tbuckley/cabot-search huggingface dataset:
HCC Immune Surveillance and Antiviral Therapy of Hepatitis C Virus Infection
Authors: Solomon Owusu Sekyere, Bernhard Schlevogt, Friederike Mettke, Mohammad Kabbani, Katja Deterding, Thomas Christian Wirth, Arndt Vogel, Michael Peter Manns, Christine Susanne Falk, Markus Cornberg, Heiner Wedemeyer
Journal: Liver Cancer (2018)

HCV clearance by current antiviral therapies improves clinical outcomes but falls short in eliminating the risk for hepatocellular carcinoma (HCC) emergence. As the HCC immune surveillance establishment is vital for the control of neoplastic development and growth, we investigated its correlation with on-/post-treatment HCC emergence, and further analyzed the influence of viral eradication on this setup in patients with HCV-related liver cirrhosis.PBMC isolated at baseline and longitudinally during therapy were analyzed for tumor-associated antigen (TAA)-specific CD8+ T cell responses against glypican-3 overlapping peptides in vitro using high-definition flow cytometry. Multianalyte profiling of fifty soluble inflammatory mediators (SIM) in the plasma was also performed using Luminex-based multiplex technology.Cirrhosis patients were characterized by an altered profile of distinct SIMs at baseline. At this time point, immune-surveilling T cells targeting specific HCC-associated antigens were readily detectable in HCV-free cirrhosis patients whilst being rather weak in such patients who further developed HCC upon virus eradication. Therapy-induced cure of HCV infection analogously reduced the strength of the prevailing HCC immune surveillance machinery, particularly by CD8+ T cells in cirrhosis patients. These results were further validated by T cell reactivities to six immuno-dominant HCC-associated HLA-A2-restricted epi-topes. Further, we demonstrated that this phenomenon was likely orchestrated by alterations in SIMs - with evidence of IL-12 being a major culprit.Given the relationship between the baseline HCC-specific immune surveilling T cell responses and therapy-associated HCC emergence, and the impact of HCV clearance on its strength and magnitude, we recommend a continued HCC screening in cirrhotic HCV patients despite HCV resolution.
Duvelisib, an oral dual PI3K‐δ, γ inhibitor, shows clinical activity in indolent non‐Hodgkin lymphoma in a phase 1 study
Authors: Ian W. Flinn, Manish Patel, Yasuhiro Oki, Steven Horwitz, Francine F. Foss, Kerstin Allen, Mark Douglas, Howard Stern, Jennifer Sweeney, Jahnavi Kharidia, Patrick Kelly, Virginia M. Kelly, Brad Kahl
Journal: American Journal of Hematology (2018)

Abstract Duvelisib (IPI‐145) is an oral dual inhibitor of phosphoinositide‐3‐kinase (PI3K)‐δ and ‐γ in clinical development for the treatment of hematologic malignancies, including indolent non‐Hodgkin lymphoma (iNHL). In a Phase 1, open‐label study to determine the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, clinical activity, and safety of duvelisib monotherapy in patients with advanced hematologic malignancies, duvelisib was administered at eight dose levels (8‐100 mg BID) in a dose‐escalation phase ( n = 31 evaluable patients). Two dose‐limiting toxicities (DLTs), Grade 3 transaminase elevations and Grade 3 rash, occurred at 100 mg BID, and the MTD was determined to be 75 mg BID. Across all doses, 58.1% of iNHL patients had a response (19.4% complete, 35.5% partial, and 3.2% minor); median time to response was 1.84 months and duration of response was 16.9 months. Median progression‐free survival was 14.7 months, and the probability of overall survival at 24 months was 71.7%. Severe (Grade ≥ 3) adverse events included elevated liver enzymes (38.7%), diarrhea (25.8%), and neutropenia (29.0%). Three patients, all in the 75 mg BID cohort, experienced fatal AEs: E. coli sepsis, acute respiratory failure, and fungal pneumonia. No iNHL patients experienced Pneumocystis pneumonia. Duvelisib demonstrated favorable clinical activity and an acceptable safety profile in these high‐risk, heavily pretreated, relapsed/refractory iNHL patients, with 25 mg BID selected for further clinical development.
On the pathogenicity of the plasminogen K330E mutation for hereditary angioedema
Authors: A. E. Germenis, G. Loules, M. Zamanakou, F. Psarros, T. González‐Quevedo, M. Speletas, K. Bork, K. Wulff, L. Steinmüller‐Magin, I. Brænne, P. Staubach‐Renz, G. Witzke, J. Hardt
Journal: Allergy (2018)
Unproven Efficacy of Low-Dose Bisphosphonates as a Means of Decreasing Bone Metastases and Death in Early Breast Cancer
Authors: Trevor J. Powles, Alexander H. G. Paterson
Journal: JAMA Oncology (2018)

