tbuckley/cabot-search huggingface dataset:
Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy
Authors: Rahul Goli, Jian Li, Jeff Brandimarto, Lisa D. Levine, Valerie Riis, Quentin McAfee, Steven DePalma, Alireza Haghighi, J. G. Seidman, Christine E. Seidman, Daniel Jacoby, George Macones, Daniel P. Judge, Sarosh Rana, Kenneth B. Margulies, Thomas P. Cappola, Rami Alharethi, Julie Damp, Eileen Hsich, Uri Elkayam, Richard Sheppard, Jeffrey D. Alexis, John Boehmer, Chizuko Kamiya, Finn Gustafsson, Peter Damm, Anne S. Ersbøll, Sorel Goland, Denise Hilfiker-Kleiner, Dennis M. McNamara, Zolt Arany
Journal: Circulation (2021)

Background: Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in TTN (TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM. Methods: Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including TTN , and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated. Results: Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected P [ P *]=1.2×10 –46 ). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, P *=7.0×10 –8 ), DSP (odds ratio=14.9, P *=1.0×10 –8 ), and BAG3 (odds ratio=53.1, P *=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%, P =2.5×10 –4 ), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery. Conclusions: This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.
Phase I/Ib Clinical Trial of Sabatolimab, an Anti–TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti–PD-1 Antibody, in Advanced Solid Tumors
Authors: Giuseppe Curigliano, Hans Gelderblom, Nicolas Mach, Toshihiko Doi, David Tai, Patrick M. Forde, John Sarantopoulos, Philippe L. Bedard, Chia-Chi Lin, F. Stephen Hodi, Sofie Wilgenhof, Armando Santoro, Catherine A. Sabatos-Peyton, Tyler A. Longmire, Alexandros Xyrafas, Haiying Sun, Sabine Gutzwiller, Luigi Manenti, Aung Naing
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors. Patients and Methods: Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W. Results: Enrolled patients (n = 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12–27 months) in colorectal cancer (n = 2), non–small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had &amp;gt;10% TIM-3–positive staining, including one patient with NSCLC who received prior PD-1 therapy. Conclusions: Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.
European Respiratory Society clinical practice guidelines for the diagnosis of asthma in children aged 5–16 years
Authors: Erol A. Gaillard, Claudia E. Kuehni, Steve Turner, Myrofora Goutaki, Karl A. Holden, Carmen C.M. de Jong, Christiane Lex, David K.H. Lo, Jane S. Lucas, Fabio Midulla, Rebeca Mozun, Giorgio Piacentini, David Rigau, Bart Rottier, Mike Thomas, Thomy Tonia, Jakob Usemann, Ozge Yilmaz, Angela Zacharasiewicz, Alexander Moeller
Journal: European Respiratory Journal (2021)

Diagnosing asthma in children represents an important clinical challenge. There is no single gold-standard test to confirm the diagnosis. Consequently, over- and under-diagnosis of asthma is frequent in children.A task force supported by the European Respiratory Society has developed these evidence-based clinical practice guidelines for the diagnosis of asthma in children aged 5-16 years using nine Population, Intervention, Comparator and Outcome (PICO) questions. The task force conducted systematic literature searches for all PICO questions and screened the outputs from these, including relevant full-text articles. All task force members approved the final decision for inclusion of research papers. The task force assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.The task force then developed a diagnostic algorithm based on the critical appraisal of the PICO questions, preferences expressed by lay members and test availability. Proposed cut-offs were determined based on the best available evidence. The task force formulated recommendations using the GRADE Evidence to Decision framework.Based on the critical appraisal of the evidence and the Evidence to Decision framework, the task force recommends spirometry, bronchodilator reversibility testing and exhaled nitric oxide fraction as first-line diagnostic tests in children under investigation for asthma. The task force recommends against diagnosing asthma in children based on clinical history alone or following a single abnormal objective test. Finally, this guideline also proposes a set of research priorities to improve asthma diagnosis in children in the future.
SARS-CoV-2 Antibody Response in Persons with Past Natural Infection
Authors: Gabriele Anichini, Chiara Terrosi, Claudia Gandolfo, Gianni Gori Savellini, Simonetta Fabrizi, Giovanni B. Miceli, M. Grazia Cusi
Journal: New England Journal of Medicine (2021)

