tbuckley/cabot-search huggingface dataset:
Grade Migration of Prostate Cancer in the United States During the Last Decade
Authors: Leonardo D Borregales, Gina DeMeo, Xiangmei Gu, Emily Cheng, Vanessa Dudley, Edward M Schaeffer, Himanshu Nagar, Sigrid Carlsson, Andrew Vickers, Jim C Hu
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Prostate cancer (PC) screening guidelines have changed over the last decade to reduce overdiagnosis and overtreatment of low-grade disease. We sought to examine and attempt to explain how changes in screening strategies have impacted temporal trends in Gleason grade group (GG) PC at diagnosis and radical prostatectomy pathology. Methods Using the Surveillance, Epidemiology, and End Results Registry database, we identified 438 432 men with newly diagnosed PC during 2010-2018. Temporal trends in incidence of GG at biopsy, radical prostatectomy pathology, prostate-specific antigen (PSA) level, and metastasis at diagnosis were examined. The National Health Interview Survey database was examined to evaluate trends in PSA-screening rates, and a literature review evaluating magnetic resonance imaging and biomarkers utilization during this period was performed. Results Between 2010 and 2018, the incidence of low-grade PC (GG1) decreased from 52 to 26 cases per 100 000 (P &amp;lt; .001). The incidence of GG1 as a proportion of all PC decreased from 47% to 32%, and the proportion of GG1 at radical prostatectomy pathology decreased from 32% to 10% (P &amp;lt; .001). However, metastases at diagnosis increased from 3.0% to 5.2% (P &amp;lt; .001). During 2010-2013, PSA screening rates in men aged 50-74 years declined from 39 to 32 per 100 men and remained stable. Utilization rates of magnetic resonance imaging and biomarkers modestly increased from 7.2% in 2012 to 17% in 2019 and 1.3% in 2012 to 13% in 2019, respectively. Conclusions We found a significant decrease in the diagnosis and treatment of GG1 PC between 2010 and 2018. Changes in PSA screening practices appear as the primary contributor. Public health efforts should be directed toward addressing the increase in the diagnoses of metastatic PC.
EXERCISE TRAINING IMPROVES THE EXOSOMAL CONTENT IN PATIENTS WITH HEART FAILURE
Authors: Marisol Gouveia, Tânia Martins, Cristine Schmidt, Priscilla Gois, Manuel Teixeira, Xavier Muñoz, Pilar Ximénez-Embún, Kevin Leandro, Luís Almeida, Rui Vitorino, Rita Ferreira, Sandra Vieira, Mário Santos, Ana G. Henriques, Fernando Ribeiro
Journal: Journal of the American College of Cardiology (2022)
Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity in Neonatal Intensive Care
Authors: John H. McDermott, Ajit Mahaveer, Rachel A. James, Nicola Booth, Mark Turner, Karen E. Harvey, Gino Miele, Glenda M. Beaman, Duncan C. Stoddard, Karen Tricker, Rachel J. Corry, Julia Garlick, Shaun Ainsworth, Thomas Beevers, Iain A. Bruce, Richard Body, Fiona Ulph, Rhona MacLeod, Peter L. Roberts, Paul M. Wilson, William G. Newman, Imelda Mayor, Clare Jennings, Karen Dockery, Jenna Hill, Joanne Windrow, Patrick McGowan, Amy Ingham, Sarah Rushton, Poly Kirkilli, Suzanne Parsons, Ruth Gottstein, Ngozi Edi-Osagie, Christine Ashworth, Maxine Brandall, Kath Eaton
Journal: JAMA Pediatrics (2022)

Aminoglycosides are commonly prescribed antibiotics used for the treatment of neonatal sepsis. The MT-RNR1 m.1555A>G variant predisposes to profound aminoglycoside-induced ototoxicity (AIO). Current genotyping approaches take several days, which is unfeasible in acute settings. To develop a rapid point-of-care test (POCT) for the m.1555A>G variant before implementation of this technology in the acute neonatal setting to guide antibiotic prescribing and avoid AIO. This pragmatic prospective implementation trial recruited neonates admitted to 2 large neonatal intensive care units between January 6, 2020, and November 30, 2020, in the UK. Neonates were tested for the m.1555A>G variant via the rapid POCT on admission to the neonatal intensive care unit. The primary outcome assessed the proportion of neonates successfully tested for the variant of all infants prescribed antibiotics. Secondary outcomes measured whether implementation was negatively associated with routine clinical practice and the performance of the system. The study was statistically powered to detect a significant difference between time to antibiotic administration before and after implementation of the MT-RNR1 POCT. A total of 751 neonates were recruited and had a median (range) age of 2.5 (0-198) days. The MT-RNR1 POCT was able to genotype the m.1555A>G variant in 26 minutes. Preclinical validation demonstrated a 100% sensitivity (95% CI, 93.9%-100.0%) and specificity (95% CI, 98.5%-100.0%). Three participants with the m.1555A>G variant were identified, all of whom avoided aminoglycoside antibiotics. Overall, 424 infants (80.6%) receiving antibiotics were successfully tested for the variant, and the mean time to antibiotics was equivalent to previous practice. The MT-RNR1 POCT was integrated without disrupting normal clinical practice, and genotype was used to guide antibiotic prescription and avoid AIO. This approach identified the m.1555A>G variant in a practice-changing time frame, and wide adoption could significantly reduce the burden of AIO.