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Spiky Skin in a Renal Transplant Recipient
Authors: Flora Poon, Olivia Espinosa, Rubeta N. Matin
Journal: JAMA Dermatology (2018)

A woman in her 70s with a cadaveric renal transplant presented with a 1-year history of a facial cutaneous eruption and mildly pruritic lesions, initially affecting malar cheeks and eyebrows and subsequently spreading to involve the nose, chin, upper trunk, and extremities. What is your diagnosis?
Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension
Authors: Nina Rol, Michiel A de Raaf, Xiaoqing Q Sun, Vincent P Kuiper, Denielli da Silva Gonçalves Bos, Chris Happé, Kondababu Kurakula, Chris Dickhoff, Raphael Thuillet, Ly Tu, Christophe Guignabert, Ingrid Schalij, Kirsten Lodder, Xiaoke Pan, Franziska E Herrmann, Geerten P van Nieuw Amerongen, Pieter Koolwijk, Anton Vonk-Noordegraaf, Frances S de Man, Lutz Wollin, Marie-José Goumans, Robert Szulcek, Harm J Bogaard
Journal: Cardiovascular Research (2018)

Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors such as platelet derived growth factor, fibroblast growth factor and vascular endothelial growth factor. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH). Proliferation was assessed in control and PAH MVEC exposed to nintedanib. PH was induced in rats by subcutaneous injection of Sugen (SU5416) and subsequent exposure to 10% hypoxia for 4 weeks (SuHx model). Four weeks after re-exposure to normoxia, nintedanib was administered once daily for 3 weeks. Effects of the treatment were assessed with echocardiography, right heart catheterization, and histological analysis of the heart and lungs. Changes in extracellular matrix production was assessed in human cardiac fibroblasts stimulated with nintedanib. Decreased proliferation with nintedanib was observed in control MVEC, but not in PAH patient derived MVEC. Nintedanib treatment did not affect right ventricular (RV) systolic pressure or total pulmonary resistance index in SuHx rats and had no effects on pulmonary vascular remodelling. However, despite unaltered pressure overload, the right ventricle showed less dilatation and decreased fibrosis, hypertrophy, and collagen type III with nintedanib treatment. This could be explained by less fibronectin production by cardiac fibroblasts exposed to nintedanib. Nintedanib inhibits proliferation of pulmonary MVECs from controls, but not from PAH patients. While in rats with experimental PH nintedanib has no effects on the pulmonary vascular pathology, it has favourable effects on RV remodelling.
The increase in FDA-approved novel cancer drugs over the last 5 years: What factors are involved?
Authors: Idoroenyi Usua Amanam, Austin Blake Gardner, Nichole Young-Lin, John K. Chan
Journal: Journal of Clinical Oncology (2016)

