tbuckley/cabot-search huggingface dataset:
Do endocannabinoids acting via hepatic CB-1 contribute to NAFLD and hepatic insulin resistance?
Authors: George Kunos, Tony Jourdan, Joseph Tam
Journal: Journal of Clinical Investigation (2022)

The article by Wang et al. (1) challenges the concept, proposed and developed by us, that endocannabinoids acting via hepatic cannabinoid receptor 1 (CB-1) contribute to nonalcoholic fatty liver disease (NAFLD) and related hepatic insulin resistance.Our rebuttal is based on several points.In three published studies using genetically altered mice to explore the role of hepatocyte CB-1 in NAFLD, we used a diet rich in saturated fat (TD97070), which increased hepatic anandamide levels (2), a critical factor in the increased signaling of hepatic CB-1 in NAFLD.In contrast, the D12492 diet used by the authors (1) has less saturated fat and much larger amounts of monounsaturated fat acids (MUFAs) and polyunsaturated fatty acids (PUFAs), and it did not affect hepatic anandamide in a side-by-side comparison of these two diets (3).Hepatic CB-1 is autoinduced by its endogenous ligand (4), which may be one reason why D12492 did not induce hepatic CB-1 expression (1), although the authors' use of C57Bl6/N mice instead of the C57Bl6/J mice we used may also be a factor.Furthermore, the paltry weight gain (10 g over chow-fed mice) and minimal diet-induced whole-body insulin resistance (Supplemental Figure 3 in ref. 1) may have been insufficient to induce the hepatic endocannabinoid system, as a robust obesity-related upregulation of the CB1b isoform in human liver was observed only in individuals with a BMI above 30 (5).Documenting organ-specific insulin resistance requires the use of hyperinsulinemic/euglycemic clamps, which showed that a high-fat diet (HFD) elicits CB-1-mediated hepatic insulin resistance due to increased glycogenolysis (2).CB-1 is functional even in healthy liver, as indicated by CB-1-mediated inhibition of insulin-induced Akt phosphorylation in primary hepatocytes from lean mice (2).Neither approach has been used or discussed by the authors.Information obtained using hepatocyte-specific Cnr1 -/-mice should be verified using a rescue model in which Cnr1 is reexpressed in hepatocytes of global Cnr1 -/-mice.Using such a model reinforced our conclusions of a partial contribution of hepatocyte CB-1 to NAFLD and insulin resistance (2); the authors did not utilize such a model.The phenotype of hCnr1 -/-mice should have been further confirmed by pharmacological antagonism using a peripheral CB-1 blocker.In numerous studies, including our own, this resulted in near-complete reversal of HFD-induced steatosis and insulin resistance.Pharmacological blockade was not tested by the authors.
Deaths
Journal: JAMA (1928)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Seroprevalence of Antibodies Specific to Receptor Binding Domain of SARS-CoV-2 and Vaccination Coverage Among Adults in Los Angeles County, April 2021: The LA Pandemic Surveillance Cohort Study
Authors: Neeraj Sood, Olivier Pernet, Chun Nok Lam, Angela Klipp, Rani Kotha, Andrea Kovacs, Howard Hu
Journal: JAMA Network Open (2022)

This cross-sectional study estimates the seroprevalence of antibodies specific to the receptor binding domain of the spike protein of SARS-CoV-2 and vaccination coverage among adults in Los Angeles County, California, in April 2021.
Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial
Authors: Jung Yong Hong, Hee Jin Cho, Jason K. Sa, Xiaoqiao Liu, Sang Yun Ha, Taehyang Lee, Hajung Kim, Wonseok Kang, Dong Hyun Sinn, Geum-Youn Gwak, Moon Seok Choi, Joon Hyeok Lee, Kwang Cheol Koh, Seung Woon Paik, Hee Chul Park, Tae Wook Kang, Hyunchul Rhim, Su Jin Lee, Razvan Cristescu, Jeeyun Lee, Yong Han Paik, Ho Yeong Lim
Journal: Genome Medicine (2022)

