tbuckley/cabot-search huggingface dataset:
Chemotherapy-induced adenosine A2B receptor expression mediates epigenetic regulation of pluripotency factors and promotes breast cancer stemness
Authors: Jie Lan, Guangyao Wei, Jia Liu, Fan Yang, Rong Sun, Haiquan Lu
Journal: Theranostics (2022)

Rationale: Triple-negative breast cancer (TNBC) is characterized by its unique molecular profile, aggressive nature and lack of targeted therapy.Chemotherapy induces expression of pluripotency factors and mediates an active induction of breast cancer stem cells (BCSCs) in TNBC, which potentiates the risk of tumor recurrence and metastasis and increases patient mortality.Adenosine receptor 2B (A2BR) expression and activation of its downstream signaling pathway has been implied to promote breast cancer metastasis.This study is to investigate the role of A2BR in the regulation of chemotherapy-induced BCSC enrichment.Methods: We generated shRNA-mediated A2BR knockdown subclones in TNBC cell lines and evaluated the effect on the BCSC phenotype by Aldefluor and mammosphere assays in vitro.We performed chromatin immunoprecipitation (ChIP) assay to investigate recruitment of transcription factor FOXO3 and histone modification enzymes KDM6A and p300 to the regulatory regions of pluripotency factors, as well as levels of histone modification marks H3K27ac and H3K27me3 on these regions.We employed both xenograft model and genetically engineered, autochthonous breast cancer model to evaluate the effect of A2BR on chemotherapy-induced BCSC enrichment in vivo.Results: We demonstrated that chemotherapy increased protein level of A2BR, which contributed to chemotherapy-induced pluripotency factor expression and BCSC enrichment in TNBC.A2BR mediated activation of p38 MAPK and nuclear translocation of chromatin remodeling factor SMARCD3, which interacted and recruited histone demethylase KDM6A and histone acetyltransferase p300 specifically to the pluripotency factor genes NANOG, SOX2 and KLF4.Recruitment of KDM6A and p300 decreased histone H3K27me3 and increases H3K27ac marks, and increased transcription factor FOXO3 binding to NANOG, SOX2 and KLF4 genes, leading to transcriptional activation of these genes and BCSC specification.Genetic or pharmacological inhibition of A2BR blocked chemotherapy-mediated epigenetic activation of pluripotency factor genes and BCSC enrichment in vitro and in vivo, and delayed tumor recurrence after chemotherapy was discontinued.Conclusion: Chemotherapy-induced A2BR expression mediates epigenetic activation of pluripotency factors and promotes breast cancer stemness.Targeting A2BR in combination with chemotherapy may block BCSC enrichment and improve outcome in TNBC.
Generalizability in mixed models: Lessons from corpus linguistics
Authors: Freek Van de Velde, Stefano De Pascale, Dirk Speelman
Journal: Behavioral and Brain Sciences (2022)

Abstract Part of the generalizability issues that haunt controlled lab experiment designs in psychology, and more particularly in psycholinguistics, can be alleviated by adopting corpus linguistic methods. These work with natural data. This advantage comes at a cost: in corpus studies, lexemes and language users can show different kinds of skew. We discuss a number of solutions to bolster the control.
Abstract 043: Real-World Evidence Demonstrating The Association Of SGLT2 Inhibitors With Reduced Cardiovascular Disease In Patients With Type 2 Diabetes
Authors: Wendy Wang, Lin Y Chen, Rob Walker, Lisa Chow, Faye L Norby, Alvaro Alonso, Jim S Pankow, Pamela L Lutsey
Journal: Circulation (2022)

Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of antihyperglycemic drugs recommended to patients with type 2 diabetes (T2D) as a 2 nd line therapy after metformin. Recent evidence suggests they may reduce the risk for cardiovascular disease (CVD); however, prior studies have been clinical trials, which do not reflect real-world data, and did not conduct head-to-head comparisons of SGLT2 inhibitors. Therefore, utilizing data from the US MarketScan administrative databases in 2013-19, we tested the hypothesis that patients with T2D taking SGLT2 inhibitors have a lower risk of CVD compared to those taking other 2 nd line therapies. Methods: We included 313,626 patients with T2D who were taking metformin and a 2 nd line therapy (SGLT2 vs. other). SGLT2 inhibitor users were matched with up to 5 users of other 2 nd line therapies by age, sex, date of enrollment, and date of 2 nd line therapy initiation. The primary CVD outcome was a composite of stroke, atrial fibrillation, myocardial infarction, and heart failure. Patients with prevalent CVD were excluded. We also conducted head-to-head comparisons of SGLT2 inhibitors. Cox proportional hazards models were used to estimate hazard ratios (HR). Results: Participants were on average age 53±10 years at baseline and 47% were female. Median follow-up time was 1.4 years. After multivariable adjustments, SGLT2 inhibitor users had a lower risk of CVD than those taking other 2 nd line therapies [Table; HR (95% CI): 0.66 (0.62, 0.71)]. Significant associations were also observed when each CVD outcome was assessed separately, with the strongest associations for stroke and heart failure. No differences were observed when comparing individual SGLT2 inhibitors. Conclusion: Using MarketScan data in patients with T2D, we found that users of SGLT2 inhibitors had a lower risk of CVD compared to users of other 2 nd line therapies. By using real-world data, these findings complement clinical trial results supporting the effectiveness of SGLT2 inhibitors in reducing risk of CVD.
Abstract EP70: Adolescent Arterial Stiffness Precedes Elevated Resting Heart Rate In Young Adulthood: A 7-year Temporal Longitudinal Analysis Using Cross-lagged Structural Equation Model
Authors: Andrew O Agbaje, Alan R Barker, Tomi-Pekka Tuomainen
Journal: Circulation (2022)

Introduction: Elevated resting heart rate in adults is an established risk factor in the lifelong process of atherogenesis and its intermediate process such as arterial stiffness. Arterial stiffness is an independent predictor of cardiovascular events. However, it is unclear whether resting heart rate temporally and bi-directionally associates with arterial stiffness especially among healthy adolescents and young adults. Hence, plausible biologic pathways through which elevated resting heart rate associate with arterial stiffness in the young population remains unknown. Hypothesis: To examine the temporal longitudinal associations of carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, with resting heart rate among adolescents aged 17.7 years. Methods: We studied 3862 (55.5% female) British adolescents followed up for 7 years until 24.5 years of age, using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, England, UK. At baseline and follow-up, fat mass and lean mass were measured by dual-energy Xray absorptiometry, systolic blood pressure and heart rate by Omron BP/pulse monitor, and cfPWV by Vicorder ultrasound scan. We conducted logistic regression and cross-lagged autoregressive structural equation model analyses and adjusted for age at baseline, sex, moderate to vigorous physical activity, smoking status, family history of cardiometabolic diseases, time in years between measurement at 17.7 and 24.5 years, systolic blood pressure, fat mass, lean mass, and fasting plasma samples viz. low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, high-sensitivity C-reactive protein, glucose, and insulin. Results: Participants' mean (SD) age in years was 17.72 (0.33) and 24.54 (0.73) at baseline and follow-up, respectively. Among 3862 adolescents, 10% were at moderate to high risk of elevated resting heart rate at 24.5 years. Higher cfPWV at 17.7 years was associated with the risk of elevated resting heart rate at follow-up [ Odds ratio = 1.32 (95% confidence interval 1.06 - 1.65); p=0.014]. In the cross-lagged temporal analysis, higher cfPWV at 17.7 years was associated with higher resting heart rate [ Standardized regression coefficient (β) = 0.06 standard error (SE) = 3.85, p&lt;0.0001] at 24.5 years, however, higher resting heart rate at 17.7 years was not associated with cfPWV [β = -0.03, SE &lt;0.0001, p=0.179] at 24.5 years. Conclusion: We observed, for the first time, in a large healthy cohort of adolescents that arterial stiffness temporally preceded elevated resting heart rate in young adulthood, after controlling for cardiometabolic and lifestyle factors. This evidence informs that public health and clinical effort may be targeted at early detection and prevention of arterial stiffness from adolescence.
Angiotensin Receptor–Neprilysin Inhibition in Acute Myocardial Infarction
Authors: Marc A. Pfeffer, Brian Claggett, Eldrin F. Lewis, Christopher B. Granger, Lars Køber, Aldo P. Maggioni, Douglas L. Mann, John J.V. McMurray, Jean-Lucien Rouleau, Scott D. Solomon, Philippe G. Steg, Otavio Berwanger, Maja Cikes, Carmine G. De Pasquale, Cara East, Alberto Fernandez, Karola Jering, Ulf Landmesser, Roxana Mehran, Béla Merkely, Freny Vaghaiwalla Mody, Mark C. Petrie, Ivo Petrov, Morten Schou, Michele Senni, David Sim, Peter van der Meer, Martin Lefkowitz, Yinong Zhou, Jianjian Gong, Eugene Braunwald
Journal: New England Journal of Medicine (2021)