ELECTROCARDIOGRAPHIC FINDINGS IN HYPERTENSIVE PATIENTS IN THE RURAL AREAS OF THE DOMINICAN REPUBLIC
Authors: MIGUEL Antonio Rodriguez Guerra, Ana Paula Urena, Ramona Lappot, Jorge Tarafa, Madeline Santana, Claudia Almonte, Ingrid E. Valdez, Gisselle Ramirez, Freddy Madera, Pedro Urena Velasquez
Journal: Journal of the American College of Cardiology (2022)
Author Correction: EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood
Authors: Michael Weller, Martin van den Bent, Matthias Preusser, Emilie Le Rhun, Jörg C. Tonn, Giuseppe Minniti, Martin Bendszus, Carmen Balana, Olivier Chinot, Linda Dirven, Pim French, Monika E. Hegi, Asgeir S. Jakola, Michael Platten, Patrick Roth, Roberta Rudà, Susan Short, Marion Smits, Martin J. B. Taphoorn, Andreas von Deimling, Manfred Westphal, Riccardo Soffietti, Guido Reifenberger, Wolfgang Wick
Journal: Nature Reviews Clinical Oncology (2022)

Fig. 3 contained errors regarding unfavourable factors for IDH-wild-type glioblastomas, WHO grade 4. The box label originally mentioning "KPS <70 years" has been corrected to "age <70 years; KPS <70 years".In addition, greater clarity has been provided by changing "age >70 years" in other boxes to "age ≥70 years".Fig.
Abstract P5-10-08: Inflammation drives NOS2-Akt2 signaling in triple negative breast cancer
Authors: Su Chung, William Montfort
Journal: Cancer Research (2022)

Abstract Triple negative breast cancer (TNBC) is aggressive and represents nearly 20% of all breast cancer cases. It is associated with poor prognosis due to its high metastatic capabilities and lack of targeted therapeutic treatments. To improve TNBC treatment, our goal is to better understand the molecular mechanisms that drive TNBC. Recently, inducible nitric oxide synthase (NOS2), a nitric oxide (NO) producing enzyme, has emerged as a key player in TNBC progression. High NOS2 expression in TNBC patient correlates with poor prognosis marked with increased metastasis and disease recurrence. NOS2 catalyzes L-arginine and dioxygen (O2) to produce citrulline and high, sustained levels of NO which has been shown to alter the activity of numerous signaling pathways. Depending on NO concentration and temporal and spatial levels, it has been reported to have both tumor-promoting and tumor-suppressing functions. However, the mechanism by which NOS2 drives TNBC is unclear. Akt is major oncogenic signaling pathway that regulates various aspects of tumor progression, and it has been shown that NO can activate Akt activity. The Akt family has three members, Akt1, Akt2, and Akt3, that seem to have similar and non-redundant functions in cancer. We have discovered for the first time that NOS2 specifically activates Akt2 in TNBC cells. Thus, we hypothesize that Akt2 plays a major role in NOS2 driven TNBC. Inflammatory cytokines (IFN-γ, IL-1β, and TNF-α) highly induce NOS2 in mouse 4T1 TNBC cells. We developed a real-time NO detection assay to measure NO levels in 4T1 cells and confirmed that these cells produce high levels of NO. By pharmacologically and genetically inhibiting NOS2 in the 4T1 cells, we found that NOS2 suppresses Akt2 phosphorylation but not the total levels. Furthermore, NOS2 had no effect on Akt1. The decrease in Akt2 phosphorylation was accompanied by inhibition of its downstream targets, GSK3β and FOXO3a, suggesting that NOS2 is regulating Akt2 activity. Conversely, treatment of 4T1 and human MDA-MD-231 TNBC cells with DETA/NO, a slow releasing NO donor, resulted in increased Akt2 phosphorylation with no effect on Akt1. Akt2 has been shown to promote migration, invasion, and metastasis. Using 4T1 cells, we are presently studying the function of NOS2-Akt2 signaling in TNBC. We have orthotopically injected 4T1 cells into immunocompetent mice and have found that 4T1 tumors express high levels of NOS2 as well as phosphorylated Akt2. We have knocked out NOS2 in the 4T1 cells to examine the effects of NOS2 inhibition in the mouse tumor model. Understanding the link between NOS2 and Akt2 will give further understanding on how NOS2 drives TNBC. Citation Format: Su Chung, William Montfort. Inflammation drives NOS2-Akt2 signaling in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-10-08.
