tbuckley/cabot-search huggingface dataset:
mTOR Inhibition Mitigates Enhanced mRNA Translation Associated with the Metastatic Phenotype of Osteosarcoma Cells <i>In Vivo</i>
Authors: James J. Morrow, Arnulfo Mendoza, Allyson Koyen, Michael M. Lizardo, Ling Ren, Timothy J. Waybright, Ryan J. Hansen, Daniel L. Gustafson, Ming Zhou, Timothy M. Fan, Peter C. Scacheri, Chand Khanna
Journal: Clinical Cancer Research (2016)

To successfully metastasize, tumor cells must respond appropriately to biological stressors encountered during metastatic progression. We sought to test the hypothesis that enhanced efficiency of mRNA translation during periods of metastatic stress is required for metastatic competence of osteosarcoma and that this metastasis-specific adaptation is amenable to therapeutic intervention.We employ novel reporter and proteomic systems that enable tracking of mRNA translation efficiency and output in metastatic osteosarcoma cells as they colonize the lungs. We test the potential to target mRNA translation as an antimetastatic therapeutic strategy through pharmacokinetic studies and preclinical assessment of the prototypic mTOR inhibitor, rapamycin, across multiple models of metastasis.Metastatic osteosarcoma cells translate mRNA more efficiently than nonmetastatic cells during critical stressful periods of metastatic colonization of the lung. Rapamycin inhibits translational output during periods of metastatic stress, mitigates lung colonization, and prolongs survival. mTOR-inhibiting exposures of rapamycin are achievable in mice using treatment schedules that correspond to human doses well below the MTDs defined in human patients, and as such are very likely to be tolerated over long exposures alone and in combination with other agents.Metastatic competence of osteosarcoma cells is dependent on efficient mRNA translation during stressful periods of metastatic progression, and the mTOR inhibitor, rapamycin, can mitigate this translation and inhibit metastasis in vivo Our data suggest that mTOR pathway inhibitors should be reconsidered in the clinic using rationally designed dosing schedules and clinical metrics related to metastatic progression. Clin Cancer Res; 22(24); 6129-41. ©2016 AACR.
P-280 Pembrolizumab versus physician-choice chemotherapy for previously treated patients with advanced/metastatic squamous or adenocarcinoma of the esophagus or Siewert I adenocarcinoma of the esophagogastric junction (EGJ): Randomized, phase 3 KEYNOTE-18
Authors: Doi Toshihiko, Bennouna Jaafar, Shen Lin, Enzinger Peter, Wang Ruixue, Csiki Ildiko, Koshiji Minori, Shah Manish
Journal: Annals of Oncology (2016)
Structural Basis for Plexin Activation and Regulation
Authors: Youxin Kong, Bert J.C. Janssen, Tomas Malinauskas, Vamshidhar R. Vangoor, Charlotte H. Coles, Rainer Kaufmann, Tao Ni, Robert J.C. Gilbert, Sergi Padilla-Parra, R. Jeroen Pasterkamp, E. Yvonne Jones
Journal: Neuron (2016)

Class A plexins (PlxnAs) act as semaphorin receptors and control diverse aspects of nervous system development and plasticity, ranging from axon guidance and neuron migration to synaptic organization. PlxnA signaling requires cytoplasmic domain dimerization, but extracellular regulation and activation mechanisms remain unclear. Here we present crystal structures of PlxnA (PlxnA1, PlxnA2, and PlxnA4) full ectodomains. Domains 1–9 form a ring-like conformation from which the C-terminal domain 10 points away. All our PlxnA ectodomain structures show autoinhibitory, intermolecular "head-to-stalk" (domain 1 to domain 4-5) interactions, which are confirmed by biophysical assays, live cell fluorescence microscopy, and cell-based and neuronal growth cone collapse assays. This work reveals a 2-fold role of the PlxnA ectodomains: imposing a pre-signaling autoinhibitory separation for the cytoplasmic domains via intermolecular head-to-stalk interactions and supporting dimerization-based PlxnA activation upon ligand binding. More generally, our data identify a novel molecular mechanism for preventing premature activation of axon guidance receptors.
Will we save the homeless mentally ill?
Authors: H R Lamb
Journal: American Journal of Psychiatry (1990)

