysis, i.e. BL 116 (77.3%) and NBL 34 (22.67%). In this study, CK 5/6, CK 14 and P-cadherin were used as markers for identifying BL tumors. The immunohistochemical reaction was positive for CK 5/6 in 37%, for CK 14 in 50.86% and for P-cadherin in 68.34% of cases. The subclassification of triple negative breast cancer using the basal markers CK 5/6, CK 14 and P-cadherin has enabled identification of BL and NBL breast cancers in a proportion that is in line with the only accurate analysis of TNT gene expression. Using the mentioned combination of markers in daily practice is easy to perform and economically affordable. PMID:27333711

  14. Mergers and obliquities in stellar triples

    SciTech Connect

    Naoz, Smadar; Fabrycky, Daniel C.

    2014-10-01

    Many close stellar binaries are accompanied by a faraway star. The 'eccentric Kozai-Lidov' (EKL) mechanism can cause dramatic inclination and eccentricity fluctuations, resulting in tidal tightening of inner binaries of triple stars. We run a large set of Monte Carlo simulations, including the secular evolution of the orbits, general relativistic precession, and tides, and we determine the semimajor axis, eccentricity, inclination, and spin-orbit angle distributions of the final configurations. We find that the efficiency of forming tight binaries (≲ 16 days) when taking the EKL mechanism into account is ∼21%, and about 4% of all simulated systems ended up in a merger event. These merger events can lead to the formation of blue stragglers. Furthermore, we find that the spin-orbit angle distribution of the inner binaries carries a signature of the initial setup of the system; thus, observations can be used to disentangle close binaries' birth configuration. The resulting inner and outer final orbits' period distributions and their estimated fraction suggest that secular dynamics may be a significant channel for the formation of close binaries in triples and even blue stragglers.

  15. Triple galaxies and a hidden mass problem

    NASA Technical Reports Server (NTRS)

    Karachentsev, I. D.; Karachentseva, V. E.; Lebedev, V. S.

    1990-01-01

    The authors consider a homogeneous sample of 84 triple systems of galaxies with components brighter than m = 15.7, located in the northern sky and satisfying an isolation criterion with respect to neighboring galaxies in projection. The distributions of basic dynamical parameters for triplets have median values as follows: radial velocity dispersion 133 km/s, mean harmonic radius 63 kpc, absolute magnitude of galaxies M sub B equals -20.38, crossing time tau = 0.04 H(sup minus 1). For different ways of estimation the median mass-to-luminosity ratio is (20 - 30). A comparison of the last value with the ones for single and binary galaxies shows the presence of a virial mass excess for triplets by a factor 4. The mass-to-luminosity ratio is practically uncorrelated with linear size of triplets or with morphological types of their components. We note that a significant part of the virial excess may be explained by the presence of nonisolated triple configurations in the sample, which are produced by debris of more populous groups of galaxies.

  16. Triple Oxygen Isotopes: Fundamental Relationships and Applications

    NASA Astrophysics Data System (ADS)

    Bao, Huiming; Cao, Xiaobin; Hayles, Justin A.

    2016-06-01

    The element oxygen has three stable isotopes: 16O, 17O, and 18O. For a defined process, a change in 18O/16O scales with the corresponding change in 17O/16O, or the fractionation factors 18α and 17α have a relationship of θ = ln17α/ln18α, in which the triple oxygen isotope exponent θ is relatively fixed but does vary with reaction path, temperature, and species involved. When the small variation is of interest, the distinction of three concepts—θ, S (a slope through data points in δ17O-δ18O space), and C (an arbitrary referencing number for the degree of 17O deviation)—becomes important. Triple oxygen isotope variations can be measured by modern instruments and thus offer an additional line of information on the underlying reaction processes and conditions. Analytical methods and Earth science applications have recently been developed for air oxygen, carbon dioxide, water, silicates, oxides, sulfates, carbonates, and phosphates.

  17. Triple Oxygen Isotopes: Fundamental Relationships and Applications

    NASA Astrophysics Data System (ADS)

    Bao, Huiming; Cao, Xiaobin; Hayles, Justin A.

    2016-06-01

    The element oxygen has three stable isotopes: 16O, 17O, and 18O. For a defined process, a change in 18O/16O scales with the corresponding change in 17O/16O, or the fractionation factors 18α and 17α have a relationship of θ = ln17α/ln18α, in which the triple oxygen isotope exponent θ is relatively fixed but does vary with reaction path, temperature, and species involved. When the small variation is of interest, the distinction of three concepts—θ, S (a slope through data points in δ17O–δ18O space), and C (an arbitrary referencing number for the degree of 17O deviation)—becomes important. Triple oxygen isotope variations can be measured by modern instruments and thus offer an additional line of information on the underlying reaction processes and conditions. Analytical methods and Earth science applications have recently been developed for air oxygen, carbon dioxide, water, silicates, oxides, sulfates, carbonates, and phosphates.

  18. Triple-activated blast furnace slag

    SciTech Connect

    Clarke, W.J.

    1995-12-31

    The current shortage of portland cement in the world will require the use of Ground Granulated Blast Furnace Slag (GGBFS) to fill demands in many industrialized countries. Therefore, an extensive series of triple-activated slag experiments have been undertaken to optimize an economical combination of mechanical properties for alkali-activated slags. Na{sub 2}OSiO{sub 2} (N Grade), Ca(OH){sub 2}, H{sub 2}O and Na{sub 2}CO{sub 3} have been added as activators in 5 to 10, 0 to 5 and 0 to 5 weight percentages of water and slag in a mix with a water:cement ratio of 1:1. Silica Fume and Sika 10 superplasticizer have been added as 1 and 10 weight percent of slag. Set times, initial hardening times and compressive strengths at percentages of the mix to identify more refined formulations. Finally, the resulting aggregate to develop a triple-activated slag formulation with the ultimate objective of contributing toward satisfying the world shortage of high performance concrete.

  19. Kappa Fornaci, A Triple Radio Star

    NASA Astrophysics Data System (ADS)

    Tokovinin, Andrei

    2013-03-01

    Bright and nearby (22 pc) solar-type dwarf κ For (HIP 11072) is a triple system. The close pair of M-type dwarfs Ba,Bb with a tentative period of 3.7 days moves around the main component A on a 26 yr orbit. The mass of the "dark companion" Ba+Bb is comparable to the mass of A, causing large motion of the photo-center. The combined spectro-interferometric orbit of AB is derived, and the relative photometry of the components A and B is given. A weak signature of Ba and Bb is detected in the high-resolution spectra by cross-correlation and by variable emission in the Balmer hydrogen lines. The activity of the M dwarfs, manifested by a previously detected radio flare, is likely maintained by synchronization with their tight orbit. We discuss the frequency of similar hidden triple systems, methods of their detection, and the implications for multiple-star statistics. Based on observations obtained with CHIRON spectrometer at the 1.5 m CTIO telescope operated by SMARTS (NOAO program 2012B-0075), at the SOAR telescope, and at the Gemini Observatory (program GS-2012B-Q-71, PI: M. Hartung).

  20. Recovery and normalization of triple coincidences in PET

    SciTech Connect

    Lage, Eduardo Parot, Vicente; Dave, Shivang R.; Herraiz, Joaquin L.; Moore, Stephen C.; Sitek, Arkadiusz; Park, Mi-Ae; Udías, Jose M.; Vaquero, Juan J.

    2015-03-15

    Purpose: Triple coincidences in positron emission tomography (PET) are events in which three γ-rays are detected simultaneously. These events, though potentially useful for enhancing the sensitivity of PET scanners, are discarded or processed without special consideration in current systems, because there is not a clear criterion for assigning them to a unique line-of-response (LOR). Methods proposed for recovering such events usually rely on the use of highly specialized detection systems, hampering general adoption, and/or are based on Compton-scatter kinematics and, consequently, are limited in accuracy by the energy resolution of standard PET detectors. In this work, the authors propose a simple and general solution for recovering triple coincidences, which does not require specialized detectors or additional energy resolution requirements. Methods: To recover triple coincidences, the authors’ method distributes such events among their possible LORs using the relative proportions of double coincidences in these LORs. The authors show analytically that this assignment scheme represents the maximum-likelihood solution for the triple-coincidence distribution problem. The PET component of a preclinical PET/CT scanner was adapted to enable the acquisition and processing of triple coincidences. Since the efficiencies for detecting double and triple events were found to be different throughout the scanner field-of-view, a normalization procedure specific for triple coincidences was also developed. The effect of including triple coincidences using their method was compared against the cases of equally weighting the triples among their possible LORs and discarding all the triple events. The authors used as figures of merit for this comparison sensitivity, noise-equivalent count (NEC) rates and image quality calculated as described in the NEMA NU-4 protocol for the assessment of preclinical PET scanners. Results: The addition of triple-coincidence events with the

  1. BROWN DWARF BINARIES FROM DISINTEGRATING TRIPLE SYSTEMS

    SciTech Connect

    Reipurth, Bo; Mikkola, Seppo E-mail: Seppo.Mikkola@utu.fi

    2015-04-15

    Binaries in which both components are brown dwarfs (BDs) are being discovered at an increasing rate, and their properties may hold clues to their origin. We have carried out 200,000 N-body simulations of three identical stellar embryos with masses drawn from a Chabrier IMF and embedded in a molecular core. The bodies are initially non-hierarchical and undergo chaotic motions within the cloud core, while accreting using Bondi–Hoyle accretion. The coupling of dynamics and accretion often leads to one or two dominant bodies controlling the center of the cloud core, while banishing the other(s) to the lower-density outskirts, leading to stunted growth. Eventually each system transforms either to a bound hierarchical configuration or breaks apart into separate single and binary components. The orbital motion is followed for 100 Myr. In order to illustrate 200,000 end-states of such dynamical evolution with accretion, we introduce the “triple diagnostic diagram,” which plots two dimensionless numbers against each other, representing the binary mass ratio and the mass ratio of the third body to the total system mass. Numerous freefloating BD binaries are formed in these simulations, and statistical properties are derived. The separation distribution function is in good correspondence with observations, showing a steep rise at close separations, peaking around 13 AU and declining more gently, reaching zero at separations greater than 200 AU. Unresolved BD triple systems may appear as wider BD binaries. Mass ratios are strongly peaked toward unity, as observed, but this is partially due to the initial assumptions. Eccentricities gradually increase toward higher values, due to the lack of viscous interactions in the simulations, which would both shrink the orbits and decrease their eccentricities. Most newborn triple systems are unstable and while there are 9209 ejected BD binaries at 1 Myr, corresponding to about 4% of the 200,000 simulations, this number has grown to

  2. Brown Dwarf Binaries from Disintegrating Triple Systems

    NASA Astrophysics Data System (ADS)

    Reipurth, Bo; Mikkola, Seppo

    2015-04-01

    Binaries in which both components are brown dwarfs (BDs) are being discovered at an increasing rate, and their properties may hold clues to their origin. We have carried out 200,000 N-body simulations of three identical stellar embryos with masses drawn from a Chabrier IMF and embedded in a molecular core. The bodies are initially non-hierarchical and undergo chaotic motions within the cloud core, while accreting using Bondi-Hoyle accretion. The coupling of dynamics and accretion often leads to one or two dominant bodies controlling the center of the cloud core, while banishing the other(s) to the lower-density outskirts, leading to stunted growth. Eventually each system transforms either to a bound hierarchical configuration or breaks apart into separate single and binary components. The orbital motion is followed for 100 Myr. In order to illustrate 200,000 end-states of such dynamical evolution with accretion, we introduce the “triple diagnostic diagram,” which plots two dimensionless numbers against each other, representing the binary mass ratio and the mass ratio of the third body to the total system mass. Numerous freefloating BD binaries are formed in these simulations, and statistical properties are derived. The separation distribution function is in good correspondence with observations, showing a steep rise at close separations, peaking around 13 AU and declining more gently, reaching zero at separations greater than 200 AU. Unresolved BD triple systems may appear as wider BD binaries. Mass ratios are strongly peaked toward unity, as observed, but this is partially due to the initial assumptions. Eccentricities gradually increase toward higher values, due to the lack of viscous interactions in the simulations, which would both shrink the orbits and decrease their eccentricities. Most newborn triple systems are unstable and while there are 9209 ejected BD binaries at 1 Myr, corresponding to about 4% of the 200,000 simulations, this number has grown to

  3. Triple reuptake inhibitors as potential next-generation antidepressants: a new hope?

    PubMed Central

    Sharma, Horrick; Santra, Soumava; Dutta, Aloke

    2015-01-01

    The current therapy for depression is less than ideal with remission rates of only 25–35% and a slow onset of action with other associated side effects. The persistence of anhedonia originating from depressed dopaminergic activity is one of the most treatment-resistant symptoms of depression. Therefore, it has been hypothesized that triple reuptake inhibitors (TRIs) with potency to block dopamine reuptake in addition to serotonin and norepinephrine transporters should produce higher efficacy. The current review comprehensively describes the development of TRIs and discusses the importance of evaluation of in vivo transporter occupancy of TRIs, which should correlate with efficacy in humans. PMID:26619226

  4. Novel therapeutic strategies for patients with triple-negative breast cancer

    PubMed Central

    Zhang, Jun-Fei; Liu, Jia; Wang, Yu; Zhang, Bin

    2016-01-01

    Triple-negative breast cancer (TNBC) represents a very heterogeneous group of breast diseases. Currently, the backbone of therapy for TNBC is mainly chemotherapy as there are no effective specific targeted agents approved to treat TNBC. Despite initial responses to chemotherapy, resistance frequently and rapidly develops and metastatic TNBC has a poor prognosis. Therefore, new targeted strategies are, accordingly, urgently needed. This article discusses the recent developments in targeted agents explored for TNBC, aiming to offer novel therapeutic strategies that can potentially assist in designing personalized therapeutics in the future as well as provide the basis for further research in an attempt to target TNBC. PMID:27799799

  5. Thermodynamic characterization of non-sequence-specific DNA-binding by the Sso7d protein from Sulfolobus solfataricus.

    PubMed

    Lundbäck, T; Hansson, H; Knapp, S; Ladenstein, R; Härd, T

    1998-03-01

    We used isothermal titration calorimetry and fluorescence spectroscopy to investigate the thermodynamics of non-sequence-specific DNA-binding by the Sso7d protein from the archaeon Sulfolobus solfataricus. We report the Sso7d-poly(dGdC) binding thermodynamics as a function of buffer composition (Tris-HCl or phosphate), temperature (15 to 45 degrees C), pH (7.1 to 8.0), osmotic stress and solvent (H2O/2H2O), and compare it to poly (dAdT) binding; and we have previously also reported the salt concentration dependence. Binding isotherms can be represented by the McGhee-von Hippel model for non-cooperative binding, with a binding site size of four to five DNA base-pairs and binding free energies in the range DeltaG degrees approximately -7 to DeltaG degrees approximately -10 kcal mol-1, depending on experimental conditions. The non-specific nature of the binding is reflected in similar thermodynamics for binding to poly(dAdT) and poly(dGdC). The native lysine methylation of Sso7d has only minor effects on the binding thermodynamics. Sso7d binding to poly(dGdC) is endothermic at 25 degrees C with a binding enthalpy DeltaH degrees approximately 10 kcal mol-1 in both phosphate and Tris-HCl buffers at pH 7.6, indicating that DeltaH degrees does not include large contributions from coupled buffer ionization equilibria at this pH. The binding enthalpy is temperature dependent with a measured heat capacity change DeltaCp degrees=-0.25(+/-0.01) kcal mol-1 K-1 and extrapolations of thermodynamic data indicate that the complex is heat stable with exothermic binding close to the growth temperature (75 to 80 degreesC) of S. solfataricus. Addition of neutral solutes (osmotic stress) has minor effects on DeltaG degrees and the exchange of H2O for 2H2O has only a small effect on DeltaH degrees, consistent with the inference that complex formation is not accompanied by net changes in surface hydration. Thus, other mechanisms for the heat capacity change must be found. The observed

  6. Triple junction polymer solar cells for photoelectrochemical water splitting.

    PubMed

    Esiner, Serkan; van Eersel, Harm; Wienk, Martijn M; Janssen, René A J

    2013-06-01

    A triple junction polymer solar cell in a novel 1 + 2 type configuration provides photoelectrochemical water splitting in its maximum power point at V ≈ 1.70 V with an estimated solar to hydrogen energy conversion efficiency of 3.1%. The triple junction cell consists of a wide bandgap front cell and two identical small bandgap middle and back cells.

  7. 22. DETAIL OF TRIPLE WINDOW, SOUTHEAST ROOM, FIRST FLOOR. Typical ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    22. DETAIL OF TRIPLE WINDOW, SOUTHEAST ROOM, FIRST FLOOR. Typical for all triple windows on first and second floors. Single swing jib door under center sash opening out. Door thickness measures from flush with exterior siding to 3/4' inside bottom sash. See also Photo 12. SC-291-12. - John Joyner Smith House, 400 Wilmington Street, Beaufort, Beaufort County, SC

  8. On Twisting Real Spectral Triples by Algebra Automorphisms

    NASA Astrophysics Data System (ADS)

    Landi, Giovanni; Martinetti, Pierre

    2016-08-01

    We systematically investigate ways to twist a real spectral triple via an algebra automorphism and in particular, we naturally define a twisted partner for any real graded spectral triple. Among other things, we investigate consequences of the twisting on the fluctuations of the metric and possible applications to the spectral approach to the Standard Model of particle physics.

  9. Spin waves in triple-q structures: Application to USb

    SciTech Connect

    Jensen, J.; Bak, P.

    1981-06-01

    The spin-wave spectrum in a system with triple-q magnetic structure is calculated. The spin waves differ distinctly from those in the corresponding single-q structure, but agree with the excitations observed by Lander and Stirling in uranium antimonide (USb). Their experiments thus directly verify that the spins in USb are ordered in the triple-q structure.

  10. On Twisting Real Spectral Triples by Algebra Automorphisms

    NASA Astrophysics Data System (ADS)

    Landi, Giovanni; Martinetti, Pierre

    2016-11-01

    We systematically investigate ways to twist a real spectral triple via an algebra automorphism and in particular, we naturally define a twisted partner for any real graded spectral triple. Among other things, we investigate consequences of the twisting on the fluctuations of the metric and possible applications to the spectral approach to the Standard Model of particle physics.

  11. Regional Dimensions of the Triple Helix Model: Setting the Context

    ERIC Educational Resources Information Center

    Todeva, Emanuela; Danson, Mike

    2016-01-01

    This paper introduces the rationale for the special issue and its contributions, which bridge the literature on regional development and the Triple Helix model. The concept of the Triple Helix at the sub-national, and specifically regional, level is established and examined, with special regard to regional economic development founded on…

  12. Government and Governance of Regional Triple Helix Interactions

    ERIC Educational Resources Information Center

    Danson, Mike; Todeva, Emanuela

    2016-01-01

    This conceptual paper contributes to the discussion of the role of regional government and regional Triple Helix constellations driving economic development and growth within regional boundaries. The impact of regionalism and subsidiarity on regional Triple Helix constellations, and the questions of governmentality, governance and institutional…

  13. The effect of triple-junction drag on grain growth

    SciTech Connect

    Gottstein, G.; King, A.H.; Shvindlerman, L.S.

    2000-01-24

    Current theories of grain growth presume that grain boundary migration is the rate-limiting step, and either explicitly or implicitly assume that triple junctions can always move with sufficient speed to accommodate the changing positions of the grain boundaries. Following from some recent observations of triple-junction drag effects in tricrystals of zinc and in molecular dynamics models, an analytical theory is developed to explore the effects of triple-junction drag upon grain growth, for a two-dimensional solid. The theory is developed in the framework of the Von Neumann-Mullins formulation, and demonstrates that drag effects operating exclusively at the triple junctions result in a retardation of grain growth. The stability of six-sided grains in the isotropic, drag-free case of the Von Neumann-Mullins analysis is successively extended to grains of 6 {+-} N sides, where N increases with the strength of the triple-junction drag.

  14. MicroRNA-544 down-regulates both Bcl6 and Stat3 to inhibit tumor growth of human triple negative breast cancer.

    PubMed

    Zhu, Zhengzhi; Wang, Shengying; Zhu, Jinhai; Yang, Qifeng; Dong, Huiming; Huang, Jiankang

    2016-10-01

    Triple negative breast cancer lacking estrogen receptor (ER), progesterone receptor and Her2 account for account for the majority of the breast cancer deaths, due to the lack of specific gene targeted therapy. Our current study aimed to investigate the role of miR-544 in triple negative breast cancer. Endogenous levels of miR-544 were significantly lower in breast cancer cell lines than in human breast non-tumorigenic and mammary epithelial cell lines. We found that miR-544 directly targeted the 3'-untranslated region (UTR) on both Bcl6 and Stat3 mRNAs, and overexpression of miR-544 in triple negative breast cancer cells significantly down-regulated expressions of Bcl6 and Stat3, which in turn severely inhibited cancer cell proliferation, migration and invasion in vitro. Employing a mouse xenograft model to examine the in vivo function of miR-544, we found that expression of miR-544 significantly repressed the growth of xenograft tumors. Our current study reported miR-544 as a tumor-suppressor microRNA particularly in triple negative breast cancer. Our data supported the role of miR-544 as a potential biomarker in developing gene targeted therapies in the clinical treatment of triple negative breast cancer.

  15. Maximiscin Induces DNA Damage, Activates DNA Damage Response Pathways, and Has Selective Cytotoxic Activity against a Subtype of Triple-Negative Breast Cancer.

    PubMed

    Robles, Andrew J; Du, Lin; Cichewicz, Robert H; Mooberry, Susan L

    2016-07-22

    Triple-negative breast cancers are highly aggressive, and patients with these types of tumors have poor long-term survival. These breast cancers do not express estrogen or progesterone receptors and do not have gene amplification of human epidermal growth factor receptor 2; therefore, they do not respond to available targeted therapies. The lack of targeted therapies for triple-negative breast cancers stems from their heterogeneous nature and lack of a clear definition of driver defects. Studies have recently identified triple-negative breast cancer molecular subtypes based on gene expression profiling and representative cell lines, allowing for the identification of subtype-specific drug leads and molecular targets. We previously reported the identification of a new fungal metabolite named maximiscin (1) identified through a crowdsourcing program. New results show that 1 has selective cytotoxic efficacy against basal-like 1 MDA-MB-468 cells compared to cell lines modeling other triple-negative breast cancer molecular subtypes. This compound also exhibited antitumor efficacy in a xenograft mouse model. The mechanisms of action of 1 in MDA-MB-468 cells were investigated to identify potential molecular targets and affected pathways. Compound 1 caused accumulation of cells in the G1 phase of the cell cycle, suggesting induction of DNA damage. Indeed, treatment with 1 caused DNA double-strand breaks with concomitant activation of the DNA damage response pathways, indicated by phosphorylation of p53, Chk1, and Chk2. Collectively, these results suggest basal-like triple-negative breast cancer may be inherently sensitive to DNA-damaging agents relative to other triple-negative breast cancer subtypes. These results also demonstrate the potential of our citizen crowdsourcing program to identify new lead molecules for treating the subtypes of triple-negative breast cancer. PMID:27310425

  16. Mathematical modelling of triple arterial stenoses.

    PubMed

    Ang, K C; Mazumdar, J

    1995-06-01

    This paper examines the effects of triple stenoses (ie. three stenoses in series) in a reasonably large artery. The model developed is axi-symmetric and blood is assumed to be a Newtonian fluid. The governing equations are the Navier-Stokes equations and the continuity equation. These equations are solved using the Finite Element Method and the FIDAP computational fluid dynamics (C.F.D.) package. Various combinations of differing degrees of stenosis in the triplet are considered. Pressure drop profiles and streamline plots of the solutions to these models show that the effects of milder stenoses are diminished in the presence of more severe ones. Also, a pressure recovery is observed whenever a mild stenosis follows a more severe stenosis in multiply stenosed arteries.

  17. [Triple fracture of the shoulder suspensory complex].

    PubMed

    Tamimi Mariño, I; Martin Rodríguez, I; Mora Villadeamigo, J

    2013-01-01

    The superior suspensory complex of the shoulder (SSCS) is a ring shaped structure composed of bones and soft tissues that play a fundamental role in the stability of the shoulder joint. Isolated injuries of the SSCS are relatively common, but injuries that affect 3 components are extremely unusual. We present a triple injury of the SSCS in a 26 year old patient with a Neer type ii clavicular fracture, a Kuhn type iii acromion fracture and an Ogawa type i coracoid fracture. An open reduction and stabilization of the clavicle was performed with 2 Kirschner nails. The acromial fracture was synthesized with 2 cannulated screws, and the coracoid fracture was treated conservatively. After 24 months of follow up the patient had an excellent functional outcome according to the Constat-Murley shoulder score and QuickDASH scoring system, and all the fractures healed correctly.

  18. Triple flames in microgravity flame spread

    NASA Technical Reports Server (NTRS)

    Wichman, Indrek S.

    1995-01-01

    The purpose of this project is to examine in detail the influence of the triple flame structure on the flame spread problem. It is with an eye to the practical implications that this fundamental research project must be carried out. The microgravity configuration is preferable because buoyancy-induced stratification and vorticity generation are suppressed. A more convincing case can be made for comparing our predictions, which are zero-g, and any projected experiments. Our research into the basic aspects will employ two models. In one, flows of fuel and oxidizer from the lower wall are not considered. In the other, a convective flow is allowed. The non-flow model allows us to develop combined analytical and numerical solution methods that may be used in the more complicated convective-flow model.

  19. Roles, Stacks, Histories: A Triple for Hoare

    NASA Astrophysics Data System (ADS)

    Borgström, Johannes; Gordon, Andrew D.; Pucella, Riccardo

    Behavioural type and effect systems regulate properties such as adherence to object and communication protocols, dynamic security policies, avoidance of race conditions, and many others. Typically, each system is based on some specific syntax of constraints, and is checked with an ad hoc solver. Instead, weadvocate types refined with first-order logic formulas as a basis for behavioural type systems, and general purpose automated theorem provers as an effective means of checking programs. To illustrate this approach, we define a triple of security-related type systems: for role-based access control, for stack inspection, and for history-based access control. The three are all instances of a refined state monad. Our semantics allows a precise comparison of the similarities and differences of these mechanisms. In our examples, the benefit of behavioural type-checking is to rule out the possibility of unexpected security exceptions, a common problem with code-based access control.

  20. HD 207651: A composite spectrum triple system

    SciTech Connect

    Fekel, Francis C.

    2015-02-01

    From numerous radial velocities obtained at KPNO and Fairborn Observatory, we have determined the orbital elements of the composite spectrum triple system HD 207651. This system consists of a broad-lined A8 V star and an unseen M dwarf companion in a 1.470739 days orbit. Variations of the center-of-mass velocity of this short-period system and velocity variations of a narrow-lined F7: V star have an orbital period of 724.1 days or 1.98 yr and an eccentricity of 0.39. The revised Hipparcos parallax, corresponding to a distance of 255 pc, appears to be too small to yield consistent properties. Instead, we adopt a distance of 150 pc.

  1. The triple system KR Comae Berenices

    NASA Astrophysics Data System (ADS)

    Zasche, P.; Uhlář, R.

    2010-09-01

    Aims: We present the detailed analysis of triple system KR Com with different observational techniques - photometry, interferometry, and period variation. Methods: The use of BVR photometry of the close-contact binary KR Com, which is the primary component of a triple system, helps us to better describe the properties of the components. The interferometric data obtained during the last 30 years sufficiently determine the visual orbit, but the use of minima timings of KR Com for the study of period variation together with the visual orbit is a novel approach in this system. Results: Basic physical parameters resulting from the light curve analysis agree well with the previous results from spectroscopy. The temperatures for the primary and secondary component resulted in 5549 and 6072 K, respectively, and the amount of the third light in all filters is about 1/3 of the total luminosity. The distant third component revolves around the common barycenter on 11 yr orbit with a very high eccentricity (0.934) and this movement is also detectable via the period variation, which is clearly visible in the O-C diagram of times of minima observations. The use of minima times for the combined analysis helps us to independently determine the distance to the system (64.02 ± 9.42 pc) and also to confirm the orientation of the orbit in space. Conclusions: New minima observations and also spectroscopy would be very profitable, especially during the next periastron passage in the year 2017. Photometric tables are only available in electronic form at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (130.79.128.5) or via http://cdsweb.u-strasbg.fr/cgi-bin/qcat?J/A+A/519/A78

  2. [Period-tripling in Multiscale Physical and Biological Events].

    PubMed

    Bondar, A T; Fedorov, M V; Kolombet, V A

    2015-01-01

    A recent paper by S.J. Puetz et al. (Chaos, Solitons -& Fractals, v. 62-63, p. 55, 2014) described a fundamental period-tripled model. It involves periods of different astronomical (quasars, Sun), geophysical (geomagnetic, climatic, volcanic) and some biological processes. This work contains statistics for sixteen pairs of a period-tripled sequence. These periods range from -50 years to 1.5 billion years and no signs of the timescale limitations are found. We believe that the universal scope of the fundamental period-tripled model can be used for the development of new methodology of research data analysis: the main idea is that the spectrum of the periods of the studied event should be tested for the similarity with the spectrum of fundamental period-tripling pattern (because of the fundamental nature of the period-tripled model). Using this method, in this study we complement an already described period-tripled model with periods of human memory performance ranging from one minute to one month also adding seven relevant periods/frequencies of the period-tripled model in the range of human hearing. We make a conclusion that these characteristic frequencies may form the basis for music and singing phenomena. The new methodology is particularly appropriate for being applied in medicine and engineering.

  3. [Period-tripling in Multiscale Physical and Biological Events].

    PubMed

    Bondar, A T; Fedorov, M V; Kolombet, V A

    2015-01-01

    A recent paper by S.J. Puetz et al. (Chaos, Solitons -& Fractals, v. 62-63, p. 55, 2014) described a fundamental period-tripled model. It involves periods of different astronomical (quasars, Sun), geophysical (geomagnetic, climatic, volcanic) and some biological processes. This work contains statistics for sixteen pairs of a period-tripled sequence. These periods range from -50 years to 1.5 billion years and no signs of the timescale limitations are found. We believe that the universal scope of the fundamental period-tripled model can be used for the development of new methodology of research data analysis: the main idea is that the spectrum of the periods of the studied event should be tested for the similarity with the spectrum of fundamental period-tripling pattern (because of the fundamental nature of the period-tripled model). Using this method, in this study we complement an already described period-tripled model with periods of human memory performance ranging from one minute to one month also adding seven relevant periods/frequencies of the period-tripled model in the range of human hearing. We make a conclusion that these characteristic frequencies may form the basis for music and singing phenomena. The new methodology is particularly appropriate for being applied in medicine and engineering. PMID:26841519

  4. Vectorized data acquisition and fast triple-correlation integrals for Fluorescence Triple Correlation Spectroscopy

    NASA Astrophysics Data System (ADS)

    Ridgeway, William K.; Millar, David P.; Williamson, James R.

    2013-04-01

    Fluorescence Correlation Spectroscopy (FCS) is widely used to quantify reaction rates and concentrations of molecules in vitro and in vivo. We recently reported Fluorescence Triple Correlation Spectroscopy (F3CS), which correlates three signals together instead of two. F3CS can analyze the stoichiometries of complex mixtures and detect irreversible processes by identifying time-reversal asymmetries. Here we report the computational developments that were required for the realization of F3CS and present the results as the Triple Correlation Toolbox suite of programs. Triple Correlation Toolbox is a complete data analysis pipeline capable of acquiring, correlating and fitting large data sets. Each segment of the pipeline handles error estimates for accurate error-weighted global fitting. Data acquisition was accelerated with a combination of off-the-shelf counter-timer chips and vectorized operations on 128-bit registers. This allows desktop computers with inexpensive data acquisition cards to acquire hours of multiple-channel data with sub-microsecond time resolution. Off-line correlation integrals were implemented as a two delay time multiple-tau scheme that scales efficiently with multiple processors and provides an unprecedented view of linked dynamics. Global fitting routines are provided to fit FCS and F3CS data to models containing up to ten species. Triple Correlation Toolbox is a complete package that enables F3CS to be performed on existing microscopes. Catalogue identifier: AEOP_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEOP_v1_0.html Program obtainable from: CPC Program Library, Queen’s University, Belfast, N. Ireland Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 50189 No. of bytes in distributed program, including test data, etc.: 6135283 Distribution format: tar.gz Programming language: C/Assembly. Computer: Any with GCC and

  5. Downregulation of androgen receptor is strongly associated with diabetes in triple negative breast cancer patients

    PubMed Central

    Collina, Francesca; Cerrone, Margherita; Peluso, Valentina; Laurentiis, Michelino De; Caputo, Roberta; Cecio, Rossella De; Liguori, Giuseppina; Botti, Gerardo; Cantile, Monica; Bonito, Maurizio Di

    2016-01-01

    Developing of personalized therapies for Triple Negative Breast Cancer (TNBC) requires a more detailed knowledge of its biology and a correct stratification of molecular subtypes. Androgen Receptor (AR) is expressed in a large part of TNBCs but its prognostic role in this Breast Cancer (BC) subtype is highly debated. In this study, we analyzed AR expression in a series of 238 TNBCs and correlated its expression with clinical-pathological features, survival, and metabolic profile. We showed a consistent association between AR expression and a better prognosis of TNBC patients, while its downregulation appeared strongly associated with diabetic disease. Since a recent prospective study reported a lower BC risk in diabetic women treated with drugs able to reduce circulating levels of glucose compared with non-diabetic woman, and in vitro studies showed that AR level are regulated directly by hyperglycemia, we speculate on the perspective of new integrated therapies for TNBC.

