tbuckley/cabot-search huggingface dataset:
Knockout of ULK1/2 protects against acetaminophen‐induced acute liver injury independent of autophagy?
Authors: Cuiqin Zhang, Fuyong Song
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. To the Editor: Acetaminophen (APAP) overdose can produce a severe hepatic necrosis in humans. Oxidative stress, mitochondrial dysfunction, and c‐Jun N‐terminal kinase (JNK) activation have been considered critical events in APAP‐induced liver injury. Following APAP overdose, mitochondrial glutathione depletion can enhance reactive oxygen species production and promote JNK activation. In turn, activated JNK further amplifies oxidative stress and mitochondrial dysfunction. In recent years, increasing evidence supports that autophagy is associated with APAP‐induced liver injury.1 Of all the Atg proteins, the Atg1/Unc‐51‐like kinase 1(ULK1) complex is at the most upstream step of the autophagy pathway. In an article published in hepatology, Sun et al. reported that mice with double knockout of Ulk1 and Ulk2 are more resistant to APAP‐induced liver injury. However, Ulk1/2 double knockout does not affect the autophagic activity in hepatocytes.2 Mechanistically, APAP inhibits the activity of mammalian target of rapamycin complex 1, thus releasing the suppression of ULK. Consequently, activated ULK promotes JNK phosphorylation through MKK4/7.2 Together, these findings have identified that ULK1/2 is a novel upstream signal of JNK and highlighted a critical role of ULK1/2 in APAP hepatotoxicity. Meanwhile, this work also sets the stage for further investigation. Open questions include the following. This study has not determined whether or not mitophagy is affected by Ulk1/2 knockout. As a form of selective autophagy, mitophagy is being paid more and more attention. Following APAP administration, damaged mitochondria are frequently observed within autophagosomes.1 Furthermore, some experiments also provide compelling evidence that supports the protective role of mitophagy in APAP hepatotoxicity. Therefore, a comprehensive analysis of mitophagy will provide more valuable evidence for a protective role of Ulk1/2 knockout independent of autophagy. Moreover, the results of p62 in this study are surprising. Although the decline of p62 is usually observed in starvation‐induced or drug‐induced autophagy, the level of p62 is not only dependent on its degradation but also regulated by its transcription. In our recent study, APAP administration resulted in a marked increase of p62 and p‐p62(ser351) in a dose‐dependent manner.3 By contrast, no increase was observed in either the control or Ulk1/2 knockout mice in the Sun et al. study. The discrepancy indicates different models of response to APAP intoxication in wild‐type and genetically modified mice. Given that p62 can regulate the Nrf2‐ARE signaling pathway, a better understanding of the interaction between p62 and Nrf2 in Ulk1/2 knockout mice could not only help to clarify how Ulk1/2 knockout protects against APAP liver injury but also contribute to the development of targeted therapeutic treatments for patients suffering from APAP overdose.
Understanding the patient-perceived impact of nonalcoholic steatohepatitis: Raising the volume on a silent disease
Authors: Lynda Doward, Maria-Magdalena Balp, James Twiss, Christina Slota, D Cryer, A Langford, R Collen, N Agashivala, CA Brass, QM Anstee, AJ Sanyal
Journal: Hepatology (2017)
Identifying a novel function for hepatic Fxr-Shp axis in regulating glycosylation
Authors: Bhoomika Mathur, Waqar Arif, Auinash Kalsotra, Kristina Schoonjans, Sayee Anakk
Journal: Hepatology (2017)

Reference EPFL-CONF-232291View record in Web of Science Record created on 2017-11-08, modified on 2017-12-04
Air Pollution and Suicide in 10 Cities in Northeast Asia: A Time-Stratified Case-Crossover Analysis
Authors: Yoonhee Kim, Chris Fook Sheng Ng, Yeonseung Chung, Ho Kim, Yasushi Honda, Yue Leon Guo, Youn-Hee Lim, Bing-Yu Chen, Lisa A. Page, Masahiro Hashizume
Journal: Environmental Health Perspectives (2018)

