tbuckley/cabot-search huggingface dataset:
Pharmacological depletion of microglia and perivascular macrophages prevents vascular Cognitive Impairment in Ang II-induced Hypertension
Authors: Danielle Kerkhofs, Britt T. van Hagen, Irina V. Milanova, Kimberly J. Schell, Helma van Essen, Erwin Wijnands, Pieter Goossens, W. Matthijs Blankesteijn, Thomas Unger, Jos Prickaerts, Erik A. Biessen, Robert J. van Oostenbrugge, Sébastien Foulquier
Journal: Theranostics (2020)

Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Angiotensin II infusion is associated with increased permeability of the blood-brain barrier (BBB), chronic activation of microglia and myelin loss. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach. Methods: For this study, adult Cx3Cr1gfp/wtxThy1yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF1R tyrosine kinase inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory was assessed during an Object Location task and a Morris Water Maze task (MWM). Microglia depletion efficacy was assessed by flow cytometry and immunohistochemistry. BBB leakages, microglia phenotype and myelin integrity were assessed by immunohistochemistry. Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, and partly prevented in Ang II mice treated with PLX5622. Histological and flow cytometry analysis revealed almost complete ablation of microglia and a 60% depletion of brain resident perivascular macrophages upon CSF1R inhibition. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Microglia acquired a pro-inflammatory phenotype at the site of BBB leakages in both Saline and Ang II mice and were successfully depleted by PLX5622. There was however no significant change in myelin integrity at the site of leakages. Conclusion: Our results show that depletion of microglia and PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. We suggest this beneficial effect is mediated by the major decrease of pro-inflammatory microglia within BBB leakages. This novel finding supports the critical role of brain immune cells in the pathogenesis of hypertension-related cognitive impairment. An adequate modulation of microglia /PVM density and phenotype may constitute a relevant approach to prevent and/or limit the progression of vascular cognitive impairment.
Prevalence of SARS-CoV-2 Infection Among Asymptomatic Health Care Workers in the Greater Houston, Texas, Area
Authors: Farhaan S. Vahidy, David W. Bernard, Marc L. Boom, Ashley L. Drews, Paul Christensen, Jeremy Finkelstein, Roberta L. Schwartz
Journal: JAMA Network Open (2020)

This cross-sectional study examines rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among asymptomatic health care workers and community residents in the greater Houston, Texas, area.
Ethical Challenges in Advance Care Planning During the COVID-19 Pandemic
Authors: Anveet S. Janwadkar, Trevor M. Bibler
Journal: The American Journal of Bioethics (2020)

This article refers to:Ethics Lessons From Seattle’s Early Experience With COVID-19Ethical Challenges Arising in the COVID-19 Pandemic: An Overview from the Association of Bioethics Program Directors (ABPD) Task ForceCOVID in NYC: What We Could Do Better
Current Topics in the Management of Non–Muscle-Invasive Bladder Cancer
Authors: Philippe E. Spiess
Journal: Journal of the National Comprehensive Cancer Network (2020)

The current NCCN Guidelines for Bladder Cancer reflect the most up-to-date, evidence-based data relating to the evaluation and management of non–muscle-invasive bladder cancer (NMIBC). The most notable revision to the guidelines this year is the addition of pembrolizumab for a high-risk subset of patients not responding to bacillus Calmette-Guérin (BCG). It is anticipated that current BCG shortages will offer unique opportunities to promote and enhance clinical trials for patients with bladder cancer. Recent efforts to more precisely define BCG-unresponsive disease (adopted by the FDA) have been critical to standardizing definitions and evaluating the efficacy of clinical trials in bladder cancer.
Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans
Authors: Christoph Grander, Benedikt Schaefer, Julian Schwärzler, Felix Grabherr, Dennis M de Graaf, Barbara Enrich, Georg Oberhuber, Lisa Mayr, Moris Sangineto, Nikolai Jaschke, Timon E Adolph, Maria Effenberger, Alexander R Moschen, Charles A Dinarello, Heinz Zoller, Herbert Tilg
Journal: Gut (2020)

Alcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by
Phase Ib Study of Wnt Inhibitor Ipafricept with Gemcitabine and nab-paclitaxel in Patients with Previously Untreated Stage IV Pancreatic Cancer
Authors: Efrat Dotan, Dana B. Cardin, Heinz-Josef Lenz, Wells Messersmith, Bert O'Neil, Steven J. Cohen, Crystal S. Denlinger, Safi Shahda, Igor Astsaturov, Ann M. Kapoun, Rainer K. Brachmann, Shailaja Uttamsingh, Robert J. Stagg, Colin Weekes
Journal: Clinical Cancer Research (2020)

The recombinant fusion protein ipafricept blocks Wnt signaling, and in combination with gemcitabine and nab-paclitaxel caused tumor regression in xenografts. This phase Ib study evaluated the combination of ipafricept with nab-paclitaxel + gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma (mPDAC).Dose escalation started with standard dose nab-paclitaxel + gemcitabine and ipafricept (3.5 mg/kg days 1, 15). Because of fragility fractures seen with different anti-Wnt agents, following cohorts had ≥6 patients treated with ipafricept 3 to 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. On the basis of preclinical data, sequential dosing was evaluated in cohort 4 (ipafricept day 1 followed nab-paclitaxel + gemcitabine day 3). Objectives included safety, MTD, recommended phase II dose, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy.A total of 26 patients were enrolled, five in cohort 1 and seven each in cohorts 2-4. ipafricept-related adverse events (AEs) of any grade included fatigue, nausea, vomiting, anorexia, and pyrexia. ipafricept-related AEs grade ≥3 included two events of aspartate aminotransferase elevation, and one each of nausea, rash, vomiting, and leucopenia. No dose-limiting toxicities or fragility fractures were observed. Nine patients (34.6%) had partial response, 12 (46.2%) stable disease as best response, with clinical benefit rate of 81%. Median progression-free survival was 5.9 m [95% confidence interval (CI), 3.4-18.4], median overall survival was 9.7 m (95% CI, 7.0-14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use.Ipafricept can be administered with nab-paclitaxel + gemcitabine with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.
Reducing Global Traffic Deaths With Seatbelts and Other Technology
Authors: Bridget M. Kuehn
Journal: JAMA (2020)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Crosstalks between inflammasome and autophagy in cancer
Authors: Chaeuk Chung, Wonhyoung Seo, Prashanta Silwal, Eun-Kyeong Jo
Journal: Journal of Hematology & Oncology (2020)

Abstract Both inflammasomes and autophagy have important roles in the intracellular homeostasis, inflammation, and pathology; the dysregulation of these processes is often associated with the pathogenesis of numerous cancers. In addition, they can crosstalk with each other in multifaceted ways to influence various physiological and pathological responses, including cancer. Multiple molecular mechanisms connect the autophagy pathway to inflammasome activation and, through this, may influence the outcome of pro-tumor or anti-tumor responses depending on the cancer types, microenvironment, and the disease stage. In this review, we highlight the rapidly growing literature on the various mechanisms by which autophagy interacts with the inflammasome pathway, to encourage additional applications in the context of tumors. In addition, we provide insight into the mechanisms by which pathogen modulates the autophagy-inflammasome pathway to favor the infection-induced carcinogenesis. We also explore the challenges and opportunities of using multiple small molecules/agents to target the autophagy/inflammasome axis and their effects upon cancer treatment. Finally, we discuss the emerging clinical efforts assessing the potential usefulness of targeting approaches for either autophagy or inflammasome as anti-cancer strategies, although it remains underexplored in terms of their crosstalks.
The progress and perspective of nanoparticle-enabled tumor metastasis treatment
Authors: Wei Zhang, Fei Wang, Chuan Hu, Yang Zhou, Huile Gao, Jiang Hu
Journal: Acta Pharmaceutica Sinica B (2020)

