tbuckley/cabot-search huggingface dataset:
Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24
Authors: Sophia Davidson, Chien-Hsiung Yu, Annemarie Steiner, Frédéric Ebstein, Paul J. Baker, Valentina Jarur-Chamy, Katja Hrovat Schaale, Pawat Laohamonthonkul, Klara Kong, Dale J. Calleja, Cassandra R. Harapas, Katherine R. Balka, Jacob Mitchell, Jacob T. Jackson, Niall D. Geoghegan, Fiona Moghaddas, Kelly L. Rogers, Katrin D. Mayer-Barber, Adriana A. De Jesus, Dominic De Nardo, Benjamin T. Kile, Anthony J. Sadler, M. Cecilia Poli, Elke Krüger, Raphaela Goldbach Mansky, Seth L. Masters
Journal: Science Immunology (2022)

Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-αβ) and NF-κB signaling; however, the innate immune pathway driving this is currently unknown. Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in multiple cell types from patients with proteasome-associated autoinflammatory disease (PRAAS). Furthermore, genetic deletion or small-molecule inhibition of PKR in vitro ameliorated inflammation driven by proteasome deficiency. In vivo, proteasome inhibitor-induced inflammatory gene transcription was blunted in PKR-deficient mice compared with littermate controls. PKR also acted as a rheostat for proteotoxic stress by triggering phosphorylation of eIF2α, which can prevent the translation of new proteins to restore homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24). When misfolded IL-24 egress into the cytosol was blocked by inhibition of the endoplasmic reticulum-associated degradation pathway, PKR activation and subsequent inflammatory signaling were blunted. Cytokines such as IL-24 are normally secreted from cells; therefore, cytoplasmic accumulation of IL-24 represents an internal danger-associated molecular pattern. Thus, we have identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS.
Interferon: cloudy but intriguing future
Authors: R. S. Johnson
Journal: JAMA (1981)

Interferon was celebrated at the first annual International Congress for Interferon Research in Washington, DC. The conference, organized by the<i>Journal of Interferon Research</i>and Scherago Associates, Inc, an advertising and marketing company in New York City, had an air of upstage scientific excitement and backstage financial intrigue. With some of the biggest stars of the interferon research and business worlds crowded together in one hotel, it was difficult to mask the conflict with smiles and diplomacy. Real and potential interferon producers and brokerage companies were gleaning information instead of selling or exhibiting products. There were even stories of black market interferon and of a wealthy cancer patient offering half a million dollars to researchers for interferon therapy. On the second day of the conference, clinicians from Europe and the United States reported on the results of several clinical trials of interferon in cancer and antiviral therapy. The results were
Disrupting the MYC-TFEB Circuit Impairs Amino Acid Homeostasis and Provokes Metabolic Anergy
Authors: Mario R. Fernandez, Franz X. Schaub, Chunying Yang, Weimin Li, Seongseok Yun, Stephanie K. Schaub, Frank C. Dorsey, Min Liu, Meredith A. Steeves, Andrea Ballabio, Alexandar Tzankov, Zhihua Chen, John M. Koomen, Anders E. Berglund, John L. Cleveland
Journal: Cancer Research (2022)

MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eμ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA transport. Reactivation of the autophagy-lysosomal pathway by TFEB disabled the malignant state by disrupting mitochondrial functions, proteasome activity, AA transport, and AA and nucleotide metabolism, leading to metabolic anergy, growth arrest, and apoptosis. This phenotype provides therapeutic opportunities to disable MYC-driven malignancies, including AA restriction and treatment with proteasome inhibitors.MYC suppresses TFEB and autophagy and controls amino acid homeostasis by upregulating amino acid transport and the proteasome, and reactivation of TFEB disables the metabolism of MYC-driven tumors.
Fertility control
Authors: Michael J. K. Harper
Journal: Medicinal Research Reviews (1982)

