tbuckley/cabot-search huggingface dataset:
Hepatic Krüppel-like factor 16 (KLF16) targets PPARα to improve steatohepatitis and insulin resistance
Authors: Nannan Sun, Chuangpeng Shen, Lei Zhang, Xiaojie Wu, Yuanyuan Yu, Xiaoying Yang, Chen Yang, Chong Zhong, Zhao Gao, Wei Miao, Zehong Yang, Weihang Gao, Ling Hu, Kevin Williams, Changhui Liu, Yongsheng Chang, Yong Gao
Journal: Gut (2020)

Objective Impaired hepatic fatty acids oxidation results in lipid accumulation and redox imbalance, promoting the development of fatty liver diseases and insulin resistance. However, the underlying pathogenic mechanism is poorly understood. Krüppel-like factor 16 (KLF16) is a transcription factor that abounds in liver. We explored whether and by what mechanisms KLF16 affects hepatic lipid catabolism to improve hepatosteatosis and insulin resistance. Design KLF16 expression was determined in patients with non-alcoholic fatty liver disease (NAFLD) and mice models. The role of KLF16 in the regulation of lipid metabolism was investigated using hepatocyte-specific KLF16-deficient mice fed a high-fat diet (HFD) or using an adenovirus/adeno-associated virus to alter KLF16 expression in mouse primary hepatocytes (MPHs) and in vivo livers. RNA-seq, luciferase reporter gene assay and ChIP analysis served to explore the molecular mechanisms involved. Results KLF16 expression was decreased in patients with NAFLD, mice models and oleic acid and palmitic acid (OA and PA) cochallenged hepatocytes. Hepatic KLF16 knockout impaired fatty acid oxidation, aggravated mitochondrial stress, ROS burden, advancing hepatic steatosis and insulin resistance. Conversely, KLF16 overexpression reduced lipid deposition and improved insulin resistance via directly binding the promoter of peroxisome proliferator-activated receptor α (PPARα) to accelerate fatty acids oxidation and attenuate mitochondrial stress, oxidative stress in db/db and HFD mice. PPARα deficiency diminished the KLF16-evoked protective effects against lipid deposition in MPHs. Hepatic-specific PPARα overexpression effectively rescued KLF16 deficiency-induced hepatic steatosis, altered redox balance and insulin resistance. Conclusions These findings prove that a direct KLF16–PPARα pathway closely links hepatic lipid homeostasis and redox balance, whose dysfunction promotes insulin resistance and hepatic steatosis.
15162 Effectiveness of adalimumab in hidradenitis suppurativa: A real-world study
Authors: Lya Magdalena Moneva-Leniz, Ramón García-Ruiz, Eva María Sánchez Martínez, Hector Gegundez Hernández, Javier Melgosa Ramos, María Isabel García Briz, Almudena Mateu Puchades
Journal: Journal of the American Academy of Dermatology (2020)
Ventricular tachycardia, premature ventricular contractions, and mortality in unselected patients with lung, colon, or pancreatic cancer: a prospective study
Authors: Markus S. Anker, Stephan von Haehling, Andrew J.S. Coats, Hanno Riess, Jan Eucker, Jan Porthun, Javed Butler, Mahir Karakas, Wilhelm Haverkamp, Ulf Landmesser, Stefan D. Anker
Journal: European Journal of Heart Failure (2020)
15807 Efficacy of tildrakizumab in patients with moderate to severe psoriasis according to disease duration: Pooled analysis from reSURFACE 1 and reSURFACE 2 phase 3 trials at week 28
Authors: Diamant Thaçi, Lars Iversen, Ignasi Pau-Charles, Andreu Schoenenberger López, Andrew Blauvelt, Lluís Puig
Journal: Journal of the American Academy of Dermatology (2020)
Effect of complexing lipids on cellular uptake and expression of messenger RNA in human skin explants
Authors: Anna K. Blakney, Polina Deletic, Paul F. McKay, Clément R. Bouton, Marianne Ashford, Robin J. Shattock, Alan Sabirsh
Journal: Journal of Controlled Release (2020)