Background: There is growing evidence suggesting an association between air pollution and suicide. However, previous findings varied depending on the type of air pollutant and study location. Objectives: We examined the association between air pollutants and suicide in 10 large cities in South Korea, Japan, and Taiwan. Methods: We used a two-stage meta-analysis. First, we conducted a time-stratified case-crossover analysis to estimate the short-term association between nitrogen dioxide (NO2), sulfur dioxide (SO2), and particulate matter [aerodynamic diameter ≤10μm (PM10), aerodynamic diameter ≤2.5μm (PM2.5), and PM10−2.5] and suicide, adjusted for weather factors, day-of-week, long-term time trends, and season. Then, we conducted a meta-analysis to combine the city-specific effect estimates for NO2, SO2, and PM10 across 10 cities and for PM2.5 and PM10−2.5 across 3 cities. We first fitted single-pollutant models, followed by two-pollutant models to examine the robustness of the associations. Results: Higher risk of suicide was associated with higher levels of NO2, SO2, PM10, and PM10−2.5 over multiple days. The combined relative risks (RRs) were 1.019 for NO2 (95% confidence interval [CI]: 0.999, 1.039), 1.020 for SO2 (95% CI: 1.005, 1.036), 1.016 for PM10 (95% CI: 1.004, 1.029), and 1.019 for PM10−2.5 (95% CI: 1.005, 1.033) per interquartile range (IQR) increase in the 0–1 d average level of each pollutant. We found no evidence of an association for PM2.5. Some of the associations, particularly for SO2 and NO2, were attenuated after adjusting for a second pollutant. Conclusions: Our findings suggest that higher levels of air pollution may be associated with suicide, and further research is merited to understand the underlying mechanisms. https://doi.org/10.1289/EHP2223
Discovery and Validation of Circulating Biomarkers of Colorectal Adenoma by High-Depth Small RNA Sequencing
Authors: Brian S. Roberts, Andrew A. Hardigan, Dianna E. Moore, Ryne C. Ramaker, Angela L. Jones, Meredith B. Fitz-Gerald, Gregory M. Cooper, C. Mel Wilcox, Robert P. Kimberly, Richard M. Myers
Journal: Clinical Cancer Research (2018)

Purpose: Colorectal cancer is the third most common cancer worldwide, causing approximately 700,000 deaths each year. The majority of colorectal cancers begin as adenomas. Definitive screening for colorectal adenomas is currently accomplished through colonoscopy but, owing largely to costs and invasiveness, is typically limited to patient groups at higher risk by virtue of age or family history. We sought to determine if blood-based small RNA markers could detect colorectal adenoma.Experimental Design: We applied high-depth small RNA sequencing to plasma from a large (n = 189) cohort of patients, balanced for age, sex, and ancestry. Our analytical methodology allowed for the detection of both microRNAs and other small RNA species. We replicated sequencing results by qPCR on plasma samples from an independent cohort (n = 140).Results: We found several small RNA species with significant associations to colorectal adenoma, including both microRNAs and non-microRNA small RNAs. These associations were robust to correction for patient covariates, including age. Among the adenoma-associated small RNAs, two, a miR-335-5p isoform and an un-annotated small RNA, were validated by qPCR in an independent cohort. A classifier trained on measures of these two RNAs in the discovery cohort yields an AUC of 0.755 (0.775 with age) for adenoma detection in the independent cohort. This classifier accurately detects adenomas in patients under 50 and is robust to sex or ancestry.Conclusions: Circulating small RNAs (including but not limited to miRNAs) discovered by sequencing and validated by qPCR identify patients with colorectal adenomas effectively. Clin Cancer Res; 24(9); 2092-9. ©2018 AACR.
Closing the gap in surveillance of tuberculosis and HIV co-infection, and the need for clinician–public health alliances
Authors: Gerard de Vries, Susan van den Hof, Eline Op de Coul, Reinout van Crevel
Journal: European Respiratory Journal (2018)

We read with much interest the editorial by Van der Werf et al. [1] in the European Respiratory Journal ( ERJ ). The authors rightly advocate for the need to improve completeness, accuracy and timeliness of tuberculosis (TB)/HIV co-infection data in Europe, pledging for more cooperation between primary care physicians, medical specialists and social workers. We agree with them and others [2] that much can be gained from closer collaboration between TB and HIV control programmes, and would like to share our experience from the Netherlands. In addition, we would like to comment on the incompleteness of surveillance registers in our country, as raised by the authors. Collaboration between professionals working in TB and HIV clinics and programmes improves TB/HIV surveillance <http://ow.ly/sety30hXdqk>
Paraneoplastic Pemphigus Associated With Castleman Disease Detected by 18F-FDG PET/CT
Authors: Zhanli Fu, Meng Liu, Xueqi Chen, Xing Yang, Qian Li
Journal: Clinical Nuclear Medicine (2018)

