tbuckley/cabot-search huggingface dataset:
Abstract PL03-02: (Re)emerging principles of cancer therapy
Authors: William George Kaelin
Journal: Cancer Research (2021)

Abstract It is likely that some of the mutations that occur late during evolution, whether passenger mutations or passenger mutations, are likely only tolerated (let alone advantageous to the cancer cell) because of the mutations that preceded them. If so, targeting mutations that occur early during tumor evolution should selectively kill cancer cells by unmasking the otherwise deleterious effects of subsequent mutations. There are now many precision cancer drugs that target such early mutations, including EGFR inhibitors for lung cancer, c-Kit mutations for GI stromal tumors, and B-Raf inhibitors for B-Raf mutant melanomas. Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) is an early event in kidney cancer. Inactivated proteins can sometimes be tackled by exploiting epistatic relationships or synthetic lethality. For example, pVHL suppresses the HIF2 transcription factor, which in turn regulates VEGF. VEGF inhibitors are now mainstays of kidney cancer treatment. HIF2 was viewed as “undruggable”, but undruggable proteins can sometimes be targeted by allosteric modulators or degraders. A first-in-class allosteric HIF2 inhibitor has advanced to phase 3 trials based on promising early data. Most cancer drugs work better in the frontline setting, and a recent study of previously untreated von Hippel-Lindau disease patients strongly suggests this will be true for the HIF2 inhibitor. Combination therapy will be required to cure most cancer. It is tempting to combine drugs that have interdependent actions in an attempt to achieve synergy, but this increases the risk of cross-resistance. The classical way to prevent resistance is to combine drugs that have distinct mechanisms of action (to minimize toxicity and cross-resistance). In this regard, immunotherapy has emerged as a powerful modality to treat cancer cells, and complements therapies aimed at inducing cancer cell death. Both kidney cancer and melanomas are highly immunogenic and can respond to immune checkpoint blockade, yet kidney cancer has a much lower mutational burden than melanoma. Recent work suggests that kidney cancers promiscuously express endogenous retroviruses, which might serve as a source of neoantigens. If true, it might be possible to pharmacologically enhance ERV expression to augment immunotherapy. Citation Format: William George Kaelin. (Re)emerging principles of cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL03-02.
Abstract 317: Med12 is a Transcriptional Mediator of Cardiac Contractile Function
Authors: Kedryn K Baskin, Catherine A Makarewich, Susan DeLeon, Rhonda Bassel-Duby, Eric N Olson
Journal: Circulation Research (2016)

The Mediator complex serves as a central governor of gene transcription by linking the basal transcriptional machinery with DNA-bound transcription factors. The activity of the Mediator complex is modulated by a kinase submodule comprised of four proteins: MED12, MED13, CDK8, and Cyclin C. The kinase submodule components are ubiquitously expressed, however recent studies support the hypothesis that these proteins differentially regulate gene expression in a tissue-specific manner. We previously demonstrated that MED13 acts in the heart to modulate systemic energy homeostasis through signaling to extracardiac tissues, but the role of the other kinase components in the heart has not yet been investigated. MED12 regulates development in a variety of cell types, and MED12 null mice are embryonically lethal. To investigate the cardiac functions of MED12, we generated mice with conditional cardiac-specific deletion of MED12. MED12 mutant mice displayed postnatal cardiomyopathy seven days after birth with a continual decline in cardiac function with age. RNAseq experiments identified specific dysregulation of genes involved in calcium homeostasis and contractility in the ventricles as early as postnatal day one. Defects in calcium handling were detected in cardiomyocytes isolated just after birth, suggesting that perturbed calcium transients lead to altered cardiac contractility and dysfunction. The consequences of cardiac deletion of MED12 and MED13 are clearly distinct, underscoring the unique functions of these Mediator components. These findings highlight the importance of the kinase submodule of the mediator complex in the control of cardiac function and reveal highly specific and distinct transcriptional actions of MED12 and MED13.
Abstract 396: Successful Virtual Reality Cardiopulmonary Resuscitation Training in Schools: Digitally Linking a Physical Manikin to a Virtual Lifesaving Scenario
Authors: Lana Gent, David Sarno, Kent Coppock, David M. Axelrod
Journal: Circulation (2019)

