tbuckley/cabot-search huggingface dataset:
N-terminus-independent activation of c-Src via binding to a tetraspan(in) TM4SF5 in hepatocellular carcinoma is abolished by the TM4SF5 C-terminal peptide application
Authors: Haeng Eun Song, Yoonji Lee, Eunmi Kim, Chang Yun Cho, Oisun Jung, Doohyung Lee, Eun Goo Lee, Seo Hee Nam, Minkyung Kang, Stephani Joy Y. Macalino, Ji Eon Kim, Jae Woo Jung, Sung Won Kwon, Sun Choi, Jung Weon Lee
Journal: Theranostics (2021)

Active c-Src non-receptor tyrosine kinase localizes to the plasma membrane via N-terminal lipid modification.Membranous c-Src causes cancer initiation and progression.Even though transmembrane 4 L six family member 5 (TM4SF5), a tetraspan(in), can be involved in this mechanism, the molecular and structural influence of TM4SF5 on c-Src remains unknown.Methods: Here, we investigated molecular and structural details by which TM4SF5 regulated c-Src devoid of its N-terminus and how cell-penetrating peptides were able to interrupt c-Src activation via interference of c-Src-TM4SF5 interaction in hepatocellular carcinoma models.Results: The TM4SF5 C-terminus efficiently bound the c-Src SH1 kinase domain, efficiently to the inactively-closed form.The complex involved protein tyrosine phosphatase 1B able to dephosphorylate Tyr530.The c-Src SH1 domain alone, even in a closed form, bound TM4SF5 to cause c-Src Tyr419 and FAK Y861 phosphorylation.Homology modeling and molecular dynamics simulation studies predicted the directly interfacing residues, which were further validated by mutational studies.Cell penetration of TM4SF5 C-terminal peptides blocked the interaction of TM4SF5 with c-Src and prevented c-Src-dependent tumor initiation and progression in vivo.Conclusions: Collectively, these data demonstrate that binding of the TM4SF5 C-terminus to the kinase domain of inactive c-Src leads to its activation.Because this binding can be abolished by cell-penetrating peptides containing the TM4SF5 C-terminus, targeting this direct interaction may be an effective strategy for developing therapeutics that block the development and progression of hepatocellular carcinoma.
Is the lung microbiome alive? Lessons from Antarctic soil
Authors: Jennifer M. Baker, Robert P. Dickson
Journal: European Respiratory Journal (2021)

<b>Is the lung microbiome alive? What we can learn from 1) the cold, dry, salty soil of Antarctica and 2) an elegant new translational study in the <i>European Respiratory Journal</i>. A new essay by @robertpdickson and @jenn_bak_.</b>https://bit.ly/3p76a0L
Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy
Authors: Yanan Li, Chaorong Wang, Tiantian Xu, Peichen Pan, Qing Yu, Lei Xu, Xiufang Xiong, Tingjun Hou, Sunliang Cui, Yi Sun
Journal: Acta Pharmaceutica Sinica B (2021)

Protein neddylation is catalyzed by a three-enzyme cascade, namely an E1 NEDD8-activating enzyme (NAE), one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases. The physiological substrates of neddylation are the family members of cullin, the scaffold component of cullin RING ligases (CRLs). Currently, a potent E1 inhibitor, MLN4924, also known as pevonedistat, is in several clinical trials for anti-cancer therapy. Here we report the discovery, through virtual screening and structural modifications, of a small molecule compound HA-1141 that directly binds to NAE in both in vitro and in vivo assays and effectively inhibits neddylation of cullins 1-5. Surprisingly, unlike MLN4924, HA-1141 also triggers non-canonical endoplasmic reticulum (ER) stress and PKR-mediated terminal integrated stress response (ISR) to activate ATF4 at an early stage, and to inhibit protein synthesis and mTORC1 activity at a later stage, eventually leading to autophagy induction. Biologically, HA-1141 suppresses growth and survival of cultured lung cancer cells and tumor growth in in vivo xenograft lung cancer models at a well-tolerated dose. Taken together, our study has identified a small molecule compound with the dual activities of blocking neddylation and triggering ER stress, leading to growth suppression of cancer cells.
Turning the tide: a history and review of hyperhidrosis treatment
Authors: K.Y.C Lee, N. J. Levell
Journal: British Journal of Dermatology (2012)