This review of fertility control focuses on recent prospects for fertility control, perspectives on fertility control drugs under investigation (established drugs and novel structure and biological activities), and future prospects for fertility control. Most of the research being conducted on new contraceptive devices is concentrated on 2 progestational steroids--norethisterone and its ester norethisterone enanthate, and levonorgestrel. Norethisterone is no longer under patent protection, and levonorgestrel, while still protected by patent, has been the benchmark as far as potent progestational steroids are concerned. Its potency allows the use of smaller daily quantities to be released to achieve the same biological action. This enables the life span of the device to be prolonged. In the IUD field, the devices being developed are able to release either copper progestational steroids. A new derivative of levonorgestrel, called desogestrel has recently been described and is reported to be twice as potent as levonorgestrel. If this proves to be the case, it might supplant levonorgestrel as the contraceptive steroid of choice for new device development. New developments are under way to produce both better and more acceptable barrier contraceptive methods. An area that has immediate promise for development of new contraceptive or fertility control methods is the development of nonsurgical methods for female sterilization. There are 3 candidate chemicals which seem to be effective and have been widely used clinically. The chemical used most extensively has been quinacrine, but it is known to have toxic properties. It has caused amenorrhea, intrauterine adhesions, chemical vaginitis, skin rash, and central nervous system excitation in women. There are 3 main classes of chemical compounds which fall into the general category of established drugs. For these drugs there are data from clinical studies which include both Phase 1 studies and efficacy studies. These agents, which can be classified into the groupings of steroids, prostaglandins, and analogs of luteinizing hormone releasing hormone (LRH, LHRH, LRF), are reviewed. It does appear that without some fresh impetus, such as the elucidation of certain physiological control processes, identification of the structure of native hormones like inhibin, and characterization of the structure of the progesterone receptor, further progress will be slow and limited.
Traumatic Brain Injury and Veteran Mortality After the War in Afghanistan
Authors: Mark A. Reger, Lisa A. Brenner, Alta du Pont
Journal: JAMA Network Open (2022)

On August 30, 2021, the last US military service members left Afghanistan, marking the end of America's longest war.It is important to continue to examine the impact of the war on service members, veterans, family members, clinicians, and health care systems.Traumatic brain injuries (TBIs) are often described as one of the signature injuries of the war.Estimates of TBI among service members who have returned from military operations in Iraq and Afghanistan vary moderately, which highlights the critical importance of TBI definitions and methods to ascertain TBI exposure.Estimates suggest that between 9% and 28% of service members experienced a TBI. 1 Complicating matters further, many veterans experienced 1 or more TBIs before their military service, thereby suggesting that military-related injuries may be neither the first nor the worst lifetime injury sustained.
EASL Clinical Practice Guidelines: Management of hepatitis C virus infection
Journal: Journal of Hepatology (2011)

Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide [1]. The long-term hepatic impact of HCV infection is highly variable, from minimal changes to chronic hepatitis, extensive fibrosis, and cirrhosis with or without hepatocellular carcinoma (HCC). The number of chronically infected persons worldwide may exceed 200 million, but most of them have no knowledge of their infection or of the ensuing hepatic condition. Clinical care for patients with HCV-related liver disease has advanced considerably during the last two decades, as a result of growing knowledge about the mechanisms of the disease, remarkable developments in diagnostic procedures, and advances in therapeutic and preventative approaches.
Questions and Answers
Journal: JAMA (1964)

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
Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma: An Open-Label Phase I Trial
Authors: Funda Meric-Bernstam, Nizar M. Tannir, Othon Iliopoulos, Richard J. Lee, Melinda L. Telli, Alice C. Fan, Angela DeMichele, Naomi B. Haas, Manish R. Patel, James J. Harding, Martin H. Voss, Taofeek K. Owonikoko, Bradley Carthon, Ramaprasad Srinivasan, Johanna C. Bendell, Yonchu Jenkins, Sam H. Whiting, Keith Orford, Mark K. Bennett, Todd M. Bauer
Journal: Clinical Cancer Research (2022)

