tbuckley/cabot-search huggingface dataset:
Targeting impaired nutrient sensing with repurposed therapeutics to prevent or treat age-related cognitive decline and dementia: A systematic review
Authors: Benjamin Kioussis, Camilla S.L. Tuttle, Daniel S. Heard, Brian K. Kennedy, Nicola T. Lautenschlager, Andrea B. Maier
Journal: Ageing Research Reviews (2021)

Dementia is a debilitating syndrome that significantly impacts individuals over the age of 65 years. There are currently no disease-modifying treatments for dementia. Impairment of nutrient sensing pathways has been implicated in the pathogenesis of dementia, and may offer a novel treatment approach for dementia.This systematic review collates all available evidence for Food and Drug Administration (FDA)-approved therapeutics that modify nutrient sensing in the context of preventing cognitive decline or improving cognition in ageing, mild cognitive impairment (MCI), and dementia populations.PubMed, Embase and Web of Science databases were searched using key search terms focusing on available therapeutics such as 'metformin', 'GLP1', 'insulin' and the dementias including 'Alzheimer's disease' and 'Parkinson's disease'. Articles were screened using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia). The risk of bias was assessed using the Cochrane Risk of Bias tool v 2.0 for human studies and SYRCLE's risk of bias tool for animal studies.Out of 2619 articles, 114 were included describing 31 different 'modulation of nutrient sensing pathway' therapeutics, 13 of which specifically were utilized in human interventional trials for normal ageing or dementia. Growth hormone secretagogues improved cognitive outcomes in human mild cognitive impairment, and potentially normal ageing populations. In animals, all investigated therapeutic classes exhibited some cognitive benefits in dementia models. While the risk of bias was relatively low in human studies, this risk in animal studies was largely unclear.Modulation of nutrient sensing pathway therapeutics, particularly growth hormone secretagogues, have the potential to improve cognitive outcomes. Overall, there is a clear lack of translation from animal models to human populations.
Apolipoprotein C3 aggravates diabetic nephropathy in type 1 diabetes by activating the renal TLR2/NF-κB pathway
Authors: Huan Wang, Xiaomin Huang, Pengfei Xu, Xuejing Liu, Zihao Zhou, Fuhua Wang, Jingyi Li, Yuhui Wang, Xunde Xian, George Liu, Wei Huang
Journal: Metabolism (2021)
Early Cryoprecipitate Use—Time to Change Our Pediatric Massive Transfusion Protocol?
Authors: Gary W. Nace, Michael L. Nance
Journal: JAMA Surgery (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 Surgery 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 Surgery journal
CXCL9-expressing tumor-associated macrophages: new players in the fight against cancer
Authors: Paola Marie Marcovecchio, Graham Thomas, Shahram Salek-Ardakani
Journal: Journal for ImmunoTherapy of Cancer (2021)

Tumor-associated macrophages (TAMs) are among the main contributors to immune suppression in the tumor microenvironment, however, TAM depletion strategies have yielded little clinical benefit. Here, we discuss the concept that TAMs are also key regulators of anti-PD(L)-1-mediated CD8 T cell-dependent immunity. Emerging data suggest that expression of the chemokine CXCL9 by TAMs regulates the recruitment and positioning of CXCR3-expressing stem-like CD8 T (T stem ) cells that underlie clinical responses to anti-PD(L)-1 treatment. We evaluate clinical and mechanistic studies that establish relationships between CXCL9-expressing TAMs, T stem and antitumor immunity. Therapies that enhance anti-PD(L)-1 response rates must consider TAM CXCL9 expression. In this perspective, we discuss opportunities to enhance the frequency and function of CXCL9 expressing TAMs and draw on comparative analyzes from infectious disease models to highlight potential functions of these cells beyond T stem recruitment.
Abstract SP159: EMT
Authors: J Yang
Journal: Cancer Research (2021)