Progress in alleviating the plight of the homeless mentally ill has been very slow and disappointing. After reviewing the needs of the homeless mentally ill, the author makes recommendations for immediate action. Extensive case management services should be implemented rather than simply discussed. All incompetent and/or dangerous or gravely disabled homeless mentally ill persons should be brought to hospitals, involuntarily if necessary. Cost-effective alternatives to hospitals with varying degrees of structure should be provided. Involuntary mechanisms such as conservatorship and outpatient commitment should be used when needed. The emphasis should be on timely transfer to acceptable treatment and living situations rather than waiting for the ideal.
T-Cell Receptor Vβ Repertoire Analysis in Patients with Chronic Idiopathic Neutropenia: Evidence for Presence of Predominant T-Cell Clones with Possible Pathogenetic Significance.
Authors: Helen A. Papadaki, Michael Spanoudakis, Kostas Stamatopoulos, Helen Koutala, Maria Velegraki, Maria Ximeri, George D. Eliopoulos
Journal: Blood (2007)
Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome
Authors: C Y Cher, G M K Leung, C H Au, T L Chan, E S K Ma, J P Y Sim, H Gill, A K W Lie, R Liang, K F Wong, L L P Siu, C S P Tsui, C C So, H W W Wong, S F Yip, H K K Lee, H S Y Liu, J S M Lau, T H Luk, C K Lau, S Y Lin, Y L Kwong, A Y H Leung
Journal: Blood Cancer Journal (2016)

Abstract Clinical outcome and mutations of 96 core-binding factor acute myeloid leukemia (AML) patients 18–60 years old were examined. Complete remission (CR) after induction was 94.6%. There was no significant difference in CR, leukemia-free-survival (LFS) and overall survival (OS) between t(8;21) ( N =67) and inv(16) patients ( N =29). Univariate analysis showed hematopoietic stem cell transplantation at CR1 as the only clinical parameter associated with superior LFS. Next-generation sequencing based on a myeloid gene panel was performed in 72 patients. Mutations in genes involved in cell signaling were associated with inferior LFS and OS, whereas those in genes involved in DNA methylation were associated with inferior LFS. KIT activation loop (AL) mutations occurred in 25 patients, and were associated with inferior LFS ( P =0.003) and OS ( P =0.001). TET2 mutations occurred in 8 patients, and were associated with significantly shorter LFS ( P =0.015) but not OS. Patients negative for KIT -AL and TET2 mutations ( N =41) had significantly better LFS ( P &lt;0.001) and OS ( P =0.012) than those positive for both or either mutation. Multivariate analysis showed that KIT -AL and TET2 mutations were associated with inferior LFS, whereas age ⩾40 years and marrow blast ⩾70% were associated with inferior OS. These observations provide new insights that may guide better treatment for this AML subtype.
New bone turnover measure is more accurate predictor of postmenopausal bone loss
Authors: Susan Mayor
Journal: BMJ (2016)

A new measure of bone turnover—bone balance—that assesses bone breakdown and formation across the whole skeleton, based on urine and blood samples, is a more accurate predictor of bone loss in postmenopausal women than measures of bone breakdown or formation alone, a US study has shown.1

One of the study authors, Albert Shieh, from the University of California, Los Angeles, said, “Researchers have previously shown that it is difficult to predict an individual’s bone loss by testing the blood or urine for proteins that reflect either bone breakdown or bone formation alone.

“Since …
US Dietary Recommendations
Authors: Randall S. Stafford
Journal: JAMA (2016)

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
Anticancer efficacy of the combination of low-dose cisplatin and trichostatin A or 5-aza-2’-deoxycytidine in ovarian cancer cells.
Authors: Fanliang Meng, Guigin Sun, Mei Zhong, Yanhong Yu, Molly Brewer
Journal: Journal of Clinical Oncology (2012)

