tbuckley/cabot-search huggingface dataset:
Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma Patients
Authors: Umamaheswar Duvvuri, Jonathan George, Seungwon Kim, Diego Alvarado, Veronique M. Neumeister, Ahmed Chenna, Richard Gedrich, Thomas Hawthorne, Theresa LaVallee, Jennifer R. Grandis, Julie E. Bauman
Journal: Clinical Cancer Research (2019)

ErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A "window-of-opportunity" study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 mAb, in patients with HNSCC.Twelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1,000 mg) at a 2-week interval prior to tumor resection. The primary study objective was to achieve ≥50% reduction in tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3) in ≥30% of patients. Other potential tumor biomarkers, pharmacokinetics, safety, and tumor measurements were also assessed.pErbB3 was detectable in all tumors prior to treatment and decreased for 10 of 12 (83%) patients following CDX-3379 dosing, with ≥50% reduction in 7 of 12 (58%; P = 0.04; 95% confidence interval, 27.7%-84.8%). Target trough CDX-3379 serum levels were achieved in all patients. CDX-3379 treatment-related toxicity was grade 1-2 and included diarrhea, fatigue, and acneiform dermatitis. Five of 12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with human papillomavirus-negative oral cavity HNSCC. All patients with tumor shrinkage had tumors that expressed both NRG1 and ErbB3 and demonstrated reduced pErbB3 with CDX-3379 treatment.This study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase II study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC.
The MISSION Act: Challenges to Sleep Medicine and Other Specialties in the Veterans Health Administration
Authors: Samuel T. Kuna
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

septum than patients with idiopathic pulmonary arterial hypertension, although increased fibrosis did not seem to explain RV diastolic dysfunction, which was quite similar in these two groups of patients (7).PA stiffness occurs early in the development of PH, causes an increase in pulsatile afterload that affect RV remodeling, and is associated with poor outcomes (8-10).However, whether RV fibrosis is a consequence of PA stiffness, and whether RV fibrosis represents maladaptive RV remodeling remain unclear.Although determinants of RV fibrosis are largely unexplored, a recent preclinical study demonstrated that galectin 3 was an important driver of RV fibrosis through the expansion of PDGFRa (platelet-derived growth factor receptor a)/vimentin-expressing cardiac fibroblasts.Curiously, interventions that successfully targeted fibrosis failed, however, to improve RV function, suggesting a potential disconnect between fibrosis and RV dysfunction in this animal model (11).Future studies should prospectively examine temporal relationships among RV fibrosis, metrics of RV function, and clinical outcomes in homogeneous cohorts consisting of patients belonging to a single WSPH group.It would be particularly interesting to use serial ECV assessments to study the extent to which RV fibrosis is reversible with PH therapies and interventional or surgical procedures that unload the RV.The ability to reliably assess the extent of RV fibrosis noninvasively with novel imaging techniques raises new questions and invites a host of investigative possibilities.The particular circumstances under which RV fibrosis develops and progresses, and the clinical consequences of such progression, are now amenable to longitudinal study.With further study, we may come to recognize RV fibrosis as a maladaptive clinical feature of disease progression that should prompt escalation or tailoring of specific PH therapies.The study by Jankowich and colleagues marks an important initial step in the overall investigation into the clinical relevance of RV fibrosis in PH.
Prevalence and Risk Factors Associated With Long-term Opioid Use After Injury Among Previously Opioid-Free Workers
Authors: Zoe Durand, Sarah Nechuta, Shanthi Krishnaswami, Eric L. Hurwitz, Melissa McPheeters
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Using opioids for acute pain can lead to long-term use and associated morbidity and mortality. Injury has been documented as a gateway to long-term opioid use in some populations, but data are limited for injured workers. <h3>Objective</h3> To evaluate the prevalence and risk factors of long-term opioid use after injury among workers in Tennessee who were opioid free at the time of injury. <h3>Design, Setting, and Participants</h3> This cohort study identified injured workers aged 15 to 99 years who reported only 1 injury to the Tennessee Bureau of Workers' Compensation from March 2013 to December 2015 and had no opioid prescription in the 60 days before injury. Participants were matched to their prescription history in Tennessee's prescription drug monitoring program. Analysis was conducted from November 2017 to March 2018. Logistic regression models were used to calculate adjusted odds ratios (ORs) and 95% CIs for associations of demographic, injury, and opioid use variables with long-term use. <h3>Main Outcomes and Measures</h3> The primary outcome was long-term opioid use, defined as having an opioid supplied for 45 or more days in the 90 days after injury. <h3>Results</h3> Among 58 278 injured workers who received opioids after injury (18 977 [32.5%] aged 15-34 years, 27 514 [47.2%] aged 35-54 years, and 11 787 [20.2%] aged 55-99 years; 32 607 [56.0%] men), 46 399 (79.6%) were opioid free at the time of injury. Among opioid-free injured workers, 1843 (4.0%) began long-term opioid use. After controlling for covariates, long-term use was associated with receiving 20 or more days' supply in the initial opioid prescription compared with receiving less than 5 days' supply (OR, 28.94; 95% CI, 23.44-35.72) and visiting 3 or more prescribers in the 90 days after injury compared with visiting 1 prescriber (OR, 14.91; 95% CI, 12.15-18.29). However, even just 5 days' to 9 days' supply was associated with an increase in the odds of long-term use compared with less than 5 days' supply (OR, 1.83; 95% CI, 1.56-2.14). <h3>Conclusions and Relevance</h3> In this study of injured workers, injury was associated with long-term opioid use. The number of days' supply of the initial opioid prescription was the strongest risk factor of developing long-term use, highlighting the importance of careful prescribing for initial opioid prescriptions.
De novo generation of a functional human thymus from induced pluripotent stem cells
Authors: Amiet R. Chhatta, Martijn Cordes, Maaike A.J. Hanegraaf, Sandra Vloemans, Tom Cupedo, Jan J. Cornelissen, Francoise Carlotti, Daniela Salvatori, Karin Pike-Overzet, Willem E. Fibbe, Rob C. Hoeben, Harald M.M. Mikkers, Frank J.T. Staal
Journal: Journal of Allergy and Clinical Immunology (2019)
Stop violence against women. Fight AIDS.
Authors: Steiner Mj, Cates W, Winer Rl, Hughes Jp, Feng Q, OReilly S, Kiviat Nb, Sangi-Haghpeykar H, Ali N, Posner S, Poindexter An, Kifetew K, Kungu Rw, Parekh N, Sluzhynska O, Graham T
Journal: New England Journal of Medicine (2006)

