tbuckley/cabot-search huggingface dataset:
Survival outcomes among patients with advanced hepatocellular carcinoma (aHCC) treated with systemic therapies.
Authors: Machaon Bonafede, Qian Cai, Prianka Singh, Krutika Jariwala-Parikh, Katherine Cappell, Neehar D. Parikh, Bruce Sill, Beata Korytowsky
Journal: Journal of Clinical Oncology (2018)

503 Background: HCC is the most common primary liver cancer. Despite the wide use of screening among high-risk individuals, about 45% of cases are diagnosed at the advanced stage. Sorafenib is the only FDA-approved first-line (1L) treatment for aHCC. This study aims to characterize survival by lines of therapy among commercially insured patients with aHCC treated with systemic therapy in the United States. Methods: Adults with ≥ 2 medical claims (30–180 days apart) for primary HCC ( ICD-9 155.0x) from 1/1/2008 to 9/30/2015 were identified in the MarketScan Research Databases. Continuous enrollment was required 6 months before and 1 month after diagnosis. Patients were further categorized into 1L and 2L cohorts if they initiated a targeted therapy, immunotherapy, or chemotherapy. Index date of 1L was the date of the first claim for a systemic agent after diagnosis; index date of 2L was the date of the first claim for a different agent after the end of 1L therapy. Date of death was determined based on records from the linked Social Security Administration Master Death File or on inpatient discharge status. Survival time was measured from the 1L/2L index date to the death date; patients without a death date were censored at end of continuous enrollment or study period, whichever occurred first. Results: 758 patients met the selection criteria for the 1L cohort (mean age, 62.5 ± 10.3 y; 21.9% female); 87 patients (11.5%) went on to receive 2L therapy (mean age, 61.8 ± 9.8 y; 20.7% female). Over half the patients (1L, 54.0%; 2L, 52.9%) died during the follow-up period; median survival time was 205 days (interquartile range [IQR], 290 days) in 1L patients and 280 days (IQR, 232 days) in 2L patients. 32.6% of 1L patients and 34.5% of 2L patients survived ≥ 1 year, and 12.4% of 1L patients and 16.1% of 2L patients survived ≥ 2 years after treatment initiation. Conclusions: Findings suggest that the vast majority of patients with aHCC do not receive 2L therapy. A high 1-year mortality rate represents the lack of effective treatment options in aHCC. Improved therapies are urgently needed for this highly morbid malignancy.
Effective silencing of ENaC by siRNA delivered with epithelial-targeted nanocomplexes in human cystic fibrosis cells and in mouse lung
Authors: Aristides D Tagalakis, Mustafa M Munye, Rositsa Ivanova, Hanpeng Chen, Claire M Smith, Ahmad M Aldossary, Luca Z Rosa, Dale Moulding, Josephine L Barnes, Konstantinos N Kafetzis, Stuart A Jones, Deborah L Baines, Guy W J Moss, Christopher O’Callaghan, Robin J McAnulty, Stephen L Hart
Journal: Thorax (2018)

Introduction Loss of the cystic fibrosis transmembrane conductance regulator in cystic fibrosis (CF) leads to hyperabsorption of sodium and fluid from the airway due to upregulation of the epithelial sodium channel (ENaC). Thickened mucus and depleted airway surface liquid (ASL) then lead to impaired mucociliary clearance. ENaC regulation is thus a promising target for CF therapy. Our aim was to develop siRNA nanocomplexes that mediate effective silencing of airway epithelial ENaC in vitro and in vivo with functional correction of epithelial ion and fluid transport. Methods We investigated translocation of nanocomplexes through mucus and their transfection efficiency in primary CF epithelial cells grown at air–liquid interface (ALI).Short interfering RNA (SiRNA)-mediated silencing was examined by quantitative RT-PCR and western analysis of ENaC. Transepithelial potential (V t ), short circuit current (I sc ), ASL depth and ciliary beat frequency (CBF) were measured for functional analysis. Inflammation was analysed by histological analysis of normal mouse lung tissue sections. Results Nanocomplexes translocated more rapidly than siRNA alone through mucus. Transfections of primary CF epithelial cells with nanocomplexes targeting αENaC siRNA, reduced αENaC and βENaC mRNA by 30%. Transfections reduced V t , the amiloride-sensitive I sc and mucus protein concentration while increasing ASL depth and CBF to normal levels. A single dose of siRNA in mouse lung silenced ENaC by approximately 30%, which persisted for at least 7 days. Three doses of siRNA increased silencing to approximately 50%. Conclusion Nanoparticle-mediated delivery of ENaCsiRNA to ALI cultures corrected aspects of the mucociliary defect in human CF cells and offers effective delivery and silencing in vivo.
FDA's Approval of the First Biosimilar to Bevacizumab
Authors: Sandra J. Casak, Steven J. Lemery, Jee Chung, Chana Fuchs, Sarah J. Schrieber, Edwin C.Y. Chow, Weishi Yuan, Lisa Rodriguez, Thomas Gwise, Anne Rowzee, Sue Lim, Patricia Keegan, Amy E. McKee, Richard Pazdur
Journal: Clinical Cancer Research (2018)