e14111 Background: In 2015, The FDA approved the most number of novel drugs in the last 19-years. We propose to evaluate the factors associated with the significant increase in FDA approved oncologic drugs over the last 5 years. Methods: Data was extracted from all novel drug license applications to the FDA. SAS was used to conduct Chi-squared tests. Results: The FDA approved 47 novel cancer drugs from 2011 to 2015, of which, 34 (72.3%) were new drug applications and 13 (27.7%) were biologic license applications. Of these, 35 (64.5%) were orphan and 19 (40.4%) were first-in-class drugs. Based on expedited approval, 36 (76.6%) underwent priority review, 27 (57.5%) fast track, 17 (36.2%) accelerated, and 11 (23.4%) had breakthrough designation. 31 (66%) were for solid and 16 (34%) for liquid cancers. 20 (42.6%) drugs were approved based on clinical response, 16 (34.0%) on progression-free survival and 11 (23.4%) on overall survival as primary endpoints. The median time from initiation of clinical trial to approval was 42 months (range: 17 to 78 months). Trials completed within a shorter time ( < 42 months, median) were more likely to receive fast track designation compared to those requiring a longer time (36.2% vs. 21.3%; p = 0.03). We divided the 5-year study over 3 time periods from Jan 2011 - Aug 2012, Sept 2012 - April 2014, and May 2014 - Dec 2015. 13 (27.7%), 15 (31.9%), and 19 (40.4%) drugs were approved in those periods, respectively. Over time, there was a trend towards an increase in orphan-designated drugs from 14.9%, to 25.5%, to 34.0% (p = 0.13). The proportion of accelerated drugs increased from 15.4%, to 33.3%, to 52.6% over the study period, though not statistically significant (p = 0.09). There was also no change with respect to application type, phase of clinical trial, and type of trial endpoint over time. Conclusions: The majority (65%) of new cancer drugs were approved under the orphan drug designation which has increased over the past 5 years. The median time from clinical trial initiation to FDA approval was 42 months. The increasing trend for novel drug approvals through these expedited programs based on shorter and smaller clinical trials warrants further investigation.
Abstract 16940: Heart Transplant After Failed Single Ventricle Palliation in Young Infants Carries Excess Mortality Risk: A Multi-Institutional Study
Authors: Melanie D Everitt, Gerard Boyle, Kenneth B Schechtman, Jie Zheng, Aditya K Kaza, Emily A Bullock, Anne I Dipchand, David C Naftel, James K Kirklin, Charles E Canter
Journal: Circulation (2011)

BACKGROUND: Infant heart transplant (HT) recipients have the best long term survival of any age group, but small donor pool and high early mortality limit the therapeutic efficacy. We aimed to determine the relationship between pre-HT diagnosis and early HT outcome to identify infants most likely to benefit from HT. METHODS: The Pediatric Heart Transplant Study (PHTS) database was used to identify 739 infants s/p HT at age ≤6 mths between 1993-2008 divided into the following etiologic groups: cardiomyopathy (CM: 132, 18%); hypoplastic left heart syndrome without prior surgery (HLHS_WOS: 303, 41%); HLHS with surgery (HLHS_WS: 69, 9%); other congenital heart disease without surgery (CHD_WOS: 121, 16%; and other congenital heart disease with surgery (CHD_WS: 114, 15%). Severity of illness at HT, post HT survival, and era effects were compared among the 4 groups. RESULTS: The 1 yr survival for HLHS_WOS (79%) was similar to CHD_WOS (79%) and CHD_WS (82%) but worse than CM (89%). HLHS_WS had the highest mortality w 1 yr survival of 70%, p=0.03. Hazard function analysis showed the difference occurred within the 1st 6 mths after HT. Survival remained poor in the current surgical era for HLHS_WS, 71% (1993-1998) v 70% (1999-2008). Risk factors at HT associated w mortality included age &lt;1 mth (OR 2.5; CI 1.3-4.7, p=0.01), ECMO (OR 3.7; CI 2-6.8, p&lt;0.01), ventilator use (OR 1.8; CI 1-3.2, p=0.04), and HLHS_WS (OR 2.3; CI 1.3-4.1, p&lt;0.01). After adjusting for illness severity, differences in mortality risk persisted across etiologic groups. HLHS_WS (HR 2.3, CI 1.3-4, P&lt;0.01), CHD_WOS (HR 1.8, 1.1-3.1, P= 0.03), and HLHS_WOS (HR 1.7, 1.1-2.8, P=0.02) had significantly higher risk for mortality compared to CM. CONCLUSIONS: Infant HT recipients with different pre-HT diagnoses have strikingly different outcomes after HT that are unchanged over time and seem unrelated to clinical acuity at HT. CM infants have excellent survival, but HLHS_WS represent a high risk group for early mortality after HT.
Annual Rate of Transvenous Defibrillation Lead Defects in Implantable Cardioverter-Defibrillators Over a Period of >10 Years
Authors: ThomasKleemann, TorstenBecker, KlausDoenges, MargitVater, JochenSenges, SteffenSchneider, WernerSaggau, UdoWeisse, KarlheinzSeidl
Journal: Circulation (2007)

