tbuckley/cabot-search huggingface dataset:
Abstract B12: Investigating the specificity of the small molecule inhibitor INI-43 for Kpnβ1 in cancer cells
Authors: Sarah Carden, Pauline van der Watt, Patrizia Lavia, Virna Leaner
Journal: Cancer Research (2017)

Abstract Karyopherin β1 (Kpnβ1) is the major nuclear import protein involved in the shuttling of cargo proteins and mRNAs into the cell nucleus. Recent studies have found that Kpnβ1 levels are significantly upregulated in cancer cells, and that targeted inhibition of Kpnβ1 with siRNA results in reduced proliferation and the induction of apoptosis, suggesting that Kpnβ1 is important for cancer cell survival. Inhibitor of Nuclear Import-43 (INI-43) is a small molecule inhibitor identified in our laboratory as having the potential to interfere with the nuclear import function of Kpnβ1. It has been shown to inhibit the nuclear localization of both Kpnβ1 and known Kpnβ1 cargoes such as NFκB and NFAT, as well as inhibit the proliferation of cancer cells of different tissue origins. This study aimed to investigate the specificity of INI-43 for Kpnβ1 by performing experiments to determine whether expression of exogenous Kpnβ1-GFP was able to rescue cells from the effects of INI-43 treatment. Results show that Kpnβ1 overexpression rescues cell viability, as well as the inhibitory effects that INI-43 has on the nuclear import of NFκB/p65 and NFAT. Overexpression of Kpnβ1 also rescues cells from an INI-43 induced G2/M cell cycle block. In addition, treatment of cells with INI-43 enhances degradation of Kpnβ1, but not of other members of the Karyopherin family. These results suggest that the small molecule inhibitor INI-43 is acting, at least in part, by targeting Kpnβ1. Citation Format: Sarah Carden, Pauline van der Watt, Patrizia Lavia, Virna Leaner. Investigating the specificity of the small molecule inhibitor INI-43 for Kpnβ1 in cancer cells [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B12.
Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic nsclc (IMPOWER150)
Authors: M. Reck, M.A. Socinski, F. Cappuzzo, F. Orlandi, D. Stroyakovskii, N. Nogami, D. Rodríguez-Abreu, D. Moro-Sibilot, C.A. Thomas, F. Barlesi, G. Finley, C. Kelsch, A. Lee, S. Coleman, Y. Shen, M. Kowanetz, A. Lopez-Chavez, A. Sandler, R. Jotte
Journal: Annals of Oncology (2017)
Morning Enzymatic Activity of DPP-4 Is Differentially Altered by Sleep Loss in Women and Men
Authors: Frida H. Rångtell, Felix Schmidt, Josefine Würfel, Swathy Karamchedu, Peter Andersson, Heike Vogel, Christian Benedict
Journal: Diabetes Care (2017)

No study to date has investigated whether the activity of circulating dipeptidyl peptidase 4 (DPP-4) is affected by sleep loss. DPP-4 is an enzyme that catalyzes a variety of important physiological processes in humans by cleavage of, e.g., the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (1). Both chronic sleep loss and an increased activity of DPP-4 have been implicated in the development of several diseases, including type 2 diabetes (1–4).

Twenty-five normal-weight healthy adults (aged 18–28 years; 13 women, using oral monophasic contraceptives) participated in two in-laboratory experimental conditions separated by about 1 week: one night of regular sleep (scheduled 2230–0630) and one night of total sleep loss, in a counterbalanced order. In the morning (∼0730), fasting blood samples were taken to measure the enzymatic activity of DPP-4, as previously described (3). The effects of sleep loss on DPP-4 activity were examined by using a linear mixed model (restricted maximum likelihood method; scaled identity as covariance matrix) with the fixed factors experimental condition (sleep/total sleep deprivation) and sex (women/men), as well as their interaction. All participants gave written informed consent, and the study was approved by the regional ethics review board …
Ban evergreening and restricting generics to reduce drug prices, says US academy
Authors: Bob Roehr
Journal: BMJ (2017)

The pharmaceutical industry should be restricted from “evergreening” drugs to extend their patents and “pay-to-delay”—where drug makers pay generics manufacturers not to enter the market—should be banned, a report from a US think tank has said.

The report from the National Academies of Science, Engineering, and Medicine on making drugs more affordable also recommended reducing the number of drugs that can be prescribed through Medicare and restricting direct to consumer advertising.