Passage of the Biologics Price Competition and Innovation Act of 2009 created an abbreviated licensure pathway for biosimilar products. The FDA approved ABP215 (MVASI, bevacizumab-awwb; Amgen) as a biosimilar to U.S.-licensed Avastin (bevacizumab; Genentech) based on an extensive comparative analytic characterization, data obtained in a pharmacokinetic similarity study in healthy subjects, and a comparative clinical study in patients with non-small cell lung cancer. The totality of the evidence for biosimilarity supported extrapolation of the data to support licensure as a biosimilar for other approved indications of U.S.-licensed Avastin, without the need of additional clinical studies. Clin Cancer Res; 24(18); 4365-70. ©2018 AACR.
An Intelligent Neural Stem Cell Delivery System for Neurodegenerative Diseases Treatment
Authors: Shupei Qiao, Yi Liu, Fengtong Han, Mian Guo, Xiaolu Hou, Kangruo Ye, Shuai Deng, Yijun Shen, Yufang Zhao, Haiying Wei, Bing Song, Lifen Yao, Weiming Tian
Journal: Advanced Healthcare Materials (2018)

Abstract Transplanted stem cells constitute a new therapeutic strategy for the treatment of neurological disorders. Emerging evidence indicates that a negative microenvironment, particularly one characterized by the acute inflammation/immune response caused by physical injuries or transplanted stem cells, severely impacts the survival of transplanted stem cells. In this study, to avoid the influence of the increased inflammation following physical injuries, an intelligent, double‐layer, alginate hydrogel system is designed. This system fosters the matrix metalloproeinases (MMP) secreted by transplanted stem cell reactions with MMP peptide grafted on the inner layer and destroys the structure of the inner hydrogel layer during the inflammatory storm. Meanwhile, the optimum concentration of the arginine‐glycine‐aspartate (RGD) peptide is also immobilized to the inner hydrogels to obtain more stem cells before arriving to the outer hydrogel layer. It is found that blocking Cripto‐1, which promotes embryonic stem cell differentiation to dopamine neurons, also accelerates this process in neural stem cells. More interesting is the fact that neural stem cell differentiation can be conducted in astrocyte‐differentiation medium without other treatments. In addition, the system can be adjusted according to the different parameters of transplanted stem cells and can expand on the clinical application of stem cells in the treatment of this neurological disorder.
Non-invasive measurement of HVPG using graph analysis of dynamic contrast-enhanced ultrasound: the CLEVER study
Authors: A. Berzigotti, F. Piscaglia, I. Amat-Roldan, R. Gilabert, B. Procopet, H. Stefanescu, I. Bilbao, V. Sansone, G. Allegretti, S. Lens, G.P.J. Carlos, J. Bosch
Journal: Journal of Hepatology (2018)
Increased Reticulon 3 (RTN3) Leads to Obesity and Hypertriglyceridemia by Interacting With Heat Shock Protein Family A (Hsp70) Member 5 (HSPA5)
Authors: Rong Xiang, Liang-liang Fan, Hao Huang, Ya-qin Chen, Wanxia He, Shuai Guo, Jing-Jing Li, Jie-yuan Jin, Ran Du, Riqiang Yan, Kun Xia
Journal: Circulation (2018)

