Outcomes with ibrutinib by line of therapy and post‐ibrutinib discontinuation in patients with chronic lymphocytic leukemia: Phase 3 analysis

The efficacy of ibrutinib has been demonstrated in patients with chronic lymphocytic leukemia (CLL), including as first‐line therapy. However, outcomes after ibrutinib discontinuation have previously been limited to higher‐risk populations with relapsed/refractory (R/R) disease. The objective of this study was to evaluate outcomes of ibrutinib‐treated patients based on prior lines of therapy, including after ibrutinib discontinuation. Data were analyzed from two multicenter phase 3 studies of single‐agent ibrutinib: RESONATE (PCYC‐1112) in patients with R/R CLL and RESONATE‐2 (PCYC‐1115) in patients with treatment‐naive (TN) CLL without del(17p). This integrated analysis included 271 ibrutinib‐treated non‐del(17p) patients with CLL (136 TN and 135 R/R). Median progression‐free survival (PFS) was not reached for subgroups with 0 and 1/2 prior therapies but was 40.6 months for patients with ≥3 therapies (median follow‐up: TN, 36 months; R/R, 44 months). Median overall survival (OS) was not reached in any subgroup. Overall response rate (ORR) was 92% in TN and 92% in R/R, with depth of response increasing over time. Adverse events (AEs) and ibrutinib discontinuation due to AEs were similar between patient groups. Most patients (64%) remain on treatment. OS following discontinuation was 9.3 months in R/R patients (median follow‐up 18 months, n = 51) and was not reached in TN patients (median follow‐up 10 months, n = 30). In this integrated analysis, ibrutinib was associated with favorable PFS and OS, and high ORR regardless of prior therapies in patients with CLL. The best outcomes following ibrutinib discontinuation were for patients receiving ibrutinib in earlier lines of therapy

Carbon dioxide fluxes across the Sierra de Guadarrama, Spain

Understanding the spatial and temporal variation in soil respiration within small geographic areas is essential to accurately assess the carbon budget on a global scale. In this study, we investigated the factors controlling soil respiration in an altitudinal gradient in a southern Mediterranean mixed pine–oak forest ecosystem in the north face of the Sierra de Guadarrama in Spain. Soil respiration was measured in five Pinus sylvestris L. plots over a period of 1 year by means of a closed dynamic system (LI-COR 6400). Soil temperature and water content were measured at the same time as soil respiration. Other soil physico-chemical and microbiological properties were measured during the study. Measured soil respiration ranged from 6.8 to 1.4 lmol m-2 s-1, showing the highest values at plots situated at higher elevation. Q10 values ranged between 1.30 and 2.04, while R10 values ranged between 2.0 and 3.6. The results indicate that the seasonal variation of soil respiration was mainly controlled by soil temperature and moisture. Among sites, soil carbon and nitrogen stocks regulate soil respiration in addition to soil temperature and moisture. Our results suggest that application of standard models to estimate soil respiration for small geographic areas may not be adequate unless other factors are considered in addition to soil temperature

Characterization of MTAP gene expression in breast cancer patients and cell lines

MTAP is a ubiquitously expressed gene important for adenine and methionine salvage. The gene is located at 9p21, a chromosome region often deleted in breast carcinomas, similar to CDKN2A, a recognized tumor suppressor gene. Several research groups have shown that MTAP acts as a tumor suppressor, and some therapeutic approaches were proposed based on a tumors\ub4 MTAP status. We analyzed MTAP and CDKN2A gene (RT-qPCR) and protein (western-blotting) expression in seven breast cancer cell lines and evaluated their promoter methylation patterns to better characterize the contribution of these genes to breast cancer. Cytotoxicity assays with inhibitors of de novo adenine synthesis (5-FU, AZA and MTX) after MTAP gene knockdown showed an increased sensitivity, mainly to 5-FU. MTAP expression was also evaluated in two groups of samples from breast cancer patients, fresh tumors and paired normal breast tissue, and from formalin-fixed paraffin embedded (FFPE) core breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors (TNBC). The difference of MTAP expression between fresh tumors and normal tissues was not statistically significant. However, MTAP expression was significantly higher in Luminal-A breast tumors than in TNBC, suggesting the lack of expression in more aggressive breast tumors and the possibility of using the new approaches based on MTAP status in TNB

Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) and serine biosynthetic pathway genes are co-ordinately increased during anabolic agent-induced skeletal muscle growth

We aimed to identify novel molecular mechanisms for muscle growth during administration of anabolic agents. Growing pigs (Duroc/(Landrace/Large-White)) were administered Ractopamine (a beta-adrenergic agonist; BA; 20ppm in feed) or Reporcin (recombinant growth hormone; GH; 10mg/48hours injected) and compared to a control cohort (feed only; no injections) over a 27-day time course (1, 3, 7, 13 or 27-days). Longissimus Dorsi muscle gene expression was analyzed using Agilent porcine transcriptome microarrays and clusters of genes displaying similar expression profiles were identified using a modified maSigPro clustering algorithm. Anabolic agents increased carcass (p=0.002) and muscle weights (Vastus Lateralis: p<0.001; Semitendinosus: p=0.075). Skeletal muscle mRNA expression of serine/one-carbon/glycine biosynthesis pathway genes (Phgdh, Psat1 and Psph) and the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase-M (Pck2/PEPCK-M), increased during treatment with BA, and to a lesser extent GH (p<0.001, treatment x time interaction). Treatment with BA, but not GH, caused a 2-fold increase in phosphoglycerate dehydrogenase (PHGDH) protein expression at days 3 (p<0.05) and 7 (p<0.01), and a 2-fold increase in PEPCK-M protein expression at day 7 (p<0.01). BA treated pigs exhibit a profound increase in expression of PHGDH and PEPCK-M in skeletal muscle, implicating a role for biosynthetic metabolic pathways in muscle growth