  6. Triple Negative Breast Cancers Have a Reduced Expression of DNA Repair Genes

    PubMed Central

    Andreis, Daniele; Bertoni, Ramona; Giardini, Roberto; Fox, Stephen B.; Broggini, Massimo; Bottini, Alberto; Zanoni, Vanessa; Bazzola, Letizia; Foroni, Chiara; Generali, Daniele; Damia, Giovanna

    2013-01-01

    DNA repair is a key determinant in the cellular response to therapy and tumor repair status could play an important role in tailoring patient therapy. Our goal was to evaluate the mRNA of 13 genes involved in different DNA repair pathways (base excision, nucleotide excision, homologous recombination, and Fanconi anemia) in paraffin embedded samples of triple negative breast cancer (TNBC) compared to luminal A breast cancer (LABC). Most of the genes involved in nucleotide excision repair and Fanconi Anemia pathways, and CHK1 gene were significantly less expressed in TNBC than in LABC. PARP1 levels were higher in TNBC than in LABC. In univariate analysis high level of FANCA correlated with an increased overall survival and event free survival in TNBC; however multivariate analyses using Cox regression did not confirm FANCA as independent prognostic factor. These data support the evidence that TNBCs compared to LABCs harbour DNA repair defects. PMID:23825533

  7. Downregulation of androgen receptor is strongly associated with diabetes in triple negative breast cancer patients

    PubMed Central

    Collina, Francesca; Cerrone, Margherita; Peluso, Valentina; Laurentiis, Michelino De; Caputo, Roberta; Cecio, Rossella De; Liguori, Giuseppina; Botti, Gerardo; Cantile, Monica; Bonito, Maurizio Di

    2016-01-01

    Developing of personalized therapies for Triple Negative Breast Cancer (TNBC) requires a more detailed knowledge of its biology and a correct stratification of molecular subtypes. Androgen Receptor (AR) is expressed in a large part of TNBCs but its prognostic role in this Breast Cancer (BC) subtype is highly debated. In this study, we analyzed AR expression in a series of 238 TNBCs and correlated its expression with clinical-pathological features, survival, and metabolic profile. We showed a consistent association between AR expression and a better prognosis of TNBC patients, while its downregulation appeared strongly associated with diabetic disease. Since a recent prospective study reported a lower BC risk in diabetic women treated with drugs able to reduce circulating levels of glucose compared with non-diabetic woman, and in vitro studies showed that AR level are regulated directly by hyperglycemia, we speculate on the perspective of new integrated therapies for TNBC. PMID:27648143

  8. A Novel Triple Medicine Combination Injection for the Resolution of Keloids and Hypertrophic Scars

    PubMed Central

    Gold, Michael H.

    2014-01-01

    Keloids and hypertrophic scars remain one of the more difficult treatment concerns for clinicians. A variety of therapies have been used in the past with moderate success. On occasion, combination therapy has been used to treat these lesion, in an attempt to lessen the symptoms of pain and pruritus that often accompanies keloids and hypertrophic scars, as well as treating the actual lesions themselves. A novel triple combination injection process is introduced here in an attempt to further reduce the signs and symptoms of these lesions. The combination includes 5-fluoruracil, triamcinolone acetonide, and hyaluronidase. All three work in concert to treat keloids and hypertrophic scars, and this is the first work at looking at these medicines given together, at the same time, in a series of recalcitrant keloids and hypertrophic scars. The positive results warrant further investigation and hope for those with keloids and hypertrophic scars. PMID:25489380

  9. Downregulation of androgen receptor is strongly associated with diabetes in triple negative breast cancer patients.

    PubMed

    Collina, Francesca; Cerrone, Margherita; Peluso, Valentina; Laurentiis, Michelino De; Caputo, Roberta; Cecio, Rossella De; Liguori, Giuseppina; Botti, Gerardo; Cantile, Monica; Bonito, Maurizio Di

    2016-01-01

    Developing of personalized therapies for Triple Negative Breast Cancer (TNBC) requires a more detailed knowledge of its biology and a correct stratification of molecular subtypes. Androgen Receptor (AR) is expressed in a large part of TNBCs but its prognostic role in this Breast Cancer (BC) subtype is highly debated. In this study, we analyzed AR expression in a series of 238 TNBCs and correlated its expression with clinical-pathological features, survival, and metabolic profile. We showed a consistent association between AR expression and a better prognosis of TNBC patients, while its downregulation appeared strongly associated with diabetic disease. Since a recent prospective study reported a lower BC risk in diabetic women treated with drugs able to reduce circulating levels of glucose compared with non-diabetic woman, and in vitro studies showed that AR level are regulated directly by hyperglycemia, we speculate on the perspective of new integrated therapies for TNBC. PMID:27648143

  10. On Pythagoras Theorem for Products of Spectral Triples

    NASA Astrophysics Data System (ADS)

    D'Andrea, Francesco; Martinetti, Pierre

    2013-05-01

    We discuss a version of Pythagoras theorem in noncommutative geometry. Usual Pythagoras theorem can be formulated in terms of Connes' distance, between pure states, in the product of commutative spectral triples. We investigate the generalization to both non-pure states and arbitrary spectral triples. We show that Pythagoras theorem is replaced by some Pythagoras inequalities, that we prove for the product of arbitrary (i.e. non-necessarily commutative) spectral triples, assuming only some unitality condition. We show that these inequalities are optimal, and we provide non-unital counter-examples inspired by K-homology.

  11. Non-resonant Triple- α Reaction Rate at Low Temperature

    NASA Astrophysics Data System (ADS)

    Tamii, A.; Aoi, N.; Fujita, H.; Fujita, Y.; Hatanaka, K.; Hashimoto, T.; Kawabata, T.; Miki, K.; Itoh, M.; Itoh, T.; Kamimura, M.; Ogata, K.; Ong, H. J.; Sakaguchi, H.; Shima, T.; Suzuki, T.; Yamamoto, T.

    2013-08-01

    The triple α reaction rate in stars is quite important in many astrophysical scenarios including the stellar evolution and carbon synthesis in stars. Recently the non-resonant triple α reaction rate has been reevaluated using a calculation with the continuum-discretized coupled-channels (CDCC) method, which dramatically increased the rate at low temperature compared to the widely-used NACRE compilation. Since the enhancement influences strongly on astrophysical model simulations, we have planned an experiment for drawing conclusion on the non-resonant triple α reaction rate at low temperature by measuring the three- α continuum state in 12C. We report the present situation of the experiment.

  12. Effects of Gravity on Triple Flame Propagation and Stability

    NASA Technical Reports Server (NTRS)

    Chen, J.-Y.; Echekki, Tarek; Hugde, Uday

    2001-01-01

    Numerical simulations of 2-D triple flames under gravity force have been implemented to identify the effects of gravity on triple flame structure and propagation properties and to understand the mechanisms of instabilities resulting from both heat release and buoyancy effects. A wide range of gravity conditions, heat release and mixing widths for a scalar mixing layer are computed for downward-propagating (in the same direction with the gravity vector) and upward-propagating (in the opposite direction of the gravity vector) triple flames.

  13. Effect of nanowires SiO2 on superconducting properties of YBa2Cu3O7-d bulks

    NASA Astrophysics Data System (ADS)

    Salem, M. K. Ben; Hannachi, E.; Slimani, Y.; Hamrita, A.; Bessais, L.; Azzouz, F. Ben; Salem, M. Ben

    2013-12-01

    The effects of SiO2 nanowires on the superconducting properties of YBa2Cu3O7-d (YBCO) compound were studied. Samples were synthesized in air using a standard solid state reaction technique by adding nanowires SiO2 up to 1wt.%. Phase analysis by X-ray diffraction (XRD), microstructure investigation by scanning electron microscopy (SEM) coupled with energy dispersive X-ray spectroscopy (EDXS), critical current density dependence on applied magnetic field Jc(H) and electrical resistivity as a function of temperature ρ(T) were carried out to evaluate the relative performance of samples. We find that Tco does not change much (90.8-90.2 K) with the low concentration of SiO2 (≤ 0.1 wt.%) and Jc(H) is enhanced.

  14. DNA repair genes implicated in triple negative familial non-BRCA1/2 breast cancer predisposition

    PubMed Central

    Ollier, Marie; Radosevic-Robin, Nina; Kwiatkowski, Fabrice; Ponelle, Flora; Viala, Sandrine; Privat, Maud; Uhrhammer, Nancy; Bernard-Gallon, Dominique; Penault-Llorca, Frédérique; Bignon, Yves-Jean; Bidet, Yannick

    2015-01-01

    Among breast cancers, 10 to 15% of cases would be due to hereditary risk. In these familial cases, mutations in BRCA1 and BRCA2 are found in only 15% to 20%, meaning that new susceptibility genes remain to be found. Triple-negative breast cancers represent 15% of all breast cancers, and are generally aggressive tumours without targeted therapies available. Our hypothesis is that some patients with triple negative breast cancer could share a genetic susceptibility different from other types of breast cancers. We screened 36 candidate genes, using pyrosequencing, in all the 50 triple negative breast cancer patients with familial history of cancer but no BRCA1 or BRCA2 mutation of a population of 3000 families who had consulted for a familial breast cancer between 2005 and 2013. Any mutations were also sequenced in available relatives of cases. Protein expression and loss of heterozygosity were explored in tumours. Seven deleterious mutations in 6 different genes (RAD51D, MRE11A, CHEK2, MLH1, MSH6, PALB2) were observed in one patient each, except the RAD51D mutation found in two cases. Loss of heterozygosity in the tumour was found for 2 of the 7 mutations. Protein expression was absent in tumour tissue for 5 mutations. Taking into consideration a specific subtype of tumour has revealed susceptibility genes, most of them in the homologous recombination DNA repair pathway. This may provide new possibilities for targeted therapies, along with better screening and care of patients. PMID:26328243

  15. A phase 1/2 of a combination of cetuximab and taxane for "triple negative" breast cancer patients.

    PubMed

    Nechushtan, Hovav; Vainer, Gilad; Stainberg, Hana; Salmon, Asher Y; Hamburger, Tamar; Peretz, Tamar

    2014-08-01

    50-70% of tumors of the so called "triple negative" subtype of breast cancer express EGFR. We hypothesized that addition of anti EGFR to Taxanes will result in increased effectiveness in EGFR expressing tumors. Here we set out to obtain data regarding the safety, tolerability and also the effectivity of the combination of weekly Taxane treatments with Cetuximab -an anti EGFR antibody in this subgroup of breast cancer. 18 triple negative breast cancer patients were treated with weekly Cetuximab and Taxane therapy. Addition of Cetuximab resulted in controllable Dermatologic toxicity in most patients -with grade 3 in two patients. Some impressive results were noted including one CR, one near CR and regression of chemotherapy and radiation resistance skin metastasis. Median TTF -and overall survival -6 and 12 months. Administration of Taxane Cetuximab weekly therapy for triple negative breast cancer patients is feasible. Use of anti EGFR-Taxane combinations should be assessed in larger clinical trials in this patient population perhaps in a similar manner to the lung cancer patients only in those with strong EGFR expression.

  16. DNA repair genes implicated in triple negative familial non-BRCA1/2 breast cancer predisposition.

    PubMed

    Ollier, Marie; Radosevic-Robin, Nina; Kwiatkowski, Fabrice; Ponelle, Flora; Viala, Sandrine; Privat, Maud; Uhrhammer, Nancy; Bernard-Gallon, Dominique; Penault-Llorca, Frédérique; Bignon, Yves-Jean; Bidet, Yannick

    2015-01-01

    Among breast cancers, 10 to 15% of cases would be due to hereditary risk. In these familial cases, mutations in BRCA1 and BRCA2 are found in only 15% to 20%, meaning that new susceptibility genes remain to be found. Triple-negative breast cancers represent 15% of all breast cancers, and are generally aggressive tumours without targeted therapies available. Our hypothesis is that some patients with triple negative breast cancer could share a genetic susceptibility different from other types of breast cancers. We screened 36 candidate genes, using pyrosequencing, in all the 50 triple negative breast cancer patients with familial history of cancer but no BRCA1 or BRCA2 mutation of a population of 3000 families who had consulted for a familial breast cancer between 2005 and 2013. Any mutations were also sequenced in available relatives of cases. Protein expression and loss of heterozygosity were explored in tumours. Seven deleterious mutations in 6 different genes (RAD51D, MRE11A, CHEK2, MLH1, MSH6, PALB2) were observed in one patient each, except the RAD51D mutation found in two cases. Loss of heterozygosity in the tumour was found for 2 of the 7 mutations. Protein expression was absent in tumour tissue for 5 mutations. Taking into consideration a specific subtype of tumour has revealed susceptibility genes, most of them in the homologous recombination DNA repair pathway. This may provide new possibilities for targeted therapies, along with better screening and care of patients. PMID:26328243

  17. A Study of Neoadjuvant Paclitaxel in Combination With Bavituximab in Early- Stage Triple- Negative Breast Cancer

    ClinicalTrials.gov

    2016-02-12

    Breast Cancer; Triple Negative Breast Neoplasms; Triple-Negative Breast Neoplasm; Triple-Negative Breast Cancer; Triple Negative Breast Cancer; ER-Negative PR-Negative HER2-Negative Breast Neoplasms; ER-Negative PR-Negative HER2-Negative Breast Cancer

  18. Uncovering the triple omeron vertex from Wilson line formalism

    SciTech Connect

    Chirilli, G. A.; Szymanowski, L.; Wallon, S.

    2011-01-01

    We compute the triple omeron vertex from the Wilson line formalism, including both planar and nonplanar contributions, and get perfect agreement with the result obtained in the Extended Generalized Logarithmic Approximation based on Reggeon calculus.

  19. Elevation of north facades of #156158 (triple wards) National ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Elevation of north facades of #156-158 (triple wards) - National Home for Disabled Volunteer Soldiers, Pacific Branch, Mental Health Buildings, 11301 Wilshire Boulevard, West Los Angeles, Los Angeles County, CA

  20. Triple junction and grain boundary character distributions in metallic materials

    SciTech Connect

    Fortier, P.; Miller, W.A.; Aust, K.T.

    1997-08-01

    Triple junction and grain boundary orientations were obtained by electron backscattered diffraction in high purity aluminium and copper, and in copper-bismuth alloys, and were then characterized using the CSL, CAD and I-line (O-lattice) geometrical models. A computer simulation was also performed and compared to the experimental results. Relationships were established between triple junction and grain boundary character distributions using both experimental and computer simulated results. A general trend was observed which shows an increase in special triple junction character density with increasing special grain boundary character content. An increased frequency of low angle and twin boundaries is shown to lead to an increase in the I-line triple junction density.

  1. Morita equivalence and spectral triples on noncommutative orbifolds

    NASA Astrophysics Data System (ADS)

    Harju, Antti J.

    2016-08-01

    Let G be a finite group. Noncommutative geometry of unital G-algebras is studied. A geometric structure is determined by a spectral triple on the crossed product algebra associated with the group action. This structure is to be viewed as a representative of a noncommutative orbifold. Based on a study of classical orbifold groupoids, a Morita equivalence for the crossed product spectral triples is developed. Noncommutative orbifolds are Morita equivalence classes of the crossed product spectral triples. As a special case of this Morita theory one can study freeness of the G-action on the noncommutative level. In the case of a free action, the crossed product formalism reduced to the usual spectral triple formalism on the algebra of G-invariant functions.

  2. 4. DETAIL VIEW OF TRIPLE TONGUE AND GROOVE CRIBBING USED ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    4. DETAIL VIEW OF TRIPLE TONGUE AND GROOVE CRIBBING USED IN DAM CONSTRUCTION, NORTH EAST OF EAST DAM, LOOKING NORTH - Three Bears Lake & Dams, East Dam, North of Marias Pass, East Glacier Park, Glacier County, MT

  3. Triple parton scattering in collinear approximation of perturbative QCD

    NASA Astrophysics Data System (ADS)

    Snigirev, A. M.

    2016-08-01

    Revised formulas for the inclusive cross section of a triple parton scattering process in a hadron collision are suggested based on the modified collinear three-parton distributions. The possible phenomenological issues are discussed.

  4. Kondo effects in triangular triple quantum dots

    NASA Astrophysics Data System (ADS)

    Oguri, Akira; Numata, Takahide; Nisikawa, Yunori; Hewson, A. C.

    2009-03-01

    We study the conductance through a triangular triple quantum dot, which is connected to two noninteracting leads, using the numerical renormalization group (NRG). It is found that the system shows a variety of Kondo effects depending on the filling of the triangle. The SU(4) Kondo effect occurs at half-filling, and a sharp conductance dip due to a phase lapse appears in the gate-voltage dependence. Furthermore, when four electrons occupy the three sites on average, a local S=1 moment, which is caused by the Nagaoka mechanism, is induced along the triangle. The temperature dependence of the entropy and spin susceptibility of the triangle shows that this moment is screened by the conduction electrons via two separate stages at different temperatures. The two-terminal and four-terminal conductances show a clear difference at the gate voltages, where the SU(4) or the S=1 Kondo effects occur[1]. We will also discuss effects of deformations of the triangular configuration, caused by the inhomogeneity in the inter-dot couplings and in the gate voltages. [4pt] [1] T.Numata, Y.Nisikawa, A.Oguri, and A.C.Hewson: arXiv:0808.3496.

  5. Triple jump examinations for dental student assessment.

    PubMed

    Navazesh, Mahvash; Rich, Sandra K; Chopiuk, Nasrin Bahari; Keim, Robert G

    2013-10-01

    The triple jump examination (TJE) attempts to assess a higher level of learning with demand for analysis, critical thinking, and resolution of problems presented by written scenarios based on patient care situations. The purpose of this study was to examine the internal consistency, scale reliability, and interrater reliability of the TJE used at the Ostrow School of Dentistry, University of Southern California. On the sample of 2,227 examinations administered by seventy-seven raters across a three-year time period, the Cronbach's coefficient alpha for internal consistency of the overall TJE was found to be good (a=0.869). The internal consistency of the three subscales was found to be acceptable (a=0.731), good (a=0.820), and good (a=0.820). Average and single measures intraclass correlation coefficients (ICC) for scale reliability were significant at p<0.001, indicating strong interrater reliability. There were no statistically significant differences (p≤0.05) in the mean scores assigned on the TJE between rater groups defined by rater experience level with the TJE. A very high level of agreement among rater pairs was also observed. Across the entire three-year study period, with over 19,152 ratings, the seventy-seven raters were in general agreement 99.5 percent of the time and in exact agreement 77.2 percent of the time.

  6. Double and triple photoionization of Li and Be

    SciTech Connect

    Colgan, J.; Pindzola, M.S.; Robicheaux, F.

    2005-08-15

    We present calculations for the double photoionization (with excitation) and the triple photoionization of Li and Be. We extend and more fully discuss the previous calculations made for Li by Colgan et al. [Phys. Rev. Lett. 93, 053201 (2004)] and present calculations for Be. The Be triple photoionization cross sections are compared with previous double shake-off model calculations of Kheifets and Bray [J. Phys. B 36, L211 (2003)], and our calculations are found to be significantly lower.

  7. Polygonal Triples and the Double Ruling of a Hyperboloid

    ERIC Educational Resources Information Center

    Yiu, Paul

    2012-01-01

    For a given positive integer k [not equal] 4, let "P[subscript k,n]" denote the "n"-th "k"-gonal number. We study "k"-gonal triples ("a", "b", "c") satisfying P[subscript k,a] + P[subscript k,b] = P[subscript k,c]. A "k"-gonal triple corresponds to a rational point on the rectangular hyperboloid x[squared] + y[squared] = z[squared] + 1. The simple…

  8. Neutral triple and quartic gauge couplings at LEP

    NASA Astrophysics Data System (ADS)

    Ofierzynski, R.

    2002-06-01

    The possible existence of neutral triple ZZZ, ZZγ and Zγγ and quartic ZZγγ gauge boson couplings is investigated. Based on data collected at LEP2 at centre-of-mass energies up to 208 GeV no evidence has been found for such couplings. Preliminary limits for neutral triple gauge couplings as obtained from the combination of the LEP experiments are presented.

  9. Triple, simultaneous, very late coronary stent thrombosis.

    PubMed

    Vieira, Miguel Silva; Luz, André; Anjo, Diana; Antunes, Nuno; Santos, Mário; Carvalho, Henrique; Torres, Severo

    2013-03-01

    Coronary artery stent thrombosis is an uncommon but potentially catastrophic complication. The risk of very late stent thrombosis (VLST) raises important safety issues regarding the first generation of drug-eluting stents (DES). Although several complex mechanisms for VLST have been suggested and various predictors have been described, its pathophysiology is not completely understood and it is not known whether longer-term dual antiplatelet therapy reduces the risk. We present a rare case of simultaneous very late DES thrombosis in the three vascular territories, following discontinuation of antiplatelet therapy seven years after stent placement, presenting as cardiogenic shock.

  10. A directional nucleation-zipping mechanism for triple helix formation.

    PubMed

    Alberti, Patrizia; Arimondo, Paola B; Mergny, Jean-Louis; Garestier, Thérèse; Hélène, Claude; Sun, Jian-Sheng

    2002-12-15

    A detailed kinetic study of triple helix formation was performed by surface plasmon resonance. Three systems were investigated involving 15mer pyrimidine oligonucleotides as third strands. Rate constants and activation energies were validated by comparison with thermodynamic values calculated from UV-melting analysis. Replacement of a T.A base pair by a C.G pair at either the 5' or the 3' end of the target sequence allowed us to assess mismatch effects and to delineate the mechanism of triple helix formation. Our data show that the association rate constant is governed by the sequence of base triplets on the 5' side of the triplex (referred to as the 5' side of the target oligopurine strand) and provides evidence that the reaction pathway for triple helix formation in the pyrimidine motif proceeds from the 5' end to the 3' end of the triplex according to the nucleation-zipping model. It seems that this is a general feature for all triple helices formation, probably due to the right-handedness of the DNA double helix that provides a stronger base stacking at the 5' than at the 3' duplex-triplex junction. Understanding the mechanism of triple helix formation is not only of fundamental interest, but may also help in designing better triple helix-forming oligonucleotides for gene targeting and control of gene expression.

  11. Improving species-specific IDMS: the advantages of triple IDMS.

    PubMed

    Frank, Claudia; Rienitz, Olaf; Swart, Claudia; Schiel, Detlef

    2013-02-01

    Triple isotope dilution mass spectrometry (triple IDMS) has been applied for the first time on protein quantification, especially on transferrin. Transferrin as an acute phase protein is a marker for several inflammation processes in the human body. Therefore, in Germany, the accurate and precise measurement of this important analyte is required. In this work, a new approach to triple IDMS is described and compared to double IDMS. Also, complete uncertainty budgets for both methods were set up to demonstrate the ability of this method to be used as a reference procedure. The relative expanded uncertainty (k=2) for triple IDMS (3.6 %) is smaller than the one for double IDMS (4.0 %). The content of transferrin found in the human serum reference material ERM-DA470k/IFCC ((2.41±0.08) g/kg) with both methods was in good agreement with each other and with the certificate. For triple IDMS ((2.426±0.086) g/kg) and for double IDMS ((2.317±0.092) g/kg), transferrin was determined. Although triple IDMS is a little more time consuming compared to double IDMS, there is the advantage that the isotopic composition of the spike material does not have to be determined. This is very useful especially in case of a marginal isotopic enrichment in the spike or problems with the accurate measurement of the spike isotope ratio.

  12. Triple loop heat exchanger for an absorption refrigeration system

    DOEpatents

    Reimann, Robert C.

    1984-01-01

    A triple loop heat exchanger for an absorption refrigeration system is disclosed. The triple loop heat exchanger comprises portions of a strong solution line for conducting relatively hot, strong solution from a generator to a solution heat exchanger of the absorption refrigeration system, conduit means for conducting relatively cool, weak solution from the solution heat exchanger to the generator, and a bypass system for conducting strong solution from the generator around the strong solution line and around the solution heat exchanger to an absorber of the refrigeration system when strong solution builds up in the generator to an undesirable level. The strong solution line and the conduit means are in heat exchange relationship with each other in the triple loop heat exchanger so that, during normal operation of the refrigeration system, heat is exchanged between the relatively hot, strong solution flowing through the strong solution line and the relatively cool, weak solution flowing through the conduit means. Also, the strong solution line and the bypass system are in heat exchange relationship in the triple loop heat exchanger so that if the normal flow path of relatively hot, strong solution flowing from the generator to an absorber is blocked, then this relatively, hot strong solution which will then be flowing through the bypass system in the triple loop heat exchanger, is brought into heat exchange relationship with any strong solution which may have solidified in the strong solution line in the triple loop heat exchanger to thereby aid in desolidifying any such solidified strong solution.

  13. Features of triple-negative breast cancer

    PubMed Central

    Plasilova, Magdalena L.; Hayse, Brandon; Killelea, Brigid K.; Horowitz, Nina R.; Chagpar, Anees B.; Lannin, Donald R.

    2016-01-01

    Abstract The aim of this study was to determine the features of triple-negative breast cancer (TNBC) using a large national database. TNBC is known to be an aggressive subtype, but national epidemiologic data are sparse. All patients with invasive breast cancer and known molecular subtype diagnosed in 2010 to 2011 were identified from the National Cancer Data Base (NCDB). Patients with and without TNBC were compared with respect to their sociodemographic and clinicopathologic features. TNBC was present in 38,628 of 295,801 (13%) female patients compared to 185 of 3136 (6%) male patients (P < 0.001). The incidence of TNBC varied by region from 10.8% in New England to 15.8% in the east south central US (P < 0.001), as well as by race with the highest rates in African-Americans (23.7%), and lowest in Filipino patients (8.9%). The incidence of TNBC also varied by histology, accounting for 76% of metaplastic cancers, but only 2% of infiltrating lobular carcinomas. TNBCs were significantly larger than non-TNBC (mean 2.8 cm vs 2.1 cm, P < 0.001), and more TNBC were poorly differentiated compared to other subtypes (79.7% vs 25.8%, P < 0.001). On univariate analysis, TNBC was no more likely than non-TNBC to have node-positive disease (32.0% vs 31.7%, respectively, P = 0.218) but in a multivariable analysis controlling for tumor size and grade, TNBC was associated with significantly less node-positivity (OR = 0.59; 95% confidence interval [CI]: 0.57–0.60). TNBC has distinct features regarding age, gender, geographic, and racial distribution. Compared to non-TNBC, TNBC is larger and higher grade, but less likely to have lymph node metastases. PMID:27583878

  14. Predicted thermal performance of triple vacuum glazing

    SciTech Connect

    Fang, Yueping; Hyde, Trevor J.; Hewitt, Neil

    2010-12-15

    The simulated triple vacuum glazing (TVG) consists of three 4 mm thick glass panes with two vacuum gaps, with each internal glass surface coated with a low-emittance coating with an emittance of 0.03. The two vacuum gaps are sealed by an indium based sealant and separated by a stainless steel pillar array with a height of 0.12 mm and a pillar diameter of 0.3 mm spaced at 25 mm. The thermal transmission at the centre-of-glazing area of the TVG was predicted to be 0.26 W m{sup -2} K{sup -1}. The simulation results show that although the thermal conductivity of solder glass (1 W m{sup -1} K{sup -1}) and indium (83.7 W m{sup -1} K{sup -1}) are very different, the difference in thermal transmission of TVGs resulting from the use of an indium and a solder glass edge seal was 0.01 W m{sup -2} K{sup -1}. This is because the edge seal is so thin (0.12 mm), consequently there is a negligible temperature drop across it irrespective of the material that the seal is made from relative to the total temperature difference across the glazing. The results also show that there is a relatively large increase in the overall thermal conductance of glazings without a frame when the width of the indium edge seal is increased. Increasing the rebate depth in a solid wood frame decreased the heat transmission of the TVG. The overall heat transmission of the simulated 0.5 m by 0.5 m TVG was 32.6% greater than that of the 1 m by 1 m TVG, since heat conduction through the edge seal of the small glazing has a larger contribution to the total glazing heat transfer than that of the larger glazing system. (author)

  15. The triple-A supply chain.

    PubMed

    Lee, Hau L

    2004-10-01

    Building a strong supply chain is essential for business success. But when it comes to improving their supply chains, few companies take the right approach. Many businesses work to make their chains faster or more cost-effective, assuming that those steps are the keys to competitive advantage. To the contrary: Supply chains that focus on speed and costs tend to deteriorate over time. The author has spent 15 years studying more than 60 companies to gain insight into this and other supply chain dilemmas. His conclusion: Only companies that build supply chains that are agile, adaptable, and aligned get ahead of their rivals. All three components are essential; without any one of them, supply chains break down. Great companies create supply chains that respond to abrupt changes in markets. Agility is critical because in most industries, both demand and supply fluctuate rapidly and widely. Supply chains typically cope by playing speed against costs, but agile ones respond both quickly and cost-efficiently. Great companies also adapt their supply networks when markets or strategies change. The best supply chains allow managers to identify structural shifts early by recording the latest data, filtering out noise, and tracking key patterns. Finally, great companies align the interests of the partners in their supply chains with their own. That's important because every firm is concerned solely with its own interests. If its goals are out of alignment with those of other partners in the supply chain, performance will suffer. When companies hear about the triple-A supply chain, they assume that building one will require increased technology and investment. But most firms already have the infrastructure in place to create one. A fresh attitude alone can go a long way toward making it happen.

  16. Laser speckle strain and deformation sensor using linear array image cross-correlation method for specifically arranged triple-beam triple-camera configuration

    NASA Technical Reports Server (NTRS)

    Sarrafzadeh-Khoee, Adel K. (Inventor)

    2000-01-01

    The invention provides a method of triple-beam and triple-sensor in a laser speckle strain/deformation measurement system. The triple-beam/triple-camera configuration combined with sequential timing of laser beam shutters is capable of providing indications of surface strain and structure deformations. The strain and deformation quantities, the four variables of surface strain, in-plane displacement, out-of-plane displacement and tilt, are determined in closed form solutions.

  17. Inhibition of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin

    SciTech Connect

    Wang, Feng; Yang, Yong

    2014-11-21

    Highlights: • Suppression of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin. • Repression of PKM2 affects the glycolysis and decreases ATP production. • Downregulation of PKM2 increases the intracellular accumulation of doxorubicin. • Inhibition of PKM2 enhances the antitumor efficacy of doxorubicin in vivo. - Abstract: Cancer cells alter regular metabolic pathways in order to sustain rapid proliferation. One example of metabolic remodeling in cancerous tissue is the upregulation of pyruvate kinase isoenzyme M2 (PKM2), which is involved in aerobic glycolysis. Indeed, PKM2 has previously been identified as a tumor biomarker and as a potential target for cancer therapy. Here, we examined the effects of combined treatment with doxorubicin and anti-PKM2 small interfering RNA (siRNA) on triple-negative breast cancer (TNBC). The suppression of PKM2 resulted in changes in glucose metabolism, leading to decreased synthesis of adenosine triphosphate (ATP). Reduced levels of ATP resulted in the intracellular accumulation of doxorubicin, consequently enhancing the therapeutic efficacy of this drug in several triple-negative breast cancer cell lines. Furthermore, the combined effect of PKM2 siRNA and doxorubicin was evaluated in an in vivo MDA-MB-231 orthotopic breast cancer model. The siRNA was systemically administered through a polyethylenimine (PEI)-based delivery system that has been extensively used. We demonstrate that the combination treatment showed superior anticancer efficacy as compared to doxorubicin alone. These findings suggest that targeting PKM2 can increase the efficacy of chemotherapy, potentially providing a new approach for improving the outcome of chemotherapy in patients with TNBC.

  18. Collagenolytic Matrix Metalloproteinase Activities toward Peptomeric Triple-Helical Substrates.

    PubMed

    Stawikowski, Maciej J; Stawikowska, Roma; Fields, Gregg B

    2015-05-19

    Although collagenolytic matrix metalloproteinases (MMPs) possess common domain organizations, there are subtle differences in their processing of collagenous triple-helical substrates. In this study, we have incorporated peptoid residues into collagen model triple-helical peptides and examined MMP activities toward these peptomeric chimeras. Several different peptoid residues were incorporated into triple-helical substrates at subsites P3, P1, P1', and P10' individually or in combination, and the effects of the peptoid residues were evaluated on the activities of full-length MMP-1, MMP-8, MMP-13, and MMP-14/MT1-MMP. Most peptomers showed little discrimination between MMPs. However, a peptomer containing N-methyl Gly (sarcosine) in the P1' subsite and N-isobutyl Gly (NLeu) in the P10' subsite was hydrolyzed efficiently only by MMP-13 [nomenclature relative to the α1(I)772-786 sequence]. Cleavage site analysis showed hydrolysis at the Gly-Gln bond, indicating a shifted binding of the triple helix compared to the parent sequence. Favorable hydrolysis by MMP-13 was not due to sequence specificity or instability of the substrate triple helix but rather was based on the specific interactions of the P7' peptoid residue with the MMP-13 hemopexin-like domain. A fluorescence resonance energy transfer triple-helical peptomer was constructed and found to be readily processed by MMP-13, not cleaved by MMP-1 and MMP-8, and weakly hydrolyzed by MT1-MMP. The influence of the triple-helical structure containing peptoid residues on the interaction between MMP subsites and individual substrate residues may provide additional information about the mechanism of collagenolysis, the understanding of collagen specificity, and the design of selective MMP probes.

