tbuckley/cabot-search huggingface dataset:
Disrupting the DREAM transcriptional repressor complex induces apolipoprotein overexpression and systemic amyloidosis in mice
Authors: Pirunthan Perampalam, Haider M. Hassan, Grace E. Lilly, Daniel T. Passos, Joseph Torchia, Patti K. Kiser, Andrea Bozovic, Vathany Kulasingam, Frederick A. Dick
Journal: Journal of Clinical Investigation (2021)

DREAM (Dp, Rb-like, E2F, and MuvB) is a transcriptional repressor complex that regulates cell proliferation, and its loss causes neonatal lethality in mice. To investigate DREAM function in adult mice, we used an assembly-defective p107 protein and conditional deletion of its redundant family member p130. In the absence of DREAM assembly, mice displayed shortened survival characterized by systemic amyloidosis but no evidence of excessive cellular proliferation. Amyloid deposits were found in the heart, liver, spleen, and kidneys but not the brain or bone marrow. Using laser-capture microdissection followed by mass spectrometry, we identified apolipoproteins as the most abundant components of amyloids. Intriguingly, apoA-IV was the most detected amyloidogenic protein in amyloid deposits, suggesting apoA-IV amyloidosis (AApoAIV). AApoAIV is a recently described form, whereby WT apoA-IV has been shown to predominate in amyloid plaques. We determined by ChIP that DREAM directly regulated Apoa4 and that the histone variant H2AZ was reduced from the Apoa4 gene body in DREAM's absence, leading to overexpression. Collectively, we describe a mechanism by which epigenetic misregulation causes apolipoprotein overexpression and amyloidosis, potentially explaining the origins of nongenetic amyloid subtypes.
Evaluation of Aspirin Use With Cancer Incidence and Survival Among Older Adults in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Authors: Holli A. Loomans-Kropp, Paul Pinsky, Asad Umar
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Many studies have evaluated the long-term benefits of aspirin use; however, the association of aspirin use with cancer incidence and survival in older individuals remains uncertain. Additional population-based evidence of this association is necessary to better understand any possible protective effects of aspirin in older adults. <h3>Objective</h3> To investigate the association of aspirin use with risk of developing new cancers and site-specific cancer-associated survival in bladder, breast, esophageal, gastric, pancreatic, and uterine cancers. <h3>Design, Setting, and Participants</h3> This cohort study used data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Participants were aged 65 years or older at baseline (1993-2001) or reached age 65 during follow-up. Data analysis was conducted from January to June 2020. <h3>Main Outcomes and Measures</h3> Incidence of and survival from the investigated cancer types. Univariable and multivariable hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards regression modeling, adjusting for covariates. Multivariable models for incidence included time-varying covariates. <h3>Results</h3> A total of 139 896 individuals (mean [SD] age at baseline, 66.4 [2.4] years; 71 884 [51.4%] women; 123 824 [88.5%] non-Hispanic White individuals) were included in the analysis. During the study period, 32 580 incident cancers (1751 [5.4%] bladder, 4552 [14.0%] breast, 332 [1.0%] esophageal, 397 [1.2%] gastric, 878 [2.7%] pancreatic, and 716 [2.2%] uterine cancers) were reported. Aspirin use was not associated with incidence of any of the investigated cancer types among individuals aged 65 years or older. Multivariable regression analysis demonstrated that aspirin use at least 3 times/week was associated with increased survival among patients with bladder (HR, 0.67; 95% CI, 0.51-0.88) and breast (HR, 0.75; 95% CI, 0.59-0.96) cancers but not among those with esophageal, gastric, pancreatic, or uterine cancer. A similar association of any aspirin use with bladder (HR, 0.75; 95% CI, 0.58-0.98) and breast (HR, 0.79; 95% CI, 0.63-0.99) cancer survival was observed. <h3>Conclusions and Relevance</h3> In the current study, any aspirin use and aspirin use at least 3 times/week was associated with improved bladder and breast cancer survival. Associations between aspirin use and incidence of any of the investigated cancers or between aspirin use and esophageal, gastric, pancreatic, or uterine cancer survival were not observed.
Rho-GTPase Activating Protein myosin MYO9A identified as a novel candidate gene for monogenic focal segmental glomerulosclerosis
Authors: Qi Li, Ashima Gulati, Mathieu Lemaire, Timothy Nottoli, Allen Bale, Alda Tufro
Journal: Kidney International (2021)

