tbuckley/cabot-search huggingface dataset:
N-glycanase NGLY1 regulates mitochondrial homeostasis and inflammation through NRF1
Authors: Kun Yang, Ryan Huang, Haruhiko Fujihira, Tadashi Suzuki, Nan Yan
Journal: The Journal of Experimental Medicine (2018)

Mutations in the NGLY1 (N-glycanase 1) gene, encoding an evolutionarily conserved deglycosylation enzyme, are associated with a rare congenital disorder leading to global developmental delay and neurological abnormalities. The molecular mechanism of the NGLY1 disease and its function in tissue and immune homeostasis remain unknown. Here, we find that NGLY1-deficient human and mouse cells chronically activate cytosolic nucleic acid–sensing pathways, leading to elevated interferon gene signature. We also find that cellular clearance of damaged mitochondria by mitophagy is impaired in the absence of NGLY1, resulting in severely fragmented mitochondria and activation of cGAS–STING as well as MDA5–MAVS pathways. Furthermore, we show that NGLY1 regulates mitochondrial homeostasis through transcriptional factor NRF1. Remarkably, pharmacological activation of a homologous but nonglycosylated transcriptional factor NRF2 restores mitochondrial homeostasis and suppresses immune gene activation in NGLY1-deficient cells. Together, our findings reveal novel functions of the NGLY1–NRF1 pathway in mitochondrial homeostasis and inflammation and uncover an unexpected therapeutic strategy using pharmacological activators of NRF2 for treating mitochondrial and immune dysregulation.
Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer
Authors: B. Basu, M.G. Krebs, R. Sundar, R.H. Wilson, J. Spicer, R. Jones, M. Brada, D.C. Talbot, N. Steele, A.H. Ingles Garces, W. Brugger, E.A. Harrington, J. Evans, E. Hall, H. Tovey, F.M. de Oliveira, S. Carreira, K. Swales, R. Ruddle, F.I. Raynaud, B. Purchase, J.C. Dawes, M. Parmar, A.J. Turner, N. Tunariu, S. Banerjee, J.S. de Bono, U. Banerji
Journal: Annals of Oncology (2018)

BackgroundWe have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients.Patients and methodsIn dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively.ResultsThe dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28–18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76–21.25).DiscussionIn this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC.Clinical trial registrationClinicialTrials.gov identifier: CNCT02193633
Sulfur-enriched alkaloids from the root of Isatis indigotica
Authors: Qinglan Guo, Chengbo Xu, Minghua Chen, Sheng Lin, Yuhuan Li, Chenggen Zhu, Jiandong Jiang, Yongchun Yang, Jiangong Shi
Journal: Acta Pharmaceutica Sinica B (2018)

Five new sulfur-enriched alkaloids isatithioetherins A–E (1–5), and two pairs of scalemic enantiomers (+)- and (−)-isatithiopyrin B (6a and 6b) and isoepigoitrin and isogoitrin (7a and 7b), along with the known scalemic enantiomers epigoitrin and goitrin (8a and 8b), were isolated and characterized from an aqueous extract of the Isatis indigotica roots. Their structures were determined by extensive spectroscopic data analysis, including 2D NMR and theoretical calculations of electronic circular dichroism (ECD) spectra based on the quantum-mechanical time-dependent density functional theory (TDDFT). Compounds 1–5 represent a novel group of sulfur-enriched alkaloids, biogenetically originating from stereoselective assemblies of epigoitrin-derived units. Isolation and structure characterization of 6a and 6b support the postulated biosynthetic pathways for the diastereomers 9a and 9b via a rare thio-Diels–Alder reaction. Compounds 2 and 4 showed antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2, IC50 0.60 and 1.92 μmol/L) and the herpes simplex virus 1 (HSV-1, IC50 3.70 and 2.87 μmol/L), and 2 also inhibited Coxsackie virus B3 (IC50 0.71 μmol/L).
Coccidioidomycosis Outbreak Among Workers Constructing a Solar Power Farm — Monterey County, California, 2016–2017
Authors: Rebecca L. Laws, Gail Sondermeyer Cooksey, Seema Jain, Jason Wilken, Jennifer McNary, Edward Moreno, Kristy Michie, Christy Mulkerin, Ann McDowell, Duc Vugia, Barbara Materna
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