  19. Pursuing the Triple Aim: The First 7 Years

    PubMed Central

    Whittington, John W; Nolan, Kevin; Lewis, Ninon; Torres, Trissa

    2015-01-01

    Context In 2008, researchers at the Institute for Healthcare Improvement (IHI) described the Triple Aim as simultaneously “improving the individual experience of care; improving the health of populations; and reducing the per capita costs of care for populations.” IHI and its close colleagues had determined that both individual and societal changes were needed. Methods In 2007, IHI began recruiting organizations from around the world to participate in a collaborative to implement what became known as the Triple Aim. The 141 participating organizations included health care systems, hospitals, health care insurance companies, and others closely tied to health care. In addition, key groups outside the health care system were represented, such as public health agencies, social services groups, and community coalitions. This collaborative provided a structure for observational research. By noting the contrasts between the contexts and structures of those sites in the collaborative that progressed and those that did not, we were able to develop an ex post theory of what is needed for an organization or community to successfully pursue the Triple Aim. Findings Drawing on our 7 years of experience, we describe the 3 major principles that guided the organizations and communities working on the Triple Aim: creating the right foundation for population management, managing services at scale for the population, and establishing a learning system to drive and sustain the work over time. Conclusions The concept of the Triple Aim is now widely used, because of IHI's work with many organizations and also because of the adoption of the Triple Aim as part of the national strategy for US health care, developed during the implementation of the Patient Protection and Affordable Care Act of 2010. Even those organizations working on the Triple Aim before IHI coined the term found our concept to be useful because it helped them think about all 3 dimensions at once and organize their

  20. Role of metronidazole resistance in therapy of Helicobacter pylori infections.

    PubMed Central

    Rautelin, H; Seppälä, K; Renkonen, O V; Vainio, U; Kosunen, T U

    1992-01-01

    Susceptibility to metronidazole was determined by disk diffusion tests for 559 strains of Helicobacter pylori isolated from patients. The overall metronidazole resistance was 26%. In males metronidazole-resistant strains made 18% of all H. pylori strains, and in females the corresponding figure was 40% (P less than 0.001). MICs of metronidazole were determined for H. pylori strains from 86 patients undertaking triple therapy, i.e., treatment with colloidal bismuth subcitrate, amoxicillin, and metronidazole. Of the nonresponders who remained culture positive despite the therapy, 69% had strains with metronidazole MICs of greater than or equal to 32 micrograms/ml before the therapy, and all nonresponders had metronidazole-resistant strains after the therapy. Metronidazole resistance was, however, also found in 27% of responders before therapy. To find whether the MICs of metronidazole for H. pylori strains remained constant for longer periods, consecutive isolates sampled several years apart from the same patients were tested in parallel and no changes in the MICs were found. H. pylori was successfully eradicated by the triple therapy from 91% of patients with metronidazole-susceptible pretreatment strains and from 63% of patients with metronidazole-resistant strains before the therapy (P less than 0.01). Although resistance to metronidazole has a significant role in treatment failures in H. pylori infections, high eradication rates can be achieved with the use of the present triple therapy even in populations with a high overall metronidazole resistance rate. PMID:1590683

  1. Comparative genotyping of the Saccharomyces cerevisiae laboratory strains S288C and CEN.PK113-7D using oligonucleotide microarrays.

    PubMed

    Daran-Lapujade, Pascale; Daran, Jean Marc; Kötter, Peter; Petit, Thomas; Piper, Matthew D W; Pronk, Jack T

    2003-12-01

    To analyse the reliability and accuracy of genotype analysis with high-density oligonucleotide microarrays, this method and other experimental approaches were used to analyse genomic DNA of two popular Saccharomyces cerevisiae laboratory strains. S288C was used for systematic sequencing of 'the' S. cerevisiae genome; CEN.PK113-7D is a popular strain for physiological studies and functional genomics. Random amplified polymorphic DNA, electrophoretic karyotyping and microarray analysis all indicated a high level of sequence similarity between the two strains. In the microarray analysis, as few as 288 (4.5%) of the ca. 6300 represented yeast genes were identified that yielded significantly different hybridisation intensities between the two strains. These could be classified as amplified, absent, or with sequence polymorphism in CEN.PK113-7D compared to S288C. A detailed analysis focused on the subset of 25 genes called absent in CEN.PK113-7D. Among these absent genes, 17 were clustered together on five chromosomes, mainly in subtelomeric regions. Thorough analysis of these regions by polymerase chain reaction (PCR) and restriction fragment length polymorphism confirmed the absence of these genes in CEN.PK113-7D. Surprisingly, three of these regions were not smaller in CEN.PK113-7D chromosomes, indicating that they may harbour unidentified and potentially new sequences. In addition, eight genes called absent by the microarrays were scattered over the chromosomes. Using diagnostic PCR most of these genes were actually found to be present in CEN.PK113-7D, but after sequencing were found to differ significantly at the DNA level from S288C, explaining the poor hybridisation to the arrays. Our results indicate that DNA microarrays are a powerful tool for determining genotypic similarity between different yeast strains. However, to obtain meaningful information at the individual gene level, this method should be backed up by additional techniques.

  2. Potentiation of human papilloma vaccine candidate using naloxone/alum mixture as an adjuvant: increasing immunogenicity of HPV-16E7d vaccine

    PubMed Central

    Yasaghi, Mahsa; Mahdavi, Mehdi

    2016-01-01

    Objective(s): Many types of human papillomaviruses (HPVs) have been identified, with some leading to cancer and others to skin lesions such as anogenital warts. Studies have demonstrated an association between oncogenic HPV and cervical cancer and many researchers have focused on therapeutic vaccines development. At present, the modulatory effect of opioids on the innate and acquired immune system is characterized. Antagonists of opioid receptors such as naloxone (NLX) can contribute to the shifting Th2 response toward Th1. Herein; we studied the adjuvant activity of NLX/Alum mixture for improvement of the immunogenicity of HPV-16E7d vaccine. Materials and Methods: The mice were administered different regimens of vaccine; E7d, E7d-NLX, E7d-Alum, E7d-NLX-Alum, NLX, alum and PBS via subcutaneous route for three times with two weeks interval. Two weeks after the last immunization, the sera were assessed for total antibody, IgG1 and IgG2a with an optimized ELISA method. The splenocytes culture supernatant was analyzed by ELISA for the presence of IL-4, IFN-γ and IL-17 cytokines and lymphocyte proliferation was evaluated with Brdu method. Results: Immunization of mice with HPV-16 E7d vaccine formulated in NLX/Alum mixture significantly increased lymphocyte proliferation and Th1 and Th17 cytokines responses compared to other experimental groups. Analysis of humoral immune responses revealed that administration of vaccine with NLX/Alum mixture significantly increased specific IgG responses and also isotypes compared to control groups. Conclusion: NLX/Alum mixture as an adjuvant could improve cellular and humoral immune responses and the adjuvant maybe useful for HPV vaccines model for further studies in human clinical trial. PMID:27803788

  3. AAA-DDD triple hydrogen bond complexes.

    PubMed

    Blight, Barry A; Camara-Campos, Amaya; Djurdjevic, Smilja; Kaller, Martin; Leigh, David A; McMillan, Fiona M; McNab, Hamish; Slawin, Alexandra M Z

    2009-10-01

    Experiment and theory both suggest that the AAA-DDD pattern of hydrogen bond acceptors (A) and donors (D) is the arrangement of three contiguous hydrogen bonding centers that results in the strongest association between two species. Murray and Zimmerman prepared the first example of such a system (complex 3*2) and determined the lower limit of its association constant (K(a)) in CDCl(3) to be 10(5) M(-1) by (1)H NMR spectroscopy (Murray, T. J. and Zimmerman, S. C. J. Am. Chem. Soc. 1992, 114, 4010-4011). The first cationic AAA-DDD pair (3*4(+)) was described by Bell and Anslyn (Bell, D. A. and Anslyn, E. A. Tetrahedron 1995, 51, 7161-7172), with a K(a) > 5 x 10(5) M(-1) in CH(2)Cl(2) as determined by UV-vis spectroscopy. We were recently able to quantify the strength of a neutral AAA-DDD arrangement using a more chemically stable AAA-DDD system, 6*2, which has an association constant of 2 x 10(7) M(-1) in CH(2)Cl(2) (Djurdjevic, S., Leigh, D. A., McNab, H., Parsons, S., Teobaldi, G. and Zerbetto, F. J. Am. Chem. Soc. 2007, 129, 476-477). Here we report on further AA(A) and DDD partners, together with the first precise measurement of the association constant of a cationic AAA-DDD species. Complex 6*10(+)[B(3,5-(CF(3))(2)C(6)H(3))(4)(-)] has a K(a) = 3 x 10(10) M(-1) at RT in CH(2)Cl(2), by far the most strongly bound triple hydrogen bonded system measured to date. The X-ray crystal structure of 6*10(+) with a BPh(4)(-) counteranion shows a planar array of three short (NH...N distances 1.95-2.15 A), parallel (but staggered rather than strictly linear; N-H...N angles 165.4-168.8 degrees), primary hydrogen bonds. These are apparently reinforced, as theory predicts, by close electrostatic interactions (NH-*-N distances 2.78-3.29 A) between each proton and the acceptor atoms of the adjacent primary hydrogen bonds.

  4. The impoverished gut--a triple burden of diarrhoea, stunting and chronic disease.

    PubMed

    Guerrant, Richard L; DeBoer, Mark D; Moore, Sean R; Scharf, Rebecca J; Lima, Aldo A M

    2013-04-01

    More than one-fifth of the world's population live in extreme poverty, where a lack of safe water and adequate sanitation enables high rates of enteric infections and diarrhoea to continue unabated. Although oral rehydration therapy has greatly reduced diarrhoea-associated mortality, enteric infections still persist, disrupting intestinal absorptive and barrier functions and resulting in up to 43% of stunted growth, affecting one-fifth of children worldwide and one-third of children in developing countries. Diarrhoea in children from impoverished areas during their first 2 years might cause, on average, an 8 cm growth shortfall and 10 IQ point decrement by the time they are 7-9 years old. A child's height at their second birthday is therefore the best predictor of cognitive development or 'human capital'. To this 'double burden' of diarrhoea and malnutrition, data now suggest that children with stunted growth and repeated gut infections are also at increased risk of developing obesity and its associated comorbidities, resulting in a 'triple burden' of the impoverished gut. Here, we Review the growing evidence for this triple burden and potential mechanisms and interventions that must be understood and applied to prevent the loss of human potential and unaffordable societal costs caused by these vicious cycles of poverty.

  5. CDK7-Dependent Transcriptional Addiction in Triple-Negative Breast Cancer

    PubMed Central

    Wang, Yubao; Zhang, Tinghu; Kwiatkowski, Nicholas; Abraham, Brian J.; Lee, Tong Ihn; Xie, Shaozhen; Yuzugullu, Haluk; Von, Thanh; Li, Heyuan; Lin, Ziao; Stover, Daniel G.; Lim, Elgene; Wang, Zhigang C.; Iglehart, J. Dirk; Young, Richard A.; Gray, Nathanael S.; Zhao, Jean J.

    2015-01-01

    SUMMARY Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing kinase inhibitors and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not hormone receptor-positive breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of TNBC-specific genes is especially sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be a useful therapy for this challenging cancer. PMID:26406377

  6. The impoverished gut—a triple burden of diarrhoea, stunting and chronic disease

    PubMed Central

    Guerrant, Richard L.; DeBoer, Mark D.; Moore, Sean R.; Scharf, Rebecca J.; Lima, Aldo A. M.

    2013-01-01

    More than one-fifth of the world’s population live in extreme poverty, where a lack of safe water and adequate sanitation enables high rates of enteric infections and diarrhoea to continue unabated. Although oral rehydration therapy has greatly reduced diarrhoea-associated mortality, enteric infections still persist, disrupting intestinal absorptive and barrier functions and resulting in up to 43% of stunted growth, affecting one-fifth of children worldwide and one-third of children in developing countries. Diarrhoea in children from impoverished areas during their first 2 years might cause, on average, an 8 cm growth shortfall and 10 IQ point decrement by the time they are 7–9 years old. A child’s height at their second birthday is therefore the best predictor of cognitive development or ‘human capital’. To this ‘double burden’ of diarrhoea and malnutrition, data now suggest that children with stunted growth and repeated gut infections are also at increased risk of developing obesity and its associated comorbidities, resulting in a ‘triple burden’ of the impoverished gut. Here, we Review the growing evidence for this triple burden and potential mechanisms and interventions that must be understood and applied to prevent the loss of human potential and unaffordable societal costs caused by these vicious cycles of poverty. PMID:23229327

  7. Polymer-Coated Hollow Mesoporous Silica Nanoparticles for Triple-Responsive Drug Delivery.

    PubMed

    Zhang, Yuanyuan; Ang, Chung Yen; Li, Menghuan; Tan, Si Yu; Qu, Qiuyu; Luo, Zhong; Zhao, Yanli

    2015-08-19

    In this study, pH, reduction and light triple-responsive nanocarriers based on hollow mesoporous silica nanoparticles (HMSNs) modified with poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) were developed via surface-initiated atom transfer radical polymerization. Both reduction-cleavable disulfide bond and light-cleavable o-nitrobenzyl ester were used as the linkages between HMSNs and pH-sensitive PDEAEMA polymer caps. A series of characterization techniques were applied to characterize and confirm the structures of the intermediates and final nanocarriers. Doxorubicin (DOX) was easily encapsulated into the nanocarriers with a high loading capacity, and quickly released in response to the stimuli of reducing agent, acid environment or UV light irradiation. In addition, flow cytometry analysis, confocal laser scanning microscopy observations and cytotoxicity studies indicated that the nanocarriers were efficiently internalized by HeLa cancer cells, exhibiting (i) enhanced release of DOX into the cytoplasm under external UV light irradiation, (ii) better cytotoxicity against HeLa cells, and (iii) superior control over drug delivery and release. Thus, the triple-responsive nanocarriers present highly promising potentials as a drug delivery platform for cancer therapy. PMID:26221866

  8. Development of 600 kV triple resonance pulse transformer.

    PubMed

    Li, Mingjia; Zhang, Faqiang; Liang, Chuan; Xu, Zhou

    2015-06-01

    In this paper, a triple-resonance pulse transformer based on an air-core transformer is introduced. The voltage across the high-voltage winding of the air-core transformer is significantly less than the output voltage; instead, the full output voltage appears across the tuning inductor. The maximum ratio of peak load voltage to peak transformer voltage is 2.77 in theory. By analyzing pulse transformer's lossless circuit, the analytical expression for the output voltage and the characteristic equation of the triple-resonance circuit are presented. Design method for the triple-resonance pulse transformer (iterated simulation method) is presented, and a triple-resonance pulse transformer is developed based on the existing air-core transformer. The experimental results indicate that the maximum ratio of peak voltage across the load to peak voltage across the high-voltage winding of the air-core transformer is approximately 2.0 and the peak output voltage of the triple-resonance pulse transformer is approximately 600 kV.

  9. Triple-star Candidates among the Kepler Binaries

    NASA Astrophysics Data System (ADS)

    Rappaport, S.; Deck, K.; Levine, A.; Borkovits, T.; Carter, J.; El Mellah, I.; Sanchis-Ojeda, R.; Kalomeni, B.

    2013-05-01

    We present the results of a search through the photometric database of Kepler eclipsing binaries looking for evidence of hierarchical triple-star systems. The presence of a third star orbiting the binary can be inferred from eclipse timing variations. We apply a simple algorithm in an automated determination of the eclipse times for all 2157 binaries. The "calculated" eclipse times, based on a constant period model, are subtracted from those observed. The resulting O - C (observed minus calculated times) curves are then visually inspected for periodicities in order to find triple-star candidates. After eliminating false positives due to the beat frequency between the ~1/2 hr Kepler cadence and the binary period, 39 candidate triple systems were identified. The periodic O - C curves for these candidates were then fit for contributions from both the classical Roemer delay and so-called physical delay, in an attempt to extract a number of the system parameters of the triple. We discuss the limitations of the information that can be inferred from these O - C curves without further supplemental input, e.g., ground-based spectroscopy. Based on the limited range of orbital periods for the triple-star systems to which this search is sensitive, we can extrapolate to estimate that at least 20% of all close binaries have tertiary companions.

  10. TRIPLE-STAR CANDIDATES AMONG THE KEPLER BINARIES

    SciTech Connect

    Rappaport, S.; Deck, K.; Sanchis-Ojeda, R.; Levine, A.; Borkovits, T.; Carter, J.; El Mellah, I.; Kalomeni, B. E-mail: kdeck@mit.edu E-mail: aml@space.mit.edu E-mail: jacarter@cfa.harvard.edu

    2013-05-01

    We present the results of a search through the photometric database of Kepler eclipsing binaries looking for evidence of hierarchical triple-star systems. The presence of a third star orbiting the binary can be inferred from eclipse timing variations. We apply a simple algorithm in an automated determination of the eclipse times for all 2157 binaries. The ''calculated'' eclipse times, based on a constant period model, are subtracted from those observed. The resulting O - C (observed minus calculated times) curves are then visually inspected for periodicities in order to find triple-star candidates. After eliminating false positives due to the beat frequency between the {approx}1/2 hr Kepler cadence and the binary period, 39 candidate triple systems were identified. The periodic O - C curves for these candidates were then fit for contributions from both the classical Roemer delay and so-called physical delay, in an attempt to extract a number of the system parameters of the triple. We discuss the limitations of the information that can be inferred from these O - C curves without further supplemental input, e.g., ground-based spectroscopy. Based on the limited range of orbital periods for the triple-star systems to which this search is sensitive, we can extrapolate to estimate that at least 20% of all close binaries have tertiary companions.

  11. Probiotics for standard triple Helicobacter pylori eradication: a randomized, double-blind, placebo-controlled trial.

    PubMed

    Hauser, Goran; Salkic, Nermin; Vukelic, Karina; JajacKnez, Alenka; Stimac, Davor

    2015-05-01

    The primary objective in the study is determination of efficacy of probiotic preparation as a supportive therapy in eradication of Helicobacter pylori.The study was multicenter, prospective, randomized, placebo controlled, and double-blind. The subjects first filled out a specially designed questionnaire to assess the severity of the 10 symptoms, which can be related to eradication therapy to be monitored during the trial. Each subject then received 28 capsules of probiotic preparation or matching placebo capsules, which they were supposed to take over the following 14 days, twice a day, at least 2 hours prior to or after the antibiotic therapy administration.A total of 804 patients were enrolled in the trial, of which 650 (80.85%) were included in the analysis. The results show a significantly larger share of cured subjects in the probiotic arm versus the placebo arm (87.38% vs 72.55%; P < 0.001). Additionally, presence and intensity of epigastric pain, bloating, flatulence, taste disturbance, loss of appetite, nausea, vomiting, heartburn, rash, and diarrhea were monitored over the study period. At 15 days postinclusion, probiotic treatment was found superior to placebo in 7 of 10 mentioned symptoms. Average intensity for symptoms potentially related to antibiotic therapy was significantly higher in the placebo group, 0.76 vs 0.55 (P < 0.001).Adding probiotics to the standard triple therapy for H pylori eradication significantly contributes to treatment efficacy and distinctly decreases the adverse effects of therapy and the symptoms of the underlying disease.

  12. Numerical Study of Buoyancy and Differential Diffusion Effects on the Structure and Dynamics of Triple Flames

    NASA Technical Reports Server (NTRS)

    Chen, J. -Y.; Echekki, T.

    1999-01-01

    Triple flames arise in a number of practical configurations where fuel and oxidizer are partially premixed, such as in the base of a lifted jet flame. Past experimental studies, theoretical analyses, and numerical modeling of triple flames suggested the potential role of triple flames in stabilizing turbulent flames and in promoting flame propagation. From recent numerical simulations of laminar triple flames, a strong influence of differential diffusion among species and heat on the triple flame structure has been gradually appreciated. This paper reports preliminary numerical results on the influence of gravity and differential diffusion effects on the structure and dynamics of triple flames with a one-step global irreversible chemistry model.

  13. THE ALGOL TRIPLE SYSTEM SPATIALLY RESOLVED AT OPTICAL WAVELENGTHS

    SciTech Connect

    Zavala, R. T.; Hutter, D. J.; Hummel, C. A.; Boboltz, D. A.; Ojha, R.; Shaffer, D. B.; Tycner, C.; Richards, M. T. E-mail: djh@nofs.navy.mi E-mail: dboboltz@usno.navy.mi E-mail: shaffer@alumni.caltech.ed E-mail: mrichards@astro.psu.ed

    2010-05-20

    Interacting binaries typically have separations in the milliarcsecond regime, and hence it has been challenging to resolve them at any wavelength. However, recent advances in optical interferometry have improved our ability to discern the components in these systems and have now enabled the direct determination of physical parameters. We used the Navy Prototype Optical Interferometer to produce for the first time images resolving all three components in the well-known Algol triple system. Specifically, we have separated the tertiary component from the binary and simultaneously resolved the eclipsing binary pair, which represents the nearest and brightest eclipsing binary in the sky. We present revised orbital elements for the triple system, and we have rectified the 180{sup 0} ambiguity in the position angle of Algol C. Our directly determined magnitude differences and masses for this triple star system are consistent with earlier light curve modeling results.

  14. Triple and quartic gauge couplings at LEP 2

    NASA Astrophysics Data System (ADS)

    Brunelière, R.

    We review the status of published and preliminary measurements of triple and quartic gauge boson couplings from the four LEP experiments. Charged current triple gauge boson couplings (WWZ and WWγ) are measured using W-pair, single-W and single-γ productions with the data collected between 1997 and 2000 (700\\ pb-1 per experiment). Neutral current triple gauge boson couplings are studied with Zγ (Zγγ* and ZγZ* vertices) and ZZ (ZZγ* and ZZZ* vertices) events. Limits on anomalous quartic gauge boson couplings with at least one photon (WWγγ, WWZγ and ZZγγ) are set from WWγ, q¯ {q}γ γ and ν ¯ {ν }γ γ events. No strong deviations from the Standard Model expectations are found.

  15. Mesoscopic resonating valence bond system on a triple dot.

    PubMed

    Le Hur, Karyn; Recher, Patrik; Dupont, Emilie; Loss, Daniel

    2006-03-17

    We theoretically introduce a mesoscopic pendulum from a triple dot. The pendulum is fastened through a singly occupied dot (spin qubit). Two other strongly capacitively coupled islands form a double-dot charge qubit with one electron in excess oscillating between the two low-energy charge states (1,0) and (0,1). The triple dot is placed between two superconducting leads. Under realistic conditions, the main proximity effect stems from the injection of resonating singlet (valence) bonds on the triple dot. This gives rise to a Josephson current that is charge- and spin-dependent and, as a consequence, exhibits a distinct resonance as a function of the superconducting phase difference. PMID:16605773

  16. Differential cytotoxic and radiosensitizing effects of silver nanoparticles on triple-negative breast cancer and non-triple-negative breast cells

    PubMed Central

    Swanner, Jessica; Mims, Jade; Carroll, David L; Akman, Steven A; Furdui, Cristina M; Torti, Suzy V; Singh, Ravi N

    2015-01-01

    Identification of differential sensitivity of cancer cells as compared to normal cells has the potential to reveal a therapeutic window for the use of silver nanoparticles (AgNPs) as a therapeutic agent for cancer therapy. Exposure to AgNPs is known to cause dose-dependent toxicities, including induction of oxidative stress and DNA damage, which can lead to cell death. Triple-negative breast cancer (TNBC) subtypes are more vulnerable to agents that cause oxidative stress and DNA damage than are other breast cancer subtypes. We hypothesized that TNBC may be susceptible to AgNP cytotoxicity, a potential vulnerability that could be exploited for the development of new therapeutic agents. We show that AgNPs are highly cytotoxic toward TNBC cells at doses that have little effect on nontumorigenic breast cells or cells derived from liver, kidney, and monocyte lineages. AgNPs induced more DNA and oxidative damage in TNBC cells than in other breast cells. In vitro and in vivo studies showed that AgNPs reduce TNBC growth and improve radiation therapy. These studies show that unmodified AgNPs act as a self-therapeutic agent with a combination of selective cytotoxicity and radiation dose-enhancement effects in TNBC at doses that are nontoxic to noncancerous breast and other cells. PMID:26185437

  17. Adjuvant systemic treatment for individual patients with triple negative breast cancer.

    PubMed

    Oakman, Catherine; Moretti, Erica; Galardi, Francesca; Biagioni, Chiara; Santarpia, Libero; Biganzoli, Laura; Di Leo, Angelo

    2011-10-01

    Chemotherapy is the only evidence based adjuvant systemic treatment option in triple negative breast cancer (TNBC). Despite emerging results for targeted biological therapies for this subpopulation, lack of robust results does not currently support their use beyond the confines of a clinical trial. Conventional systemic chemotherapy remains the standard of care and is curative in a minority of patients. There is no defined standard chemotherapy and there is currently no robust, prospective, randomized data to advise different use of specific chemotherapy agents in TNBC as compared to non-TNBC. Data suggest high sensitivity to chemotherapy, however it is yet to be determined whether this increased sensitivity is agent/regimen specific or whether it reflects general chemosensitivity. This review will focus on systemic chemotherapy in early TNBC, particularly anthracyclines and platinums, and potential predictive tools to guide chemotherapy use. PMID:22015281

  18. "Targeting" triple-negative breast cancer: the lessons learned from BRCA1-associated breast cancers.

    PubMed

    Nanda, Rita

    2011-04-01

    Breast cancer has long been recognized as a heterogeneous entity, with distinct subsets characterized by differences in tumor biology and response to therapy. With the advent of molecular profiling, we have gained a further appreciation of the heterogeneity of this complex disease. While the last decade has seen advances in the treatment of hormone receptor (HR) and human epidermal growth factor receptor 2/erb-B2 (HER2)-positive breast cancers, outcomes for women with estrogen receptor (ER)-, progesterone receptor (PR)-, and HER2-negative-or "triple-negative"-breast cancer (TNBC) remain poor. A better understanding of the shared biology of BRCA1-associated breast cancer and sporadic TNBC holds much promise for changing the outlook for women with this aggressive disease. This review focuses on our current understanding of the clinicopathological features of TNBC, therapeutic options and ongoing research efforts.

  19. CRITICAL CURVES AND CAUSTICS OF TRIPLE-LENS MODELS

    SciTech Connect

    Daněk, Kamil; Heyrovský, David E-mail: heyrovsky@utf.mff.cuni.cz

    2015-06-10

    Among the 25 planetary systems detected up to now by gravitational microlensing, there are two cases of a star with two planets, and two cases of a binary star with a planet. Other, yet undetected types of triple lenses include triple stars or stars with a planet with a moon. The analysis and interpretation of such events is hindered by the lack of understanding of essential characteristics of triple lenses, such as their critical curves and caustics. We present here analytical and numerical methods for mapping the critical-curve topology and caustic cusp number in the parameter space of n-point-mass lenses. We apply the methods to the analysis of four symmetric triple-lens models, and obtain altogether 9 different critical-curve topologies and 32 caustic structures. While these results include various generic types, they represent just a subset of all possible triple-lens critical curves and caustics. Using the analyzed models, we demonstrate interesting features of triple lenses that do not occur in two-point-mass lenses. We show an example of a lens that cannot be described by the Chang–Refsdal model in the wide limit. In the close limit we demonstrate unusual structures of primary and secondary caustic loops, and explain the conditions for their occurrence. In the planetary limit we find that the presence of a planet may lead to a whole sequence of additional caustic metamorphoses. We show that a pair of planets may change the structure of the primary caustic even when placed far from their resonant position at the Einstein radius.

  20. A piecewise linear approach to volume tracking a triple point

    NASA Astrophysics Data System (ADS)

    Choi, Benjamin Y.; Bussmann, Markus

    2007-02-01

    An approach to volume tracking three materials is presented that, in contrast with the so-called onion-skin methodology, assumes the existence of a triple point at which two interfaces between three materials intersect. The reconstruction of any cell that contains three materials is iterative: the approach is to locate a point of intersection between two interfaces that minimizes a given error expression. The advantages and limitations of the algorithm are presented via a series of advection tests that demonstrate that triple points can be reconstructed and advected just as well as simpler interfaces in typical applications.

  1. Gas turbine bottoming cycles: Triple-pressure steam versus Kalina

    SciTech Connect

    Marston, C.H.; Hyre, M.

    1995-01-01

    The performance of a triple-pressure steam cycle has been compared with a single-stage Kalina cycle and an optimized three-stage Kalina cycle as the bottoming sections of a gas turbine combined cycle power plant. A Monte Carlo direct search was used to find the optimum separator temperature and ammonia mass fraction for the three-stage Kalina cycle for a specific plant configuration. Both Kalina cycles were more efficient than the triple pressure steam cycle. Optimization of the three-stage Kalina cycle resulted in almost a two percentage point improvement.

  2. Non-resonant triple alpha reaction rate at low temperature

    SciTech Connect

    Itoh, T.; Tamii, A.; Aoi, N.; Fujita, H.; Hashimoto, T.; Miki, K.; Ogata, K.; Carter, J.; Donaldson, L.; Sideras-Haddad, E.; Furuno, T.; Kawabata, T.; Kamimura, M.; Nemulodi, F.; Neveling, R.; Smit, F. D.; Swarts, C.

    2014-05-02

    Our experimental goal is to study the non-resonant triple alpha reaction rate at low temperture (T < 10{sup 8} K). The {sup 13}C(p,d) reaction at 66 MeV has been used to probe the alpha-unbound continuum state in {sup 12}C just below the 2{sup nd} 0{sup +} state at 7.65 MeV. The transition strength to the continuum state is predicted to be sensitive to the non-resonant triple alpha reaction rate. The experiment has been performed at iThemba LABS. We report the present status of the experiment.

  3. Triple-mode squeezing with dressed six-wave mixing.

    PubMed

    Wen, Feng; Li, Zepei; Zhang, Yiqi; Gao, Hong; Che, Junling; Che, Junling; Abdulkhaleq, Hasan; Zhang, Yanpeng; Wang, Hongxing

    2016-05-12

    The theory of proof-of-principle triple-mode squeezing is proposed via spontaneous parametric six-wave mixing process in an atomic-cavity coupled system. Special attention is focused on the role of dressed state and nonlinear gain on triple-mode squeezing process. Using the dressed state theory, we find that optical squeezing and Autler-Towns splitting of cavity mode can be realized with nonlinear gain, while the efficiency and the location of maximum squeezing point can be effectively shaped by dressed state in atomic ensemble. Our proposal can find applications in multi-channel communication and multi-channel quantum imaging.

  4. Triple-mode squeezing with dressed six-wave mixing

    PubMed Central

    Wen, Feng; Li, Zepei; Zhang, Yiqi; Gao, Hong; Che, Junling; Che, Junling; Abdulkhaleq, Hasan; Zhang, Yanpeng; Wang, Hongxing

    2016-01-01

    The theory of proof-of-principle triple-mode squeezing is proposed via spontaneous parametric six-wave mixing process in an atomic-cavity coupled system. Special attention is focused on the role of dressed state and nonlinear gain on triple-mode squeezing process. Using the dressed state theory, we find that optical squeezing and Autler-Towns splitting of cavity mode can be realized with nonlinear gain, while the efficiency and the location of maximum squeezing point can be effectively shaped by dressed state in atomic ensemble. Our proposal can find applications in multi-channel communication and multi-channel quantum imaging. PMID:27169878

  5. Lack of evidence for KRAS oncogenic mutations in triple-negative breast cancer

    PubMed Central

    2010-01-01

    Background Mutational analysis of the KRAS gene has recently been established as a complementary in vitro diagnostic tool for the identification of patients with colorectal cancer who will not benefit from anti-epidermal growth factor receptor (EGFR) therapies. Assessment of the mutation status of KRAS might also be of potential relevance in other EGFR-overexpressing tumors, such as those occurring in breast cancer. Although KRAS is mutated in only a minor fraction of breast tumors (5%), about 60% of the basal-like subtype express EGFR and, therefore could be targeted by EGFR inhibitors. We aimed to study the mutation frequency of KRAS in that subtype of breast tumors to provide a molecular basis for the evaluation of anti-EGFR therapies. Methods Total, genomic DNA was obtained from a group of 35 formalin-fixed paraffin-embedded, triple-negative breast tumor samples. Among these, 77.1% (27/35) were defined as basal-like by immunostaining specific for the established surrogate markers cytokeratin (CK) 5/6 and/or EGFR. KRAS mutational status was determined in the purified DNA samples by Real Time (RT)-PCR using primers specific for the detection of wild-type KRAS or the following seven oncogenic somatic mutations: Gly12Ala, Gly12Asp, Gly12Arg, Gly12Cys, Gly12Ser, Gly12Val and Gly13Asp. Results We found no evidence of KRAS oncogenic mutations in all analyzed tumors. Conclusions This study indicates that KRAS mutations are very infrequent in triple-negative breast tumors and that EGFR inhibitors may be of potential benefit in the treatment of basal-like breast tumors, which overexpress EGFR in about 60% of all cases. PMID:20385028

  6. miRNAs and Other Epigenetic Changes as Biomarkers in Triple Negative Breast Cancer

    PubMed Central

    Mathe, Andrea; Scott, Rodney J.; Avery-Kiejda, Kelly A.

    2015-01-01

    Triple negative breast cancer (TNBC) is characterised by the lack of receptors for estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2). Since it cannot be treated by current endocrine therapies which target these receptors and due to its aggressive nature, it has one of the worst prognoses of all breast cancer subtypes. The only treatments remain chemo- and/or radio-therapy and surgery and because of this, novel biomarkers or treatment targets are urgently required to improve disease outcomes. MicroRNAs represent an attractive candidate for targeted therapies against TNBC, due to their natural ability to act as antisense interactors and regulators of entire gene sets involved in malignancy and their superiority over mRNA profiling to accurately classify disease. Here we review the current knowledge regarding miRNAs as biomarkers in TNBC and their potential use as therapeutic targets in this disease. Further, we review other epigenetic changes and interactions of these changes with microRNAs in this breast cancer subtype, which may lead to the discovery of new treatment targets for TNBC. PMID:26633365

  7. Triple Diuretics and Aquaretic Strategy for Acute Decompensated Heart Failure due to Volume Overload

    PubMed Central

    Estrada, Chelsea; Patel, Sagar; Weisfelner Bloom, Michelle; Wadhwa, Nand K.

