tbuckley/cabot-search huggingface dataset:
Improving communication with older patients with cancer using geriatric assessment (GA): A University of Rochester NCI Community Oncology Research Program (NCORP) cluster randomized controlled trial (CRCT).
Authors: Supriya Gupta Mohile, Ronald M. Epstein, Arti Hurria, Charles E. Heckler, Paul Duberstein, Beverly E. Canin, Nikesha Gilmore, Megan Wells, Huiwen Xu, Eva Culakova, Lisa M. Lowenstein, Marie Anne Flannery, Allison Magnuson, Kah Poh Loh, Karen Michelle Mustian, Judith O. Hopkins, Jijun Liu, Nataliya Melnyk, Gary R. Morrow, William Dale
Journal: Journal of Clinical Oncology (2018)

LBA10003 Background: GA includes validated measures that assess age-related health domains (e.g., function, cognition) known to increase adverse outcomes. In this PCORI and NCI funded CRCT, we evaluated if providing a GA summary and recommendations for GA-guided interventions improves communication about age-related concerns for older patients (pts) with cancer. Methods: Pts aged ≥ 70 with advanced solid tumors or lymphoma and at least 1 impaired GA domain were enrolled. Oncology practices were randomized to intervention (oncologists received GA summary) or usual care (no summary provided). The primary outcomes were: 1) number of discussions about age-related concerns (the clinic visit after GA was audio-recorded and transcribed; 2 blinded coders evaluated quality of communication and plan for follow-up interventions) and 2) telephone surveys of patient satisfaction (modified Health Care Climate Questionnaire [HCCQ-age] scored 7-35). Outcomes were analyzed using linear mixed models with arm as the fixed effect, controlling for practice. Results: From 2014-17, 544 pts (295 in GA) were enrolled from 31 practices. There were no differences in demographics by arm (mean age 77 yrs; 49% female). More patients in usual care had impaired physical performance (96% vs 92%, p = 0.03) and social support (33% vs 25%, p = 0.05). In 530 evaluable pts, the overall mean number of discussions was 6.3 (SD: 4.0). The GA arm had 3.5 more discussions about age-related concerns (95%CI: 2.28-4.72, p = 10 -6 ; intraclass correlation coefficient [ICC] = 0.24) compared to usual care; of these, in the GA arm, 2.0 more discussions on average had higher quality communication (95%CI: 1.20-2.69; p = 6x10 -6 ) and 1.9 more led to interventions (95% CI: 1.14-2.73; p = 1.6x10 -5 ). The GA arm had significantly more discussions for almost all GA domains. In 511 pts with HCCQ-age, the mean score was 22.9 (SD 4.5); the score was 1.12 points higher in the GA arm (95%CI: 0.23-2.03; p = .027; ICC = 0.02). Conclusions: Providing a GA summary to oncologists increases the number and quality of discussions about age-related concerns and improves pt satisfaction. Clinical trial information: NCT02107443.
Wait Time for Hip Fracture Surgery and Mortality—Reply
Authors: Daniel Pincus, Bheeshma Ravi, Walter P. Wodchis
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Gold nanorods together with HSP inhibitor-VER-155008 micelles for colon cancer mild-temperature photothermal therapy
Authors: Xichuan Tang, Liwei Tan, Kun Shi, Jinrong Peng, Yao Xiao, Wenting Li, Lijuan Chen, Qian Yang, Zhiyong Qian
Journal: Acta Pharmaceutica Sinica B (2018)

Enhancing the heat-sensitivity of tumor cells provides an alternative solution to maintaining the therapeutic outcome of photothermal therapy (PTT). In this study, we constructed a therapeutic system, which was composed of methoxy-polyethylene-glycol-coated-gold-nanorods (MPEG-AuNR) and VER-155008-micelles, to evaluate the effect of VER-155008 on the sensitivity of tumor cells to heat, and further investigate the therapeutic outcome of MPEG-AuNR mediated PTT combined with VER-155008- micelles. VER-155008- micelles down-regulate the expression of heat shock proteins and attenuate the heat-resistance of tumor cell. The survival of HCT116 cells treated with VER-155008- micelles under 45 °C is equal to that treated with high temperature hyperthermia (55 °C) in vitro. Furthermore, we proved either the MPEG-AuNR or VER-155008- micelles can be accumulate in the tumor site by photoacoustic imaging and fluorescent imaging. In vivo anti-cancer evaluation showed that tumor size remarkably decreased (smaller than 100 mm3 or vanished) when treated with combing 45 °C mild PTT system, which contrasted to the tumor size when treated with individual 45 °C mild PTT (around 500 nm3) or normal saline as control (larger than 2000 nm3). These results proved that the VER-155008- micelles can attenuate the heat-resistance of tumor cells and enhance the therapeutic outcome of mild-temperature photothermal therapy.
Vex-seq: high-throughput identification of the impact of genetic variation on pre-mRNA splicing efficiency
Authors: Scott I. Adamson, Lijun Zhan, Brenton R. Graveley
Journal: Genome biology (2018)