Focal segmental glomerulosclerosis (FSGS) is a podocytopathy leading to kidney failure, whose molecular cause frequently remains unresolved. Here, we describe a rare MYO9A loss of function nonsense heterozygous mutation (p.Arg701∗) as a possible contributor to disease in a sibling pair with familial FSGS/proteinuria. MYO9A variants of uncertain significance were identified by whole exome sequencing in a cohort of 94 biopsy proven patients with FSGS. MYO9A is an unconventional myosin with a Rho-GAP domain that controls epithelial cell junction assembly, crosslinks and bundles actin and deactivates the small GTPase protein encoded by the RHOA gene. RhoA activity is associated with cytoskeleton regulation of actin stress fiber formation and actomyosin contractility. Myo9A was detected in mouse and human podocytes in vitro and in vivo. Knockin mice carrying the p.Arg701∗MYO9A (Myo9AR701X) generated by gene editing developed proteinuria, podocyte effacement and FSGS. Kidneys and podocytes from Myo9AR701X/+ mutant mice revealed Myo9A haploinsufficiency, increased RhoA activity, decreased Myo9A-actin-calmodulin interaction, impaired podocyte attachment and migration. Our results indicate that Myo9A is a novel component of the podocyte cytoskeletal apparatus that regulates RhoA activity and podocyte function. Thus, Myo9AR701X/+ knock-in mice recapitulate the proband FSGS phenotype, demonstrate that p.R701X Myo9A is an FSGS-causing mutation in mice and suggest that heterozygous loss-of-function MYO9A mutations may cause a novel form of human autosomal dominant FSGS. Hence, identification of MYO9A pathogenic variants in additional individuals with familial or sporadic FSGS is needed to ascertain the gene contribution to disease.
Estimation of pregnancy losses attributable to exposure to ambient fine particles in south Asia: an epidemiological case-control study
Authors: Tao Xue, Tianjia Guan, Guannan Geng, Qiang Zhang, Yong Zhao, Tong Zhu
Journal: The Lancet Planetary Health (2021)