In January 2017, two local health departments notified the California Department of Public Health (CDPH) of three cases of coccidioidomycosis among workers constructing a solar power installation (solar farm) in southeastern Monterey County. Coccidioidomycosis, or Valley fever, is an infection caused by inhalation of the soil-dwelling fungus Coccidioides, which is endemic in the southwestern United States, including California. After a 1-3 week incubation period, coccidioidomycosis most often causes influenza-like symptoms or pneumonia, but rarely can lead to severe disseminated disease or death (1). Persons living, working, or traveling in areas where Coccidioides is endemic can inhale fungal spores; workers who are performing soil-disturbing activities are particularly at risk. CDPH previously investigated one outbreak among solar farm construction workers that started in 2011 and made recommendations for reducing risk for infection, including worker education, dust suppression, and use of personal protective equipment (2,3). For the current outbreak, the CDPH, in collaboration with Monterey County and San Luis Obispo County public health departments, conducted an investigation that identified nine laboratory-confirmed cases of coccidioidomycosis among 2,410 solar farm employees and calculated a worksite-specific incidence rate that was substantially higher than background county rates, suggesting that illness was work-related. The investigation assessed risk factors for potential occupational exposures to identify methods to prevent further workplace illness.
Locum ophthalmologist is struck off for “sustained pattern of appalling behaviour”
Authors: Clare Dyer
Journal: BMJ (2018)

A locum consultant ophthalmologist has been struck off the UK medical register for a “sustained and repeated pattern of appalling behaviour” that included calling locum agency staff “apes and primates” and slapping another doctor’s dictaphone from his hand and trying to stamp on it.

While working in four different hospitals in England, Wales, and Scotland from 2013 to 2015, Erkan Mutlukan was also found to have been rude and aggressive to several patients, in one case twice hitting a table so forcefully that it struck an elderly woman patient, without offering an apology.

On another occasion he was so aggressive with telephone operators at Betsi Cadwaladr University Health Board in Wales that they agreed to dial 999 if he came in …
Inherited Breast Cancer in Nigerian Women
Authors: Yonglan Zheng, Tom Walsh, Suleyman Gulsuner, Silvia Casadei, Ming K. Lee, Temidayo O. Ogundiran, Adeyinka Ademola, Adeyinka G. Falusi, Clement A. Adebamowo, Abideen O. Oluwasola, Adewumi Adeoye, Abayomi Odetunde, Chinedum P. Babalola, Oladosu A. Ojengbede, Stella Odedina, Imaria Anetor, Shengfeng Wang, Dezheng Huo, Toshio F. Yoshimatsu, Jing Zhang, Gabriela E.S. Felix, Mary-Claire King, Olufunmilayo I. Olopade
Journal: Journal of Clinical Oncology (2018)

Among Nigerian women, breast cancer is diagnosed at later stages, is more frequently triple-negative disease, and is far more frequently fatal than in Europe or the United States. We evaluated the contribution of an inherited predisposition to breast cancer in this population.
Duodenal and Rectal Mucosa Inflammation in Patients With Non-celiac Wheat Sensitivity
Authors: Antonio Carroccio, Giulio Giannone, Pasquale Mansueto, Maurizio Soresi, Francesco La Blasca, Francesca Fayer, Rosario Iacobucci, Rossana Porcasi, Tiziana Catalano, Girolamo Geraci, Andrea Arini, Alberto D’Alcamo, Vincenzo Villanacci, Ada M. Florena
Journal: Clinical Gastroenterology and Hepatology (2018)
Abstract 19270: Large Genomic Rearrangements of Desmosomal Genes in Arrhythmogenic Cardiomyopathy
Authors: Kalliopi Pilichou, Elisabetta Lazzarini, Ilaria Rigato, Rudy Celeghin, Marco Cason, Marzia De Bortoli, Alessandra Rampazzo, Peter van Tintelen, Luciano Daliento, Pietro Delise, Domenico Corrado, Gaetano Thiene, Cristina Basso, Barbara Bauce, Alessandra Lorenzon, Gianluca Occhi
Journal: Circulation (2016)