e15563 Background: We investigated the combination of low dose cisplatin with histone deacetylase inhibitor trichostatin A and methyl transferase inhibitor 5-aza-2’-deoxycytidine to determine if these agents could improve the sensitivity of ovarian cancer cell lines to cisplatin. The goal was to improve efficacy and decrease the toxicity of conventional chemotherapy in human ovarian cancer. Methods: Two chemoresistant ovarian cancer cell lines HEY, SKOV3 and one immortalized cell line IOSE were were treated with increasing doses of each drug alone and in combination to determine optimal cytotoxicity at the lowest dose. Markers of adhesion, metastasis, proliferation, self renewal, and measures of epigenetic regulation were measured. Spheroids, treated with single and combination drugs, were measured for cell viability. SCID mice were injected with pretreated cells and with untreated cells and then treated sequentially. Results: TSA or 5-aza-2’-deoxycytidine combined with Cisplatin had a marked reduction in E-cadherin and N-cadherin (adhesion and migration), proliferation protein Akt and Akt-1, self-renewal markers Oct4/Nanog/Sox2, and the drug transporter ABCG2. DNA methylase, DNMT3a/3b, histone deacetylase HDAC1/2 and histone demethylase LSD1, measures of epigenetic regulation, were suppressed with combined treatment. Histone methylation markers H3K4 and H3K9 were regulated differentially, with the trimethyled-H3K9 significantly suppressed, suggesting bivalent chromatin regulation. Cisplatin/TSA suppressed spheroid formation, growth, and viability. Cisplatin/TSA suppressed tumorigenesis in SCID mice when cells were pretreated. Animals treated after tumor formation with epigenetic modifiers followed by cisplatin achieved significant tumor regression, suggesting that both approaches enhance anticancer effects. Conclusions: Our research suggests the combination of low dose cisplatin with epigenetic modifiers administered together or sequentially may be promising treatments for ovarian cancer with reduced toxicity and may reverse platinum resistance.
GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction
Authors: Pablo Alonso-Coello, Holger J Schünemann, Jenny Moberg, Romina Brignardello-Petersen, Elie A Akl, Marina Davoli, Shaun Treweek, Reem A Mustafa, Gabriel Rada, Sarah Rosenbaum, Angela Morelli, Gordon H Guyatt, Andrew D Oxman
Journal: BMJ (2016)

#### Summary points

Healthcare decision making is complex. Decision-making processes and the factors (criteria) that decision makers should consider vary for different types of decisions, including clinical recommendations, coverage decisions, and health system or public health recommendations or decisions.1 2 3 4 However, some criteria are relevant for all of these decisions, including the anticipated effects of the options being considered, the certainty of the evidence for those effects (also referred to as quality of evidence or confidence in effect estimates), and the costs and feasibility of the options. Decision makers must make judgments about each relevant factor, informed by the best evidence that is available to them.

Often, the processes that decision makers use, the criteria that they consider and the evidence that they …
Narrative Review: The U.S. Pharmacopeia and Model Guidelines for Medicare Part D Formularies
Journal: Annals of Internal Medicine (2006)

The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 includes a provision directing the Secretary of the U.S. Department of Health and Human Services to request that the U.S. Pharmacopeia (USP) develop a list of categories and classes (the USP Model Guidelines) that can be used by prescription drug plans in developing their formularies for the Part D prescription drug benefit. The Centers for Medicare & Medicaid Services (CMS) used the Model Guidelines and USP's related listing, termed the Formulary Key Drug Types, to evaluate prescription drug plan formularies submitted by prescription drug plan sponsors intending to provide the new Part D benefit. This article recounts how USP's all-volunteer Model Guidelines Expert Committee developed the USP Model Guidelines and Formulary Key Drug Types, working under a cooperative agreement with CMS in response to the Secretary's request. The Model Guidelines and Formulary Key Drug Types are updated annually to reflect advances in evidence-based medicine, thereby offering timely guidance to CMS and to prescription drug plans based on USP's demonstrated expertise in setting standards. *For members of the USP Model Guidelines Expert Committee and the U.S. Pharmacopeia staff who contributed to this manuscript, see Appendix 1.
P0237 : Hepatocellular carcinoma: Applied genomics to diagnostic and personalized therapy
Authors: S. Llerena, N. García, C. Rodriguez de Lope, L. Cereceda, L. Martin, C. Lopez, C. Cagigas, F. Castillo, A. Azueta, M.A. Piris, J.P. Vaqué, J. Crespo
Journal: Journal of Hepatology (2015)
Analysis of overall survival by number of radium-223 injections received in an international expanded access program (iEAP).
Authors: Fred Saad, Daniel Keizman, Joe M. O'Sullivan, Joan Carles, Manfred Wirth, Silke Gillessen, Camilla Thellenberg-Karlsson, Kurt Miller, Marcello Tucci, Giovanni Paganelli, Giuseppe Procopio, Jeremy Gratt, Monica Seger, Sten Nilsson, Daniel Heinrich
Journal: Journal of Clinical Oncology (2016)

