tbuckley/cabot-search huggingface dataset:
Survival and Left Ventricular Function Changes in Fulminant Versus Nonfulminant Acute Myocarditis
Authors: Enrico Ammirati, Manlio Cipriani, Marzia Lilliu, Paola Sormani, Marisa Varrenti, Claudia Raineri, Duccio Petrella, Andrea Garascia, Patrizia Pedrotti, Alberto Roghi, Edgardo Bonacina, Antonella Moreo, Maurizio Bottiroli, Maria P. Gagliardone, Michele Mondino, Stefano Ghio, Rossana Totaro, Fabio M. Turazza, Claudio F. Russo, Fabrizio Oliva, Paolo G. Camici, Maria Frigerio
Journal: Circulation (2017)

Previous reports have suggested that despite their dramatic presentation, patients with fulminant myocarditis (FM) might have better outcome than those with acute nonfulminant myocarditis (NFM). In this retrospective study, we report outcome and changes in left ventricular ejection fraction (LVEF) in a large cohort of patients with FM compared with patients with NFM.The study population consists of 187 consecutive patients admitted between May 2001 and November 2016 with a diagnosis of acute myocarditis (onset of symptoms <1 month) of whom 55 required inotropes and/or mechanical circulatory support (FM) and the remaining 132 were hemodynamically stable (NFM). We also performed a subanalysis in 130 adult patients with acute viral myocarditis and viral prodrome within 2 weeks from the onset, which includes 34 with FM and 96 with NFM. Patients with giant-cell myocarditis, eosinophilic myocarditis, or cardiac sarcoidosis and those <15 years of age were excluded from the subanalysis.In the whole population (n=187), the rate of in-hospital death or heart transplantation was 25.5% versus 0% in FM versus NFM, respectively (P<0.0001). Long-term heart transplantation-free survival at 9 years was lower in FM than NFM (64.5% versus 100%, log-rank P<0.0001). Despite greater improvement in LVEF during hospitalization in FM versus NFM forms (median, 32% [interquartile range, 20%-40%] versus 3% [0%-10%], respectively; P<0.0001), the proportion of patients with LVEF <55% at last follow-up was higher in FM versus NFM (29% versus 9%; relative risk, 3.32; 95% confidence interval, 1.45-7.64, P=0.003). Similar results for survival and changes in LVEF in FM versus NFM were observed in the subgroup (n=130) with viral myocarditis. None of the patients with NFM and LVEF ≥55% at discharge had a significant decrease in LVEF at follow-up.Patients with FM have an increased mortality and need for heart transplantation compared with those with NFM. From a functional viewpoint, patients with FM have a more severely impaired LVEF at admission that, despite steep improvement during hospitalization, remains lower than that in patients with NFM at long-term follow-up. These findings also hold true when only the viral forms are considered and are different from previous studies showing better prognosis in FM.
Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial
Authors: Michael A Davies, Philippe Saiag, Caroline Robert, Jean-Jacques Grob, Keith T Flaherty, Ana Arance, Vanna Chiarion-Sileni, Luc Thomas, Thierry Lesimple, Laurent Mortier, Stergios J Moschos, David Hogg, Iván Márquez-Rodas, Michele Del Vecchio, Céleste Lebbé, Nicolas Meyer, Ying Zhang, Yingjie Huang, Bijoyesh Mookerjee, Georgina V Long
Journal: The Lancet Oncology (2017)
Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases
Authors: Robert P. Schleimer, Sergejs Berdnikovs
Journal: Journal of Allergy and Clinical Immunology (2017)

Epithelial barriers of the skin, gastrointestinal tract, and airway serve common critical functions, such as maintaining a physical barrier against environmental insults and allergens and providing a tissue interface balancing the communication between the internal and external environments. We now understand that in patients with allergic disease, regardless of tissue location, the homeostatic balance of the epithelial barrier is skewed toward loss of differentiation, reduced junctional integrity, and impaired innate defense. Importantly, epithelial dysfunction characterized by these traits appears to pre-date atopy and development of allergic disease. Despite our growing appreciation of the centrality of barrier dysfunction in initiation of allergic disease, many important questions remain to be answered regarding mechanisms disrupting normal barrier function. Although our external environment (proteases, allergens, and injury) is classically thought of as a principal contributor to barrier disruption associated with allergic sensitization, there is a need to better understand contributions of the internal environment (hormones, diet, and circadian clock). Systemic drivers of disease, such as alterations of the endocrine system, metabolism, and aberrant control of developmental signaling, are emerging as new players in driving epithelial dysfunction and allergic predisposition at various barrier sites. Identifying such central mediators of epithelial dysfunction using both systems biology tools and causality-driven laboratory experimentation will be essential in building new strategic interventions to prevent or reverse the process of barrier loss in allergic patients.
Prognostic and predictive value of microRNA-34a expression in colorectal cancer.
Authors: Albert Y. Lin, Natalia B. Kouzminova, Jonathan Pollack, Gerard Nuovo
Journal: Journal of Clinical Oncology (2014)