Introduction: Arrhythmogenic Cardiomyopathy (AC) is an inherited heart muscle disease associated with point mutations in genes encoding mainly components of the cardiac desmosome. Hypothesis: Since conventional mutation screening fails to uncover approximately 50% of AC genetic variants, we aimed to assess the prevalence of copy number variants (CNVs) involving desmosomal genes in a large cohort of unrelated genotype negative AC index cases and evaluated the pathogenic role of these CNVs by family co-segregation. Methods: 160 AC genotype negative probands for 5 AC-associated genes underwent Multiplex Ligation-dependent Probe Amplification (MLPA) and sequencing on a ABI 3500 (Thermoscientific). MLPA detected CNVs were further confirmed by quantitative Real-Time polymerase chain reaction on a Light Cycler 480 (Roche) and additional point mutations were excluded in other AC-related genes by targeted re-sequencing on a MiSeq platform (Illumina). Results: CNVs analysis revealed 4 different plakophilin-2 (PKP2)...
The cascade of HIV care among key populations in Indonesia: a prospective cohort study
Authors: Pande Putu Januraga, Joanne Reekie, Tri Mulyani, Bony Wiem Lestari, Shelly Iskandar, Rudi Wisaksana, Nur Aini Kusmayanti, Yanri Wijayanti Subronto, Desak Nyoman Widyanthini, Dewa Nyoman Wirawan, Lydia Verina Wongso, Anindita Gabriella Sudewo, Evi Sukmaningrum, Tiara Nisa, Bagus Rahmat Prabowo, Matthew Law, David A Cooper, John M Kaldor
Journal: The Lancet HIV (2018)
Identifying and Addressing Disparities in Survival Outcomes for Rural Patients With Cancer
Authors: Lauren E. McCullough, Christopher R. Flowers
Journal: JAMA Network Open (2018)

Joseph M. Unger, PhD, MS; Anna Moseley, MS; Banu Symington, MD; Mariana Chavez-MacGregor, MD, MS; Scott D. Ramsey, MD; Dawn L. Hershman, MD
Abstract 14198: Changes in ECG Characteristics are Related to Prognosis and Etiology in Pulseless Electrical Activity
Authors: Gunnar W Skjeflo, Trond Nordseth, Jan Pål Loennechen, Daniel Bergum, Eirik Skogvoll
Journal: Circulation (2016)

Introduction: Pulseless electrical activity (PEA) is a frequent initial rhythm in cardiac arrest. ECG characteristics have been linked to prognosis, and recognition of the cause of arrest may impro...
A novel plectin/integrin-targeted bispecific molecular probe for magnetic resonance/near-infrared imaging of pancreatic cancer
Authors: Qian Wang, Hao Yan, Yushen Jin, Zihua Wang, Wenhui Huang, Jia Qiu, Feiyu Kang, Kun Wang, Xinming Zhao, Jie Tian
Journal: Biomaterials (2018)
External Validation of the DAPT Score in a Nationwide Population
Authors: Peter Ueda, Tomas Jernberg, Stefan James, Joakim Alfredsson, David Erlinge, Elmir Omerovic, Jonas Persson, Annica Ravn-Fischer, Per Tornvall, Bodil Svennblad, Christoph Varenhorst
Journal: Journal of the American College of Cardiology (2018)
Abstract 11472: Higher Level of Chronic Illness Management in Heart Transplant Centers is associated With Better Patient Survival: The Intercontinental BRIGHT Study
Authors: Sabina M De Geest, Kris Denhaerynck, Lut Berben, Johan Vanhaecke, Cynthia Russell, Fabienne Dobbels
Journal: Circulation (2015)

Innovation in care processes based on chronic illness management (CIM) has shown to improve outcomes in chronically ill. We hypothesized that higher level of CIM in post-heart transplant (HTx) follow-up care is associated with better patient survival. The BRIGHT study, a multi-center, cross sectional study included a convenience sample of 36 HTx centers in 11 countries and 4 continents. Patients were selected by stratified random sampling. CIM was assessed both by clinicians’ report (N=82, mean age: 47.6±10.2 y., 85% f.) (55 item CIMI BRIGHT instrument) and patients’ report (N=1026, mean age: 54.0±13.2 y., 27% f., mean years post-HTx; 3.4±1.4)(11 item PACIC scale). CIM data were aggregated at center level. Three groups were built: (1) positive deviants: both patients’ and clinicians’ median CIM scores above median CIM score of 36 centers;(2) negative deviants: both median CIM scores below median of all centers; (3) mixed group: incongruence in median CIM scores between patients and clinicians. Center's mean patient survival at 1, 3, 5, 10 and 15 years was reported by the HTx center director using a structured questionnaire. We used mixed regression analysis, contrasting positive to negative deviants in a confounder-adjusted analysis. We found major variability in CIM scores (PACIC mean 39±10.5; CIMI BRIGHT mean 165±17.1, range: 136-197) and mean survival rates (1 year: 84%±5.3 ; 5 year 73%±15.8) among HTx centers. Thirty-two percent of centers were positive deviants, 32% negative deviants and 36% belonged to the mixed group. Figure 1 shows center's mean patient survival at 1, 3, 5, 10 and 15 years for the 3 groups. As hypothesized, mortality was lower in positive vs. negative deviants especially at 1 year post-HTx (p&lt;0.008). The association between higher levels of CIM and lower mortality in HTx patients highlights a potential pathway for improving outcomes after HTx by investing in innovative systems of care based on principles of CIM.
Abstract 16288: A Practical Freezing Method of Human-Induced Pluripotent Stem Cells-Derived Cardiomyocytes Toward a Clinical Application
Authors: Fumiya Ohashi, Shigeru Miyagawa, Satsuki Fukushima, Shohei Yoshida, Atsuhiro Saito, Shigeo Masuda, Hiroko Iseoka, Emiko Ito, Tsuyoshi Ishikawa, Tadashi Sameshima, Yoji Sato, Yoshiki Sawa
Journal: Circulation (2016)