Violence against women is a global health crisis of epidemic proportions and often a cause and consequence of HIV. Violence and the threat of violence dramatically increase the vulnerability of women and girls to HIV by making it difficult or impossible for women to abstain from sex to get their partners to be faithful or to use a condom. Violence is also a barrier for women in accessing HIV prevention care and treatment services. That is why the UNAIDS-led Global Coalition on Women and AIDS has made stopping violence against women a top priority.  (excerpt)
Ultrasound/microbubble-mediated targeted delivery of anticancer microRNA-loaded nanoparticles to deep tissues in pigs
Authors: Tommaso Di Ianni, Rajendran J.C. Bose, Uday K. Sukumar, Sunitha Bachawal, Huaijun Wang, Arsenii Telichko, Carl Herickhoff, Elise Robinson, Sam Baker, José G. Vilches-Moure, Stephen A. Felt, Sanjiv S. Gambhir, Ramasamy Paulmurugan, Jeremy D. Dahl
Journal: Journal of Controlled Release (2019)
Diabetes Is Associated With Increased Risk of Hepatocellular Carcinoma in Patients With Cirrhosis From Nonalcoholic Fatty Liver Disease
Authors: Ju Dong Yang, Fowsiyo Ahmed, Kristin C. Mara, Benyam D. Addissie, Alina M. Allen, Gregory J. Gores, Lewis R. Roberts
Journal: Hepatology (2019)