Abstract During metastasis, epithelial tumor cells dissociate from each other, disseminate into the systemic circulation, and then establish secondary tumors in distant sites. A developmental program termed Epithelial-Mesenchymal Transition (EMT) is implicated in promoting the dissemination of single carcinoma cells during metastasis. Our recent studies aim to understand how EMT is dynamically regulated in response to signals from the tumor microenvironment and from the intracellular machineries to impact EMT and tumor metastasis. Specifically, I will present a mechanotransduction pathway that senses and transmits mechanincal cues from stiff matrix in the tumor microenvironment to promote EMT and invasion during tumor progression. Breast tumors are often detected due to their apparent “hardness” compared to normal tissues, and increasing matrix stiffness correlates with distant metastasis and poor survival in breast cancer patients. These observations raise the question of how mechanical forces generated by the rigid tumor ECM impact tumor progression and metastasis. In a hydrogel coupled with 3D Matrigel overlay culture system that recapitulates the range of physiological stiffness from normal mammary glands to breast tumors, increased ECM stiffness triggers Epithelial-Mesenchymal Transition (EMT), invasion and metastasis. We previously reported that the transcription factor Twist1 is an essential mechano-mediator that promotes EMT and metastasis in response to ECM stiffness. High matrix stiffness promotes Twist1 nuclear localization through phosphorylation-dependent regulation of its interaction with cytoplasmic anchor G3BP2. Using kinase screening and protein affinity purification, we identified a novel mechanoresponsive protein complex including an ephrin receptor and a Src-family kinase that promotes Twist1 phosphorylation and subsequent nuclear translocation in response to high matrix rigidity. Pharmacological and genetic inhibition of this mechanotransduction pathway blocks ECM stiffness-induced EMT and invasion in vitro and inhibits metastasis in human breast tumor xenografts. Our findings reveal a novel mechanotransduction pathway that responds to mechanical signals from the tumor microenvironment to drive EMT, invasion, and metastasis. Citation Format: J Yang. EMT [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP159.
Abstract SP059: Toxicities of breast cancer treatment
Authors: N Henry
Journal: Cancer Research (2021)

Abstract Advances in screening and treatment of breast cancer have led to reductions in breast cancer recurrence and mortality. However, systemic therapies can cause long-term and late effects that negatively impact the quality of life of patients with breast cancer. It is important for patients to be aware of the potential risks, and for providers to be knowledgeable about symptom management options. For example, taxane chemotherapies reduce the risk of disease recurrence but can cause long-lasting neuropathy that interferes with activities of daily living. Unfortunately, few effective interventions for preventing or treating neuropathy have thus far been identified. Similarly, endocrine therapies significantly reduce the risk of recurrence of hormone receptor positive breast cancer. However, tamoxifen and the aromatase inhibitors can cause menopausal symptoms and arthralgias that affect survivors of breast cancer of all ages. Interventions that can effectively treat these symptoms in some, but not all, patients have been identified. In this educational session, prevention and treatment approaches for key long-term and late effects in patients with breast cancer will be discussed. Citation Format: N Henry. Toxicities of breast cancer treatment [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP059.
Risk of skin cancer in new users of thiazides and thiazide‐like diuretics: a cohort study using an active comparator group*
Authors: R. Schneider, D. Reinau, S. Stoffel, S.S. Jick, C.R. Meier, J. Spoendlin
Journal: British Journal of Dermatology (2021)

Case-control studies report a dose-dependent increased risk of skin cancer in users of hydrochlorothiazide (HCTZ) vs. nonusers. The degree to which other thiazides and thiazide-like diuretics (TZs) are associated with skin cancer is less certain.To assess the risk of skin cancer in new users of different TZs compared with new users of calcium channel blockers (CCBs).We conducted a cohort study using a UK primary-care database (1998-2017), including 271 154 new TZ users [87·6% bendroflumethiazide (BFT), 5·8% indapamide and 3·6% HCTZ] and 275 263 CCB users. The outcomes were basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM). We estimated incidence rates (IRs) and IR ratios (IRRs) in short-term (< 20 prescriptions) and long-term (≥ 20 prescriptions) users of TZs and CCBs using negative binomial regression, and calculated rate differences (RDs) for selected results. We used fine stratification on the propensity score (PS) to control for 23 baseline covariates.Long-term use of HCTZ increased absolute and relative risks of SCC [PS-weighted IRR 1·95; 95% confidence interval (CI) 1·87-2·02; RD per 100 000 person-years 87.4], but not of BCC or CMM. Long-term use of indapamide was associated with an increased incidence of CMM (IRR 1·43; 95% CI 1·35-1·50). BFT was not meaningfully associated with the risk of any type of skin cancer.Our results corroborate the previously reported increased risk of SCC (but not of BCC or CMM) for long-term use of HCTZ. BFT may be a safer alternative for patients at increased risk of skin cancer.
MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT
Authors: Tao Shen, Wei Wang, Wolong Zhou, Ilsa Coleman, Qinbo Cai, Bingning Dong, Michael M. Ittmann, Chad J. Creighton, Yingnan Bian, Yanling Meng, David R. Rowley, Peter S. Nelson, David D. Moore, Feng Yang
Journal: Journal of Clinical Investigation (2021)