Background: Reticulon 3 (RTN3) is an endoplasmic reticulum protein that has previously been shown to play a role in neurodegenerative diseases, but little is known about its role in lipid metabolism. Methods: Obese patients (n=149), hypertriglyceridemic patients (n=343), and healthy control subjects (n=84) were enrolled to assess their levels of RTN3. To explore the pathophysiological roles of RTN3 in the control of lipid metabolism, we used transgenic mice overexpressing the wild-type human RTN3 gene, the RTN3-null transgenic mouse model, and multiple Caenorhabditis legans strains for molecular characterization. The underlying mechanisms were studied with 3T3L1 cell cultures in vitro. Results: We report that overexpressed RTN3 in mice induces obesity and higher accumulation of triglycerides. Increased RTN3 expression is also found in patients with obesity and hypertriglyceridemia. We reveal that RTN3 plays critical roles in regulating the biosynthesis and storage of triglycerides and in controlling lipid droplet expansion. Mechanistically, RTN3 regulates these events through its interactions with heat shock protein family A (Hsp70) member 5, and this enhanced interaction increases sterol regulatory element-binding protein 1c and AMP-activated kinase activity. Conclusions: This study provides evidence for a role of RTN3 in inducing obesity and triglyceride accumulation and suggests that inhibiting the expression of RTN3 in fat tissue may be a novel therapeutic approach to treat obesity and hypertriglyceridemia.
Zika Virus Selectively Kills Aggressive Human Embryonal CNS Tumor Cells <i>In Vitro</i> and <i>In Vivo</i>
Authors: Carolini Kaid, Ernesto Goulart, Luiz C. Caires-Júnior, Bruno H.S. Araujo, Alessandra Soares-Schanoski, Heloisa M.S. Bueno, Kayque A. Telles-Silva, Renato M. Astray, Amanda F. Assoni, Antônio F.R. Júnior, Daniella C. Ventini, Ana L.P. Puglia, Roselane P. Gomes, Mayana Zatz, Oswaldo K. Okamoto
Journal: Cancer Research (2018)

Zika virus (ZIKV) is largely known for causing brain abnormalities due to its ability to infect neural progenitor stem cells during early development. Here, we show that ZIKV is also capable of infecting and destroying stem-like cancer cells from aggressive human embryonal tumors of the central nervous system (CNS). When evaluating the oncolytic properties of Brazilian Zika virus strain (ZIKVBR) against human breast, prostate, colorectal, and embryonal CNS tumor cell lines, we verified a selective infection of CNS tumor cells followed by massive tumor cell death. ZIKVBR was more efficient in destroying embryonal CNS tumorspheres than normal stem cell neurospheres. A single intracerebroventricular injection of ZIKVBR in BALB/c nude mice bearing orthotopic human embryonal CNS tumor xenografts resulted in a significantly longer survival, decreased tumor burden, fewer metastasis, and complete remission in some animals. Tumor cells closely resembling neural stem cells at the molecular level with activated Wnt signaling were more susceptible to the oncolytic effects of ZIKVBR Furthermore, modulation of Wnt signaling pathway significantly affected ZIKVBR-induced tumor cell death and viral shedding. Altogether, these preclinical findings indicate that ZIKVBR could be an efficient agent to treat aggressive forms of embryonal CNS tumors and could provide mechanistic insights regarding its oncolytic effects.Significance: Brazilian Zika virus strain kills aggressive metastatic forms of human CNS tumors and could be a potential oncolytic agent for cancer therapy. Cancer Res; 78(12); 3363-74. ©2018 AACR.
β-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway
Authors: Yonglin Chen, Xinshou Ouyang, Rafaz Hoque, Irma Garcia-Martinez, Muhammad Nadeem Yousaf, Sarah Tonack, Stefan Offermanns, Laurent Dubuquoy, Alexandre Louvet, Philippe Mathurin, Veronica Massey, Bernd Schnabl, Ramon Alberola Bataller, Wajahat Zafar Mehal
Journal: Journal of Hepatology (2018)
Implications of the New USPSTF Prostate Cancer Screening Recommendation—Attaining Equipoise
Authors: Richard M. Hoffman
Journal: JAMA Internal Medicine (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Targeting Galectin-1 Impairs Castration-Resistant Prostate Cancer Progression and Invasion
Authors: Tsung-Chieh Shih, Ruiwu Liu, Chun-Te Wu, Xiaocen Li, Wenwu Xiao, Xiaojun Deng, Sophie Kiss, Ting Wang, Xiao-Jia Chen, Randy Carney, Hsing-Jien Kung, Yong Duan, Paramita M. Ghosh, Kit S. Lam
Journal: Clinical Cancer Research (2018)