Diabetes increases the risk of liver disease progression and cirrhosis development in patients with nonalcoholic steatohepatitis (NASH). The association between diabetes and the risk of hepatocellular carcinoma (HCC) in NASH patients with cirrhosis is not well quantified. All patients with the diagnosis of NASH cirrhosis seen at Mayo Clinic Rochester between January 2006 and December 2015 were identified. All adult liver transplant registrants with NASH between 2004 and 2017 were identified using the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation registry for external validation. Cox proportional hazard analysis was performed to investigate the association between diabetes and HCC risk. Among 354 Mayo Clinic patients with NASH cirrhosis, 253 (71%) had diabetes and 145 (41%) were male. Mean age at cirrhosis evaluation was 62. During a median follow-up of 47 months, 30 patients developed HCC. Diabetes was associated with an increased risk of developing HCC in univariate (hazard ratio [HR] = 3.6; 95% confidence interval [CI] = 1.1-11.9; P = 0.04) and multivariable analysis (HR = 4.2; 95% CI = 1.2-14.2; P = 0.02). In addition, age (per decade, HR = 1.8; 95% CI = 1.2-2.6; P < 0.01) and low serum albumin (HR = 2.1; 95% CI = 1.5-2.9; P < 0.01) were significantly associated with an increased risk of developing HCC in multivariable analysis. Other metabolic risk factors, including body mass index, hyperlipidemia, and hypertension, were not associated with HCC risk. Among UNOS NASH registrants (N = 6,630), 58% had diabetes. Diabetes was associated with an increased risk of developing HCC in univariate (HR = 1.4; 95% CI = 1.1-1.8; P < 0.01) and multivariable (HR = 1.3; 95% CI = 1.0-1.7; P = 0.03) analysis. Conclusion: Diabetes is associated with an increased risk of HCC in patients with NASH cirrhosis.
Unbiased Metabolic Profiling Predicts Sensitivity of High MYC-Expressing Atypical Teratoid/Rhabdoid Tumors to Glutamine Inhibition with 6-Diazo-5-Oxo-L-Norleucine
Authors: Sabrina Z. Wang, Brad Poore, Jesse Alt, Antoinette Price, Sariah J. Allen, Allison R. Hanaford, Harpreet Kaur, Brent A. Orr, Barbara S. Slusher, Charles G. Eberhart, Eric H. Raabe, Jeffrey A. Rubens
Journal: Clinical Cancer Research (2019)

Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive infantile brain tumors with poor survival. Recent advancements have highlighted significant molecular heterogeneity in AT/RT with an aggressive subgroup featuring overexpression of the MYC proto-oncogene. We perform the first comprehensive metabolic profiling of patient-derived AT/RT cell lines to identify therapeutic susceptibilities in high MYC-expressing AT/RT.Metabolites were extracted from AT/RT cell lines and separated in ultra-high performance liquid chromatography mass spectrometry. Glutamine metabolic inhibition with 6-diazo-5-oxo-L-norleucine (DON) was tested with growth and cell death assays and survival studies in orthotopic mouse models of AT/RT. Metabolic flux analysis was completed to identify combination therapies to act synergistically to improve survival in high MYC AT/RT.Unbiased metabolic profiling of AT/RT cell models identified a unique dependence of high MYC AT/RT on glutamine for survival. The glutamine analogue, DON, selectively targeted high MYC cell lines, slowing cell growth, inducing apoptosis, and extending survival in orthotopic mouse models of AT/RT. Metabolic flux experiments with isotopically labeled glutamine revealed DON inhibition of glutathione (GSH) synthesis. DON combined with carboplatin further slowed cell growth, induced apoptosis, and extended survival in orthotopic mouse models of high MYC AT/RT.Unbiased metabolic profiling of AT/RT identified susceptibility of high MYC AT/RT to glutamine metabolic inhibition with DON therapy. DON inhibited glutamine-dependent synthesis of GSH and synergized with carboplatin to extend survival in high MYC AT/RT. These findings can rapidly translate into new clinical trials to improve survival in high MYC AT/RT.
CDKN2B upregulation prevents teratoma formation in multipotent fibromodulin-reprogrammed cells
Authors: Zhong Zheng, Chenshuang Li, Pin Ha, Grace X. Chang, Pu Yang, Xinli Zhang, Jong Kil Kim, Wenlu Jiang, Xiaoxiao Pang, Emily A. Berthiaume, Zane Mills, Christos S. Haveles, Eric Chen, Kang Ting, Chia Soo
Journal: Journal of Clinical Investigation (2019)