Dual inhibition of glucose and glutamine metabolism results in synergistic anticancer effects in solid tumor models. Telaglenastat, an investigational, small-molecule, glutaminase inhibitor, exhibits modest single-agent activity in renal cell carcinoma (RCC) patients. This phase Ib trial evaluated telaglenastat plus cabozantinib or everolimus, agents known to impair glucose metabolism in patients with metastatic RCC (mRCC).mRCC patients received escalating doses of telaglenastat [400-800 mg per os (p.o.) twice daily] in a 3 + 3 design, plus either everolimus (10 mg daily p.o.; TelaE) or cabozantinib (60 mg daily p.o.; TelaC). Tumor response (RECISTv1.1) was assessed every 8 weeks. Endpoints included safety (primary) and antitumor activity.Twenty-seven patients received TelaE, 13 received TelaC, with median 2 and 3 prior therapies, respectively. Treatment-related adverse events were mostly grades 1 to 2, most common including decreased appetite, anemia, elevated transaminases, and diarrhea with TelaE, and diarrhea, decreased appetite, elevated transaminases, and fatigue with TelaC. One dose-limiting toxicity occurred per cohort: grade 3 pruritic rash with TelaE and thrombocytopenia with TelaC. No maximum tolerated dose (MTD) was reached for either combination, leading to a recommended phase II dose of 800-mg telaglenastat twice daily with standard doses of E or C. TelaE disease control rate (DCR; response rate + stable disease) was 95.2% [20/21, including 1 partial response (PR)] among 21 patients with clear cell histology and 66.7% (2/3) for papillary. TelaC DCR was 100% (12/12) for both histologies [5/10 PRs as best response (3 confirmed) in clear cell].TelaE and TelaC showed encouraging clinical activity and tolerability in heavily pretreated mRCC patients.
JAMA Reference Directories
Journal: JAMA (1988)

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
Salivary biomarkers of neurodegenerative and demyelinating diseases and biosensors for their detection
Authors: Riccardo Goldoni, Carolina Dolci, Elisa Boccalari, Francesco Inchingolo, Alessandro Paghi, Lucanos Strambini, Daniela Galimberti, Gianluca Martino Tartaglia
Journal: Ageing Research Reviews (2022)

Salivary analysis is gaining increasing interest as a novel and promising field of research for the diagnosis of neurodegenerative and demyelinating diseases related to aging. The collection of saliva offers several advantages, being noninvasive, stress-free, and repeatable. Moreover, the detection of biomarkers directly in saliva could allow an early diagnosis of the disease, leading to timely treatments. The aim of this manuscript is to highlight the most relevant researchers' findings relatively to salivary biomarkers of neurodegenerative and demyelinating diseases, and to describe innovative and advanced biosensing strategies for the detection of salivary biomarkers. This review is focused on five relevant aging-related neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Multiple Sclerosis) and the salivary biomarkers most commonly associated with them. Advanced biosensors enabling molecular diagnostics for the detection of salivary biomarkers are presented, in order to stimulate future research in this direction and pave the way for their clinical application.
Microfluidic Seeding of Cells on the Inner Surface of Alginate Hollow Microfibers
Authors: Saurabh S. Aykar, Nima Alimoradi, Mehrnoosh Taghavimehr, Reza Montazami, Nicole N. Hashemi
Journal: Advanced Healthcare Materials (2022)

Mimicking microvascular tissue microenvironment in vitro calls for a cytocompatible technique of manufacturing biocompatible hollow microfibers suitable for cell-encapsulation/seeding in and around them. The techniques reported to date either have a limit on the microfiber dimensions or undergo a complex manufacturing process. Here, a microfluidic-based method for cell seeding inside alginate hollow microfibers is designed whereby mouse astrocytes (C8-D1A) are passively seeded on the inner surface of these hollow microfibers. Collagen I and poly-d-lysine, as cell attachment additives, are tested to assess cell adhesion and viability; the results are compared with nonadditive-based hollow microfibers (BARE). The BARE furnishes better cell attachment and higher cell viability immediately after manufacturing, and an increasing trend in the cell viability is observed between Day 0 and Day 2. Swelling analysis using percentage initial weight and width is performed on BARE microfibers furnishing a maximum of 124.1% and 106.1%, respectively. Degradation analysis using weight observed a 62% loss after 3 days, with 46% occurring in the first 12 h. In the frequency sweep test performed, the storage modulus (G') remains comparatively higher than the loss modulus (G″) in the frequency range 0-20 Hz, indicating high elastic behavior of the hollow microfibers.
Nitric oxide.
Authors: A J Farrell, D R Blake
Journal: Annals of the Rheumatic Diseases (1996)