Hyperhidrosis is a potential cause of severe physical and psychological distress, interfering in activities of daily living. Over the past 100 years, advances have been made regarding the treatment of this debilitating condition with some success. Surgical treatment with sympathectomy was successfully performed for hyperhidrosis in the early part of the 20th century, with various modifications of the technique over the past 100 years. Topical aluminium salt antiperspirants, anticholinergic medications, iontophoresis and botulinum toxin introduced less invasive ways to manage this condition. This historical review will enable dermatologists and non-dermatologists to manage this distressing condition.
Burden of nosocomial COVID-19 in Wales: results from a multicentre retrospective observational study of 2508 hospitalised adults
Authors: Mark J Ponsford, Rhys Jefferies, Chris Davies, Daniel Farewell, Ian R Humphreys, Stephen Jolles, Sara Fairbairn, Keir Lewis, Daniel Menzies, Amit Benjamin, Favas Thaivalappil, Chris Williams, Simon M Barry
Journal: Thorax (2021)

The burden of nosocomial SARS-CoV-2 infection remains poorly defined. We report on the outcomes of 2508 adults with molecularly-confirmed SARS-CoV-2 admitted across 18 major hospitals, representing over 60% of those hospitalised across Wales between 1 March and 1 July 2020. Inpatient mortality for nosocomial infection ranged from 38% to 42%, consistently higher than participants with community-acquired infection (31%-35%) across a range of case definitions. Those with hospital-acquired infection were older and frailer than those infected within the community. Nosocomial diagnosis occurred a median of 30 days following admission (IQR 21-63), suggesting a window for prophylactic or postexposure interventions, alongside enhanced infection control measures.
O13-3 Tepotinib in patients with MET exon 14 (METex14) skipping advanced NSCLC: Updated efficacy results from VISION cohort A
Authors: Hiroshi Sakai, Masahiro Morise, Enriqueta Felip, Remi Veillon, Marina Chiara Garassino, Jo Raskin, Santiago Viteri, Julien Mazieres, Alexis B. Cortot, Egbert Smit, Michael Thomas, Byoung Chul Cho, Pierfranco Conte, James Chih-Hsin Yang, Yuh-Min Chen, Keunchil Park, Maya Gottfried, Christian Britschgi, Xiuning Le, Paul Paik
Journal: Annals of Oncology (2021)
Timely Family Meetings or Time-Limited Trials?
Authors: Sonal Admane, David Hui
Journal: JAMA Internal Medicine (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
循環器病の診断と治療に関するガイドライン(2007-2008年度合同研究班報告)冠動脈病変の非侵襲的診断法に関するガイドライン
Authors: Yamashina Akira, Ueshima Kenji, Kimura Kazuo, Kuribayashi Sachio, Sakuma Hajime, Tamaki Nagara, Yoshida Kiyoshi, Kitagawa Tadanari, Kosuge Masami, Otsuji Yutaka, Kihara Yasuki, Jinzaki Masahiro, Chikamori Daijiro, Teraoka Kunihiko, Hayashida Akihiro, Harada Masaki, Yoshioka Kunihiro, Yoshinaga Keiichiro, Watanabe Nozomi, Nishimura Shigeyuki, Mizuno Kyoichi, Yoshino Hideaki
Journal: Circulation (2009)
SARS-CoV-2 vaccination in rituximab-treated patients: B cells promote humoral immune responses in the presence of T-cell-mediated immunity
Authors: Daniel Mrak, Selma Tobudic, Maximilian Koblischke, Marianne Graninger, Helga Radner, Daniela Sieghart, Philipp Hofer, Thomas Perkmann, Helmuth Haslacher, Renate Thalhammer, Stefan Winkler, Stephan Blüml, Karin Stiasny, Judith H Aberle, Josef S Smolen, Leonhard X Heinz, Daniel Aletaha, Michael Bonelli
Journal: Annals of the Rheumatic Diseases (2021)