Understanding the functional impact of genomic variants is a major goal of modern genetics and personalized medicine. Although many synonymous and non-coding variants act through altering the efficiency of pre-mRNA splicing, it is difficult to predict how these variants impact pre-mRNA splicing. Here, we describe a massively parallel approach we use to test the impact on pre-mRNA splicing of 2059 human genetic variants spanning 110 alternative exons. This method, called variant exon sequencing (Vex-seq), yields data that reinforce known mechanisms of pre-mRNA splicing, identifies variants that impact pre-mRNA splicing, and will be useful for increasing our understanding of genome function.
Abstract 13219: Adult Mammalian Hearts Restore Intrinsic Regenerative Capacity Through Signal Transducer and Activation of Transcription 3 in the Resolution Phase of Myocarditis
Authors: Akimitsu Miyawaki, Masanori Obana, Yusuke Mitsuhara, Aya Orimoto, Yusuke Nakayasu, Tomomi Yamashita, So-ichiro Fukada, Makiko Maeda, Yasushi Sakata, Hiroyuki Nakayama, Yasushi Fujio
Journal: Circulation (2016)

Background and Aims: It is widely accepted that mammalian cardiomyocytes can hardly proliferate in response to injury, which limits regeneration of the heart. On the contrary, spontaneous recovery in cardiac function is frequently observed in clinical settings of myocarditis. Therefore, we investigated the molecular mechanisms underlying the recovery from myocarditis with regard to cardiomyocyte proliferation using an experimental autoimmune myocarditis (EAM) model. Methods and Results: EAM was induced by immunizing 8 week old male BALB/c mice with α-myosin heavy chain twice. Three weeks after the first immunization (EAM3w), cardiac tissue was severely disrupted by infiltration of inflammatory cells, and substantial loss of cardiomyocytes was observed. However, cardiomyocytes displayed proliferative signature as demonstrated by increased expression of proliferative markers, i.e., Ki-67 and Aurora B, and BrdU incorporation at EAM3w, leading to dramatic tissue restoration at EAM5w. Consistently, the number of cardiomyocytes in the inflamed area was significantly increased at EAM5w compared to EAM3w. Additionally, we employed genetic cell fate mapping methods to trace pre-existing cardiomyocytes with YFP expression and found that pre-existing cardiomyocytes, rather than precursors/stem cells, were the source of proliferating cardiomyocytes at EAM3w. Immunoblot analyses for isolated cardiomyocytes demonstrated that signal transducer and activation of transcription 3 (STAT3), but not Akt or ERK, signaling was robustly activated in the inflamed heart, in consistence with upregulation of various IL-6 family cytokines. Conditional ablation of STAT3 in cardiomyocytes significantly suppressed cardiomyocyte proliferation at EAM3w without preventing the resolution of inflammation, resulting in impaired tissue restoration and cardiac dysfunction at EAM5w. Conclusions: Adult mammalian hearts restored intrinsic regenerative capacity in response to myocardial inflammation. STAT3 plays a critical role in cardiomyocyte proliferation in the recovery process from inflammation-induced cardiac damage.
Sixty seconds on . . . digitalisation of pharma
Authors: Ann Robinson
Journal: BMJ (2018)

It’s the new way to make drugs. Manufacturers, including the pharmaceutical industry, are increasingly automating production. Computers continually analyse multiple variables, predict errors, use machine learning to improve systems, and allow products to be modified. The aim of this “process analysis technology” is to get drug production right first time.