Introduction: Cardiomyocytes (CMs) derived from human iPS cells (hiPSCs) implantation have the potential to lead to new heart failure therapy, while additional technology, such as an efficient cryo...
Molecular Diagnostics for <i>Mycobacterium tuberculosis</i> Infection
Authors: Kristen V. Dicks, Jason E. Stout
Journal: Annual Review of Medicine (2018)

Resistance to antimycobacterial drugs is a major barrier to effective treatment of Mycobacterium tuberculosis infection. Molecular diagnostic techniques based on the association between specific gene mutations and phenotypic resistance to certain drugs offer the opportunity to rapidly ascertain whether drug resistance is present and to alter treatment before further resistance develops. Current barriers to successful implementation of rapid diagnostics include imperfect knowledge regarding the full spectrum of mutations associated with resistance, limited utilization of molecular diagnostics where they are most needed, and the requirement for specialized laboratory facilities to perform molecular testing. Further understanding of genotypic-phenotypic correlates of resistance and streamlined implementation platforms will be necessary to optimize the public health impact of molecular resistance testing for M. tuberculosis.
Abstract P088: Race is Associated with Endothelial Responses to Acute Mental Stress
Authors: Kobina A Wilmot, Ayman Alkhoder, Nino Isakadze, Malik Obideen, Amit J Shah, Pratik Pimple, Ibhar Al Mheid, Michael Kutner, Qi Long, Tene Lewis, Paolo Raggi, J. Douglas Bremner, Arshed A Quyyumi, I. Viola Vaccarino
Journal: Circulation (2016)

Introduction: Endothelial dysfunction is associated with short term and long term cardiovascular events. African Americans (AA) have worse cardiovascular outcomes than Non-African Americans (NAA). AAs have higher chronic stress exposure due to socioeconomic deprivation which may affect vascular responses to stress and contribute to health disparities. Our hypothesis was that AA would have abnormal microvascular function after a standardized mental stress as compared to NAA. Methods: We evaluated 692 patients (208 AA) with confirmed coronary artery disease (CAD), who underwent a standardized mental stress challenge. Endothelial function measurements were obtained before and 30 minutes after mental stress testing using a speaking task. Reactive hyperemia index (RHI) was measured using peripheral arterial tonometry (PAT) (Itamar Inc) as the ratio of hyperemic to baseline finger-tip microvascular blood flow signal. Flow-mediated dilation (FMD) was measured using ultrasound as the ratio of hyperemic to baseline brachial artery diameter. Results: As compared to NAA, AA patients were younger, had lower levels of education, and income, and a higher prevalence of co-morbidities. AA patients prior to stress had similar mean RHI (2.07 vs 2.13, p=0.3) but lower mean FMD (3.54 vs 4.76, p=0.0005) as compared to NAA. However, after mental stress, mean RHI was significantly lower in AA, (1.98 vs 2.2, p=0.0002) and mean FMD continued to be lower in AA (2.87 vs 3.81, p=0.005). After adjusting for baseline RHI in addition to age, sex, BMI, cardiovascular risk factors, and depression in a multivariable model, race remained significantly associated with post-stress RHI (p= 0.004). However, race was no longer associated with post-stress FMD after adjusting for pre-stress FMD. (p=0.37). Conclusion: AA patients with CAD, compared with NAA, have worse baseline endothelial-dependent function, which persists after mental stress. Furthermore, AA have a more pronounced decrease in endothelial function with mental stress compared with NAA. Whether this more adverse vascular reactivity with stress is implicated in race-based disparities in cardiovascular disease requires further study.
LncRNA ANRIL regulates AML development through modulating the glucose metabolism pathway of AdipoR1/AMPK/SIRT1
Authors: Lin-Yu Sun, Xiao-Juan Li, Yu-Meng Sun, Wei Huang, Ke Fang, Cai Han, Zhen-Hua Chen, Xue-Qun Luo, Yue-Qin Chen, Wen-Tao Wang
Journal: Molecular Cancer (2018)