Introduction: The AHA trains over 20 million people in CPR skills annually. Virtual Reality (VR) education may improve student engagement, but the efficacy of VR-CPR programs has not been adequately studied. We performed the largest study to-date evaluating the feasibility of VR-enhanced CPR training. Hypothesis: We hypothesized that an immersive, VR-enhanced CPR training program, digitally linked to a physical manikin, can teach middle/high-school students Hands-Only CPR skills resulting in strong learner engagement. Methods: We linked a VR-enhanced CPR training program to a standard manikin with an optical “time of flight” sensor and hand-tracking gloves. Based on AHA’s Hands-Only CPR protocol, training included compression rate (100-120/min), depth (2-2.4”), hand position, and full chest recoil, with 124 students from 3 middle/high-schools in Florida (n= 38) and California (n=42, n=44). Iterations to streamline the user experience were implemented for Pilots 2 and 3. Results: VR-enhanced CPR training significantly improved compression rate, depth, and hand position; chest recoil was not statistically changed. Post-training, students were tested on CPR knowledge: 78% (96/124) were correct on nature of cardiac arrest, 88% (109/124) on compression rate, and 83% (103/124) on compression depth. Of students with prior CPR training, 79% stated VR-CPR training was more effective than prior training. Iterations in Pilots 2 and 3 were associated with additional learning gains at those sites. Conclusions: In this first-of-its-kind study, middle/high school students learned Hands-Only CPR skills and knowledge with a VR-enhanced CPR training program digitally linked to a physical manikin. Our VR-CPR training uniquely separates each of 4 Hands-Only CPR skills into separate training modules in which students receive instant feedback. Future study and development of VR-CPR is warranted, especially as learning gains were associated with user experience iterations.
Nasopharyngeal carcinoma: an evolving paradigm
Authors: Kenneth C. W. Wong, Edwin P. Hui, Kwok-Wai Lo, Wai Kei Jacky Lam, David Johnson, Lili Li, Qian Tao, Kwan Chee Allen Chan, Ka-Fai To, Ann D. King, Brigette B. Y. Ma, Anthony T. C. Chan
Journal: Nature Reviews Clinical Oncology (2021)
Transplant Outcome for Secondary Acute Myeloid Leukemia Based on Prior Hematological Disease or Solid Malignancy — on Behalf of the ALWP of the EBMT
Authors: Bipin N. Savani, Myriam Labopin, Ariane Boumendil, Jürgen Finke, Arnold Ganser, Matthias Stelljes, Gerhard Ehninger, Dietrich W Beelen, Dietger Niederwieser, Didier Blaise, Peter Dreger, Ghulam Mufti, Patrice Chevallier, Audrey Mailhol, Norbert Claude Gorin, Jordi Esteve, Fabio Ciceri, Frederic Baron, Christoph Schmid, Sebastian Giebel, Mohamad Mohty, Arnon Nagler
Journal: Blood (2017)
The Clinical Significance of Chromosome 17 Abnormalities in Myelodysplastic Syndrome Treated with 5-Azacytidine. Results from the Hellenic 5-Azacytidine Registry
Authors: Panagiotis Theodorou Diamantopoulos, Ioannis Kotsianidis, Vassiliki Pappa, Argiris Symeonidis, Athanasios Galanopoulos, Panagiotis Zikos, Helen A. Papadaki, Panayiotis Panayiotidis, Maria Dimou, Eleftheria Hatzimichael, George Vassilopoulos, Sossana Delibasi, Despina Mparmparousi, Eleni Variami, Aikaterini Megalakaki, Maria Kotsopoulou, Panagiotis Repoussis, Ioannis Adamopoulos, Flora Kontopidou, Dimitrios Christoulas, Alexandra Kourakli, Dimitrios Tsokanas, Menelaos Konstantinos Papoutselis, Georgios Kyriakakis, Nora-Athina Viniou
Journal: Blood (2017)
Tuberculosis national registries and data on diagnosis delay – Is there room for improvement?
Authors: Bárbara Seabra, Raquel Duarte
Journal: Pulmonology (2021)