Evidence suggests that B cell-depleting therapy with rituximab (RTX) affects humoral immune response after vaccination. It remains unclear whether RTX-treated patients can develop a humoral and T-cell-mediated immune response against SARS-CoV-2 after immunisation.Patients under RTX treatment (n=74) were vaccinated twice with either mRNA-1273 or BNT162b2. Antibodies were quantified using the Elecsys Anti-SARS-CoV-2 S immunoassay against the receptor-binding domain (RBD) of the spike protein and neutralisation tests. SARS-CoV-2-specific T-cell responses were quantified by IFN-γ enzyme-linked immunosorbent spot assays. Prepandemic healthy individuals (n=5), as well as healthy individuals (n=10) vaccinated with BNT162b2, served as controls.All healthy controls developed antibodies against the SARS-CoV-2 RBD of the spike protein, but only 39% of the patients under RTX treatment seroconverted. Antibodies against SARS-CoV-2 RBD significantly correlated with neutralising antibodies (τ=0.74, p<0.001). Patients without detectable CD19+ peripheral B cells (n=36) did not develop specific antibodies, except for one patient. Circulating B cells correlated with the levels of antibodies (τ=0.4, p<0.001). However, even patients with a low number of B cells (<1%) mounted detectable SARS-CoV-2-specific antibody responses. SARS-CoV-2-specific T cells were detected in 58% of the patients, independent of a humoral immune response.The data suggest that vaccination can induce SARS-CoV-2-specific antibodies in RTX-treated patients, once peripheral B cells at least partially repopulate. Moreover, SARS-CoV-2-specific T cells that evolved in more than half of the vaccinated patients may exert protective effects independent of humoral immune responses.
Erythropoietin promotes abdominal aortic aneurysms in mice through angiogenesis and inflammatory infiltration
Authors: Meng Zhang, Wenhai Sui, Cheng Cheng, Fei Xue, Zhenyu Tian, Jing Cheng, Jie Zhang, Tao Zhang, Jianlin Zhang, Weiwei Wang, Wenjing Xiong, Panpan Hao, Jing Ma, Xingli Xu, Shuangxi Wang, Shangwen Sun, Meng Zhang, Yun Zhang, Cheng Zhang
Journal: Science Translational Medicine (2021)

Erythropoietin dose-dependently induces abdominal aortic aneurysm in mice via JAK2/STAT5 signaling, even without angiotensin II infusion.
EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis
Authors: György Nagy, Nadia M T Roodenrijs, Paco M J Welsing, Melinda Kedves, Attila Hamar, Marlies C van der Goes, Alison Kent, Margot Bakkers, Polina Pchelnikova, Etienne Blaas, Ladislav Senolt, Zoltan Szekanecz, Ernest H Choy, Maxime Dougados, Johannes WG Jacobs, Rinie Geenen, Johannes WJ Bijlsma, Angela Zink, Daniel Aletaha, Leonard Schoneveld, Piet van Riel, Sophie Dumas, Yeliz Prior, Elena Nikiphorou, Gianfranco Ferraccioli, Georg Schett, Kimme L Hyrich, Ulf Mueller-Ladner, Maya H Buch, Iain B McInnes, Désirée van der Heijde, Jacob M van Laar
Journal: Annals of the Rheumatic Diseases (2021)

To develop evidence-based European Alliance of Associations for Rheumatology (EULAR) points to consider (PtCs) for the management of difficult-to-treat rheumatoid arthritis (D2T RA).
Association of Elevated Maternal Serum Total Bile Acids With Low Birth Weight and Intrauterine Fetal Growth Restriction
Authors: Fuzhen Song, Yuanyuan Chen, Lei Chen, Huan Li, Xiajin Cheng, Weibin Wu
Journal: JAMA Network Open (2021)

