tbuckley/cabot-search huggingface dataset:
Response and progression-free survival according to planned treatment duration in patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) in the phase III ASPIRE study
Authors: Meletios Dimopoulos, Michael Wang, Vladimir Maisnar, Jiri Minarik, William Bensinger, Maria-Victoria Mateos, Mihaela Obreja, Julie Blaedel, Philippe Moreau
Journal: Journal of Hematology & Oncology (2018)

In ASPIRE, carfilzomib, lenalidomide, and dexamethasone (KRd) significantly improved progression-free survival (PFS) and response rates versus lenalidomide and dexamethasone (Rd) in patients with relapsed multiple myeloma. Per protocol, patients received KRd for a maximum of 18 cycles followed by Rd to progression, so the benefit/risk profile of KRd to progression was not established. This post hoc analysis evaluated the efficacy and safety of KRd versus Rd at 18 months from randomization. Cumulative rates of complete response (CR) or better over time and PFS hazard ratio (HR) at 18 months were evaluated for KRd versus Rd. PFS HRs were also assessed according to cytogenetic risk, prior lines of therapy, and prior bortezomib treatment. Cox regression analysis was used to evaluate PFS HRs. The hazard ratio (HR) for PFS at 18 months was 0.58 versus 0.69 for the overall ASPIRE study. Patients with high-risk cytogenetics, ≥ 1 prior lines of therapy, and prior bortezomib exposure benefited from KRd up to 18 months versus Rd. The HRs for PFS at 18 months in the pre-defined subgroups were lower than those in the overall study. The difference in the proportion of KRd and Rd patients achieving at least a complete response (CR) increased dramatically over the first 18 months and then remained relatively constant. The safety profile at 18 months was consistent with previous findings. The improved PFS HR at 18 months and the continued increase in CR rates for KRd through 18 cycles suggest that there may be a benefit of continued carfilzomib treatment. Clinical trials.gov NCT01080391 . Registered 2 March 2010.
Abstract 13976: Predictors of Death, Heart Transplantation and Relapse in Biopsy-proven and Clinically Suspected Myocarditis: a Prospective Study
Authors: Alida L Caforio, Alessandro Schiavo, Martina Testolina, Martina Perazzolo Marra, Loira Leoni, Claudio Bilato, Renzo Marcolongo, Annalisa Angelini, Cristina Basso, Marco Panfili, Giambattista Isabella, Giuseppe Tarantini, Massimo Napodano, Gaetano Thiene, Gino Gerosa, Sabino Iliceto
Journal: Circulation (2013)

Myocarditis may resolve, relapse or lead to dilated cardiomyopathy, death or transplantation. A positive result for serum autoantibodies, anti-heart (AHA), anti-intercalated disk (AIDA), and anti-nucleus (ANA), identifies autoimmune forms. Predictors of poor prognosis in biopsy-proven myocarditis (BPM) and in clinically suspected myocarditis (CSM) are not well defined.   Purpose:  To identify predictors of death, cardiac transplantation and relapse in BPM and in CSM, defined on the basis of a plausible clinical scenario, normal coronary arteries, and Cardiac Magnetic Resonance (CMR) findings.   Methods:  We studied 466 patients (317 male, mean age 37 ± 17 years, median follow-up 50 months), of whom 250 BPM and 216 CSM. All patients underwent selective coronary angiography. Serum AHA, AIDA, and ANA were measured by indirect immunofluorescence. Univariate and multivariable Cox regression analysis was used.   Results:  At the last follow-up, 366 were alive (89.7%), 42 were dead or transplanted (10.3%) and 58 patients were lost. Survival free from death or transplantation at 10 years was 83% in the whole group and was lower in BPM compared to CSM (76% vs 94% respectively, p   Conclusions:  Independent predictors of death and cardiac transplantation in myocarditis included ventricular dysfunction at presentation, female gender and autoimmune markers, in particular high titre AHA and ANA. Independent predictors of relapse were young age and history of myocarditis. Prognostic predictors did not differ between BPM and CSM, suggesting that the latter is part of the myocarditis spectrum.
Does pilocytic astrocytoma (PA) in adults have a different prognosis than PA in children?
Authors: Daniel Fernandes Marques, Iuri amorim Santana, Rodrigo Santa Cruz Guindalini, Hugo Sterman Neto, Marcela Alves Teixeira Crosara, Manoel Jacobsen Teixeira, Paulo Marcelo Hoff, Olavo Feher
Journal: Journal of Clinical Oncology (2012)

