tbuckley/cabot-search huggingface dataset:
IRF3 promotes adipose inflammation and insulin resistance and represses browning
Authors: Manju Kumari, Xun Wang, Louise Lantier, Anna Lyubetskaya, Jun Eguchi, Sona Kang, Danielle Tenen, Hyun Cheol Roh, Xingxing Kong, Lawrence Kazak, Rasheed Ahmad, Evan D. Rosen
Journal: Journal of Clinical Investigation (2016)

The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other dysfunctional adaptations in adipose tissue. Cellular and secreted factors promote the inflammatory milieu of obesity, but the transcriptional pathways that drive these processes are not well described. Although the canonical inflammatory transcription factor NF-κB is considered to be the major driver of adipocyte inflammation, members of the interferon regulatory factor (IRF) family may also play a role in this process. Here, we determined that IRF3 expression is upregulated in the adipocytes of obese mice and humans. Signaling through TLR3 and TLR4, which lie upstream of IRF3, induced insulin resistance in murine adipocytes, while IRF3 knockdown prevented insulin resistance. Furthermore, improved insulin sensitivity in IRF3-deficient mice was associated with reductions in intra-adipose and systemic inflammation in the high fat-fed state, enhanced browning of subcutaneous fat, and increased adipose expression of GLUT4. Taken together, the data indicate that IRF3 is a major transcriptional regulator of adipose inflammation and is involved in maintaining systemic glucose and energy homeostasis.
California’s new assisted suicide law is challenged in court
Authors: Owen Dyer
Journal: BMJ (2016)

Five southern California physicians and a Christian doctors’ organization have filed suit to strike down the state’s new law on physician assisted suicide, which has been in force since last week.

The plaintiffs include two oncologists, a neurologist, two palliative care specialists, and the American Academy of Medical Ethics, which has around 15 000 physician members across the United States, including 600 in California.

In papers filed with Riverside County Superior Court they argued that the End of Life Option Act “violates the equal protection and due process guarantees of the California Constitution in that it fails to make rational distinctions between [eligible patients] with supposedly terminal diseases, and the vast majority of Californians …
Case 19-2016
Authors: Mayra E. Lorenzo, Joi B. Carter, Jeffrey A. Barnes, Rosalynn M. Nazarian
Journal: New England Journal of Medicine (2016)

A 65-year-old man with end-stage renal disease and a history of syphilis presented with a leg injury and a diffuse pruritic rash. A recent serologic test had been positive for human T-lymphotropic virus type 1. A diagnostic procedure was performed.
Provocative testing of the pulmonary circulation: advances and unresolved issues
Authors: Edmund M. Lau, Robert Naeije
Journal: European Respiratory Journal (2016)

In this issue of the European Respiratory Journal , Oliveira et al. [1] from Harvard Medical School (Boston, MA, USA) report on rapid recovery of pulmonary vascular pressures after maximum incremental cycling exercise. The authors combined right heart catheterisation with concurrent cardiopulmonary exercise test in 95 patients referred for unexplained dyspnoea. 36 patients had precapillary pulmonary hypertension (PH) during exercise, defined by the authors as displaying a peak exercise mean pulmonary artery pressure (mPAP) ≥30 mmHg, a peak wedged pulmonary artery pressure (PAWP) <20 mmHg and a peak pulmonary vascular resistance (PVR) ≥1.5 Wood units (WU). 28 patients had postcapillary PH during exercise defined by a peak PAWP ≥20 mmHg. 31 matched controls with normal resting mPAP were selected based on a maximum oxygen uptake ≥80% predicted in the absence of exercise PH based on the aforementioned criteria. Workload and oxygen uptake at the ventilatory threshold and at peak exercise were lower in the exercise PH patients, which confirm the relevance of exercise pulmonary haemodynamic measurements in unexplained dyspnoea. However, most of the exercise-induced increase in PAWP and mPAP was reversed within 2 min of recovery. The important message is that pulmonary haemodynamics have to be measured during, but not after, an exercise stress test for the diagnosis of exercise PH. Expert consensus standardisation of provocative testing of the pulmonary circulation is needed <http://ow.ly/4nsNbU>
Authors’ reply to Rafi
Authors: Joel G Ray, Emily Bartsch
Journal: BMJ (2016)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Authors’ reply to Rafi Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Acute Myocardial Infarction
Authors: Gautam R. Shroff
Journal: Annals of Internal Medicine (2015)