The academies said that it did not believe that its 27 recommendations will significantly affect market incentives for the industry to continue to develop new drugs.

“The cost of biopharmaceuticals now represents about 17% of the total cost of healthcare in America,” said Norman Augustine, chairman of the group …
Abstract 30: Small molecule profiling uncovers the landscape of combinatorial PI3K inhibitor responses in HNSCC
Authors: Nicole L. Michmerhuizen, Elizabeth Leonard, Micah Harris, Susan K. Foltin, Aditi Kulkarni, Thomas E. Carey, Carol R. Bradford, Jiang Hui, J. Chad Brenner
Journal: Clinical Cancer Research (2017)

Abstract Recent sequencing studies of head and neck squamous cell carcinomas (HNSCCs) have identified the phosphatidylinositol 3-kinase (PI3K) pathway as the most frequently mutated oncogenic pathway in this cancer type. Although activating mutations or amplification in PIK3CA (the gene encoding the catalytic subunit of PI3K) are frequently observed in HNSCC, monotherapies targeting PI3K have shown limited clinical efficacy. We tested a panel of more than 20 patient-derived oral cavity squamous cell carcinoma (OCSCC) cell lines, which were profiled by Nimblegen V3 exome sequencing. Despite PIK3CA copy number amplification and/or mutations, we observed resistance to PI3K inhibitors in these models. Of six inhibitors tested, the only agents with marginal effects were alpha-isoform selective and pan-PI3K agents; these inhibitors, despite on-target and downstream activity, did not cause an appreciable reduction in cell viability when administered at submicromolar concentrations. We hypothesized that other oncogenic pathways, such as the Ras-MEK-ERK pathway, might still be functional in the presence of PI3K inhibitors and serve as compensatory mechanisms of resistance to these drugs. In order to more fully characterize other novel co-dependent pathway in PI3K inhibitor resistant HNSCC models, we have developed a high-throughput screening approach that utilizes a resazurin cell viability assay. This approach is an unbiased means of testing ~1400 inhibitors as monotherapies and in combination with alpha-isoform selective PI3K inhibitor HS-173 and pan-PI3K inhibitor BKM120 and has been utilized in several in vitro models of OCSCC to date. Testing of additional cellular models and validation of “hits” from this screen, which are drugs that are effective in combination but not as monotherapies, may identify additional resistance mechanisms and are currently ongoing. Developing a better understanding of these combination therapies and the patients in which they might be most effective may lead to improved prognosis for this disease. Citation Format: Nicole L. Michmerhuizen, Elizabeth Leonard, Micah Harris, Susan K. Foltin, Aditi Kulkarni, Thomas E. Carey, Carol R. Bradford, Jiang Hui, J. Chad Brenner. Small molecule profiling uncovers the landscape of combinatorial PI3K inhibitor responses in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 30.
Comment on Hakvoort et al.
Authors: Natalia Qvartskhava, Cheng Jun Jin, Boris Görg, Dieter Häussinger
Journal: Hepatology (2017)

View this article online at wileyonlinelibrary.com. Potential conflict of interest: Nothing to report. TO THE EDITOR We read with great interest the article by Hakvoort and colleagues published in the January issue of hepatology.1 The findings of the study corroborate our previous data showing that glutamine synthetase in liver is essential for systemic ammonia clearance.2 Hakvoort and colleagues claim that knockdown of glutamine synthetase in the liver induces pericentral steatosis. However, this was not found in our knockout mouse model.2 One possible explanation for this discrepancy could be that Hakvoort and colleagues used Alfp‐Cre+ mice for liver‐specific Cre recombinase expression. From the literature it is known that Alfp‐Cre+ mice per se develop liver steatosis. Therefore, it was recommended to use Alfp‐Cre+ mice that do not express the floxed gene as appropriate controls.4 Unfortunately, in the study of Hakvoort et al., Alfp‐Cre–/Glulfl/fl mice were used as controls.1
Hepatitis C transmission from seropositive, nonviremic donors to non–hepatitis C liver transplant recipients
Authors: Khurram Bari, Keith Luckett, Tiffany Kaiser, Tayyab Diwan, Madison Cuffy, Michael R. Schoech, Kamran Safdar, Jason T. Blackard, Senu Apewokin, Flavio Paterno, Kenneth E. Sherman, Stephen D. Zucker, Nadeem Anwar, Shimul A. Shah
Journal: Hepatology (2017)