Abstract Background A limited number of studies have characterized genomic properties of hepatocellular carcinoma (HCC) patients in response to anti-PD-1 immunotherapy. Methods Herein, we performed comprehensive molecular characterization of immediate (D-42 to D-1) pre-treatment tumor biopsy specimens from 60 patients with sorafenib-failed HCC in a single-arm prospective phase II trial of pembrolizumab. Objective response rate was the primary efficacy endpoint. We used whole-exome sequencing, RNA sequencing, and correlative analysis. In addition, we performed single-cell RNA sequencing using peripheral blood mononuclear cells. Results The overall response rate of pembrolizumab in sorafenib-failed HCC patients was 10% ([6/60] 95% CI , 2.4–17.6). In a univariate analysis using clinicopathological features, female gender, PD-L1 positivity, and low neutrophil-to-lymphocyte ratio (NLR) were identified as contributing factors to pembrolizumab response. Somatic mutations in CTNNB1 and genomic amplifications in MET were found only in non-responders. Transcriptional profiles through RNA sequencing identified that pembrolizumab responders demonstrated T cell receptor (TCR) signaling activation with expressions of MHC genes, indicating increased levels of T cell cytotoxicity. In single-cell sequencing from 10 pre- and post-treatment peripheral blood mononuclear cells (PBMCs), patients who achieved a partial response or stable disease exhibited immunological shifts toward cytotoxic CD8+ T cells. Conversely, patients with progressive disease showed an increased number of both CD14+ and CD16+ monocytes and activation of neutrophil-associated pathways. Conclusions Taken together, HCC patients with infiltration of cytotoxic T cells, along with increased active circulating CD8+ T cells during pembrolizumab treatment and down-regulation of neutrophil-associated markers, significantly benefited from pembrolizumab treatment. Trial registration NCT#03163992 (first posted: May 23, 2017)
Editor’s Note: RhoA activation and interaction with Caveolin-1 are critical for pressure-induced myogenic tone in rat mesenteric resistance arteries [<i>Cardiovasc Res</i> 2007;73:190-197]
Journal: Cardiovascular Research (2020)

Journal Article Editor’s Note: RhoA activation and interaction with Caveolin-1 are critical for pressure-induced myogenic tone in rat mesenteric resistance arteries [Cardiovasc Res 2007;73:190-197] Get access Cardiovascular Research, Volume 117, Issue 10, 1 September 2021, Page 2215, https://doi.org/10.1093/cvr/cvaa104 Published: 01 April 2021
Antibodies elicited by SARS-CoV-2 infection or mRNA vaccines have reduced neutralizing activity against Beta and Omicron pseudoviruses
Authors: Benjamin L. Sievers, Saborni Chakraborty, Yong Xue, Terri Gelbart, Joseph C. Gonzalez, Arianna G. Cassidy, Yarden Golan, Mary Prahl, Stephanie L. Gaw, Prabhu S. Arunachalam, Catherine A. Blish, Scott D. Boyd, Mark M. Davis, Prasanna Jagannathan, Kari C. Nadeau, Bali Pulendran, Upinder Singh, Richard H. Scheuermann, Matthew B. Frieman, Sanjay Vashee, Taia T. Wang, Gene S. Tan
Journal: Science Translational Medicine (2022)

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that have mutations associated with increased transmission and antibody escape have arisen over the course of the current pandemic. Although the current vaccines have largely been effective against past variants, the number of mutations found on the Omicron (B.1.1.529) spike protein appear to diminish the protection conferred by preexisting immunity. Using vesicular stomatitis virus (VSV) pseudoparticles expressing the spike protein of several SARS-CoV-2 variants, we evaluated the magnitude and breadth of the neutralizing antibody response over time in individuals after infection and in mRNA-vaccinated individuals. We observed that boosting increases the magnitude of the antibody response to wild-type (D614), Beta, Delta, and Omicron variants; however, the Omicron variant was the most resistant to neutralization. We further observed that vaccinated healthy adults had robust and broad antibody responses, whereas responses may have been reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations. Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines.
Allergen immunotherapy and/or biologicals for IgE‐mediated food allergy: A systematic review and meta‐analysis
Authors: Debra de Silva, Pablo Rodríguez del Río, Nicolette W. de Jong, Ekaterina Khaleva, Chris Singh, Anna Nowak‐Wegrzyn, Antonella Muraro, Philippe Begin, Giovanni Pajno, Alessandro Fiocchi, Angel Sanchez, Carla Jones, Caroline Nilsson, Carsten Bindslev‐Jensen, Gary Wong, Hugh Sampson, Kirsten Beyer, Mary‐Jane Marchisotto, Montserrat Fernandez Rivas, Rosan Meyer, Susanne Lau, Ulugbek Nurmatov, Graham Roberts
Journal: Allergy (2022)