5082 Background: In ALSYMPCA, 6 injections (inj) of radium-223 (Ra-223) at 50 kBq/kg v placebo, improved overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Early identification of pts likely to receive the planned 6 inj of radium-223 is important. Here are OS analyses by number of Ra-223 inj from iEAP and ALSYMPCA, including prognostic factors associated with 1-4 v 5-6 inj, respectively. Methods: The open-label, single-arm, phase 3b iEAP provided Ra-223 to bone-predominant mCRPC pts. OS was analyzed post hoc by number of Ra-223 inj (1-4 v 5-6) and compared with ALSYMPCA data. Stepwise logistic and stepwise Cox regression analyses of number of inj and OS, respectively, were done. Results: Baseline characteristics for iEAP v ALSYMPCA pts are presented (Table). In iEAP, median (med) OS was 6.3 mo in pts with 1-4 inj and not reached with 5-6 inj. In ALSYMPCA, med OS was 6.2 mo in pts with 1-4 inj and 17.9 mo with 5-6 inj. In a logistic regression analysis from iEAP, receipt of 5-6 inj was associated with less pain (none-mild v moderate-severe; P<.0001), lower ECOG score (0-1 v ≥2; P=.0081), lower PSA level (med <141 µg/L v ≥141 µg/L; P<.0001), and higher Hgb (≥10 g/dL v <10 g/dL; P=.0227) at baseline. Stepwise Cox regression analysis showed that 5-6 inj was associated with longer OS (P<.0001). Conclusions: These exploratory analyses suggest that pts with less pain, lower ECOG score, lower PSA level, and higher Hgb level at baseline are more likely to receive 5-6 Ra-223 inj. A prospective randomized trial is needed to confirm a causal relationship between number of inj and OS. Clinical trial information: NCT01618370. iEAP N=696 ALSYMPCA Ra-223 Arm N=599 1-4 inj, n (%) 5-6 inj, n (%) 1-4 inj, n (%) 5-6 inj, n (%) Baseline Characteristic 224 (32) 472 (68) 163 (27) 436 (73) Age, med (range), y 72 (45-91) 72 (48-94) 72 (49-88) 71 (49-90) Baseline moderate-severe pain, n (%) 75 (35)* 83 (18)* 96 (59)† 241 (55)† ECOG ≥2, n (%) 45 (20) 42 (9) 29 (18) 43 (10) Lab values, med (range) Hgb, g/dL 11 (8-16) 12 (9-18) 12 (9-15) 12 (9-16) PSA, µg/L 306 (0-9697) 97 (0-12150) 200 (8-5790) 122 (4-6026) ALP, U/L 215 (41-3440) 134 (19-4236) 291 (32-2819)‡ 181 (40-6431)‡ *BPI-SF pain scale; †WHO ladder pain score ≥2; ‡total ALP.
Soundings: Specialisation creep
Authors: Kevin Barraclough
Journal: BMJ (2005)

Over the past 15 years the service provided by our local hospitals has altered dramatically. Juniors are less visible and there are large numbers of new consultants. Mostly these changes have been beneficial. The old diagnosis, ubiquitous in elderly people, of someone with “a bit of heart failure and a chest infection” is less common, and not everyone who has a transient neurological episode has a “TIA.” Whereas back then you got the impression that the air around the patient was rarely disturbed by someone with more than three years' clinical experience, now it is definitely a consultant led service.

But these days overspecialisation, too, can be a bit of a bane. It was one of the vanities that the British doctor Richard Asher warned against a generation ago. The legions of new medical consultants, now bunched rather than single, have a tendency to further subsegregate themselves. Charlie now only does “solid organs,” so refers on to his colleague who does “tubular organs.” Weeks pass. “I saw your referral in the `white matter clinic' but will refer it on to my colleague in the `movement disorder clinic.'”

Is all this really necessary? In surgery I would like my knee replacement done by someone who does lots. But in medicine the patient is usually better served by clinical common sense than by super-specialist knowledge.