In patients with symptomatic heart failure, sacubitril–valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting–enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking.
Writing up your clinical trial report for a scientific journal: the REPORT trial guide for effective and transparent research reporting without spin
Authors: Thomas Bandholm, Kristian Thorborg, Clare L Ardern, Robin Christensen, Marius Henriksen
Journal: British Journal of Sports Medicine (2022)

The REPORT guide is a ‘How to’ guide to help you report your clinical research in an effective and transparent way. It is intended to supplement established first choice reporting tools, such as Consolidated Standards of Reporting Trials (CONSORT), by adding tacit knowledge (ie, learnt, informal or implicit knowledge) about reporting topics that we have struggled with as authors or see others struggle with as journal reviewers or editors. We focus on the randomised controlled trial, but the guide also applies to other study designs. Topics included in the REPORT guide cover reporting checklists, trial report structure, choice of title, writing style, trial registry and reporting consistency, spin or reporting bias, transparent data presentation (figures), open access considerations, data sharing and more. Preprint (open access): https://doi.org/10.31219/osf.io/qsxdz .
Abstract P040: Dyslipidemia And The Incidence Of Subclinical And Clinical Cardiovascular Disease In Adolescents And Young Adults: The Strong Heart Family Study (SHFS)
Authors: Jessica Reese, Mary J Roman, Jason Deen, Tauqeer Ali, Shelley Cole, Richard B Devereux, Amanda M Fretts, Barbara V Howard, Wm. James Howard, Elisa T Lee, Kimberly Malloy, Parmanand SINGH, Jason G Umans, Ying Zhang
Journal: Circulation (2022)

Introduction: Dyslipidemia is characterized by high levels of total cholesterol (TC), LDL cholesterol (LDL-C), triglycerides (TG), or low levels of HDL cholesterol (HDL-C) and is an established risk factor for subclinical and clinical cardiovascular disease (CVD) among adults. Although several investigations exist in older American Indian (AI) adults, the data on AI adolescents and young adults are scarce. Hypothesis: Dyslipidemia will be prevalent, and the incidence of subclinical and clinical CVD will be higher in young AI with than without baseline dyslipidemia. Methods: We evaluated AI participants from the SHFS, who were 14-39 years old at the baseline examination, 2001-2003 (n=1,436). To measure lipids, we drew blood after a 12-hour fast and defined dyslipidemia as any of the following: TC ≥ 200 mg/dL, LDL-C ≥ 100 mg/dL, TG ≥ 150 mg/dL, HDL-C &lt; 40 mg/dL for men, HDL-C &lt; 50mg/dL for women, non-HDL-C ≥ 130 mg/dL or taking lipid lowering medication. We used carotid ultrasound to detect atherosclerotic plaque at baseline and at the follow-up examination, 2006-2009. We identified CVD events through 2019 with a median follow-up of 17.8 years. We used log-rank tests to determine if the incidence of plaque or CVD events differed according to different categories of dyslipidemia. Results: Prevalence of dyslipidemia was 42%, 65%, and 73% for participants &lt;20, 20-29, and 30-39 years old, respectively. During follow-up, 109 (9.9%) participants had incident plaque (of 1,107 plaque free participants) and 128 (9%) had a fatal or non-fatal CVD event (of 1,424 CVD free participants). Plaque incidence was higher in participants with high TC, LDL-C, TG, non-HDL-C, and dyslipidemia at baseline. CVD incidence was higher for participants with high TC, TG, and non-HDL-C (Table 1). Conclusions: AI adolescents and young adults have an unexpectedly high prevalence of dyslipidemia, which leads to higher incident plaque and CVD events later in life. These data provide evidence for the benefits of lipid screening and intervention among this population.
18F-FDG PET/CT Findings of G-CSF–Producing Gallbladder Cancer
Authors: Fumi Sasaki, Ryusuke Nakamoto, Koji Tokunaga, Ayami Ishida, Shigeaki Umeoka
Journal: Clinical Nuclear Medicine (2022)

