tbuckley/cabot-search huggingface dataset:
Sensitivity analyses for radiographic progression-free survival (rPFS): Results from the phase 3 PREVAIL trial comparing enzalutamide to placebo.
Authors: Michael J. Morris, Yohann Loriot, Tomasz M. Beer, Celestia S. Higano, Andrew J. Armstrong, Cora N. Sternberg, Johann Sebastian De Bono, Bertrand F. Tombal, Sarah B. Noonberg, Harry H. Mansbach, Suman Bhattacharya, Frank Perabo, De Phung, Dana E. Rathkopf
Journal: Journal of Clinical Oncology (2014)

5054 Background: In the PREVAIL trial, enzalutamide (ENZ), an androgen receptor inhibitor, significantly improved overall survival (HR: 071, P<0.0001) and rPFS (HR: 0.19, P<0.0001) compared with placebo in asymptomatic/mildly symptomatic chemotherapy-naive men with mCRPC (Beer, ASCO GUCS 2014, LBA1). Sensitivity analyses (SA) were performed to assess the impact of different sources of progression on the prespecified rPFS analysis. We also analyzed concordance between central and local reviewers. Methods: In this double-blind, placebo-controlled, multinational study (NCT01212991), 1,717 patients were randomized 1:1 to ENZ 160 mg/day (n=872) or placebo (n=845). rPFS was a co-primary endpoint defined as time from randomization to the earliest objective evidence of radiographic progression by central review or death within 169 days of treatment discontinuation. Radiographic progression was defined by PCWG2 guidelines for bone disease or by RECIST 1.1 for soft tissue disease; bone progression was captured using a validated bone scan data capture assay. The primary rPFS analysis was event driven (at least 410 events). Characteristics of representative SA are reported in the Table. Results: Concordance between central and local assessment of progression was 87.6%. Results of the SA were statistically significant in favor of ENZ (see Table). Conclusions: rPFS sensitivity analyses in PREVAIL demonstrated a consistent and robust treatment benefit with ENZ. Central and local assessment showed good concordance using a quantitative definition of radiographic progression and validated bone scan data assay. Clinical trial information: NCT01212991. Analysis Modifications from primary analysis Total events Hazard ratio* (95% CI) Primary None 439 0.19 (0.15, 0.23) SA 1 · Skeletal-related events, initiation of radiotherapy, and new anti-neoplastic therapy counted as PFS events 621 0.18 (0.15, 0.22) SA 2 · Investigator assessment used in lieu of central review 413 0.22 (0.18, 0.27) SA3 · Investigator assessment with same data cutoff as OS analysis 889 0.31 (0.27, 0.35) SA4 · Discontinued for clinical progression counted as PFS event 482 0.18 (0.14, 0.22) *All p values <0.0001.
Abstract 3527: Inhibition of autophagosome closure promotes iDISC-mediated apoptosis in AML cells
Authors: Zhenyuan Tang, Yoshinori Takahashi, Hong-Gang Wang
Journal: Cancer Research (2016)

Abstract Macroautophagy (hereafter referred to as autophagy) is a lysosomal degradation process whereby cellular components, such as damaged organelles, are enclosed in double-membrane structures called autophagosomes and delivered to lysosomes for degradation and recycling. Autophagy is known to be essential for cancer pathogenesis and progression through its intimate crosstalk with programed cell death machinery, apoptosis. However, the role of autophagy in apoptosis pathway remains highly controversial and context-dependent, which makes developing autophagy-targeted anti-cancer treatments hard to achieve. We have previously reported that autophagosomal membranes can serve as a platform for caspase-8 activation through the assembly of an intracellular Death-Inducing Signaling Complex (iDISC). In the present study, we demonstrate that inhibition of phagophore closure by depleting Atg2A/B stabilizes iDISCs and induces caspase-8-initiated apoptosis in acute myeloid leukemia (AML) cells. We found that knockout of Atg2A/B, but not Atg7, promotes the oligomerization of caspase-8 on Atg16L- and LC3-positive phagophore membranes upon nutrient starvation. Starvation-induced capase-8 activation and apoptosis induction in Atg2A/B-deficient cells were strongly suppressed by the inhibition of caspase-8. These results suggest that autophagy inhibition at the phagophore closure step can shift cytoprotective autophagy to a pro-death mechanism and thus may be a promising strategy to enhance the efficacy of anticancer therapy. Citation Format: Zhenyuan Tang, Yoshinori Takahashi, Hong-Gang Wang. Inhibition of autophagosome closure promotes iDISC-mediated apoptosis in AML cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3527.
Hepcidin in Male Double Red Blood Cell Donors - Relationship Between Parameters of Iron Metabolism and Erythropoiesis
Authors: Shuo Wang, Huihui Li, Lisa Sarran, Gordana Olbina, Mark Westerman, Elizabeta Nemeth, Eric E. Bouhassira, Tomas Ganz, Yelena Ginzburg
Journal: Blood (2011)
Eradication of<i>Helicobacter pylori</i>and Gastric Cancer: A Systematic Review and Meta-analysis of Cohort Studies
Authors: Eva Doorakkers, Jesper Lagergren, Lars Engstrand, Nele Brusselaers
Journal: JNCI Journal of the National Cancer Institute (2016)