<h2>Summary</h2><h3>Background</h3> Maternal exposure to ambient particulate matter (PM<sub>2·5</sub>) is associated with pregnancy loss (ie, stillbirth and miscarriage). South Asia has the highest burden of pregnancy loss globally and is one of the most PM<sub>2·5</sub> polluted regions in the world. However, knowledge of the relevant exposure–response function for mothers is insufficient. <h3>Methods</h3> In this epidemiological case-control study, we collected data from Demographic and Health Surveys from India, Pakistan, and Bangladesh for the period 1998–2016 for women who reported at least one pregnancy loss and one or more livebirths. We assessed ambient exposure during gestation with satellite-based PM<sub>2·5</sub> measurements for the period. To derive the exposure–response function, we did a self-compared case-control study in which each case of pregnancy loss was compared with a successful livebirth control or controls by the same mother. Using the estimated exposure–response function, we quantified pregnancy losses attributable to PM<sub>2·5</sub> in the region for the period 2000–16 using a standard risk assessment approach. <h3>Findings</h3> We assessed data for 34 197 mothers, who had at least one pregnancy loss and one or more livebirth, of whom 26 282 (76·9%) were from India, 4228 (12·4%) were from Pakistan, and 3687 (10·8%) were from Bangladesh. The 34 197 cases of pregnancy loss were matched with 76 282 livebirth controls. The mean level of PM<sub>2·5</sub> exposure was 56·00 μg/m<sup>3</sup> (SD 30·82) for cases and 54·57 μg/m<sup>3</sup> (31·73) for controls. After adjustment for maternal age, non-linear terms for temperature and humidity, seasonal variation, and long-term trends, each 10 μg/m<sup>3</sup> increment in PM<sub>2·5</sub> was associated with an odds ratio for pregnancy loss of 1·03 (95% CI 1·02–1·05). According to the estimated non-linear exposure–response function by age and urban residence versus rural residence, for the period 2000–16, an estimated 349 681 (95% CI 152 932–489 493) pregnancy losses per year were attributed to ambient air exposure of more than 40 μg/m<sup>3</sup> (the annual PM<sub>2·5</sub> standard of India), accounting for 7·1% (95% CI 3·3–31·2) of the total annual pregnancy loss burden in south Asia for this period. However, our estimates could be biased because of the limitations of the data (eg, misclassification of induced and spontaneous pregnancy losses). <h3>Interpretation</h3> Our findings add to epidemiological evidence of the association between pregnancy loss and PM<sub>2·5</sub>. Suboptimal air quality contributes to a considerable fraction of total pregnancy loss in south Asia. Controlling PM<sub>2·5</sub> pollution will promote maternal health in south Asia. <h3>Funding</h3> Chinese Natural Science Foundation and Ministry of Science and Technology of China.
Abstract 17079: Lower Socioeconomic Status Portends Higher Long Term Mortality Following Isolated Mitral Valve Surgery
Authors: Mark R Helmers, William Patrick, Cody Fowler, Amit Iyengar, Jason J Han, Peter Altshuler, W. C Hargrove, Pavan Atluri
Journal: Circulation (2020)

Introduction: Lower socioeconomic status (SES) has been associated with worse outcomes in patients undergoing cardiac surgery; however, this has not been fully elucidated in mitral valve (MV) surgery. We sought to determine the effect of SES on short-term outcomes and long-term mortality following MV surgery. Hypothesis: Lower SES is associated with higher mortality following isolated MV surgery. Methods: Retrospective analysis of our institution’s MV database was performed between November 1998 and March 2019 for all adult patients undergoing isolated MV surgery in our state and 4 neighboring states. Patients for whom address data was missing were excluded. SES was determined by the Area Deprivation Index (ADI). The ADI uses 17 social determinants of heath to estimate the average SES for all US Census Block Groups (mean 1500 people). This score is then nationally indexed from 1 to 100, with lower SES represented by higher scores. Patients were stratified by ADI quartiles. Baseline characteristics and postoperative outcomes were compared between quartiles. Results: Overall, 3,860 surgeries met inclusion criteria during the study period. Of these, 1,795 (46.5%) patients fell into the lowest ADI quartile, 1,216 (31.5%) in the second quartile, 476 (12.3%) in the third quartile, and 344 (8.9%) in the highest quartile. 30-day mortality was not significantly different between ADI quartiles and ADI was not a significant determinate of 30-day survival in a multivariable logistical regression. Figure 1 show the distribution of patient addresses within Census Block Groups as well as 10-year survival by Kaplan-Meier estimates, stratified by ADI quartiles. Cox proportional hazards model revealed that lower SES as determined by ADI was associated with increased 10-year mortality (P = 0.008). Conclusions: Lower SES is associated with worse long-term survival in patients undergoing isolated MV surgery. Social interventions to bridge this survival gap are warranted.
Clinical Olfactory Working Group consensus statement on the treatment of postinfectious olfactory dysfunction
Authors: Alfred B. Addison, Billy Wong, Tanzime Ahmed, Alberto Macchi, Iordanis Konstantinidis, Caroline Huart, Johannes Frasnelli, Alexander W. Fjaeldstad, Vijay R. Ramakrishnan, Philippe Rombaux, Katherine L. Whitcroft, Eric H. Holbrook, Sophia C. Poletti, Julien W. Hsieh, Basile N. Landis, James Boardman, Antje Welge-Lüssen, Devina Maru, Thomas Hummel, Carl M. Philpott
Journal: Journal of Allergy and Clinical Immunology (2021)
Abstract 17183: Genetic Variants Primarily Associated with Rheumatoid Arthritis (RA) Do Not Effect Coronary Artery Disease Risk
Authors: Henning Jansen, Wolfgang Lieb, Christina Loley, Sekar Kathiresan, Muredach P Reilly, Themistocles L. Assimes, Eric Boerwinkle, Alistair S Hall, Klaus Stark, Christian Hengstenberg, Reijo Laaksonen, Ruth McPherson, Unnur Thorsteinsdottir, Annette Peters, John R Thompson, Inke R Koenig, Jeanette Erdmann, Nilesh J Samani, Heribert Schunkert
Journal: Circulation (2012)