e22045 Background: Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. MicroRNA-34a (miR-34a), a tumor suppressor gene, is known to be down-regulated in CRC cell lines and recently shown to be a cell-fate determinant in colon cancer stem cells and implicated as a factor regulating the resistance to 5-FU in vitro. However, its prognostic and predictive roles in CRC are unclear. Methods: MiR-34a detection was performed by in situ hybridization on a CRC tissue microarray (n=127; stage I, 21 patients; II: 42; III: 33; IV: 31). Its expression was graded as negative (no signal), low (expression in 1-19% of cancer cells), moderate (20-49% of cancer cells) and strong (50-100% of cancer cells). The correlations between miR-34a expression and EGFR, Osteopontin (OPN), p53, Ki67, LEF1, VEGF, COX2, MMR, stage and grade were evaluated by chi-squared test and Spearman's rank correlation coefficient. Kaplan-Meier survival analysis, log-rank test and Cox regression model were used to assess the association of miR-34a expression with recurrence-free survival (RFS) and disease specific survival (DSS). Results: MiR-34a expression is correlated with genes associated with tissue proliferation and invasion, such as Ki67 (Spearman's r=0.28, p=0.002), EGFR (r=0.2, p=0.02) and LEF1 (r=0.18, p=0.039). In the subgroup of patients (n=75; stage II/III) with negative OPN expression (n=25), weak or negative miR-34a expression was associated with worse RFS (HR=4.1; 95%CI=1.1-15.9; p=0.036) and DSS (HR=10.5; 95%CI=1.2-94.5; p=0.036), which seem to be significant only in strata with spared p53 expression (p=0.002, n=16). However, miR-34a expression status did not appear to be associated with RFS after 5FU-based chemotherapy neither in OPN negative group (p=0.37, n=14) or for all chemotherapy cases (p=0.65, n=35). Conclusions: Our data suggest that down-regulated or absent expression of miR-34a correlates with worse RFS and DSS in stage II - III CRC patients with negative OPN expression. However, it does not support miR-34a as a predictive biomarker for response to 5FU-based adjuvant chemotherapy. Further large-scale clinical studies are warranted to clarify the role of miR-34a as a novel prognostic biomarker in CRC.
A putative stemness biomarker gene set suggests γ-secretase inhibitor targets self-renewal and pluripotency programs in tumors
Authors: Xudong Dai, Michele Cleary, Peter Strack, Pradip Majumder, Sudhir Rao, Cole Liberator, James Watters, James Hardwi, Jennifer O'Neil, A. Thomas Look, Peter Linsley, Hongyue Dai, Nancy Kohl, Pamela Carroll, Christopher Winter
Journal: Clinical Cancer Research (2008)

B41  Emerging evidence suggests that tumor initiating cell subpopulations bearing characteristics of stem cells may play an important role in drug resistance, tumor recurrence, and metastasis-- major challenges for today9s battle against cancer (1-8). Therefore, it is critical to identify biomarkers for assessing self-renewal and pluripotency programs, or “stemness”activity within tumors. However, it remains a challenge to reliably isolate pure stem cell-like subpopulations of cancer cells based on the activity of stemness using cell surface proteins. We report a novel approach to define a stemness signature by first identifying a set of genes whose expression levels are associated with the changes in self-renewal and pluripotency in both embryonic cells and tumor cell lines. The stemness gene is elevated in genetically manipulated tissue with elevated stem cells numbers. In human cancers, expression of the identified stemness genes is associated with distinct pathological phenotypes and the course of disease progression in breast cancer and chronic myelogenous leukemia. For instance, the expression of stemness genes was significantly anti-correlated with the probability of overall survival and metastasis free survival in retrospective analysis of breast cancer data. This correlation was supported by data from four independent studies. Therefore, our set of stemness genes may not only unveil the feature of stem cells within tumors, but also provide a novel measure of tumor progression and patient prognosis. Finally, we discovered that a γ-Secretase inhibitor (GSI) significantly down-regulated the stemness genes in T-ALL cell lines and in a murine model for breast cancer. These observations are in agreement with recent reports that Notch plays a critical role in regulating the fate of somatic stem cells, including its requirement to maintain the pluripotency and proliferative capacity of stem and progenitor cells at the base of gastrointestinal crypts. Our findings support the idea that GSIs target a sub-population of tumor cells with ectopic stemness activity. These cancer initiating cell sub-populations are thought to evade standard of care treatments with chemotherapy and radiation. Therefore it will be important to determine whether GSIs can provide increased clinical benefit when used in combination with cytotoxic therapies.
<i>Plasmodium</i> products persist in the bone marrow and promote chronic bone loss
Authors: Michelle S. J. Lee, Kenta Maruyama, Yukiko Fujita, Aki Konishi, Patrick M. Lelliott, Sawako Itagaki, Toshihiro Horii, Jing-wen Lin, Shahid M. Khan, Etsushi Kuroda, Shizuo Akira, Ken J. Ishii, Cevayir Coban
Journal: Science Immunology (2017)