The long noncoding RNA ANRIL has been found to be abnormally expressed and play important roles in different cancers. However, the expression and function of ANRIL in acute myeloid leukemia (AML) remain to be declared. In this study, we found that ANRIL is up-regulated in AML patients at diagnosis and down-regulated in patients after complete remission (CR). Functional studies showed that knockdown of ANRIL expression resulted in a decline in glucose uptake and inhibition of AML cell maintenance in vitro and in vivo. Mechanically, ANRIL was found to repress the expression of Adiponectin receptor (AdipoR1), a key regulator of glucose metabolism. Both ANRIL and AdipoR1 knockdown reduced the expression levels of phosphorylation of AMPK and SIRT1, implying a previously unappreciated ANRIL-AdipoR1-AMPK/SIRT1 signaling pathway in regulating cell glucose metabolism and survival in AML. The study is the first to demonstrate that ANRIL promotes malignant cell survival and cell glucose metabolism to accelerate AML progression and is a potential prognostic marker and therapeutic target in AML treatment.
Abstract 16662: Association of Potassium Values in Hospitalized Patients With Mortality: Data From a Metropolitan Safety-net Hospital
Authors: Charles A Herzog, James B Wetmore, Wendy L St. Peter, David T Gilbertson
Journal: Circulation (2016)

Introduction: Extremes of serum potassium (K) levels have been associated with adverse outcomes. We examined the association between K values with mortality in patients hospitalized at a metropolitan safety-net hospital. Methods: We obtained K values for all patients hospitalized over a 1-yr period (July 2014-June 2015) and analyzed the association between K level and in-hospital mortality. We also assessed the % of patients with K > 5.0 by race and comorbidity: Diabetes Mellitus (DM), Chronic Kidney Disease (CKD), and Congestive Heart Failure (CHF). Results: 17,317 hospitalizations with K values were included. The mean age was 50.2 yrs, 57.3% of patients were male, 47.7% white, 33.7% black; for comorbidities, 25.9% had DM, 14.1% CKD, and 6.2% CHF. The distribution of K   5.0 for patients with DM was 4.0%,...
Epigenetic silencing of tumor suppressor Par-4 promotes chemoresistance in recurrent breast cancer
Authors: Nathaniel W. Mabe, Douglas B. Fox, Ryan Lupo, Amy E. Decker, Stephanie N. Phelps, J. Will Thompson, James V. Alvarez
Journal: Journal of Clinical Investigation (2018)

Tumor relapse is the leading cause of death in breast cancer, largely due to the fact that recurrent tumors are frequently resistant to chemotherapy. We previously reported that downregulation of the proapoptotic protein Par-4 promotes tumor recurrence in genetically engineered mouse models of breast cancer recurrence. In the present study, we examined the mechanism and functional significance of Par-4 downregulation in recurrent tumors. We found that epithelial-to-mesenchymal transition (EMT) promotes epigenetic silencing of Par-4 in recurrent tumors. Par-4 silencing proceeded through binding of the EMT transcription factor Twist to the Par-4 promoter, where Twist induced a unique bivalent chromatin domain. This bivalent configuration conferred plasticity at the Par-4 promoter, and Par-4 silencing could be reversed with pharmacologic inhibitors of Ezh2 and HDAC1/2. Using an epigenome editing approach to reexpress Par-4 by specifically reversing the histone modifications found in recurrent tumors, we found that Par-4 reexpression sensitized recurrent tumors to chemotherapy in vitro and in vivo. Upon reexpression, Par-4 bound to the protein phosphatase PP1, caused widespread changes in phosphorylation of cytoskeletal proteins, and cooperated with microtubule-targeting drugs to induce mitotic defects. These results identify Twist-induced epigenetic silencing of Par-4 as a targetable axis that promotes chemoresistance in recurrent breast cancer.
Improved short- and long-term outcome of allogeneic stem cell recipients admitted to the intensive care unit: a retrospective longitudinal analysis of 942 patients
Authors: Catherina Lueck, Michael Stadler, Christian Koenecke, Marius M. Hoeper, Elke Dammann, Andrea Schneider, Jan T. Kielstein, Arnold Ganser, Matthias Eder, Gernot Beutel
Journal: Intensive Care Medicine (2018)
Symptomatic osteonecrosis as a treatment complication in Hodgkin lymphoma: an analysis of the German Hodgkin Study Group (GHSG)
Authors: Sven Borchmann, Horst Müller, Heinz Haverkamp, Christian Baues, Jana Marková, Andreas Hüttmann, Axel Glunz, Michael Fuchs, Peter Borchmann, Andreas Engert
Journal: Leukemia (2018)