Messenger RNA (mRNA) represents a promising next-generation approach for both treatment and vaccination. Lipid based particles are one of the most investigated delivery systems for mRNA formulations. Here we explore how the complexing lipid affects uptake and translation of lipoplex-delivered RNA in resident cells in human skin explants and, we explore a more modular delivery system that utilizes mRNA added to pre-formed nanoparticles prior to dosing. We prepared formulations of lipoplexes with ionizable, cationic or zwitterionic lipids, externally complexed these with mRNA, and observed which cells internalized and/or expressed the mRNA over 72 h after intradermal injections into primary, human, skin explants. Using a flow cytometry panel to assess cellular phenotypes, mRNA uptake and mRNA expression, we found that, unlike other cell types, adipocytes expressed mRNA efficiently at 4 and 24 h after mRNA-lipoplex injection and contributed the greatest proportion of total RNA-encoded protein expression, despite being the lowest frequency cell type. Other cell types (epithelial cells, fibroblasts, T cells, B cells, dendritic cells, monocytes, NK cells, Langerhans cells, and leukocytes) had increasing mRNA expression over the course of 72 h, irrespective of lipoplex formulation. We observed that overall charge of the particle, but not the complexing lipid classification, was predictive for the pattern of mRNA uptake and expression among resident cell types in this model. This study provides insight into maximizing protein expression, using modular mRNA lipoplexes that are more compatible with product development, in a clinically relevant, human skin explant model.
Recent advances in nanotherapeutics for the treatment and prevention of acute kidney injury
Authors: Hui Yu, Di Liu, Gaofeng Shu, Feiyang Jin, Yongzhong Du
Journal: Asian Journal of Pharmaceutical Sciences (2020)

Acute kidney injury (AKI) is a serious kidney disease without specific medications currently except for expensive dialysis treatment. Some potential drugs are limited due to their high hydrophobicity, poor in vivo stability, low bioavailability and possible adverse effects. Besides, kidney-targeted drugs are not common and small molecules are cleared too quickly to achieve effective drug concentrations in injured kidneys. These problems limit the development of pharmacological therapy for AKI. Nanotherapeutics based on nanotechnology have been proved to be an emerging and promising treatment strategy for AKI, which may solve the pharmacological therapy dilemma. More and more nanotherapeutics with different physicochemical properties are developed to efficiently deliver drugs, increase accumulation and control release of drugs in injury kidneys and also directly as effective antioxidants. Here, we discuss the recent nanotherapeutics applied in the treatment and prevention of AKI with improved effectiveness and few side effects.
18847 A case-control study evaluating impact on tumor response and Survival outcomes of bullous pemphigoid following anti–PD-1 therapy
Authors: Sean Singer, Caroline Nelson, Tianqi Chen, Ashleigh Eberly-Puelo, Christine G. Lian, Erin Wei, Anita Giobbe-Hurder, Arash Mostaghimi, Nicole LeBoeuf
Journal: Journal of the American Academy of Dermatology (2020)
Adoptive cell therapy: Living drugs against cancer
Authors: Tamara Laskowski, Katayoun Rezvani
Journal: The Journal of Experimental Medicine (2020)

Immunotherapy has made a profound impact in the treatment of cancer in the last decade. Insights from the study of the intricate relationships between immune cells and cancer have led to the clinical development of strategies that redirect the power of the immune system to target and eliminate cancer. Today, immunotherapy represents a rapidly expanding and transformative force comprising multiple modalities.
Pandemic communications: follow the science but lead with psychology
Authors: Joseph Zacharias, Megan Joffe
Journal: BMJ (2020)

The evolving pandemic has exposed weaknesses in our society. This is particularly obvious in countries where democracy and autonomy are paramount.1 “Follow the science” is a phrase we hear from politicians. But science is not a straight and narrow stream that flows steadily in one direction. It often meanders along, taking the occasional wrong turn, trying to course around areas of resistance. Eventually, it finds a way through when the …
72MO Selinexor in combination with standard chemotherapy in patients with advanced solid tumours: Results of an open label, single-center, multi-arm phase Ib study
Authors: K.Z. Thein, A.M. Tsimberidou, S.A. Piha-Paul, F. Janku, D.D. Karp, S. Fu, A. Zarifa, J. Gong, D.S. Hong, T.A. Yap, V. Subbiah, S. Pant, F. Meric-Bernstam, A. Naing
Journal: Annals of Oncology (2020)
Life course psychological distress and cardiovascular disease risk factors in middle age: birth cohort study
Authors: G D Batty, Mark Hamer, Catharine R Gale
Journal: Cardiovascular Research (2020)