Breakthroughs in hepatitis C virus (HCV) treatment and rising rates of intravenous drug use have led to an increase in the number of organ donors who are HCV antibody-positive but serum nucleic acid test (NAT)-negative. The risk of HCV transmission from the liver grafts of these donors to recipients is unknown. To estimate the incidence of HCV transmission, we prospectively followed 26 consecutive HCV antibody-negative (n = 25) or NAT-negative (n = 1) transplant recipients who received a liver graft from donors who were HCV antibody-positive but serum NAT-negative between March 2016 and March 2017. HCV transmission was considered to have occurred if recipients exhibited a positive HCV PCR test by 3 months following transplantation. Drug overdose was listed as the cause of death in 15 (60%) of the donors. One recipient died 18 days after transplantation from primary graft nonfunction and was excluded. Of the remaining 25 recipients, HCV transmission occurred in 4 (16%), at a median follow-up of 11 months, all from donors who died of drug overdose. Three of these patients were treated with direct-acting antiviral therapy, with two achieving a sustained virologic response and one an end-of-treatment response. One patient with HCV transmission died after a complicated postoperative course and did not receive antiviral therapy.In this prospective cohort of non-HCV liver recipients receiving grafts from HCV antibody-positive/NAT-negative donors, the incidence of HCV transmission was 16%, with the highest risk conferred by donors who died of drug overdose; given the availability of safe and highly effective antiviral therapies, use of such organs could be considered to expand the donor pool. (Hepatology 2018;67:1673-1682).
Associations of pet ownership with biomarkers of ageing: population based cohort study
Authors: G David Batty, Paola Zaninotto, Richard G Watt, Steven Bell
Journal: BMJ (2017)

To examine the prospective relation between animal companionship and biomarkers of ageing in older people.Analyses of data from the English Longitudinal Study of Ageing, an ongoing, open, prospective cohort study initiated in 2002-03.Nationally representative study from England.8785 adults (55% women) with a mean age of 67 years (SD 9) at pet ownership assessment in 2010-11 (wave 5).Established biomarkers of ageing in the domains of physical, immunological, and psychological function, as assessed in 2012-13 (wave 6).One third of study members reported pet ownership: 1619 (18%) owned a dog, 1077 (12%) a cat, and 274 (3%) another animal. After adjustment for a range of covariates, there was no evidence of a clear association of any type of pet ownership with walking speed, lung function, chair rise time, grip strength, leg raises, balance, three markers of systemic inflammation, memory, or depressive symptoms.In this population of older adults, the companionship of creatures great and small seems to essentially confer no relation with standard ageing phenotypes.
Abstract 16879: The Release of Mir-29b into the Coronary Circulation Correlates With Thin-cap-fibroatheroma, Positive Coronary Remodeling and Decreased Plaque Fibrosis in Patients With Stable Cad
Authors: Roberta De Rosa, Niels Boeckel, David Leistner, Sophia Reis, Claudia Thome, Tino Roexe, Stephan Fichtlscherer, Stefanie Dimmeler, Andreas M Zeiher
Journal: Circulation (2016)

Introduction:  Circulating microRNAs (miRs) can be measured in the blood and may reflect pathophysiologically relevant processes. MiR29b plays a crucial role in matrix degradation and tissue fibrosis. We hypothesized that circulating levels of miR29b may be associated with coronary atherosclerotic plaque morphology and arterial remodeling in patients with CAD.   Methods:  Coronary atherosclerotic plaque phenotype and extent of remodeling were assessed by optical coherence tomography (OCT) in 47 patients with stable CAD undergoing coronary angiography. Circulating miR29b levels were measured in blood samples simultaneously obtained from the aortic bulb (Ao) and coronary venous sinus (CVS), and the transcoronary concentration gradients were calculated in order to ensure the coronary release of miR29b.   Results:  CVS levels of miR29b were significantly and inversely correlated with the extent of plaque fibrosis (r=-0.38, p=0.008), but not with other phenotypic features of coronary plaques. Likewise, miR29b levels in the CVS directly correlated with the extent of outward remodeling of coronary atherosclerotic plaques (r=0.373, p=0.010). Most importantly, transcoronary concentration gradients of miR29b were significantly related to the presence of thin-cap-fibroatheroma (TCFA, r=0.364, p=0.008) and to the extent of positive remodelling of coronary plaques (r= 0.308, p=0.035). In order to establish whether circulating miR29b levels reflect pathophysiological mechanisms within the coronary arterial wall, we measured circulating levels of ADAMTS7, a secreted disintegrin and metalloproteinase involved in arterial remodeling and an experimentally well-established target of miR29b. Indeed, CVS concentrations of miR29b were closely and inversely correlated with ADAMTS7 levels (r=-0.64, p   Conclusions:  The release of miR29b into the coronary circulation is associated with decreased plaque fibrosis, increased extent of TCFA and arterial remodeling of coronary atherosclerotic plaques. The close inverse correlation with its target, ADAMTS7, indicates that circulating levels of miR29b reflect pathophysiologically processes in the atherosclerotic wall and may be useful as prognostic biomarkers in patients with CAD.
A Peculiar Adenocarcinoma
Authors: Ameet Patel, Anjan Patel
Journal: JAMA Oncology (2017)