Excessive delay in the diagnosis of Tuberculosis may have a negative impact on the epidemiological control and elimination of this disease. An accurate determination and analysis of delay times may help identify where and how to improve Tuberculosis diagnosis according to local needs. The Portuguese Tuberculosis Surveillance System – SVIG-TB – is the main source of data regarding diagnosis delay. However, to our knowledge, there has been no recent evaluation of its data. This study's primary aim was to conduct a thorough quantitative and qualitative evaluation of data obtained from the SVIG-TB registry concerning the delay in Tuberculosis diagnosis in Matosinhos, a Portuguese municipality. All patients living in the Matosinhos municipality diagnosed with Tuberculosis between January 1st 2012 and December 31st 2019 were identified and individual SVIG-TB records retrieved. Patient-related, Healthcare-related and Total delay in Tuberculosis diagnosis were determined based on data obtained from this source and compared to data recovered from patient record review. Missing data, registering errors and differences in diagnosis delay between these two sources were analysed and compared. Subsequently, diagnosis delay data from a recent Portuguese nationwide SVIG-TB paper, covering years 2010 to 2014, was compared to local SVIG-TB and patient record review data. This study identified a significantly greater percentage of cases with missing data on delay in SVIG-TB records when compared to Patient Record Review (57.2% versus 1.11%). The median patient-related, healthcare-related and Total delay in Tuberculosis diagnosis were of 17, 30 and 68 days, respectively, in the SVIG-TB based data. A significant underestimation of healthcare-related and total Tuberculosis diagnosis delay was identified in SVIG-TB data when compared to Patient Record Review. There was no significant difference between Patient-related delays determined from these two sources. Compared to the national study results, missing values were more common in this data set (57.2 vs 44.6%), mainly due to the absence of patient-related delay data. Median Total and Healthcare-related delays were significantly greater in Matosinhos Municipality, regardless of the data source (SVIG-TB or Patient Record Review). The patient-related delay was, conversely, shorter. SVIG-TB has been crucial in guiding National Public Health policies on the path towards Tuberculosis elimination in Portugal. However, there is still room for improvement. These results provide a basis for further reflection on the shortcomings and potential of SVIG-TB in guiding the national Tuberculosis program.
Painful Palmar and Plantar Purpura
Authors: Yoshihito Minami, Youichi Ogawa, Katsuhiko Tsukamoto
Journal: JAMA Dermatology (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 Dermatology 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 Dermatology journal
Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial
Authors: Julio Rosenstock, Carol Wysham, Juan P Frías, Shizuka Kaneko, Clare J Lee, Laura Fernández Landó, Huzhang Mao, Xuewei Cui, Chrisanthi A Karanikas, Vivian T Thieu
Journal: The Lancet (2021)
High tumour mutational burden and EGFR/MAPK pathway activation are therapeutic targets in metastatic porocarcinoma*
Authors: D. Westphal, M. Garzarolli, M. Sergon, P. Horak, B. Hutter, J.C. Becker, M. Wiegel, E. Maczey, S. Blum, S. Grosche‐Schlee, A. Rütten, S. Ugurel, A. Stenzinger, H. Glimm, D. Aust, G. Baretton, S. Beissert, S. Fröhling, S. Redler, H. Surowy, F. Meier
Journal: British Journal of Dermatology (2021)

Eccrine porocarcinoma (EPC) is a rare skin cancer arising from the eccrine sweat glands. Due to the lack of effective therapies, metastasis is associated with a high mortality rate.To investigate the drivers of EPC progression.We carried out genomic and transcriptomic profiling of metastatic EPC (mEPC), validation of the observed alterations in an EPC patient-derived cell line, confirmation of relevant observations in a large patient cohort of 30 tumour tissues, and successful treatment of a patient with mEPC under the identified treatment regimens.mEPC was characterized by a high tumour mutational burden (TMB) with an ultraviolet signature, widespread copy number alterations and gene expression changes that affected cancer-relevant cellular processes such as cell cycle regulation and proliferation, including a pathogenic TP53 (tumour protein 53) mutation, a copy number deletion in the CDKN2A (cyclin dependent kinase inhibitor 2A) region and a CTNND1/PAK1 [catenin delta 1/p21 (RAC1) activated kinase 1] gene fusion. The overexpression of EGFR (epidermal growth factor receptor), PAK1 and MAP2K1 (mitogen-activated protein kinase kinase 1; also known as MEK1) genes translated into strong protein expression and respective pathway activation in the tumour tissue. Furthermore, a patient-derived cell line was sensitive to EGFR and MEK inhibition, confirming the functional relevance of the pathway activation. Immunohistochemistry analyses in a large patient cohort showed the relevance of the observed changes to the pathogenesis of EPC. Our results indicate that mEPC should respond to immune or kinase inhibitor therapy. Indeed, the advanced disease of our index patient was controlled by EGFR-directed therapy and immune checkpoint inhibition for more than 2 years.Molecular profiling demonstrated high TMB and EGFR/MAPK pathway activation to be novel therapeutic targets in mEPC.
Genetically increased circulating FUT3 level leads to reduced risk of idiopathic pulmonary fibrosis: a Mendelian randomisation study
Authors: Tomoko Nakanishi, Agustin Cerani, Vincenzo Forgetta, Sirui Zhou, Richard J. Allen, Olivia C. Leavy, Masaru Koido, Deborah Assayag, R. Gisli Jenkins, Louise V. Wain, Ivana V. Yang, G. Mark Lathrop, Paul J. Wolters, David A. Schwartz, J. Brent Richards
Journal: European Respiratory Journal (2021)

Background Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF. Methods To identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data. For instruments, we used genetic determinants of circulating proteins which reside cis to the encoded gene ( cis -single nucleotide polymorphisms (SNPs)), identified by two genome-wide association studies (GWASs) in European individuals (3301 and 3200 subjects). We then applied MR methods to test if the levels of these circulating proteins influenced IPF susceptibility in the largest IPF GWAS (2668 cases and 8591 controls). We validated the MR results using colocalisation analyses to ensure that both the circulating proteins and IPF shared a common genetic signal. Results MR analyses of 834 proteins found that a 1 sd increase in circulating galactoside 3(4)- l -fucosyltransferase (FUT3) and α-(1,3)-fucosyltransferase 5 (FUT5) was associated with a reduced risk of IPF (OR 0.81, 95% CI 0.74–0.88; p=6.3×10 −7 and OR 0.76, 95% CI 0.68–0.86; p=1.1×10 −5 , respectively). Sensitivity analyses including multiple cis -SNPs provided similar estimates both for FUT3 (inverse variance weighted (IVW) OR 0.84, 95% CI 0.78–0.91; p=9.8×10 −6 and MR-Egger OR 0.69, 95% CI 0.50–0.97; p=0.03) and FUT5 (IVW OR 0.84, 95% CI 0.77–0.92; p=1.4×10 −4 and MR-Egger OR 0.59, 95% CI 0.38–0.90; p=0.01). FUT3 and FUT5 signals colocalised with IPF signals, with posterior probabilities of a shared genetic signal of 99.9% and 97.7%, respectively. Further transcriptomic investigations supported the protective effects of FUT3 for IPF. Conclusions An efficient MR scan of 834 circulating proteins provided evidence that genetically increased circulating FUT3 level is associated with reduced risk of IPF.
High efficacy of tetra-PEG hydrogel sealants for sutureless dural closure
Authors: Tengjiao Zhu, Hufei Wang, Zehao Jing, Daoyang Fan, Zhongjun Liu, Xing Wang, Yun Tian
Journal: Bioactive Materials (2021)

Advances in meticulous dural closure technique remain a great challenge for watertight dural closure in the aged society, because the cerebrospinal fluid (CSF) leakage after spinal surgery is often accompanied with the disgusting wound infection, meningitis and pseudomeningocele. Here, a tetra-poly (ethylene glycol) (PEG)-based hydrogel sealant is developed with collective advantages of facile operation, high safety, quick set time, easy injectability, favorable mechanical strength and powerful tissue adhesion for effective sutureless dural closure during the surgery procedure. Impressively, this tetra-PEG sealant can instantaneously adhere to the irregular tissue surfaces even in a liquid environment, and effectively prevent or block off the intraoperative CSF leakage for sutureless dural closure and dura regeneration. Together, this sutureless tetra-PEG adhesive can be utilized as a very promising alternative for high-efficient watertight dural closure of the clinical patients who incidentally or deliberately undergo the durotomy during the spinal surgery.
Jarid2 Restricts Long-Term Repopulating Stem Cell Capacity in Multipotent Progenitors and Acts As Tumor Suppressor in Chronic Myeloid Neoplasms
Authors: Hamza Celik, Won Kyun Koh, Elizabeth Leigh Ostrander, Ashley C. Kramer, William C Wilson, Greg Fishberger, Cates Mallaney, Alok Kothari, Grant Anthony Challen
Journal: Blood (2017)
Abstract 435: The Mitochondrial Calcium Uniporter is Necessary for Cardiac Energetic Signaling During Chronic Stress
Authors: Timothy S Luongo, John W Elrod
Journal: Circulation Research (2016)