Inflammatory conditions like rheumatoid arthritis (RA) have been suspected to affect the risk of coronary artery disease (CAD). Specifically, RA has been shown repeatedly to increase the risk of CA...
Blood–Brain Barrier Dynamics to Maintain Brain Homeostasis
Authors: Marta Segarra, Maria R. Aburto, Amparo Acker-Palmer
Journal: Trends in Neurosciences (2021)

The blood-brain barrier (BBB) is a dynamic platform for exchange of substances between the blood and the brain parenchyma, and it is an essential functional gatekeeper for the central nervous system (CNS). While it is widely recognized that BBB disruption is a hallmark of several neurovascular pathologies, an aspect of the BBB that has received somewhat less attention is the dynamic modulation of BBB tightness to maintain brain homeostasis in response to extrinsic environmental factors and physiological changes. In this review, we summarize how BBB integrity adjusts in critical stages along the life span, as well as how BBB permeability can be altered by common stressors derived from nutritional habits, environmental factors and psychological stress.
Gastrostomy Tube for Nutrition and Malignant Bowel Obstruction in Patients With Cancer
Authors: Gabrielle Gauvin, Chi Chi Do-Nguyen, Johanna Lou, Eileen Anne O’Halloran, Leigh T. Selesner, Elizabeth Handorf, Molly E. Collins, Jeffrey M. Farma
Journal: Journal of the National Comprehensive Cancer Network (2021)

Gastrostomy tubes (G-tubes) are invaluable clinical tools that play a role in palliation and nutrition in patients with cancer. This study aimed to better understand the risks and benefits associated with the placement and maintenance of G-tubes.Patients who underwent placement of a G-tube for cancer from January 2013 through December 2017 at a tertiary care center were considered for inclusion. Clinical data were retrospectively collected from medical records.A total of 242 patients with cancer, whose average age at diagnosis was 61 years (range, 21-94 years), underwent G-tube placement for nutrition (76.4%), decompression (22.7%), or both (0.8%). Successful insertion was achieved in 96.8%, but 8 patients required >1 attempted method of insertion. In the decompression group, minor postplacement complications were less common (23.6% vs 53.5%; P<.001) and survival was shorter (P<.001) compared with the nutrition group. For those with decompressive G-tubes, 45.5% had a palliative care consult; 56.4% were seen by social workers; and 46.3% went to hospice. The frequency of hospice discharge was higher in patients who had consults (53.7% vs 23.1%; P=.01).Half of the patients who received decompressive G-tubes presented with stage IV disease and died within 1 month of placement. Those with >1 consult were more likely to be discharged to hospice. Patients with G-tubes for nutrition saw no change in functionality, complication rate, or survival, regardless of adjunct chemotherapy status. These findings illustrate the need for a tool to allow a better multidisciplinary approach and interventional decision-making for patients with cancer.
Abstract 18163: The Effects of the Administration of Natural Chios Mastic on Endothelial Function and Arterial Stiffness in Smokers
Authors: Evangelos Oikonomou, Vasiliki Tsigkou, Gerasimos Siasos, Konstantinos Mourouzis, Georgios Angelos Papamikroulis, Eleni Kokkou, Georgia Vogiatzi, Nikolaos Gouliopoulos, Sotirios Tsalamandris, Nikolaos Papageorgiou, Savvas Mazaris, Manolis Vavuranakis, Christodoulos Stefanadis, Dimitris Tousoulis
Journal: Circulation (2017)