Letters21 July 2015Acute Myocardial InfarctionGautam R. Shroff, MB, BSGautam R. Shroff, MB, BSFrom Hennepin County Medical Center and University of Minnesota, Minneapolis, Minnesota.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L15-5113-2 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:Whereas my article explored the ramifications of a unique diagnostic code for type 2 MI, Dr. Singh and colleagues focus on indiscriminate use of troponin assays for noncardiac symptoms. As they point out, an uncritical and unscrutinized pattern of troponin measurement can lead to an unintended cascade of downstream testing that can be medically unnecessary, expensive, time-consuming, and potentially anxiety-provoking for the patient and therefore should be discouraged and avoided. Most cardiologists would agree that the management of a patient with an elevated troponin level obtained out of the clinical context for which troponin measurement was fundamentally designed ...Reference1. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al; Joint ESC/ACCF/AHA/WHF Task Force for Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60:1581-98. [PMID: 22958960] doi:10.1016/j.jacc.2012.08.001 CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From Hennepin County Medical Center and University of Minnesota, Minneapolis, Minnesota.Disclosures: The author has disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=M14-2259. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoAcute Myocardial Infarction: What's in a Name? Gautam R. Shroff Acute Myocardial Infarction: What's in a Name? Gautam R. Shroff Acute Myocardial Infarction Sukhchain Singh , Amandeep Singh , and Sandeep Khosla Acute Myocardial Infarction Sukhchain Singh , Amandeep Singh , and Sandeep Khosla Metrics 21 July 2015Volume 163, Issue 2Page: 152KeywordsAcute myocardial infarctionConflicts of interestDisclosureExtrapolationIschemiaTroponin ePublished: 21 July 2015 Issue Published: 21 July 2015 Copyright & PermissionsCopyright © 2015 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Perspectives on psychotherapy with the elderly
Authors: G D Cohen
Journal: American Journal of Psychiatry (1981)

There is probably no area in which there has been more misinformation, inconsistency, and stereotyping than in discussions about the role and efficacy of psychotherapy with the elderly. In this paper the author attempts to lay the foundation for an improved perspective on psychotherapeutic work with older people. He reviews concepts, techniques, process, and historical views as they relate to psychotherapy in later life.
Radiocarbon dating reveals minimal collagen turnover in both healthy and osteoarthritic human cartilage
Authors: Katja M. Heinemeier, Peter Schjerling, Jan Heinemeier, Mathias B. Møller, Michael R. Krogsgaard, Tomas Grum-Schwensen, Michael M. Petersen, Michael Kjaer
Journal: Science Translational Medicine (2016)

The poor regenerative capacity of articular cartilage presents a major clinical challenge and may relate to a limited turnover of the cartilage collagen matrix. However, the collagen turnover rate during life is not clear, and it is debated whether osteoarthritis (OA) can influence it. Using the carbon-14 ((14)C) bomb-pulse method, life-long replacement rates of collagen were measured in tibial plateau cartilage from 23 persons born between 1935 and1997 (15 and 8 persons with OA and healthy cartilage, respectively). The (14)C levels observed in cartilage collagen showed that, virtually, no replacement of the collagen matrix happened after skeletal maturity and that neither OA nor tissue damage, per se, influenced collagen turnover. Regional differences in (14)C content across the joint surface showed that cartilage collagen located centrally on the joint surface is formed several years earlier than collagen located peripherally. The collagen matrix of human articular cartilage is an essentially permanent structure that has no significant turnover in adults, even with the occurrence of disease.
P105 Identification of ‘large’ alveolar macrophages and pulmonary intra-vascular macrophages in COPD patients: Abstract P105 Table 1
Authors: AK Ravi, J Plumb, S Mason, G Booth, J Vestbo, SD Singh
Journal: Thorax (2015)