Prostate cancer (PCa) is the second leading cause of cancer death in American men. Androgen receptor (AR) signaling is essential for PCa cell growth/survival and remains a key therapeutic target for lethal castration-resistant PCa (CRPC). GATA2 is a pioneer transcription factor crucial for inducing AR expression/activation. We recently reported that MAPK4, an atypical MAPK, promotes tumor progression via noncanonical activation of AKT. Here, we demonstrated that MAPK4 activated AR by enhancing GATA2 transcriptional expression and stabilizing GATA2 protein through repression of GATA2 ubiquitination/degradation. MAPK4 expression correlated with AR activation in human CRPC. Concerted activation of both GATA2/AR and AKT by MAPK4 promoted PCa cell proliferation, anchorage-independent growth, xenograft growth, and castration resistance. Conversely, knockdown of MAPK4 decreased activation of both AR and AKT and inhibited PCa cell and xenograft growth, including castration-resistant growth. Both GATA2/AR and AKT activation were necessary for MAPK4 tumor-promoting activity. Interestingly, combined overexpression of GATA2 plus a constitutively activated AKT was sufficient to drive PCa growth and castration resistance, shedding light on an alternative, MAPK4-independent tumor-promoting pathway in human PCa. We concluded that MAPK4 promotes PCa growth and castration resistance by cooperating parallel pathways of activating GATA2/AR and AKT and that MAPK4 is a novel therapeutic target in PCa, especially CRPC.
Clonal expansion and activation of tissue-resident memory-like T <sub>H</sub> 17 cells expressing GM-CSF in the lungs of patients with severe COVID-19
Authors: Yu Zhao, Christoph Kilian, Jan-Eric Turner, Lidia Bosurgi, Kevin Roedl, Patricia Bartsch, Ann-Christin Gnirck, Filippo Cortesi, Christoph Schultheiß, Malte Hellmig, Leon U.B. Enk, Fabian Hausmann, Alina Borchers, Milagros N. Wong, Hans-Joachim Paust, Francesco Siracusa, Nicola Scheibel, Marissa Herrmann, Elisa Rosati, Petra Bacher, Dominik Kylies, Dominik Jarczak, Marc Lütgehetmann, Susanne Pfefferle, Stefan Steurer, Julian Schulze zur Wiesch, Victor G. Puelles, Jan-Peter Sperhake, Marylyn M. Addo, Ansgar W. Lohse, Mascha Binder, Samuel Huber, Tobias B. Huber, Stefan Kluge, Stefan Bonn, Ulf Panzer, Nicola Gagliani, Christian F. Krebs
Journal: Science Immunology (2021)

Tissue-resident memory-like T H 17 cells are clonally expanded in bronchoalveolar lavage fluid of patients with severe COVID-19.
Impact of physical distancing measures against COVID-19 on contacts and mixing patterns: repeated cross-sectional surveys, the Netherlands, 2016–17, April 2020 and June 2020
Authors: Jantien A Backer, Liesbeth Mollema, Eric RA Vos, Don Klinkenberg, Fiona RM van der Klis, Hester E de Melker, Susan van den Hof, Jacco Wallinga
Journal: Eurosurveillance (2021)