Although malaria is a life-threatening disease with severe complications, most people develop partial immunity and suffer from mild symptoms. However, incomplete recovery from infection causes chronic illness, and little is known of the potential outcomes of this chronicity. We found that malaria causes bone loss and growth retardation as a result of chronic bone inflammation induced by Plasmodium products. Acute malaria infection severely suppresses bone homeostasis, but sustained accumulation of Plasmodium products in the bone marrow niche induces MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, leading to increased RANKL expression and overstimulation of osteoclastogenesis, favoring bone resorption. Infection with a mutant parasite with impaired hemoglobin digestion that produces little hemozoin, a major Plasmodium by-product, did not cause bone loss. Supplementation of alfacalcidol, a vitamin D3 analog, could prevent the bone loss. These results highlight the risk of bone loss in malaria-infected patients and the potential benefits of coupling bone therapy with antimalarial treatment.
Advising women with diabetes in pregnancy to express breastmilk in late pregnancy (Diabetes and Antenatal Milk Expressing [DAME]): a multicentre, unblinded, randomised controlled trial
Authors: Della A Forster, Anita M Moorhead, Susan E Jacobs, Peter G Davis, Susan P Walker, Kerri M McEgan, Gillian F Opie, Susan M Donath, Lisa Gold, Catharine McNamara, Amanda Aylward, Christine East, Rachael Ford, Lisa H Amir
Journal: The Lancet (2017)
Sleeping Beauty Modified CAR+ Lymphocytes Engraft and Exhibit Anti-Tumor Activity in Patient-Derived Xenograft Models of Acute Lymphoblastic Leukemia
Authors: Chiara F. Magnani, Claudia Mezzanotte, Claudia Cappuzzello, Fabrizio Benedicenti, Michela Bardini, Sarah Tettamanti, Grazia Fazio, Gianni Cazzaniga, Laurence J.N. Cooper, Eugenio Montini, Andrea Biondi, Ettore Biagi
Journal: Blood (2016)
Half of CCGs plan treatment cutbacks to meet financial targets
Authors: Adrian O’Dowd
Journal: BMJ (2017)

Around half of clinical commissioning groups (CCGs) in England plan to delay or cancel spending on treatment this year to meet their financial targets alongside a steadily growing workload in primary care, a report by the King’s Fund has shown.1

The health think tank’s latest quarterly monitoring report of NHS performance found that half of CCG finance leads thought that achieving this year’s financial forecast would probably depend on delaying or cancelling spending in their area.

The report contains results from an online survey carried out from April to May, with responses from 84 NHS trust finance directors and 42 CCG finance leads …
Frequent capsule switching in ‘ultra-virulent’ meningococci – Are we ready for a serogroup B ST-11 complex outbreak?
Authors: Jay Lucidarme, Aiswarya Lekshmi, Sydel R. Parikh, James E. Bray, Dorothea M. Hill, Holly B. Bratcher, Steve J. Gray, Anthony D. Carr, Keith A. Jolley, Jamie Findlow, Helen Campbell, Shamez N. Ladhani, Mary E. Ramsay, Martin C.J. Maiden, Ray Borrow
Journal: Journal of Infection (2017)
Healthcare professionals need more training about human trafficking and the safe use of interpreters
Authors: Toby Bonvoisin
Journal: BMJ (2017)