Recent findings suggest that psychological distress in childhood-a combination of symptoms of anxiety and depression-particularly when persistent across the life course is related to an elevated rate of cardiovascular disease mortality in older age. 1 Several mechanisms have been implicated with one possibility being that people who experience distress in early life, and particularly its recurrence across the life course, may become more susceptible to vascular disease via differences in physiological development.There is, however, a paucity of studies holding data on early distress and biological risk factors for cardiovascular disease in adulthood.To the best of our knowledge, only two studies have examined these pathways.In an extended follow-up of the National Collaborative Perinatal Project, a small US prospective study, 2 there was a suggestion that a single measurement of poor emotional functioning at age 7 was associated with the activation of the inflammatory system as indicated by higher levels of C-reactive protein at age 42 years.Furthermore, in a large study of a UK population, 3 investigators explored the links between psychological distress across the life course and an amalgamation of cardio-metabolic risk factors in middle age which included blood pressure and glycosylated haemoglobin.Psychological distress at any point across the life course was associated with a less favourable risk profile in middle age, although effects were typically modest.Given the rarity of data in this area, we tested the hypothesis that individuals who reported persistent distress across the life course will experience the most unfavourable levels of cardiovascular disease risk factors, including inflammatory indices, glucose metabolism, and lipids, some of which are also important health outcomes in their own right.The 1970 British Cohort Study is an ongoing, prospective cohort study.Based on a representative sample of people born in the UK in a single week of that year, 4 for the purposes of the present analyses, we used distress data from sweeps administered at ages 5, 10, and 26.In childhood, the Rutter A scale was used to ask teachers and parents about the behavioural and emotional problems of the study member. 5In adulthood, the Malaise inventory, which has been validated against psychiatric morbidity and service use, 6 was administered directly to the study members.At ages 5 and 10 years, values above the 80th centile denoted distress on the Rutter scale, 5 while at age 26 a score of > _8 on
The Promise of Quantitative Computed Tomography Coronary Angiography and Noninvasive Segmental Coronary Plaque Quantification: Pushing the “Edge”⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: John A. Rumberger
Journal: Journal of the American College of Cardiology (2006)
Changes in iron status may affect breast cancer outcomes in pre- and post-menopausal women
Authors: Xi Huang, Jisen Dai, Jinlong Jian, Stuart Brown, Jonathan Eckard, Daniel Maes, Edward Pelle
Journal: Cancer Research (2008)

3698  Estrogen and family history are two of the most important risk factors in breast cancer. Yet, estrogen and family history cannot explain the differences in breast cancer recurrence and incidence rates between pre- and post-menopausal women. In the present study, we have tested a hypothesis that in pre-menopausal women, an iron deficiency due to menstruation stabilizes hypoxia inducible factor-1α, a transcriptional signaling factor which increases vascular endothelial growth factor (VEGF) formation. This mechanism makes the pre-menopausal patients more susceptible to angiogenesis and, consequently, leads to higher recurrence rates. Conversely, increased iron levels in post-menopausal women due to menstrual period cessation contribute to higher breast cancer incidence rates via oxidative stress pathway. Because there is a lack of animal models simultaneously mimicking menopausal transition of both iron and estrogen levels, we first tested our hypothesis in a tissue culture model of high estrogen and low iron (17β-estradiol and apo-transferrin) or low estrogen and high iron (holo-transferrin and ferritin), simulating pre- and post-menopausal conditions. We found that breast cancer MCF-7 cells and primary human normal epidermal keratinocytes (NHEK) cells grown under pre-menopausal conditions lead to significantly higher levels of VEGF than those from the same cells grown under post-menopausal conditions. By testing each component separately, we further found that estrogen slightly up-regulated VEGF and it was ferritin that significantly suppressed VEGF. On the contrary, more alterations in oxidative stress were observed in cells grown under post- as compared to the same cells grown under pre-menopausal conditions. Using Affymetrix genechip® technology, we identified approximately 140 genes that were altered in primary NHEK cells by post-menopausal conditions but no gene modifications in cells grown under pre-menopausal conditions as compared to cells without treatment. We then extended our studies using human biopsies from pre- and post-menopausal skin. It was found that levels of ferritin inversely correlated with levels of VEGF. Our study indicates that iron, a growth nutrient as important as estrogen in female metabolism and development, and its change during menopausal transition, may hold key information and explanations to breast cancer outcomes. This work is partly supported by R21 CA132684.
Offline: COVID-19—what have we learned so far?
Authors: Richard Horton
Journal: The Lancet (2020)