BackgroundDuring the COVID-19 pandemic, many countries have implemented physical distancing measures to reduce transmission of SARS-CoV-2.AimTo measure the actual reduction of contacts when physical distancing measures are implemented.MethodsA cross-sectional survey was carried out in the Netherlands in 2016-17, in which participants reported the number and age of their contacts the previous day. The survey was repeated among a subsample of the participants in April 2020, after strict physical distancing measures were implemented, and in an extended sample in June 2020, after some measures were relaxed.ResultsThe average number of community contacts per day was reduced from 14.9 (interquartile range (IQR): 4-20) in the 2016-17 survey to 3.5 (IQR: 0-4) after strict physical distancing measures were implemented, and rebounded to 8.8 (IQR: 1-10) after some measures were relaxed. All age groups restricted their community contacts to at most 5, on average, after strict physical distancing measures were implemented. In children, the number of community contacts reverted to baseline levels after measures were eased, while individuals aged 70 years and older had less than half their baseline levels.ConclusionStrict physical distancing measures greatly reduced overall contact numbers, which likely contributed to curbing the first wave of the COVID-19 epidemic in the Netherlands. However, age groups reacted differently when measures were relaxed, with children reverting to normal contact numbers and elderly individuals maintaining restricted contact numbers. These findings offer guidance for age-targeted measures in future waves of the pandemic.
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Authors: Lauren A. Henderson, Kevin G. Friedman, Mary Beth F. Son, Kate F. Kernan, Scott W. Canna, Mark Gorelik, Sivia K. Lapidus, Anne Ferris, Grant S. Schulert, Philip Seo, Adriana H. Tremoulet, Rae S. M. Yeung, David R. Karp, Hamid Bassiri, Edward M. Behrens, Jay J. Mehta
Journal: Arthritis & Rheumatology (2021)
Abstract 16813: Epidemiology and Microbiology of Central Line-Associated Bloodstream Infections in the Cardiac Intensive Care Unit
Authors: Aldo L Schenone, Zariyat Mannan, Kevin Chen, Deborah Klein, Paul Cremer, Thomas Fraser, Venu Menon
Journal: Circulation (2018)

Introduction: Extensive literature exists on the incidence, risk factors and impact of Central Line-Associated Bloodstream Infections (CLABSI) in the general ICU, but is lacking for the Cardiac Intensive Care Unit (CICU). Hypothesis: We describe the epidemiology and microbiology of CLABSI in patients admitted to a CICU. Methods: We retrospectively reviewed all critically-ill cardiac patients who met the definition for CLABSI while admitted at a Quaternary CICU between May-10 to Feb-18. Data on CLABSI rate per 1000 line days was only available since Jan 13. CLABSI data were collected prospectively by the Infectious Diseases Nurse Specialist. Patient demographics and clinical data were retrospectively collected using a predefined collection tool. Results: Out of approximately 21,070 individual CICU admissions within the study period, 46 patients met criteria for CLABSI with an average of 1.4 CLABSI per 1000 line days. The mean age was 67±11 years, 59% male with an observed in-hospital mortality of 39%. Most patients who developed CLABSI sustained a cardiac arrest (34%), cardiogenic shock (28%) or acute decompensated heart failure (24%). Line burden prior to CLABSI was estimated as a median of 2 (2-3 Q 1-3 ) lines per patient. Most central lines were venous (86%) with jugular access predominance (76.5%) over femoral (22.5%). Inotropic, vasopressor and mechanical circulatory support was commonly encountered in this population. (Figure 1) Gram-positive cocci (64%) were the most common organism detected in blood cultures, but gram-negative bacilli represented a significant proportion (26%) of the implicated microbiology. Conclusion: A definition of CLABSI is met in the CICU mainly in the setting of cardiac arrest, cardiogenic shock and/or decompensated heart failure. The emergent placement of lines in hemodynamically unstable patients and the potential for gut translocation in this population may play a potential role and deserves further exploration.
Cerebral Embolic Protection and Outcomes of Transcatheter Aortic Valve Replacement: Results From the Transcatheter Valve Therapy Registry
Authors: Neel M. Butala, Raj Makkar, Eric A. Secemsky, Dianne Gallup, Guillaume Marquis-Gravel, Andrzej S. Kosinski, Sreekanth Vemulapalli, Javier A. Valle, Steven M. Bradley, Tarun Chakravarty, Robert W. Yeh, David J. Cohen
Journal: Circulation (2021)