We report a case of granulocyte colony-stimulating factor (G-CSF)-producing gallbladder cancer in a 64-year-old man. Contrast-enhanced CT showed an exophytic hypoattenuation mass with peripheral enhancement in the gallbladder. 18F-FDG PET/CT showed avid FDG uptake in the gallbladder mass and diffuse FDG uptake in the bone marrow. The patient was diagnosed with G-CSF-producing gallbladder cancer based on an elevated serum level of G-CSF and histological findings. G-CSF-producing tumors are associated with a poor prognosis because of rapid progression. Early and accurate diagnosis of G-CSF-producing tumors based on characteristic PET/CT findings is important to determine treatment strategies and improve prognosis of patients.
Progressive Multifocal Leukoencephalopathy Mimicking Malignancy on 68Ga-FAPI PET/CT
Authors: Weidong Gong, Meng Fu, Yaling Zhang, Xiao Yang, Chunyin Zhang
Journal: Clinical Nuclear Medicine (2022)

A 43-year-old man presented with weakness in his right upper limb for 2 months. Head MRI showed intracranial multiple abnormal signal foci. Malignancy was suspected. The patient was subsequently enrolled in the clinical trial of 68Ga-FAPI PET/CT. 68Ga-FAPI PET/CT showed intracranial multiple FAPI-avid foci. It was also highly suggestive of malignancy. However, the combination of clinical manifestations, imaging findings, cerebral spinal fluid examinations, and effective immunotherapy confirmed the diagnosis of progressive multifocal leukoencephalopathy. 68Ga-FAPI may have potential advantages in the diagnosis of progressive multifocal leukoencephalopathy.
Cholesterol Auxotrophy as a Targetable Vulnerability in Clear Cell Renal Cell Carcinoma
Authors: Romain Riscal, Caroline J. Bull, Clementina Mesaros, Jennifer M. Finan, Madeleine Carens, Elaine S. Ho, Jimmy P. Xu, Jason Godfrey, Paul Brennan, Mattias Johansson, Mark P. Purdue, Stephen J. Chanock, Daniela Mariosa, Nicholas J. Timpson, Emma E. Vincent, Brian Keith, Ian A. Blair, Nicolas Skuli, M. Celeste Simon
Journal: Cancer Discovery (2021)

Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses based on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell-cycle arrest, apoptosis, elevated intracellular reactive oxygen species levels, and decreased PI3K/AKT signaling. Collectively, we reveal a cholesterol dependency in ccRCC and implicate SCARB1 as a novel therapeutic target for treating kidney cancer. We demonstrate that ccRCC cells are auxotrophic for exogenous cholesterol to maintain PI3K/AKT signaling pathway and ROS homeostasis. Blocking cholesterol import through the HDL transporter SCARB1 compromises ccRCC cell survival and tumor growth, suggesting a novel pharmacologic target for this disease. This article is highlighted in the In This Issue feature, p. 2945.
68Ga-DOTANOC PET/CT in Multiple Endocrine Neoplasia 1 With Associated Adrenocortical Carcinoma
Authors: Shyma Basheer, Ramkesh Ratheesan, Manjit Sarma, Shanmuga Sundaram Palaniswamy, Anitha Mathews
Journal: Clinical Nuclear Medicine (2022)