Abstract Purpose: The majority of patients with prostate cancer who are treated with androgen-deprivation therapy (ADT) will eventually develop fatal metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no effective durable therapies for patients with mCRPC. High expression of galectin-1 (Gal-1) is associated with prostate cancer progression and poor clinical outcome. The role of Gal-1 in tumor progression is largely unknown. Here, we characterized Gal-1 functions and evaluated the therapeutic effects of a newly developed Gal-1 inhibitor, LLS30, in mCRPC. Experimental Design: Cell viability, colony formation, migration, and invasion assays were performed to examine the effects of inhibition of Gal-1 in CRPC cells. We used two human CRPC xenograft models to assess growth-inhibitory effects of LLS30. Genome-wide gene expression analysis was conducted to elucidate the effects of LLS30 on metastatic PC3 cells. Results: Gal-1 was highly expressed in CRPC cells, but not in androgen-sensitive cells. Gal-1 knockdown significantly inhibited CRPC cells' growth, anchorage-independent growth, migration, and invasion through the suppression of androgen receptor (AR) and Akt signaling. LLS30 targets Gal-1 as an allosteric inhibitor and decreases Gal-1–binding affinity to its binding partners. LLS30 showed in vivo efficacy in both AR-positive and AR-negative xenograft models. LLS30 not only can potentiate the antitumor effect of docetaxel to cause complete regression of tumors, but can also effectively inhibit the invasion and metastasis of prostate cancer cells in vivo. Conclusions: Our study provides evidence that Gal-1 is an important target for mCRPC therapy, and LLS30 is a promising small-molecule compound that can potentially overcome mCRPC. Clin Cancer Res; 24(17); 4319–31. ©2018 AACR.
Verification of staging systems and treatment algorithms for hepatocellular carcinoma: perspectives from a Japanese field practice
Authors: S. Ogasawara, Y. Ooka, M. Inoue, T. Chiba, E. Suzuki, M. Yokoyama, T. Maeda, T. Wakamatsu, K. Kobayashi, S. Kiyono, M. Nakamura, T. Saito, S. Nakamoto, S. Yasui, A. Tawada, M. Arai, H. Maruyama, S. Kuboki, M. Miyazaki, M. Ohtsuka, N. Kato
Journal: Journal of Hepatology (2018)
In COPD, new use of long-acting bronchodilators was linked to CV events at ≤ 30 days, but not &gt; 30 days
Authors: Matthew B. Stanbrook
Journal: Annals of Internal Medicine (2018)

Source Citation Wang MT, Liou JT, Lin CW, et al. Association of cardiovascular risk with inhaled long-acting bronchodilators in patients with chronic obstructive pulmonary disease: a nested case–control study. JAMA Intern Med. 2018;178:229-38. 29297057
Sixty seconds on . . . the WannaCry cyberattack
Authors: Susan Mayor
Journal: BMJ (2018)

Although the NHS has learnt lessons from the WannaCry cyberattack on 12 May 2017, trusts need to do more to improve cybersecurity and introduce strategies to take action quickly “when, and not if, there is a further attack.” This was the conclusion of a new Public Accounts Committee report,1 which said that the attack, which affected 80 of 236 NHS trusts across England and a further 603 NHS organisations, …
Evolution of Darwin’s Peloric Gloxinia (Sinningia speciosa) Is Caused by a Null Mutation in a Pleiotropic TCP Gene
Authors: Yang Dong, Jing Liu, Peng-Wei Li, Chao-Qun Li, Tian-Feng Lü, Xia Yang, Yin-Zheng Wang
Journal: Molecular Biology and Evolution (2018)

Unlike most crops, which were domesticated through long periods of selection by ancient humans, horticultural plants were primarily domesticated through intentional selection over short time periods. The molecular mechanisms underlying the origin and spread of novel traits in the domestication process have remained largely unexplored in horticultural plants. Gloxinia (Sinningia speciosa), whose attractive peloric flowers influenced the thoughts of Darwin, have been cultivated since the early 19th century, but its origin and genetic basis are currently unknown. By employing multiple experimental approaches including genetic analysis, genotype–phenotype associations, gene expression analysis, and functional interrogations, we showed that a single gene encoding a TCP protein, SsCYC, controls both floral orientation and zygomorphy in gloxinia. We revealed that a causal mutation responsible for the development of peloric gloxinia lies in a 10-bp deletion in the coding sequence of SsCYC. By combining genetic inference and literature searches, we have traced the putative ancestor and reconstructed the domestication path of the peloric gloxinia, in which a 10-bp deletion in SsCYC under selection triggered its evolution from the wild progenitor. The results presented here suggest that a simple genetic change in a pleiotropic gene can promote the elaboration of floral organs under intensive selection pressure.
Trump promises to reduce drug prices but drops campaign promises
Authors: Janice Hopkins Tanne
Journal: BMJ (2018)

President Donald Trump has outlined measures to reduce the prices US consumers pay for prescription drugs through a program called American Patients First,1 but he did not follow through on two campaign promises.