    2013-01-01

    Diuretics, including furosemide, metolazone, and spironolactone, have historically been the mainstay of therapy for acute decompensated heart failure patients. The addition of an aquaretic-like vasopressin antagonist may enhance diuresis further. However, clinical experience with this quadruple combination is lacking in the acute setting. We present two hospitalized patients with acute decompensated heart failure due to massive fluid overload treated with a combination strategy of triple diuretics in conjunction with the aquaretic tolvaptan. The first patient lost 72.1 lbs. (32.7 kg) with an average urine output of 3.5 to 7.5 L/day over eight days on combined therapy with furosemide, metolazone, spironolactone, and tolvaptan. The second patient similarly achieved a weight loss of 28.2 lbs. (12.8 kg) over 4 days on the same treatment. Both patients maintained stable serum sodium, potassium, and creatinine over this period and remained out of the hospital for more than 30 days. Thus, patients hospitalized with acute decompensated heart failure due to volume overload can achieve euvolemia rapidly and without electrolytes disturbances using this regimen, while being under the close supervision of a team of cardiologists and nephrologists. Additionally, this therapy can potentially decrease the need for ultrafiltration and the length of hospital stay. PMID:24829808

  8. TH-C-BRD-04: Beam Modeling and Validation with Triple and Double Gaussian Dose Kernel for Spot Scanning Proton Beams

    SciTech Connect

    Hirayama, S; Takayanagi, T; Fujii, Y; Fujimoto, R; Fujitaka, S; Umezawa, M; Nagamine, Y; Hosaka, M; Yasui, K; Toshito, T

    2014-06-15

    Purpose: To present the validity of our beam modeling with double and triple Gaussian dose kernels for spot scanning proton beams in Nagoya Proton Therapy Center. This study investigates the conformance between the measurements and calculation results in absolute dose with two types of beam kernel. Methods: A dose kernel is one of the important input data required for the treatment planning software. The dose kernel is the 3D dose distribution of an infinitesimal pencil beam of protons in water and consists of integral depth doses and lateral distributions. We have adopted double and triple Gaussian model as lateral distribution in order to take account of the large angle scattering due to nuclear reaction by fitting simulated inwater lateral dose profile for needle proton beam at various depths. The fitted parameters were interpolated as a function of depth in water and were stored as a separate look-up table for the each beam energy. The process of beam modeling is based on the method of MDACC [X.R.Zhu 2013]. Results: From the comparison results between the absolute doses calculated by double Gaussian model and those measured at the center of SOBP, the difference is increased up to 3.5% in the high-energy region because the large angle scattering due to nuclear reaction is not sufficiently considered at intermediate depths in the double Gaussian model. In case of employing triple Gaussian dose kernels, the measured absolute dose at the center of SOBP agrees with calculation within ±1% regardless of the SOBP width and maximum range. Conclusion: We have demonstrated the beam modeling results of dose distribution employing double and triple Gaussian dose kernel. Treatment planning system with the triple Gaussian dose kernel has been successfully verified and applied to the patient treatment with a spot scanning technique in Nagoya Proton Therapy Center.

  9. Hoogsteen-position pyrimidines promote the stability and function of the MALAT1 RNA triple helix.

    PubMed

    Brown, Jessica A; Kinzig, Charles G; DeGregorio, Suzanne J; Steitz, Joan A

    2016-05-01

    Triple-stranded RNA was first deduced to form in vitro more than 50 years ago and has since been implicated in RNA catalysis, stability, and small molecule binding. Despite the emerging biological significance of RNA triple helices, it remains unclear how their nucleotide composition contributes to their thermodynamic stability and cellular function. To investigate these properties, we used in vitro RNA electrophoretic mobility shift assays (EMSAs) and in vivo intronless β-globin reporter assays to measure the relative contribution of 20 RNA base triples (N•A-U, N•G-C, N•C-G, N•U-A, and N•G-U) to triple-helical stability. These triples replaced a single internal U•A-U within the known structure of the triple-helical RNA stability element of human metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), which contains 10 major-groove base triples. In addition to the canonical C•G-C triple, the noncanonical base triples U•G-C, U•G-U, C•C-G, and U•C-G exhibited at least 30% stability relative to the wild-type U•A-U base triple in both assays. Of these triples, only U•A-U, C•G-C, and U•G-C, when tested as four successive triples, formed stabilizing structures that allowed accumulation of the intronless β-globin reporter. Overall, we find that Hoogsteen-position pyrimidines support triple helix stability and function and that thermodynamic stability, based on EMSA results, is necessary but not sufficient for stabilization activity of the MALAT1 triple helix in cells. These results suggest that additional RNA triple helices containing noncanonical triples likely exist in nature.

  10. Software for goniometer control in the Triple Ion Implantation Facility

    SciTech Connect

    Allen, W.R.

    1994-02-01

    A computer program is described tat controls the goniometer employed in the ion scattering chamber of the Triple Ion Implantation Facility (TIF) in the Metals and Ceramics Division at Oak Ridge National Laboratory. Details of goniometer operation and its incorporation into the ion scattering setup specific to the TIF are also discussed.

  11. Efficient tandem and triple-junction polymer solar cells.

    PubMed

    Li, Weiwei; Furlan, Alice; Hendriks, Koen H; Wienk, Martijn M; Janssen, René A J

    2013-04-17

    We demonstrate tandem and triple-junction polymer solar cells with power conversion efficiencies of 8.9% and 9.6% that use a newly designed, high molecular weight, small band gap semiconducting polymer and a matching wide band gap polymer.

  12. Carboplatin and Eribulin Mesylate in Triple Negative Breast Cancer Patients

    ClinicalTrials.gov

    2016-06-30

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Male Breast Cancer; Progesterone Receptor-negative Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

  13. Aluminum Silicate System: Experimental Determination of the Triple Point.

    PubMed

    Bell, P M

    1963-03-15

    The kyanite-sillimanite-andalusite triple point exists in the pressure-temperature plane at 8 +/- 0.5 kb and 300 +/- 50 degrees C. Reactions are accomplished experimentally with a Bridgman opposed-anvil press (with an external furnace), modified to provide shearing of the sample charges. All three equilibrium boundaries are proved by reversed reactions. PMID:17812984

  14. Triple effect absorption chiller utilizing two refrigeration circuits

    DOEpatents

    DeVault, Robert C.

    1988-01-01

    A triple effect absorption method and apparatus having a high coefficient of performance. Two single effect absorption circuits are combined with heat exchange occurring between a condenser and absorber of a high temperature circuit, and a generator of a low temperature circuit. The evaporators of both the high and low temperature circuits provide cooling to an external heat load.

  15. Residential Density: The Effects of Tripling College Students

    ERIC Educational Resources Information Center

    Clark, Elizabeth A.; Jackson, Shannon; Everhart, Deborah

    2012-01-01

    Due to a greater number of students enrolling in higher educational institutions, an increase in demand for housing on college campuses exists putting a strain on infrastructure. In order to accommodate the students, some universities are tripling students in residential settings by putting three students in a room originally designed for two.…

  16. Quadrupolar, Triple [Delta]-Function Potential in One Dimension

    ERIC Educational Resources Information Center

    Patil, S. H.

    2009-01-01

    The energy and parity eigenstates for quadrupolar, triple [delta]-function potential are analysed. Using the analytical solutions in specific domains, simple expressions are obtained for even- and odd-parity bound-state energies. The Heisenberg uncertainty product is observed to have a minimum for a specific strength of the potential. The…

  17. Evaluation of assumptions in soil moisture triple collocation analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Triple collocation analysis (TCA) enables estimation of error variances for three or more products that retrieve or estimate the same geophysical variable using mutually-independent methods. Several statistical assumptions regarding the statistical nature of errors (e.g., mutual independence and ort...

  18. Beyond triple collocation: Applications to satellite soil moisture

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Triple collocation is now routinely used to resolve the exact (linear) relationships between multiple measurements and/or representations of a geophysical variable that are subject to errors. It has been utilized in the context of calibration, rescaling and error characterisation to allow comparison...

  19. Large-area, triple junction a-Si alloy production

    SciTech Connect

    Oswald, R.; Jansen, K.; Johnson, B.; Willing, F.; Raquet, J.; Kloss, T.; Morris, J.; Weiss, P.; Yang, L.; Hainsworth, M.C.; Ashenfelter, W.; Stabinsky, B.; Twesme, E.; Chen, L.F.; O'Dowd, J. )

    1994-06-30

    Amorphous silicon alloy based triple junction 0.1 m[sup 2] modules with initial efficiencies greater than 11% have been produced using manufacturing equipment. Scale-up of equipment to process substrates 0.56 m[sup 2] in area is nearly complete.

  20. Scalable in-memory RDFS closure on billions of triples.

    SciTech Connect

    Goodman, Eric L.; Mizell, David

    2010-06-01

    We present an RDFS closure algorithm, specifically designed and implemented on the Cray XMT supercomputer, that obtains inference rates of 13 million inferences per second on the largest system configuration we used. The Cray XMT, with its large global memory (4TB for our experiments), permits the construction of a conceptually straightforward algorithm, fundamentally a series of operations on a shared hash table. Each thread is given a partition of triple data to process, a dedicated copy of the ontology to apply to the data, and a reference to the hash table into which it inserts inferred triples. The global nature of the hash table allows the algorithm to avoid a common obstacle for distributed memory machines: the creation of duplicate triples. On LUBM data sets ranging between 1.3 billion and 5.3 billion triples, we obtain nearly linear speedup except for two portions: file I/O, which can be ameliorated with the additional service nodes, and data structure initialization, which requires nearly constant time for runs involving 32 processors or more.

  1. Stellar evolution and the triple-α reactions

    SciTech Connect

    Suda, Takuma

    2014-05-02

    Nuclear reaction rates play a crucial role in the evolution of stars. For low-mass stars, the triple-α reaction controls the helium burning stars in the red giant and asymptotic giant branch (AGB) phase. More importantly, the cross section of the triple-α reaction has a great impact on the helium ignition at the center of the electron degenerate helium core of red giants and on the helium shell flashes of AGB stars. It is to be noted that stellar evolution models are influenced not only by the value of the cross section, but also by the temperature dependence of the reaction rate. In this paper, I present the impact of the triple-α reaction rates on the evolution of low-mass metal-free stars and intermediate-mass AGB stars. According to the previous study, the constraint on the triple-α reaction rate is derived based on stellar evolution theory. It is found that the recent revisions of the rate proposed by nuclear physics calculations satisfy the condition for the ignition of the helium core flash in low-mass stars.

  2. Efficient tandem and triple-junction polymer solar cells.

    PubMed

    Li, Weiwei; Furlan, Alice; Hendriks, Koen H; Wienk, Martijn M; Janssen, René A J

    2013-04-17

    We demonstrate tandem and triple-junction polymer solar cells with power conversion efficiencies of 8.9% and 9.6% that use a newly designed, high molecular weight, small band gap semiconducting polymer and a matching wide band gap polymer. PMID:23544881

  3. Recent advances in (soil moisture) triple collocation analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To date, triple collocation (TC) analysis is one of the most important methods for the global scale evaluation of remotely sensed soil moisture data sets. In this study we review existing implementations of soil moisture TC analysis as well as investigations of the assumptions underlying the method....

  4. Triple-stack multigap resistive plate chamber with strip readout

    NASA Astrophysics Data System (ADS)

    Babkin, V.; Basilev, S.; Buryakov, M.; Golovatyuk, V.; Lobastov, S.; Petrov, V.; Rumyantsev, M.; Schipunov, A.; Shutov, A.; Slepnev, I.; Slepnev, V.

    2016-07-01

    A triple-stack MRPC for the TOF system of the BM@N and the MPD experiments at the future collider NICA was tested. We use three stacks of glass to have symmetrical construction which allows to decrease dispersion and reflections of the signal from the readout strip.

  5. Hindfoot Deformity Corrected With Double Versus Triple Arthrodesis: Radiographic Comparison.

    PubMed

    DeVries, J George; Scharer, Brandon

    2015-01-01

    Hindfoot fusion is capable of correcting hindfoot deformities. Typically, this has been done through triple arthrodesis. Recently, there has been some discussion of a double arthrodesis, sparing the calcaneocuboid joint. We compared the radiographic corrective ability of these 2 fusion techniques. A retrospective radiographic review was performed of 20 consecutive triple arthrodeses (triple) and 20 consecutive talonavicular and subtalar arthrodesis with calcaneocuboid preservation (double). Additional midfoot arthrodesis or osteotomy was performed as needed in each group. The preoperative measurements were compared to those from standing weightbearing films after fusion postoperatively. The angular measurements included the anteroposterior and lateral talar–first metatarsal line (Meary's and Simmons) and the anteroposterior and lateral talocalcaneal angle. Both groups demonstrated a statistically significant reduction in deformity and a return to more normal radiographic findings after arthrodesis (p < .05). The 2 groups did not differ statistically in preoperative deformity or correction obtained (p > .05). Traditionally, triple arthrodesis has been advocated for significant hindfoot deformity that is irreducible. Recent studies have questioned the need for inclusion of the calcaneocuboid joint in the arthrodesis, in particular, in a pronated, valgus-type foot. In addition, others have advocated a strictly medial approach to hindfoot fusion, necessarily avoiding the calcaneocuboid joint. Our findings agree with the assertion that hindfoot deformity can be adequately and reliably corrected through hindfoot arthrodesis whether or not the calcaneocuboid joint is included. PMID:25432460

  6. Triple Science GCSEs: Strategies for Raising Attainment. GCSEs in Biology, Chemistry and Physics

    ERIC Educational Resources Information Center

    Learning and Skills Network (NJ3), 2007

    2007-01-01

    This publication provides advice for schools exploring the possibility of introducing Triple Science GCSEs. It focuses on strategies for raising attainment generally but within the context of Triple Science. The document is split into six sections: The introduction, titled "Preparing to Implement Triple Science Courses," introduces some of the…

  7. 49 CFR 383.115 - Requirements for double/triple trailers endorsement.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 5 2010-10-01 2010-10-01 false Requirements for double/triple trailers... § 383.115 Requirements for double/triple trailers endorsement. In order to obtain a Double/Triple Trailers endorsement each applicant must have knowledge covering: (a) Procedures for assembly and hookup...

  8. 49 CFR 383.115 - Requirements for double/triple trailers endorsement.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 5 2012-10-01 2012-10-01 false Requirements for double/triple trailers... § 383.115 Requirements for double/triple trailers endorsement. In order to obtain a double/triple trailers endorsement each applicant must have knowledge covering: (a) Procedures for assembly and hookup...

  9. 49 CFR 383.115 - Requirements for double/triple trailers endorsement.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 5 2014-10-01 2014-10-01 false Requirements for double/triple trailers... § 383.115 Requirements for double/triple trailers endorsement. In order to obtain a double/triple trailers endorsement each applicant must have knowledge covering: (a) Procedures for assembly and hookup...

  10. 49 CFR 383.115 - Requirements for double/triple trailers endorsement.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 5 2013-10-01 2013-10-01 false Requirements for double/triple trailers... § 383.115 Requirements for double/triple trailers endorsement. In order to obtain a double/triple trailers endorsement each applicant must have knowledge covering: (a) Procedures for assembly and hookup...

  11. 49 CFR 383.115 - Requirements for double/triple trailers endorsement.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 5 2011-10-01 2011-10-01 false Requirements for double/triple trailers... § 383.115 Requirements for double/triple trailers endorsement. In order to obtain a double/triple trailers endorsement each applicant must have knowledge covering: (a) Procedures for assembly and hookup...

  12. Combinatorics of RNA Secondary Structures with Base Triples.

    PubMed

    Müller, Robert; Nebel, Markus E

    2015-07-01

    The structure of RNA has been the subject of intense research over the last decades due to its importance for the correct functioning of RNA molecules in biological processes. Hence, a large number of models for RNA folding and corresponding algorithms for structure prediction have been developed. However, previous models often only consider base pairs, although every base is capable of up to three edge-to-edge interactions with other bases. Recently, Höner zu Siederdissen et al. presented an extended model of RNA secondary structure, including base triples together with a folding algorithm-the first thermodynamics-based algorithm that allows the prediction of secondary structures with base triples. In this article, we investigate the search space processed by this new algorithm, that is, the combinatorics of extended RNA secondary structures with base triples. We present generalized definitions for structural motifs like hairpins, stems, bulges, or interior loops occurring in structures with base triples. Furthermore, we prove precise asymptotic results for the number of different structures (size of search space) and expectations for various parameters associated with structural motifs (typical shape of folding). Our analysis shows that the asymptotic number of secondary structures of size n increases exponentially to [Formula: see text] compared to the classic model by Stein and Waterman for which [Formula: see text] structures exist. A comparison with the classic model reveals large deviations in the expected structural appearance, too. The inclusion of base triples constitutes a significant refinement of the combinatorial model of RNA secondary structure, which, by our findings, is quantitatively characterized. Our results are of special theoretical interest, because a closer look at the numbers involved suggests that extended RNA secondary structures constitute a new combinatorial class not bijective with any other combinatorial objects studied so far.

  13. Combinatorics of RNA Secondary Structures with Base Triples.

    PubMed

    Müller, Robert; Nebel, Markus E

    2015-07-01

    The structure of RNA has been the subject of intense research over the last decades due to its importance for the correct functioning of RNA molecules in biological processes. Hence, a large number of models for RNA folding and corresponding algorithms for structure prediction have been developed. However, previous models often only consider base pairs, although every base is capable of up to three edge-to-edge interactions with other bases. Recently, Höner zu Siederdissen et al. presented an extended model of RNA secondary structure, including base triples together with a folding algorithm-the first thermodynamics-based algorithm that allows the prediction of secondary structures with base triples. In this article, we investigate the search space processed by this new algorithm, that is, the combinatorics of extended RNA secondary structures with base triples. We present generalized definitions for structural motifs like hairpins, stems, bulges, or interior loops occurring in structures with base triples. Furthermore, we prove precise asymptotic results for the number of different structures (size of search space) and expectations for various parameters associated with structural motifs (typical shape of folding). Our analysis shows that the asymptotic number of secondary structures of size n increases exponentially to [Formula: see text] compared to the classic model by Stein and Waterman for which [Formula: see text] structures exist. A comparison with the classic model reveals large deviations in the expected structural appearance, too. The inclusion of base triples constitutes a significant refinement of the combinatorial model of RNA secondary structure, which, by our findings, is quantitatively characterized. Our results are of special theoretical interest, because a closer look at the numbers involved suggests that extended RNA secondary structures constitute a new combinatorial class not bijective with any other combinatorial objects studied so far. PMID

  14. Giant cell tumor of cervicothoracic region treated by triple corpectomy from posterior only approach: A case report with review of literature.

    PubMed

    Mahajan, Rajat; Chhabra, Harvinder Singh; Tandon, Vikas; Venkatesh, Raghavendra

    2015-01-01

    Giant cell tumor (GCT) is a benign aggressive tumor, which affects axial as well as a peripheral skeleton. It affects epiphysis of long bones and can result in pathological fractures. GCT affects cervical spine rarely and has been known to affect almost all vertebra in the human body. It has a predilection for fixed spine, that is, sacrum though it can affect mobile spine as well. GCT of cervicothoracic region poses a challenge for the surgeon because of the difficulty in approaching this region anteriorly. This situation is further compounded when GCT involves multiple contiguous vertebral bodies in this region and has already spread beyond the confines of its capsule. We report a case of GCT involving three vertebral bodies C7, D1, and D2 at cervicothoracic region who presented to us and was treated with triple corpectomy from the posterior only approach. This is the first ever case report of triple corpectomy and anterior reconstruction by a posterior only approach for GCT at the cervicothoracic junction to the best of author's knowledge.

  15. Effect of Formula Feeding and Breastfeeding on Child Growth, Infant Mortality, and HIV Transmission in Children Born to HIV-Infected Pregnant Women Who Received Triple Antiretroviral Therapy in a Resource-Limited Setting: Data from an HIV Cohort Study in India.

    PubMed

    Alvarez-Uria, Gerardo; Midde, Manoranjan; Pakam, Raghavakalyan; Bachu, Lakshminarayana; Naik, Praveen Kumar

    2012-01-01

    We describe a programme for the prevention of mother-to-child transmission (PMTCT) of HIV that provided universal antiretroviral therapy (ART) to all pregnant women regardless of the CD4 lymphocyte count and formula feeding for children with high risk of HIV transmission through breastfeeding in a district of India. The overall rate of HIV transmission was 3.7%. Although breastfeeding added a 3.1% additional risk of HIV acquisition, formula-fed infants had significantly higher risk of death compared to breastfed infants. The cumulative 12-month mortality was 9.6% for formula-fed infants versus 0.68% for breastfed infants. Anthropometric markers (weight, length/height, weight for length/height, body mass index, head circumference, mid-upper arm circumference, triceps skinfold, and subscapular skinfold) showed that formula-fed infants experience severe malnutrition during the first two months of life. We did not observe any death after rapid weaning at 5-6 months in breastfed infants. The higher-free-of HIV survival in breastfed infants and the low rate of HIV transmission found in this study support the implementation of PMTCT programmes with universal ART to all HIV-infected pregnant women and breastfeeding in order to reduce HIV transmission without increasing infant mortality in developing countries. PMID:22701801

  16. Triple combination of irradiation, chemotherapy (pemetrexed), and VEGFR inhibition (SU5416) in human endothelial and tumor cells

    SciTech Connect

    Bischof, Marc; Abdollahi, Amir; Gong Ping; Stoffregen, Clemens; Lipson, Kenneth E.; Debus, Juergen; Weber, Klaus J.; Huber, Peter E. . E-mail: p.huber@dkfz.de

    2004-11-15

    Purpose: This is the first preclinical report evaluating a trimodal therapy consisting of irradiation, chemotherapy, and antiangiogenesis in the context of a multimodal anticancer strategy. The combination of the folate antimetabolite pemetrexed, SU5416, a receptor tyrosine kinase inhibitor of VEGFR2, and irradiation was investigated in human endothelial cells and tumor cell lines. Methods and materials: Primary isolated human umbilical vein endothelial cells (HUVEC), human dermal microvascular endothelial cells (HDMEC), and human glioblastoma (U87) and prostate cancer cells (PC3) were exposed to pemetrexed (2 h) alone and in combination with SU5416 (2 h). When combined with irradiation up to 8 Gy, fixed concentrations of pemetrexed (1.06 {mu}M) and SU5416 (1.0 {mu}M) were used. Proliferation and clonogenic assays were conducted with endothelial and tumor cells. The migration/invasion ability of endothelial cells and the ability to produce tubular structures were tested in Matrigel and tube formation assays. Apoptosis was measured by sub-G1 DNA and caspase-3 flow cytometry. To investigate underlying cell signaling, immunocytochemistry was used to detect Akt survival signaling involvement. Results: Triple combination using only a low-toxicity drug exposure of pemetrexed and SU5416 results in greater response than each treatment alone or than each combination of two modalities in all tested endothelial and tumor cell models. Triple combination substantially inhibits proliferation, migration/invasion, tube formation, and clonogenic survival. Triple combination also induced the highest rate of apoptosis in HDMEC and HUVEC as indicated by sub-1 G1 and caspase-3 assessment. Interestingly, triple combination therapy also reduces proliferation and clonogenic survival significantly in U87 and PC3 tumor cell lines. SU5416 potently inhibited Akt phosphorylation which could be induced by radiation and radiochemotherapy in human endothelial cells. Conclusions: Our findings

  17. One-step fabrication of triple-layered microcapsules by a tri-axial flow focusing device for microencapsulation of soluble drugs and imaging agents

    NASA Astrophysics Data System (ADS)

    Yuan, Shuai; Wu, Qiang; Lei, Fan; Li, Guangbin; Si, Ting; Xu, Ronald X.

    2016-04-01

    In this work, the microencapsulation of water-soluble drug (doxorubicin, Dox) and imaging agent (perfluorocarbon, PFC) is performed by a novel liquid driven tri-axial flow focusing (LDTFF) device. The formation of stable triple-layered cone-jet mode can be observed in the simple well-assembled LDTFF device, providing an easy approach to fabricate mono-disperse triple-layered microcapsules with high encapsulation efficiency, high throughput and low cost in just one step. The fluorescence images show that the microcapsules have a satisfactory core-shell structure. The SEM micrographs show spherical and smooth surface views of the triple-layered microcapsules after being stirred 72h to remove the organic solvent totally. The results of thermo-responsive release experiments of the produced triple-layered microcapsules show these multifunctional capsules can be well stimulated when the environment temperature is beyond 55 degree centigrade. In a word, this novel approach has a great potential in applications such as drug delivery and image-guided therapy.

  18. Selective Androgen Receptor Modulators (SARMs) Negatively Regulate Triple-Negative Breast Cancer Growth and Epithelial:Mesenchymal Stem Cell Signaling

    PubMed Central

    Narayanan, Ramesh; Ahn, Sunjoo; Cheney, Misty D.; Yepuru, Muralimohan; Miller, Duane D.; Steiner, Mitchell S.; Dalton, James T.

    2014-01-01

    Abstract Introduction The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75–95% of estrogen receptor (ER)-positive and 40–70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Materials and Methods Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) co-culture signaling studies were performed to understand the mechanisms of action. Results Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. Conclusion 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer. PMID:25072326

  19. Zoledronate and Molecular Iodine Cause Synergistic Cell Death in Triple Negative Breast Cancer through Endoplasmic Reticulum Stress.

    PubMed

    Tripathi, Ranu; Singh, Preeti; Singh, Aru; Chagtoo, Megha; Khan, Sajid; Tiwari, Swasti; Agarwal, Gaurav; Meeran, Syed Musthapa; Godbole, Madan M

    2016-01-01

    Women consuming molecular iodine (I2) through seaweeds suffer the least from breast cancers. Zoledronate (Zol) is in clinical use for alleviation of bone pain in cancer patients. Triple negative breast cancers exhibit high mortality due to lack of neoadjuvant chemotherapy. I2 and Zol independently cause weak antiproliferative and apoptotic effect. So far, their combined effects have not been tested. We analyzed the effect of combination of I2 with Zol as a potent adjuvant therapeutic agent for triple negative breast cancer cells (MDA-MBA-231) and in the mice model of breast cancer. Cell viability, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, Western blotting, real-time PCR, flow cytometry, and other assays were performed for assessing cell death, calcium levels, and migration potential, respectively, in treated cells. The increased caspase 8, increased [Ca(2+)]c levels, and endoplasmic reticulum (ER) stress resulted in apoptosis. Real time and fluorescence-based analysis demonstrated that the combination treatment targets ER Ca(2+) homeostasis chaperons leading to apoptosis. Combination therapy reduces metalloproteinases 2 and 9, inhibits invasion/migration of cells, and prevents growth of tumor in mice. I2 + Zol combination treatment induces synergistic increase in ER-mediated apoptosis, reduces invasion/migration potential of MDA-MB-231 cells, and exhibits antiproliferative property in vivo demonstrating its potential as combination therapy.

  20. An ultrasensitive optical label-free polymeric biosensor based on concentric triple microring resonators with a central microdisk resonator

    NASA Astrophysics Data System (ADS)

    Malmir, Kiana; Habibiyan, Hamidreza; Ghafoorifard, Hassan

    2016-04-01

    In this paper we propose an optical label-free biosensor based on a polymeric platform. Label-free biosensors have not the drawbacks and stability problems of commercialized devices which are used for detection of labeled molecules. In addition, we choose polymeric platform, due to simple and low cost fabrication process and also high biocompatibility properties. The suggested structure consists of concentric triple ring resonators along with a disk resonator which offers deeper notches, higher sensitivity and vaster detection area with respect to other similar configurations such as single ring resonator, double concentric ring resonators, etc. Our numerical simulations based on the finite difference time domain (FDTD) method, show that in optimized structure, a transmission notch depth of -48.7 dB for sensor at rest and a free spectral range of 56 nm are achievable. In addition, resonance wavelength sensitivity and output power sensitivity of sensor are 1000 nm/RIU and 1.8×104 dB/RIU, respectively. The external radius of outer ring resonator is only 5 μm, and detection area of the sensor is 40.37 μm2. With this small size, to the best of our knowledge, the obtained notch depth and sensitivity parameters are one of the highest values in ring resonator-based biosensors reported to date.

  1. Improvement in symptoms after H2-receptor antagonist-based therapy for eradication of H pylori infection

    PubMed Central

    Hagiwara, Takeshi; Kato, Mototsugu; Anbo, Tomonori; Imamura, Akimichi; Suga, Toshihiro; Uchida, Takumi; Fujinaga, Akira; Nakagawa, Manabu; Nakagawa, Soichi; Shimizu, Yuichi; Yamamoto, Jyunji; Takeda, Hiroshi; Asaka, Masahiro

    2007-01-01

    AIM: To investigate the therapeutic effects of triple therapy combining lafutidine with clarithromycin and amoxicillin on H pylori infection and the resolution of gastroesophageal symptoms after eradication. METHODS: We conducted a randomized, multicenter, open-label controlled trial to compare the effectiveness of a triple therapy of lafutidine, clarithromycin, and amoxicillin (lafutidine group) with that of a triple therapy of lansoprazole, clarithromycin, and amoxicillin (lansoprazole group) in patients with H pylori infection. The study group comprised 22 patients with gastric ulcers and 18 patients with duodenal ulcers who had H pylori infection. RESULTS: H pylori eradication rates were similar in the lafutidine group (14/20, 70%) and the lansoprazole group (14/20, 70%). Gastroesophageal reflux and abdominal symptoms improved after eradication therapy in both groups, whereas abdominal discomfort, diarrhea, and constipation were unchanged. H pylori status had no apparent effect on improvement of gastroesophageal reflux or abdominal symptoms after treatment. Adverse events were similar in both groups. CONCLUSION: The triple therapy including lafutidine is equivalent to triple therapy including lansoprazole in terms of H pylori eradication rates and improvement in gastroesophageal reflux and abdominal symptoms. These results are attributed to the fact that lafutidine has strong, continuous antisecretory activity, unaffected by CYP2C19 polymorphisms. PMID:17657838

  2. Substance abuse treatment in persons with HIV/AIDS: challenges in managing triple diagnosis.

    PubMed

    Durvasula, Ramani; Miller, Theodore R

    2014-01-01

    Clinical management of HIV must account for the "triple diagnosis" of HIV, psychiatric diagnosis, and substance use disorders and requires integrated treatment services that focus beyond just mitigation of substance use and psychiatric and medical symptoms but also address other health behaviors. Because clinical management of HIV/AIDS has shifted significantly with the advent of highly active antiretroviral therapies (HAART) in the mid 1990s, a literature review focusing on literature published since 2000, and using relevant key words was conducted using a wide range of literature search databases. This literature review was complemented by studies to expand on specific treatment modalities for which there was a dearth of literature addressing HIV infected cohorts and to provide discussion of issues around substance abuse treatment as an HIV prevention tool. Existing models of substance abuse treatment including cognitive behavioral therapy and motivational interviewing have proven to be useful for enhancing adherence and reducing substance use in outpatient populations, while methadone maintenance and directly observed treatment have been useful with specific subgroups of users. Contextualization of services heightens the likelihood of successful outcomes and relapse prevention.

  3. Neoadjuvant strategies for triple negative breast cancer: 'state-of-the-art' and future perspectives.

    PubMed

    Carbognin, Luisa; Furlanetto, Jenny; Vicentini, Cecilia; Nortilli, Rolando; Pilotto, Sara; Brunelli, Matteo; Pellini, Francesca; Pollini, Giovanni Paolo; Bria, Emilio; Tortora, Giampaolo

    2015-01-01

    Neoadjuvant therapy for triple negative breast cancer (TNBC) has recently generated growing interest given the more aggressive biologic characteristics of such subtype and the lack of approved targeted therapies. Systemic chemotherapy represents the mainstay of treatment for TNBC. Although neoadjuvant chemotherapy has consistently demonstrated higher response rates for TNBC compared to non-TNBC, and the pathological complete response predicts long-term outcome, most patient display residual disease with a higher risk of relapse. In order to improve the outcome of TNBC new chemotherapic combinations, including platinum agents, and different targeted agents such as antiangiogenetics, poly-ADP ribose polymerase (PARP) inhibitors and other small molecule inhibitors are being evaluated in neoadjuvant setting. Currently, the research is ongoing to further characterize TNBC from a phenotypical and molecular perspective, in order to identify potential new target agents and to individualize the treatment. In this regard, the neoadjuvant setting may represent the best potential scenario to assess the activity and the sensitivity of novel agents.

  4. Dynamic Reprogramming of the Kinome In Response to Targeted MEK Inhibition In Triple Negative Breast Cancer

    PubMed Central

    Duncan, James S.; Whittle, Martin C.; Nakamura, Kazuhiro; Abell, Amy N.; Midland, Alicia A.; Zawistowski, Jon S.; Johnson, Nancy L.; Granger, Deborah A.; Jordan, Nicole Vincent; Darr, David B.; Usary, Jerry; Kuan, Pei-Fen; Smalley, David M.; Major, Ben; He, Xiaping; Hoadley, Katherine A.; Zhou, Bing; Sharpless, Norman E.; Perou, Charles M.; Kim, William Y.; Gomez, Shawn M.; Chen, Xin; Jin, Jian; Frye, Stephen V.; Earp, H. Shelton; Graves, Lee M.; Johnson, Gary L.

    2012-01-01

    SUMMARY Kinase inhibitors have limited success in cancer treatment because tumors circumvent their action. Using a quantitative proteomics approach, we assessed kinome activity in response to MEK inhibition in triple negative breast cancer (TNBC) cells and genetically engineered mice (GEMMs). MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases (RTKs). RNAi knockdown of ERK or c-Myc mimicked RTK induction by MEK inhibitors, whereas prevention of proteasomal c-Myc degradation blocked kinome reprogramming. MEK inhibitor-induced RTK stimulation overcame MEK2 but not MEK1 inhibition, reactivating ERK and producing drug resistance. The C3Tag GEMM for TNBC similarly induced RTKs in response to MEK inhibition. The inhibitor-induced RTK profile suggested a kinase inhibitor combination therapy that produced GEMM tumor apoptosis and regression where single agents were ineffective. This approach defines mechanisms of drug resistance, allowing rational design of combination therapies for cancer. PMID:22500798

  5. Highly Adaptable Triple-Negative Breast Cancer Cells as a Functional Model for Testing Anticancer Agents

    PubMed Central

    Singh, Balraj; Shamsnia, Anna; Raythatha, Milan R.; Milligan, Ryan D.; Cady, Amanda M.; Madan, Simran; Lucci, Anthony

    2014-01-01

    A major obstacle in developing effective therapies against solid tumors stems from an inability to adequately model the rare subpopulation of panresistant cancer cells that may often drive the disease. We describe a strategy for optimally modeling highly abnormal and highly adaptable human triple-negative breast cancer cells, and evaluating therapies for their ability to eradicate such cells. To overcome the shortcomings often associated with cell culture models, we incorporated several features in our model including a selection of highly adaptable cancer cells based on their ability to survive a metabolic challenge. We have previously shown that metabolically adaptable cancer cells efficiently metastasize to multiple organs in nude mice. Here we show that the cancer cells modeled in our system feature an embryo-like gene expression and amplification of the fat mass and obesity associated gene FTO. We also provide evidence of upregulation of ZEB1 and downregulation of GRHL2 indicating increased epithelial to mesenchymal transition in metabolically adaptable cancer cells. Our results obtained with a variety of anticancer agents support the validity of the model of realistic panresistance and suggest that it could be used for developing anticancer agents that would overcome panresistance. PMID:25279830

  6. Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer.