2038 Background: Pilocytic astrocytoma (PA) accounts for up to 25% of all brain tumors in children. A 75% progression-free survival rate at 5 years and overall survival rates of 95.8% at 10 years have been reported after a complete resection. However, the incidence in adults is low and the outcome less well characterized. We conducted a retrospective analysis of adult PAs identified in order to review the clinical characteristics and outcome of this neoplasm in this age group. Methods: A descriptive, cross-sectional study was undertaken in patients over 16 y.o., diagnosed with PA between January 1990 and December 2010 at our center. Clinical characteristics, date and extent of surgery, tumor location, postoperative treatment, complications and recurrences were collected from hospital records. Results: From May, 1990 to December, 2010, 18 eligible adult patients (pts) with the diagnosis of PA were identified. Median age was 25,5 (16-52) years, 72,2% female and 83,3% had an ECOG performance status ≤ 2. The most frequent tumor sites were the cerebellum (44,4%), followed by the cerebral hemispheres (38%). All patients underwent surgery as primary treatment, 72% had a complete macroscopic resection (CMR) and 28% had a partial resection (PR). Two patients received postoperative radiotherapy: one following a PR and the other after tumor relapse following a CMR. Two patients relapsed five months and 44 months after initial complete gross resection. Salvage surgery achieved CMR in both. With a median follow-up of 89 months, all patients are alive, except for one who died in the postoperative period due to fungal meningitis. Of note, none of 5 pts undergoing a partial resection progressed and 3 are alive for more than 10 years. Conclusions: As it occurs in the pediatric population, PA in adults seems to carry a similarly favorable prognosis. It is conceivable that after initial surgical resection a watch and wait type of approach is appropriate, even following partial resection. The role of upfront radiotherapy is uncertain and it should probably be left for progressive tumors.
Identification of a Genomic Region between <i>SLC29A1</i> and <i>HSP90AB1</i> Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance)
Authors: Megan Li, Flora Mulkey, Chen Jiang, Bert H. O’Neil, Bryan P. Schneider, Fei Shen, Paula N. Friedman, Yukihide Momozawa, Michiaki Kubo, Donna Niedzwiecki, Howard S. Hochster, Heinz-Josef Lenz, James N. Atkins, Hope S. Rugo, Susan Halabi, William Kevin Kelly, Howard L. McLeod, Federico Innocenti, Mark J. Ratain, Alan P. Venook, Kouros Owzar, Deanna L. Kroetz
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood. Experimental Design: To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 patients treated with bevacizumab (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes. Results: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (P = 0.01; OR, 2.4) and systolic blood pressure &amp;gt;180 mm Hg (P = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure. Conclusions: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension. Clin Cancer Res; 24(19); 4734–44. ©2018 AACR.
Abstract 19085: Circulating Long Noncoding RNA Signature Predicts Internal Carotid Artery Stenosis and Associated Cerebral Ischemia
Authors: Chih-Fan Yeh, Yen-Ting Chen, Mao-Shin Lin, Hsien-Li Kao, Kai-Chien Yang
Journal: Circulation (2016)