As one of the most serious threats to human being, cancer is hard to be treated when metastasis happens. What's worse, there are few identified targets of metastasis for drug development. Therefore, it is important to develop strategies to prevent metastasis or treat existed metastasis. This review focuses on the procedure of metastasis, and first summarizes the targeting delivery strategies, including primary tumor targeting drug delivery, tumor metastasis targeting drug delivery and hijacking circulation cells. Then, as a promising treatment, the application of immunotherapy in tumor metastasis treatment is introduced, and strategies that stimulating immune response are reviewed, including chemotherapy, photothermal therapy, photodynamic therapy, ferroptosis, sonodynamic therapy, and nanovaccines. Finally, the challenges and perspective about nanoparticle-enabled tumor metastasis treatment are discussed.
Abstract DP-011: PRE-DIAGNOSIS USE OF MENOPAUSAL HORMONE THERAPY ASSOCIATED WITH BETTER OVARIAN CANCER SURVIVAL
Authors: Alice W. Lee, Siri Peterson, Ashley Wiensch, Malcolm C. Pike, Celeste L. Pearce
Journal: Clinical Cancer Research (2019)

Abstract BACKGROUND: Several lifestyle factors have consistently been associated with survival of ovarian cancer, including body mass index, analgesic medications, physical activity, and smoking. Menopausal hormone therapy (HT), which can comprise of estrogen only (ET) or a combination of estrogen and progestin (EPT), has also been studied for its impact on ovarian survival. Randomized trials as well as a recent meta-analysis have shown better survival for women who took HT after their diagnosis in comparison to women who did not (HR=0.67, 95% CI 0.47-0.97). However, the relationship between use of HT prior to ovarian cancer diagnosis and survival is less clear. METHODS: Approximately 4,700 ovarian cancer patients across nine population-based studies participating in the Ovarian Cancer Association Consortium (OCAC) were included in our analysis. Information on HT use prior to diagnosis and potential confounders was obtained via phone or in-person interviews. To estimate the effect of pre-diagnostic HT use on ovarian cancer survival, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models with left and right truncation to account for different observation times. Effects by type and duration of HT use as well as disease histotype were also evaluated. RESULTS: Women who used HT before diagnosis had an 11% decreased risk of death in comparison to those who did not use HT (95% CI 0.82-0.97). Similar effects were observed for both types of HT (HR=0.86, 95% CI 0.75-0.98 for ET and HR=0.89, 95% CI 0.80-0.99 for EPT). In addition, there appeared to be a duration effect with longer HT use conferring better survival (p-trend=0.07 for ET, p-trend=0.003 for EPT). When histotype was considered, the overall decreased risk was driven by serous and mucinous ovarian cancers (HR=0.85, 95% CI 0.77-0.93 and HR=0.54, 95% CI 0.28-1.07, respectively). CONCLUSIONS: Use of HT after diagnosis also affords a survival advantage based on published observational and clinical trials data. We now report that pre-diagnosis HT use may confer a survival advantage among women with ovarian cancer. Interestingly, use of ET prior to diagnosis is associated with increased risk of ovarian cancer, but better survival among women diagnosed with the disease. These observations taken together demonstrate the complex nature of ovarian cancer. Citation Format: Alice W. Lee, Siri Peterson, Ashley Wiensch, Malcolm C. Pike, Celeste L. Pearce on behalf of the Ovarian Cancer Association Consortium. PRE-DIAGNOSIS USE OF MENOPAUSAL HORMONE THERAPY ASSOCIATED WITH BETTER OVARIAN CANCER SURVIVAL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr DP-011.
Managing Grief, Loss, and Connection in Oncology—What COVID-19 Has Taken
Authors: Hanna K. Sanoff
Journal: JAMA Oncology (2020)