You’d be surprised. Take chimeric antigen receptor T cells; a novel form of immunotherapy offering potentially …
Non-Canonical Wnt-5a Compromises Endogenous Lung Repair In COPD
Authors: H. A. Baarsma, W. Skronska-Wasek, K. Mutze, F. Ciolek, G. John-Schuster, M. Dagouassat, A. Gunther, J. Boczkowski, R. Smits, A. Yildirim, M. Königshoff
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Reg proteins direct accumulation of functionally distinct macrophage subsets after myocardial infarction
Authors: Holger Lörchner, Yunlong Hou, Juan M Adrian-Segarra, Jennifer Kulhei, Julia Detzer, Stefan Günther, Praveen Gajawada, Henning Warnecke, Hans W Niessen, Jochen Pöling, Thomas Braun
Journal: Cardiovascular Research (2018)

Myocardial infarction (MI) causes a massive increase of macrophages in the heart, which serve various non-redundant functions for cardiac repair. The identities of signals controlling recruitment of functionally distinct cardiac macrophages to sites of injury are only partially known. Previous work identified Regenerating islet-derived protein 3 beta (Reg3β) as a novel factor directing macrophages to sites of myocardial injury. Herein, we aim to characterize functionally distinct macrophage subsets and understand the impact of different members of the Reg protein family including Reg3β, Reg3γ, and Reg4 on their accumulation in the infarcted heart. We have determined dynamic changes of three phenotypically distinct tissue macrophage subpopulations in the mouse heart after MI by flow cytometry. RNA sequencing and bioinformatics analysis identified inflammatory gene expression patterns in MHC-IIhi/Ly6Clo and MHC-IIlo/Ly6Clo cardiac tissue macrophages while Ly6Chi cardiac tissue macrophages are characterized by gene activities associated with healing and revascularization of damaged tissue. Loss- and gain-of-function experiments revealed specific roles of Reg proteins for recruitment of cardiac tissue macrophage subpopulations to the site of myocardial injury. We found that expression of Reg3β, Reg3γ, and Reg4 is strongly increased after MI in mouse and human hearts with Reg3β providing the lead, followed by Reg3γ and Reg4. Inactivation of the Reg3β gene prevented the increase of all types of cardiac tissue macrophages shortly after MI whereas local delivery of Reg3β, Reg3γ, and Reg4 selectively stimulated recruitment of MHC-IIhi/Ly6Clo and MHC-IIlo/Ly6Clo but repressed accumulation of Ly6Chi cardiac tissue macrophages. We conclude that distinct cardiac macrophage subpopulations are characterized by substantially different gene expression patterns reflecting their pathophysiological role after MI. We argue that sequential, local production of Reg proteins orchestrates accumulation of macrophage subsets, which seem to act in a parallel or partially overlapping rather than in a successive manner.
Precision medicine: Clinical outcomes including long-term survival according to the pathway targeted and treatment period–The IMPACT study.
Authors: Apostolia Maria Tsimberidou, David S. Hong, Jennifer J. Wheler, Gerald Steven Falchook, Aung Naing, Siqing Fu, Sarina Anne Piha-Paul, Filip Janku, Carrie Cartwright, Russell Broaddus, Graciela M. Nogueras-Gonzalez, Patrick Hwu, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2018)