The Interleukin-6 inflammation pathway from cholesterol to aging – Role of statins, bisphosphonates and plant polyphenols in aging and age-related diseases

We describe the inflammation pathway from Cholesterol to Aging. Interleukin 6 mediated inflammation is implicated in age-related disorders including Atherosclerosis, Peripheral Vascular Disease, Coronary Artery Disease, Osteoporosis, Type 2 Diabetes, Dementia and Alzheimer's disease and some forms of Arthritis and Cancer. Statins and Bisphosphonates inhibit Interleukin 6 mediated inflammation indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion. Polyphenolic compounds found in plants, fruits and vegetables inhibit Interleukin 6 mediated inflammation by direct inhibition of the signal transduction pathway. Therapeutic targets for the control of all the above diseases should include inhibition of Interleukin-6 mediated inflammation

Living with prostate cancer: randomised controlled trial of a multimodal supportive care intervention for men with prostate cancer

Background: Prostate cancer is the most common male cancer in developed countries and diagnosis and treatment carries with it substantial morbidity and related unmet supportive care needs. These difficulties may be amplified by physical inactivity and obesity. We propose to apply a multimodal intervention approach that targets both unmet supportive care needs and physical activity.Methods/design: A two arm randomised controlled trial will compare usual care to a multimodal supportive care intervention &ldquo;Living with Prostate Cancer&rdquo; that will combine self-management with tele-based group peer support. A series of previously validated and reliable self-report measures will be administered to men at four time points: baseline/recruitment (when men are approximately 3-6 months post-diagnosis) and at 3, 6, and 12 months after recruitment and intervention commencement. Social constraints, social support, self-efficacy, group cohesion and therapeutic alliance will be included as potential moderators/mediators of intervention effect. Primary outcomes are unmet supportive care needs and physical activity levels. Secondary outcomes are domain-specific and healthrelated quality of life (QoL); psychological distress; benefit finding; body mass index and waist circumference. Disease variables (e.g. cancer grade, stage) will be assessed through medical and cancer registry records. An economic evaluation will be conducted alongside the randomised trial.Discussion: This study will address a critical but as yet unanswered research question: to identify a populationbased way to reduce unmet supportive care needs; promote regular physical activity; and improve disease-specific and health-related QoL for prostate cancer survivors. The study will also determine the cost-effectiveness of the intervention.<br /

Factors affecting adherence to guidelines for antithrombotic therapy in elderly patients with atrial fibrillation admitted to internal medicine wards

Current guidelines for ischemic stroke prevention in atrial fibrillation or flutter (AFF) recommend Vitamin K antagonists (VKAs) for patients at high-intermediate risk and aspirin for those at intermediate-low risk. The cost-effectiveness of these treatments was demonstrated also in elderly patients. However, there are several reports that emphasize the underuse of pharmacological prophylaxis of cardio-embolism in patients with AFF in different health care settings. AIMS: To evaluate the adherence to current guidelines on cardio-embolic prophylaxis in elderly (> 65 years old) patients admitted with an established diagnosis of AFF to the Italian internal medicine wards participating in REPOSI registry, a project on polypathologies/polytherapies stemming from the collaboration between the Italian Society of Internal Medicine and the Mario Negri Institute of Pharmacological Research; to investigate whether or not hospitalization had an impact on guidelines adherence; to test the role of possible modifiers of VKAs prescription. METHODS: We retrospectively analyzed registry data collected from January to December 2008 and assessed the prevalence of patients with AFF at admission and the prevalence of risk factors for cardio-embolism. After stratifying the patients according to their CHADS(2) score the percentage of appropriateness of antithrombotic therapy prescription was evaluated both at admission and at discharge. Univariable and multivariable logistic regression models were employed to verify whether or not socio-demographic (age >80years, living alone) and clinical features (previous or recent bleeding, cranio-facial trauma, cancer, dementia) modified the frequency and modalities of antithrombotic drugs prescription at admission and discharge. RESULTS: Among the 1332 REPOSI patients, 247 were admitted with AFF. At admission, CHADS(2) score was ≥ 2 in 68.4% of patients, at discharge in 75.9%. Among patients with AFF 26.5% at admission and 32.8% at discharge were not on any antithrombotic therapy, and 43.7% at admission and 40.9% at discharge were not taking an appropriate therapy according to the CHADS(2) score. The higher the level of cardio-embolic risk the higher was the percentage of antiplatelet- but not of VKAs-treated patients. At admission or at discharge, both at univariable and at multivariable logistic regression, only an age >80 years and a diagnosis of cancer, previous or active, had a statistically significant negative effect on VKAs prescription. Moreover, only a positive history of bleeding events (past or present) was independently associated to no VKA prescription at discharge in patients who were on VKA therapy at admission. If heparin was considered as an appropriate therapy for patients with indication for VKAs, the percentage of patients admitted or discharged on appropriate therapy became respectively 43.7% and 53.4%. CONCLUSION: Among elderly patients admitted with a diagnosis of AFF to internal medicine wards, an appropriate antithrombotic prophylaxis was taken by less than 50%, with an underuse of VKAs prescription independently of the level of cardio-embolic risk. Hospitalization did not improve the adherence to guideline