Stroke remains a devastating complication of transcatheter aortic valve replacement (TAVR), which has persisted despite refinements in technique and increased operator experience. While cerebral embolic protection devices (EPDs) have been developed to mitigate this risk, data regarding their impact on stroke and other outcomes after TAVR are limited.
The short isoform of PRLR suppresses the pentose phosphate pathway and nucleotide synthesis through the NEK9-Hippo axis in pancreatic cancer
Authors: Huizhen Nie, Pei-Qi Huang, Shu-Heng Jiang, Qin Yang, Li-Peng Hu, Xiao-Mei Yang, Jun Li, Ya-Hui Wang, Qing Li, Yi-Fan Zhang, Lei Zhu, Yan-Li Zhang, Yanqiu Yu, Gary Guishan Xiao, Yong-Wei Sun, Jianguang Ji, Zhi-Gang Zhang
Journal: Theranostics (2021)

Prolactin binding to the prolactin receptor exerts pleiotropic biological effects in vertebrates. The prolactin receptor (PRLR) has multiple isoforms due to alternative splicing. The biological roles and related signaling of the long isoform (PRLR-LF) have been fully elucidated. However, little is known about the short isoform (PRLR-SF), particularly in cancer development and metabolic reprogramming, a core hallmark of cancer. Here, we reveal the role and underlying mechanism of PRLR-SF in pancreatic ductal adenocarcinoma (PDAC).
How to conduct written online consultations with patients in primary care
Authors: Minal Bakhai, Helen Atherton
Journal: BMJ (2021)

### What you need to know

A written online consultation is a two-way written exchange between a healthcare professional and a patient using an online medium (such as an online web platform or email portal). Such exchanges offer an alternative route of access for patients alongside telephone and face-to-face consultations. This article offers a guide to help clinicians, particularly those working in primary care, use written online consultations effectively with their patients.

Use of written online consultations has increased over the past decade, with many health systems adopting them as a way for primary care staff to interact with patients.1234 Arrangements for written online consultation vary between different countries and healthcare providers. In Denmark, offering patients email consultation has been mandatory in general practice since 2007, and 21% of all consultations were conducted this way in 2019.5 In England, general practices have been encouraged by NHS England and NHS Improvement to adopt online triage platforms. These offer patients a secure way to send a request or message to their practice via a structured online form.67 US health maintenance organisations have for many years used patient portals to facilitate this type of communication.89 The covid-19 pandemic has accelerated adoption of written online consultation because it offers communication without proximity.1011 Many primary care health professionals will now be encountering this form of consultation with patients for the first time.

Evaluating online written consultations …
Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics
Authors: Henrik Zetterberg, Kaj Blennow
Journal: Molecular Neurodegeneration (2021)

Abstract Four fluid-based biomarkers have been developed into diagnostic tests for Alzheimer’s disease (AD) pathology: the ratio of 42 to 40 amino acid-long amyloid β, a marker of plaque pathology; total-tau and phosphorylated tau, markers of AD-related changes in tau metabolism and secretion; and neurofilament light, a marker of neurodegeneration. When measured in cerebrospinal fluid, these biomarkers can be used in clinical practice to support a diagnosis of mild cognitive impairment or dementia due to AD. Recently, technological breakthroughs have made it possible to measure them in standard blood samples as well. Here, we give an updated account of the current state of the fluid-based AD biomarker research field. We discuss how the new blood tests may be used in research and clinical practice, and what role they may play in relation to more established diagnostic tests, such as CSF biomarkers and amyloid and tau positron emission tomography, to facilitate the effective implementation of future disease-modifying therapies.
Two Minds, One Patient: Clearing up Confusion About “Ambivalence”
Authors: Bryanna Moore, Ryan H. Nelson, Peter A. Ubel, Jennifer Blumenthal-Barby
Journal: The American Journal of Bioethics (2021)

Patients who experience difficulty making medical decisions are often referred to as "ambivalent." However, the current lack of attention to the nuances between a cluster of phenomena that resemble ambivalence means that we are not always recognizing what is really going on with a patient. Importantly, different kinds of "ambivalence" may call for different approaches. In this paper, we present a taxonomy of ambivalence-related phenomena, provide normative analysis of some of the effects of-and common responses to-such mental states, and sketch some practical strategies for addressing ambivalence. In applying lessons from the philosophical literature and decision theory, our aim is to provide ethicists and clinicians with the tools to better understand and effectively intervene in cases of ambivalence.