Introduction:  Internal carotid artery stenosis (ICAS) can lead to cerebral ischemia. Stress image studies have limited sensitivity to detect cerebral ischemia caused by ICAS. Currently, there are no biomarkers for ICAS and associated cerebral ischemia, precluding early intervention before clinical events occur. This study aimed to test the hypothesis that circulating long non-coding RNAs (lncRNAs) can be a useful biomarker to detect ICAS and associated cerebral ischemia.   Methods:  Cell free, circulating lncRNA profiling was conducted using plasma RNA from subjects with significant (>70%) ICAS with cerebral ischemia on perfusion scan (n=14), significant ICAS without cerebral ischemia (n=8), coronary artery disease (CAD) without ICAS (n=8), and healthy subjects without CAD or ICAS (n=7), by RNA sequencing.   Results:  A total of 127 million sequencing reads were obtained from 37 plasma RNA samples. Among the detected 1243 lncRNAs, 17 (14 up, 3 down) and 38 (all down) were significantly dysregulated with CAD and ICAS, respectively. Hierarchical clustering analysis revealed that plasma lncRNA profile discriminates ICAS from CAD and control samples. Among the 38 dysregulated lncRNAs with ICAS (ICAS lncRNA), only 3% were similarly dysregulated with CAD. Pathway analysis of ICAS lncRNAs based on their nearby mRNAs ( cis -mRNA) showed significant enrichment of genes involved in cell junction dynamics and lipoid acid metabolism, both of which have been implicated in the pathogenesis of carotid atherosclerosis. Analysis on an independent microarray dataset obtained from the carotid arterial plaques from 32 hypertensive patients and paired normal arterial tissues from the same subjects (GSE43292) revealed that 24% (9 out of 38) of the  cis -mRNA of the ICAS lncRNAs were similarly dysregulated in carotid arterial plaques, suggesting that circulating RNA expression can mirror, at least in part, the transcriptomal changes in atherosclerotic carotid lesions. Finally, lncRNA lnc-BMP2K-3:1 could discriminate between ICAS patients with and without cerebral ischemia (ROC curve AUC 0.73,  p =0.02).   Conclusion:  Circulating lncRNAs reflect the disease states of carotid atherosclerosis and could serve as a novel biomarker to detect ICAS and associated cerebral ischemia.
Neoadjuvant trastuzumab + pertuzumab in HER2 positive breast cancer in a country with limited resources: Evaluation of complete pathological response in a real world practice.
Authors: Semir Beslija, Anes Pasic, Elma Kapisazovic, Berisa Hasanbegovic, Emir Sokolovic, Faruk Skenderi, Timur Ceric
Journal: Journal of Clinical Oncology (2018)

e12661 Background: Neoadjuvant treatment is one of cornerstones of HER2 directed treatment in breast cancer. Today it is considered that patients with complete pathological response (pCR) to neoadjuvant therapy have a better disease-free survival and overall survival, especially with Her2-positive breast cancer. Current standard is use of dual anti-HER2 blockade, but this therapeutic approach in real life is often inaccessible, particularly in countries with limited resources. Aim of this study was to investigate neoadjuvant effects of trastuzumab + pertuzumab in patients with locally advanced Her2-positive disease in a country with limited resources. Methods: During the period 2017-2018, we identified 27 patients with locally advanced Her2 positive breast cancer. All patients were treated with neoadjuvant therapy that included trastuzumab and pertuzumab and conventional chemotherapy regimens. All patients underwent surgery and a pathologist evaluated pCR using MD Anderson Residual Burden Calculator (RCB). The tumors were considered pCR if ypT0/is ypN0 or ypTis. Results: The study included 9 luminal B (ER+/Her2 3+) and 18 Her2 positive breast cancers ( Er- / HER 2 3+) .Out of 18 patients with Her2 positive disease, 11 had pCR (61%), 7 patients (39%) had a partial response. Out of 9 Luminal B, 4 had pCR (44, 4%), and 5 had partial response. (56%). Her2-positive breast cancers had a higher pCR compared with luminal B tumors (69.5% vs. 50%). No significant difference in pCR was observed regarding different chemotherapy regimens. Conclusions: Neoadjuvant dual blockade in patients with locally advanced Her2 positive breast cancer is a valuable approach in obtaining a pCR, particularly in patients with Her2 subtype of breast cancer. The obtained results in Bosnia and Herzegovina in this small series are comparable with the data from the developed world or even more significant. Further larger prospective studies should confirm these preliminary data.
Abstract 12954: A Novel-Particle Image Velocimetry (PIV) Assay to Measure the Maturity and Functional Cardiomyocytes Contractility
Authors: Johnson Rajasingh, Sheeja Rajasingh, Andras Czirok, Saheli Samanta, Dona G Isai, Edina Kosa, Buddhadeb Dawn
Journal: Circulation (2015)