Helicobacter pylori (H. pylori) is associated with an increased risk of gastric adenocarcinoma and gastric mucosa associated lymphoid tissue (MALT) lymphoma and a decreased risk of esophageal adenocarcinoma. We aimed to assess how eradication therapy for H. pylori influences the risk of developing these cancers.This was a systematic review and meta-analysis. We searched PubMed, Web of Science, Embase, and the Cochrane Library and selected articles that examined the risk of gastric cancer, MALT lymphoma, or esophageal cancer following eradication therapy, compared with a noneradicated control group.Among 3629 articles that were considered, nine met the inclusion criteria. Of these, eight cohort studies assessed gastric cancer while one randomized trial assessed esophageal cancer. Out of 12 899 successfully eradicated patients, 119 (0.9%) developed gastric cancer, compared with 208 (1.1%) out of 18 654 noneradicated patients. The pooled relative risk of gastric cancer in all eight studies was 0.46 (95% confidence interval [CI] = 0.32 to 0.66, I(2) = 32.3%) favoring eradication therapy. The four studies adjusting for time of follow-up and confounders showed a relative risk of 0.46 (95% CI = 0.29 to 0.72, I(2) = 44.4%).This systematic review and meta-analysis indicates that eradication therapy for H. pylori prevents gastric cancer. There was insufficient literature for meta-analysis of MALT lymphoma or esophageal cancer.
Comment on Fedorko et al. Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial. Diabetes Care 2016;39:392–399
Authors: M. Hassan Murad
Journal: Diabetes Care (2016)

I read with interest the trial by Fedorko et al. (1) and have concerns about whether this trial has produced evidence of relevance to patients. The U.S. Patient Protection and Affordable Care Act of 2010 created the Patient-Centered Outcomes Research Institute (PCORI) to fund and promote research that evaluates questions that matter to patients. Patient-centered outcomes research evaluates questions and outcomes that are meaningful and important to patients and their caregivers …
Abstract 2947: MicroRNA 10b, 27a and 27b are involved in the resistance to treatment with epidermal growth factor tyrosine inhibitor (EGFR-TKI) in EGFR mutant lung cancer cell line
Authors: Hannah Montes, Emma B D Reyes, Mukut Sharma, Chao H. Huang
Journal: Cancer Research (2016)