LBA2553 Background: We evaluated the impact of pathway targeted and long-term follow-up of patients (pts) with refractory cancers referred to phase I trials. Methods: Pts referred to our program (2007-2013) had CLIA molecular testing. Pts treated with matched targeted therapy (MTT) vs. non-matched therapy (NMT) were analyzed. Results: Of 3,743 pts who had testing, 1,307 had ≥1 alteration and received therapy (MTT 711, NMT 596): med. age 57 yrs, range 16-86; 39% men; med. no. of prior therapies 4, range 0-16. The most common tumors were gastrointestinal 24.2%, gynecologic 19.4%, breast 13.5%, melanoma 11.9%, and lung 8.7%. Targeting MEK/RAF and RET pathways correlated with higher rates of CR/PR/SD≥6 months (mos), PFS and OS compared to others (all P &lt; .001) (Table). Plateau was noted in OS (start, 38 mos): 74 of 711 (10.4%) in the MTT (max 10.7+ yrs) vs. 24 of 596 (4%) in the NMT (max 6 yrs) group were alive (p &lt; .0001). In the MTT group, factors predicting longer PFS were non-PI3K pathway MTT (p &lt; .001), no liver metastases (p &lt; .001), PS &lt; 2 (p = .006), normal LDH (p &lt; .001) and albumin (p = .01) levels, and non-single agent therapy (p = .02). Factors predicting longer OS were non-PI3K pathway MTT (p &lt; .001), no liver metastases (p &lt; .001), PS &lt; 2 (p &lt; .001), normal LDH (p &lt; .001) and albumin (p = .001) levels, and normal PLT counts (p = .03). Conclusions: Outcomes were superior in pts matched to RET and MEK/RAF inhibitors. Factors predicting longer PFS and OS were identified. In the MTT group, 10.4% of patients had OS ≥ 38 mos, the plateau starting point. Clinical trial information: NCT00851032. [Table: see text]
Risk of Heroin Dependence in Newly Incident Heroin Users
Authors: Olga J. Santiago Rivera, Jennifer R. Havens, Maria A. Parker, James C. Anthony
Journal: JAMA Psychiatry (2018)

Risk of Heroin Dependence in Newly Incident Heroin UsersSome 30 to 50 US residents die of heroin overdoses each day. 1 By comparison, an estimated 300 to 520 individuals start heroin use each day. 2 For first-time users, these odds of overdose death might seem remote.For this reason, clinicians and public health practitioners deserve more compelling evidence to share with people who contemplate trying heroin.Seeking reproducible results via 15 US epidemiological samples, we estimate how often newly incident heroin users become dependent on heroin.Estimation focuses on the first 1 to 12 months after first heroin use.Methods | Each year from 2002 to 2016, the National Survey on Drug Use and Health (NSDUH) research staff drew a new US probability sample of noninstitutionalized civilians age 12 years and older.In each year, staff assessed heroin use and dependence using DSM-IV criteria via institutional review board-approved protocols for recruitment and standardized computer-assisted self-interviews.
Abstract 16238: Intracellular Targeting of Hsp70 for Myocardial Cytoprotection After an Infarction
Authors: Takashi Tanimoto, Artiom D Petrov, Takehiro Nakahara, Hideki Kawai, Robert Nishimura, Richard H Weisbart, Grace Chan, Richard A Richieri, Glenn T Reynolds, Robert Newcomb, Partho P Sengupta, H. W Strauss, Jagat Narula, Missag H Parseghian
Journal: Circulation (2015)

Background: Myocardial cells affected by an infarction endure oxidative stress during reperfusion. It has been suggested that the induction of a heat-shock protein 70 (Hsp72) in myocardial cells counteracts oxidative stress and improves post-ischemic contractile recovery, but clinically relevant methods of inducing Hsp70 in myocardium have yet to be successfully employed. Methods: Mab 3E10 binds extracellular nucleosides, a target that is quite accessible in damaged tissues, allowing 3E10 to penetrate still viable cells through an equilibrative nucleoside salvage pathway. We have developed the scFv fragment of the cell-penetrating 3E10 as an intracellular transporter to deliver exogenous Hsp70. Primary cardiomyocytes exposed to H 2 O 2 were incubated in vitro with a 3E10 scFv-Hsp70 fusion (Fv-Hsp) to demonstrate cytoprotection against oxidative damage. In addition, rabbits were subjected to occlusion of the left coronary artery followed by reperfusion of the heart and intravenous injection of Fv-Hsp (20 mg) or a molar equivalent of a sham control. SPECT imaging and tissue gamma counting of 99m Tc-labeled annexin V was used to visualize the infarct volume and quantify cell death, respectively. Results: In vitro , 30-40% fewer dead cells were observed with Fv-Hsp treatment 30 minutes after exposure, even when 3E10 scFv was added as a competitor (p&lt;0.0003). Reduced to oxidized glutathione ratios were greater in treated cells suggesting less oxidative stress. Measurement of annexin uptake (% injected dose of 99m Tc /gram tissue) revealed Fv-Hsp-treated rabbits had less uptake compared to controls (ANOVA); 49% less in the entire area of risk (p&lt;0.0001) and 43% less at the heart apex (p=0.01) where the maximum damage was expected/occurred. The annexin-verified damage was substantially higher in the control rabbits injected either with PBS or with a molar equivalent of 3E10 scFv. Echocardiographic left ventricular ejection fraction demonstrated recovery of significantly superior contractility in Fv-Hsp-treated rabbits 3 hours after reperfusion compared with no recovery in control rabbits. Conclusion: Targeted accumulation of Hsp70 at infarcted tissue is achievable and worth investigating further for clinical cytoprotection post-infarction.
IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN
Authors: Paul Diefenhardt, Anna Nosko, Malte A. Kluger, Johannes V. Richter, Claudia Wegscheid, Yasushi Kobayashi, Gisa Tiegs, Samuel Huber, Richard A. Flavell, Rolf A.K. Stahl, Oliver M. Steinmetz
Journal: Journal of the American Society of Nephrology (2018)