Multiple endocrine neoplasia 1 (MEN1) syndrome is an autosomal dominant syndrome comprising a triad of pancreatic, pituitary, and parathyroid tumors. Adrenal cortical carcinoma occurs rarely in MEN1 syndrome. Here, we have presented a case of a 62-year-old woman with adrenal mass and elevated serum parathormone levels, who underwent 68Ga-DOTANOC PET/CT. 68Ga-DOTANOC PET/CT showed intense tracer concentration in the left adrenal mass and lesions in the liver, pancreas, and peritoneum. Biopsy of the peritoneal deposit revealed metastatic adrenocortical carcinoma, and further genetic testing showed MEN1 mutation.
Physical exercise, immune response, and susceptibility to infections—current knowledge and growing research areas
Authors: Marcin Kurowski, Sven Seys, Matteo Bonini, Stefano Del Giacco, Luis Delgado, Zuzana Diamant, Marek L. Kowalski, André Moreira, Maia Rukhadze, Mariana Couto
Journal: Allergy (2022)

Abstract This review presents state‐of‐the‐art knowledge and identifies knowledge gaps for future research in the area of exercise‐associated modifications of infection susceptibility. Regular moderate‐intensity exercise is believed to have beneficial effects on immune health through lowering inflammation intensity and reducing susceptibility to respiratory infections. However, strenuous exercise, as performed by professional athletes, may promote infection: in about half of athletes presenting respiratory symptoms, no causative pathogen can be identified. Acute bouts of exercise enhance the release of pro‐inflammatory mediators, which may induce infection‐like respiratory symptoms. Relatively few studies have assessed the influence of regularly repeated exercise on the immune response and systemic inflammation compared to the effects of acute exercise. Additionally, ambient and environmental conditions may modify the systemic inflammatory response and infection susceptibility, particularly in outdoor athletes. Both acute and chronic regular exercise influence humoral and cellular immune response mechanisms, resulting in decreased specific and non‐specific response in competitive athletes. The most promising areas of further research in exercise immunology include detailed immunological characterization of infection‐prone and infection‐resistant athletes, examining the efficacy of nutritional and pharmaceutical interventions as countermeasures to infection symptoms, and determining the influence of various exercise loads on susceptibility to infections with respiratory viruses, including SARS‐CoV‐2. By establishing a uniform definition of an “elite athlete,” it will be possible to make a comparable and straightforward interpretation of data from different studies and settings.
A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia
Authors: Danielle E. Whittaker, Roberto Oleari, Louise C. Gregory, Polona Le Quesne-Stabej, Hywel J. Williams, John G. Torpiano, Nancy Formosa, Mario J. Cachia, Daniel Field, Antonella Lettieri, Louise A. Ocaka, Alyssa J.J. Paganoni, Sakina H. Rajabali, Kimberley L.H. Riegman, Lisa B. De Martini, Taro Chaya, Iain C.A.F. Robinson, Takahisa Furukawa, Anna Cariboni, M. Albert Basson, Mehul T. Dattani
Journal: Journal of Clinical Investigation (2021)

The positive regulatory (PR) domain containing 13 (PRDM13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia and normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the cooccurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.
Free-Floating Cyst in the Vitreous
Authors: Chuan-bin Sun
Journal: New England Journal of Medicine (2022)

A healthy 18-year-old man presented to the eye clinic with a 1-day history of seeing a “floating ball” in his left eye when he blinked. Slit-lamp examination (shown in a video) revealed a spherical, brown-pigmented mass floating freely in the vitreous when the patient blinked. A diagnosis of iris pigment epithelium cyst was made.
Diagnostic Red Blood Cell Distribution Width As a Prognostic Factor in Acute Myeloid Leukemia
Authors: Vladan Vucinic, Leo Ruhnke, Katja Sockel, Maximilian Alexander Röhnert, Donata Backhaus, Dominic Brauer, Georg-Nikolaus Franke, Dietger Niederwieser, Martin Bornhäuser, Christoph Rollig, Uwe Platzbecker, Sebastian Schwind, Madlen Jentzsch
Journal: Blood (2021)