Abstract A 36-year-old woman suffering from oral ulcerations, skin rash, and dyspnea was suspected of having paraneoplastic pemphigus. An 18 F-FDG PET/CT was performed to detect the underlying neoplasms and revealed an 18 F-FDG–avid mass in the lower right retroperitoneum. The mucocutaneous lesions and dyspnea were relieved after the tumor excision, and the pathology indicated Castleman disease.
Mitochondrial HSP90 Accumulation Promotes Vascular Remodeling in Pulmonary Arterial Hypertension
Authors: Olivier Boucherat, Thibaut Peterlini, Alice Bourgeois, Valérie Nadeau, Sandra Breuils-Bonnet, Stéphanie Boilet-Molez, François Potus, Jolyane Meloche, Sophie Chabot, Caroline Lambert, Eve Tremblay, Young Chan Chae, Dario C. Altieri, Gopinath Sutendra, Evangelos D. Michelakis, Roxane Paulin, Steeve Provencher, Sébastien Bonnet
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with a poor prognosis and limited therapeutic options. Although the mechanisms contributing to vascular remodeling in PAH are still unclear, several features, including hyperproliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs), have led to the emergence of the cancer-like concept. The molecular chaperone HSP90 (heat shock protein 90) is directly associated with malignant growth and proliferation under stress conditions. In addition to being highly expressed in the cytosol, HSP90 exists in a subcellular pool compartmentalized in the mitochondria (mtHSP90) of tumor cells, but not in normal cells, where it promotes cell survival.We hypothesized that mtHSP90 in PAH-PASMCs represents a protective mechanism against stress, promoting their proliferation and resistance to apoptosis.Expression and localization of HSP90 were analyzed by Western blot, immunofluorescence, and immunogold electron microscopy. In vitro, effects of mtHSP90 inhibition on mitochondrial DNA integrity, bioenergetics, cell proliferation and resistance to apoptosis were assessed. In vivo, the therapeutic potential of Gamitrinib, a mitochondria-targeted HSP90 inhibitor, was tested in fawn-hooded and monocrotaline rats.We demonstrated that, in response to stress, HSP90 preferentially accumulates in PAH-PASMC mitochondria (dual immunostaining, immunoblot, and immunogold electron microscopy) to ensure cell survival by preserving mitochondrial DNA integrity and bioenergetic functions. Whereas cytosolic HSP90 inhibition displays a lack of absolute specificity for PAH-PASMCs, Gamitrinib decreased mitochondrial DNA content and repair capacity and bioenergetic functions, thus repressing PAH-PASMC proliferation (Ki67 labeling) and resistance to apoptosis (Annexin V assay) without affecting control cells. In vivo, Gamitrinib improves PAH in two experimental rat models (monocrotaline and fawn-hooded rat).Our data show for the first time that accumulation of mtHSP90 is a feature of PAH-PASMCs and a key regulator of mitochondrial homeostasis contributing to vascular remodeling in PAH.
Phase I/II study of low-dose cyclophosphamide, tumor-associated peptide antigen-pulsed dendritic cell and low dose GM-CSF for solid and hematological tumors.
Authors: Leonardo Mirandola, Jose A. Figueroa, Diane Duyen Thuy Nguyen, Scott Dahlbeck, Maurizio Chiriva-Internati
Journal: Journal of Clinical Oncology (2018)

TPS216 Background: Despite advances in understanding the biology of hematologic malignancies (HM) and solid malignancies (SM), and the availability of new treatment options, many patients with HM and SM remain incurable. Since the majority of cancer patients display a defective immune response to tumor antigens, the ex-vivo activation of dendritic cells (DC), through their exposure to tumor associated antigens, is an attractive and active area of investigation. We and others have explored the potential immunotherapeutic targets included our DC vaccine, i.e., SP17, Ropporin, AKAP4, PTTG1, SpanxB, NY-ESO-1, MAGE-1, HM1.24, Her2/Neu. Notably, SP17-pulsed DC have been reported to induce a safe and clinically significant response in patients with multiple myeloma and ovarian cancer. Methods: We hypothesize that treatment of patients with HM or metastatic SM using autologous DC will result in antigen-specific CD4+ T-cell and/or CD8+ CTL responses without significant toxicities. We also hypothesize that the responses generated against specific antigens may translate into clinical anti-tumor activity. Primary Objective: Phase I (6 subjects). To determine safety of intradermal/subcutaneous DC vaccine therapy, low-dose cyclophosphamide and GM-CSF, in patients with metastatic SM or HM who demonstrate a response, or whose disease remains stable, after conventional first-line systemic therapy, or who have failed conventional systemic therapy. Secondary Objective: Phase II (up to 17 subjects). To determine immune responses associated with intradermal/subcutaneous DC vaccine therapy, low-dose cyclophosphamide and GM-CSF, in patients with metastatic SM or HM who demonstrate a response, or whose disease remains stable, after conventional first-line systemic therapy, or who have failed conventional systemic therapy. The study population is currently drawn from patients at various clinical institutions following contractual agreements. Clinical trial information: NCT02709993; NCT02705703; NCT02224599; NCT02223312.
Evidence of Drug-Free Interventions for Postoperative Pain Management After Total Knee Arthroplasty—Reply
Authors: Tina Hernandez-Boussard, Davide Gori, Dario Tedesco
Journal: JAMA Surgery (2018)

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GMC to review training for disabled medical students and junior doctors
Authors: Helen Jaques
Journal: BMJ (2012)

The General Medical Council has announced a review of the challenges faced by and support provided to medical students and trainees with disabilities or physical or mental health problems.

The new working group will evaluate whether organisations are making reasonable adjustments to help disabled students and trainees study and work safely in a clinical environment. In addition, it will look at the experiences of people with disabilities or …
RIGHT VENTRICLE DYSFUNCTION PREDICTS CARDIOGENIC SHOCK IN PATIENTS WITH ACUTE CORONARY SYNDROME
Authors: Abdulfattah Saidi, Elizabeth Dranow, Gregory Stoddard, James Fang, Omar Wever-Pinzon, Brigham Smith, Anu Abraham, Stavros Drakos, Homam Ibrahim, Anwar Tandar, Rhet Bennion, Prem Senthilkumar, Teshia Sorensen, Josef Stehlik, Frederick Welt, Theophilus Owan
Journal: Journal of the American College of Cardiology (2018)
Abstract 13382: Urgent Control of Rapid Atrial Tachyarrhythmia Using Landiolol in Patients With Heart Failure With Severely Reduced Ejection Fraction : An Ultra-Short-Acting β-blocker for Emergency ADHF
Authors: Noriaki Iwahashi, Masaomi Gohbara, Shunsuke Kataoka, Yugo Minamimoto, Eiichi Akiyama, Nobuhiko Maejima, Kengo Tsukahara, Kiyoshi Hibi, Masami Kosuge, Masami Kosuge, Toshiaki Ebina, Satoshi Umemura, Kazuo Kimura
Journal: Circulation (2015)

Backgounds: To control heart rate(HR) of atrial tachyarrhythmia is important in patients with acute decompensated heart failure(ADHF) in their critical phase. Landiolol is newly developed an ultra-short-acting β-blocker. We explored the hemodynamic effect of Landiolol treatment for atrial tachyarrhythmia in patients with ADHF in their critical phase. Hypothesis: Landiolol is useful to control HR of atrial tachyarrhythmia without any adverse events and it can make their status better. Methods: Consecutive 35 ADHF patients were enrolled(74 years, 25 men, EF25%, HR137/min, BNP837pg/ml). 34 out of 35 patients had atrial fibrillation (AF) or atrial flutter (AFL), and one patient had atrial tachcardia (AT). We treated them with low dose landiolol immediately after admission. Among them, 17 patients were monitored by Swan-Ganz (S-G) catheterization to explore the hemodynamic effect of Landiolol. Results: The average maximum dose of Landiolol was 3.3γ. No patients had serious adverse events. HR (93/min, p&lt;0.0001) and BNP (618pg/ml, p&lt;0.05 ) decreased after treatment and In S-G data, PCWP and PAP decreased after Landiolol treatment, on the other hand CO increased. Three patients out of 17 patients with S-G could not achieve adequate HR decrease (110&lt;min) even with their maximum dose, their ΔHR were -28, -28, +1/min.. They had higher PCWP (32 vs 20, p&lt;0.05) and relatively lower CO (2.7 vs 3.0, NS) compared with responders. One patient had AT and his HR didn’t decrease (ΔHR= +1/min) and hemodynamic condition didn't improve. Conclusions: Low dose Landiolol that is an ultra-short-acting β-blocker, was effective for controlling rapid HR in AF/AFL patients with LV dysfunction despite being in the critical state. The patients with extremely severe condition and atrial tachycardia might not be suitable for Landiolol treatment in their critical states.
Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study
Authors: Devin Abrahami, Antonios Douros, Hui Yin, Oriana Hoi Yun Yu, Christel Renoux, Alain Bitton, Laurent Azoulay
Journal: BMJ (2018)