Abstract EGFR TKIs are now standard of care in lung cancer patients with EGFR mutation. Invariably, these patients develop resistance and require treatment with another EGFR TKI or chemotherapy. The gate-keeper mutation T790M is responsible for about 50% of resistance. Rocelitinib(R) is a third generation EGFR TKI active in lung cancer cells with T790M mutation. Other mechanisms may also confer resistance in these patients. High expression of microRNA (miR)-10 is associated with worse prognosis in resected lung cancer patients with EGFR mutation. Both miR-27a and 27b are associated with increased expression of c-met which is a potential mechanism of resistance to EGFR TKI. We hypothesized that miR 10b and 27a and 27b modulate resistance in E-resistant lung cancer cells. Material and Methods Lung cancer cell lines with EGFR mutation HCC827 and HCC4006 were treated with 5 nM of Erlotinib (E) for 72 hours. E-resistant cells were then treated with R at 21.5 nM for 72h. The cells were harvested and microRNA profiling was performed by real time PCR. HTB177 cell line without EGFR mutation was used as control. Results We observed increased expression of miR-10b and miR-27a in HCC4006 compared to control cells HTB 177 cells; miR-27b is upregulated in HCC827 cell line. The increased expression of miR-10b and miR 27a were higher in CRL-2871 than the control cells 9-fold and 8-fold, respectively. MicroRNA- 27b was increased 300-fold in HCC827 compared with control. Treatment with R reduced the proliferation in HCC827 to 30% and in HCC4006 to 50% compared to control. It did not inhibit the proliferation of HTB177 cells. R increase miR-10b in HCC4006 by 3-fold, miR-27a by 1.5-fold; in HCC827 it reduced miR-10b to 0.4, miR-27a to 0.4 and miR-27B 0.5. Conclusion We observed upregulation of miR-10b, 27a and 27b in lung cancer cells lines with EGFR mutation that were resistant to E treatment. Treatment of E resistant cells with R reduced proliferation and changed the expression of miR-10b, 27a and 27b. Our results suggest an epigenetic mechanism of resistance in addition to the T790M mutation. MicroRNAs may be studied as targets for developing novel approach for to treating patients with EGFR TKI resistance. Citation Format: Hannah Montes, Emma B D Reyes, Mukut Sharma, Chao H. Huang. MicroRNA 10b, 27a and 27b are involved in the resistance to treatment with epidermal growth factor tyrosine inhibitor (EGFR-TKI) in EGFR mutant lung cancer cell line. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2947.
Mutations in <i>STN1</i> cause Coats plus syndrome and are associated with genomic and telomere defects
Authors: Amos J. Simon, Atar Lev, Yong Zhang, Batia Weiss, Anna Rylova, Eran Eyal, Nitzan Kol, Ortal Barel, Keren Cesarkas, Michalle Soudack, Noa Greenberg-Kushnir, Michele Rhodes, David L. Wiest, Ginette Schiby, Iris Barshack, Shulamit Katz, Elon Pras, Hana Poran, Haike Reznik-Wolf, Elena Ribakovsky, Carlos Simon, Wadi Hazou, Yechezkel Sidi, Avishay Lahad, Hagar Katzir, Shira Sagie, Haifa A. Aqeilan, Galina Glousker, Ninette Amariglio, Yehuda Tzfati, Sara Selig, Gideon Rechavi, Raz Somech
Journal: The Journal of Experimental Medicine (2016)

The analysis of individuals with telomere defects may shed light on the delicate interplay of factors controlling genome stability, premature aging, and cancer. We herein describe two Coats plus patients with telomere and genomic defects; both harbor distinct, novel mutations in STN1, a member of the human CTC1-STN1-TEN1 (CST) complex, thus linking this gene for the first time to a human telomeropathy. We characterized the patients' phenotype, recapitulated it in a zebrafish model and rescued cellular and clinical aspects by the ectopic expression of wild-type STN1 or by thalidomide treatment. Interestingly, a significant lengthy control of the gastrointestinal bleeding in one of our patients was achieved by thalidomide treatment, exemplifying a successful bed-to-bench-and-back approach.
Improved GP retainer scheme with increased funding is launched
Authors: Abi Rimmer
Journal: BMJ (2016)

NHS England has announced a range of improvements to its GP retainer scheme, including increased funding for GPs and practices. The scheme provides financial incentives and development support to encourage GPs who might otherwise leave the profession to remain in general practice.