Introduction: The most important functional property of cardiomyocytes (CMCs) from a therapeutic standpoint is the ability to produce contractile force. Current methods of assessing the same, such as patch clamping and confocal calcium imaging, are labor-intensive, invasive or require fluo-dye in culture medium, which can affect the cells’ contractility. No optimal method is currently available to assess CMC functionality. Hypothesis: We hypothesized that a novel particle image velocimetry (PIV) method would provide accurate assessment of CMC contractility and maturity. Methods: We generated induced pluripotent stem cells (iPSCs) from adult human cells using a highly efficient viral-free transfection of DNA and mRNA combination. iPSCs were further differentiated into functional CMCs with defined culture conditions. Results: To analyze the contractility of iPSC-derived CMCs (iCMCs), we recorded the same areas of culture plate at various time-points using high frame-rate video microscopy (Fig. A, n=11). A novel image analysis technique provided beat patterns time series data of cell displacement, measured relative to a resting reference state (Fig. B, C). As beat patterns of recordings in video microscopic images revealed, the contractility of early CMC nodes was asynchronous in space and irregular in time (Fig. D1-D2, three beating fields are marked as red, green and blue). During subsequent days after the onset of beating, however, the spatially distinct contractile centers became synchronous even as their frequency remained unstable (Fig. D3-D6). The transmission electron microscopic images confirmed a well-developed pattern of sarcomeres in late-stage (day 30) CMCs. Conclusions: This PIV image analysis is a novel method that enables assessment of CMC contractility multiple times, if necessary, without jeopardizing the biology of cells. This method may also prove beneficial for drug screening and detection of cardiotoxicity in iPSC-derived CMCs.
Interleukin-32 promotes detachment and activation of human Langerhans cells in a human skin explant model
Authors: J. Gonnet, H. Perrin, A.J. Hutton, D. Boccara, O. Bonduelle, M. Mimoun, M. Atlan, A. Soria, B. Combadière
Journal: British Journal of Dermatology (2018)

Cross-talk between skin keratinocytes (KCs) and Langerhans cells (LCs) plays a fundamental role in the body's first line of immunological defences. However, the mechanism behind the interaction between these two major epidermal cells is unknown. Interleukin (IL)-32 is produced in inflammatory skin disorders. We questioned the role of IL-32 in the epidermis.We aimed to determine the role of IL-32 produced by KCs on surrounding LCs.We used an ex vivo human explant model from healthy donors and investigated the role of IL-32 on LC activation using imaging, flow cytometry, reverse transcriptase quantitative polymerase chain reaction and small interfering (si)RNA treatment.Modified vaccinia virus ankara (MVA) infection induced KC death alongside the early production of the proinflammatory cytokine IL-32. We demonstrated that IL-32 produced by MVA-infected KCs induced modest but significant morphological changes in LCs and downregulation of adhesion molecules, such as epithelial cell adhesion molecule and very late antigen-4, and CXCL10 production. The treatment of KCs with IL-32-specific siRNA, and anti-IL-32 blocking antibody significantly inhibited LC activation, demonstrating the role of IL-32 in LC activation. We also found that some Toll-like receptor ligands induced a very high level of IL-32 production by KCs, which initiated LC activation.We propose, for the first time, that IL-32 is a molecular link between KCs and LCs in healthy skin, provoking LC migration from the epidermis to the dermis prior to their migration to the draining lymph nodes.
Dabigatran versus Warfarin in Patients with Atrial Fibrillation
Authors: Haruo Tomoda
Journal: New England Journal of Medicine (2009)

ConclusionsIn patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage.Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage.(ClinicalTrials.govnumber, NCT00262600.)
Association of Exercise With Mortality in Adult Survivors of Childhood Cancer
Authors: Jessica M. Scott, Nan Li, Qi Liu, Yutaka Yasui, Wendy Leisenring, Paul C. Nathan, Todd Gibson, Saro H. Armenian, Tormod S. Nilsen, Kevin C. Oeffinger, Kirsten K. Ness, Scott C. Adams, Leslie L. Robison, Gregory T. Armstrong, Lee W. Jones
Journal: JAMA Oncology (2018)