    PubMed

    Tuomela, Johanna; Sandholm, Jouko; Kauppila, Joonas H; Lehenkari, Petri; Harris, Kevin W; Selander, Katri S

    2013-12-01

    Toll-like receptor-9 (TLR9) is an intracellular DNA receptor that is widely expressed in breast and other cancers. We previously demonstrated that low tumor TLR9 expression upon diagnosis is associated with significantly shortened disease-specific survival times in patients with triple-negative breast cancer (TNBC). There are no targeted therapies for this subgroup of patients whose prognosis is among the worst in breast cancer. Due to the previously detected in vitro anti-invasive effects of chloroquine in these cell lines, the present study aimed to investigate the in vivo effects of chloroquine against two clinical subtypes of TNBC that differ in TLR9 expression. Chloroquine suppressed matrix metalloproteinase (MMP)-2 and MMP-9 mRNA expression and protein activity, whereas MMP-13 mRNA expression and proteolytic activity were increased. Despite enhancing TLR9 mRNA expression, chloroquine suppressed TLR9 protein expression in vitro. Daily treatment of mice with intraperitoneal (i.p.) chloroquine (80 mg/kg/day) for 22 days, did not inhibit the growth of control siRNA or TLR9 siRNA MDA-MB-231 breast cancer cells. In conclusion, despite the favorable in vitro effects on TNBC invasion and viability, particularly in hypoxic conditions, chloroquine does not prevent the growth of the triple-negative MDA-MB-231 cells with high or low TLR9 expression levels in vivo. This may be explained by the activating effects of chloroquine on MMP-13 expression or by the fact that chloroquine, by suppressing TLR9 expression, permits the activation of currently unknown molecular pathways, which allow the aggressive behavior of TNBC cells with low TLR9 expression in hypoxia. PMID:24273604

  7. Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer

    PubMed Central

    TUOMELA, JOHANNA; SANDHOLM, JOUKO; KAUPPILA, JOONAS H.; LEHENKARI, PETRI; HARRIS, KEVIN W.; SELANDER, KATRI S.

    2013-01-01

    Toll-like receptor-9 (TLR9) is an intracellular DNA receptor that is widely expressed in breast and other cancers. We previously demonstrated that low tumor TLR9 expression upon diagnosis is associated with significantly shortened disease-specific survival times in patients with triple-negative breast cancer (TNBC). There are no targeted therapies for this subgroup of patients whose prognosis is among the worst in breast cancer. Due to the previously detected in vitro anti-invasive effects of chloroquine in these cell lines, the present study aimed to investigate the in vivo effects of chloroquine against two clinical subtypes of TNBC that differ in TLR9 expression. Chloroquine suppressed matrix metalloproteinase (MMP)-2 and MMP-9 mRNA expression and protein activity, whereas MMP-13 mRNA expression and proteolytic activity were increased. Despite enhancing TLR9 mRNA expression, chloroquine suppressed TLR9 protein expression in vitro. Daily treatment of mice with intraperitoneal (i.p.) chloroquine (80 mg/kg/day) for 22 days, did not inhibit the growth of control siRNA or TLR9 siRNA MDA-MB-231 breast cancer cells. In conclusion, despite the favorable in vitro effects on TNBC invasion and viability, particularly in hypoxic conditions, chloroquine does not prevent the growth of the triple-negative MDA-MB-231 cells with high or low TLR9 expression levels in vivo. This may be explained by the activating effects of chloroquine on MMP-13 expression or by the fact that chloroquine, by suppressing TLR9 expression, permits the activation of currently unknown molecular pathways, which allow the aggressive behavior of TNBC cells with low TLR9 expression in hypoxia. PMID:24273604

  8. Novel targets for paclitaxel nano formulations: Hopes and hypes in triple negative breast cancer.

    PubMed

    Bakrania, Anita K; Variya, Bhavesh C; Patel, Snehal S

    2016-09-01

    Triple negative breast cancer is defined as one of the utmost prevailing breast cancers worldwide, possessing an inadequate prognosis and treatment option limited to chemotherapy and radiotherapy, creating a challenge for researchers as far as developing a specific targeted therapy is concerned. The past research era has shown several promising outcomes for TNBC such as nano-formulations of the chemotherapeutic agents already used for the management of the malignant tumor. Taking a glance at paclitaxel nano formulations, it has been proven beneficial in several researches in the past decade; nevertheless its solubility is often a challenge to scientists in achieving success. We have henceforth discussed the basic heterogeneity of triple negative breast cancer along with the current management options as well as a brief outlook on pros and cons of paclitaxel, known as the most widely used chemotherapeutic agent for the treatment of the disease. We further analyzed the need of nanotechnology pertaining to the problems encountered with the current paclitaxel formulations available discussing the strategic progress in various nano-formulations till date taking into account the basic research strategies required in terms of solubility, permeability, physicochemical properties, active and passive targeting. A thorough review in recent advances in active targeting for TNBC was carried out whereby the various ligands which are at present finding its way into TNBC research such as hyaluronic acid, folic acid, transferrin, etc. were discussed. These ligands have specific receptor affinity to TNBC tumor cells hence can be beneficial for novel drug targeting approaches. Conversely, there are currently several novel strategies in the research pipeline whose targeting ligands have not yet been studied. Therefore, we reviewed upon the numerous novel receptor targets along with the respective nano-formulation aspects which have not yet been fully researched upon and could be

  9. Tumor suppressor role of microRNA-1296 in triple-negative breast cancer

    PubMed Central

    Phan, Binh; Majid, Shahana; Ursu, Sarah; de Semir, David; Nosrati, Mehdi; Bezrookove, Vladimir; Kashani-Sabet, Mohammed; Dar, Altaf A.

    2016-01-01

    Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis, which lacks effective targeted therapies. There is an urgent need to better understand the underlying molecular mechanisms of TNBC aggressiveness and identify novel, efficient targets for therapeutic intervention. Methods miRNA qRT-PCR was used to determine the expression of miR-1296 in cell lines. The miR-1296 overexpression effects in TNBC cell lines were investigated using assays of colony formation, cell cycle and apoptosis. Immunoblotting was performed to determine the expression of the miR-1296 target protein, and luciferase assays were performed to confirm the target of miR-1296 action. Results miR-1296 expression was significantly suppressed in TNBC cell lines and tissues samples. Overexpression of miR-1296 significantly suppressed cell proliferation of two TNBC cell lines when compared to control miRNA-expressing cells. A significant decrease in the S-phase of the cell cycle was observed following miR-1296 overexpression, accompanied by induction of apoptosis in TNBC cells. Cyclin D1 (CCND1) was identified as a target of miR-1296 action. miR-1296 overexpression significantly suppressed the luciferase activity of reporter plasmid containing the 3′UTR of CCND1 and protein expression levels of CCND1 in TNBC cells. The effects of miR-1296 overexpression on TNBC cell growth were reversed by CCND1 overexpression. miR-1296 expression sensitized TNBC cells to cisplatin treatment. Conclusion Our results demonstrate a novel tumor suppressor role for miR-1296 in triple-negative breast cancer cell lines, identify CCND1 as its target of action, and demonstrate a potential role for miR-1296 in sensitizing breast cancer cells to cisplatin. PMID:26799586

  10. Studying the triple - α reaction in hyperspherical harmonic approach

    NASA Astrophysics Data System (ADS)

    Nguyen, Ngoc; Nunes, Filomena

    2010-11-01

    The triple-α reaction is studied by using hyperspherical harmonic (HH) method [1]. Starting from three body model, we determine the 2^+ state and the 0^+ resonance as well as the quadrupole strength function B(E2). The triple-α reaction rate are calculated. We also carefully consider the contributions of the nonresonant continuum states to the reaction rate at low temperature (T <=10^8 K). The results are compared with [2,3].[4pt] [1] I. J. Thompson, F. M. Nunes, B. V. Danilin, Comput.Phys.Comm. 161, 87-107 (2004).[0pt] [2] K.Ogata, M.Kan, M.Kamimura, Prog. Theor. Phys. 122, 1055 (2009).[0pt] [3] R. de Diego, E. Garrido, D.V. Fedorov, A.S. Jensen, arXiv:1005.5647v1.

  11. A triple risk model for unexplained late stillbirth

    PubMed Central

    2014-01-01

    Background The triple risk model for sudden infant death syndrome (SIDS) has been useful in understanding its pathogenesis. Risk factors for late stillbirth are well established, especially relating to maternal and fetal wellbeing. Discussion We propose a similar triple risk model for unexplained late stillbirth. The model proposed by us results from the interplay of three groups of factors: (1) maternal factors (such as maternal age, obesity, smoking), (2) fetal and placental factors (such as intrauterine growth retardation, placental insufficiency), and (3) a stressor (such as venocaval compression from maternal supine sleep position, sleep disordered breathing). We argue that the risk factors within each group in themselves may be insufficient to cause the death, but when they interrelate may produce a lethal combination. Summary Unexplained late stillbirth occurs when a fetus who is somehow vulnerable dies as a result of encountering a stressor and/or maternal condition in a combination which is lethal for them. PMID:24731396

  12. Grain boundary and triple junction diffusion in nanocrystalline copper

    SciTech Connect

    Wegner, M. Leuthold, J.; Peterlechner, M.; Divinski, S. V.; Song, X.; Wilde, G.

    2014-09-07

    Grain boundary and triple junction diffusion in nanocrystalline Cu samples with grain sizes, 〈d〉, of ∼35 and ∼44 nm produced by spark plasma sintering were investigated by the radiotracer method using the {sup 63}Ni isotope. The measured diffusivities, D{sub eff}, are comparable with those determined previously for Ni grain boundary diffusion in well-annealed, high purity, coarse grained, polycrystalline copper, substantiating the absence of a grain size effect on the kinetic properties of grain boundaries in a nanocrystalline material at grain sizes d ≥ 35 nm. Simultaneously, the analysis predicts that if triple junction diffusion of Ni in Cu is enhanced with respect to the corresponding grain boundary diffusion rate, it is still less than 500⋅D{sub gb} within the temperature interval from 420 K to 470 K.

  13. A Halogen-Bond-Induced Triple Helicate Encapsulates Iodide.

    PubMed

    Massena, Casey J; Wageling, Nicholas B; Decato, Daniel A; Martin Rodriguez, Enrique; Rose, Ariana M; Berryman, Orion B

    2016-09-26

    The self-assembly of higher-order anion helicates in solution remains an elusive goal. Herein, we present the first triple helicate to encapsulate iodide in organic and aqueous media as well as the solid state. The triple helicate self-assembles from three tricationic arylethynyl strands and resembles a tubular anion channel lined with nine halogen bond donors. Eight strong iodine⋅⋅⋅iodide halogen bonds and numerous buried π-surfaces endow the triplex with remarkable stability, even at elevated temperatures. We suggest that the natural rise of a single-strand helix renders its linear halogen-bond donors non-convergent. Thus, the stringent linearity of halogen bonding is a powerful tool for the synthesis of multi-strand anion helicates. PMID:27411932

  14. A compact triple-band bandpass filter based on metamaterials

    NASA Astrophysics Data System (ADS)

    Zhao, Ya-juan; Jiang, Bo; Li, Bao-yi; Wang, Dong-hong

    2016-07-01

    This paper presents a compact triple-band bandpass filter based on metamaterials. The miniaturization is realized by the principle of phase compensation of metamaterial. Compared with the conventional half-wavelength filter, the metamaterial filter has a small size of 10 mm×10 mm. The triple-band bandpass filter performance has been validated by the electromagnetic simulation software of high frequency structure simulator (HFSS). The results illustrate that the filter is designed with center frequencies of 2.4 GHz, 5.1 GHz and 8.8 GHz, bandwidths of about 7.9% (2.31—2.50 GHz), 7.8% (5.0—5.4 GHz) and 7.4% (8.50—9.15 GHz), respectively, and it shows good band pass characteristics.

  15. Triple dividends of water consumption charges in South Africa

    NASA Astrophysics Data System (ADS)

    Letsoalo, Anthony; Blignaut, James; de Wet, Theuns; de Wit, Martin; Hess, Sebastiaan; Tol, Richard S. J.; van Heerden, Jan

    2007-05-01

    The South African government is exploring ways to address water scarcity problems by introducing a water resource management charge on the quantity of water used in sectors such as irrigated agriculture, mining, and forestry. It is expected that a more efficient water allocation, lower use, and a positive impact on poverty can be achieved. This paper reports on the validity of these claims by applying a computable general equilibrium model to analyze the triple dividend of water consumption charges in South Africa: reduced water use, more rapid economic growth, and a more equal income distribution. It is shown that an appropriate budget-neutral combination of water charges, particularly on irrigated agriculture and coal mining, and reduced indirect taxes, particularly on food, would yield triple dividends, that is, less water use, more growth, and less poverty.

  16. Triple Helix Formation in a Topologically Controlled DNA Nanosystem.

    PubMed

    Yamagata, Yutaro; Emura, Tomoko; Hidaka, Kumi; Sugiyama, Hiroshi; Endo, Masayuki

    2016-04-11

    In the present study, we demonstrate single-molecule imaging of triple helix formation in DNA nanostructures. The binding of the single-molecule third strand to double-stranded DNA in a DNA origami frame was examined using two different types of triplet base pairs. The target DNA strand and the third strand were incorporated into the DNA frame, and the binding of the third strand was controlled by the formation of Watson-Crick base pairing. Triple helix formation was monitored by observing the structural changes in the incorporated DNA strands. It was also examined using a photocaged third strand wherein the binding of the third strand was directly observed using high-speed atomic force microscopy during photoirradiation. We found that the binding of the third strand could be controlled by regulating duplex formation and the uncaging of the photocaged strands in the designed nanospace.

  17. Photodissociation of methyl formate: Conical intersections, roaming and triple fragmentation

    SciTech Connect

    Lin, King-Chuen; Tsai, Po-Yu; Chao, Meng-Hsuan; Kasai, Toshio; Lombardi, Andrea; Palazzetti, Federico; Aquilanti, Vincenzo

    2015-12-31

    The photodissociation channels of methyl formate have been extensively investigated by two different advanced experimental techniques, ion imaging and Fourier-Transform-Infrared emission spectroscopy, combined with quantum chemical calculations and molecular dynamics simulations. Our aim is to characterize the role of alternative routes to the conventional transition-state mediated pathway: the roaming and the triple fragmentation processes. The photolysis experiments, carried out at a range of laser wavelengths in the vicinity of the triple fragmentation threshold, beside the simulation of large bunches of classical trajectories with different initial conditions, have shown that both mechanisms share a common path that involves a conical intersection during the relaxation process from the electronic excited state S{sub 1} to the ground state S{sub 0}.

  18. Triple line kinetics in solid-state dewetting

    NASA Astrophysics Data System (ADS)

    Tripathi, Ashwani; Pierre-Louis, Olivier

    Solid-state dewetting has been studied in a large number of experimental systems, such as SOI (Si on amorphous SiO2), or metal films on various substrates. Several theoretical approaches have been proposed in the past 10 years to understand this phenomena, ranging from Kinetic Monte Carlo to phase field, and continuum Mullins-like models. We present a continuum model which addresses the question of the limit of validity of the usual approximation of a constant contact angle at the triple line between the solid, the film, and the vacuum (or vapor). Our results suggest that the Young relation is subject to systematic deviations, which could be measured in experiments. In addition, the so-called mass shedding effect, which leads to the breakup of the film at a finite distance from the triple-line, can be accelerated by orders of magnitude due to wetting effects. Supported by LOTUS Grant 11-13AP20.

  19. Triple neutral gauge boson couplings in noncommutative Standard Model

    NASA Astrophysics Data System (ADS)

    Deshpande, N. G.; He, Xiao-Gang

    2002-05-01

    It has been shown recently that the triple neutral gauge boson couplings are not uniquely determined in noncommutative extension of the Standard Model (NCSM). Depending on specific schemes used, the couplings are different and may even be zero. To distinguish different realizations of the NCSM, additional information either from theoretical or experimental considerations is needed. In this Letter we show that these couplings can be uniquely determined from considerations of unification of electroweak and strong interactions. Using SU(5) as the underlying theory and integrating out the heavy degrees of freedom, we obtain unique non-zero new triple γγγ, γγZ, γZZ, ZZZ, γGG, ZGG and GGG couplings at the leading order in the NCSM. We also briefly discuss experimental implications.

  20. Targeting and mimicking collagens via triple helical peptide assembly

    PubMed Central

    Li, Yang; Yu, S. Michael

    2013-01-01

    As the major structural component of the extracellular matrix, collagen plays a crucial role in tissue development and regeneration. Since structural and metabolic abnormalities of collagen are associated with numerous debilitating diseases and pathologic conditions, the ability to target collagens of diseased tissues could lead to new diagnostics and therapeutics. Collagen is also a natural biomaterial widely used in drug delivery and tissue engineering, and construction of synthetic collagen-like materials is gaining interests in the biomaterials community. The unique triple helical structure of collagen has been explored for targeting collagen strands, and for engineering collagen-like functional assemblies and conjugates. This review focuses on the forefront of research activities in the use of the collagen mimetic peptide for both targeting and mimicking collagens via its triple helix mediated strand hybridization and higher order assembly. PMID:24210894

  1. Dynamical Evolution of the Alpha and Proxima Centauri Triple System

    NASA Astrophysics Data System (ADS)

    Worth, Rachel; Sigurdsson, Steinn

    2015-01-01

    Proxima Centauri is approximately 15,000 AU from the Alpha Centauri binary and moving through the galaxy on a similar path, and is thought to be in a loosely bound orbit about the binary. Dynamic simulations show that this configuration can form from a less extreme triple system. As our nearest neighbors, these stars command great interest as potential planet hosts, and the dynamics of the stars govern the formation of any planets within the system. Here we present a scenario for the evolution of Alpha Centauri A and B and Proxima Centauri as a triple system, to establish limits on the evolution of the binary since formation and allow for a better understanding of planet formation therein.

  2. Treatment options for patients with triple-negative breast cancer

    PubMed Central

    2010-01-01

    Breast cancer is a heterogeneous disease composed of different subtypes, characterized by their different clinicopathological characteristics, prognoses and responses to treatment. In the past decade, significant advances have been made in the treatment of breast cancer sensitive to hormonal treatments, as well as in patients whose malignant cells overexpress or amplify HER2. In contrast, mainly due to the lack of molecular targets, little progress has been made in the treatment of patients with triple-negative breast cancer. Recent improved understanding of the natural history, pathophysiology, and molecular features of triple-negative breast cancers have provided new insights into management and therapeutic strategies for women affected with this entity. Ongoing and planned translational clinical trials are likely to optimize and improve treatment of women with this disease. PMID:20979652

  3. Prognostic significance of Bcl-2 in invasive mammary carcinomas: a comparative clinicopathologic study between "triple-negative" and non-"triple-negative" tumors.

    PubMed

    Tawfik, Kareem; Kimler, Bruce F; Davis, Marilyn K; Fan, Fang; Tawfik, Ossama

    2012-01-01

    Bcl-2 is a tumorigenic protein that is expressed in 25% to 50% of breast cancers. Although its expression has been widely accepted as a favorable prognostic marker, its protective mechanism of action remains unclear. "Triple-negative" tumors are an aggressive subgroup known to carry a poor prognosis. Studies documenting prognostic significance of Bcl-2 expression in triple-negative in comparison to non-triple-negative breast cancers are limited. Bcl-2 expression was correlated with tumor size, grade, histologic type, lymphovascular invasion, lymph node status, patients' overall survival, estrogen receptor, progesterone receptor, Her-2, p53, and epidermal growth factor receptor in 124 triple-negative and 458 non-triple-negative tumors. There were significant differences between triple-negative and non-triple-negative tumors in their relationship to Bcl-2 expression (81% versus 29%, respectively) and tumor aggression. As previously reported, in non-triple-negative tumors, Bcl-2 positivity correlated with less aggressive tumors (94% of grade I tumors were Bcl-2+ versus 62% of grade III tumors, P < .011) and overall survival (P = .008). However, the opposite was true in patients with triple-negative tumors, where Bcl-2 positivity was associated with poorer survival (P = .64). In triple-negative tumors, Bcl-2 positivity was not associated with any of the aforementioned parameters except for a lower incidence of lymph node metastasis. Moreover, by Cox regression analysis of all variables, in patients with triple-negative tumors, lymphovascular invasion (P = .009) and Bcl-2 expression (P = .028) were predictors of poor survival. In conclusion, there are major clinicopathologic differences between breast cancer phenotypes. Our results establish the value of using Bcl-2 in prognostic stratification of patients and its potential therapeutic implications in selecting patients for treatment.

  4. Velocity selection problem in the presence of the triple junction.

    PubMed

    Brener, E A; Hüter, C; Pilipenko, D; Temkin, D E

    2007-09-01

    Melting of a bicrystal along the grain boundary is discussed. A triple junction plays a crucial role in the velocity selection problem in this case. In some range of the parameters an entirely analytical solution of this problem is given. This allows us to present a transparent picture of the structure of the selection theory. We also discuss the selection problem in the case of the growth of a "eutectoid dendrite."

  5. Targeting Thyroid Hormone Receptor Beta in Triple Negative Breast Cancer

    PubMed Central

    Gu, Guowei; Gelsomino, Luca; Covington, Kyle R.; Beyer, Amanda R.; Wang, John; Rechoum, Yassine; Huffman, Kenneth; Carstens, Ryan; Ando, Sebastiano; Fuqua, Suzanne A.W.

    2015-01-01

    Purpose Discover novel nuclear receptor targets in triple negative breast cancer Methods Expression microarray, western blot, qRT-PCR, MTT growth assay, soft agar anchorage-independent growth assay, TRE reporter transactivation assay, statistical analysis. Results We performed microarray analysis using 227 triple negative breast tumors, and clustered the tumors into five groups according to their nuclear receptor expression. Thyroid hormone receptor beta (TRβ) was one of the most differentially expressed nuclear receptors in group 5 compared to other groups. TRβ low expressing patients were associated with poor outcome. We evaluated the role of TRβ in triple negative breast cancer cell lines representing group 5 tumors. Knockdown of TRβ increased soft agar colony and reduced sensitivity to docetaxel and doxorubicin treatment. Docetaxel or doxorubicin long-term cultured cell lines also expressed decreased TRβ protein. Microarray analysis revealed cAMP/PKA signaling was the only KEGG pathways upregulated in TRβ knockdown cells. Inhibitors of cAMP or PKA, in combination with doxorubicin further enhanced cell apoptosis and restored sensitivity to chemotherapy. TRβ-specific agonists enhanced TRβ expression, and further sensitized cells to both docetaxel and doxorubicin. Sensitization was mediated by increased apoptosis with elevated cleaved PARP and caspase 3. Conclusions TRβ represents a novel nuclear receptor target in triple negative breast cancer; low TRβ levels were associated with enhanced resistance to both docetaxel and doxorubicin treatment. TRβ-specific agonists enhance chemosensitivity to these two agents. Mechanistically enhanced cAMP/PKA signaling was associated with TRβ’s effects on response to chemotherapy. PMID:25820519

  6. View north towards yard Triple Stub Switch in foreground. The ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View north towards yard Triple Stub Switch in foreground. The three tracks lead into the East Railroad's Shop complex and Roundhouse. The Steel Hopper Car was used to haul coal and was in the process of being rebuilt but in 1956, when the railroad ended freight operations. As a result it was never completed and was left outside - East Broad Top Railroad & Coal Company, State Route 994, West of U.S. Route 522, Rockhill Furnace, Huntingdon County, PA

  7. UNIDENTIFIED CATENARY SUSPENSION BRIDGE WITH TRIPLE PIPE TOWERS, SHOWING HOWE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    UNIDENTIFIED CATENARY SUSPENSION BRIDGE WITH TRIPLE PIPE TOWERS, SHOWING HOWE PIPE TRUSS RAILING AND TRUSSED DECK BEAMS TYPICAL TO BRIDGES BUILT BY FLINN-MOYER COMPANY. NOTE THAT TOWER PIPES LIE IN ONE PLANE, UNLIKE TRIPODAL ARRANGEMENT AT CLEAR FORK OF THE BRAZOS SUSPENSION BRIDGE. ELEVATION VIEW. - Clear Fork of Brazos River Suspension Bridge, Spanning Clear Fork of Brazos River at County Route 179, Albany, Shackelford County, TX

  8. Triple AIM evaluation and application in advanced node

    NASA Astrophysics Data System (ADS)

    Wang, Gary C.; Lio, En Chuan; Hung, Yuting; Chen, Charlie; Wang, Sybil; Weng, Tang Chun; Lin, Bill; Yu, Chun Chi

    2016-03-01

    A novel method on advanced node for IBO (Image Based Overlay) data extraction accuracy is demonstrated in this work, and here some special design in triple-AIM (Advanced Imaging Metrology) is able to realize the approach. Since triple AIM design has 3 locations left for patterning layers insertion, a new design with 2 layers locations, location-A (inner) and location-B (middle), are generated by 1st pattering, i.e. once lithography exposure, and the 2 marks grouping are formed on dielectric through lithography and etching process with a predetermined overlay "zero offset" through original mask layout design, as illustrated in Fig. (1). And then, as following top photo resist layer, assumed location-C (outer), lithography patterning process, PR coating, exposure and development complete, full triple-AIM patterns is generated, and 3 sets of overlay data could be obtained, A to B, C to B, C to A. Through re-calculating the overlay raw data of current (2nd patterning layer) to previous (1st patterning layer) layer by averaging [C to B] and [C to A], then theoretically the data extraction of sites would be more accuracy, since the variation of local marks signal, induced by inline process instability, could be minimized through the raw data averaging procedure. Moreover, from raw data [A to B], an extra monitor function for detections of the inline process variation, marks selection and recipe setting optimization could be obtained, since marks in [A] and [BB] locations are both generated in 1st patterning, and with the target "zero". So if the raw data [A to BB] is bigger or smaller than "zero" in some degree, there should be some process issue or marks condition setting error in triple-AIM design.

  9. Study of Neutral Triple Gauge Couplings in DELPHI

    NASA Astrophysics Data System (ADS)

    Pieri, Lidia

    2002-04-01

    Neutral Triple Gauge boson Couplings ZZZ, ZZ γ and Z γ γ are studied using data collected by the DELPHI detector at LEP at energies between 189 and 208 GeV. The reactions e^+ e^- arrow Z γ, e^+ e^- arrow Z Z and e^+ e^- arrow Z γ^* are used. A summary of the main theoretical aspects of NTGC is given. A summary of the reactions used for deriving limits on these couplings is reported. Current limits are shown.

  10. Light pressure acceleration with frequency-tripled laser pulse

    SciTech Connect

    Wang, Xiaofeng; Shen, Baifei E-mail: zhxm@siom.ac.cn; Zhang, Xiaomei E-mail: zhxm@siom.ac.cn; Ji, Liangliang; Wang, Wenpeng; Zhao, Xueyan; Xu, Jiancai; Yu, Yahong; Yi, Longqing; Shi, Yin; Xu, Tongjun; Zhang, Lingang

    2014-08-15

    Light pressure acceleration of ions in the interaction of the frequency-tripled (3ω) laser pulse and foil target is studied, and a promising method to increase accelerated ion energy is shown. Results show that at a constant laser energy, much higher ion energy peak value is obtained for 3ω laser compared with that using the fundamental frequency laser. The effect of energy loss during frequency conversion on ion acceleration is considered, which may slightly decrease the acceleration effect.

  11. Mapping the chemical potential landscape of a triple quantum dot

    NASA Astrophysics Data System (ADS)

    Broome, M. A.; Gorman, S. K.; Keizer, J. G.; Watson, T. F.; Hile, S. J.; Baker, W. J.; Simmons, M. Y.

    2016-08-01

    We investigate the nonequilibrium charge dynamics of a triple quantum dot and demonstrate how electron transport through these systems can give rise to nontrivial tunneling paths. Using a real-time charge sensing method, we establish tunneling pathways taken by particular electrons under well-defined electrostatic configurations. We show how these measurements map to the chemical potentials for different charge states across the system. We use a modified Hubbard Hamiltonian to describes the system dynamics and show is reproduces all experimental observations.

  12. Tulczyjew triples in the constrained dynamics of strings

    NASA Astrophysics Data System (ADS)

    Grabowski, J.; Grabowska, K.; Urbański, P.

    2016-09-01

    We show that there exists a natural Tulczyjew triple in the dynamics of objects for which the standard (kinematic) configuration space TM is replaced with ∧n TM . In this framework, which is completely covariant, we derive geometrically phase equations, as well as Euler-Lagrange equations, including nonholonomic constraints into the picture. Dynamics of strings and a constrained Plateau problem in statics are particular cases of this framework.

  13. Period Tripling Causes Rotating Spirals in Agitated Wet Granular Layers

    NASA Astrophysics Data System (ADS)

    Huang, Kai; Rehberg, Ingo

    2011-07-01

    Pattern formation of a thin layer of vertically agitated wet granular matter is investigated experimentally. Rotating spirals with three arms, which correspond to the kinks between regions with different colliding phases, are the dominating pattern. This preferred number of arms corresponds to period tripling of the agitated granular layer, unlike predominantly subharmonic Faraday crispations in dry granular matter. The chirality of the spatiotemporal pattern corresponds to the rotation direction of the spirals.

  14. Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel-cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines.

    PubMed

    Ye, Jun; Xia, Xuejun; Dong, Wujun; Hao, Huazhen; Meng, Luhua; Yang, Yanfang; Wang, Renyun; Lyu, Yuanfeng; Liu, Yuling

    2016-01-01

    There is no effective clinical therapy for triple-negative breast cancers (TNBCs), which have high low-density lipoprotein (LDL) requirements and express relatively high levels of LDL receptors (LDLRs) on their membranes. In our previous study, a novel lipid emulsion based on a paclitaxel-cholesterol complex (PTX-CH Emul) was developed, which exhibited improved safety and efficacy for the treatment of TNBC. To date, however, the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul have not been investigated. In order to offer powerful proof for the therapeutic effects of PTX-CH Emul, we systematically studied the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul and made a comparative evaluation of antineoplastic effects on TNBC (MDA-MB-231) and non-TNBC (MCF7) cell lines through in vitro and in vivo experiments. The in vitro antineoplastic effects and in vivo tumor-targeting efficiency of PTX-CH Emul were significantly more enhanced in MDA-MB-231-based models than those in MCF7-based models, which was associated with the more abundant expression profile of LDLR in MDA-MB-231 cells. The results of the cellular uptake mechanism indicated that PTX-CH Emul was internalized into breast cancer cells through the LDLR-mediated internalization pathway via clathrin-coated pits, localized in lysosomes, and then released into the cytoplasm, which was consistent with the internalization pathway and intracellular trafficking of native LDL. The findings of this paper further confirm the therapeutic potential of PTX-CH Emul in clinical applications involving TNBC therapy. PMID:27601899

  15. Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel–cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines

    PubMed Central

    Ye, Jun; Xia, Xuejun; Dong, Wujun; Hao, Huazhen; Meng, Luhua; Yang, Yanfang; Wang, Renyun; Lyu, Yuanfeng; Liu, Yuling

    2016-01-01

    There is no effective clinical therapy for triple-negative breast cancers (TNBCs), which have high low-density lipoprotein (LDL) requirements and express relatively high levels of LDL receptors (LDLRs) on their membranes. In our previous study, a novel lipid emulsion based on a paclitaxel–cholesterol complex (PTX-CH Emul) was developed, which exhibited improved safety and efficacy for the treatment of TNBC. To date, however, the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul have not been investigated. In order to offer powerful proof for the therapeutic effects of PTX-CH Emul, we systematically studied the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul and made a comparative evaluation of antineoplastic effects on TNBC (MDA-MB-231) and non-TNBC (MCF7) cell lines through in vitro and in vivo experiments. The in vitro antineoplastic effects and in vivo tumor-targeting efficiency of PTX-CH Emul were significantly more enhanced in MDA-MB-231-based models than those in MCF7-based models, which was associated with the more abundant expression profile of LDLR in MDA-MB-231 cells. The results of the cellular uptake mechanism indicated that PTX-CH Emul was internalized into breast cancer cells through the LDLR-mediated internalization pathway via clathrin-coated pits, localized in lysosomes, and then released into the cytoplasm, which was consistent with the internalization pathway and intracellular trafficking of native LDL. The findings of this paper further confirm the therapeutic potential of PTX-CH Emul in clinical applications involving TNBC therapy. PMID:27601899

  16. Cellular uptake mechanism and comparative evaluation of antineoplastic effects of paclitaxel–cholesterol lipid emulsion on triple-negative and non-triple-negative breast cancer cell lines

    PubMed Central

    Ye, Jun; Xia, Xuejun; Dong, Wujun; Hao, Huazhen; Meng, Luhua; Yang, Yanfang; Wang, Renyun; Lyu, Yuanfeng; Liu, Yuling

    2016-01-01

    There is no effective clinical therapy for triple-negative breast cancers (TNBCs), which have high low-density lipoprotein (LDL) requirements and express relatively high levels of LDL receptors (LDLRs) on their membranes. In our previous study, a novel lipid emulsion based on a paclitaxel–cholesterol complex (PTX-CH Emul) was developed, which exhibited improved safety and efficacy for the treatment of TNBC. To date, however, the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul have not been investigated. In order to offer powerful proof for the therapeutic effects of PTX-CH Emul, we systematically studied the cellular uptake mechanism and intracellular trafficking of PTX-CH Emul and made a comparative evaluation of antineoplastic effects on TNBC (MDA-MB-231) and non-TNBC (MCF7) cell lines through in vitro and in vivo experiments. The in vitro antineoplastic effects and in vivo tumor-targeting efficiency of PTX-CH Emul were significantly more enhanced in MDA-MB-231-based models than those in MCF7-based models, which was associated with the more abundant expression profile of LDLR in MDA-MB-231 cells. The results of the cellular uptake mechanism indicated that PTX-CH Emul was internalized into breast cancer cells through the LDLR-mediated internalization pathway via clathrin-coated pits, localized in lysosomes, and then released into the cytoplasm, which was consistent with the internalization pathway and intracellular trafficking of native LDL. The findings of this paper further confirm the therapeutic potential of PTX-CH Emul in clinical applications involving TNBC therapy.

  17. A theory of triple hysteresis in ferroelectric crystals

    NASA Astrophysics Data System (ADS)

    Weng, George J.