Bile acids play essential roles in metabolic modulation. Excessive serum total bile acid (sTBA) levels during pregnancy are associated with adverse perinatal outcomes; however, their association with the risk of intrauterine growth restriction (IUGR) remains unclear.To investigate the association between maternal sTBA concentration during pregnancy and the risk of IUGR.This retrospective cohort study included pregnant individuals who delivered live singleton neonates and had regular antenatal examination records available at a hospital-based center in Shanghai, China, from 2014 to 2018. Data were analyzed from July to November 2020.Maternal sTBA concentration during pregnancy.Fetal birth weight and probability of low birth weight (LBW) and IUGR.This study included 68 245 singleton pregnancies with live births for analysis. The mean (SD) age of the pregnant individuals was 30.5 (3.8) years, 67 168 patients (98.4%) were Han, and 50 155 (73.5%) were nulliparous. Nonlinear regression models suggested that there was an inverted J-shaped association between maternal sTBA level during pregnancy and fetal birth weight, with a steep decrease in birth weight at high sTBA levels (estimated mean [SE] birth weight for sTBA of 40.8 ug/mL, 2879 [39.9] g) and greater birth weights at lower sTBA levels (estimated mean [SE] birth weight for sTBA 0.4 μg/mL, 3290 [3.9] g; and for 4.1 μg/mL, 3334 [1.6] g). Lower birth weight and a higher incidence of IUGR were observed in patients with gestational hypercholanemia (sTBA ≥4.08 μg/mL) compared with those without gestational hypercholanemia (birth weight: estimated adjusted mean [SE], 3309 [3.32] vs 3338 [0.80] g; P = .005; incidence of IUGR: 62 of 4467 [1.4%] vs 312 of 63 778 [0.5%]; P < .001). Moreover, compared with patients with sTBA concentrations of less than 4.08 μg/mL, those with gestational hypercholanemia had an increased risk of LBW (adjusted odds ratio [aOR], 1.29; 95% CI, 1.09-1.53) and IUGR (aOR, 2.18; 95% CI, 1.62-2.91). In addition, there was an additive interaction between hypertensive disorders in pregnancy (HDP) and hypercholanemia on LBW and IUGR risk. The highest risks of LBW and IUGR were found in pregnant individuals with both HDP and hypercholanemia compared with those with normotensive pregnancies with sTBA concentrations less than 4.08 μg/mL (LBW: aOR, 9.13; 95% CI, 6.88-12.12; IUGR: aOR, 19.14; 95% CI, 12.09-30.28).This study found that gestational hypercholanemia was associated with an increased risk of LBW and IUGR, especially in pregnant individuals with HDP. Therefore, it would be meaningful to monitor sTBA concentration during the follow-up of pregnancies with potential IUGR.
Biodegradable manganese engineered nanocapsules for tumor-sensitive near-infrared persistent luminescence/magnetic resonance imaging and simultaneous chemotherapy
Authors: Rui Zou, Junwei Li, Ting Yang, Yong Zhang, Ju Jiao, Ka-Leung Wong, Jing Wang
Journal: Theranostics (2021)

Rationale: Near-Infrared persistent luminescence (NIR-PL) nanomaterials that can continually emit low-energy photons after ceasing excitation has emerged as a new generation of theranostic nanoparticle drug delivery systems (NDDSs) for imaging-guided cancer therapy, which stems from their special ability to completely avoid tissue autofluorescence interference.However, unresponsive diagnostic capability, inefficient drug delivery, and poor biodegradability limit the efficacy of most reported NIR-PL-based NDDSs.Methods: Herein, a multifaceted tumor microenvironment (TME)-degradable theranostic drug delivery nanocapsule based on an ultrasmall persistent phosphor with a hollow mesoporous manganese-doped, DOX-loaded silica shell (Mn-ZGOCS-PEG) is developed to overcome the above drawbacks.Results: We demonstrate that the well-designed nanocapsule enables tumor-responsive controlled drug release with ameliorated therapeutic efficacy, TME-responsive autofluorescence interference-free NIR-PL tracing, and manganese-enhanced magnetic resonance (Mn-MR) monitoring for practical dual-modality image-guided antitumor treatment in vivo. Conclusion:Our results indicate that Mn-ZGOCS-PEG nanocapsules enable tumor-targeting augmented chemotherapy under the guidance of TME-responsive dual-MR/NIR-PL-modality imaging in vivo.We believe that our work provides a new paradigm for the development of smart NIR-PL-based NDDSs with ultrasensitive multimodal diagnostic capability, enhanced anticancer effect, and efficient biodegradability.
CD137 and PD-L1 targeting with immunovirotherapy induces a potent and durable antitumor immune response in glioblastoma models
Authors: Montserrat Puigdelloses, Marc Garcia-Moure, Sara Labiano, Virginia Laspidea, Marisol Gonzalez-Huarriz, Marta Zalacain, Lucia Marrodan, Naiara Martinez-Velez, Daniel De la Nava, Iker Ausejo, Sandra Hervás-Stubbs, Guillermo Herrador, ZhiHong Chen, Dolores Hambardzumyan, Ana Patino Garcia, Hong Jiang, Candelaria Gomez-Manzano, Juan Fueyo, Jaime Gállego Pérez-Larraya, Marta Alonso
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Glioblastoma (GBM) is a devastating primary brain tumor with a highly immunosuppressive tumor microenvironment, and treatment with oncolytic viruses (OVs) has emerged as a promising strategy for these tumors. Our group constructed a new OV named Delta-24-ACT, which was based on the Delta-24-RGD platform armed with 4-1BB ligand (4-1BBL). In this study, we evaluated the antitumor effect of Delta-24-ACT alone or in combination with an immune checkpoint inhibitor (ICI) in preclinical models of glioma. Methods The in vitro effect of Delta-24-ACT was characterized through analyses of its infectivity, replication and cytotoxicity by flow cytometry, immunofluorescence (IF) and MTS assays, respectively. The antitumor effect and therapeutic mechanism were evaluated in vivo using several immunocompetent murine glioma models. The tumor microenvironment was studied by flow cytometry, immunohistochemistry and IF. Results Delta-24-ACT was able to infect and exert a cytotoxic effect on murine and human glioma cell lines. Moreover, Delta-24-ACT expressed functional 4-1BBL that was able to costimulate T lymphocytes in vitro and in vivo. Delta-24-ACT elicited a more potent antitumor effect in GBM murine models than Delta-24-RGD, as demonstrated by significant increases in median survival and the percentage of long-term survivors. Furthermore, Delta-24-ACT modulated the tumor microenvironment, which led to lymphocyte infiltration and alteration of their immune phenotype, as characterized by increases in the expression of Programmed Death 1 (PD-1) on T cells and Programmed Death-ligand 1 (PD-L1) on different myeloid cell populations. Because Delta-24-ACT did not induce an immune memory response in long-term survivors, as indicated by rechallenge experiments, we combined Delta-24-ACT with an anti-PD-L1 antibody. In GL261 tumor-bearing mice, this combination showed superior efficacy compared with either monotherapy. Specifically, this combination not only increased the median survival but also generated immune memory, which allowed long-term survival and thus tumor rejection on rechallenge. Conclusions In summary, our data demonstrated the efficacy of Delta-24-ACT combined with a PD-L1 inhibitor in murine glioma models. Moreover, the data underscore the potential to combine local immunovirotherapy with ICIs as an effective therapy for poorly infiltrated tumors.
Introducing rotavirus vaccine in eight sub-Saharan African countries: a cost–benefit analysis
Authors: Charles E Okafor, Obinna I Ekwunife
Journal: The Lancet Global Health (2021)