Constraints imposed by coronavirus disease 2019 have changed every part of my life, but disruption of human connection with patients has been the most unsettling to me.Over 15 years as a gastrointestinal medical oncologist, I have learned from patients how to help them through terminal disease, attended workshops on how to speak about the end of life, and strived to share in patients' grief without losing myself.But I find myself wholly unprepared to speak of death and dying across cell phones or video links with unreliable connections.I have not yet figured out how to help guide patients' struggles with cancer-leading them toward a death with dignity and finding personal reward in our relationship-when I cannot see them, hug them, or see their love for each other.What does it take to find balance and connection in virtual oncology?Like all gastrointestinal oncologists, I have had the conversation so many times before: "Unfortunately, the chemotherapy is no longer working.We no longer have any options that offer a meaningful chance of controlling the cancer.We're in a different place with your cancer now."Though the words are similar, each of these experiences differs, shaped by the emotional response of the individual receiving this news.In our usual venue of face-to-face visits, I am able to see and feel these responses fully.I have seen the beauty of a sad but peaceful acceptance of the end of a life well lived, imbued with hope for some joy yet to come.I have seen anger, denial, and the lashing out that comes with unfathomable distress.And sometimes I have seen a grief so profound in the face of horrifying loss of love that I can hardly bear witness to the depths of the patient's sorrow.It was into this sorrowful depth that I stared yesterday, in the new, unsettling format of a video visit.Unsure of how to proceed, I started by acknowledging the inadequacy of our virtual interaction, and how I wished we could meet in person.I then shared the news of pancreatic cancer progression with my kind-hearted patient who loves life, who feels love and laughter-and pain and sadness-intensely.And I shared it with her gentle, spiritual, loving wife.From afar I watched grief overtake them, gutted by sorrow for the loss of a love so deeply shared.From my laptop screen, I also saw how COVID-19 has brought new losses to the terminally ill who now grieve for what stay-at-home orders have taken away.This couple lost their final trip to "their place"; they will not get their bittersweet final swim in the warm Caribbean.Patients with terminal cancer are losing the time our society had promised them with our talk of bucket lists and choosing quality of life.They are mourning their death and trying not to rage at the arbitrary injustice of a premature loss of love's shared joys.
Association of Social Distancing, Population Density, and Temperature With the Instantaneous Reproduction Number of SARS-CoV-2 in Counties Across the United States
Authors: David Rubin, Jing Huang, Brian T. Fisher, Antonio Gasparrini, Vicky Tam, Lihai Song, Xi Wang, Jason Kaufman, Kate Fitzpatrick, Arushi Jain, Heather Griffis, Koby Crammer, Jeffrey Morris, Gregory Tasian
Journal: JAMA Network Open (2020)

Local variation in the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across the United States has not been well studied.
The differing pathophysiologies that underlie COVID‐19‐associated perniosis and thrombotic retiform purpura: a case series
Authors: C.M. Magro, J.J. Mulvey, J. Laurence, S. Sanders, A.N. Crowson, M. Grossman, J. Harp, G. Nuovo
Journal: British Journal of Dermatology (2020)