CHARACTERIZATION OF THE FIRST 391 REPORTS OF MYOCARDITIS AFTER MRNA COVID-19 VACCINES SUBMITTED TO THE VACCINE ADVERSE EVENT REPORTING SYSTEM - UNITED STATES
Authors: Guillermo Rodriguez-Nava, Goar Egoryan, Paritosh Prasai, Maria Adriana Yanez-Bello, Daniela Patricia Trelles-Garcia
Journal: Journal of the American College of Cardiology (2022)
HYPERTROPHIC CARDIOMYOPATHY: BEYOND THE SARCOMERE
Authors: Felice Borrelli, Garret Storm, Maria Angela Losi, Grazia Canciello, Fiorenzo Manganelli, Stefano Tozza, Giovanni Esposito, Matthew R. Taylor, Luisa Mestroni, Raffaella Lombardi
Journal: Journal of the American College of Cardiology (2022)
OBESITY BLUNT GAS EXCHANGE EVIDENCE OF VENTILATORY INEFFICIENCY IN PATIENTS WITH CHRONIC THROMBOEMBOLIC DISEASE
Authors: Estefania Oliveros Soles, Madeline Lee, Kaitlyn Mcsurdy, Vladimir Lakhter, Riyaz Bashir, William Auger, Anjali Vaidya, Paul Forfia
Journal: Journal of the American College of Cardiology (2022)
CONGESTIVE HEART FAILURE AND IMPACT OF COEXISTING CARCINOID SYNDROME: AN INSIGHT FROM NATIONAL INPATIENT SAMPLE (NIS) 2016-2019
Authors: Suman Biswas, Neelkumar Patel, Dhrubajyoti Bandyopadhyay, Sandipan Chakraborty, Birendra Amgai, Adrija Hajra, Zeel Patel
Journal: Journal of the American College of Cardiology (2022)
TREATMENT OF MECHANICAL COMPLICATIONS OF ACUTE MYOCARDIAL INFARCTION DURING THE COVID-19 ERA: A COMPARISON WITH THE PRE-COVID-19 PERIOD
Authors: Cristiano Spadaccio, Angelo Pisani, Antonio Salsano, Antonio Nenna, David D'Alessandro, David Rose, Thoralf M. Sundt
Journal: Journal of the American College of Cardiology (2022)
ASSOCIATION OF ORAL CALCIUM AND VITAMIN D SUPPLEMENTATION WITH MORTALITY AND PROGRESSION OF AORTIC VALVE STENOSIS: A 10-YEAR LONGITUDINAL STUDY
Authors: Essa Hariri, Nicholas Kassis, Antonette K. Karrthik, Keerat Rai Ahuja, Serge C. Harb, Samir R. Kapadia
Journal: Journal of the American College of Cardiology (2022)
Covid-19: Public inquiry must include effects on children, say experts
Authors: Jacqui Wise
Journal: BMJ (2022)

As a bioactive signaling lipid, lysophosphatidic acid (LPA) is in the same phospholipid family as sphingosine-1-phosphate (S1P) yet its impact on immune cells remains unclear, despite that all immune cells express specific LPA receptors. Generated systemically through the extracellular enzyme Autotaxin, LPA exerts its biological influence through 6 known G protein couple receptors (GPCRs), LPAR1-6. Aberrant LPA production has been linked to multiple “hallmarks” of tumorigenesis, including enhancing tumor promoting inflammation, metastasis, and angiogenesis. We propose that up regulation of tumor-derived LPA can also dampen adaptive immune responses, thereby creating an immune suppressive tumor microenvironment. CD8+ T cells are known to be able to eliminate nascent tumors, yet over time are often rendered functionally silent due to tumor-derived signals that act on <i>inhibitory receptors</i> such as CTLA4 and PD1. Work from our lab has found that pathological levels of LPA can also dampen TCR signaling suggesting an additional mechanism by which cancers avoid elimination. Strikingly, ablation of LPAR5 on CD8+ T cells significantly reduced tumor burden compared to wild type CD8+ T cells, suggesting that LPAR5 is a novel <i>inhibitory lipid receptor</i>. Given the recent success of checkpoint blockade therapy for the treatment of cancers, we are currently characterizing this novel inhibitory interaction between CD8+ T cells and LPA generated in the tumor microenvironment.