COVID-19 has left little time for reflection about lessons to be learned. This coronavirus has provoked us, mobilised us, and distracted us. But with a vaccine on the horizon, it's perhaps time to pause. What have we discovered this past year? And how do these discoveries inform our future? Our annual Lancet–Chinese Academy of Medical Sciences conference—held virtually last week—provided a moment for such contemplation.
In Science We Trust? Being Honest About the Limits of Medical Research During COVID-19
Authors: Walter Veit, Rebecca Brown, Brian D. Earp
Journal: The American Journal of Bioethics (2020)

Click to increase image sizeClick to decrease image sizeThis article refers to:Self-Defeating Codes of Medical Ethics and How to Fix Them: Failures in COVID-19 Response and Beyond Notes1 So, too, should the steps between primary evidence collection, drawing of inferences about the real-world meaning of any observed effects, and the formulation and roll-out of public health policy typically be slow, with adequate attention paid to complex contextual (e.g., sociocultural) factors, robust translational research, and the use of realistic models of human behavior, i.e., outside of relatively tightly-controlled clinical or experimental contexts (Earp and Darby Citation2019; Fish et al Citation2020; Ijzerman et al. Citation2020).2 Of course, it is important that the current advice is given with ‘confidence intervals’ around it, with appropriate qualifications about the sources and strength of evidence, its limitations and generalizability, and so on. By contrast, if the current advice is given in an overly confident, definitive way—and then it needs to be updated in light of new evidence—this may contribute to the perception that science and medicine are unreliable.
CMR Imaging for Diastolic Hemodynamic Assessment: Fantasy or Reality?⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Jae K. Oh, Sung-A. Chang, Yeon-Hyeon Choe, Phillip M. Young
Journal: JACC. Cardiovascular imaging (2012)
Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: a systematic analysis for the Global Burden of Disease Study 2019
Authors: Alarcos Cieza, Kate Causey, Kaloyan Kamenov, Sarah Wulf Hanson, Somnath Chatterji, Theo Vos
Journal: The Lancet (2020)

Rehabilitation has often been seen as a disability-specific service needed by only few of the population. Despite its individual and societal benefits, rehabilitation has not been prioritised in countries and is under-resourced. We present global, regional, and country data for the number of people who would benefit from rehabilitation at least once during the course of their disabling illness or injury.To estimate the need for rehabilitation, data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 were used to calculate the prevalence and years of life lived with disability (YLDs) of 25 diseases, impairments, or bespoke aggregations of sequelae that were selected as amenable to rehabilitation. All analyses were done at the country level and then aggregated to seven regions: World Bank high-income countries and the six WHO regions (ie, Africa, the Americas, Southeast Asia, Europe, Eastern Mediterranean, and Western Pacific).Globally, in 2019, 2·41 billion (95% uncertainty interval 2·34-2·50) individuals had conditions that would benefit from rehabilitation, contributing to 310 million [235-392] YLDs. This number had increased by 63% from 1990 to 2019. Regionally, the Western Pacific had the highest need of rehabilitation services (610 million people [588-636] and 83 million YLDs [62-106]). The disease area that contributed most to prevalence was musculoskeletal disorders (1·71 billion people [1·68-1·80]), with low back pain being the most prevalent condition in 134 of the 204 countries analysed.To our knowledge, this is the first study to produce a global estimate of the need for rehabilitation services and to show that at least one in every three people in the world needs rehabilitation at some point in the course of their illness or injury. This number counters the common view of rehabilitation as a service required by only few people. We argue that rehabilitation needs to be brought close to communities as an integral part of primary health care to reach more people in need.Bill & Melinda Gates Foundation.
Abstract IA21: Metabolic phenotypes and liabilities in human cancer
Authors: Ralph J. DeBerardinis
Journal: Cancer Research (2020)