Response to Vaccine after Recovery from Covid-19 The response to the BNT162b2 vaccine was evaluated in 100 health care workers, 38 of whom had recovered from Covid-19. Neutralizing antibody levels ...
The BBSome: a nexus controlling energy metabolism in the brain
Authors: Sandra Blaess, Dagmar Wachten
Journal: Journal of Clinical Investigation (2021)

Bardet-Biedl syndrome (BBS) is a syndromic ciliopathy that has obesity as a cardinal feature. BBS is caused by mutations in BBS genes. BBS proteins control primary cilia function, and BBS mutations therefore lead to dysfunctional primary cilia. Obesity in patients with BBS is mainly caused by hyperphagia due to dysregulated neuronal function in the brain, in particular in the hypothalamus. However, the mechanism by which mutations in BBS genes result in dysfunction in hypothalamic neurons is not well understood. In this issue of the JCI, Wang et al. used BBS and non-BBS patient-derived induced pluripotent stem cells to generate neurons and hypothalamic neurons. Using this human model system, the authors demonstrated that mutations in BBS genes affected primary cilia function, neuronal morphology, and signaling pathways regulating the function of hypothalamic neurons, which control energy homeostasis. This study provides important insights into the mechanisms of BBS-induced obesity.
Effect of Sodium Benzoate on Cognitive Function Among Patients With Behavioral and Psychological Symptoms of Dementia
Authors: Chieh-Hsin Lin, Ping-Kun Chen, Shi-Heng Wang, Hsien-Yuan Lane
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Female gender is a major risk factor for dementia; however, gender has not yet been adequately addressed by clinical trials. A recent study demonstrated that sodium benzoate, a D-amino acid oxidase inhibitor, improved cognitive function in early-phase Alzheimer disease. <h3>Objective</h3> To examine the potential gender difference in the effects of benzoate treatment on the behavioral and psychological symptoms of dementia (BPSD). <h3>Design, Setting, and Participants</h3> This post hoc secondary analysis used data from a randomized, double-masked, placebo-controlled trial conducted in 3 major medical centers in Taiwan and enrolled 97 patients with BPSD. Data were analyzed between February 2014 and November 2017. <h3>Interventions</h3> Six weeks of treatment of 250 to 1500 mg/d of sodium benzoate or placebo. <h3>Main Outcomes and Measures</h3> The primary outcome measures were Alzheimer disease assessment scale–cognitive subscale (ADAS-cog) and Behavioral Pathology in Alzheimer Disease Rating Scale (BEHAVE-AD) scores. <h3>Results</h3> Among 97 total participants (62 [64%] women; mean [SD] age, 75.4 [7.7] years), 49 patients (30 women and 19 men) were randomized to sodium benzoate, and 48 (32 women and 16 men) were randomized to placebo. Among 62 women, 6-week benzoate treatment significantly surpassed placebo in the effects on ADAS-cog performance (mean [SD] difference in score between baseline and end point, −3.1 [6.4] points vs 0 [4.5] points; Cohen<i>d</i> = 0.56;<i>P</i> = .04) but not BEHAVE-AD performance. In contrast, among 35 men, the 2 treatment groups did not differ significantly in both ADAS-cog and BEHAVE-AD scores. Compared with placebo, benzoate treatment also increased estradiol to follicle-stimulating hormone ratios among women (mean [SD] difference between baseline and end point, 0 [0.2] vs −0.1 [0.3];<i>P</i> = .03). <h3>Conclusions and Relevance</h3> These findings suggest that benzoate treatment may improve cognitive function in women with later-phase dementia. In the future, longer dose-finding trials are warranted to further clarify the efficacy of benzoate for later-phase dementia and investigate the role of sex hormones and other factors in the pathogenesis of dementia. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02103673
Nodal-induced L1CAM/CXCR4 subpopulation sustains tumor growth and metastasis in colorectal cancer derived organoids
Authors: Donatella Delle Cave, Xavier Hernando-Momblona, Marta Sevillano, Gabriella Minchiotti, Enza Lonardo
Journal: Theranostics (2021)