NHS England said that, from 1 July 2016, it would increase the money for practices employing a retained GP and the annual payment towards professional expenses for GPs in the scheme. “The additional resource is part of an ongoing commitment to retain more doctors in general practice …
Statins and Exercise Training Response in Heart Failure Patients
Authors: Jacob P. Kelly, Allison Dunning, Phillip J. Schulte, Mona Fiuzat, Eric S. Leifer, Jerome L. Fleg, Lawton S. Cooper, Steven J. Keteyian, Dalane W. Kitzman, Ileana L. Pina, William E. Kraus, David J. Whellan, Christopher M. O'Connor, Robert J. Mentz
Journal: JACC Heart Failure (2016)
Allogeneic Hematopoietic Stem Cell Transplantation Of Patients With Wiskott-Aldrich Syndrome With Total Body Irradiation (TBI), Thiotepa and Fludarabine Or Cyclophosphamide Followed By T-Cell Depleted Grafts From Alternative Donors
Authors: Susan E. Prockop, Farid Boulad, Nancy A. Kernan, Ramzi Khalif, Rachel Kobos, Andromachi Scaradavou, Richard J. O'Reilly
Journal: Blood (2013)
The impact of time to adjuvant chemotherapy on outcomes in breast and colorectal cancer: A systematic review.
Authors: J. J. Biagi, M. Raphael, C. M. Booth
Journal: Journal of Clinical Oncology (2010)

e16537 Background: Adjuvant chemotherapy (ACT) improves survival among patients with resected breast cancer (BC) and colorectal cancer (CRC). However, the optimal timing from surgery to initiation of ACT is unknown. Here we report a systematic review to explore the relationship of time to adjuvant chemotherapy (TTAC) on outcomes in BC and CRC. Methods: A structured search of published literature (MEDLINE 1950-July 2009) and conference proceedings (ASCO 2007-09) was conducted. Studies were eligible if the met the following inclusion criteria: all patients were treated with ACT; time from surgery to initiation of ACT was clearly reported; a correlation between TTAC and patient outcome was reported. Studies were excluded if additional adjuvant therapies were part of the study. Two reviewers independently assessed studies for inclusion in the final cohort and completed data abstraction; disagreements were resolved by consensus. TTAC data within these studies were classified as being of higher quality if comparative groups were balanced and/or the results were adjusted for important prognostic variables. Abstracted TTAC data was pooled using standard meta-analytic techniques. Results: 40 studies (22 BC, 18 CRC) were identified of which 24 were eligible (11 BC and 13 CRC, published 1982-2009). Study data came from randomized trials (n = 10), population-based (n = 8) and single institution (n = 6) data sources. 15 studies were published in full and 9 were abstracts. TTAC was correlated with overall survival in 18/24 studies (75%). 22/24 studies (92%) TTAC datasets were deemed to be of higher quality. Among such studies, 5/22 (23%) reported improved outcomes with earlier initiation of ACT and 8/22 (36%) reported inferior outcomes with delayed TTAC. Overall, 59% (13/22) of studies found an association between TTAC and patient outcome, including 7 of 11 BC (64%) and 6 of 11 CRC (55%) studies. Conclusions: The majority of studies which have evaluated TTAC for breast and colorectal cancer have reported an association between time to initiation of ACT and patient outcomes. Available evidence substantiates the need to initiate ACT in a timely manner. A quantitative analysis that indicates the optimum TTAC will be presented. No significant financial relationships to disclose.
Abstract 2270: A BRCA1 deficient, NFκB driven immune signal predicts good outcome in triple negative breast cancer
Authors: Niamh E. Buckley, Paula Haddock, Ricardo De Matos Simoes, Eileen Parkes, Gareth Irwin, Frank Emmert-Streib, Stephen McQuaid, Richard D. Kennedy, Paul B. Mullan
Journal: Cancer Research (2016)