During his campaign Trump had promised to allow the government to negotiate drug prices for the Medicare insurance program, which provides drugs for about 60 million older people, and to allow US consumers to import drugs from Canada. Stock prices of drug and healthcare companies immediately rose after the new announcement.2

The United States had the world’s highest per capita spending on pharmaceutical drugs in 2015 …
Exposure to passive smoking and rheumatoid arthritis risk: results from the Swedish EIRA study
Authors: Anna Karin Hedström, Lars Klareskog, Lars Alfredsson
Journal: Annals of the Rheumatic Diseases (2018)

Introduction Smoking has consistently been associated with increased risk of developing rheumatoid arthritis (RA). The aim of this study was to estimate the influence of passive smoking on the risk of developing anti-cyclic citrullinated peptide antibodies (ACPA)-positive and ACPA-negative RA. Methods A population-based case–control study using incident cases of RA was performed in Sweden, and the study population in this report was restricted to include never-smokers (589 cases, 1764 controls). The incidence of RA among never-smokers who had been exposed to passive smoking was compared with that of never-smokers who had never been exposed, by calculating the OR with a 95% CI employing logistic regression. Results No association was observed between exposure to passive smoking and RA risk (OR 1.0, 95% CI 0.8 to 1.2 for ACPA-positive RA, and OR 0.9, 95% CI 0.7 to 1.2, for ACPA-negative RA). No suggestion of a trend between duration of passive smoking and RA risk was observed. Discussions No association was observed between exposure to passive smoking and RA risk, which may be explained by a threshold below which no association between smoke exposure and RA occurs.
Abstract 20371: Non-Cardiomyocyte MicroRNA-34a Mediates Dysregulation of Angiogenesis in RV Failure
Authors: Sushma Reddy, Dong-Qing Hu, Mingming Zhao, Gwanghyun Jung, Edda Spiekerkoetter, Elizabeth A Barnes, Giovanni Fajardo, Daniel Bernstein
Journal: Circulation (2016)

Introduction:  The right ventricle (RV) is uniquely at risk in patients with complex congenital heart disease (CHD) involving right-sided obstructive lesions. In the left ventricle (LV) angiogenesis is a key adaptation to pressure overload, induced during adaptive hypertrophy via Hif-1α and VEGF, and declining with LV failure. In contrast, early capillary rarefaction occurs in RV hypertrophy (RVH), the mechanism of which is unknown. We hypothesize that microRNA (miR) 34a is responsible for the attenuated angiogenic response in RVH and RV failure (RVF).   Methods:  Adult, male FVB mice were subject to pulmonary artery banding (PAB) to induce RVH and RVF and compared to sham-operated controls. In vitro miR overexpression studies using lipofectamine miR-34a and in vivo miR inhibition studies using LNA-antimiR-34a (25mg/kg IP) were performed. RNA and protein expression was evaluated from the RV free wall. Student’s t test was used for two group comparisons and Kaplan Meier for survival analysis. Data are presented as mean±SEM (*p   Results:  miR-34a is upregulated (6.5 fold) in RVH/RVF and is associated with capillary rarefaction (1.5±0.1 vs. 1.2±0.1*) and decreased VEGF signaling. miR-34a originates from fibroblasts and endothelial cells in RVH/RVF. miR-34a overexpression in endothelial cells induces cell senescence (10±1 vs. 30±4%*) by suppressing SIRT1 expression (1.8±0.5 vs. 0.8±0.1*), decreases proliferation (0.5±0.04 vs. 0.3±0.01*) and decreases tube formation by 50% via suppression of Hif-1α (0.9±0.1 vs. 0.5±0.02*), VEGF A (0.7±0.2 vs. 0.5±0.03*), VEGF B (0.4±0.1 vs. 0.1±0.01*) and VEGFR2. AntimiR-34a suppresses miR-34a in PAB, reverses the decrease in capillarity and VEGF, and improves survival half-time by 44%*. miR-34a is also increased in children with RVF (2-fold) and capillarity is decreased compared to those with RVH.   Conclusions:  Capillary rarefaction is a feature of RVH/RVF in murine models of CHD and children with CHD. Capillary rarefaction is due to the uncoupling of HIF-1α and VEGF signaling which maybe mediated by non-cardiomyocyte miR-34a. Inhibition of miR-34a rescues capillarity and delays the onset of heart failure thereby raising its potential for therapeutic manipulation and translation into clinical practice.
MPs criticise government’s child mental health plans as unambitious
Authors: Adrian O’Dowd
Journal: BMJ (2018)

The government’s plans to overhaul and improve young people’s mental health services are not ambitious enough and will not help most of those who need support, MPs on two influential select committees have said.

In a joint report published on 9 May,1 the education committee and health and social care committee were highly critical of a government green paper published in December 2017.2

The green paper pledged to implement various measures to improve mental health support for young people in England, backed by a £350m (€400m; $475m) investment. Proposals included encouraging every school and college to have a designated senior …