Background: Colorectal cancer (CRC) is currently the third leading cause for cancer-related mortality. Cancer stem cells have been implicated in colorectal tumor growth, but their specific role in tumor biology, including metastasis, is still uncertain. Methods: Increased expression of L1CAM, CXCR4 and NODAL was identified in tumor section of patients with CRC and in patients-derived-organoids (PDOs). The expression of L1CAM, CXCR4 and NODAL was evaluated using quantitative real-time PCR, western blotting, immunofluorescence, immunohistochemistry and flow cytometry. The effects of the L1CAM, CXCR4 and NODAL on tumor growth, proliferation, migration, invasion, colony-formation ability, metastasis and chemoresistance were investigated both in vitro and in vivo. Results: We found that human colorectal cancer tissue contains cancer stem cells defined by L1CAMhigh/CXCR4high expression that is activated by Nodal in hypoxic microenvironment. This L1CAMhigh/CXCR4high population is tumorigenic, highly resistant to standard chemotherapy, and determines the metastatic phenotype of the individual tumor. Depletion of the L1CAMhigh/CXCR4high population drastically reduces the tumorigenic potential and the metastatic phenotype of colorectal tumors. Conclusion: In conclusion, we demonstrated that a subpopulation of migrating L1CAMhigh/CXCR4high is essential for tumor progression. Together, these findings suggest that strategies aimed at modulating the Nodal signaling could have important clinical applications to inhibit colorectal cancer-derived metastasis.
Abstract IA-015: Hypoxia-induced SETX links replication stress with the unfolded protein response
Authors: Ester M. Hammond
Journal: Clinical Cancer Research (2021)

Abstract Tumor hypoxia is associated with poor patient prognosis and radiation resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, DNA replication rates decrease and radiosensitivity increases. Importantly, we show that the mechanism of SETX induction is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways. Citation Format: Ester M. Hammond. Hypoxia-induced SETX links replication stress with the unfolded protein response [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-015.
Abstract IA-026: Gaps alone kill BRCA deficient cancer cells
Authors: Sharon B. Cantor, Nicholas Panzarino
Journal: Clinical Cancer Research (2021)

Abstract Defects in DNA repair and/or the protection of stalled DNA replication forks are thought to underlie the chemosensitivity of tumors deficient in the hereditary breast cancer genes, BRCA1 and BRCA2 (BRCA). Challenging this assumption, recent findings indicate that chemotherapies such as cisplatin used to treat BRCA-deficient tumors do not initially cause DNA double-strand-breaks (DSBs). Here, we show that single stranded DNA (ssDNA) replication gaps underlie the hypersensitivity of BRCA-deficient cancer, and we propose that defects in homologous recombination (HR) or fork protection (FP) do not. Specifically, in BRCA-deficient cells, ssDNA gaps develop because replication is not effectively restrained in response to stress. Gap suppression by either restoration of fork restraint or gap filling confers therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored FP and HR can be uncoupled from therapy resistance when gaps are present. Moreover, we find that DSBs are not detected after therapy when apoptosis is inhibited, supporting a framework in which DSBs are not directly induced by genotoxic agents, but rather from cell death nucleases. Together, this data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, “BRCAness,” and we propose are fundamental to the mechanism-of-action of genotoxic chemotherapies. Citation Format: Sharon B. Cantor, Nicholas Panzarino. Gaps alone kill BRCA deficient cancer cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-026.
Recanalization of a distorted duodenal metal stent using a fine-gauge electrocautery dilator
Authors: Atsushi Okuda, Takeshi Ogura, Masanori Yamada, Saori Ueno, Kazuhide Higuchi
Journal: Endoscopy (2021)

Duodenal obstruction sometimes occurs due to pancreaticobiliary carcinoma. Because the prognosis of the advanced stage is limited, duodenal metal stents are often deployed as conservative treatment [1] [2] [3] [4]. However, if a transpapillary bile duct stent has previously been deployed, duodenal stents can become distorted by the bile duct stent. We herein describe technical tips for recanalization of a distorted duodenal metal stent using a novel fine-gauge electrocautery dilator (Medico’s Hirata Inc., Osaka Japan) [5]. This device can reduce adverse events due to burning effects compared with a conventional electrocautery dilator.
Nucleophosmin blocks 12-O-tetradecanoylphorbol-13-acetate mediated mitochondrial localization of p53 and apoptosis
Authors: Sanjit Dhar, Daret St. Clair
Journal: Cancer Research (2008)