<h3>Abstract</h3> <h3>Objective</h3> To assess whether the use of dipeptidyl peptidase-4 inhibitors is associated with the incidence of inflammatory bowel disease in patients with type 2 diabetes. <h3>Design</h3> Population based cohort study. <h3>Setting</h3> More than 700 general practices contributing data to the United Kingdom Clinical Practice Research Datalink. <h3>Participants</h3> A cohort of 141 170 patients, at least 18 years of age, starting antidiabetic drugs between 1 January 2007 and 31 December 2016, with follow-up until 30 June 2017. <h3>Main outcome measures</h3> Adjusted hazard ratios for incident inflammatory bowel disease associated with use of dipeptidyl peptidase-4 inhibitors overall, by cumulative duration of use, and by time since initiation, estimated using time dependent Cox proportional hazards models. Use of dipeptidyl peptidase-4 inhibitors was modelled as a time varying variable and compared with use of other antidiabetic drugs, with exposures lagged by six months to account for latency and diagnostic delays. <h3>Results</h3> During 552 413 person years of follow-up, 208 incident inflammatory bowel disease events occurred (crude incidence rate of 37.7 (95% confidence interval 32.7 to 43.1) per 100 000 person years). Overall, use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease (53.4 <i>v</i> 34.5 per 100 000 person years; hazard ratio 1.75, 95% confidence interval 1.22 to 2.49). Hazard ratios gradually increased with longer durations of use, reaching a peak after three to four years of use (hazard ratio 2.90, 1.31 to 6.41) and decreasing after more than four years of use (1.45, 0.44 to 4.76). A similar pattern was observed with time since starting dipeptidyl peptidase-4 inhibitors. These findings remained consistent in several sensitivity analyses. <h3>Conclusions</h3> In this first population based study, the use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease. Although these findings need to be replicated, physicians should be aware of this possible association.
Altered HDL Remodeling and Functionality in Familial Hypercholesterolemia
Authors: Lídia Cedó, Núria Plana, Jari Metso, Miriam Lee-Rueckert, Jose Luis Sanchez-Quesada, Petri T. Kovanen, Matti Jauhiainen, Luís Masana, Joan Carles Escolà-Gil, Francisco Blanco-Vaca
Journal: Journal of the American College of Cardiology (2018)
Conflicting asthma guidelines reflect different motives
Authors: Dermot Ryan
Journal: BMJ (2018)

Having a single guideline for the management of asthma in the UK would, of course, be desirable, but the British Thoracic Society (working with the Scottish Intercollegiate Guideline Network) and the National Institute for Health and Care Excellence (NICE) have two separate and differing philosophies, which make this highly unlikely.1

The British Thoracic Society strives for clinical excellence, and its guidelines are internationally recognised and respected. NICE’s motive is cost …
PREDICTORS OF IN-HOSPITAL MORTALITY IN PATIENTS UNDERGOING VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION (VA-ECMO)
Authors: Anna Koulova, Venkata Buddharaju, Rudrick Ledesma, Savneek Chugh, Maureen Brogan, Joshua Goldberg, Masashi Kai, Ramin Malekan, David Spielvogel, Wilbert Aronow, Chul Ahn, Alan Gass
Journal: Journal of the American College of Cardiology (2018)