SD and ZA’s article was a good insight into how clinicians can communicate sensitively and effectively through family translators, while considering them as people too.1 It is important to bear in mind, however, that a small minority of patients bring someone along to translate who isn’t who they say they are or does not have the patient’s best interests …
Trends in Reoperation After Initial Lumpectomy for Breast Cancer
Authors: Monica Morrow, Paul Abrahamse, Timothy P. Hofer, Kevin C. Ward, Ann S. Hamilton, Allison W. Kurian, Steven J. Katz, Reshma Jagsi
Journal: JAMA Oncology (2017)

Surgery after initial lumpectomy to obtain more widely clear margins is common and may lead to mastectomy.To describe surgeons' approach to surgical margins for invasive breast cancer, and changes in postlumpectomy surgery rates, and final surgical treatment following a 2014 consensus statement endorsing a margin of "no ink on tumor."This was a population-based cohort survey study of 7303 eligible women ages 20 to 79 years with stage I and II breast cancer diagnosed in 2013 to 2015 and identified from the Georgia and Los Angeles County, California, Surveillance, Epidemiology, and End Results registries. A total of 5080 (70%) returned a survey. Those with bilateral disease, missing stage or treatment data, and with ductal carcinoma in situ were excluded, leaving 3729 patients in the analytic sample; 98% of these identified their attending surgeon. Between April 2015 and May 2016, 488 surgeons were surveyed regarding lumpectomy margins; 342 (70%) responded completely. Pathology reports of all patients having a second surgery and a 30% sample of those with 1 surgery were reviewed. Time trends were analyzed with multinomial regression models.Rates of final surgical procedure (lumpectomy, unilateral mastectomy, bilateral mastectomy) and rates of additional surgery after initial lumpectomy over time, and surgeon attitudes toward an adequate lumpectomy margin.The 67% rate of initial lumpectomy in the 3729 patient analytic sample was unchanged during the study. The rate of final lumpectomy increased by 13% from 2013 to 2015, accompanied by a decrease in unilateral and bilateral mastectomy (P = .002). Surgery after initial lumpectomy declined by 16% (P < .001). Pathology review documented no significant association between date of treatment and positive margins. Of 342 responding surgeons, 69% endorsed a margin of no ink on tumor to avoid reexcision in estrogen receptor-positive progesterone receptor-positive cancer and 63% for estrogen receptor-negative progesterone- receptor-negative cancer. Surgeons treating more than 50 breast cancers annually were significantly more likely to report this margin as adequate (85%; n = 105) compared with those treating 20 cases or fewer (55%; n = 131) (P < .001).Additional surgery after initial lumpectomy decreased markedly from 2013 to 2015 concomitant with dissemination of clinical guidelines endorsing a minimal negative margin. These findings suggest that surgeon-led initiatives to address potential overtreatment can reduce the burden of surgical management in patients with cancer.
Abstract 389: Alterations of Mitochondrial Calcium Handling in Heart Failure
Authors: An-Chi Wei, Ting Liu, Brian O’Rourke
Journal: Circulation Research (2015)

Heart failure (HF) and sudden cardiac death (SCD) are major public health concerns that are increasing in incidence, yet the mechanisms underlying SCD in patients with HF are poorly understood. In a novel guinea pig model of HF/SCD, we showed that in vivo treatment with a mitochondrial Na+/Ca2+ exchanger (mNCE) inhibitor attenuates cardiac remodeling, preserves cardiac contractile function, and improves survival, supporting a critical role for altered mitochondrial Ca2+ dynamics in the pathophysiology. Here, we investigate whether the intrinsic mitochondrial Ca2+ transport rates are altered in this HF model. Methods: Ascending aortic constriction, combined with daily i.p. injection of isoproterenol (ISO), were used to induce HF (ACi) with acquired long QT. This group was compared with animals subjected to aortic constriction alone (AC), or sham-operated animals with (SHAMi) or without (SHAM) ISO treatment. Ca2+ Green-5N was used to measure total mitochondrial Ca2+ uptake and to quantify mitochondrial Ca2+ influx and efflux rates in isolated cardiac mitochondria. Results: Both the total mitochondrial Ca2+ load and the Ca2+ capacity prior to triggering permeability transition pore (mPTP) opening were reduced in HF mitochondria (5mM NaCl present). Mitochondrial Ca2+ fluxes, individually measured with sequential additions of 15μM free Ca2+, 10nM Ru360 and 5mM NaCl, showed that initial Ca2+ uptake rate through the mitochondrial Ca2+ uniporter (mCU: 0.55 nmol/sec/mg) was not significantly changed in HF; however, the Ca2+ extrusion rate through mNCE was larger in HF (AC:0.022 nmol/sec/mg; SHAM:0.018; ACi:0.013; SHAMi:0.009), but with a lower affinity for Na+. Interestingly, Na+-independent efflux via mPTP increased in HF (AC:0.0040 nmol/sec/mg; SHAM:0.0022; ACi:0.0013; SHAMi:0.012). Mitochondria from failing hearts also showed decreased respiration and increased ROS emission. Conclusions: The data indicate that an increase of intrinsic Ca2+ efflux and the increase in cytoplasmic Na+ in HF could both contribute to blunted mitochondrial Ca2+ in HF, which will affect cardiac energetics and ROS balance. Inhibitors of mNCE or mPTP are thus proposed to be therapeutic interventions that would improve mitochondrial Ca2+ balance and function in HF.
The Gαh-PLCδ1 signaling axis drives metastatic progression in triple-negative breast cancer
Authors: Shang-Pen Huang, Pei-Yao Liu, Chih-Jung Kuo, Chi-Long Chen, Wei-Jiunn Lee, Yu-Hui Tsai, Yuan-Feng Lin
Journal: Journal of Hematology & Oncology (2017)