Adult survivors of childhood cancer are at excess risk for mortality compared with the general population. Whether exercise attenuates this risk is not known.To examine the association between vigorous exercise and change in exercise with mortality in adult survivors of childhood cancer.Multicenter cohort analysis among 15 450 adult cancer survivors diagnosed before age 21 years from pediatric tertiary hospitals in the United States and Canada between 1970 and 1999 enrolled in the Childhood Cancer Survivor Study, with follow-up through December 31, 2013.Self-reported vigorous exercise in metabolic equivalent task (MET) hours per week. The association between vigorous exercise and change in vigorous exercise and cause-specific mortality was assessed using multivariable piecewise exponential regression analysis to estimate rate ratios.The primary outcome was all-cause mortality. Secondary end points were cause-specific mortality (recurrence/progression of primary malignant neoplasm and health-related mortality). Outcomes were assessed via the National Death Index.The 15 450 survivors had a median age at interview of 25.9 years (interquartile range [IQR], 9.5 years) and were 52.8% male. During a median follow-up of 9.6 years (IQR, 15.5 years), 1063 deaths (811 health-related, 120 recurrence/progression of primary cancer, 132 external/unknown causes) were documented. At 15 years, the cumulative incidence of all-cause mortality was 11.7% (95% CI, 10.6%-12.8%) for those who exercised 0 MET-h/wk, 8.6% (95% CI, 7.4%-9.7%) for 3 to 6 MET-h/wk, 7.4% (95% CI, 6.2%-8.6%) for 9 to 12 MET-h/wk, and 8.0% (95% CI, 6.5%-9.5%) for 15 to 21 MET-h/wk (P < .001). There was a significant inverse association across quartiles of exercise and all-cause mortality after adjusting for chronic health conditions and treatment exposures (P = .02 for trend). Among a subset of 5689 survivors, increased exercise (mean [SD], 7.9 [4.4] MET-h/wk) over an 8-year period was associated with a 40% reduction in all-cause mortality rate compared with maintenance of low exercise (rate ratio, 0.60; 95% CI, 0.44-0.82; P = .001).Vigorous exercise in early adulthood and increased exercise over 8 years was associated with lower risk of mortality in adult survivors of childhood cancer.
Anthony Fairclough Lever
Authors: Anna Dominiczak, John Connell, J Ian S Robertson
Journal: BMJ (2018)

Anthony Fairclough Lever (“Tony”), who was the director and driving force of the Medical Research Council blood pressure unit in Glasgow, Scotland, between 1967 and 1994, and, latterly, professor emeritus in the Department of Cardiovascular and Medical Sciences at the University of Glasgow, died peacefully on Sunday 25 March 2018, aged 89 years.

Born on 18 March 1929 in Surrey and educated in London, Tony graduated BSc in 1952 and bachelor of medicine and surgery in 1955. An outstanding student, he was awarded gold medals in pathology and medicine. His postgraduate career was equally impressive, and he became a house physician to the legendary Sir George Pickering at St Mary’s Hospital in London. A research fellowship and a lectureship, together with membership and then fellowship of the Royal College of Physicians of London, all followed in rapid succession.

In 1956, George Pickering moved to Oxford as Regius professor of medicine, and Stanley Peart took over the medical unit at St Mary’s Hospital. Peart had purified and sequenced angiotensin II, the product of the action of the renal enzyme renin and the most potent vasopressor agent known at the time. Tony Lever, together with J Ian S Robertson and Jehoiada J Brown, joined the research team as clinician scientists to tackle the challenge of whether renin and/or angiotensin were the cause of the hypertension caused by renal artery constriction.

In 1964, Tony Lever and Ian Robertson devised the world’s first reliable and …
Systems Biology in Translational Oncology: Computational and Experimental Study of EGFR and IGF1R Pathways in NSCLC Cell Lines
Authors: F. Bianconi, K. Perruccio, V. Ludovini, E. Baldelli, G. Bellezza, A. Flacco, P. Valigi, L. Crinò
Journal: Annals of Oncology (2012)