Nitric oxide is a gas generally known by its chemical formula NO, or NO.The dot denotes an unpaired electron, which is the definition of a free radical; pbssessing this, NO is highly reactive and quite -different from the anaesthetic agent nitrous oxide (N20), which is extremely stable.Until recently, NO was best known as a constituent of car exhaust fumes, contributing to the photochemical smog of cities such as Los Angeles.In contrast, the work which crucially altered this perception was performed in a leafy Kentish suburb at the Wellcome Foundation in Beckenham, UK.In 1987, it was shown that NO was the long sought endothelium derived relaxing factor (EDRF).'This was a crucial discovery for cardiovascular biology, and it soon became evident that NO was produced by many cell types and performed diverse functions, including inhibition of platelet aggregation and mediation of the cytotoxic action of activated macrophages, and had a role in central and peripheral neurotransmission.NO is enzymically synthesised from L-arginine by oxidation of one of the terminal guanidino nitrogen atoms of L-arginine,2a process inhibited by L-arginine analogues such as N0-monomethyl-L-arginine (LNMMA).'nNOS' have been used for the cNOS of endothelial and neuronal cells, respectively, though neither is confined to its respective cell type.The genes for the human eNOS, nNOS, and iNOS are located on chromosomes 7, 12, and 17 respectively.3740Cloning26 and other studies4' also suggest that NOS are cytochrome P-450-type haemoproteins.Essentially, these function by transferring electrons via flavin moieties to haem, and it is likely that FAD/FMN fulfil a similar role in relation to NOS during the oxidation of L-arginine to NO.It is also clear that the tight binding of calmodulin to iNOS explains its Ca2+/calmodulin independence,42 that cNOS phosphorylation via several protein kinases may be an important influence on NOS
BENZYL ALCOHOL FOR TOOTHACHE
Journal: JAMA (1920)

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
Medical treatments for idiopathic pulmonary fibrosis: a systematic review and network meta-analysis
Authors: Tyler Pitre, Jasmine Mah, Wryan Helmeczi, Muhammad Faran Khalid, Sonya Cui, Melanie Zhang, Renata Husnudinov, Johnny Su, Laura Banfield, Brent Guy, Jade Coyne, Ciaran Scallan, Martin RJ Kolb, Aaron Jones, Dena Zeraatkar
Journal: Thorax (2022)

Background Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder with a poor prognosis. Our objective is to assess the comparative effectiveness of 22 approved or studied IPF drug treatments. Methods We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov from inception to 2 April 2021. We included randomised controlled trials (RCTs) for adult patients with IPF receiving one or more of 22 drug treatments. Pairs of reviewers independently identified randomised trials that compared one or more of the target medical treatments in patients with IPF. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for network meta-analysis. We calculated pooled relative risk (RR) ratios and presented direct or network estimates with 95% credibility intervals (95% CI), within the GRADE framework. Results We identified 48 (10 326 patients) eligible studies for analysis. Nintedanib [RR 0.69 (0.44 to 1.1), pirfenidone [RR 0.63 (0.37 to 1.09); direct estimate), and sildenafil [RR (0.44 (0.16 to 1.09)] probably reduce mortality (all moderate certainty). Nintedanib (2.92% (1.51 to 4.14)), nintedanib+sildenafil (157 mL (–88.35 to 411.12)), pirfenidone (2.47% (–0.1 to 5)), pamrevlumab (4.3% (0.5 to 8.1)) and pentraxin (2.74% (1 to 4.83)) probably reduce decline of overall forced vital capacity (all moderate certainty). Only sildenafil probably reduces acute exacerbation and hospitalisations (moderate certainty). Corticosteroids+azathioprine+N-acetylcysteine increased risk of serious adverse events versus placebo (high certainty). Conclusion and relevance Future guidelines should consider sildenafil for IPF and further research needs to be done on promising IPF treatments such as pamrevlumab and pentraxin as phase 3 trials are completed.
Nivolumab Plus Ipilimumab for Previously Treated Stage IV Squamous Cell Lung Cancer
Authors: Binghao Zhao, Wenbin Ma
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal