tbuckley/cabot-search huggingface dataset:
Abstract 156: Lower Body Temperature ’Dose’ Associated With Higher Likelihood of Survival Following Cardiac Arrest
Authors: David G Buckler, Konstantinos Totolos, Nabil M Abdulhay, Alexis M Zebrowski, Benjamin S Abella
Journal: Circulation (2019)

Introduction: Post-cardiac arrest pyrexia is associated with poor outcomes following successful resuscitation and return of spontaneous circulation (ROSC). Prior studies have used highest recorded temperature and duration of fever as markers for the severity of pyrexic events. The objective of this research was to evaluate the association of body temperature and survival to discharge. We hypothesized that a lower body temperature “dose” in the 8 days post-arrest would be associated with a higher likelihood of survival. Methods: Using consecutive cardiac arrest cases from a single healthcare system with integrated electronic medical record (EMR), we identified cardiac arrest patients with ROSC. Vital signs for these patients, including body temperature, were queried from the EMR and linked to individual records. We included all temperature measures within 8 days of the cardiac arrest event. Patients with fewer than 5 temperature values during the study period were excluded. For each temperature observation the difference between the recorded temperature value and 37 degrees Celsius, the time since the last observation, and the product of these values was calculated. For each patient, the total ‘dose’ was calculated as the sum of these dose products. The resulting measure has units of degree*hours and represents a measure of duration about or below normal. Multiple logistic regression was used to assess the relationship between body temperature dose and survival to discharge, controlling for age and sex. Results: Between 3/2006 and 3/2016, 352 patients were linked to serial body temperature measurements. 58% were male, mean age was 61 ± 16 years, and 52% survived to discharge. The median body temperature dose measure was 28 degree*hours, (IQR: -0.6 - 98, min: -740, max 390). Results from the multiple logistic regression indicated that for every 10 degree*hour increase in patient body temperature, the odds of survival decreased 3.1 percent (OR: 0.969, p = 0.01) when controlling for age and sex. Conclusion: In this study, lower serial body temperature ‘dose’ was associated with increased odds of survival. These findings are consistent with international guidance around the strong avoidance of fever in post-arrest patients.
Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury
Authors: Laura Wrzosek, Dragos Ciocan, Cindy Hugot, Madeleine Spatz, Margot Dupeux, Camille Houron, Vanessa Lievin-Le Moal, Virginie Puchois, Gladys Ferrere, Nicolas Trainel, Françoise Mercier-Nomé, Sylvere Durand, Guido Kroemer, Cosmin Sebastian Voican, Patrick Emond, Marjolène Straube, Harry Sokol, Gabriel Perlemuter, Anne-Marie Cassard
Journal: Gut (2020)

Chronic alcohol consumption is an important cause of liver-related deaths. Specific intestinal microbiota profiles are associated with susceptibility or resistance to alcoholic liver disease in both mice and humans. We aimed to identify the mechanisms by which targeting intestinal microbiota can improve alcohol-induced liver lesions.We used human associated mice, a mouse model of alcoholic liver disease transplanted with the intestinal microbiota of alcoholic patients and used the prebiotic, pectin, to modulate the intestinal microbiota. Based on metabolomic analyses, we focused on microbiota tryptophan metabolites, which are ligands of the aryl hydrocarbon receptor (AhR). Involvement of the AhR pathway was assessed using both a pharmacological approach and AhR-deficient mice.Pectin treatment modified the microbiome and metabolome in human microbiota-associated alcohol-fed mice, leading to a specific faecal signature. High production of bacterial tryptophan metabolites was associated with an improvement of liver injury. The AhR agonist Ficz (6-formylindolo (3,2-b) carbazole) reduced liver lesions, similarly to prebiotic treatment. Conversely, inactivation of the ahr gene in alcohol-fed AhR knock-out mice abrogated the beneficial effects of the prebiotic. Importantly, patients with severe alcoholic hepatitis have low levels of bacterial tryptophan derivatives that are AhR agonists.Improvement of alcoholic liver disease by targeting the intestinal microbiota involves the AhR pathway, which should be considered as a new therapeutic target.
Improved Noninvasive In Vivo Tracking of AAV-9 Gene Therapy Using the Perchlorate-Resistant Sodium Iodide Symporter from Minke Whale
Authors: Susanna C. Concilio, Lukkana Suksanpaisan, Linh Pham, Kah-Whye Peng, Stephen J. Russell
Journal: Molecular Therapy (2020)

The sodium iodide symporter (NIS) is widely used as a reporter gene to noninvasively monitor the biodistribution and durability of vector-mediated gene expression via gamma scintigraphy, single-photon emission computed tomography (SPECT), and positron-emission tomography (PET). However, the approach is limited by background signal due to radiotracer uptake by endogenous NIS-expressing tissues. In this study, using the SPECT tracer pertechnetate (99mTcO4) and the PET tracer tetrafluoroborate (B18F4), in combination with the NIS inhibitor perchlorate, we compared the transport properties of human NIS and minke whale (Balaenoptera acutorostrata scammoni) NIS in vitro and in vivo. Based on its relative resistance to perchlorate, the NIS protein from minke whale appeared to be the superior candidate reporter gene. SPECT and PET imaging studies in nude mice challenged with NIS-encoding adeno-associated virus (AAV)-9 vectors confirmed that minke whale NIS, in contrast to human and endogenous mouse NIS, continues to function as a reliable reporter even when background radiotracer uptake by endogenous NIS is blocked by perchlorate.
Use of Model-Informed Drug Development to Streamline Development of Long-Acting Products: Can These Successes Be Translated to Long-Acting Hormonal Contraceptives?
Authors: Li Li, Doanh Tran, Hao Zhu, Praveen Balimane, Gerald Willett, Ping Zhao, Stephen E. Gerrard, Kirsten M. Vogelsong, Yaning Wang, Shirley K. Seo
Journal: The Annual Review of Pharmacology and Toxicology (2020)

Long-acting contraceptives are the most effective reversible contraceptive methods. Increasing patients' access to these contraceptives may translate into fewer unintended pregnancies and lead to substantial individual and public health benefits. However, development of long-acting products can be complex and challenging. This review provides (a) an overview of representative development programs for long-acting antipsychotics as cases for conceptual translation to long-acting contraceptives, (b) several case examples on how modeling and simulation have been used to streamline the development of long-acting products, and (c) examples of challenges andopportunities in developing long-acting contraceptives and information on how exposure-response relationships of commonly used progestins may enable regulators and developers to rely on prior findings of effectiveness and safety from an approved contraceptive to streamline the development of long-acting contraceptives. The US Food and Drug Administration is seeking assistance from stakeholders to provide data from studies in which pharmacokinetic and pharmacodynamic or clinical outcomes of hormonal contraceptives were evaluated and not previously submitted.
A 12 Month Multicenter, Parallel, Randomized Trial Of Continuous Positive Airway Pressure In Older People With Obstructive Sleep Apnea Syndrome
Authors: A McMillan, D J Bratton, R Faria, M Laskawiec-Szkonter, S Griffin, R J Davies, A J Nunn, Stradling, R L Riha, M J Morrell, Investigators Predict.
Journal: American Journal of Respiratory and Critical Care Medicine (2014)
Patterns and Predictors of Stress Testing Modality After Percutaneous Coronary Stenting
Authors: Jerome J. Federspiel, Daniel W. Mudrick, Bimal R. Shah, Sally C. Stearns, Frederick A. Masoudi, Patricia A. Cowper, Cynthia L. Green, Pamela S. Douglas
Journal: JACC. Cardiovascular imaging (2012)
Black babies cared for by black doctors less likely to die in US: revolutionise medical education to tackle problem in UK
Authors: Edward J Towning, Akul Purohit
Journal: BMJ (2020)

If the recent wave of anti-racism protests has taught us anything, it is that racial inequality is woven into the fabric of a variety of our most distinguished establishments. From black and minority ethnic (BAME) medical students in the UK being ostracised to discrimination in care homes, it is evident that rampant injustice exists in the health system.

The US has long shown evidence …
Instability of sputum molecular phenotypes in U-BIOPRED severe asthma
Authors: Nazanin Z. Kermani, Stelios Pavlidis, Jiaxing Xie, Kai Sun, Matthew Loza, Fred Baribaud, Steve J. Fowler, Dominic E. Shaw, Louise J. Fleming, Peter H. Howarth, Ana R. Sousa, Julie Corfield, Charles Auffray, Bertrand De Meulder, Peter J. Sterk, Yike Guo, Mohib Uddin, Ratko Djukanovic, Ian M. Adcock, Kian Fan Chung
Journal: European Respiratory Journal (2020)

<b>At 1 year, 45% of severe asthma change molecular phenotype as determined by sputum transcriptomic analysis. Together with concomitant shift in sputum granulocytic markers, this may indicate variability of driving mechanisms in this unstable group.</b>https://bit.ly/35aj489
Epigenome‐Wide Analysis of Methylation Changes in the Sequence of Gallstone Disease, Dysplasia, and Gallbladder Cancer
Authors: Johannes Brägelmann, Carol Barahona Ponce, Katherine Marcelain, Stephanie Roessler, Benjamin Goeppert, Ivan Gallegos, Alicia Colombo, Verónica Sanhueza, Erik Morales, María Teresa Rivera, Gonzalo de Toro, Alejandro Ortega, Bettina Müller, Fernando Gabler, Dominique Scherer, Melanie Waldenberger, Eva Reischl, Felix Boekstegers, Valentina Garate‐Calderon, Sinan U. Umu, Trine B. Rounge, Odilia Popanda, Justo Lorenzo Bermejo
Journal: Hepatology (2020)

Background and Aims Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract. Most cases of GBC are diagnosed in low‐income and middle‐income countries, and research into this disease has long been limited. In this study we therefore investigate the epigenetic changes along the model of GBC carcinogenesis represented by the sequence gallstone disease → dysplasia → GBC in Chile, the country with the highest incidence of GBC worldwide. Approach and Results To perform epigenome‐wide methylation profiling, genomic DNA extracted from sections of formalin‐fixed, paraffin‐embedded gallbladder tissue was analyzed using Illumina Infinium MethylationEPIC BeadChips. Preprocessed, quality‐controlled data from 82 samples (gallstones n = 32, low‐grade dysplasia n = 13, high‐grade dysplasia n = 9, GBC n = 28) were available to identify differentially methylated markers, regions, and pathways as well as changes in copy number variations (CNVs). The number and magnitude of epigenetic changes increased with disease development and predominantly involved the hypermethylation of cytosine–guanine dinucleotide islands and gene promoter regions. The methylation of genes implicated in Wnt signaling, Hedgehog signaling, and tumor suppression increased with tumor grade. CNVs also increased with GBC development and affected cyclin‐dependent kinase inhibitor 2A, MDM2 proto‐oncogene, tumor protein P53, and cyclin D1 genes. Gains in the targetable Erb‐B2 receptor tyrosine kinase 2 gene were detected in 14% of GBC samples. Conclusions Our results indicate that GBC carcinogenesis comprises three main methylation stages: early (gallstone disease and low‐grade dysplasia), intermediate (high‐grade dysplasia), and late (GBC). The identified gradual changes in methylation and CNVs may help to enhance our understanding of the mechanisms underlying this aggressive disease and eventually lead to improved treatment and early diagnosis of GBC.
An evaluation of no‐treatment decisions in patients with newly diagnosed acute myeloid leukemia
Authors: Joseph M. Brandwein, Darren Hallett, Mohammad Karkhaneh, Nancy Zhu, Elena Liew, Lauren Bolster, Marlene Hamilton, Jeffrey Patterson, Minakshi Taparia, Cynthia Wu, Tiffany Van Slyke, Aniket Bankar, Lalit Saini
Journal: American Journal of Hematology (2020)
A Targeted Activatable NIR‐IIb Nanoprobe for Highly Sensitive Detection of Ischemic Stroke in a Photothrombotic Stroke Model
Authors: Xiaohu Yang, Zan Wang, Haoying Huang, Sisi Ling, Rong Zhang, Yejun Zhang, Guangcun Chen, Chunyan Li, Qiangbin Wang
Journal: Advanced Healthcare Materials (2020)

Abstract Ischemic stroke is a devastating disease resulting in high morbidity and mortality. To date, its early diagnosis still faces challenges. Herein, an efficient detection strategy is proposed, in which a targeted activatable NIR‐IIb nanoprobe (V&amp;C/PbS@Ag 2 Se) is constructed for in vivo highly sensitive detection of early ischemic stroke in a photothrombotic stroke model. At first, the fluorescence of V&amp;C/PbS@Ag 2 Se displays an “off” state due to the competitive absorption of excitation irradiation between Cy7.5 fluorophores and PbS@Ag 2 Se quantum dots (QDs). Upon intravenous injection, the V&amp;C/PbS@Ag 2 Se quickly accumulates in the lesion regions based on VCAM1 binding peptide target to the inflamed vascular endothelium of ischemic stroke. Later, the nanoprobes can be rapidly activated via Cy7.5 oxidation by peroxynitrite (ONOO − ), the prodromal biomarker of ischemic stroke, instantly illuminating the lesion regions. Such a targeted activatable strategy offers a favorable approach for in vivo early real‐time assessment of ischemic stroke, which can be expanded to other diseases as a general mothed for in vivo precise diagnosis.
Activation of 4-1BBL+ B cells with CD40 agonism and IFNγ elicits potent immunity against glioblastoma
Authors: Catalina Lee-Chang, Jason Miska, David Hou, Aida Rashidi, Peng Zhang, Rachel A. Burga, Ignacio Jusué-Torres, Ting Xiao, Victor A. Arrieta, Daniel Y. Zhang, Aurora Lopez-Rosas, Yu Han, Adam M. Sonabend, Craig M. Horbinski, Roger Stupp, Irina V. Balyasnikova, Maciej S. Lesniak
Journal: The Journal of Experimental Medicine (2020)

Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B cell–based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNγ stimulation. BVax migrates to key secondary lymphoid organs and is proficient at antigen cross-presentation, which promotes both the survival and the functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunological memory that prevented the growth of new tumors upon subsequent reinjection in cured mice. GBM patient–derived BVax was successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.
Transcriptome analysis of non human primate-induced pluripotent stem cell-derived cardiomyocytes in 2D monolayer culture vs. 3D engineered heart tissue
Authors: Huaxiao Yang, Ningyi Shao, Alexandra Holmström, Xin Zhao, Tony Chour, Haodong Chen, Ilanit Itzhaki, Haodi Wu, Mohamed Ameen, Nathan J Cunningham, Chengyi Tu, Ming-Tao Zhao, Alice F Tarantal, Oscar J Abilez, Joseph C Wu
Journal: Cardiovascular Research (2020)

Stem cell therapy has shown promise for treating myocardial infarction via re-muscularization and paracrine signalling in both small and large animals. Non-human primates (NHPs), such as rhesus macaques (Macaca mulatta), are primarily utilized in preclinical trials due to their similarity to humans, both genetically and physiologically. Currently, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are delivered into the infarcted myocardium by either direct cell injection or an engineered tissue patch. Although both approaches have advantages in terms of sample preparation, cell-host interaction, and engraftment, how the iPSC-CMs respond to ischaemic conditions in the infarcted heart under these two different delivery approaches remains unclear. Here, we aim to gain a better understanding of the effects of hypoxia on iPSC-CMs at the transcriptome level.
Abstract IA11: The War on Melanoma: Oregon’s early detection experiment
Authors: Sancy A. Leachman, Jodi Lapidus, Kemal Sonmez, Michael Heath, Brian Detweiler-Bedell, Jerusha Detweiler-Bedell, Elizabeth G. Berry, Elizabeth Stoos
Journal: Cancer Research (2020)

Abstract Early detection of melanoma has several advantages over treatment of late-stage disease. Cure rates are higher, disfigurement is reduced, both short-term and long-term side effects from unnecessary systemic therapies are avoided, and most importantly, a large number of lives of individuals who would never have responded to these treatments in the first place are saved. Early detection is also likely to reduce the overall cost of care because early-stage treatments are far less expensive than those used in advanced disease. Despite the potential benefits of screening and early detection, relatively few prospective interventional studies have been performed to objectively demonstrate effectiveness or quantify the effects. However, multivariate data do show that a basic awareness of skin health and appearance (not requiring specialized knowledge of melanoma features) is associated with early detection of melanoma. The purpose of the War on Melanoma research study is to prospectively test whether a statewide early-detection campaign can improve melanoma outcomes. We will compare three objective metrics before and after the intervention (the education campaign): (1) melanoma knowledge in the general public by survey of a representative population sample; (2) state cancer registry data on stage, mortality, etc.; and (3) cost information from an all-claims, all-payers database. We hypothesize that there will be an increase in melanoma-specific knowledge in the general public, an improved prognosis at the time of diagnosis, and a decrease in melanoma mortality in Oregon compared to two control states (Utah and Washington). We will also quantify the difference in cost of care for melanoma before and after the campaign and will determine if these costs are associated with knowledge levels and/or prognostic/mortality data. These results will provide a model for future early-detection campaigns in other states or for other cancers, by providing evidence for the impact of public health education. Citation Format: Sancy A. Leachman, Jodi Lapidus, Kemal Sonmez, Michael Heath, Brian Detweiler-Bedell, Jerusha Detweiler-Bedell, Elizabeth G. Berry, Elizabeth Stoos. The War on Melanoma: Oregon’s early detection experiment [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr IA11.
Transient Activation of the Hedgehog-Gli Pathway Rescues Radiotherapy-Induced Dry Mouth via Recovering Salivary Gland Resident Macrophages
Authors: Qingguo Zhao, Linying Zhang, Bo Hai, Jun Wang, Courtney L. Baetge, Michael A. Deveau, Geoffrey M. Kapler, Jian Q. Feng, Fei Liu
Journal: Cancer Research (2020)

Irreversible hypofunction of salivary glands is a common side effect of radiotherapy for head and neck cancer and is difficult to remedy. Recent studies indicate that transient activation of Hedgehog signaling rescues irradiation-impaired salivary function in animal models, but the underlying mechanisms are largely unclear. Here, we show in mice that activation of canonical Gli-dependent Hedgehog signaling by Gli1 gene transfer is sufficient to recover salivary function impaired by irradiation. Salivary gland cells responsive to Hedgehog/Gli signaling comprised small subsets of macrophages, epithelial cells, and endothelial cells, and their progeny remained relatively rare long after irradiation and transient Hedgehog activation. Quantities and activities of salivary gland resident macrophages were substantially and rapidly impaired by irradiation and restored by Hedgehog activation. Conversely, depletion of salivary gland macrophages by clodronate liposomes compromised the restoration of irradiation-impaired salivary function by transient Hedgehog activation. Single-cell RNA sequencing and qRT-PCR of sorted cells indicated that Hedgehog activation greatly enhances paracrine interactions between salivary gland resident macrophages, epithelial progenitors, and endothelial cells through Csf1, Hgf, and C1q signaling pathways. Consistently, expression of these paracrine factors and their receptors in salivary glands decreased following irradiation but were restored by transient Hedgehog activation. These findings reveal that resident macrophages and their prorepair paracrine factors are essential for the rescue of irradiation-impaired salivary function by transient Hedgehog activation and are promising therapeutic targets of radiotherapy-induced irreversible dry mouth. SIGNIFICANCE: These findings illuminate a novel direction for developing effective treatment of irreversible dry mouth, which is common after radiotherapy for head and neck cancer and for which no effective treatments are available. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5531/F1.large.jpg.See related commentary by Coppes, p. 5462.
From Basic Science to Clinical Application of Polygenic Risk Scores
Authors: Naomi R. Wray, Tian Lin, Jehannine Austin, John J. McGrath, Ian B. Hickie, Graham K. Murray, Peter M. Visscher
Journal: JAMA Psychiatry (2020)

Polygenic risk scores (PRS) are predictors of the genetic susceptibilities of individuals to diseases. All individuals have DNA risk variants for all common diseases, but genetic susceptibility differences between people reflect the cumulative burden of these. Polygenic risk scores for an individual are calculated as weighted counts of thousands of risk variants that they carry, where the risk variants and their weights have been identified in genome-wide association studies. Here, we review the underlying basic science of PRS, providing a foundation for understanding the potential clinical utility and limitations of PRS.Polygenic risk scores can be calculated for a wide range of diseases from a saliva or blood sample using genotyping technologies that are inexpensive. While genotyping only needs to be done once for each individual in their lifetime, the PRS can be recalculated as identification of risk variants improves. On their own, PRS will never be able to establish or definitively predict future diagnoses of common complex conditions because genetic factors only contribute part of the risk, and PRS will only ever capture part of the genetic contributions. Nonetheless, just as clinical medicine uses a multitude of other predictive measures, PRS either on their own or as part of multivariable predictive algorithms could play a role.Utility of PRS in clinical medicine and ethical issues related to their use should be evaluated in the context of realistic expectations of what PRS can and cannot deliver. For different diseases, PRS could have utility in community settings (stratification to better triage people into established screening programs) or could contribute to clinical decision-making for those presenting with symptoms but where formal diagnosis is unclear. In principle, PRS could contribute to treatment choices, but more data are needed to allow development of PRS in this context.
Synaptic vesicles transiently dock to refill release sites
Authors: Grant F. Kusick, Morven Chin, Sumana Raychaudhuri, Kristina Lippmann, Kadidia P. Adula, Edward J. Hujber, Thien Vu, M. Wayne Davis, Erik M. Jorgensen, Shigeki Watanabe
Journal: Nature Neuroscience (2020)