<h3>Background</h3> A population of small macrophages with increased pro-inflammatory activity has been reported in COPD sputum. We have investigated macrophage size in the alveoli of COPD patients using immunofluorescence for the markers CX3CR1 and CD68. <h3>Methods</h3> Formalin fixed paraffin embedded tissue blocks were obtained from an area of the lung as far distal to the tumour as possible from COPD patients, smokers (S) and healthy non-smokers (HNS) undergoing lung resection for lung carcinoma. Sections were labelled with an anti-CX3CR1 antibody and detected using an Alexafluor conjugated secondary antibody. Immunohistochemical detection of CD68 (enzymatic non-biotin amplification technique) confirmed the macrophage phenotype of CX3CR1+ cells. <h3>Results</h3> All CX3CR1+ cells expressed CD68. The diameters of COPD macrophages were greater than controls (Table 1). Intravascular CX3CR1+CD68<sup>+</sup> macrophages were observed in COPD and S (Table 1). <h3>Conclusion</h3> Increased macrophage size in COPD may be linked to altered function. Pulmonary intravascular macrophages have been observed in other mammalian species and may promote pulmonary inflammation through direct release of cytokines into the pulmonary circulation.
Phase 1 Clinical Results of the ZUMA-1 (KTE-C19-101) Study: A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of Anti-CD19 CAR T Cells (KTE-C19) in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)
Authors: Frederick L. Locke, Sattva S. Neelapu, Nancy L Bartlett, Tanya Siddiqi, Julio C. Chavez, Chitra M. Hosing, Armin Ghobadi, Lihua E. Budde, Lynn Navale, Jeff S. Aycock, Jeff Wiezorek, William Y. Go
Journal: Blood (2015)
What information do patients need about medicines
Authors: David Dickinson, D. K. Raynor, James G. Kennedy, Silvia Bonaccorso, Jeffrey L. Sturchio
Journal: BMJ (2004)

People have a broad range of information preferences that may differ at different times and for different reasons. They may want more information than prescribers want to give?for example, about the possi ble side effects of a drug.14 They may place different interpretations on information about likely risks, and they may question the benefits of taking a drug when they are not greatly concerned by the medical problem that the treatment is meant to solve. They may well rate the practicalities of how to take a drug higher than the details of the inert components of the pills or the drug manufacturer's address. In interviewing people about drug treatments,5 6 we have consistently noticed that people respond to four essential aspects of a drug: Side effects What it does and what it's for Do's and don'ts How to take it.
Increased ATP Requirement for Activity of and Complex Formation by DNA Topoisomerase II from Human Leukemic CCRF-CEM Cells Selected for Resistance to Teniposide
Authors: M K Danks, C A Schmidt, D A Deneka, W T Beck
Journal: Cancer Communications (1989)

We showed previously that nuclear extracts from teniposide (VM-26)-resistant sublines of the human leukemic cell line, CCRF-CEM, exhibited decreased DNA topoisomerase II activity and ability to form drug-stabilized covalent protein-DNA complexes (Danks et al., Biochemistry 27:8861-8869; 1988). In the present study, we found that nuclear extracts of these sublines (approximately 50- and approximately 140-fold resistant to VM-26) required 2 and 8 times more adenosine 5'-triphosphate (ATP), respectively, to achieve half-maximal stimulation of unknotting activity compared to extracts from the sensitive cells. When novobiocin, a competitive inhibitor of ATP binding to topoisomerase II, was included in the reaction, this ATP requirement increased 2.5- to 4-fold with the CEM cell extracts and 3.5- to 12-fold with the resistant cell extracts. ATP produced a dose-dependent increase in VM-26-stabilized topoisomerase II-DNA covalent complexes with nuclear extracts from all three cell lines. Extracts from resistant cells, however, formed 40-80% fewer complexes than those from sensitive cells. A similar decrease was seen with 4'-[(9-acridinyl)amino]methanesulphon-m-anisidide, to which the cells are cross-resistant. With nuclear extracts from sensitive cells, the tetralithium salt of 5'-adenylylimidodiphosphate (AMP-PNP), a nonhydrolyzable analog of ATP, was as effective as ATP in promoting the formation of drug-stabilized enzyme-DNA complexes. With extracts from the resistant cell nuclei, however, AMP-PNP was about half as effective as ATP in promoting complex formation. Our results demonstrate that the effect of ATP on strand passing activity of and drug-stabilized complex formation by topoisomerase II is decreased in the nuclear extracts from the drug-resistant cells and suggest a possible basis for this form of drug resistance.
P-085 The efficacy of colonoscopy in patients with early gastric cancer who underwent endoscopic submucosal dissection
Authors: D.H. Kang, H.W. Kim, C.W. Choi, S.B. Park, S.J. Kim, H.S. Nam, H.H. Jang, W.H. Choi, Y.H. Choi, K.J. Oh
Journal: Annals of Oncology (2016)
Economic evaluation of the TAX 324 trial comparing docetaxel plus cisplatin and 5-fluorouracil (TPF) versus standard treatment with cisplatin and 5-fluorouracil (PF) as induction chemotherapy followed by concurrent chemoradiation therapy in locally advanced squamous cell carcinoma of the head and neck (SCCHN)
Authors: A. Parthan, M. R. Posner, C. Brammer, P. Beltran, J. Jansen
Journal: Journal of Clinical Oncology (2007)

