tbuckley/cabot-search huggingface dataset:
Combining IMGN779, a Novel Anti-CD33 Antibody-Drug Conjugate (ADC), with the PARP Inhibitor, Olaparib, Results in Enhanced Anti-Tumor Activity in Preclinical Acute Myeloid Leukemia (AML) Models
Authors: Scott Portwood, Robert A Puchalski, Russell M Walker, Eunice S. Wang
Journal: Blood (2016)
CheckMate 384: A phase 3b/4 dose-frequency optimization trial of nivolumab in advanced or metastatic non-small cell lung cancer
Authors: N. Reinmuth, R. Harris, P. Mitchell, E.B. Garon, J. Zhu, I.-F. Chang, G. Selvaggi, E. Pichon
Journal: Annals of Oncology (2017)
Declining Trends of Cardiovascular-Renal Complications and Mortality in Type 2 Diabetes: The Hong Kong Diabetes Database
Authors: Andrea O.Y. Luk, Eric M.T. Hui, Ming-Chuen Sin, Chun-Yip Yeung, Wing-Sun Chow, Andrew Y.Y. Ho, Hin-Fai Hung, Eva Kan, Chiu-Ming Ng, Wing-Yee So, Chi-Kin Yeung, Kin-Sang Chan, Kin-Wah Chan, Pang-Fai Chan, Shing-Chung Siu, Sau-Cheung Tiu, Vincent T.F. Yeung, Juliana C.N. Chan, Frank W.K. Chan, Clement Cheung, Ngai-Tseung Cheung, Siu-Tung Ho, Karen S.L. Lam, Linda W.L. Yu, David Chao, Ip-Tim Lau
Journal: Diabetes Care (2017)

Nationwide studies on secular trends of diabetes complications are not available in Asia. We examined changes in risk factor control and incidence of complications from diabetes and death in a large longitudinal cohort of Chinese adults with type 2 diabetes in Hong Kong.Between 1 January 2000 and 31 December 2012, 338,908 Chinese adults with type 2 diabetes underwent metabolic and complication assessment in 16 diabetes centers operated by Hong Kong Hospital Authority that provided care to a large majority of diagnosed patients. Patients were followed for incident acute myocardial infarction (AMI), stroke, end-stage renal disease (ESRD), and death until 31 December 2012. Risk factor levels between enrollment periods were compared. Incidence of clinical events, stratified by diabetes duration, was examined over time.Incidence of complications from diabetes and death declined over the observation period in patients at varying disease duration. Among the high-risk group with diabetes for at least 15 years, crude incidence of AMI decreased from 8.7 to 5.8, stroke from 13.5 to 10.1, ESRD from 25.8 to 22.5, and death from 29.0 to 26.6 per 1,000 person-year between the periods 2000 to 2002 and 2010 to 2012. Improvements in levels of metabolic risk factors were detected. Proportion of patients achieving HbA1c <7.0% (53 mmol/mol) was increased from 32.9 to 50.0%, blood pressure ≤130/80 mmHg from 24.7 to 30.7%, and LDL cholesterol <2.6 mmol/L from 25.8 to 38.1%.From this territory-wide Hong Kong Diabetes Database, we observed decreases in incidence of cardiovascular-renal complications and death and corresponding improvements in risk factor control over a 13-year period.
Fasting serum bile acids profile and insulin resistance in healthy blood donors
Authors: F. Azzaroli, P. Simoni, R. Arena, R.M. Zagari, A. Porro, C. Camborata, A. Belardinelli, S. Spinozzi, M. Montagnani, F. Bazzoli, A. Roda, G. Mazzella
Journal: Journal of Hepatology (2017)
Formation of bile canaliculi in liver progenitor cell-derived hepatocytes determines clinical outcome of acute-on-chronic liver failure
Authors: X. Yuan, W. Gu, F. Wandrer, B. Dewidar, S. Munker, B. Hähnel, R. Liebe, M.P. Ebert, X. Qiang, H. Bantel, S. Dooley, H. Li, H. Weng
Journal: Journal of Hepatology (2017)
Mutant TDP-43 does not impair mitochondrial bioenergetics in vitro and in vivo
Authors: Hibiki Kawamata, Pablo Peixoto, Csaba Konrad, Gloria Palomo, Kirsten Bredvik, Meri Gerges, Federica Valsecchi, Leonard Petrucelli, John M. Ravits, Anatoly Starkov, Giovanni Manfredi
Journal: Molecular Neurodegeneration (2017)

Mitochondrial dysfunction has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Functional studies of mitochondrial bioenergetics have focused mostly on superoxide dismutase 1 (SOD1) mutants, and showed that mutant human SOD1 impairs mitochondrial oxidative phosphorylation, calcium homeostasis, and dynamics. However, recent reports have indicated that alterations in transactivation response element DNA-binding protein 43 (TDP-43) can also lead to defects of mitochondrial morphology and dynamics. Furthermore, it was proposed that TDP-43 mutations cause oxidative phosphorylation impairment associated with respiratory chain defects and that these effects were caused by mitochondrial localization of the mutant protein. Here, we investigated the presence of bioenergetic defects in the brain of transgenic mice expressing human mutant TDP-43 (TDP-43A315T mice), patient derived fibroblasts, and human cells expressing mutant forms of TDP-43.In the brain of TDP-43A315T mice, TDP-43 mutant fibroblasts, and cells expressing mutant TDP-43, we tested several bioenergetics parameters, including mitochondrial respiration, ATP synthesis, and calcium handling. Differences between mutant and control samples were evaluated by student t-test or by ANOVA, followed by Bonferroni correction, when more than two groups were compared. Mitochondrial localization of TDP-43 was investigated by immunocytochemistry in fibroblasts and by subcellular fractionation and western blot of mitochondrial fractions in mouse brain.We did not observe defects in any of the mitochondrial bioenergetic functions that were tested in TDP-43 mutants. We detected a small amount of TDP-43A315T peripherally associated with brain mitochondria. However, there was no correlation between TDP-43 associated with mitochondria and respiratory chain dysfunction. In addition, we observed increased calcium uptake in mitochondria from TDP-43A315T mouse brain and cells expressing A315T mutant TDP-43.While alterations of mitochondrial morphology and dynamics in TDP-43 mutant neurons are well established, the present study did not demonstrate oxidative phosphorylation defects in TDP-43 mutants, in vitro and in vivo. On the other hand, the increase in mitochondrial calcium uptake in A315T TDP-43 mutants was an intriguing finding, which needs to be investigated further to understand its mechanisms and potential pathogenic implications.
Weight, skeletal muscle mass, and adipose tissue loss during lung cancer patients' treatment.
Authors: Stéphanie Chemama, Sami Antoun, Julien Hadoux, Benjamin Besse, David Planchard, Bruno Raynard, Vickie E Baracos, Emilie Lanoy
Journal: Journal of Clinical Oncology (2014)

e20627 Background: The majority of lung cancer (LC) patients experience involuntary weight loss during the course of their disease trajectory. Few studies have characterised the specific changes of body composition parameters i.e. skeletal muscle mass (SMM), and total adipose tissue (TAT). The aim of the study was to quantify these changes during LC pts trajectory. Methods: Advanced non-small cell LC treated in our hospital were selected. TAT and SMM were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues. Images were analyzed using Slice-O-Matic software V4.3. Indexed on height SMM and TAT (cm2/m2) and the ratio TAT on SMM, were computed at treatment initiation and across. Mixed linear model were adjusted for sex, age and body mass index (BMI) to estimate baseline value and evolution across the time. Results: There were 65 men with median age and BMI respectively 61 years (interquartile range=57-66) and 25 kg2/m2 (22-28) and 34 women with median age and BMI respectively 61 years (54-69) and 23 kg2/m2 (21-26). The mean baseline weight was higher in men (76 kg 95% confidence interval (CI)=[73-79]) than in women (61 kg 95%CI=[57-66] (p<0.0001)); the overall weight decrease from treatment initiation did not differ with sex (p=0.29) and was 89 g/week 95%CI=[41-136] (p=0.0003). Baseline for SMM depended on sex (p<0.0001): in men, baseline SMM was 52 cm2/m2 95%CI=[50-54] decreasing of 0.12 cm2/m2 95%CI=[0.07-0.16] (p<0.0001) whereas in women, baseline SMM was 43 cm2/m2 95%CI=[40-45] decreasing of 0.05 cm2/m2 95%CI=[-0.01-0.10] (p=0.10).The mean TAT was 91 cm2/m2 95%CI=[81-102] with a decrease of 46 cm2/m2 per week 95%CI=[20-73] in men (p=0.0008) and of 6 cm2/m2per week 95%CI=[-27-39] in women (p=0.73).The ratio TAT on MT (mean baseline 1.9;°95%CI=[1.7- 2.1]) did not vary under treatment (p=0.26).Neither BMI nor age had an impact on weight, SMM and TAT changes. Conclusions: Weight loss during lung cancer trajectory reflects both SMM and TAT loss. The rate of SMM loss depends on sex: women seem to have a slowest SMM loss. There is no influence of baseline BMI or age on body composition changes. Interestingly the ratio of TAT loss on SMM loss remains stable during the lung cancer trajectory.
Pfizer makes breast cancer drug free while NICE decides its future
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

Drug company Pfizer has made its new breast cancer drug palbociclib available to patients in the UK free of charge after it was initially rejected for routine use on the NHS.

Palbociclib (Ibrance) is licensed as a first line treatment for hormone receptor positive, HER2 negative locally advanced, and metastatic breast cancer. It is taken alongside an aromatase inhibitor.

The National Institute for Health and Care Excellence (NICE) did not recommend palbociclib for use by the NHS for patients who had not been treated for locally advanced …
Abstract B13: EGF/Ras/Erk signaling controls growth and proliferation through regulation of tRNA synthesis
Authors: Shrivani Sriskanthadevan-Pirahas, Savraj S. Grewal
Journal: Cancer Research (2017)

Abstract Ras signaling promotes growth and proliferation in many tissues throughout animal development. An important challenge is to identify how the Ras-Erk pathway alters cellular metabolism to drive growth. Here we report on the control of tRNA synthesis as growth effector of EGF/Ras/Erk signaling in Drosophila. I find that overexpression of oncogenic Ras (RasV12) leads to increased mRNA translation and protein content in Drosophila S2 cells, suggesting that Ras may promote growth through enhanced protein synthesis. The conventional view is that the Ras pathway functions by controlling translation initiation factor activity. However I have identified an alternate mechanism involving control of tRNA synthesis. My data suggest that overexpression of RasV12 or the activated versions of EGFR and the Raf1 in wing imaginal discs increases tRNA synthesis. Similarly, expression of RasV12 in S2 cells increases tRNA levels, while blocking Ras/Erk signaling using the MEK inhibitor, U0126 or RNAi reduces tRNA synthesis. We previously identified the RNA polymerase III (Pol III) factor, Brf, as regulator of cell and tissue growth in Drosophila. Here we show that knockdown of either Brf blocks the effects of Ras signaling on growth and proliferation in larval wing imaginal discs, adult midgut progenitor cells and adult intestinal stem cells. Several transcription factors have been shown to link Ras signaling to changes in mRNA expression and growth. I have identified Myc is required but not sufficient for Ras-induced cell proliferation and growth through tRNA synthesis. Previously we have shown that TOR signaling regulates protein synthesis through RNA Pol III repressor, Maf1. I found that Maf1 RNAi increases tRNA synthesis in S2 cells. In addition, the decrease in tRNA synthesis induced by the MEK inhibitor is blocked in the presence of Maf1 RNAi suggesting Maf1 is downstream of Ras signaling pathway. My data point to control of tRNA synthesis possibly through Myc and/or Maf1 as a new mechanisms by which Ras signaling enhances protein synthesis to promote cell and tissue growth. Citation Format: Shrivani Sriskanthadevan-Pirahas, Savraj S. Grewal. EGF/Ras/Erk signaling controls growth and proliferation through regulation of tRNA synthesis. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B13.
Potentiation of immune checkpoint blockade cancer immunotherapy with oncolytic virus.
Authors: Dmitriy Zamarin, Rikke Baek Holmgaard, Sumit Kumar Subudhi, Joon-Seok Park, Mena Mansour, Peter Palese, Taha Merghoub, Jedd D. Wolchok, James Patrick Allison
Journal: Journal of Clinical Oncology (2014)

3051 Background: Therapeutic efficacy of agents targeting immune checkpoints has been limited to a subset of patients and cancer types. Preexisting lymphocytic infiltration of tumors has emerged as an important biomarker predictive of clinical benefit, suggesting that therapeutic effect could be enhanced through strategies that induce tumor inflammation. Here we explored whether the inflammatory responses generated by oncolytic viruses could be harnessed to improve systemic therapeutic efficacy of agents targeting immunologic checkpoints. Methods: For our studies we utilized Newcastle Disease Virus (NDV), an avian virus with robust type I IFN-inducing properties. Metastatic disease was modeled by using bilateral flank B16 mouse melanoma model, with NDV administered unilaterally, allowing us to characterize the immune responses in both virus-injected and distant tumors. Therapeutic efficacy and immune responses utilizing intratumoral NDV with systemic immune checkpoint blocking antibodies were further characterized in several mouse models. Results: Localized intratumoral therapy of B16 melanoma with NDV induced CD4+ and CD8+ lymphocytic infiltrates and anti-tumor effect in distant (non-virally infected) tumors without viral spread to these sites. Combination therapy with localized NDV and systemic immune checkpoint blockade led to distant tumor rejection in both NDV-susceptible and resistant tumor models and protected the animals from tumor re-challenge. This effect was associated with marked tumor infiltration with activated effector, but not regulatory T cells, and was dependent on CD8 and NK cells, and type I and II interferons. To further enhance the T cell effector function in tumors, we genetically-engineered NDVs expressing co-stimulatory ligands and demonstrated further increase in therapeutic efficacy of the combination therapy in several tumor models. Conclusions: In summary, in mouse tumor models, localized therapy with NDV induces inflammatory infiltrates in distant tumors, making them susceptible to systemic therapy with immunomodulatory antibodies. This provides a strong rationale for investigation of combination therapies utilizing NDV and immune checkpoint blockade in clinic.
Prevalence and risk factors of hepatitis B virus reactivation in interferon-free direct-acting antiviral therapies for hepatitis C
Authors: N. Kawagishi, G. Suda, M. Onozawa, M. Kimura, O. Maehara, M. Ohara, T. Izumi, M. Umemura, J. Ito, M. Nakai, T. Sho, M. Natsuizka, K. Morikawa, K. Ogawa, N. Sakamoto
Journal: Journal of Hepatology (2017)
Frequency of Evidence-Based Screening for Retinopathy in Type 1 Diabetes
Authors: David M Nathan, Ionut Bebu, Dean Hainsworth, Ronald Klein, William Tamborlane, Gayle Lorenzi, Rose Gubitosi-Klug, John M Lachin
Journal: New England Journal of Medicine (2017)

In patients who have had type 1 diabetes for 5 years, current recommendations regarding screening for diabetic retinopathy include annual dilated retinal examinations to detect proliferative retinopathy or clinically significant macular edema, both of which require timely intervention to preserve vision. During 30 years of the Diabetes Control and Complications Trial (DCCT) and its longitudinal follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, retinal photography was performed at intervals of 6 months to 4 years.
PCTP (Phosphatidylcholine Transfer Protein) is Regulated By RUNX1 in Platelets/Megakaryocytes and is Associated with Adverse Cardiovascular Events
Authors: Natthapol Songdej, Guangfen Mao, Deepak Voora, Lawrence E. Goldfinger, Fabiola Del Carpio-Cano, Rachel Myers, Angara Koneti Rao
Journal: Blood (2016)
Phase 2 Trial of Smoothened (SMO) Inhibitor PF-04449913 (PF-04) in Refractory Myelodysplastic Syndromes (MDS)
Authors: Jeffrey E. Lancet, Rami S Komrokji, Kendra L. Sweet, Vu H. Duong, Kathy L McGraw, Ling Zhang, Lisa Ann Nardelli, Zhenjun Ma, Richard R Reich, Eric Padron, Alan F List
Journal: Blood (2016)
CABG at 50 (or 107?) — The Complex Course of Therapeutic Innovation
Authors: David S Jones
Journal: New England Journal of Medicine (2017)

On May 9, 1967, Cleveland Clinic surgeon René Favaloro performed his first CABG procedure. But although Favaloro’s work popularized the operation, CABG, like all significant medical interventions, is the product of innumerable innovations by many physicians.
Mortality and morbidity in cryptogenic (type C) compensated cirrhosis: a multicenter study
Authors: G. Fattovich, G. Giustina, F. Degos, F. Tremolada, G. Diodati, P. Almasio, F. Nevens, A. Solinas, D. Mura, J.T. Brouwer, H.C. Thomas, C. Njapoum, P. Bonetti, C. Casarin, P. Fuschi, J. Basho, A. Tocco, A. Bhalla, R. Galassini, F. Noventa, S.W. Schalm, G. Realdi
Journal: Hepatology (1995)
Analysis of Genetic Mutation of the Elderly Patients with Acute Myeloid Leukemia
Authors: Yusuke Fujiwara, Hiroki Yamaguchi, Atsushi Marumo, Ikuko Omori, Satoshi Yamanaka, Kazuki Terada, Shunsuke Yui, Keiko Fukunaga, Takeshi Ryotokuji, Tsuneaki Hirakawa, Masahiro Okabe, Satoshi Wakita, Yoshiki Osaki, Kunihito Arai, Tomoaki Kitano, Fumiko Kosaka, Hayato Tamai, Muneo Okamoto, Kazutaka Nakayama, Koiti Inokuchi
Journal: Blood (2016)
Genomic analysis of colitis-associated cancers.
Authors: Rona D. Yaeger, Vincent A. Miller, Judith R. Kelsen, Kai Wang, Yuting He, Eric M. Sanford, Sohail Balasubramanian, Laura H. Tang, David Paul Kelsen
Journal: Journal of Clinical Oncology (2015)

3566 Background: Patients (pts) with inflammatory bowel disease (IBD) [Crohn’s disease (CD) and ulcerative colitis (UC)], are at increased risk for small bowel or colorectal cancers (Colitis Associated Cancers, CAC). The genomic alterations (GA) associated with CAC have not been well-described. We hypothesized that GA associated with CAC are different than those seen with sporadic colorectal cancer (CRC). Identification of these alterations may lead to improved early detection and therapeutic options. Methods: We determined GA in 15 CAC cases confirmed as being associated with IBD at MSKCC including 11 UC and 4 CD, 14 primary and 1 metastasis (median age 55, range 29-77; 73% male). Primary tumor sites were ileum (2), right colon (5), and left colon (8). Histologic subtypes were moderately differentiated adenocarcinoma (4), mucinous (7), and signet ring/diffuse (4). Hybridization capture of the entire coding sequence of 405 cancer-related genes, including those associated with early onset IBD, was applied to DNA extracted from FFPE tumor specimens and sequenced to high, uniform coverage ( > 500x). All classes of GA including substitution, indel, copy number alteration and rearrangement were determined. Results: Potentially clinically relevant GA were identified in 8/15 CAC, including ERBB2 amplification (amp), ERBB2 S310F, EML4-ALK, FGFR2 amp, FGFR2 amp + FGFR2-TACC2 (same patient), PDGFRA T134M, and BRAF V600E + TSC2 truncation (same patient). IDH1 R132H/C were found in 2/4 CD cases (one concurrent with FGFR2 amp/fusion). Overall, 5.7 GA per tumor were detected (range 1-12). GA in TP53, the most commonly altered gene, occurred in 14/15 cases (93%; 10 known hot spot mutations), compared to 52% in CRC TCGA. KRAS and APC mutations occurred in 33% and 20%, respectively, compared to 43% and 76% in CRC TCGA. Other recurrently altered genes included SMAD4 (20%) and RNF43 (13%). Key GA associated with early onset IBD were not identified. Conclusions: Comprehensive genomic profiling identified a high frequency of potentially clinically relevant GA in CAC. GA seen in CAC suggest substantial differences from those of sporadic CRC; APC activation is infrequent and TP53 mutations are nearly universal including frequent possibly gain of function. Study of additional cases is ongoing.
Mental Health Outcomes After Having or Being Denied an Abortion—Reply
Authors: M. Antonia Biggs, Ushma D. Upadhyay, Diana G. Foster
Journal: JAMA Psychiatry (2017)

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Sustained efficacy and surface antigen seroconversion in the woodchuck model of chronic hepatitis B with the selective toll-like receptor 8 agonist GS-9688
Authors: S. Daffis, J. Chamberlain, J. Zheng, R. Santos, W. Rowe, M. Mish, D. Ramakrishnan, C. Yon, M. Suresh, S. Menne, P. Cote, W.E. Delaney, S.P. Fletcher, R. Mackman
Journal: Journal of Hepatology (2017)
Adverse Effects of Nutraceuticals and Dietary Supplements
Authors: Martin J.J. Ronis, Kim B. Pedersen, James Watt
Journal: The Annual Review of Pharmacology and Toxicology (2017)

Over 70% of Americans take some form of dietary supplement every day, and the supplement industry is currently big business, with a gross of over $28 billion. However, unlike either foods or drugs, supplements do not need to be registered or approved by the US Food and Drug Administration (FDA) prior to production or sales. Under the Dietary Supplement Health and Education Act of 1994, the FDA is restricted to adverse report monitoring postmarketing. Despite widespread consumption, there is limited evidence of health benefits related to nutraceutical or supplement use in well-nourished adults. In contrast, a small number of these products have the potential to produce significant toxicity. In addition, patients often do not disclose supplement use to their physicians. Therefore, the risk of adverse drug-supplement interactions is significant. An overview of the major supplement and nutraceutical classes is presented here, together with known toxic effects and the potential for drug interactions.
Assessment of glomerular filtration rate in hepatitis C virus patients after reaching sustained virologic response
Authors: N.R.R. Campos, R.Q. Castro, P.L. Torres, G.M. Arriero, L.M. Ron, D.V. Vidal, C.V. Lucas, M.J. Palacios, B.Á. Cuenllas, F.J. Plaza
Journal: Journal of Hepatology (2017)