There is substantial interest in immunotherapy and biologicals in IgE-mediated food allergy.We searched six databases for randomized controlled trials about immunotherapy alone or with biologicals (to April 2021) or biological monotherapy (to September 2021) in food allergy confirmed by oral food challenge. We pooled the data using random-effects meta-analysis.We included 36 trials about immunotherapy with 2126 mainly child participants. Oral immunotherapy increased tolerance whilst on therapy for peanut (RR 9.9, 95% CI 4.5.-21.4, high certainty); cow's milk (RR 5.7, 1.9-16.7, moderate certainty) and hen's egg allergy (RR 8.9, 4.4-18, moderate certainty). The number needed to treat to increase tolerance to a single dose of 300 mg or 1000 mg peanut protein was 2. Oral immunotherapy did not increase adverse reactions (RR 1.1, 1.0-1.2, low certainty) or severe reactions in peanut allergy (RR 1,6, 0.7-3.5, low certainty), but may increase (mild) adverse reactions in cow's milk (RR 3.9, 2.1-7.5, low certainty) and hen's egg allergy (RR 7.0, 2.4-19.8, moderate certainty). Epicutaneous immunotherapy increased tolerance whilst on therapy for peanut (RR 2.6, 1.8-3.8, moderate certainty). Results were unclear for other allergies and administration routes. There were too few trials of biologicals alone (3) or with immunotherapy (1) to draw conclusions.Oral immunotherapy improves tolerance whilst on therapy and is probably safe in peanut, cow's milk and hen's egg allergy. More research is needed about quality of life, cost and biologicals.
Abstract P098: Plasma Levels of Persistent Organochlorine Pollutants, Blood Pressure and Hypertension: A Longitudinal Study
Authors: Carolina Donat-Vargas, Agneta Åkesson, Andreas Tornevi, Maria Wennberg, Johan Sommar, Hannu Kiviranta, Panu Rantakokko, Ingvar A Bergdahl
Journal: Circulation (2018)

Background: Persistent organochlorine pollutants (POPs) include several groups of synthetic compounds with high lipophilic and bioaccumulative potential that accumulate in the food chain. Despite their long-term ban, they are still of concern and the general population is constantly exposed to these pollutants at low doses through diet. POPs are proposed to be involved in the atherosclerotic process and to cause endothelial cell dysfunction. We assess longitudinally whether plasma concentrations of different POPs were associated with blood pressure (BP) and risk of hypertension in middle-aged women and men. Methods: Study subjects were 850 participants in the Västerbotten Intervention Programme with two blood samples and BP measurements, 10 years apart, during 1990 to 2003 (baseline) and during 2001 to 2013 (follow-up). The POP measured were the fungicide hexachlorobenzene (HCB), the insecticide dichlorodiphenyl-trichloroethane (DDT) –and its persistent metabolite p,p′-dichlorodiphenyl-dichloroethylene (DDE)– and the dioxin-like and non-dioxin-like polychlorinated biphenyls (DL-PCBs, NDL-PCBs). We used generalized estimated equations to assess the associations. Results: At both sampling occasions, about 50% had hypertension. DL-PCBs and DDE, but not NDL-PCBs or HCB, were associated with hypertension, while only the association for DL-PCB remained statistically significant after lipid-standardization and adjustment for BMI and total plasma lipids. The multivariable-adjusted OR of hypertension based on repeated measurements were 1.50 (95% CI: 1.07-2.11) for DL-PCBs (3 rd vs. 1 st tertile of lipid-standardized POPs). In stratified adjusted analyses, ORs for those born after 1950 increased : 3.99 (95% CI: 2.15-7.43), while no association was observed among those born earlier. For DEE, when non-adjustment for BMI, the OR of hypertension were 1.43 (95% CI: 1.04, 1.97). Conclusions: Based on repeated measurements, the accumulated exposure to the pollutants DL-PCBs and DDE, although less clear for the latter, may disrupt the normal BP levels. Individuals born after 1950 –when early-life exposure to these substances became common– may be pre-disposed for these effects.
Safety and efficacy of encorafenib, binimetinib, plus cetuximab for BRAF V600E-mutant metastatic colorectal cancer: Results of a prospective study as an expanded access program.
Authors: Atsuo Takashima, Daisuke Kotani, Takeshi Kato, Taroh Satoh, Toshiki Masuishi, Yoshito Komatsu, Manabu Shiozawa, Taito Esaki, Naoki Izawa, Shinji Takeuchi, Hideaki Bando, Satoru Iwasa, Hiroko Hasegawa, Toshifumi Yamaguchi, Hiroya Taniguchi, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2022)