Abstract Triple negative (TNBCs) and the closely related Basal-like (BLBCs) breast cancers are a loosely defined collection of cancers with poor clinical outcomes. Both show strong similarities with BRCA1-mutant breast cancers and BRCA1 dysfunction, or ‘BRCAness’, is observed in a large proportion of sporadic BLBCs. BRCA1 expression and function has been shown in vitro to modulate responses to radiation and chemotherapy. Exploitation of this knowledge in the treatment of BRCA1-mutant patients has had varying degrees of success. This reflects the significant problem of accurately detecting those patients with BRCA1 dysfunction. Moreover, not all BRCA1 mutations/loss of function result in the same histology/pathology or indeed have similar effects in modulating therapeutic responses. Given the poor clinical outcomes and lack of targeted therapy for these subtypes, a better understanding of the biology underlying these diseases is required in order to develop novel therapeutic strategies. We have discovered a consistent NFκB hyperactivity associated with BRCA1 dysfunction as a consequence of increased Reactive Oxygen Species (ROS). This biology is found in a subset of BRCA1-mutant and triple negative breast cancer cases and confers good outcome. The increased NFκB signalling results in an anti-tumour microenvironment which may allow CD8+ cytotoxic T cells to suppress tumour progression. However, tumours lacking this NFκB-driven biology have a more tumour-promoting environment and so are associated with poorer prognosis. Tumour-derived gene expression data and cell line models imply that these tumours may benefit from alternative treatment strategies such as reprogramming the microenvironment and targeting the IGF and AR signalling pathways. Citation Format: Niamh E. Buckley, Paula Haddock, Ricardo De Matos Simoes, Eileen Parkes, Gareth Irwin, Frank Emmert-Streib, Stephen McQuaid, Richard D. Kennedy, Paul B. Mullan. A BRCA1 deficient, NFκB driven immune signal predicts good outcome in triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2270.
CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma
Authors: James R. Berenson, Alan Cartmell, Alberto Bessudo, Roger M. Lyons, Wael Harb, Dimitrios Tzachanis, Richy Agajanian, Ralph Boccia, Morton Coleman, Robert A. Moss, Robert M. Rifkin, Priti Patel, Sandra Dixon, Ying Ou, Janet Anderl, Sanjay Aggarwal, Jesus G. Berdeja
Journal: Blood (2016)
The ten wishes and hopes of the deputy editors of Intensive Care Medicine
Authors: Giuseppe Citerio, Anders Perner, Jean-Francois Timsit
Journal: Intensive Care Medicine (2016)

The number of submissions to Intensive Care Medicine (ICM) has increased continually to the point where we now reject more than 80 % of the manuscripts submitted.The ICM editors do their best to select for publication those articles that are the absolute best because they:1. Have a clinical message that changes the practice of ICU clinicians caring for patients at the bedside, 2. Add significantly to existing knowledge, 3. Are properly registered and comply fully with the relevant regulations, 4. Have a study design and methodology that enable authors to draw valid conclusions (i.e.minimal or no risk of bias).
Age and Human Regenerative Capacity Impact of Cardiovascular Risk Factors
Authors: Ibhar Al Mheid, Salim S. Hayek, Yi-An Ko, Faysal Akbik, Qunna Li, Nima Ghasemzadeh, Greg S. Martin, Qi Long, Muhammad Hammadah, A. Maziar Zafari, Viola Vaccarino, Edmund K. Waller, Arshed A. Quyyumi
Journal: Circulation Research (2016)

Rationale: We investigated aging of human endogenous reparative capacity and aimed to clarify whether it is affected by presence of cardiovascular disease or its risk factors (RFs). Objective: Circulating progenitor cell (PC) levels reflect endogenous regenerative potential. The effect on PC of healthy aging compared with aging with RFs or cardiovascular disease (CVD) is unknown. We examined whether exposure to RF and CVD leads to an accelerated decline in circulating PC with increasing age. Methods and Results: In 2792 adult subjects, 498 were free of RFs (smoking, diabetes mellitus, hypertension, or hyperlipidemia), 1036 subjects had 1 to 2 RF, and 1253 had ≥3 RFs or CVD. PC were enumerated by flow cytometry as CD45 med+ mononuclear cells expressing CD34 and subsets coexpressing CD133, CXCR4, and vascular endothelial growth factor receptor-2 epitopes. Younger age, male sex, and larger body size correlated with higher PC counts ( P &lt;0.01). After multivariable adjustment, both age and RF categories were independently associated with PC counts ( P &lt;0.05), with lower PC counts in older subjects and those with higher RF burden or CVD. PC counts remained unchanged with increasing age in healthy individuals. There were significant interactions between age and RF categories ( P ≤0.005), such that for younger subjects (&lt;40 years), RFs were associated with increased PC counts, whereas for older subjects (&gt;60 years), RFs and CVD were associated with lower PC counts. Conclusions: Circulating PC levels do not decline with healthy aging; RF exposure at a younger age stimulates PC mobilization, whereas continued exposure is associated with lower PC levels in later life. Over the lifespan, exposure to RFs and CVD is associated with an initial stimulation and subsequent decline in circulating PC levels, which reflect endogenous regenerative capacity.