Background— The number of patients with longer follow-up after implantation of an implantable cardioverter-defibrillator is increasing continuously. Defibrillation lead failure is a typical long-term complication. Therefore, the long-term reliability of implantable cardioverter-defibrillator leads has become an increasing concern. The aim of the present study was to assess the annual rate of transvenous defibrillation lead defects related to follow-up time after lead implantation. Methods and Results— A total of 990 consecutive patients who underwent first implantation of an implantable cardioverter-defibrillator between 1992 and May 2005 were analyzed. Median follow-up time was 934 days (interquartile range, 368 to 1870). Overall, 148 defibrillation leads (15%) failed during the follow-up. The estimated lead survival rates at 5 and 8 years after implantation were 85% and 60%, respectively. The annual failure rate increased progressively with time after implantation and reached 20% in 10-year-old leads (P...
68Ga-PSMA Uptake in Middle Lobe Syndrome
Authors: Mette Abildgaard Pedersen, Kirsten Bouchelouche, Mikkel Holm Vendelbo
Journal: Clinical Nuclear Medicine (2018)

Prostate cancer cells have abundant expression of the cell surface protein prostate-specific membrane antigen (PSMA). In recent years, PET radioligands detecting this protein has therefore gained substantial interest in prostate cancer staging. It turned out that PSMA expression can be evident in both malignant and benign lesions, and we have previously reported that pulmonary opacities and bronchiectasis can be avid on Ga-PSMA PET/CT. Here, we present a case with Ga-PSMA accumulation in nonobstructive middle lobe syndrome, which further indicate that benign changes in the lungs may be falsely interpreted as malignant disease.
Adventitial CXCL1/G-CSF Expression in Response to Acute Aortic Dissection Triggers Local Neutrophil Recruitment and Activation Leading to Aortic Rupture
Authors: AtsushiAnzai, MasayukiShimoda, JinEndo, TakashiKohno, YoshinoriKatsumata, TomohiroMatsuhashi, TsunehisaYamamoto, KentaroIto, XiaoxiangYan, KosukeShirakawa, RyokoShimizu-Hirota, YoshitakeYamada, SatoshiUeha, KenShinmura, YasunoriOkada, KeiichiFukuda, MotoakiSano
Journal: Circulation Research (2015)

Rationale:In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. Objective:We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. Methods and Results:When angiotensin II was administered in lysyl oxidase inhibitor–preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine cha...
Influence of Mitochondrial Inhibition on Global and Local [Ca2+]i in Rat Tail Artery
Authors: KarlSwärd, KarlDreja, AndersLindqvist, ErikPersson, PerHellstrand
Journal: Circulation Research (2002)

Inhibition of oxidative metabolism is often found to decrease contractility of systemic vascular smooth muscle, but not to reduce global [Ca2+]i. In the present study, we probe the hypothesis that it is associated with an altered pattern of intracellular Ca2+ oscillations (waves) influencing force development. In the rat tail artery, mitochondrial inhibitors (rotenone, antimycin A, and cyanide) reduced α1-adrenoceptor–stimulated force by 50% to 80%, but did not reduce global [Ca2+]i. Less relaxation (about 30%) was observed after inhibition of myosin phosphatase activity with calyculin A, suggesting that part of the metabolic sensitivity involves the regulation of myosin 20-kDa light chain phosphorylation, although no decrease in phosphorylation was found in freeze-clamped tissue. Confocal imaging revealed that the mitochondrial inhibitors increased the frequency but reduced the amplitude of asynchronous cellular Ca2+ waves elicited by α1 stimulation. The altered wave pattern, in association with increase...
Pericoronary Adipose Tissue Computed Tomography Attenuation and High-Risk Plaque Characteristics in Acute Coronary Syndrome Compared With Stable Coronary Artery Disease
Authors: Markus Goeller, Stephan Achenbach, Sebastien Cadet, Alan C. Kwan, Frederic Commandeur, Piotr J. Slomka, Heidi Gransar, Moritz H. Albrecht, Balaji K. Tamarappoo, Daniel S. Berman, Mohamed Marwan, Damini Dey
Journal: JAMA Cardiology (2018)