199 Background: The encorafenib, binimetinib, and cetuximab (triplet) regimen showed survival benefit and a higher response rate over standard chemotherapy among pretreated patients (pts) with BRAF V600E-mutant metastatic colorectal cancer (mCRC) in the phase III BEACON trial. Herein, we report the safety and efficacy of the triplet regimen in a prospective study (JapicCTI-205146) as a Japanese expanded access program (EAP). Methods: The key eligibility criteria were age ≥18 years and a diagnosis of BRAF V600E-mutant mCRC with progression observed after one or two prior systemic chemotherapy. Encorafenib (300 mg QD), binimetinib (45 mg BID), and weekly cetuximab (400 mg/m 2 , followed by 250 mg/m 2 ) were administered. Patients who had received at least one dose of any study drug were included in this analysis. Adverse events were evaluated using CTCAE v4.0. The objective response rate (ORR) was evaluated using RECIST Guideline Version 1.1. Results: A total of 86 pts were enrolled from 10 Japanese institutions from February to December 2020. Safety and efficacy were evaluated in 81 pts. The median age was 60 years. Fifty-four pts (67%) had ECOG PS 0 and 50 pts (62%) received one prior chemotherapy. Treatment-related serious adverse events and grade 3 or higher treatment-related adverse events were observed in 14 (17%) and 24 (30%) pts, respectively. Treatment-related death occurred in one pts. Among the 76 pts with target lesions, 21 pts were responders, and the confirmed ORR was 27.6%. Stable disease was observed in 42 pts, resulting in a disease control rate of 82.9%. The ORR was consistent regardless of ECOG PS status, the number of prior chemotherapy lines, and the number of metastatic organs. Conclusions: The safety and efficacy of the triplet regimen in the Japanese EAP were comparable to those in the BEACON trial. These results support the triplet regimen as a new standard-of-care treatment option in the second- or third-line treatment of pts with BRAF V600E-mutant mCRC in the Japanese population, as there was a promising response without any new safety signals. Clinical trial information: JapicCTI-205146.
Alcohol in breath, blood, and cerebrospinal fluid
Authors: J. Viamontes
Journal: JAMA (1972)

<h3>To the Editor.—</h3> The authors wonder at the phenomenon of two "bad trips" occurring in an individual who had several other pleasant experiences with lysergic acid diethylamide (LSD). I have reread the article and fail to find any clue as to how the authors know that the drugs involved were LSD. In fact, they liken the bad trips to those seen in amphetamine users, and it is well known that what is sold in the drug culture as LSD may be something else entirely or at least a combination of drugs, commonly including amphetamine. Without such proof as to the exact nature of the drugs taken, the report loses validity as a case report of a specific drug reaction.
Medical Organization.
Journal: JAMA (1905)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Equisetin is an anti-obesity candidate through targeting 11β-HSD1
Authors: Zhenlu Xu, Dongyun Liu, Dong Liu, Xue Ren, Haibo Liu, Guihong Qi, Yue Zhou, Chongming Wu, Kui Zhu, Zhongmei Zou, Jing Yuan, Wenhan Lin, Peng Guo
Journal: Acta Pharmaceutica Sinica B (2022)