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 Oncology 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 Oncology journal
HSP27-Mediated Extracellular and Intracellular Signaling Pathways Synergistically Confer Chemoresistance in Squamous Cell Carcinoma of Tongue
Authors: Guopei Zheng, Zhijie Zhang, Hao Liu, Yan Xiong, Liyun Luo, Xiaoting Jia, Cong Peng, Qiong Zhang, Nan Li, Yixue Gu, Minying Lu, Ying Song, Hao Pan, Jinbao Liu, Wanqing Liu, Zhimin He
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Squamous cell carcinoma of tongue (SCCT) is the most common type of oral cavity carcinoma. Chemoresistance in SCCT is common, and the underlying mechanism remains largely unknown. We aimed to identify key molecules and signaling pathways mediating chemoresistance in SCCT. Experimental Design: Using a proteomic approach, we found that the HSP27 was a potential mediator for chemoresistance in SCCT cells. To further validate this role of HSP27, we performed various mechanistic studies using in vitro and in vivo models as well as serum and tissue samples from SCCT patients. Results: The HSP27 protein level was significantly increased in the multidrug-resistant SCCT cells and cell culture medium. Both HSP27 knockdown and anti-HSP27 antibody treatment reversed chemoresistance. Inversely, both HSP27 overexpression and recombinant human HSP27 protein treatment enhanced chemoresistance. Moreover, chemotherapy significantly induced HSP27 protein expression in both SCCT cells and their culture medium, as well as in tumor tissues and serum of SCCT patients. HSP27 overexpression predicts a poor outcome for SCCT patients receiving chemotherapy. Mechanically, extracellular HSP27 binds to TLR5 and then activates NF-κB signaling to maintain SCCT cell survival. TLR5 knockdown or restored IκBα protein level disrupts extracellular HSP27-induced NF-κB transactivation and chemoresistance. Moreover, intracellular HSP27 binds to BAX and BIM to repress their translocation to mitochondrion and subsequent cytochrome C release upon chemotherapy, resulting in inhibition of the mitochondrial apoptotic pathway. Conclusions: HSP27 plays a pivotal role in chemoresistance of SCCT cells via a synergistic extracellular and intracellular signaling. HSP27 may represent a potential biomarker and therapeutic target for precision SCCT treatment. Clin Cancer Res; 24(5); 1163–75. ©2017 AACR.
Salivary Gland Activity Obscures Mandibular Metastasis of Prostate Carcinoma on 68Ga–Prostate-Specific Membrane Antigen PET
Authors: Thabo Lengana, Ismaheel Lawal, Tebatso Boshomane, Kehinde Ololade, Florette Reyneke, Chimbabantiu Kaoma, Neo Mokgoro, Mariza Vorster, Mike Sathekge
Journal: Clinical Nuclear Medicine (2017)

We report a case of a 65-year-old man with prostate cancer; his treatment history included radical prostatectomy followed by radiation therapy and subsequent androgen deprivation therapy for more than 5 years. He currently presented with a history of rising prostate-specific antigen and complained of jaw aches. Ga-prostate-specific membrane antigen PET/CT study performed for suspected biochemical recurrence demonstrated vertebral lesions and lesion in his jaw. Subsequent biopsy of jaw lesion demonstrated prostate cancer metastases.
Plans to boost cancer workforce are “scratching the surface,” says radiology leader
Authors: Abi Rimmer
Journal: BMJ (2017)

Plans to increase the number of clinical radiologists in the NHS by nearly 300 by 2021 do not go far enough and will not improve cancer care, the president of the Royal College of Radiologists has warned.