Introduction: Smoking is a major cardiovascular risk factor and is associated with vascular dysfunction. Natural Chios Mastic (NCM), a rich source of flavonoids, exerts numerous beneficial effects ...
S100A8 promotes epithelial‐mesenchymal transition and metastasis under TGF‐β/USF2 axis in colorectal cancer
Authors: Si Li, Jun Zhang, Senmi Qian, Xuesong Wu, Liang Sun, Tianyi Ling, Yao Jin, Wenxiao Li, Lichao Sun, Maode Lai, Fangying Xu
Journal: Cancer Communications (2021)

The transforming growth factor-β (TGF-β) pathway plays a pivotal role in inducing epithelial-mesenchymal transition (EMT), which is a key step in cancer invasion and metastasis. However, the regulatory mechanism of TGF-β in inducing EMT in colorectal cancer (CRC) has not been fully elucidated. In previous studies, it was found that S100A8 may regulate EMT. This study aimed to clarify the role of S100A8 in TGF-β-induced EMT and explore the underlying mechanism in CRC.S100A8 and upstream transcription factor 2 (USF2) expression was detected by immunohistochemistry in 412 CRC tissues. Kaplan-Meier survival analysis was performed. In vitro, Western blot, and migration and invasion assays were performed to investigate the effects of S100A8 and USF2 on TGF-β-induced EMT. Mouse metastasis models were used to determine in vivo metastasis ability. Luciferase reporter and chromatin immunoprecipitation assay were used to explore the role of USF2 on S100A8 transcription.During TGF-β-induced EMT in CRC cells, S100A8 and the transcription factor USF2 were upregulated. S100A8 promoted cell migration and invasion and EMT. USF2 transcriptionally regulated S100A8 expression by directly binding to its promoter region. Furthermore, TGF-β enhanced the USF2/S100A8 signaling axis of CRC cells whereas extracellular S100A8 inhibited the USF2/S100A8 axis of CRC cells. S100A8 expression in tumor cells was associated with poor overall survival in CRC. USF2 expression was positively related to S100A8 expression in tumor cells but negatively related to S100A8-positive stromal cells.TGF-β was found to promote EMT and metastasis through the USF2/S100A8 axis in CRC while extracellular S100A8 suppressed the USF2/S100A8 axis. USF2 was identified as an important switch on the intracellular and extracellular S100A8 feedback loop.
Abstract 365: Percutaneous Ventricular Assist Devices Versus Intra Aortic Balloon Pump in Cardiogenic Shock
Authors: Muhammad Faisal Asad Janjua, Hafiz Muhammad Zubair, Amir Shahbaz
Journal: Circulation (2019)