Distant metastasis of triple-negative breast cancer (TNBC) to other organs, e.g., the lungs, has been correlated with poor survival rates among breast cancer patients. Therefore, the identification of useful therapeutic targets to prevent metastasis or even inhibit tumor growth of TNBC is urgently needed. Gαh is a novel GTP-binding protein and known as an inactive form of calcium-dependent tissue transglutaminase. However, the functional consequences of transamidating and G-protein activities of tissue transglutaminase in promoting cancer metastasis are still controversial. Kaplan-Meier analyses were performed to estimate the prognostic values of Gαh and PLCδ1 by utilizing public databases and performing immunohistochemical staining experiments. Cell-based invasion assays and in vivo lung colony-forming and orthotropic lung metastasis models were established to evaluate the effectiveness of interrupting the protein-protein interaction (PPI) between Gαh and PLCδ1 in inhibiting the invasive ability and metastatic potential of TNBC cells. Here, we showed that the increased level of cytosolic, not extracellular, Gαh is a poor prognostic marker in breast cancer patients and correlates with the metastatic evolution of TNBC cells. Moreover, clinicopathological analyses revealed that the combined signature of high Gαh/PLCδ1 levels indicates worse prognosis in patients with breast cancer and correlates with lymph node metastasis of ER-negative breast cancer. Blocking the PPI of the Gαh/PLCδ1 complex by synthetically myristoylated PLCδ1 peptide corresponding to the Gαh-binding interface appeared to significantly suppress cellular invasiveness in vitro and inhibit lung metastatic colonies of TNBC cells in vivo. This study establishes Gαh/PLCδ1 as a poor prognostic factor for patients with estrogen receptor-negative breast cancers, including TNBCs, and provides therapeutic value by targeting the PPI of the Gαh/PLCδ1 complex to combat the metastatic progression of TNBCs.
Suicide prevention should focus on first three months after discharge, study finds
Authors: Jacqui Wise
Journal: BMJ (2017)

The risk of suicide is highest in the three months after patients are discharged from psychiatric facilities, although the risk remains high years later, a systematic review and meta-analysis has found.

Writing in JAMA Psychiatry ,1 the Australian researchers said that suicide prevention efforts should start while patients are in hospital and should focus on the period shortly after discharge. The meta-analysis included 100 …
Termination and Frameshift Mutations in ELANE Are Associated with Adverse Outcomes in Patients with Severe Chronic Neutropenia
Authors: David C. Dale, Vahagn Makaryan, Merideth L. Kelley, Audrey Anna Bolyard, Laurence A. Boxer, Peter E. Newburger, Mary Ann Bonilla, Maksim Klimiankou, Julia Skokowa, Cornelia Zeidler, Karl Welte
Journal: Blood (2016)
Determination of Plasma Renin Concentration by Angiotensin I Immunoassay
Authors: JAN R. STOCKIGT, R. DENNIS COLLINS, EDWARD G. BIGLIERI
Journal: Circulation Research (1971)

Radioimmunoassay of angiotensin I was applied to the estimation of renin concentration after incubation of human plasma with an excess of renin substrate from plasma of anephric sheep. With this me...