Nicola Strickland was responding to Health Education England’s (HEE) Cancer Workforce Plan , published on 5 December.1 While she welcomed its focus on the cancer workforce, she said that the NHS would still fail to fulfil the ambitions of the English cancer strategy “by a wide margin.”

In the plan HEE said that it would boost radiology training places by 35 a …
A Multigene Signature Based on Cell Cycle Proliferation Improves Prediction of Mortality Within 5 Yr of Radical Nephrectomy for Renal Cell Carcinoma
Authors: Todd M. Morgan, Rohit Mehra, Placede Tiemeny, J. Stuart Wolf, Shulin Wu, Zaina Sangale, Michael Brawer, Steven Stone, Chin-Lee Wu, Adam S. Feldman
Journal: European Urology (2017)
P1328 : RITPBC: B-cell depleting therapy (RITUXIMAB) as a treatment for fatigue in primary biliary cirrhosis: study protocol for a randomised controlled trial
Authors: J.L. Newton, D. Howel, J. Palmer, J. Isaacs, J. Qian, J. Wilkinson, A. Blamire, A. Floudas, D.E. Jones, L. Jopson
Journal: Journal of Hepatology (2015)
Rigorous qualitative research in sports, exercise and musculoskeletal medicine journals is important and relevant
Authors: Susan C Slade, Shilpa Patel, Martin Underwood, Jennifer L Keating
Journal: British Journal of Sports Medicine (2017)

Qualitative research enables inquiry into processes and beliefs through exploration of narratives, personal experiences and language.1 Its findings can inform and improve healthcare decisions by providing information about peoples’ perceptions, beliefs, experiences and behaviour, and augment quantitative analyses of effectiveness data. The results of qualitative research can inform stakeholders about facilitators and obstacles to exercise, motivation and adherence, the influence of experiences, beliefs, disability and capability on physical activity, exercise engagement and performance, and to test strategies that maximise physical performance.

High-quality qualitative research can also enrich interpretation of quantitative analyses and be pooled in metasyntheses for evaluation of strength of evidence; contribute to the development and implementation of clinical decision support aids, outcome measures and clinical practice guidelines2 such as the UK National Institute for Health and Care Excellence guidelines (www.nice.org.uk) and Ottawa Panel guidelines for knee osteoarthritis3; and inform health and social care.4

In 2000, just 0.6% of papers in 170 general medical, mental health …
Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses
Authors: Annette B. Vogel, Laura Lambert, Ekaterina Kinnear, David Busse, Stephanie Erbar, Kerstin C. Reuter, Lena Wicke, Mario Perkovic, Tim Beissert, Heinrich Haas, Stephen T. Reece, Ugur Sahin, John S. Tregoning
Journal: Molecular Therapy (2017)

New vaccine platforms are needed to address the time gap between pathogen emergence and vaccine licensure. RNA-based vaccines are an attractive candidate for this role: they are safe, are produced cell free, and can be rapidly generated in response to pathogen emergence. Two RNA vaccine platforms are available: synthetic mRNA molecules encoding only the antigen of interest and self-amplifying RNA (sa-RNA). sa-RNA is virally derived and encodes both the antigen of interest and proteins enabling RNA vaccine replication. Both platforms have been shown to induce an immune response, but it is not clear which approach is optimal. In the current studies, we compared synthetic mRNA and sa-RNA expressing influenza virus hemagglutinin. Both platforms were protective, but equivalent levels of protection were achieved using 1.25 μg sa-RNA compared to 80 μg mRNA (64-fold less material). Having determined that sa-RNA was more effective than mRNA, we tested hemagglutinin from three strains of influenza H1N1, H3N2 (X31), and B (Massachusetts) as sa-RNA vaccines, and all protected against challenge infection. When sa-RNA was combined in a trivalent formulation, it protected against sequential H1N1 and H3N2 challenges. From this we conclude that sa-RNA is a promising platform for vaccines against viral diseases.Graphical abstract
Stress-induced unfolded protein response contributes to Zika virus–associated microcephaly
Authors: Ivan Gladwyn-Ng, Lluís Cordón-Barris, Christian Alfano, Catherine Creppe, Thérèse Couderc, Giovanni Morelli, Nicolas Thelen, Michelle America, Bettina Bessières, Férechté Encha-Razavi, Maryse Bonnière, Ikuo K. Suzuki, Marie Flamand, Pierre Vanderhaeghen, Marc Thiry, Marc Lecuit, Laurent Nguyen
Journal: Nature Neuroscience (2017)