Introduction: Cardiogenic shock (CS) is a condition of insufficient tissue perfusion due to cardiac dysfunction. Despite the improvement in prognosis due to aggressive reperfusion strategies, in-hospital mortality from CS is around 50%. Intra-aortic balloon pump (IABP) has been used for the management of CS. Percutaneous Ventricular Assist Devices (pVAD) such as the tandem heart and the Impella have been developed to treat CS. We carry out a meta-analysis comparing the IABP versus pVAD during CS. Method: Using PubMed, Cochrane Library, and EMBASE we searched for randomized clinical trials (RCTs) that compared pVAD versus IABP in patients CS. Result: We demonstrated no difference in short-term 30 days all-cause mortality (risk ratio [RR] 1.14 [CI: 0.70+/- 1.86]. The RR of acute kidney injury (AKI) for pVAD compared to IABP is 0.96 [CI: 0.46 +/- 2.00], for limb ischemia RR is 3.31 [CI: 1.04 +/- 10.51], for infection/sepsis 0.59 [CI: 0.19+/-1.80], for bleeding 2.41 [CI: 1.41+/- 4.13] and for vascular injury 3.75 [CI: 0.19 +/- 72.49]. Although pVAD provides superior hemodynamic support in patients with CS compared with IABP, the use of these more powerful devices did not improve early survival. The use of pVAD is associated with more adverse events compared with IABP. Discussion: The use of more vigorous hemodynamic support for CS does not associate with a 30 days survival benefit but could be associated with more adverse events. The reason for these findings is unclear but could be explained by the fact that decreased cardiac output seen in CS is only a single component of the multifaceted syndrome that involves several other molecular and hemodynamic mechanisms or merely because of the increase in the cardiac output by the IABP or the pVAD is inadequate to improve outcomes. Conclusion: Use of pVAD resulted in a better hemodynamic profile compared with IABP. However, this did not translate into improved 30-day survival. Also, patients treated with a pVAD have a higher risk of leg ischemia, AKI and, device-related bleeding.
Prediction of AF in Heart Failure With Preserved Ejection Fraction
Authors: Ewelina Jasic-Szpak, Thomas H. Marwick, Erwan Donal, Monika Przewlocka-Kosmala, Quan Huynh, Anna Gozdzik, Anna K. Woznicka, Ewa A. Jankowska, Piotr Ponikowski, Wojciech Kosmala
Journal: JACC. Cardiovascular imaging (2021)
Corrigendum to “Three-dimensional self-assembling nanofiber matrix rejuvenates aged/degenerative human tendon stem/progenitor cells” [Biomaterials 236 (2020) 119,802]
Authors: Heyong Yin, Franziska Strunz, Zexing Yan, Jiaju Lu, Christoph Brochhausen, Stefanie Kiderlen, Hauke Clausen-Schaumann, Xiumei Wang, Manuela E. Gomes, Volker Alt, Denitsa Docheva
Journal: Biomaterials (2021)
Enriched metabolites that potentially promote age-associated diseases in subjects with an elderly-type gut microbiota
Authors: Shin Yoshimoto, Eri Mitsuyama, Keisuke Yoshida, Toshitaka Odamaki, Jin-zhong Xiao
Journal: Gut Microbes (2021)

We previously investigated the gut microbiota of 453 healthy Japanese subjects aged 0 to 104 years and found that the composition of the gut microbiota could be classified into some age-related clusters. In this study, we compared fecal metabolites between age-matched and age-mismatched elderly subjects to examine the roles of the gut microbiota in the health of the elderly. Fecal metabolites in 16 elderly subjects who fell into an age-matched cluster (elderly-type gut microbiota group, E-GM) and another 16 elderly subjects who fell into an age-mismatched cluster (adult-type gut microbiota group, A-GM) were measured by CE-TOF-MS. A total of eight metabolites were significantly different between the groups: cholic acid and taurocholic acid were enriched in the A-GM group, whereas choline, trimethylamine (TMA), N8-acetylspermidine, propionic acid, 2-hydroxy-4-methylvaleric acid, and 5-methylcytosine were enriched in the E-GM group. Some metabolites (choline, TMA, N8-acetylspermidine) elevated in the E-GM group were metabolites or precursors reported as risk factors for age-associated diseases such as arteriosclerosis and colorectal cancer. The abundance of some species belongs to Proteobacteria, which were known as TMA-producing bacteria, was increased in the E-GM group and correlated with fecal TMA levels. In vitro assays showed that these elderly-type fecal metabolites suppressed the expression of genes related to tight junctions in normal colonic epithelial cells and induced the expression of inflammatory cytokines in colon cancer cells. These findings suggest that metabolites produced by the aged gut microbiota could contribute to intestinal and systemic homeostasis and could be targeted for preventing aging-associated diseases.
The Clinical Emergence of Optical Coherence Tomography: Defining a Role in Intravascular Imaging⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Sotirios Tsimikas, Anthony N. DeMaria
Journal: Journal of the American College of Cardiology (2012)