The mitochondrial calcium uniporter (MCU) is a multicomponent channel that is the primary mechanism for mitochondrial Ca 2+ uptake ( m Ca 2+ ). We previously reported that the MCU is required for energetic signaling to meet contractile demand during the ‘fight or flight’ response. In addition, we showed that deletion of the pore-forming component ( Mcu gene) protected against mitochondria permeability transition pore (MPTP) opening and ischemia-reperfusion injury. However, results from our study and others questioned the physiological relevance of MCU-mediated Ca 2+ uptake during chronic stress states featuring sustained intracellular Ca 2+ load ( i Ca 2+ ). To address this, we deleted Mcu from cardiomyocytes in adult mice ( Mcu cKO) and implanted osmotic pumps to deliver the β adrenergic agonist isoproterenol (iso, 70 mg/kg/day for 14d). In contrast to controls, Mcu cKO mice lacked contractile responsiveness to chronic βAR stimulation with evidence of LV dysfunction and failure by d14 ( Fig 1 ). Next, we crossed the Mcu cKO with mice overexpressing the β2a subunit (β2a-Tg) of the L-type Ca 2+ channel (LTCC). This model displays enhanced LTCC activity and cardiac contractility, but with added stress such as iso infusion, Ca 2+ overload eventually leads to MPTP-dependent cell death and heart failure. Surprisingly, loss of Mcu in this model was lethal with all mice dying by d13 ( Fig 2 ). Baseline echocardiography revealed that loss of Mcu ablated all β2a-mediated enhancements in LV contractility and accelerated dysfunction post-iso. These findings demonstrate that MCU-mediated m Ca 2+ uptake is critical to meet energetic demand during chronic stress states featuring sustained i Ca 2+ load.
The role of interferons in melanoma resistance to immune checkpoint blockade: mechanisms of escape and therapeutic implications
Authors: K. M. Hargadon
Journal: British Journal of Dermatology (2021)

Immune checkpoint blockade (ICB) therapy has achieved unprecedented success in the treatment of metastatic melanoma, though its efficacy is often limited by innate and acquired mechanisms of resistance. Type I and type II interferons (IFNs) act as key determinants of checkpoint blockade therapeutic outcome, and tumour-intrinsic and -extrinsic factors that disrupt IFN activity confer resistance to various checkpoint inhibitors. This review highlights our current understanding of the mechanisms by which tumours disrupt IFN function in the context of ICB, and it discusses therapeutic strategies to overcome these mechanisms of resistance and improve the clinical reach of ICB therapy in patients with melanoma.
Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child
Authors: Masato Ogishi, Rui Yang, Caner Aytekin, David Langlais, Mathieu Bourgey, Taushif Khan, Fatima Al Ali, Mahbuba Rahman, Ottavia M. Delmonte, Maya Chrabieh, Peng Zhang, Conor Gruber, Simon J. Pelham, András N. Spaan, Jérémie Rosain, Wei-Te Lei, Scott Drutman, Matthew D. Hellmann, Margaret K. Callahan, Matthew Adamow, Phillip Wong, Jedd D. Wolchok, Geetha Rao, Cindy S. Ma, Yuka Nakajima, Tomonori Yaguchi, Kenji Chamoto, Samuel C. Williams, Jean-Francois Emile, Flore Rozenberg, Michael S. Glickman, Franck Rapaport, Gaspard Kerner, Garrett Allington, Ilhan Tezcan, Deniz Cagdas, Ferda O. Hosnut, Figen Dogu, Aydan Ikinciogullari, V. Koneti Rao, Leena Kainulainen, Vivien Béziat, Jacinta Bustamante, Silvia Vilarinho, Richard P. Lifton, Bertrand Boisson, Laurent Abel, Dusan Bogunovic, Nico Marr, Luigi D. Notarangelo, Stuart G. Tangye, Tasuku Honjo, Philippe Gros, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova
Journal: Nature Medicine (2021)
The government must support communities across the UK to tackle covid-19 long term
Authors: Maggie Rae
Journal: BMJ (2021)

The government must support communities across the UK to tackle covid-19 long term Working with local public health teams is key to delivering an efficient, sustainable strategy Maggie Rae presidentWith vaccination programmes driving forward across all four nations of the UK, it is certain that we have made much progress in our efforts to tackle covid-19.Public health professionals know, however, that we are far from the end of our work in tackling the wide ranging impacts of the pandemic.