Pericoronary adipose tissue (PCAT) computed tomography (CT) attenuation measured from coronary CT angiography (CTA) may be a promising metric in identifying high-risk plaques.To determine whether high-risk plaque characteristics from coronary CTA are associated with PCAT CT attenuation in patients with a first acute coronary syndrome (ACS) and matched controls with stable coronary artery disease (CAD).This retrospective, single-center case-control study (data were acquired at the University of Erlangen from 2009-2010) analyzed the CTA data sets of 19 patients who presented with ACS and 16 controls with stable CAD who were matched based on sex, age, and risk factors. Study observers were blinded to patients' clinical data. Semiautomated software was used to quantify and characterize plaques. The CT attenuation (Hounsfield unit [HU]) of PCAT was automatically measured around all lesions.To investigate the association between high-risk plaque characteristics from CTA and PCAT CT attenuation as a novel surrogate measure of coronary inflammation.A total of 35 patients (mean [SD] age, 59.5 [11.3] years; 30 men [86%] and 5 women [14%]) were included in the analysis. Low- and intermediate-attenuation noncalcified plaque (NCP) burden were increased in culprit lesions (n = 19) compared with both nonculprit lesions (n = 55) in patients with ACS (12.6% vs 3.6%; P < .001; 38.4% vs 19.4%; P < .001) and the control group's highest-grade stenosis lesions (n = 16) (12.6% vs 5.6%; P = .002; 38.4% vs 22.1%; P < .001). Pericoronary adipose tissue attenuation was increased around culprit lesions (n = 19) compared with nonculprit lesions (n = 55) in patients with ACS (-69.1 HU vs -74.8 HU; P = .01) and highest-grade stenosis lesions in control patients (n = 16) (-69.1 HU vs -76.4 HU; P = .01). Pericoronary adipose tissue CT attenuation of all lesions in patients with ACS (n = 74) correlated more strongly with intermediate-attenuation (r = 0.393; P = .001) over low-attenuation (r = 0.221; P = .06) and high-attenuation NCP burden (r = -0.103; P = .38). In a multivariable analysis, low- and intermediate-attenuation NCP burden and PCAT CT attenuation were independently associated with the presence of culprit lesions (P < .05).Pericoronary CT attenuation was increased around culprit lesions compared with nonculprit lesions of patients with ACS and the lesions of matched controls. Combined quantitative high-risk plaque features and PCAT CT attenuation may allow for a more reliable identification of vulnerable plaques.
Life support can be removed without courts if doctors and families agree
Authors: Clare Dyer
Journal: BMJ (2018)

Doctors will no longer need to seek court approval to withdraw artificial feeding and hydration from all patients in a permanent vegetative or minimally conscious state, the UK Supreme Court has ruled in a landmark judgment.1

Five justices in the UK’s highest court concluded unanimously that court applications weren’t needed where families and doctors agreed that withdrawal would be in the patient’s best interests.

The decision will provide clarity for doctors looking after the thousands of patients with what are now characterised as “prolonged disorders of consciousness” who are being kept alive by clinically assisted nutrition and hydration.

Lady Justice Black, giving judgment on behalf of the court, said neither the common law nor European human rights law required every case to go to court.

The case concerned …
Platelets kill circulating parasites of all major Plasmodium species in human malaria
Authors: Steven Kho, Bridget E. Barber, Edison Johar, Benediktus Andries, Jeanne R. Poespoprodjo, Enny Kenangalem, Kim A. Piera, Anna Ehmann, Ric N. Price, Timothy William, Tonia Woodberry, Simon Foote, Gabriela Minigo, Tsin W. Yeo, Matthew J. Grigg, Nicholas M. Anstey, Brendan J. McMorran
Journal: Blood (2018)