Obesity is increasingly prevalent globally, searching for therapeutic agents acting on adipose tissue is of great importance. Equisetin (EQST), a meroterpenoid isolated from a marine sponge-derived fungus, has been reported to display antibacterial and antiviral activities. Here, we revealed that EQST displayed anti-obesity effects acting on adipose tissue through inhibiting adipogenesis in vitro and attenuating HFD-induced obesity in mice, doing so without affecting food intake, blood pressure or heart rate. We demonstrated that EQST inhibited the enzyme activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a therapeutic target of obesity in adipose tissue. Anti-obesity properties of EQST were all offset by applying excessive 11β-HSD1's substrates and 11β-HSD1 inhibition through knockdown in vitro or 11β-HSD1 knockout in vivo. In the 11β-HSD1 bypass model constructed by adding excess 11β-HSD1 products, EQST's anti-obesity effects disappeared. Furthermore, EQST directly bond to 11β-HSD1 protein and presented remarkable better intensity on 11β-HSD1 inhibition and better efficacy on anti-obesity than known 11β-HSD1 inhibitor. Therefore, EQST can be developed into anti-obesity candidate compound, and this study may provide more clues for developing higher effective 11β-HSD1 inhibitors.
Surgical, pathological and clinical features of advanced collorectal cancers with metastasectomy. "Onco-Colon Turkey Registry" real-life data.
Authors: Nuri Karadurmus, Emre Yildirim, Suayib Yalcin, Mahmut Gumus, Cemil Bilir, Erdem Cubukcu, Eda Tanrikulu Simsek, Cagatay Arslan, Faysal Dane, Sinemis Celik, Ahmet Bilici, Mehmet Ali Nahit Sendur, Basak Bala Oven, Abdurrahman Isikdogan, Haci Mehmet Turk, Mustafa Karaca, Bulent Karabulut, Melike Ozcelik, Duygu Cevik, Umut Kefeli
Journal: Journal of Clinical Oncology (2022)

299 Background: The contribution of metastasectomy to progression-free survival (PFS) and overall survival (OS) in patients (pts) with advanced stage colorectal cancer has been demonstrated in clinical trials. However, clinical trials may not represent the efficacy of treatment given to the whole population in daily practice, therefore evaluation of real-life data is needed. Methods: The demographic, pathological and clinical characteristics of 1064 RAS wild type pts were recorded in 28 centers in Turkey between January 2016 and March 2019 as part of the Onco-Colon Registry Program ( NCT04757311 ). Metastasectomy was performed in 169 patients (15.9%). In this study, pts with and without metastasectomy were compared in terms of demographic, histopathological and clinical features and treatment results. Results: Median follow-up time was 24 months(mos) (1-74), median age was 59 years (30-81). 32.5% of the pts were women. The proportion of pts with primary right colon was determined to be 16.8%. Synchronous metastasis was detected in 76.3% of those who underwent metastasectomy. Isolated liver metastasectomy was performed in 85.8% of the pts. It has been shown that 21.1% of the pts have MSI-H and 23.3% have a mucinous component. Metastasectomy was performed after conversion therapy in 54.8% of pts. In the patient group who underwent metastasectomy after medical treatment, the median time between the beginning of treatment and metastasectomy was found to be 7 mos (2-34). When the patient characteristics were compared, no significant difference was found between the groups with and without metastasectomy (p &gt; 0.05). The median PFS (mPFS) was 13.5 mos in the group that underwent metastasectomy and 9.9 mos in the group that was not performed (p &lt; 0.0001; HR: 0.63 (95% CI: 0.51-0.77). The median OS (mOS) was 47.3 mos in the group that underwent metastasectomy and 24.3 mos in the group without metastasectomy (p &lt; 0.0001; HR: 0.36 (95% CI: 0.27-0.48). Conclusions: The significant contribution of metastasectomy on mPFS and mOS was shown in this reallife data based trial, where no difference was found in terms of general participation characteristics. In daily practice, prolonged mPFS and mOS emerges as pts who are followed-up radiologically at regular intervals from the beginning and who are appropriate for surgery have the chance of metastasectomy.