Abstract Metabolic reprogramming in cancer arises from a complex, incompletely-defined combination of factors intrinsic and extrinsic to malignant cells. In some cases, reprogrammed pathways contribute to the process of transformation, and in many others they enable cancer progression by supporting cell survival and excessive growth. The clinical relevance of cancer metabolism is emphasized by the fact that numerous imaging modalities and therapeutic strategies in cancer capitalize on the altered metabolic states present in tumors. Recent work has emphasized that metabolic phenotypes and liabilities evolve as cancer progresses, such that pathways required for cancer initiation may be dispensable in more advanced stages, and vice versa. A key challenge is to define metabolic properties that support key aspects of cancer progression, particularly metastasis and acquired therapy resistance, which account for the majority of cancer-related deaths. Because these processes are difficult to model in culture, we have developed clinical approaches to study cancer metabolism in vivo, in patients, and to uses these approaches to identify features that drive cancer progression. I will discuss approaches using metabolomics and intra-operative infusions with 13C-labeled nutrients to assess metabolic pathway utilization in human tumors. We use this approach to characterize metabolic heterogeneity among tumors arising in different organs, to identify areas of regional metabolic heterogeneity within solid tumors and to predict which activities support cancer progression. Our work to this point demonstrates marked diversity of fuel preferences in primary tumors and unexpected roles of particular pathways in cancer cell biology. Citation Format: Ralph J. DeBerardinis. Metabolic phenotypes and liabilities in human cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr IA21.
Abstract 283: Cerebral Regional Oxygen Saturation (rSO <sub>2</sub> ) Will Support to Evaluate an Oxygenation for Emergency Patients Who Can Not Measure SpO <sub>2</sub> at the Scene
Authors: Tomohiko Sakai, Tadahiko Shiozaki, Mitsuo Ohnishi, Ryosuke Takegawa, Jotaro Tachino, Arisa Muratsu, Shunichiro Nakao, Takeshi Shimazu
Journal: Circulation (2019)

Introduction: There are some critical ill patients who cannot measure oxygen saturation (SpO 2 ) by pulse oximeter at the pre-hospital settings. For example, among emergency patients who were treated by emergency medical service (EMS) personnel of Osaka Municipal Fire Department in 2016, there were 3,571 patients who had urgent conditions judged by on-scene EMS personnel but did not have cardiopulmonary arrest (CPA), but the measurement of SpO 2 at the scene could not be measured for 395 patients. On the other hand, the measurement of cerebral regional oxygen saturation (rSO 2 ) during resuscitation has been recently paid to attention. Purpose: To evaluate whether rSO 2 could be measured for these patients.Materials and Methods: We developed portable rSO 2 monitors and equipped them in nine ambulances (There are 63 ambulances in Osaka City). We measured serial changes in cerebral rSO 2 among emergency patients who had urgent conditions judged by on-scene EMS personnel and could not be measured SpO 2 at the scene from April 1st 2018 through March 31st 2019. Results: During the study period, there were 788 patients with incapable-measurement SpO 2 who had urgent conditions judged by on-scene EMS personnel but did not have CPA. We evaluated serial changes in cerebral rSO 2 among 12 patients at the pre-hospital settings. The values of many cases were lower than the normal rangemeasured from healthy adults (71.2 ± 3.9%, on room air). Some cases could not be measured at once during transport to a hospital in spite of any oxygenation. Three cases had &amp;gt; 60 mmHg of systolic blood pressure or an un-palpable radial artery. At some cases, rSO 2 value increased by oxygenation or ventilation. Conclusions: We could measure serial changes in cerebral rSO 2 among fourteen patients without the measurement of SpO 2 at the scene. Our data suggest that pre-hospital monitoring of cerebral rSO 2 might be a new physiological monitoring for urgent patients during transport.
Mild parenchymal lung disease is still lung disease
Authors: Robin Condliffe, David G. Kiely, Robert A. Lewis
Journal: European Respiratory Journal (2020)

<b>Response to correspondence regarding the recent paper: "Mild parenchymal lung disease and/or low diffusion capacity impacts survival and treatment response in patients diagnosed with idiopathic pulmonary arterial hypertension"</b>https://bit.ly/2Gy6Dco