BackgroundStimulated by the economic challenges faced by many sub-Saharan African countries and the changes in the rotavirus burden across these countries, this study aimed to inform the decision of health policy makers of eight sub-Saharan countries, who are yet to introduce the rotavirus vaccine as of Dec 31, 2020, on the health economic consequences of the introduction of the vaccine in terms of the costs and benefits.MethodsWe did a cost–benefit analysis using a simulation-based decision-analytic model for children aged younger than 1 year, who were followed up to 259 weeks, in the Central African Republic, Chad, Comoros, Equatorial Guinea, Gabon, Guinea, Somalia, and South Sudan. Data were collected and analysed between Jan 13, 2020, and Dec 11, 2020. Cost-effectiveness analysis and budget impact analysis were done as secondary analyses. Four rotavirus vaccinations (Rotarix, Rotateq, Rotavac, and Rotasiil) were compared with no vaccination. The primary outcome was disability-adjusted life-years averted, converted to monetary terms. The secondary outcomes include rotavirus gastroenteritis averted, and rotavirus vaccine-associated intussusception. The primary economic evaluation measure was the benefit–cost ratio (BCR).FindingsFor the modelling period, Jan 1, 2021, to Dec 31, 2030, we found that the benefits of introducing the rotavirus vaccine outweighed the costs in all eight countries, with Chad and the Central African Republic having the highest BCR of 19·42 and 11·36, respectively. Guinea had the lowest BCR of 3·26 amongst the Gavi-eligible countries. Equatorial Guinea and Gabon had a narrow BCR of 1·86 and 2·06, respectively. Rotarix was the optimal choice for all the Gavi-eligible countries; Rotasiil and Rotavac were the optimal choices for Equatorial Guinea and Gabon, respectively.InterpretationIntroducing the rotavirus vaccine in all eight countries, but with caution in Equatorial Guinea and Gabon, would be worthwhile. With the narrow BCR for Equatorial Guinea and Gabon, cautious, pragmatic, and stringent measures need to be employed to ensure optimal health benefits and cost minimisation of the vaccine introduction. The final decision to introduce the rotavirus vaccine should be preceded by comparing its BCR to the BCRs of other health-care projects.FundingCopenhagen Consensus Center and the Bill & Melinda Gates Foundation.