Tumorigenicity is a well-documented risk to overcome for pluripotent or multipotent cell applications in regenerative medicine. To address the emerging demand for safe cell sources in tissue regeneration, we established a novel, protein-based reprogramming method that does not require genome integration or oncogene activation to yield multipotent fibromodulin (FMOD)-reprogrammed (FReP) cells from dermal fibroblasts. When compared with induced pluripotent stem cells (iPSCs), FReP cells exhibited a superior capability for bone and skeletal muscle regeneration with markedly less tumorigenic risk. Moreover, we showed that the decreased tumorigenicity of FReP cells was directly related to an upregulation of cyclin-dependent kinase inhibitor 2B (CDKN2B) expression during the FMOD reprogramming process. Indeed, sustained suppression of CDKN2B resulted in tumorigenic, pluripotent FReP cells that formed teratomas in vivo that were indistinguishable from iPSC-derived teratomas. These results highlight the pivotal role of CDKN2B in cell fate determination and tumorigenic regulation and reveal an alternative pluripotent/multipotent cell reprogramming strategy that solely uses FMOD protein.
Safe and Effective Implementation of a Red Blood Cell (RBC) Transfusion Hemoglobin (Hb) Threshold of 7 g/Dl on an Inpatient Stem Cell Transplant Unit: A Single Institution Experience
Authors: Melissa M. Cushing, Ljiljana Vasovic, Kathleen Kane, Usama Gergis, Adriana C. Rossi, Adrienne A. Phillips, Yen-Michael S. Hsu, Craig Budzinski, Sebastian A. Mayer, Jingmei Hsu, Sangmin Lee, Tsiporah B. Shore, Koen Van Besien, Ruchika Goel
Journal: Blood (2017)
Distinct Histopathologic Patterns of Finger Eruptions in Dermatomyositis Based on Myositis-Specific Autoantibody Profiles
Authors: Naoko Okiyama, Yukie Yamaguchi, Masanari Kodera, Yasuhito Hamaguchi, Hiroo Yokozeki, Naoko Ishiguro, Manabu Fujimoto
Journal: JAMA Dermatology (2019)

patients were male; the majority (10; 67%) were non-Hispanic white with mean age 53 years.Six of the 9 participants who enrolled for 4 weeks continued for 12 weeks.There was no difference in the mean percent change in GLI1 mRNA levels between itraconazole and placebo groups at 4 weeks (132% vs 19.0% from baseline; P = .20).There was no statistically significant difference in the percent change in tumor area between itraconazole and placebo at 4 weeks (0.04% vs -10.9% from baseline; P = .40)and 12 weeks (8.9% vs 26.5%; P = .40).In post hoc analysis, the itraconazole group showed reduced BCC tumor area in the subgroup of BCCs located on the back; however, given multiple testing for different anatomic locations, this difference was ultimately not statistically significant.Using liquid chromatography-mass spectrometry, intratumor itraconazole concentration was 133 μg/g of skin at 4 weeks and 96 μg/g at 12 weeks.There was no association between change in BCC tumor area and GLI1 mRNA levels.Other major metabolites such as hydroxy-itraconazole were not measured given their weaker half maximal inhibitory concentrations (IC 50 ).One patient had grade 1 liver function test abnormalities at weeks 4 and 12, but this patient had fatty liver disease.Plasma itraconazole levels were undetectable after 4 and 12 weeks, except for 1 patient with a plasma level of 4.12 ng/mL.Topical itraconazole caused only grade 1 to2 adverse effects: application site reaction (n = 4), pruritus (n = 4), lesion pain (n = 3), dysgeusia (n = 1), and xerosis (n = 1).These adverse effects resolved by the end of the study except in 2 patients who had persistent mild lesion pain, pruritus, and xerosis.Discussion | Itraconazole, 0.7%, gel appears safe, is associated with intratumor drug concentrations after 4 weeks, and is not associated with systemic absorption.However, topical itraconazole failed to reduce GLI1 mRNA levels and tumor area.Topical and oral itraconazole are associated with BCC shrinkage in mice, 4 but topical penetration in humans is more difficult owing to a thicker epidermis.Conclusions | Itraconazole gel at the maximally soluble formulation of 0.7% did not reduce GLI1 mRNA levels and BCC tumor size.However, this study does not rule out whether other formulations of itraconazole at higher concentrations may be more effective.
Retraction: Knockdown of Contactin-1 Expression Suppresses Invasion and Metastasis of Lung Adenocarcinoma
Authors: Jen-Liang Su, Ching-Yao Yang, Jin-Yuan Shih, Lin-Hung Wei, Chang-Yao Hsieh, Yung-Ming Jeng, Ming-Yang Wang, Pan-Chyr Yang, Min-Liang Kuo
Journal: Cancer Research (2019)