There is often a knee-jerk reaction for more specialisation. The National Institute for Health and Clinical Excellence decrees that no one should diagnose or manage Parkinson's except a specialist in Parkinson's. This is because everyone else gets it wrong—as they do with hypertension, heart failure, thyroid disease, and a myriad of other conditions. This is the expert's 50% rule: the rest of us get it wrong 50% of the time—and there are only 50% of the experts necessary for their subject. There is often some truth in the former. But what about the option of better education and integration—as works with diabetes or asthma? Who considers the spiral of on-referrals, or the patients with comorbidities who spend half their lives in multiple outpatient clinics? Excessive medicalisation and fragmentation of care are harmful as well.

Maybe we should ask, to paraphrase the old war slogan: “Is your sub-specialisation really necessary?” Or is it merely vanity?
MMY-3002: A Phase 3 Study Comparing Bortezomib-Melphalan-Prednisone (VMP) with Melphalan-Prednisone (MP) in Newly Diagnosed Multiple Myeloma.
Authors: J.F. San Miguel, R. Schlag, N. Khuageva, O. Shpilberg, M. Dimopoulos, M. Kropff, I. Spicka, M. Petrucci, O. Samoilova, A. Dmoszynska, K. Abdulkadyrov, R. Schots, B. Jiang, A. Palumbo, M. Mateos, K. Liu, A. Cakana, H. Van de Velde, P. Richardson
Journal: Blood (2007)
Fullerene/photosensitizer nanovesicles as highly efficient and clearable phototheranostics with enhanced tumor accumulation for cancer therapy
Authors: Mirong Guan, Jiechao Ge, Jingyi Wu, Guoqiang Zhang, Daiqin Chen, Wei Zhang, Ying Zhang, Toujun Zou, Mingming Zhen, Chunru Wang, Taiwei Chu, Xiaojuan Hao, Chunying Shu
Journal: Biomaterials (2016)

A novel phototheranostic platform based on tri-malonate derivative of fullerene C70 (TFC70)/photosensitizer (Chlorin e6, Ce6) nanovesicles (FCNVs) has been developed for effective tumor imaging and treatment. The FCNVs were prepared from amphiphilic TFC70-oligo ethylene glycol -Ce6 molecules. The developed FCNVs possessed the following advantages: (i) high loading efficiency of Ce6 (up to ∼57 wt%); (ii) efficient absorption in near-infrared light region; (iii) enhanced cellular uptake efficiency of Ce6 in vitro and in vivo; (iv) good biocompatibility and total clearance out from the body. These unique properties suggest that the as-prepared FCNVs could be applied as an ideal theranostic agent for simultaneous imaging and photodynamic therapy of tumor. This finding may provide a good solution to highly efficient phototheranostic applications based on fullerene derivatives fabricated nanostructures.
Exhaled Breath Isoprene Rises During Hypoglycemia in Type 1 Diabetes
Authors: Sankalpa Neupane, Robert Peverall, Graham Richmond, Tom P.J. Blaikie, David Taylor, Gus Hancock, Mark L. Evans
Journal: Diabetes Care (2016)

Hypoglycemia and/or fear of hypoglycemia are major challenges for many with type 1 diabetes (T1D), limiting ability to lower glycemia. Given anecdotal reports of domestic pets alerting owners to blood glucose changes, especially hypoglycemia (1), we hypothesized that volatile organic compounds (VOCs) in exhaled breath might change at low glucose.

We studied eight female nonsmoking participants with T1D (aged 46 ± 5 years, diabetes duration 23 ± 7 years, none treated with statins) twice using a single-blinded, computer code–randomized crossover design. An independent research ethics committee approved studies in advance, and subjects provided written consent. Using a stepped insulin clamp (Actrapid; Novo Nordisk, Crawley, U.K.; 0.3 mU/kg/min increasing to 1.5 mU/kg/min), on one occasion (STEP), arterialized plasma glucose (Yellow Springs Instrument 2300 STAT Plus Analyzer) was raised sequentially (7.1 ± 0.8, 8.7 ± 0.4, and 10.7 ± 0.1 mmol/L) then lowered with higher insulin infusion to 4.3 ± 0.3 and 2.8 ± …
Novel exosome-targeted T-cell-based vaccine counteracts T-cell anergy and converts CTL exhaustion in chronic infection via CD40L signaling through the mTORC1 pathway
Authors: Rong Wang, Aizhang Xu, Xueying Zhang, Jie Wu, Andrew Freywald, Jianqing Xu, Jim Xiang
Journal: Cellular and Molecular Immunology (2016)