    2009-10-01

    In the vicinity of the transition temperature between two ferroelectric states, a ferroelectric crystal could exhibit a triple hysteresis under an ac field. For a BaTiO3 with the "c-plate" configuration slightly below this temperature, the middle loop is caused by the 0°→180° domain switch in the orthorhombic phase, whereas the upper and lower loops are the result of orthorhombic-to-tetragonal phase transition, and vice versa. In this article we first develop a micromechanics-based thermodynamic model to determine the thermodynamic driving force for phase transition and for domain switch as a function of electric field and temperature, and in the latter case, further supplement it with a kinetic equation and a homogenization scheme. The dependence of dielectric constant of the orthorhombic and tetragonal phases on temperature and electric field are also established. The developed theory is then applied to calculate the triple hysteresis loops of BaTiO3 at several levels of temperature. The calculated results for the triple loops, and for the variation of dielectric constant, are found to be in full accord with the test data of Huibregtse and Young [Phys. Rev. 103, 1705 (1956)].

  18. Correlation effects in 3D triple-Weyl semimetals

    NASA Astrophysics Data System (ADS)

    Zhang, Shi-Xin; Jian, Shao-Kai; Yao, Hong

    We study interaction effects, including short-range interactions and long-range Coulomb interactions, in three-dimensional topological triple-Weyl semimetals whose triple-Weyl points are protected by crystalline symmetries. In the low-energy effective field theory of triple-Weyl semimetals, by considering symmetries and utilizing Fierz identity, we find that there are only four independent short-range interaction terms. We then perform Wilsonian renormalization group analysis to determine the effect of short-range interactions at low energy and long distance by finding fixed points as well as stable strong-coupling limits. For those strong-coupling limits due to short-range interactions, spontaneous symmetry-breaking ordering is expected and is analyzed by self-consistent mean-field calculations combined with RG flow. For long-range Coulomb interactions, we find anisotropic screening effect, similar with the one in double-Weyl semimetals, and hence a qualitatively different fixed point from the Gaussian one.

  19. Photo-active collagen systems with controlled triple helix architecture

    PubMed Central

    Tronci, Giuseppe; Russell, Stephen J.; Wood, David J.

    2016-01-01

    The design of photo-active collagen systems is presented as a basis for establishing biomimetic materials with varied network architecture and programmable macroscopic properties. Following in-house isolation of type I collagen, reaction with vinyl-bearing compounds of varied backbone rigidity, i.e. 4-vinylbenzyl chloride (4VBC) and glycidyl methacrylate (GMA), was carried out. TNBS colorimetric assay, 1H-NMR and ATR-FTIR confirmed covalent and tunable functionalization of collagen lysines. Depending on the type and extent of functionalization, controlled stability and thermal denaturation of triple helices were observed via circular dichroism (CD), whereby the hydrogen-bonding capability of introduced moieties was shown to play a major role. Full gel formation was observed following photo-activation of functionalized collagen solutions. The presence of a covalent network only slightly affected collagen triple helix conformation (as observed by WAXS and ATR-FTIR), confirming the structural organization of functionalized collagen precursors. Photo-activated hydrogels demonstrated an increased denaturation temperature (DSC) with respect to native collagen, suggesting that the formation of the covalent network successfully stabilized collagen triple helices. Moreover, biocompatibility and mechanical competence of obtained hydrogels were successfully demonstrated under physiologically-relevant conditions. These results demonstrate that this novel synthetic approach enabled the formation of biocompatible collagen systems with defined network architecture and programmable macroscopic properties, which can only partially be obtained with current synthetic methods. PMID:27398214

  20. Prenatal diagnosis and prognosis of triple X syndrome: 47, XXX.

    PubMed

    Ben Hamouda, H; Mkacher, N; Elghezal, H; Bannour, H; Kamoun, M; Soua, H; Saad, A; Souissi, M M; Sfar, M T

    2009-11-01

    Triple X syndrome is a relatively common sex chromosomal abnormality occurring in 0,1% of live-born female infants. Most of these infants have a normal phenotype and only a few cases with 47, XXX karyotype have congenital malformations. We report three cases of triple X syndrome that were diagnosed prenatally by genetic amniocentesis for advanced maternal age and have been observed from birth to age of 3 to 12 years. A description of their growth and development is presented. The birth weight was normal in all patients and one of them had facial dysmorphism with right microphtalmia and auricular septal defect. During the first 2 years of life, the neuromotor development of these infants was not distinguishable from chromosomally normal children. By 3 years of age, two patients have a moderate developmental delay in speech and language. One girl 12-year-old had normal schooling. The diagnosis of the triple X syndrome can be never made because clinical demonstrations are not rather important to arouse the demand of a karyotype. Prenatal diagnosis is often made in front of the advanced maternal age. Expectant parents must be counseled as to the significance of this 47, XXX karyotype and prognostic information must be given.

  1. Layout compliance for triple patterning lithography: an iterative approach

    NASA Astrophysics Data System (ADS)

    Yu, Bei; Garreton, Gilda; Pan, David Z.

    2014-10-01

    As the semiconductor process further scales down, the industry encounters many lithography-related issues. In the 14nm logic node and beyond, triple patterning lithography (TPL) is one of the most promising techniques for Metal1 layer and possibly Via0 layer. As one of the most challenging problems in TPL, recently layout decomposition efforts have received more attention from both industry and academia. Ideally the decomposer should point out locations in the layout that are not triple patterning decomposable and therefore manual intervention by designers is required. A traditional decomposition flow would be an iterative process, where each iteration consists of an automatic layout decomposition step and manual layout modification task. However, due to the NP-hardness of triple patterning layout decomposition, automatic full chip level layout decomposition requires long computational time and therefore design closure issues continue to linger around in the traditional flow. Challenged by this issue, we present a novel incremental layout decomposition framework to facilitate accelerated iterative decomposition. In the first iteration, our decomposer not only points out all conflicts, but also provides the suggestions to fix them. After the layout modification, instead of solving the full chip problem from scratch, our decomposer can provide a quick solution for a selected portion of layout. We believe this framework is efficient, in terms of performance and designer friendly.

  2. New Approaches Towards Recognition of Nucleic Acid Triple Helices

    PubMed Central

    Arya, Dev P.

    2012-01-01

    We show that groove recognition of nucleic acid triple helices can be achieved with aminosugars. Among these aminosugars, neomycin is the most effective aminoglycoside (groove binder) for stabilizing a DNA triple helix. It stabilizes both the T·A·T triplex and mixed-base DNA triplexes better than known DNA minor groove binders (which usually destabilize the triplex) and polyamines. Neomycin selectively stabilizes the triplex (T·A·T and mixed base) without any effect on the DNA duplex. The selectivity of neomycin likely originates from its potential and shape complementarity to the triplex Watson–Hoogsteen groove, making it the first molecule that selectively recognizes a triplex groove over a duplex groove. The groove recognition of aminoglycosides is not limited to DNA triplexes, but also extends to RNA and hybrid triple helical structures. Intercalator–neomycin conjugates are shown to simultaneously probe the base stacking and groove surface in the DNA triplex. Calorimetric and spectrosocopic studies allow the quantification of the effect of surface area of the intercalating moiety on binding to the triplex. These studies outline a novel approach to the recognition of DNA triplexes that incorporates the use of non-competing binding sites. These principles of dual recognition should be applicable to the design of ligands that can bind any given nucleic acid target with nanomolar affinities and with high selectivity. PMID:21073199

  3. Practical solutions for reliable triple probe measurements in magnetized plasmas

    SciTech Connect

    Theiler, C.; Furno, I.; Kuenlin, A.; Marmillod, Ph.; Fasoli, A.

    2011-01-15

    The triple probe method to obtain local, time-resolved measurements of density, electron temperature and plasma potential is investigated in detail. The difficulties in obtaining reliable measurements with this technique are discussed and overcome. These include phase delay errors, ion sheath expansion and limited bandwidth due to stray capacitance to ground. In particular, a relatively simple electronic circuit is described to strongly reduce stray capacitance. Measurements with the triple probe are presented in a plasma characterized by interchange-driven turbulence in the TORPEX device. The measured time-averaged and time-dependent, conditionally averaged parameters are cross-checked with other Langmuir probe based techniques, and show good agreement. Triple probe measurements show that electron temperature fluctuations are sufficiently large, such that the identification of plasma potential fluctuations with fluctuations of the floating potential is not a good approximation. Over a large radial region, the time-averaged fluctuation-induced particle flux can, however, be deduced from floating potential only. This is because the phase shift between density and electron temperature is close to zero there and temperature fluctuations do not give rise to a net radial particle transport.

  4. Integrating Compassionate, Collaborative Care (the "Triple C") Into Health Professional Education to Advance the Triple Aim of Health Care.

    PubMed

    Lown, Beth A; McIntosh, Sharrie; Gaines, Martha E; McGuinn, Kathy; Hatem, David S

    2016-03-01

    Empathy and compassion provide an important foundation for effective collaboration in health care. Compassion (the recognition of and response to the distress and suffering of others) should be consistently offered by health care professionals to patients, families, staff, and one another. However, compassion without collaboration may result in uncoordinated care, while collaboration without compassion may result in technically correct but depersonalized care that fails to meet the unique emotional and psychosocial needs of all involved. Providing compassionate, collaborative care (CCC) is critical to achieving the "triple aim" of improving patients' health and experiences of care while reducing costs. Yet, values and skills related to CCC (or the "Triple C") are not routinely taught, modeled, and assessed across the continuum of learning and practice. To change this paradigm, an interprofessional group of experts recently recommended approaches and a framework for integrating CCC into health professional education and postgraduate training as well as clinical care. In this Perspective, the authors describe how the Triple C framework can be integrated and enhance existing competency standards to advance CCC across the learning and practice continuum. They also discuss strategies for partnering with patients and families to improve health professional education and health care design and delivery through quality improvement projects. They emphasize that compassion and collaboration are important sources of professional, patient, and family satisfaction as well as critical aspects of professionalism and person-centered, relationship-based high-quality care. PMID:26717505

  5. Integrating Compassionate, Collaborative Care (the "Triple C") Into Health Professional Education to Advance the Triple Aim of Health Care.

    PubMed

    Lown, Beth A; McIntosh, Sharrie; Gaines, Martha E; McGuinn, Kathy; Hatem, David S

    2016-03-01

    Empathy and compassion provide an important foundation for effective collaboration in health care. Compassion (the recognition of and response to the distress and suffering of others) should be consistently offered by health care professionals to patients, families, staff, and one another. However, compassion without collaboration may result in uncoordinated care, while collaboration without compassion may result in technically correct but depersonalized care that fails to meet the unique emotional and psychosocial needs of all involved. Providing compassionate, collaborative care (CCC) is critical to achieving the "triple aim" of improving patients' health and experiences of care while reducing costs. Yet, values and skills related to CCC (or the "Triple C") are not routinely taught, modeled, and assessed across the continuum of learning and practice. To change this paradigm, an interprofessional group of experts recently recommended approaches and a framework for integrating CCC into health professional education and postgraduate training as well as clinical care. In this Perspective, the authors describe how the Triple C framework can be integrated and enhance existing competency standards to advance CCC across the learning and practice continuum. They also discuss strategies for partnering with patients and families to improve health professional education and health care design and delivery through quality improvement projects. They emphasize that compassion and collaboration are important sources of professional, patient, and family satisfaction as well as critical aspects of professionalism and person-centered, relationship-based high-quality care.

  6. Influence of secreted frizzled receptor protein 1 (SFRP1) on neoadjuvant chemotherapy in triple negative breast cancer does not rely on WNT signaling

    PubMed Central

    2014-01-01

    Background Triple negative breast cancer (TNBC) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of overexpression or amplification of HER2. Despite an increased probability of response to chemotherapy, many patients resistant to current chemotherapy regimens suffer from a worse prognosis compared to other breast cancer subtypes. However, molecular determinants of response to chemotherapy specific to TNBC remain largely unknown. Thus, there is a high demand for biomarkers potentially stratifying triple negative breast cancer patients for neoadjuvant chemotherapies or alternative therapies. Methods In order to identify genes correlating with both the triple negative breast cancer subtype as well as response to neoadjuvant chemotherapy we employed publicly available gene expression profiles of patients, which had received neoadjuvant chemotherapy. Analysis of tissue microarrays as well as breast cancer cell lines revealed correlation to the triple negative breast cancer subtype. Subsequently, effects of siRNA-mediated knockdown on response to standard chemotherapeutic agents as well as radiation therapy were analyzed. Additionally, we evaluated the molecular mechanisms by which SFRP1 alters the carcinogenic properties of breast cancer cells. Results SFRP1 was identified as being significantly overexpressed in TNBC compared to other breast cancer subtypes. Additionally, SFRP1 expression is significantly correlated with an increased probability of positive response to neoadjuvant chemotherapy. Knockdown of SFRP1 in triple negative breast cancer cells renders the cells more resistant to standard chemotherapy. Moreover, tumorigenic properties of the cells are modified by knockdown, as shown by both migration or invasion capacity as well reduced apoptotic events. Surprisingly, we found that these effects do not rely on Wnt signaling. Furthermore, we show that pro-apoptotic as well as migratory pathways are differentially

  7. Desorption Kinetics of H2O from Cab-O-Sil-M-7D and Hi-Sil-233 Silica Particles

    SciTech Connect

    Dinh, L.; Balooch, M.; LeMay, J.D.

    2000-01-26

    Temperature programmed desorption (TPD) was performed at temperatures up to 850K on Cab-O-Sil-M-7D and Hi-Sil-233 silica particles. Physisorbed water molecules on both types of silica had activation energies in the range of 9-14.5 kcal/mol. However, the activation energies of desorption for chemisorbed water varied from {approx} 19 kcal/mol to > 59 kcal/mol for Cab-O-Sil-M-7D, and {approx} 23-37 kcal/mol for Hi-Sil-233. Our results suggest that physisorbed water can be effectively pumped away at room temperature (or preferably at 320 K) in a matter of hours. Chemisorbed water with high activation energies of desorption (>30 kcal/mol) will not escape the silica surfaces in 100 years even at 320 K, while a significant amount of the chemisorbed water with medium activation energies (19-26 kcal/mol) will leave the silica surfaces in that time span. Most of the chemisorbed water with activation energies < 30 kcal/mol can be pumped away in a matter of days in a good vacuum environment at 500 K. We had previously measured about 0.1-0.4 wt. % of water in M9787 polysiloxane formulations containing {approx} 21% Cab-O-Sil-M-7D and {approx} 4% Hi-Sil-233. Comparing present results with these formulations, we conclude that absorbed H{sub 2}O and Si-OH bonds on the silica surfaces are the major contributors to water outgassing from M97 series silicones.

  8. Guide to Understanding Triple-Negative Breast Cancer

    MedlinePlus

    ... Diet, Nutrition and Exercise Expressive Writing Guided Imagery Hypnosis Massage Therapy Mindfulness-Based Stress Reduction Yoga and ... Diet, Nutrition and Exercise Expressive Writing Guided Imagery Hypnosis Massage Therapy Mindfulness-Based Stress Reduction Yoga and ...

  9. Alternative Therapies

    MedlinePlus

    ... Late Effects of Poliomyelitis for Physicians and Survivors © Alternative Therapies Alternative therapies, also called complementary, can support ... of motion, pain, and fatigue are often reported. Energy work includes acupuncture and acupressure, traditional Chinese medicine ...

  10. Radiation Therapy

    MedlinePlus

    ... people who have radiation therapy may feel more tired than usual, not feel hungry, or lose their ... of radiation therapy include: Fatigue. Fatigue, or feeling tired, is the most common side effect of radiation ...

  11. Radiation therapy

    MedlinePlus

    ... Because radiation is most harmful to quickly growing cells, radiation therapy damages cancer cells more than normal cells. ... cells from growing and dividing, and leads to cell death. Radiation therapy is used to fight many types of ...

  12. Emerging targets for antidepressant therapies

    PubMed Central

    Rakofsky, Jeffrey J; Holtzheimer, Paul E; Nemeroff, Charles B

    2015-01-01

    Despite adequate antidepressant monotherapy, the majority of depressed patients do not achieve remission. Even optimal and aggressive therapy leads to a substantial number of patients who show minimal and often only transient improvement. In order to address this substantial problem of treatment-resistant depression, a number of novel targets for antidepressant therapy have emerged as a consequence of major advances in the neurobiology of depression. Three major approaches to uncover novel therapeutic interventions are: first, optimizing the modulation of monoaminergic neurotransmission; second, developing medications that act upon neurotransmitter systems other than monoaminergic circuits; and third, using focal brain stimulation to directly modulate neuronal activity. We review the most recent data on novel therapeutic compounds and their antidepressant potential. These include triple monoamine reuptake inhibitors, atypical antipsychotic augmentation, and dopamine receptor agonists. Compounds affecting extra-monoamine neurotransmitter systems include CRF1 receptor antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, NMDA receptor antagonists, nemifitide, omega-3 fatty acids, and melatonin receptor agonists. Focal brain stimulation therapies include vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS). PMID:19501541

  13. Oxygen Therapy

    MedlinePlus

    Oxygen therapy is a treatment that provides you with extra oxygen. Oxygen is a gas that your body needs to function. Normally, your lungs absorb ... in your home. A different kind of oxygen therapy is called hyperbaric oxygen therapy. It uses oxygen ...

  14. Simulations of magnetic field gradients due to micro-magnets on a triple quantum dot circuit

    SciTech Connect

    Poulin-Lamarre, G.; Bureau-Oxton, C.; Kam, A.; Zawadzki, P.; Aers, G.; Studenikin, S.; Pioro-Ladrière, M.; Sachrajda, A. S.

    2013-12-04

    To quantify the effects of local magnetic fields on triple quantum dots, the Heisenberg Hamiltonian has been diagonalized for three electrons coupled via the exchange interaction. In particular, we have investigated different geometries of micro-magnets located on top of the triple dot in order to optimize the field gradient characteristics. In this paper, we focus on two geometries which are candidates for an addressable EDSR triple quantum dot device.

  15. Elucidating pH-dependent collagen triple helix formation through interstrand hydroxyproline-glutamic acid interactions.

    PubMed

    Chen, Liwei; Cai, Shuting; Lim, Jaehong; Lee, Su Seong; Lee, Song-Gil

    2015-02-01

    Here, we describe systematic explorations into the molecular basis underlying hydroxyproline-mediated interstrand interactions on the triple-helical stability of collagen-mimetic peptides containing glutamic acid residues. Our studies reveal that the triple-helical stability of these peptides relies on the existence of interstrand interactions between hydroxyprolines and glutamic acid residues that are pH dependent. These unique interactions have been used to engineer collagen peptides that form triple helices on demand through pH control.

  16. Should quinolones come first in Helicobacter pylori therapy?

    PubMed Central

    Berning, Marco; Krasz, Susanne; Miehlke, Stephan

    2011-01-01

    New generations of fluoroquinolones, like levofloxacin and moxifloxacin, exhibit a broad-spectrum activity against Gram-positive and Gram-negative bacteria, and have been successfully introduced into the treatment of Helicobacter pylori infection. Based on a large body of evidence, current guidelines recommend the use of levofloxacin- or moxifloxacin-containing proton-pump inhibitor (PPI) triple therapies in second-line or rescue treatment of H. pylori infection. The efficacy of standard PPI triple therapies has substantially declined during the last decade, mainly due to increasing resistance against the key antibiotics clarithromycin and metronidazole. Therefore, alternative strategies for first-line therapy of H. pylori infection have been evaluated in a considerable number of clinical trials including sequential regimens, nonbismuth quadruple regimens, and quinolone-containing PPI triple therapy regimens. The aim of this paper is to summarize the current body of evidence of levofloxacin- and moxifloxacin-containing regimens in first-line treatment of H. pylori infection, and to discuss the risks and benefits of these strategies in the light of increasing resistance of H. pylori to quinolones. PMID:21694812

  17. Triple Tobacco Screen Opportunity to Help Families Become Smokefree

    PubMed Central

    Nabi-Burza, Emara; Winickoff, Jonathan P.; Finch, Stacia; Regan, Susan

    2013-01-01

    Background American Academy of Pediatrics policy recommends that pediatricians document environmental tobacco smoke (ETS) exposure of a child at every visit. The extent to which pediatricians adhere to this policy, however, is unknown. Purpose The goal of the study was to examine the extent to which pediatricians screen parents for tobacco use and home- and car-related smoking rules. Further, the potential association between factors associated with pediatrician inquiry into parental tobacco use and rules is examined. Methods Post-visit exit interviews were conducted in ten pediatric practices between June 2009 and March 2011 with parents whose children had been seen by a healthcare provider. Parents were considered to have been given the “triple tobacco screen” if they reported being asked by a pediatric healthcare provider about their smoking behavior, smokefree home rules, and smokefree car rules. Bivariate analysis and multivariable logistic regression was done to explore factors associated with parents being given any component of the triple tobacco screening. Data were analyzed between March 2012 and February 2013. Results Of 9145 parents interviewed, 20% of the parents reported being asked at least one question from the triple tobacco screen, and only 9% reported being asked all three questions. Overall, 17% of parents reported being asked about their smoking status, 16% about smokefree home rules, and 11% about smokefree car rules. Few smoking parents (23%) and fewer nonsmoking parents (19%) were screened about their tobacco use and behavior. Conclusions Pediatricians infrequently addressed ETS exposure of children among parents who do and do not smoke. Substantial missed opportunities may exist to counsel smokers and reduce ETS exposure of children in the most common exposure locations—the home and car. PMID:24237914

  18. Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples

    PubMed Central

    Nuovo, Gerard J; Garofalo, Michela; Valeri, Nicola; Roulstone, Vicki; Volinia, Stefano; Cohn, David E; Phelps, Mitch; Harrington, Kevin J; Vile, Richard; Melcher, Alan; Galanis, Evanthia; Sehl, Sarah; Adair, Rob; Scott, Karen; Rose, Ailsa; Toogood, Giles; Coffey, Matthew C

    2014-01-01

    We analyzed the in situ molecular correlates of infection from cancer patients treated with reovirus. Melanoma, colorectal, and ovarian cancer samples from such patients showed variable infection of the cancer cells but not the intermingled benign cells. RT in situ PCR showed most cancer cells contained the viral genome with threefold less having productive viral infection as documented by either tubulin or reoviral protein co-expression. Productive infection in the cancer cells was strongly correlated with co-expression of p38 and caspase-3 as well as apoptosis-related death (P<0.001). The cancer cell apoptotic death was due to a marked viral-induced inhibition of microRNA-let-7d that, in turn, upregulated caspase-3 activity. In summary, reovirus shows a striking tropism to cancer cells in clinical samples. A rate-limiting factor of reovirus-induced cancer cell death is productive viral infection that operates via the marked reduction of microRNA-let-7d and concomitant elevated caspase-3 expression. PMID:22699519

  19. Computational and anti-tumor studies of 7a-Aza-B-homostigmast-5-eno [7a, 7-d] tetrazole-3β-yl chloride

    NASA Astrophysics Data System (ADS)

    Alam, Mahboob; Alam, Mohammad Jane; Nami, Shahab A. A.; Lee, Dong-Ung; Azam, Mohammad; Ahmad, Shabbir

    2016-03-01

    The present paper reports the detailed computational study including molecular docking of a biologically active steroidal tetrazole, 7a-Aza-B-homostigmast-5-eno [7a,7-d] tetrazole-3β-yl chloride. The molecular structure, IR and NMR (13C and 1H) spectra of the tetrazole were interpreted by comparing the experimental results with the theoretical, B3LYP/6-311G(d,p) calculations. The vibrational bands appearing in the FTIR are assigned with great accuracy using animated modes. Molecular properties like HOMO-LUMO analysis, chemical reactivity descriptors, MEP mapping, dipole moment and natural atomic charges have been presented at the same level of theory. The theoretical results are found in good correlation with the experimental data. Moreover, the Hirshfeld analysis was carried out to ascertain the secondary interactions and associated 2D fingerprint plots. The in vitro anti-tumor activity of 7a-Aza-B-homostigmast-5-eno [7a,7-d] tetrazole-3β-yl chloride has also been carried out against five human tumor cell lines. Doxorubicin is used as a standard drug for the in vitro anti-tumor screening.

  20. The assignment of a Thinopyrum distichum (Thunb.) Löve-derived translocation to the long arm of wheat chromosome 7D using endopeptidase polymorphisms.

    PubMed

    Marais, G F; Marais, A S

    1990-02-01

    Endopeptidase zymograms of the translocation line 'Indis' revealed the presence of several major and minor bands that had differential expression in coleoptile and seed tissues. While 'Indis' lacks Ep-D1a, which is present in the parental cultivar 'Inia 66', it also may not express any of the Th. distichum bands. The 'Indis' zymogram was found to be identical to that of an isogenic line of 'Inia 66' possessing Lr19. Since the absence of an Ep-D1a product appears to be linked to the 7DL translocation, it is possible to use the null condition as a marker for both the Lr19 or 'Indis' translocations. The 'Indis' translocation also did not show recombination with the cn-D1 chlorophyl mutant on 7DL, confirming that a part of 7D was involved. The results of a telocentric mapping experiment involving the 7D telosomes indicated that in 'Indis' a chromosome segment from Th. distichum replaced a large section of 7DL of 'Inia 66'. PMID:24226216

  1. DFT, Hirshfeld surfaces, spectral and in vivo cytotoxic studies of 7a-Aza-B-homostigmast-5-eno [7a,7-d] tetrazole

    NASA Astrophysics Data System (ADS)

    Alam, Mahboob; Alam, Mohammad Jane; Nami, Shahab A. A.; Khan, Mohd Shoeb; Ahmad, Shabbir; Lee, Dong-Ung

    2015-11-01

    The DFT (B3LYP) calculations on a synthetic steroidal molecule 7a-Aza-B-homostigmast-5-eno [7a,7-d] tetrazole, C29H48N4, have been performed. The molecular structure, IR and NMR (13C and 1H) spectra of the present compound were interpreted using experiments (XRD, FTIR, NMR) as well as theoretical, B3LYP/6-311 + G(2d,p), calculations. The vibrational bands appearing in FTIR are assigned with great accuracy using animated modes. Molecular properties like HOMO-LUMO analysis, chemical reactivity descriptors, MEP mapping, dipole moment and Mullikan's atomic charges have been presented at the same level of theory. The theoretical results are found in good correlation with experimental data. Moreover, the Hirshfeld analysis was carried out to ascertain the secondary interactions and associated 2D fingerprint plots. The in vivo cytotoxicity of 7a-Aza-B-homostigmast-5-eno [7a,7-d] has also been carried out against brine shrimp nauplii by lethality bioassay.

  2. Computational and anti-tumor studies of 7a-Aza-B-homostigmast-5-eno [7a, 7-d] tetrazole-3β-yl chloride

    NASA Astrophysics Data System (ADS)

    Alam, Mahboob; Alam, Mohammad Jane; Nami, Shahab A. A.; Lee, Dong-Ung; Azam, Mohammad; Ahmad, Shabbir

    2016-03-01

    The present paper reports the detailed computational study including molecular docking of a biologically active steroidal tetrazole, 7a-Aza-B-homostigmast-5-eno [7a,7-d] tetrazole-3β-yl chloride. The molecular structure, IR and NMR (13C and 1H) spectra of the tetrazole were interpreted by comparing the experimental results with the theoretical, B3LYP/6-311G(d,p) calculations. The vibrational bands appearing in the FTIR are assigned with great accuracy using animated modes. Molecular properties like HOMO-LUMO analysis, chemical reactivity descriptors, MEP mapping, dipole moment and natural atomic charges have been presented at the same level of theory. The theoretical results are found in good correlation with the experimental data. Moreover, the Hirshfeld analysis was carried out to ascertain the secondary interactions and associated 2D fingerprint plots. The in vitro anti-tumor activity of 7a-Aza-B-homostigmast-5-eno [7a,7-d] tetrazole-3β-yl chloride has also been carried out against five human tumor cell lines. Doxorubicin is used as a standard drug for the in vitro anti-tumor screening.

  3. Re-emergent human adenovirus genome type 7d caused an acute respiratory disease outbreak in Southern China after a twenty-one year absence.

    PubMed

    Zhao, Suhui; Wan, Chengsong; Ke, Changwen; Seto, Jason; Dehghan, Shoaleh; Zou, Lirong; Zhou, Jie; Cheng, Zetao; Jing, Shuping; Zeng, Zhiwei; Zhang, Jing; Wan, Xuan; Wu, Xianbo; Zhao, Wei; Zhu, Li; Seto, Donald; Zhang, Qiwei

    2014-01-01

    Human adenoviruses (HAdVs) are highly contagious pathogens causing acute respiratory disease (ARD), among other illnesses. Of the ARD genotypes, HAdV-7 presents with more severe morbidity and higher mortality than the others. We report the isolation and identification of a genome type HAdV-7d (DG01_2011) from a recent outbreak in Southern China. Genome sequencing, phylogenetic analysis, and restriction endonuclease analysis (REA) comparisons with past pathogens indicate HAdV-7d has re-emerged in Southern China after an absence of twenty-one years. Recombination analysis reveals this genome differs from the 1950s-era prototype and vaccine strains by a lateral gene transfer, substituting the coding region for the L1 52/55 kDa DNA packaging protein from HAdV-16. DG01_2011 descends from both a strain circulating in Southwestern China (2010) and a strain from Shaanxi causing a fatality and outbreak (Northwestern China; 2009). Due to the higher morbidity and mortality rates associated with HAdV-7, the surveillance, identification, and characterization of these strains in population-dense China by REA and/or whole genome sequencing are strongly indicated. With these accurate identifications of specific HAdV types and an epidemiological database of regional HAdV pathogens, along with the HAdV genome stability noted across time and space, the development, availability, and deployment of appropriate vaccines are needed. PMID:25482188

  4. Dynamical formation and scattering of hierarchical triples: cross-sections, Kozai-Lidov oscillations, and collisions

    NASA Astrophysics Data System (ADS)

    Antognini, Joseph M. O.; Thompson, Todd A.

    2016-03-01

    Dynamical scattering of binaries and triple systems of stars, planets, and compact objects may produce highly inclined triple systems subject to Kozai-Lidov (KL) oscillations, potentially leading to collisions, mergers, Type Ia supernovae, and other phenomena. We present the results of more than 400 million gravitational scattering experiments of binary-binary, triple-single, and triple-binary scattering. We compute the cross-sections for all possible outcomes and explore their dependences on incoming velocity, mass, semimajor axis, and eccentricity, including analytic fits and discussion of the velocity dependence. For the production of new triple systems by scattering we find that compact triples are preferred, with ratios of outer to inner semimajor axes of ˜few-100, flat or quasi-thermal eccentricity distributions, and flat distributions in cosine of the mutual inclination. Dynamically formed triples are thus subject to strong KL oscillations, the `eccentric Kozai mechanism', and non-secular effects. For single and binary flyby encounters with triple systems, we compute the cumulative cross-section for changes to the mutual inclination, eccentricity, and semimajor axis ratio. We apply these results to scattering events in the field, open clusters, and globular clusters, and explore the implications for Type Ia supernovae via collisions and mergers, stellar collisions, and the lifetime and dynamical isolation of triple systems undergoing KL oscillations. An appendix provides an analysis of the velocity dependence of the collision cross-section in binary-single scattering.

  5. Three cases of triple A syndrome (Allgrove syndrome) in pediatric surgeons' view.

    PubMed

    Erginel, Başak; Gün, Feryal; Kocaman, Hakan; Çelik, Alaadin; Salman, Tansu

    2016-04-01

    Triple A syndrome, also known as Allgrove syndrome, is a rare disease, and presents mainly in children. Its cardinal symptoms are achalasia, alacrima, and adrenocorticotropic hormone (ACTH) insensitivity. We report three cases of Triple A syndrome. Our aim is to inform pediatric surgeons about the existence of this rare syndrome and to highlight the need for suspicion of alacrima and ACTH insensitivity in cases of pediatric achalasia. Triple A syndrome should be considered in patients presenting with achalasia. Alacrima should be investigated by a Schirmer test, and adrenal dysfunction should be tested in cases of suspected triple A. PMID:27385299

  6. Play Therapy

    PubMed Central

    Kool, Ritesh

    2010-01-01

    Play therapy represents a unique form of treatment that is not only geared toward young children, but is translated into a language children can comprehend and utilize—the language of play. For the referring provider or practitioner, questions may remain regarding the nature, course, and efficacy of play therapy. This article reviews the theoretical underpinnings of play therapy, some practical considerations, and finally a summary of the current state of research in regard to play therapy. The authors present the practicing psychiatrist with a road map for referring a patient to play therapy or initiating it in appropriate cases. PMID:21103141

  7. Controllable optomechanical coupling in serially-coupled triple resonators

    SciTech Connect

    Huang, Chenguang Zhao, Yunsong; Fan, Jiahua; Zhu, Lin

    2014-12-15

    Radiation pressure can efficiently couple mechanical modes with optical modes in an optical cavity. The coupling efficiency is quite dependent on the interaction between the optical mode and mechanical mode. In this report, we investigate a serially-coupled triple resonator system, where a freestanding beam is placed in the vicinity of the middle resonator. In this coupled system, we demonstrate that the mechanical mode of the free-standing beam can be selectively coupled to different resonance supermodes through the near field interaction.

  8. Parts, Wholes, and Context in Reading: A Triple Dissociation

    PubMed Central

    Pelli, Denis G.; Tillman, Katharine A.