[This article][1] ([1][2]) has been retracted at the request of the authors. Multiple Western blot bands were duplicated in several figures in the article as well as in another article published by the authors ([2][3]), making the findings unreliable. The authors apologize to the scientific
Low Levels of Alcohol Consumption, Obesity, and Development of Fatty Liver With and Without Evidence of Advanced Fibrosis
Authors: Yoosoo Chang, Seungho Ryu, Yejin Kim, Yong Kyun Cho, Eunju Sung, Han‐Na Kim, Jiin Ahn, Hyun‐Suk Jung, Kyung Eun Yun, Seolhye Kim, Ki‐Chul Sung, Chong Il Sohn, Hocheol Shin, Sarah H. Wild, Christopher D. Byrne
Journal: Hepatology (2019)

Background and Aims The effects of low‐level alcohol consumption on fatty liver disease and the potential for effect modification by obesity is uncertain. We investigated associations among low‐level alcohol consumption, obesity status, and the development of incident hepatic steatosis (HS), either with or without an increase in noninvasive liver fibrosis score category (from low to intermediate or high category). Approach and Results A total of 190,048 adults without HS and a low probability of fibrosis with alcohol consumption less than 30 g/day (men) and less than 20 g/day (women) were followed for up to 15.7 years. Alcohol categories of no, light, and moderate consumption were defined as 0, 1‐9.9, and 10‐29.9 g/day (10‐19.9 g/day for women), respectively. HS was diagnosed by ultrasonography, and the probability of fibrosis was estimated using the fibrosis‐4 index (FIB‐4). Parametric proportional hazards models were used to estimate multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 43,466 participants developed HS, 2,983 of whom developed HS with an increase in FIB‐4 index (to intermediate or high scores). Comparing light drinkers and moderate drinkers with nondrinkers, multivariable‐adjusted HRs (95% CI) for incident HS were 0.93 (0.90‐0.95) and 0.90 (0.87‐0.92), respectively. In contrast, comparing light drinkers and moderate drinkers with nondrinkers, multivariable‐adjusted HRs (95% CI) for developing HS plus intermediate/high FIB‐4 were 1.15 (1.04‐1.27) and 1.49 (1.33‐1.66), respectively. The association between alcohol consumption categories and incident HS plus intermediate/high FIB‐4 was observed in both nonobese and obese individuals, although the association was stronger in nonobese individuals ( P for interaction by obesity = 0.017). Conclusions Light/moderate alcohol consumption has differential effects on the development of different stages of fatty liver disease, which is modified by the presence of obesity.
Modeling Gliomas Using Two Recombinases
Authors: Toshiro Hara, Inder M. Verma
Journal: Cancer Research (2019)

Development of animal models to investigate the complex ecosystem of malignant gliomas using the Cre/loxP recombination system has significantly contributed to our understanding of the molecular underpinnings of this deadly disease. In these model systems, once the tumor is induced by activation of Cre-recombinase in a tissue-specific manner, further genetic manipulations to explore the progression of tumorigenesis are limited. To expand the application of mouse models for gliomas, we developed glial fibrillary acidic protein (GFAP)-FLP recombinase (FLPo) mice that express FLPo recombinase specifically in GFAP-positive cells. Lentivirus-based
Review: Nonpharmacologic and pharmacologic interventions improve urinary incontinence in women
Authors: Donna M. Fedorkow
Journal: Annals of Internal Medicine (2019)

Source Citation Balk EM, Rofeberg VN, Adam GP, et al. Pharmacologic and nonpharmacologic treatments for urinary incontinence in women: a systematic review and network meta-analysis of clinical outcomes. Ann Intern Med. 2019 Mar 19. [Epub ahead of print]. 30884526
Shared roles for Scl and Lyl1 in murine platelet production and function
Authors: Sung K. Chiu, Stephanie L. Orive, Mitchell J. Moon, Jesslyn Saw, Sarah Ellis, Benjamin T. Kile, Yizhou Huang, Diego Chacon, John E. Pimanda, Dominik Beck, Justin R. Hamilton, Cedric S. Tremblay, David J. Curtis
Journal: Blood (2019)