1828  Activation of p53 is an important mechanism in apoptosis. Previously, we demonstrated that p53 localization to mitochondria precedes its nuclear translocation upon activation by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). However, whether the presence of p53 in mitochondria plays an important role in p53 mediated apoptosis is unclear. Here, we demonstrate that over-expression of nucleophosmin (NPM) significantly suppresses TPA mediated apoptosis by blocking the mitochondrial localization of p53. Following TPA treatment of the skin epithelial JB6 cells p53 rapidly accumulated in mitochondria within an hour. Over-expression of NPM enhances p53 levels in the nucleus but suppresses mitochondrial p53 as determined by immunocytochemistry, sub-cellular localization and Western blot analysis. Confocal microscopy and co-localization experiments using p53 and NPM antibodies demonstrate that NPM and p53 co-localized in the nucleus. Kinetic studies reveal that p53 has longer half-life in NPM over-expressing cells compared to vector control cells treated in a similar manner. Stabilization of p53 by NPM enhances the expression of p53 target genes p21 and Bax with the concomitant increase of Bcl2 levels. However, the increased level of Bax alone in absence of p53 in the mitochondria did not led to an increase in TPA-induced apoptosis suggesting that the presence of p53 in mitochondria is important for TPA-induced apoptosis. Consistent with this finding, Bcl2 and Bax ratio was found to be higher and caspase 3 activity was lower in NPM over-expressing cells after TPA treatment. Protection from apoptosis was independent of the higher level of Bcl2 expression in NPM over-expressed cells, confirmed by co-transfection of NPM expression vector and Bcl2 siRNA coupled with apoptosis assay. Suppression of NPM by NPM siRNA leads to an increase of p53 levels in mitochondria with the concomitant increase of apoptosis as determined by Western analysis of p53 in purified mitochondria and the presence of TUNEL positive cells after TPA treatment, respectively. These results confirm the effect of NPM on p53 localization in mitochondria and apoptosis in TPA treated cells. Together, the data indicate that the presence of p53 in the mitochondria plays an important role in TPA-induced apoptosis and suggest that NPM could protect cells from TPA-induced apoptosis by preventing the translocation of p53 to mitochondria.
Radiation-Related Leukemia in Hiroshima and Nagasaki, 1946–1964
Authors: O. Joseph Bizzozero, Kenneth G. Johnson, Antonio Ciocco, Takashi Hoshino, Takashi Itoga, Shigeki Toyoda, Sho Kawasaki
Journal: New England Journal of Medicine (1966)

THE role of human exposure to radiation in the genesis of leukemia has been recognized since 1925. In recent times many authors have reported cases of leukemia occurring in irradiated persons.1 2 3 4 5 6 7 8 9 10 11 12 13 14 Several reports of the Atomic Bomb Casualty Commission have verified the development of leukemia at an excessive rate in the survivors of the atomic bombings.15 16 17 18 19 20 21 22 23 24 25 The literature on the relation of ionizing radiation to leukemia has been summarized in the past by others26 27 28 and most recently by Miller.29 The previous findings of the Commission have demonstrated an excess of leukemia developing in those more proximal to the hypocenter at . . .
COVID-19 Outbreak Associated with a SARS-CoV-2 R.1 Lineage Variant in a Skilled Nursing Facility After Vaccination Program — Kentucky, March 2021
Authors: Alyson M. Cavanaugh, Sarah Fortier, Patricia Lewis, Vaneet Arora, Matt Johnson, Karim George, Joshua Tobias, Stephanie Lunn, Taylor Miller, Douglas Thoroughman, Kevin B. Spicer
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Although COVID-19 mRNA vaccines demonstrated high efficacy in clinical trials (1), they were not 100% efficacious. Thus, some infections postvaccination are expected. Limited data are available on effectiveness in skilled nursing facilities (SNFs) and against emerging variants. The Kentucky Department for Public Health (KDPH) and a local health department investigated a COVID-19 outbreak in a SNF that occurred after all residents and health care personnel (HCP) had been offered vaccination. Among 83 residents and 116 HCP, 75 (90.4%) and 61 (52.6%), respectively, received 2 vaccine doses. Twenty-six residents and 20 HCP received positive test results for SARS-CoV-2, the virus that causes COVID-19, including 18 residents and four HCP who had received their second vaccine dose >14 days before the outbreak began. An R.1 lineage variant was detected with whole genome sequencing (WGS). Although the R.1 variant has multiple spike protein mutations, vaccinated residents and HCP were 87% less likely to have symptomatic COVID-19 compared with those who were unvaccinated. Vaccination of SNF populations, including HCP, is critical to reduce the risk for SARS-CoV-2 introduction, transmission, and severe outcomes in SNFs. An ongoing focus on infection prevention and control practices is also essential.