Background Th17 cells are central pathogenic mediators of autoimmune disease, including many forms of GN. IL-10 receptor signaling (IL-10R) in regulatory T cells (Tregs) has been implicated in the downregulation of Th17 cells, but the underlying molecular mechanisms and functional relevance of this process remain unclear. Methods We generated mice with Treg-specific IL-10Ra deficiency and subjected these mice to nephrotoxic serum–induced nephritis as a model of crescentic GN. Immune responses and Treg phenotypes were extensively analyzed. Results Compared with controls, mice with IL-10Ra −/− Tregs showed a spontaneously overshooting Th17 immune response. This hyper-Th17 phenotype was further boosted during GN and associated with aggravated renal injury. Notably, abrogation of IL-10Ra signaling in Tregs increased dendritic cell activation and production of Th17-inducing cytokines. In contrast, Treg trafficking and expression of chemokine receptor CCR6 remained unaffected, indicating mechanisms of Th17 control, differing from those of previously identified CCR6 + Treg17 cells. Indeed, the capacity for direct in vitro suppression of Th17 responses by IL-10Ra −/− Tregs was significantly impaired. As underlying pathology, analyses conducted in vitro and in vivo using double-fluorescent reporter mice revealed strikingly decreased IL-10 production by IL-10Ra −/− Tregs. To assess, whether reduced IL-10 could explain the hyper Th17 phenotype, competitive cotransfer experiments were performed. Supporting our concept, IL-10Ra −/− T cells differentiated into Th17 cells at much higher frequencies than wild type T cells did during GN. Conclusions IL-10R engagement optimizes Treg-mediated suppression of Th17 immunity. We hypothesize a feed-forward loop, in which IL-10Ra signaling reinforces IL-10 secretion by Tregs which potently controls Th17 development via direct and indirect mechanisms. IL-10R thus may be a promising therapeutic target for the treatment of GN.
Negative selection in tumor genome evolution acts on essential cellular functions and the immunopeptidome
Authors: Luis Zapata, Oriol Pich, Luis Serrano, Fyodor A. Kondrashov, Stephan Ossowski, Martin H. Schaefer
Journal: Genome biology (2018)

Natural selection shapes cancer genomes. Previous studies used signatures of positive selection to identify genes driving malignant transformation. However, the contribution of negative selection against somatic mutations that affect essential tumor functions or specific domains remains a controversial topic.Here, we analyze 7546 individual exomes from 26 tumor types from TCGA data to explore the portion of the cancer exome under negative selection. Although we find most of the genes neutrally evolving in a pan-cancer framework, we identify essential cancer genes and immune-exposed protein regions under significant negative selection. Moreover, our simulations suggest that the amount of negative selection is underestimated. We therefore choose an empirical approach to identify genes, functions, and protein regions under negative selection. We find that expression and mutation status of negatively selected genes is indicative of patient survival. Processes that are most strongly conserved are those that play fundamental cellular roles such as protein synthesis, glucose metabolism, and molecular transport. Intriguingly, we observe strong signals of selection in the immunopeptidome and proteins controlling peptide exposition, highlighting the importance of immune surveillance evasion. Additionally, tumor type-specific immune activity correlates with the strength of negative selection on human epitopes.In summary, our results show that negative selection is a hallmark of cell essentiality and immune response in cancer. The functional domains identified could be exploited therapeutically, ultimately allowing for the development of novel cancer treatments.
Voluntary Opioid Tapering—Reply
Authors: Beth D. Darnall, Maisa S. Ziadni, Richard L. Stieg
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