    2007-01-01

    Research in object recognition has tried to distinguish holistic recognition from recognition by parts. One can also guess an object from its context. Words are objects, and how we recognize them is the core question of reading research. Do fast readers rely most on letter-by-letter decoding (i.e., recognition by parts), whole word shape, or sentence context? We manipulated the text to selectively knock out each source of information while sparing the others. Surprisingly, the effects of the knockouts on reading rate reveal a triple dissociation. Each reading process always contributes the same number of words per minute, regardless of whether the other processes are operating. PMID:17668058

  9. Assignment of phycocyanobilin in HMPT using triple resonance experiments.

    PubMed

    Röben, Marco; Schmieder, Peter

    2011-09-01

    A complete assignment of all resonances of a small organic molecule is a prerequisite for a structure determination using NMR spectroscopy. This is conventionally obtained using a well-established strategy based on COSY, HMQC and HMBC spectra. In case of phycocyanobilin (PCB) in HMPT this strategy was unsuccessful due to the symmetry of the molecule and extreme signal overlap. Since (13)C and (15)N labeled material was available, an alternative strategy for resonance assignment was used. Triple resonance experiments derived from experiments conventionally performed for proteins are sensitive and easy to analyze. Their application led to a complete and unambiguous assignment using three types of experiments. PMID:21815209

  10. An acoustic vibration sensor based on tapered triple cladding fiber

    NASA Astrophysics Data System (ADS)

    Xu, Hui; Pang, Fufei; Zhao, Shiqi; Chen, Zhenyi; Wang, Tingyun

    2014-05-01

    An acoustic vibration sensor is investigated and demonstrated by using a tapered triple cladding fiber (TCF). It is fabricated by tapering a length of 2 cm TCF which is spliced between two single mode fibers (SMF). The TCF consists of core, inner cladding, middle cladding and outer cladding. After the tapering process, this structure becomes a tapered coaxial fiber coupler which presents a periodic filtering transmission spectrum. The surrounding vibration perturbation can be directly demodulated by intensity detection of the transmission power at a particular wavelength. The experimental result shows that the maximum frequency response of 700 kHz is achieved.

  11. Long-term stability test of a triple GEM detector

    NASA Astrophysics Data System (ADS)

    Adak, R. P.; Biswas, S.; Das, S.; Ghosal, D.; Ghosh, S. K.; Mondal, A.; Nag, D.; Nayak, T. K.; Patra, R. N.; Prasad, S. K.; Raha, S.; Sahu, P. K.; Sahu, S.; Swain, S.

    2016-10-01

    The main aim of the study is to perform the long-term stability test of gain of the single mask triple GEM detector. A simple method is used for this long-term stability test using a radioactive X-ray source with high activity. The test is continued till accumulation of charge per unit area > 12.0 mC/mm2. The details of the chamber fabrication, the test set-up, the method of measurement and the test results are presented in this paper.

  12. Hydrothermal Exploration at the Chile Triple Junction - ABE's last adventure?

    NASA Astrophysics Data System (ADS)

    German, C. R.; Shank, T. M.; Lilley, M. D.; Lupton, J. E.; Blackman, D. K.; Brown, K. M.; Baumberger, T.; Früh-Green, G.; Greene, R.; Saito, M. A.; Sylva, S.; Nakamura, K.; Stanway, J.; Yoerger, D. R.; Levin, L. A.; Thurber, A. R.; Sellanes, J.; Mella, M.; Muñoz, J.; Diaz-Naveas, J. L.; Inspire Science Team

    2010-12-01

    In February and March 2010 we conducted preliminary exploration for hydrothermal plume signals along the East Chile Rise where it intersects the continental margin at the Chile Triple Junction (CTJ). This work was conducted as one component of our larger NOAA-OE funded INSPIRE project (Investigation of South Pacific Reducing Environments) aboard RV Melville cruise MV 1003 (PI: Andrew Thurber, Scripps) with all shiptime funded through an award of the State of California to Andrew Thurber and his co-PI's. Additional support came from the Census of Marine Life (ChEss and CoMarge projects). At sea, we conducted a series of CTD-rosette and ABE autonomous underwater vehicle operations to prospect for and determine the nature of any seafloor venting at, or adjacent to, the point where the the East Chile Rise subducts beneath the continental margin. Evidence from in situ sensing (optical backscatter, Eh) and water column analyses of dissolved CH4, δ3He and TDFe/TDMn concentrations document the presence of two discrete sites of venting, one right at the triple junction and the other a further 10km along axis, north of the Triple Junction, but still within the southernmost segment of the East Chile Rise. From an intercomparison of the abundance of different chemical signals we can intercompare likely characteristics of these differet source sites and also differentiate between them and the high methane concentrations released from cold seep sites further north along the Chile Margin, both with the CTJ region and also at the Concepcion Methane Seep Area (CMSA). This multi-disciplinary and international collaboration - involving scientists from Chile, the USA, Europe and Japan - can serve as an excellent and exciting launchpoint for wide-ranging future investigations of the Chile Triple Junction area - the only place on Earth where an oceanic spreading center is being actively subducted beneath a continent and also the only place on Earth where all known forms of deep

  13. Triple-phase bone image abnormalities in Lyme arthritis

    SciTech Connect

    Brown, S.J.; Dadparvar, S.; Slizofski, W.J.; Glab, L.B.; Burger, M. )

    1989-10-01

    Arthritis is a frequent manifestation of Lyme disease. Limited triple-phase Tc-99m MDP bone imaging of the wrists and hands with delayed whole-body images was performed in a patient with Lyme arthritis. This demonstrated abnormal joint uptake in the wrists and hands in all three phases, with increased activity seen in other affected joints on delayed whole-body images. These findings are nonspecific and have been previously described in a variety of rheumatologic conditions, but not in Lyme disease. Lyme disease should be considered in the differential diagnosis of articular and periarticular bone scan abnormalities.

  14. Triple bridge to simultaneous heart and kidney transplantation.

    PubMed

    El-Sayed Ahmed, Magdy M; Aftab, Muhammad; Singh, Steve K; Mallidi, Hari R; Frazier, Oscar H

    2014-08-01

    We report a 40-year-old man who presented with irreversible cardiogenic shock. The patient was treated with three consecutive stages of mechanical circulatory support as a triple bridge to cardiac transplantation. Extracorporeal membrane oxygenation support was used for 5 days, followed by Levitronix CentriMag biventricular assist devices for 39 days. This was escalated to implantation of the CardioWest temporary total artificial heart for 107 days. The patient experienced concurrent end-stage renal disease and subsequently underwent both heart and kidney transplantation. On postoperative day 18 the patient was discharged with good cardiac and renal function.

  15. Imaginary-time formalism for triple-α reaction rates

    NASA Astrophysics Data System (ADS)

    Akahori, T.; Funaki, Y.; Yabana, K.

    2015-08-01

    Using imaginary-time formalism, it is shown that the triple-α reaction rate can be reliably calculated without the need to solve scattering problems involving three charged particles. The calculated reaction rate is found to agree well with the empirical NACRE rate, which is widely adopted in stellar evolution calculations. The reason for this is explained using R -matrix theory. Extremely slow convergence is found to occur when a coupled-channel expansion is introduced, which helps to explain the very different reaction rates obtained using a coupled-channel approach.

  16. Triple-material stress-strain resistivity gage

    DOEpatents

    Stout, Ray B.

    1988-01-01

    A triple material piezoresistive gage provides multi-component elastic stress or measurements. Thin foils of three piezoresistive materials, e.g. ytterbium, manganin, and constantan, are configured in a nested serpentine rectilinear grid or other grid arrangement and embedded in a medium, preferably normal to the direction of shock wave propagation. The output of the gage is a resistivity change history for each material of the gage. Each resistivity change is independent of the others so that three diagonal components of the elastic stress or strain tensor can be calculated from the resistivity measurements.

  17. Triple-material stress-strain resistivity gage

    DOEpatents

    Stout, R.B.

    1987-05-19

    A triple material piezoresistive gage provides multi-component elastic stress or strain measurements. Thin foils of three piezoresistive materials, e.g., ytterbium, manganin, and constantan, are configured in a nested serpentine rectilinear grind or other grind arrangement and embedded in a medium, preferably normal to the direction of shock wave propagation. The output of the gage is a resistivity change history for each material of gage. Each resistivity change is independent of the others so that three diagonal components of the elastic stress or strain tensor can be calculated form the resistivity measurements. 4 figs.

  18. Triple-material stress-strain resistivity gage

    DOEpatents

    Stout, R.B.

    1988-05-17

    A triple material piezoresistive gage provides multi-component elastic stress measurements is disclosed. Thin foils of three piezoresistive materials, e.g. ytterbium, manganin, and constantan, are configured in a nested serpentine rectilinear grid or other grid arrangement and embedded in a medium, preferably normal to the direction of shock wave propagation. The output of the gage is a resistivity change history for each material of the gage. Each resistivity change is independent of the others so that three diagonal components of the elastic stress or strain tensor can be calculated from the resistivity measurements. 4 figs.

  19. Argon Triple Point for Long-Stem SPRTs: Thermal Behavior

    NASA Astrophysics Data System (ADS)

    Dobre, M.; Didialaoui, I.; Hermier, Y.

    2011-08-01

    A new device for an ITS-90 triple-point-of-argon realization has been designed at LNE-CNAM. It follows the widely used principle of the cryogenic Dewar filled with pressurized liquid nitrogen, but the new construction achieves better temperature stability at the level of the argon cell. A new pressure regulation, controlled directly by a nitrogen temperature measurement, solves the problem of the influence of atmospheric-pressure variations. The paper presents the new device and the thermal tests conducted in order to optimize the pressure regulation.

  20. The involvement of collagen triple helix repeat containing 1 in muscular dystrophies.

    PubMed

    Spector, Itai; Zilberstein, Yael; Lavy, Adi; Genin, Olga; Barzilai-Tutsch, Hila; Bodanovsky, Ana; Halevy, Orna; Pines, Mark

    2013-03-01

    Fibrosis is the main complication of muscular dystrophies. We identified collagen triple helix repeat containing 1 (Cthrc1) in skeletal and cardiac muscles of mice, representing Duchenne and congenital muscle dystrophies (DMD and CMD, respectively), and dysferlinopathy. In all of the mice, Cthrc1 was associated with high collagen type I levels; no Cthrc1 or collagen was observed in muscles of control mice. High levels of Cthrc1 were also observed in biopsy specimens from patients with DMD, in whom they were reversibly correlated with that of β-dystroglycan, whereas collagen type I levels were elevated in all patients with DMD. At the muscle sites where collagen and Cthrc1 were adjacent, collagen fibers appeared smaller, suggesting involvement of Cthrc1 in collagen turnover. Halofuginone, an inhibitor of Smad3 phosphorylation downstream of the transforming growth factor-β signaling, reduced Cthrc1 levels in skeletal and cardiac muscles of mice, representing DMD, CMD, and dysferlinopathy. The myofibroblasts infiltrating the dystrophic muscles of the murine models of DMD, CMD, and dysferlinopathy were the source of Cthrc1. Transforming growth factor-β did not affect Cthrc1 levels in the mdx fibroblasts but decreased them in the control fibroblasts, in association with increased migration of mdx fibroblasts and dystrophic muscle invasion by myofibroblasts. To our knowledge, this is the first demonstration of Cthrc1 as a marker of the severity of the disease progression in the dystrophic muscles, and as a possible target for therapy.

  1. Adipose microenvironment promotes triple negative breast cancer cell invasiveness and dissemination by producing CCL5

    PubMed Central

    D’Esposito, Vittoria; Liguoro, Domenico; Ambrosio, Maria Rosaria; Collina, Francesca; Cantile, Monica; Spinelli, Rosa; Raciti, Gregory Alexander; Miele, Claudia; Valentino, Rossella; Campiglia, Pietro; De Laurentiis, Michelino; Di Bonito, Maurizio; Botti, Gerardo; Franco, Renato; Beguinot, Francesco; Formisano, Pietro

    2016-01-01

    Growing evidence indicates that adiposity is associated with raised cancer incidence, morbidity and mortality. In a subset of tumors, cancer cell growth and/or metastasis predominantly occur in adipocyte-rich microenvironment. Indeed, adipocytes represent the most abundant cell types surrounding breast cancer cells. We have studied the mechanisms by which peritumoral human adipose tissue contributes to Triple Negative Breast Cancer (TNBC) cell invasiveness and dissemination. Co-culture with human adipocytes enhanced MDA-MB231 cancer cell invasiveness. Adipocytes cultured in high glucose were 2-fold more active in promoting cell invasion and motility compared to those cultured in low glucose. This effect is induced, at least in part, by the CC-chemokine ligand 5 (CCL5). Indeed, CCL5 inhibition by specific peptides and antibodies reduced adipocyte-induced breast cancer cell migration and invasion. CCL5 immuno-detection in peritumoral adipose tissue of women with TNBC correlated with lymph node (p-value = 0.04) and distant metastases (p-value = 0.001). A positive trend was also observed between CCL5 expression and glycaemia. Finally, Kaplan-Meier curves showed a negative correlation between CCL5 staining in the peritumoral adipose tissue and overall survival of patients (p-value = 0.039). Thus, inhibition of CCL5 in adipose microenvironment may represent a novel approach for the therapy of highly malignant TNBC. PMID:27027351

  2. Exercise effects on postprandial glucose metabolism in type 1 diabetes: a triple-tracer approach.

    PubMed

    Mallad, Ashwini; Hinshaw, Ling; Schiavon, Michele; Dalla Man, Chiara; Dadlani, Vikash; Basu, Rita; Lingineni, Ravi; Cobelli, Claudio; Johnson, Matthew L; Carter, Rickey; Kudva, Yogish C; Basu, Ananda

    2015-06-15

    To determine the effects of exercise on postprandial glucose metabolism and insulin action in type 1 diabetes (T1D), we applied the triple tracer technique to study 16 T1D subjects on insulin pump therapy before, during, and after 75 min of moderate-intensity exercise (50% V̇o2max) that started 120 min after a mixed meal containing 75 g of labeled glucose. Prandial insulin bolus was administered as per each subject's customary insulin/carbohydrate ratio adjusted for meal time meter glucose and the level of physical activity. Basal insulin infusion rates were not altered. There were no episodes of hypoglycemia during the study. Plasma dopamine and norepinephrine concentrations rose during exercise. During exercise, rates of endogenous glucose production rose rapidly to baseline levels despite high circulating insulin and glucose concentrations. Interestingly, plasma insulin concentrations increased during exercise despite no changes in insulin pump infusion rates, implying increased mobilization of insulin from subcutaneous depots. Glucagon concentrations rose before and during exercise. Therapeutic approaches for T1D management during exercise will need to account for its effects on glucose turnover, insulin mobilization, glucagon, and sympathetic response and possibly other blood-borne feedback and afferent reflex mechanisms to improve both hypoglycemia and hyperglycemia.

  3. Phototheranostics of CD44-positive cell populations in triple negative breast cancer

    PubMed Central

    Jin, Jiefu; Krishnamachary, Balaji; Mironchik, Yelena; Kobayashi, Hisataka; Bhujwalla, Zaver M.

    2016-01-01

    Triple-negative breast cancer (TNBC) is one of the most lethal subtypes of breast cancer that has limited treatment options. Its high rates of recurrence and metastasis have been associated, in part, with a subpopulation of breast cancer stem-like cells that are resistant to conventional therapies. A compendium of markers such as CD44high/CD24low, and increased expression of the ABCG2 transporter and increased aldehyde dehydrogenase (ALDH1), have been associated with these cells. We developed a CD44-targeted monoclonal antibody photosensitizer conjugate for combined fluorescent detection and photoimmunotherapy (PIT) of CD44 expressing cells in TNBC. The CD44-targeted conjugate demonstrated acute cell killing of breast cancer cells with high CD44 expression. This cell death process was dependent upon CD44-specific cell membrane binding combined with near-infrared irradiation. The conjugate selectively accumulated in CD44-positive tumors and caused dramatic tumor shrinkage and efficient elimination of CD44-positive cell populations following irradiation. This novel phototheranostic strategy provides a promising opportunity for the destruction of CD44-positive populations that include cancer stem-like cells, in locally advanced primary and metastatic TNBC. PMID:27302409

  4. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.

    PubMed

    Shu, Shaokun; Lin, Charles Y; He, Housheng Hansen; Witwicki, Robert M; Tabassum, Doris P; Roberts, Justin M; Janiszewska, Michalina; Huh, Sung Jin; Liang, Yi; Ryan, Jeremy; Doherty, Ernest; Mohammed, Hisham; Guo, Hao; Stover, Daniel G; Ekram, Muhammad B; Peluffo, Guillermo; Brown, Jonathan; D'Santos, Clive; Krop, Ian E; Dillon, Deborah; McKeown, Michael; Ott, Christopher; Qi, Jun; Ni, Min; Rao, Prakash K; Duarte, Melissa; Wu, Shwu-Yuan; Chiang, Cheng-Ming; Anders, Lars; Young, Richard A; Winer, Eric P; Letai, Antony; Barry, William T; Carroll, Jason S; Long, Henry W; Brown, Myles; Liu, X Shirley; Meyer, Clifford A; Bradner, James E; Polyak, Kornelia

    2016-01-21

    Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance. PMID:26735014

  5. CXorf61 is a target for T cell based immunotherapy of triple-negative breast cancer

    PubMed Central

    Paret, Claudia; Simon, Petra; Vormbrock, Kirsten; Bender, Christian; Kölsch, Anne; Breitkreuz, Andrea; Yildiz, Özlem; Omokoko, Tana; Hubich-Rau, Stefanie; Hartmann, Christoph; Häcker, Sabine; Wagner, Meike; Roldan, Diana Barea; Selmi, Abderaouf

    2015-01-01

    Triple-negative breast cancer (TNBC) is a high medical need disease with limited treatment options. CD8+ T cell-mediated immunotherapy may represent an attractive approach to address TNBC. The objectives of this study were to assess the expression of CXorf61 in TNBCs and healthy tissues and to evaluate its capability to induce T cell responses. We show by transcriptional profiling of a broad comprehensive set of normal human tissue that CXorf61 expression is strictly restricted to testis. 53% of TNBC patients express this antigen in at least 30% of their tumor cells. In CXorf61-negative breast cancer cell lines CXorf61 expression is activated by treatment with the hypomethylating agent 5-aza-2′-deoxycytidine. By vaccination of HLA-A*02-transgenic mice with CXorf61 encoding RNA we obtained high frequencies of CXorf61-specific T cells. Cloning and characterization of T cell receptors (TCRs) from responding T cells resulted in the identification of the two HLA-A*0201-restricted T cell epitopes CXorf6166–74 and CXorf6179–87. Furthermore, by in vitro priming of human CD8+ T cells derived from a healthy donor recognizing CXorf6166–74 we were able to induce a strong antigen-specific immune response and clone a human TCR recognizing this epitope. In summary, our data confirms this antigen as promising target for T cell based therapies. PMID:26327325

  6. Targeting a cell state common to triple-negative breast cancers

    PubMed Central

    Muellner, Markus K; Mair, Barbara; Ibrahim, Yasir; Kerzendorfer, Claudia; Lechtermann, Hannelore; Trefzer, Claudia; Klepsch, Freya; Müller, André C; Leitner, Ernestine; Macho-Maschler, Sabine; Superti-Furga, Giulio; Bennett, Keiryn L; Baselga, José; Rix, Uwe; Kubicek, Stefan; Colinge, Jacques; Serra, Violeta; Nijman, Sebastian MB

    2015-01-01

    Some mutations in cancer cells can be exploited for therapeutic intervention. However, for many cancer subtypes, including triple-negative breast cancer (TNBC), no frequently recurring aberrations could be identified to make such an approach clinically feasible. Characterized by a highly heterogeneous mutational landscape with few common features, many TNBCs cluster together based on their ‘basal-like’ transcriptional profiles. We therefore hypothesized that targeting TNBC cells on a systems level by exploiting the transcriptional cell state might be a viable strategy to find novel therapies for this highly aggressive disease. We performed a large-scale chemical genetic screen and identified a group of compounds related to the drug PKC412 (midostaurin). PKC412 induced apoptosis in a subset of TNBC cells enriched for the basal-like subtype and inhibited tumor growth in vivo. We employed a multi-omics approach and computational modeling to address the mechanism of action and identified spleen tyrosine kinase (SYK) as a novel and unexpected target in TNBC. Quantitative phosphoproteomics revealed that SYK inhibition abrogates signaling to STAT3, explaining the selectivity for basal-like breast cancer cells. This non-oncogene addiction suggests that chemical SYK inhibition may be beneficial for a specific subset of TNBC patients and demonstrates that targeting cell states could be a viable strategy to discover novel treatment strategies. PMID:25699542

  7. ERα-Negative and Triple Negative Breast Cancer: Molecular Features and Potential Therapeutic Approaches

    PubMed Central

    Chen, Jin-Qiang; Russo, Jose

    2010-01-01

    Triple negative breast cancer (TNBC) is a type of aggressive breast cancer lacking the expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor-2 (HER-2). TNBC patients account for approximately 15% of total breast cancer patients and are more prevalent among young African, African-American and Latino women patients. The currently available ER-targeted and Her-2-based therapies are not effective for treating TNBC. Recent studies have revealed a number of novel features of TNBC. In the present work, we comprehensively addressed these features and discussed potential therapeutic approaches based on these features for TNBC, with particular focus on: 1) the pathological features of TNBC/basal-like breast cancer; 2) E2/ERβ – mediated signaling pathways; 3) G-protein coupling receptor-30/epithelial growth factor receptor (GPCR-30/EGFR) signaling pathway; 4) interactions of ERβ with breast cancer 1/2 (BRCA1/2); 5) chemokine CXCL8 and related chemokines; 6) altered microRNA signatures and suppression of ERα expression/ERα-signaling by micro-RNAs; 7) altered expression of several pro-oncongenic and tumor suppressor proteins; and 8) genotoxic effects caused by oxidative estrogen metabolites. Gaining better insights into these molecular pathways in TNBC may lead to identification of novel biomarkers and targets for development of diagnostic and therapeutic approaches for prevention and treatment of TNBC. PMID:19527773

  8. A Review of Systemic Treatment in Metastatic Triple-Negative Breast Cancer

    PubMed Central

    Zeichner, Simon B.; Terawaki, Hiromi; Gogineni, Keerthi

    2016-01-01

    Patients with breast cancer along with metastatic estrogen and progesterone receptor (ER/PR)- and human epidermal growth factor receptor 2 (HER2)-negative tumors are referred to as having metastatic triple-negative breast cancer (mTNBC) disease. Although there have been many new treatment options approved by the Food and Drug Administration for ER/PR-positive and Her2/neu-amplified metastatic breast cancer, relatively few new agents have been approved for patients with mTNBC. There have been several head-to-head chemotherapy trials performed within the metastatic setting, and much of what is applied in clinical practice is extrapolated from chemotherapy trials in the adjuvant setting, with taxanes and anthracyclines incorporated early on in the patient’s treatment course. Select synergistic combinations can produce faster and more significant response rates compared with monotherapy and are typically used in the setting of visceral threat or symptomatic disease. Preclinical studies have implicated other possible targets and mechanisms in mTNBC. Ongoing clinical trials are underway assessing new chemotherapeutic strategies and agents, including targeted therapy and immunotherapy. In this review, we evaluate the standard systemic and future treatment options in mTNBC. PMID:27042088

  9. β1 Integrin as a Prognostic and Predictive Marker in Triple-Negative Breast Cancer.

    PubMed

    Yin, Hsin-Ling; Wu, Chun-Chieh; Lin, Chih-Hung; Chai, Chee-Yin; Hou, Ming-Feng; Chang, Shu-Jyuan; Tsai, Hung-Pei; Hung, Wen-Chun; Pan, Mei-Ren; Luo, Chi-Wen

    2016-01-01

    Triple negative breast cancer (TNBC) displays higher risk of recurrence and distant metastasis. Due to absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), TNBC lacks clinically established targeted therapies. Therefore, understanding of the mechanism underlying the aggressive behaviors of TNBC is required for the design of individualized strategies and the elongation of overall survival duration. Here, we supported a positive correlation between β1 integrin and malignant behaviors such as cell migration, invasion, and drug resistance. We found that silencing of β1 integrin inhibited cell migration, invasion, and increased the sensitivity to anti-cancer drug. In contrast, activation of β1 integrin increased cell migration, invasion, and decreased the sensitivity to anti-cancer drug. Furthermore, we found that silencing of β1 integrin abolished Focal adhesion kinese (FAK) mediated cell survival. Overexpression of FAK could restore cisplatin-induced apoptosis in β1 integrin-depleted cells. Consistent to in vitro data, β1 integrin expression was also positively correlated with FAK (p = 0.031) in clinical tissue. More importantly, β1 integrin expression was significantly correlated with patient outcome. In summary, our study indicated that β1 integrin could regulate TNBC cells migration, invasion, drug sensitivity, and be a potential prognostic biomarker in TNBC patient survival. PMID:27589736

  10. A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer.

    PubMed

    Blau, C Anthony; Ramirez, Arturo B; Blau, Sibel; Pritchard, Colin C; Dorschner, Michael O; Schmechel, Stephen C; Martins, Timothy J; Mahen, Elisabeth M; Burton, Kimberly A; Komashko, Vitalina M; Radenbaugh, Amie J; Dougherty, Katy; Thomas, Anju; Miller, Christopher P; Annis, James; Fromm, Jonathan R; Song, Chaozhong; Chang, Elizabeth; Howard, Kellie; Austin, Sharon; Schmidt, Rodney A; Linenberger, Michael L; Becker, Pamela S; Senecal, Francis M; Mecham, Brigham H; Lee, Su-In; Madan, Anup; Ronen, Roy; Dutkowski, Janusz; Heimfeld, Shelly; Wood, Brent L; Stilwell, Jackie L; Kaldjian, Eric P; Haussler, David; Zhu, Jingchun

    2016-01-01

    Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient's evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifically for this patient. Whole-exome sequencing of 3 bone marrow samples demonstrated a novel ROS1 variant that was estimated to be present in most or all tumor cells. After an initial response to cisplatin, a hypothesis of crizotinib sensitivity was disproven. Leukapheresis followed by partial CTC enrichment allowed for the development of a differential high-throughput drug screen and demonstrated sensitivity to investigational BH3-mimetic inhibitors of BCL-2 that could not be tested in the patient because requests to the pharmaceutical sponsors were denied. The number and size of CTC clusters correlated with clinical status and eventually death. Focusing the expertise of a distributed network of investigators on an intensively monitored patient with cancer can generate high-resolution views of the natural history of cancer and suggest new opportunities for therapy. Optimization requires access to investigational drugs. PMID:26733551

  11. A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer.

    PubMed

    Blau, C Anthony; Ramirez, Arturo B; Blau, Sibel; Pritchard, Colin C; Dorschner, Michael O; Schmechel, Stephen C; Martins, Timothy J; Mahen, Elisabeth M; Burton, Kimberly A; Komashko, Vitalina M; Radenbaugh, Amie J; Dougherty, Katy; Thomas, Anju; Miller, Christopher P; Annis, James; Fromm, Jonathan R; Song, Chaozhong; Chang, Elizabeth; Howard, Kellie; Austin, Sharon; Schmidt, Rodney A; Linenberger, Michael L; Becker, Pamela S; Senecal, Francis M; Mecham, Brigham H; Lee, Su-In; Madan, Anup; Ronen, Roy; Dutkowski, Janusz; Heimfeld, Shelly; Wood, Brent L; Stilwell, Jackie L; Kaldjian, Eric P; Haussler, David; Zhu, Jingchun

    2016-01-01

    Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient's evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifically for this patient. Whole-exome sequencing of 3 bone marrow samples demonstrated a novel ROS1 variant that was estimated to be present in most or all tumor cells. After an initial response to cisplatin, a hypothesis of crizotinib sensitivity was disproven. Leukapheresis followed by partial CTC enrichment allowed for the development of a differential high-throughput drug screen and demonstrated sensitivity to investigational BH3-mimetic inhibitors of BCL-2 that could not be tested in the patient because requests to the pharmaceutical sponsors were denied. The number and size of CTC clusters correlated with clinical status and eventually death. Focusing the expertise of a distributed network of investigators on an intensively monitored patient with cancer can generate high-resolution views of the natural history of cancer and suggest new opportunities for therapy. Optimization requires access to investigational drugs.

  12. Pharmacological profiling of kinase dependency in cell lines across triple-negative breast cancer subtypes

    PubMed Central

    Fink, Lauren S.; Beatty, Alexander; Devarajan, Karthik; Peri, Suraj; Peterson, Jeffrey R.

    2014-01-01

    Triple-negative breast cancers (TNBC), negative for estrogen receptor, progesterone receptor, and Her2 amplification, are resistant to standard targeted therapies and exhibit a poor prognosis. Furthermore, they are highly heterogeneous with respect to genomic alterations, and common therapeutic targets are lacking though substantial evidence implicates dysregulated kinase signaling. Recently, six subtypes of TNBC were identified based on gene expression and were proposed to predict sensitivity to a variety of therapeutic agents including kinase inhibitors. To test this hypothesis, we screened a large collection of well-characterized, small-molecule kinase inhibitors for growth inhibition in a panel of TNBC cell lines representing all six subtypes. Sensitivity to kinase inhibition correlated poorly with TNBC subtype. Instead, unsupervised clustering segregated TNBC cell lines according to clinically relevant features including dependence on epidermal growth factor signaling and mutation of the PTEN tumor suppressor. We further report the discovery of kinase inhibitors with selective toxicity to these groups. Overall, however, TNBC cell lines exhibited diverse sensitivity to kinase inhibition consistent with the lack of common driver mutations in this disease. While our findings support specific kinase dependencies in subsets of TNBC, they are not associated with gene expression-based subtypes. Instead we find that mutation status can be an effective predictor of sensitivity to inhibition of particular kinase pathways for subsets of TNBC. PMID:25344583

  13. β1 Integrin as a Prognostic and Predictive Marker in Triple-Negative Breast Cancer

    PubMed Central

    Yin, Hsin-Ling; Wu, Chun-Chieh; Lin, Chih-Hung; Chai, Chee-Yin; Hou, Ming-Feng; Chang, Shu-Jyuan; Tsai, Hung-Pei; Hung, Wen-Chun; Pan, Mei-Ren; Luo, Chi-Wen

    2016-01-01

    Triple negative breast cancer (TNBC) displays higher risk of recurrence and distant metastasis. Due to absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), TNBC lacks clinically established targeted therapies. Therefore, understanding of the mechanism underlying the aggressive behaviors of TNBC is required for the design of individualized strategies and the elongation of overall survival duration. Here, we supported a positive correlation between β1 integrin and malignant behaviors such as cell migration, invasion, and drug resistance. We found that silencing of β1 integrin inhibited cell migration, invasion, and increased the sensitivity to anti-cancer drug. In contrast, activation of β1 integrin increased cell migration, invasion, and decreased the sensitivity to anti-cancer drug. Furthermore, we found that silencing of β1 integrin abolished Focal adhesion kinese (FAK) mediated cell survival. Overexpression of FAK could restore cisplatin-induced apoptosis in β1 integrin-depleted cells. Consistent to in vitro data, β1 integrin expression was also positively correlated with FAK (p = 0.031) in clinical tissue. More importantly, β1 integrin expression was significantly correlated with patient outcome. In summary, our study indicated that β1 integrin could regulate TNBC cells migration, invasion, drug sensitivity, and be a potential prognostic biomarker in TNBC patient survival. PMID:27589736

  14. A Distributed Network for Intensive Longitudinal Monitoring in Metastatic Triple-Negative Breast Cancer

    PubMed Central

    Blau, C. Anthony; Ramirez, Arturo B.; Blau, Sibel; Pritchard, Colin C.; Dorschner, Michael O.; Schmechel, Stephen C.; Martins, Timothy J.; Mahen, Elisabeth M.; Burton, Kimberly A.; Komashko, Vitalina M.; Radenbaugh, Amie J.; Dougherty, Katy; Thomas, Anju; Miller, Christopher P.; Annis, James; Fromm, Jonathan R.; Song, Chaozhong; Chang, Elizabeth; Howard, Kellie; Austin, Sharon; Schmidt, Rodney A.; Linenberger, Michael L.; Becker, Pamela S.; Senecal, Francis M.; Mecham, Brigham H.; Lee, Su-In; Madan, Anup; Ronen, Roy; Dutkowski, Janusz; Heimfeld, Shelly; Wood, Brent L.; Stilwell, Jackie L.; Kaldjian, Eric P.; Haussler, David; Zhu, Jingchun

    2016-01-01

    Accelerating cancer research is expected to require new types of clinical trials. This report describes the Intensive Trial of OMics in Cancer (ITOMIC) and a participant with triple-negative breast cancer metastatic to bone, who had markedly elevated circulating tumor cells (CTCs) that were monitored 48 times over 9 months. A total of 32 researchers from 14 institutions were engaged in the patient’s evaluation; 20 researchers had no prior involvement in patient care and 18 were recruited specifically for this patient. Whole-exome sequencing of 3 bone marrow samples demonstrated a novel ROS1 variant that was estimated to be present in most or all tumor cells. After an initial response to cisplatin, a hypothesis of crizotinib sensitivity was disproven. Leukapheresis followed by partial CTC enrichment allowed for the development of a differential high-throughput drug screen and demonstrated sensitivity to investigational BH3-mimetic inhibitors of BCL-2 that could not be tested in the patient because requests to the pharmaceutical sponsors were denied. The number and size of CTC clusters correlated with clinical status and eventually death. Focusing the expertise of a distributed network of investigators on an intensively monitored patient with cancer can generate high-resolution views of the natural history of cancer and suggest new opportunities for therapy. Optimization requires access to investigational drugs. PMID:26733551

  15. Histomorphological Factors Predicting the Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

    PubMed Central

    Jung, Yoon Yang; Hyun, Chang Lim; Jin, Min-Sun; Park, In Ae; Chung, Yul Ri; Shim, Bobae; Lee, Kyu Ho

    2016-01-01

    Purpose There is no standard targeted therapy for the treatment of triple-negative breast cancer (TNBC). Therefore, its management heavily depends on adjuvant chemotherapy. Using core needle biopsy, this study evaluated the histological factors of TNBC predicting the response to chemotherapy. Methods One hundred forty-three TNBC patients who received single-regimen neoadjuvant chemotherapy (NAC) with the combination of doxorubicin, cyclophosphamide, and docetaxel were enrolled. The core needle biopsy specimens acquired before NAC were used to analyze the clinicopathologic variables and overall performance of the predictive model for therapeutic response. Results Independent predictors of pathologic complete response after NAC were found to be higher number of tumor infiltrating lymphocytes (p=0.007), absence of clear cytoplasm (p=0.008), low necrosis (p=0.018), and high histologic grade (p=0.039). In the receiver operating characteristics curve analysis, the area under curve for the combination of these four variables was 0.777. Conclusion The present study demonstrated that a predictive model using the above four variables can predict therapeutic response to single-regimen NAC with the combination of doxorubicin, cyclophosphamide, and docetaxel in TNBC. Therefore, adding these morphologic variables to clinical and genomic signatures might enhance the ability to predict the therapeutic response to NAC in TNBC. PMID:27721875

  16. Response and resistance to BET bromodomain inhibitors in triple negative breast cancer

    PubMed Central

    Tabassum, Doris P.; Roberts, Justin M.; Janiszewska, Michalina; Huh, Sung Jin; Liang, Yi; Ryan, Jeremy; Doherty, Ernest; Mohammed, Hisham; Guo, Hao; Stover, Daniel G.; Ekram, Muhammad B.; Brown, Jonathan; D'Santos, Clive; Krop, Ian E.; Dillon, Deborah; McKeown, Michael; Ott, Christopher; Qi, Jun; Ni, Min; Rao, Prakash K.; Duarte, Melissa; Wu, Shwu-Yuan; Chiang, Cheng-Ming; Anders, Lars; Young, Richard A.; Winer, Eric; Letai, Antony; Barry, William T.; Carroll, Jason S.; Long, Henry; Brown, Myles; Liu, X. Shirley; Meyer, Clifford A.; Bradner, James E.; Polyak, Kornelia

    2015-01-01

    Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy1-3. BET bromodomain inhibitors, which have shown efficacy in several models of cancer4-6, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyllysine recognition modules, leading to inhibition of oncogenic transcriptional programs7-9. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance. PMID:26735014

  17. Statins affect ETS1-overexpressing triple-negative breast cancer cells by restoring DUSP4 deficiency

    PubMed Central

    Jung, Hae Hyun; Lee, Soo-Hyeon; Kim, Ji-Yeon; Ahn, Jin Seok; Park, Yeon Hee; Im, Young-Hyuck

    2016-01-01

    We investigated the molecular mechanisms underlying statin-induced growth suppression of triple-negative breast cancer (TNBC) that overexpress the transcription factor ets proto-oncogene 1(ets-1) and downregulate dual specific protein phosphatase 4(dusp4) expression. We examined the gene expression of BC cell lines using the nCounter expression assay, MTT viability assay, cell proliferation assay and Western blot to evaluate the effects of simvastatin. Finally, we performed cell viability testing in TNBC cell line-transfected DUSP4. We demonstrated that ETS1 mRNA and protein were overexpressed in TNBC cells compared with other BC cell lines (P = <0.001) and DUSP4 mRNA was downregulated (P = <0.001). MTT viability assay showed that simvastatin had significant antitumor activity (P = 0.002 in 0.1 μM). In addition, simvastatin could restore dusp4 deficiency and suppress ets-1 expression in TNBC. Lastly, we found that si-DUSP4 RNA transfection overcame the antitumor activity of statins. MAPK pathway inhibitor, U0126 and PI3KCA inhibitor LY294002 also decreased levels of ets-1, phosphor-ERK and phosphor-AKT on Western blot assay. Accordingly, our study indicates that simvastatin potentially affects the activity of transcriptional factors such as ets-1 and dusp4 through the MAPK pathway. In conclusion, statins might be potential candidates for TNBC therapy reducing ets-1 expression via overexpression of dusp4. PMID:27604655

  18. Statins affect ETS1-overexpressing triple-negative breast cancer cells by restoring DUSP4 deficiency.

    PubMed

    Jung, Hae Hyun; Lee, Soo-Hyeon; Kim, Ji-Yeon; Ahn, Jin Seok; Park, Yeon Hee; Im, Young-Hyuck

    2016-01-01

    We investigated the molecular mechanisms underlying statin-induced growth suppression of triple-negative breast cancer (TNBC) that overexpress the transcription factor ets proto-oncogene 1(ets-1) and downregulate dual specific protein phosphatase 4(dusp4) expression. We examined the gene expression of BC cell lines using the nCounter expression assay, MTT viability assay, cell proliferation assay and Western blot to evaluate the effects of simvastatin. Finally, we performed cell viability testing in TNBC cell line-transfected DUSP4. We demonstrated that ETS1 mRNA and protein were overexpressed in TNBC cells compared with other BC cell lines (P = <0.001) and DUSP4 mRNA was downregulated (P = <0.001). MTT viability assay showed that simvastatin had significant antitumor activity (P = 0.002 in 0.1 μM). In addition, simvastatin could restore dusp4 deficiency and suppress ets-1 expression in TNBC. Lastly, we found that si-DUSP4 RNA transfection overcame the antitumor activity of statins. MAPK pathway inhibitor, U0126 and PI3KCA inhibitor LY294002 also decreased levels of ets-1, phosphor-ERK and phosphor-AKT on Western blot assay. Accordingly, our study indicates that simvastatin potentially affects the activity of transcriptional factors such as ets-1 and dusp4 through the MAPK pathway. In conclusion, statins might be potential candidates for TNBC therapy reducing ets-1 expression via overexpression of dusp4.