There are two distinctive acral manifestations of COVID-19 embodying disparate clinical phenotypes. One is perniosis occurring in mildly symptomatic patients, typically children and young adults; the second is the thrombotic retiform purpura of critically ill adults with COVID-19.To compare the clinical and pathological profiles of these two different cutaneous manifestations of COVID-19.We compared the light microscopic, phenotypic, cytokine and SARS-CoV-2 protein and RNA profiles of COVID-19-associated perniosis with that of thrombotic retiform purpura in critical patients with COVID-19.Biopsies of COVID-19-associated perniosis exhibited vasocentric and eccrinotropic T-cell- and monocyte-derived CD11c+ , CD14+ and CD123+ dendritic cell infiltrates. Both COVID-associated and idiopathic perniosis showed striking expression of the type I interferon-inducible myxovirus resistance protein A (MXA), an established marker for type I interferon signalling in tissue. SARS-CoV-2 RNA, interleukin-6 and caspase 3 were minimally expressed and confined to mononuclear inflammatory cells. The biopsies from livedo/retiform purpura showed pauci-inflammatory vascular thrombosis without any MXA decoration. Blood vessels exhibited extensive complement deposition with endothelial cell localization of SARS-CoV-2 protein, interleukin-6 and caspase 3; SARS-CoV-2 RNA was not seen.COVID-19-associated perniosis represents a virally triggered exaggerated immune reaction with significant type I interferon signaling. This is important to SARS-CoV-2 eradication and has implications in regards to a more generalized highly inflammatory response. We hypothesize that in the thrombotic retiform purpura of critically ill patients with COVID-19, the vascular thrombosis in the skin and other organ systems is associated with a minimal interferon response. This allows excessive viral replication with release of viral proteins that localize to extrapulmonary endothelium and trigger extensive complement activation.
Unwanted pregnancies fall worldwide but women in poorer countries remain disadvantaged, study finds
Authors: Lynn Eaton
Journal: BMJ (2020)

Women in the world’s poorest regions face persistent and major inequalities in access to sexual and reproductive healthcare, a major global study has concluded.

The paper, published online in the Lancet Global Health ,1 examined numbers of unwanted pregnancies and subsequent abortions, divided into three categories: World Bank income groups, sustainable development goal regional groupings, and the legal status of abortion. Country specific analysis is not due to be published by the researchers until later this year.

Worldwide, the number of unwanted pregnancies has fallen since 1990. In 2015-19 there were 121 million unintended pregnancies a year, equivalent to 64 in 1000 women aged 15-49. This was down from 79 unwanted …
Illuminating the human virome in health and disease
Authors: Fatemeh Adiliaghdam, Kate L. Jeffrey
Journal: Genome Medicine (2020)

Abstract Although the microbiome is established as an important regulator of health and disease, the role of viruses that inhabit asymptomatic humans (collectively, the virome) is less defined. While we are still characterizing what constitutes a healthy or diseased virome, an exciting next step is to move beyond correlations and toward identification of specific viruses and their precise mechanisms of beneficial or harmful immunomodulation. Illuminating this will represent a first step toward developing virome-focused therapies.
Nanomaterial Additives for Fabrication of Stimuli‐Responsive Skeletal Muscle Tissue Engineering Constructs
Authors: Amy Corbin Farr, Katie J. Hogan, Antonios G. Mikos
Journal: Advanced Healthcare Materials (2020)

Abstract Volumetric muscle loss necessitates novel tissue engineering strategies for skeletal muscle repair, which have traditionally involved cells and extracellular matrix‐mimicking scaffolds and have thus far been unable to successfully restore physiologically relevant function. However, the incorporation of various nanomaterial additives with unique physicochemical properties into scaffolds has recently been explored as a means of fabricating constructs that are responsive to electrical, magnetic, and photothermal stimulation. Herein, several classes of nanomaterials that are used to mediate external stimulation to tissue engineered skeletal muscle are reviewed and the impact of these stimuli‐responsive biomaterials on cell growth and differentiation and in vivo muscle repair is discussed. The degradation kinetics and biocompatibilities of these nanomaterial additives are also briefly examined and their potential for incorporation into clinically translatable skeletal muscle tissue engineering strategies is considered. Overall, these nanomaterial additives have proven efficacious and incorporation in tissue engineering scaffolds has resulted in enhanced functional skeletal muscle regeneration.
Pragmatic global dosing recommendations for the 3-month, once-weekly rifapentine and isoniazid preventive TB regimen in children
Authors: Kendra K. Radtke, Jennifer E. Hibma, Anneke C. Hesseling, Rada M. Savic
Journal: European Respiratory Journal (2020)

<b>This study proposes a revised synchronised and pragmatic dosing table for the 3HP regimen in children that utilises available formulations. The revised doses are predicted to deliver adequate rifapentine and isoniazid exposure in children.</b>https://bit.ly/3eUHm86