6079 Background: The TAX 324 phase III trial showed that induction chemotherapy with TPF followed by chemoradiotherapy improves survival and time to progression in patients with locally advanced SCCHN compared with PF [Posner MR, et al. ASCO 2006]. A Markov state-transition model was developed to estimate the cost-effectiveness of TPF. Methods: The Markov model includes four health states (based on WHO criteria for measuring objective response): stable, responsive, progressive disease, and death. TAX 324 efficacy data were used to derive transition probabilities between health states. Adverse event rates were also derived from TAX 324. Data for resource utilization and costs from a UK perspective were derived from the literature and clinician inputs from an advisory board. The global score of the Health Related Quality of Life Questionnaire Core-30 (QLQ-C30) was mapped to the EQ-5D in order to derive utilities and quality adjusted life years (QALYs). Results: A patient in the TPF arm survived longer versus PF (5.4 vs. 2.7 years). Comparison of TPF vs. PF resulted in an incremental gain of 2.7 life years and 2.1 QALYs. The incremental discounted costs/QALY gained for TPF vs. PF was £1,988/QALY, which is below the £20,000 cost-effectiveness threshold suggested by NICE as a guide to the acceptability of a technology. At this threshold, there is a 96.1% probability that TPF is cost-effective compared with PF. Conclusion: Docetaxel, when given as induction chemotherapy followed by concurrent chemoradiotherapy in combination with cisplatin and 5-fluorouracil (TPF), leads to a substantial increase in life expectancy, and is cost-effective compared with PF for locally advanced SCCHN. No significant financial relationships to disclose.
β-Lactams against Tuberculosis — New Trick for an Old Dog?
Authors: Andreas H Diacon, Lize van der Merwe, Marinus Barnard, Florian von Groote-Bidlingmaier, Christoph Lange, Alberto L García-Basteiro, Esperança Sevene, Lluís Ballell, David Barros-Aguirre
Journal: New England Journal of Medicine (2016)

To the Editor: New treatments are needed to combat the worldwide increase in resistance to antituberculosis drugs.1 The outlook for patients with tuberculosis who do not show a response to the key agents used in treatment — isoniazid, rifampin, fluoroquinolones, and aminoglycosides — is grim and reminiscent of the plight of patients with cancer in the era before chemotherapy.2 New agents are emerging, but the obligatory evaluation of their safety and efficacy in combination with other antituberculosis and antiretroviral agents slows the pace of progress. Repurposing or combining commercially available products may offer a faster track to new antituberculosis regimens. . . .
Phase Ib study of PF-05082566 in combination with pembrolizumab in patients with advanced solid tumors.
Authors: Anthony W. Tolcher, Mario Sznol, Siwen Hu-Lieskovan, Kyriakos P. Papadopoulos, Amita Patnaik, Drew W. Rasco, Donna Di Gravio, Bo Huang, Dhiraj Gambhire, Ying Chen, Nuzhat Pathan, Kai Wang, Emmett V. Schmidt, Laura Quan Man Chow
Journal: Journal of Clinical Oncology (2016)