  19. Statins affect ETS1-overexpressing triple-negative breast cancer cells by restoring DUSP4 deficiency.

    PubMed

    Jung, Hae Hyun; Lee, Soo-Hyeon; Kim, Ji-Yeon; Ahn, Jin Seok; Park, Yeon Hee; Im, Young-Hyuck

    2016-01-01

    We investigated the molecular mechanisms underlying statin-induced growth suppression of triple-negative breast cancer (TNBC) that overexpress the transcription factor ets proto-oncogene 1(ets-1) and downregulate dual specific protein phosphatase 4(dusp4) expression. We examined the gene expression of BC cell lines using the nCounter expression assay, MTT viability assay, cell proliferation assay and Western blot to evaluate the effects of simvastatin. Finally, we performed cell viability testing in TNBC cell line-transfected DUSP4. We demonstrated that ETS1 mRNA and protein were overexpressed in TNBC cells compared with other BC cell lines (P = <0.001) and DUSP4 mRNA was downregulated (P = <0.001). MTT viability assay showed that simvastatin had significant antitumor activity (P = 0.002 in 0.1 μM). In addition, simvastatin could restore dusp4 deficiency and suppress ets-1 expression in TNBC. Lastly, we found that si-DUSP4 RNA transfection overcame the antitumor activity of statins. MAPK pathway inhibitor, U0126 and PI3KCA inhibitor LY294002 also decreased levels of ets-1, phosphor-ERK and phosphor-AKT on Western blot assay. Accordingly, our study indicates that simvastatin potentially affects the activity of transcriptional factors such as ets-1 and dusp4 through the MAPK pathway. In conclusion, statins might be potential candidates for TNBC therapy reducing ets-1 expression via overexpression of dusp4. PMID:27604655

  20. Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth

    PubMed Central

    Barbie, Thanh U.; Alexe, Gabriela; Aref, Amir R.; Li, Shunqiang; Zhu, Zehua; Zhang, Xiuli; Imamura, Yu; Thai, Tran C.; Huang, Ying; Bowden, Michaela; Herndon, John; Cohoon, Travis J.; Fleming, Timothy; Tamayo, Pablo; Mesirov, Jill P.; Ogino, Shuji; Wong, Kwok-Kin; Ellis, Matthew J.; Hahn, William C.; Barbie, David A.; Gillanders, William E.

    2014-01-01

    Triple-negative breast cancers (TNBCs) are a heterogeneous set of cancers that are defined by the absence of hormone receptor expression and HER2 amplification. Here, we found that inducible IκB kinase–related (IKK-related) kinase IKBKE expression and JAK/STAT pathway activation compose a cytokine signaling network in the immune-activated subset of TNBC. We found that treatment of cultured IKBKE-driven breast cancer cells with CYT387, a potent inhibitor of TBK1/IKBKE and JAK signaling, impairs proliferation, while inhibition of JAK alone does not. CYT387 treatment inhibited activation of both NF-κB and STAT and disrupted expression of the protumorigenic cytokines CCL5 and IL-6 in these IKBKE-driven breast cancer cells. Moreover, in 3D culture models, the addition of CCL5 and IL-6 to the media not only promoted tumor spheroid dispersal but also stimulated proliferation and migration of endothelial cells. Interruption of cytokine signaling by CYT387 in vivo impaired the growth of an IKBKE-driven TNBC cell line and patient-derived xenografts (PDXs). A combination of CYT387 therapy with a MEK inhibitor was particularly effective, abrogating tumor growth and angiogenesis in an aggressive PDX model of TNBC. Together, these findings reveal that IKBKE-associated cytokine signaling promotes tumorigenicity of immune-driven TNBC and identify a potential therapeutic strategy using clinically available compounds. PMID:25365225

  1. Hematopoietic Age at Onset of Triple-Negative Breast Cancer Dictates Disease Aggressiveness and Progression.

    PubMed

    Marsh, Timothy; Wong, Irene; Sceneay, Jaclyn; Barakat, Amey; Qin, Yuanbo; Sjödin, Andreas; Alspach, Elise; Nilsson, Björn; Stewart, Sheila A; McAllister, Sandra S

    2016-05-15

    Triple-negative breast cancer (TNBC) is considered an early onset subtype of breast cancer that carries with it a poorer prognosis in young rather than older women for reasons that remain poorly understood. Hematopoiesis in the bone marrow becomes altered with age and may therefore affect the composition of tumor-infiltrating hematopoietic cells and subsequent tumor progression. In this study, we investigated how age- and tumor-dependent changes to bone marrow-derived hematopoietic cells impact TNBC progression. Using multiple mouse models of TNBC tumorigenesis and metastasis, we found that a specific population of bone marrow cells (BMC) upregulated CSF-1R and secreted the growth factor granulin to support stromal activation and robust tumor growth in young mice. However, the same cell population in old mice expressed low levels of CSF1R and granulin and failed to promote tumor outgrowth, suggesting that age influences the tumorigenic capacity of BMCs in response to tumor-associated signals. Importantly, BMCs from young mice were sufficient to activate a tumor-supportive microenvironment and induce tumor progression in old mice. These results indicate that hematopoietic age is an important determinant of TNBC aggressiveness and provide rationale for investigating age-stratified therapies designed to prevent the protumorigenic effects of activated BMCs. Cancer Res; 76(10); 2932-43. ©2016 AACR. PMID:27197230

  2. Benign metastasizing leiomyoma in triple location: lungs, parametria and appendix.

    PubMed

    Raś, Renata; Książek, Mariusz; Barnaś, Edyta; Skręt-Magierło, Joanna; Kąziołka, Wojciech; Fudali, Ludmiła; Filipowska, Justyna; Skręt, Andrzej

    2016-06-01

    Benign metastasizing leiomyoma (BML) usually are situated in one organ, most often in lungs. BML patients typically have a history of uterine leiomyoma treated with hysterectomy, myomectomy or subtotal hysterectomy. The aim of the study was to present the case of a 53-year-old woman with triple location in the lungs, parametria and appendix. She had undergone a myomectomy 26 years earlier. In 2015, she was admitted to the surgical department because of abdominal pain, whereupon a cholecystectomy was performed. CT scans showed pelvic mass with pulmonary metastasis. Upon discharge the patient was referred to the Gynecology Clinic, where a laparotomy was performed. The intraoperative findings were: 1) uterus with multiple leiomyomas, 2) four tumors in the parametria, 3) tumor connected to the appendix. A subtotal hysterectomy, with a bilateral salpingo-oophorectomy, removal of the tumors from the parametria and appendectomy was performed. Pathology confirmed the diagnosis based on morphology and immunohistochemical staining (strongly positive for estrogen receptors and SMA, while Ki67 was very low, below 1%). Upon postoperative recovery, the patient was referred to the Thoracic Surgery Department. During the thoracotomy, multiple nodes, surrounded by lung parenchyma, were revealed. Wedge resection was performed, for localized pulmonary lesions, and sent for pathological examination. The final pathological diagnosis was benign metastasizing leiomyomatosis. In conclusion, the triple location of BML could possibly be a result of a parallel different metastasizing mechanism, although it is impossible to exclude one mechanism, which may be the cause of the metastases in three locations. PMID:27582687

  3. Bridging disparate symptoms of schizophrenia: a triple network dysfunction theory.

    PubMed

    Nekovarova, Tereza; Fajnerova, Iveta; Horacek, Jiri; Spaniel, Filip

    2014-01-01

    Schizophrenia is a complex neuropsychiatric disorder with variable symptomatology, traditionally divided into positive and negative symptoms, and cognitive deficits. However, the etiology of this disorder has yet to be fully understood. Recent findings suggest that alteration of the basic sense of self-awareness may be an essential distortion of schizophrenia spectrum disorders. In addition, extensive research of social and mentalizing abilities has stressed the role of distortion of social skills in schizophrenia.This article aims to propose and support a concept of a triple brain network model of the dysfunctional switching between default mode and central executive network (CEN) related to the aberrant activity of the salience network. This model could represent a unitary mechanism of a wide array of symptom domains present in schizophrenia including the deficit of self (self-awareness and self-representation) and theory of mind (ToM) dysfunctions along with the traditional positive, negative and cognitive domains. We review previous studies which document the dysfunctions of self and ToM in schizophrenia together with neuroimaging data that support the triple brain network model as a common neuronal substrate of this dysfunction.

  4. New flow model for the triple media carbonate reservoir

    NASA Astrophysics Data System (ADS)

    Nie, Renshi; Meng, Yingfeng; Yang, Zhaozhong; Guo, Jianchun; Jia, Yonglu

    2011-02-01

    A new flow model in triple media carbonate reservoir is established. There exists a triple total system including the matrix, fracture and vug subsystem, and the three subsystems are relatively independent in physical properties; in the process of oil flow, the inter-porosity flow of the vug subsystem to fracture subsystem would occur and the inter-porosity flow of the matrix subsystem to fracture subsystem would also occur and ignore the inter-porosity flow between the matrix subsystem and vug subsystem. Compared with the traditional model (the inter-porosity flow of vug to fracture is pseudo-steady), the new model considers the unsteady inter-porosity flow, based on the hypothesis that the shape of vug is spherical. The new model is illustrated and solved, and the standard type curves are drawn up, so the process and characteristics of flow are analysed thoroughly, and it is found that the new-style type curves in shape and characteristics are evidently different from the type curves of traditional model. The research would not only deepen the understanding of flow law but also enrich the theoretical models for carbonate reservoir. The research results on this new model could be applied to a real case study.

  5. Argon Triple-Point Device for Calibration of SPRTs

    NASA Astrophysics Data System (ADS)

    Kołodziej, B.; Manuszkiewicz, H.; Szmyrka-Grzebyk, A.; Lipiński, L.; Kowal, A.; Steur, P. P. M.; Pavese, F.

    2015-03-01

    This paper presents an apparatus for the calibration of long-stem platinum resistance thermometers at the argon triple point , designed at the Institute of Low Temperature and Structural Research, Poland (INTiBS). A hermetically sealed cell filled at the Istituto Nazionale di Ricerca Metrologica, Italy with high purity gas (6N) is the main element of this apparatus. The cell is placed in a cryostat fully immersed in liquid nitrogen. A temperature-controlled shield ensures the quasi-adiabatic condition needed for proper realization of the phase transition. A system for correcting the temperature distribution along the thermometer well is also implemented. The cell cooling and argon solidification is carried out by filling the thermometer well with liquid nitrogen. A LabVIEW computer program written at INTiBS automatically controls the triple-point realization process. The duration of a melting plateau in the apparatus lasts for about 24 h. The melting width for between 20 % and 80 % was mK. The reproducibility of the plateau temperature is better than.

  6. Viscous solution of the triple-shock reflection problem

    NASA Astrophysics Data System (ADS)

    Lau-Chapdelaine, S. S.-M.; Radulescu, M. I.

    2016-09-01

    The reflection of a triple-shock configuration was studied numerically in two dimensions using the Navier-Stokes equations. The flow field was initialized using three shock theory, and the reflection of the triple point on a plane of symmetry was studied. The conditions simulated a stoichiometric methane-oxygen detonation cell at low pressure on time scales preceding ignition when the gas was assumed to be inert. Viscosity was found to play an important role on some shock reflection mechanisms believed to accelerate reaction rates in detonations when time scales are small. A small wall jet was present in the double Mach reflection and increased in size with Reynolds number, eventually forming a small vortex. Kelvin-Helmholtz instabilities were absent, and there was no Mach stem bifurcation at Reynolds numbers corresponding to when the Mach stem had travelled distances on the scale of the induction length. Kelvin-Helmholtz instabilities are found to not likely be a source of rapid reactions in detonations at time scales commensurate with the ignition delay behind the Mach stem.

  7. High efficiency triple-junction amorphous solar cells

    NASA Astrophysics Data System (ADS)

    Ishihara, T.; Terazono, S.; Sasaki, H.; Kawabata, K.; Itagaki, T.

    A fabrication technique for high-efficiency triple-junction a-SiGe:H and a-Si:H pin solar cells is described. The interfacial characteristics of the a-SiGe:H pin cell, which is used for the bottom cell, have been improved by inserting graded bandgap layers at both p/i and n/i interfaces. The photoconductivity of the a-SiGe:H film, prepared by diluting the silane and germane discharge with a large amount of H2 gas, has also been improved. For the a-Si:H pin cell, Vocs as high as 0.99 V have been achieved by optimizing deposition conditions for the microc-Si:H p-layer and a-Si:H i-layer. Thickness of each layer in the triple-junction cell has been adjusted to get maximum output current. A cell with conversion efficiency of 10.6 percent has been obtained for a cell size of 100 sq cm.

  8. "Triple-bottom-line" assessment of urban stormwater projects.

    PubMed

    Taylor, A C; Fletcher, T D

    2006-01-01

    New guidelines have been developed and trialled in Australia to assist urban stormwater managers to assess options for projects that aim to improve urban waterway health. These guidelines help users to examine the financial, ecological and social dimensions of projects (i.e., the so-called "triple-bottom-line"). Features of the assessment process described in the guidelines include use of multi criteria analysis, input from technical experts as well as non-technical stakeholders, and provision of three alternative levels of assessment to suit stormwater managers with differing needs and resources. This paper firstly provides a background to the new guidelines and triple-bottom-line assessment. The assessment methodology promoted in the new guidelines is then briefly summarised. This methodology is compared and contrasted with European guidelines from the "SWARD" project that have been primarily developed for assessing the relative sustainability of options involving urban water supply and sewerage assets. Finally, the paper discusses how assessment methodologies that evaluate the financial, ecological and social dimensions of projects can, under some circumstances, be used to evaluate the relative progress of options for urban water management on a journey towards the widely pursued, but vaguely defined goal of "sustainable development".

  9. Bridging disparate symptoms of schizophrenia: a triple network dysfunction theory

    PubMed Central

    Nekovarova, Tereza; Fajnerova, Iveta; Horacek, Jiri; Spaniel, Filip

    2014-01-01

    Schizophrenia is a complex neuropsychiatric disorder with variable symptomatology, traditionally divided into positive and negative symptoms, and cognitive deficits. However, the etiology of this disorder has yet to be fully understood. Recent findings suggest that alteration of the basic sense of self-awareness may be an essential distortion of schizophrenia spectrum disorders. In addition, extensive research of social and mentalizing abilities has stressed the role of distortion of social skills in schizophrenia.This article aims to propose and support a concept of a triple brain network model of the dysfunctional switching between default mode and central executive network (CEN) related to the aberrant activity of the salience network. This model could represent a unitary mechanism of a wide array of symptom domains present in schizophrenia including the deficit of self (self-awareness and self-representation) and theory of mind (ToM) dysfunctions along with the traditional positive, negative and cognitive domains. We review previous studies which document the dysfunctions of self and ToM in schizophrenia together with neuroimaging data that support the triple brain network model as a common neuronal substrate of this dysfunction. PMID:24910597

  10. Automated realization of the gallium melting and triple points

    NASA Astrophysics Data System (ADS)

    Yan, X.; Duan, Y.; Zhang, J. T.; Wang, W.

    2013-09-01

    In order to improve the automation and convenience of the process involved in realizing the gallium fixed points, an automated apparatus, based on thermoelectric and heat pipe technologies, was designed and developed. This paper describes the apparatus design and procedures for freezing gallium mantles and realizing gallium melting and triple points. Also, investigations on the melting behavior of a gallium melting point cell and of gallium triple point cells were carried out while controlling the temperature outside the gallium point cells at 30 °C, 30.5 °C, 31 °C, and 31.5 °C. The obtained melting plateau curves show dentate temperature oscillations on the melting plateaus for the gallium point cells when thermal couplings occurred between the outer and inner liquid-solid interfaces. The maximum amplitude of the temperature fluctuations was about 1.5 mK. Therefore, the temperature oscillations can be used to indicate the ending of the equilibrium phase transitions. The duration and amplitude of such temperature oscillations depend on the temperature difference between the setting temperature and the gallium point temperature; the smaller the temperature difference, the longer the duration of both the melting plateaus and the temperature fluctuations.

  11. Benign metastasizing leiomyoma in triple location: lungs, parametria and appendix

    PubMed Central

    Raś, Renata; Książek, Mariusz; Skręt-Magierło, Joanna; Kąziołka, Wojciech; Fudali, Ludmiła; Filipowska, Justyna; Skręt, Andrzej

    2016-01-01

    Benign metastasizing leiomyoma (BML) usually are situated in one organ, most often in lungs. BML patients typically have a history of uterine leiomyoma treated with hysterectomy, myomectomy or subtotal hysterectomy. The aim of the study was to present the case of a 53-year-old woman with triple location in the lungs, parametria and appendix. She had undergone a myomectomy 26 years earlier. In 2015, she was admitted to the surgical department because of abdominal pain, whereupon a cholecystectomy was performed. CT scans showed pelvic mass with pulmonary metastasis. Upon discharge the patient was referred to the Gynecology Clinic, where a laparotomy was performed. The intraoperative findings were: 1) uterus with multiple leiomyomas, 2) four tumors in the parametria, 3) tumor connected to the appendix. A subtotal hysterectomy, with a bilateral salpingo-oophorectomy, removal of the tumors from the parametria and appendectomy was performed. Pathology confirmed the diagnosis based on morphology and immunohistochemical staining (strongly positive for estrogen receptors and SMA, while Ki67 was very low, below 1%). Upon postoperative recovery, the patient was referred to the Thoracic Surgery Department. During the thoracotomy, multiple nodes, surrounded by lung parenchyma, were revealed. Wedge resection was performed, for localized pulmonary lesions, and sent for pathological examination. The final pathological diagnosis was benign metastasizing leiomyomatosis. In conclusion, the triple location of BML could possibly be a result of a parallel different metastasizing mechanism, although it is impossible to exclude one mechanism, which may be the cause of the metastases in three locations. PMID:27582687

  12. Overlay metrology solutions in a triple patterning scheme

    NASA Astrophysics Data System (ADS)

    Leray, Philippe; Mao, Ming; Baudemprez, Bart; Amir, Nuriel

    2015-03-01

    Overlay metrology tool suppliers are offering today several options to their customers: Different hardware (Image Based Overlay or Diffraction Based Overlay), different target designs (with or without segmentation) or different target sizes (from 5 um to 30 um). All these variations are proposed to resolve issues like robustness of the target towards process variations, be more representative of the design or increase the density of measurements. In the frame of the development of a triple patterning BEOL scheme of 10 nm node layer, we compare IBO targets (standard AIM, AIMid and multilayer AIMid). The metrology tools used for the study are KLA-Tencor's nextgeneration Archer 500 system (scatterometry- and imaging-based measurement technologies on the same tool). The overlay response and fingerprint of these targets will be compared using a very dense sampling (up to 51 pts per field). The benefit of indie measurements compared to the traditional scribes is discussed. The contribution of process effects to overlay values are compared to the contribution of the performance of the target. Different targets are combined in one measurement set to benefit from their different strengths (performance vs size). The results are summarized and possible strategies for a triple patterning schemes are proposed.

  13. Viscous solution of the triple-shock reflection problem

    NASA Astrophysics Data System (ADS)

    Lau-Chapdelaine, S. S.-M.; Radulescu, M. I.

    2016-07-01

    The reflection of a triple-shock configuration was studied numerically in two dimensions using the Navier-Stokes equations. The flow field was initialized using three shock theory, and the reflection of the triple point on a plane of symmetry was studied. The conditions simulated a stoichiometric methane-oxygen detonation cell at low pressure on time scales preceding ignition when the gas was assumed to be inert. Viscosity was found to play an important role on some shock reflection mechanisms believed to accelerate reaction rates in detonations when time scales are small. A small wall jet was present in the double Mach reflection and increased in size with Reynolds number, eventually forming a small vortex. Kelvin-Helmholtz instabilities were absent, and there was no Mach stem bifurcation at Reynolds numbers corresponding to when the Mach stem had travelled distances on the scale of the induction length. Kelvin-Helmholtz instabilities are found to not likely be a source of rapid reactions in detonations at time scales commensurate with the ignition delay behind the Mach stem.

  14. A study of slipstreams in triple shock wave configurations

    NASA Astrophysics Data System (ADS)

    Gvozdeva, L.; Gavrenkov, S.; Nesterov, A.

    2015-05-01

    A shock wave appearing in supersonic gas flow reflects in different ways depending on flow conditions. It can take the form of regular or irregular reflection. For the irregular reflection configuration of three shock waves and a slipstream arises. Mathematical investigations of the development of parameters across slipstream in triple shock configuration have been made with variation of the angle of incidence of the shock wave, the shock wave Mach number and the adiabatic index of the gas. It has been shown that the characteristic mixing parameters of the slipstream increase with the increase of Mach number of the flow and the decrease of the heat capacity ratio. This leads to an increase of vortex formation and an increase of the angular spread of the slipstream. It also has been shown that the angle between the reflected wave and the slipstream diminishes with the decrease in heat capacity ratio so that the value may become of the same order as the spread angle. This may lead to quantitative changes in the whole reflection pattern near the triple point. The evident dependence of slipstream instability magnitude on the physical and chemical transformation intensity in the fluid was previously experimentally observed. The results of an analytical investigation appeared to be in good agreement with the experimental data.

  15. Heavy neutrino impact on the triple Higgs coupling

    NASA Astrophysics Data System (ADS)

    Baglio, J.; Weiland, C.

    2016-07-01

    We present the first calculation of the one-loop corrections to the triple Higgs coupling in the framework of a simplified 3 +1 Dirac neutrino model, that is three light neutrinos plus one heavy neutrino embedded in the Standard Model (SM). The triple Higgs coupling is a key parameter of the scalar potential triggering the electroweak symmetry-breaking mechanism in the SM. The impact of the heavy neutrino can be as large as +20 % to +30 % for parameter points allowed by the current experimental constraints depending on the tightness of the perturbative bound. This can be probed at the high-luminosity LHC, at future electron-positron colliders and at the Future Circular Collider in hadron-hadron mode, an envisioned 100 TeV p p machine. Our calculation, being done in the mass basis, can be extended to any model using the neutrino portal. In addition, the effects that we have calculated are expected to be enhanced if additional heavy fermions with large Yukawa couplings are included, as in low-scale seesaw mechanisms.

  16. Socially explosive minds: the triple imbalance hypothesis of reactive aggression.

    PubMed

    van Honk, Jack; Harmon-Jones, Eddie; Morgan, Barak E; Schutter, Dennis J L G

    2010-02-01

    The psychobiological basis of reactive aggression, a condition characterized by uncontrolled outbursts of socially violent behavior, is unclear. Nonetheless, several theoretical models have been proposed that may have complementary views about the psychobiological mechanisms involved. In this review, we attempt to unite these models and theorize further on the basis of recent data from psychological and neuroscientific research to propose a comprehensive neuro-evolutionary framework: The Triple Imbalance Hypothesis (TIH) of reactive aggression. According to this model, reactive aggression is essentially subcortically motivated by an imbalance in the levels of the steroid hormones cortisol and testosterone (Subcortical Imbalance Hypothesis). This imbalance not only sets a primal predisposition for social aggression, but also down-regulates cortical-subcortical communication (Cortical-Subcortical Imbalance Hypothesis), hence diminishing control by cortical regions that regulate socially aggressive inclinations. However, these bottom-up hormonally mediated imbalances can drive both instrumental and reactive social aggression. The TIH suggests that reactive aggression is differentiated from proactive aggression by low brain serotonergic function and that reactive aggression is associated with left-sided frontal brain asymmetry (Cortical Imbalance Hypothesis), especially observed when the individual is socially threatened or provoked. This triple biobehavioral imbalance mirrors an evolutionary relapse into violently aggressive motivational drives that are adaptive among many reptilian and mammalian species, but may have become socially maladaptive in modern humans. PMID:20433613

  17. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers

    PubMed Central

    Allaoui, Roni; Bergenfelz, Caroline; Mohlin, Sofie; Hagerling, Catharina; Salari, Kiarash; Werb, Zena; Anderson, Robin L.; Ethier, Stephen P.; Jirström, Karin; Påhlman, Sven; Bexell, Daniel; Tahin, Balázs; Johansson, Martin E.; Larsson, Christer; Leandersson, Karin

    2016-01-01

    Triple-negative (TN) breast cancers (ER−PR−HER2−) are highly metastatic and associated with poor prognosis. Within this subtype, invasive, stroma-rich tumours with infiltration of inflammatory cells are even more aggressive. The effect of myeloid cells on reactive stroma formation in TN breast cancer is largely unknown. Here, we show that primary human monocytes have a survival advantage, proliferate in vivo and develop into immunosuppressive myeloid cells expressing the myeloid-derived suppressor cell marker S100A9 only in a TN breast cancer environment. This results in activation of cancer-associated fibroblasts and expression of CXCL16, which we show to be a monocyte chemoattractant. We propose that this migratory feedback loop amplifies the formation of a reactive stroma, contributing to the aggressive phenotype of TN breast tumours. These insights could help select more suitable therapies targeting the stromal component of these tumours, and could aid prediction of drug resistance. PMID:27725631

  18. Immunohistochemical, genetic and epigenetic profiles of hereditary and triple negative breast cancers. Relevance in personalized medicine

    PubMed Central

    Murria, Rosa; Palanca, Sarai; de Juan, Inmaculada; Alenda, Cristina; Egoavil, Cecilia; Seguí, Francisco J; García-Casado, Zaida; Juan, María J; Sánchez, Ana B; Segura, Ángel; Santaballa, Ana; Chirivella, Isabel; Llop, Marta; Pérez, Gema; Barragán, Eva; Salas, Dolores; Bolufer, Pascual

    2015-01-01

    This study aims to identify the profile of immunohistochemical (IHC) parameters, copy number aberrations (CNAs) and epigenetic alterations [promoter methylation (PM) and miR expression] related to hereditary (H) and triple negative (TN) breast cancer (BC). This profile could be of relevance for guiding tumor response to treatment with targeting therapy. The study comprises 278 formalin fixed paraffin-embedded BCs divided into two groups: H group, including 88 hereditary BC (HBC) and 190 non hereditary (NHBC), and TN group, containing 79 TNBC and 187 non TNBC (NTNBC). We assessed IHC parameters (Ki67, ER, PR, HER2, CK5/6, CK18 and Cadherin-E), CNA of 20 BC related genes, and PM of 24 tumor suppressor genes employing MLPA/MS-MLPA (MRC Holland, Amsterdam). MiR-4417, miR-423-3p, miR-590-5p and miR-187-3p expression was assessed by quantitative RT-PCR (Applied Biosystems). Binary logistic regression was applied to select the parameters that better differentiate the HBC or TN groups. For HBC we found that, ER expression, ERBB2 CNA and PM in RASSF1 and TIMP3 were associated with NHBC whereas; MYC and AURKA CNA were linked to HBC. For TNBC, we found that CDC6 CNA, GSTP1 and RASSF1 PM and miR-423-3p hyperexpression were characteristic of NTNBC, while MYC aberrations, BRCA1 hypermethylation and miR-590-5p and miR-4417 hyperexpression were more indicative of TNBC. The selected markers allow establishing BC subtypes, which are characterized by showing similar etiopathogenetic mechanisms, some of them being molecular targets for known drugs or possible molecular targets. These results could be the basis to implement a personalized therapy. PMID:26328265

  19. PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

    PubMed Central

    Paul, A; Gunewardena, S; Stecklein, S R; Saha, B; Parelkar, N; Danley, M; Rajendran, G; Home, P; Ray, S; Jokar, I; Vielhauer, G A; Jensen, R A; Tawfik, O; Paul, S

    2014-01-01

    Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCλ/ι, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCλ/ι signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCλ/ι signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCλ/ι expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCλ/ι significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCλ/ι-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFβ and IL1β could activate PKCλ/ι signaling in TNBC cells and depletion of PKCλ/ι impairs NF-κB p65 (RelA) nuclear localization. We observed that cytokine-PKCλ/ι-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCλ/ι promote TNBC growth, invasion and metastasis. Thus, targeting PKCλ/ι signaling could be a

  20. Triple-controlled oncolytic adenovirus expressing melittin to exert inhibitory efficacy on hepatocellular carcinoma

    PubMed Central

    Qian, Chun-Yu; Wang, Kai-Li; Fang, Fan-Fu; Gu, Wei; Huang, Feng; Wang, Fu-Zhe; Li, Bai; Wang, Li-Na

    2015-01-01

    Hepatocellular carcinoma (HCC) is a highly malignant disease, and its outcome of routine therapies is poor. Comprehensive treatment including gene therapy is an important way to improve patients’ prognosis and survival. In this study, we successfully constructed a triple-controlled cancer-selective oncolytic adenovirus, QG511-HA-Melittin, carrying melittin gene, in which the hybrid promoter, hypoxia-response element (HRE)-AFP promoter, was used to control viral E1a expression targeting AFP-positive cancer cells in hypoxia microenviroment, and the E1b-55 kDa gene was deleted in cancer cells with p53-deficiency. The cytological experiments found that the viral replication of QG511-HA-Melittin was increased to 12800-folds in Hep3B cells within 48 h, and 130-folds in SMMC-7721, but the virus did not replicate in L-02 cells. QG511-HA-Melittin had a strong inhibition effect on AFP-positive HCC cell proliferation, such as Hep3B and HepG2, whereas, there was low or no inhibition effect of QG511-HA-Melittin on AFP-negative cancer cells SMMC-7721 and normal cells L-02. In the in vivo experiment, compared with the blank control group, QG511-HA-Melittin can significantly inhibit the growth of HCC xenografts (P<0.05). The survival of mice in QG511-HA-Melittin group was much longer than that of the blank control group. Both in vitro and in vivo experiments manifested that QG511-HA-Melittin exerts an inhibitory effect on HCC cells, which may provide a new strategy for HCC biotherapy. PMID:26617748