3002 Background: PF-05082566 (PF-2566) is a fully human IgG2 monoclonal antibody (mAb) that binds to human 4-1BB (CD137). Pembrolizumab is a humanized IgG4/kappa isotype mAb targeting PD-1. This Phase 1 study was designed to assess the overall safety, pharmacokinetics, pharmacodynamics (PD) and anti-tumor activity of this novel combination in patients with advanced solid tumors. Methods: Patients received PF-2566 (0.45 to 5.0 mg/kg) and pembrolizumab (2 mg/kg) intravenously on day 1 of 21-day cycles. Maximum tolerated dose was defined as the highest combination dose with a dose limiting toxicity (DLT) rate <25% during the first 2 cycles per the TITE-CRM method. Results: Tumor types treated included non-small cell lung cancer (NSCLC) (n=6), renal cell carcinoma (RCC) (n=5), head & neck (H&N) (n=3), pancreatic (n=2), thyroid (n=2), and one each of small cell lung cancer (SCLC), colon, sarcoma, thymoma, and melanoma. All patients received between 0 and 9 lines of previous anticancer treatment. No DLTs were reported and 6 patients remain on therapy in this ongoing study. The number of cycles patients have received across all doses ranged from 2 to 19. Treatment emergent adverse events (AEs) were mostly Grade 1/2, with no apparent relationship between increasing doses of PF-2566 and frequency or severity of AEs. No patients discontinued study medication due to treatment related AEs. No substantial changes in inflammatory cytokines or its association with clinical symptoms were noted. The PF-2566 concentrations were above the preclinical predicted efficacious concentration and appeared to increase with increasing doses. Circulating PD responses (lymphocyte subsets) were observed across all doses of PF-2566. Six out of 23 treated patients (26%, 95% CI: 10.2%, 48.4%) had confirmed complete (CR) or partial response (PR) per RECIST 1.1: CR in SCLC (n=1), PRs in RCC (n=2), NSCLC (n=1), H&N (n=1) and anaplastic thyroid (n=1). Median duration of response has not been reached. Conclusions: The safety and efficacy profile of PF-2566 in doses up to 5.0 mg/kg in combination with pembrolizumab supports further investigation in patients with advanced solid tumors. Clinical trial information: NCT02179918.
A phase I/II study of an antitumor vaccination using α (1,3) galactosyltransferase expressing allogeneic tumor cells in pancreatic cancer
Authors: Y. Oyama, M. Talamonti, M. Mulcahy, E. Gonda, R. K. Burt, N. N. Vahanian, R. Bell, L. Tennant, W. J. Ramsey, T. Adrian, C. Link
Journal: Journal of Clinical Oncology (2007)

13512 Background: Prognosis of pancreatic cancer remains poor despite surgical resection. In a phase I trial, we examined the safety and feasibility of antitumor vaccination in Pts with surgically resected pancreatic cancer with two irradiated genetically altered human pancreatic cancer cell lines engineered to express xenotransplantation antigens by retroviral transfer of the murine a(1,3) galactosyltrasferase gene {HyperAcute Pancreatic Cancer Vaccine (HAPa)}. Methods: Pts had undergone complete surgical resection for stage IA to IIB pancreatic adenocarcinoma, ECOG PS≤2, no immunosuppressive drug use and an adequate organ function were eligible. Various adjuvant treatments were allowed prior to the start of HAPa according to the institutional preferences (5FU/radiation, cisplatin/gemicitabine followed by 5FU/radiation, 5FU/radiation followed by gemicitabine or gemicitabine/capecitabine/bevasizumab/radiation). Six Pts were scheduled to receive 12 every two week-intradermal injections (initial priming dose followed by 11 boost doses). The first cohort (Pts 1–3) was to receive at lower doses (2 × 10 8 cells priming and 1 x 10 8 cells boost). The second cohort (Pts 4–6) was to receive at higher doses (5 x 10^8 cells priming and 3 x 10^8 cells boost). Toxicity was assessed using the CTC v3.0. Results: To date, 6 Pts, 3 males, 3 females, median age 59 (range 50–66) were treated. Two Pts completed all 12 injections. Others received 9, 6, 6 and 4 injections, respectively. To date no serious adverse events can be attributed to the vaccine. Adverse events (≤CTC grade 2) attributable to the vaccine include injection site pain/discomfort and local skin reaction in all Pts. Other adverse events (≤grade 2) include hyperkalemia, fever and increased LDH levels in one Pt. One Pt with non-malignant hepatic lesions at the time of initial surgery was removed from the study after confirmation of metastatic disease in the liver. At this point the median 6.5 (range 9–4) months in the study all remaining (5/6) patients have no evidence of recurrent disease. Conclusions: Preliminary data indicate that antitumor vaccination with genetically altered allogeneic human pancreatic cancer cells expressing a(1, 3) galactosyltrasferase is safe and feasible [Table: see text]
Decline of multidrug-resistant Gram negative infections with the routine use of a multiple decontamination regimen in ICU
Authors: Christophe Camus, Elise Sauvadet, Aude Tavenard, Caroline Piau, Fabrice Uhel, Pierre Bouju, Julien Letheulle, Gilles Dollo, Arnaud Gacouin, Sylvain Lavoué, Yves Le Tulzo
Journal: Journal of Infection (2016)