Association of non-alcoholic fatty liver disease with incident dementia later in life among elder adults
Authors: Seogsong Jeong, Yun Hwan Oh, Seulggie Choi, Jooyoung Chang, Sung Min Kim, Joung Sik Son, Gyeongsil Lee, Joseph C Ahn, Dong Hyeon Lee, Bo Kyung Koo, Won Kim, Sang Min Park
Journal: Clinical and Molecular Hepatology (2022)

Accumulating evidence suggests a link between non-alcoholic fatty liver disease (NAFLD) and brain health. However, population-based evidence on the association between NAFLD and dementia remains unclear. This study was conducted to determine the association between NAFLD and incident dementia.The study population included 608,994 adults aged ≥60 years who underwent health examinations between 2009 and 2010. Data were collected from the Korean National Health Insurance Service database. NAFLD was assessed using the fatty liver index (FLI). A Cox proportional hazards regression model was used to determine the association between NAFLD and dementia.During the 6,495,352 person-years of follow-up, 48,538 participants (8.0%) developed incident dementia. The participants were classified into low (FLI <30), intermediate (FLI ≥30 and <60), and high (FLI ≥60) groups. In the overall study population, the FLI groups were associated with a risk of dementia (P for trend <0.001). After propensity score matching, a low FLI was associated with a reduced risk of dementia (adjusted hazard ration [aHR], 0.96; 95% confidence interval [CI], 0.93-0.98; P=0.002), whereas a high FLI (NAFLD) was associated with an increased risk of dementia (aHR, 1.05; 95% CI, 1.02-1.08; P=0.001). A higher risk of dementia in the high FLI group than in the intermediate FLI group was attributed to Alzheimer's disease (aHR, 1.04; 95% CI, 1.01-1.07; P=0.004) rather than vascular dementia (aHR, 0.94; 95% CI, 0.75-1.18; P=0.602).NAFLD was associated with an increased risk of dementia, which was attributed to an increased risk of Alzheimer's disease.
A faecal microbiota signature with high specificity for pancreatic cancer
Authors: Ece Kartal, Thomas S B Schmidt, Esther Molina-Montes, Sandra Rodríguez-Perales, Jakob Wirbel, Oleksandr M Maistrenko, Wasiu A Akanni, Bilal Alashkar Alhamwe, Renato J Alves, Alfredo Carrato, Hans-Peter Erasmus, Lidia Estudillo, Fabian Finkelmeier, Anthony Fullam, Anna M Glazek, Paulina Gómez-Rubio, Rajna Hercog, Ferris Jung, Stefanie Kandels, Stephan Kersting, Melanie Langheinrich, Mirari Márquez, Xavier Molero, Askarbek Orakov, Thea Van Rossum, Raul Torres-Ruiz, Anja Telzerow, Konrad Zych, Vladimir Benes, Georg Zeller, Jonel Trebicka, Francisco X Real, Nuria Malats, Peer Bork
Journal: Gut (2022)

Recent evidence suggests a role for the microbiome in pancreatic ductal adenocarcinoma (PDAC) aetiology and progression.To explore the faecal and salivary microbiota as potential diagnostic biomarkers.We applied shotgun metagenomic and 16S rRNA amplicon sequencing to samples from a Spanish case-control study (n=136), including 57 cases, 50 controls, and 29 patients with chronic pancreatitis in the discovery phase, and from a German case-control study (n=76), in the validation phase.Faecal metagenomic classifiers performed much better than saliva-based classifiers and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating characteristic curve (AUROC) based on a set of 27 microbial species, with consistent accuracy across early and late disease stages. Performance further improved to up to 0.94 AUROC when we combined our microbiome-based predictions with serum levels of carbohydrate antigen (CA) 19-9, the only current non-invasive, Food and Drug Administration approved, low specificity PDAC diagnostic biomarker. Furthermore, a microbiota-based classification model confined to PDAC-enriched species was highly disease-specific when validated against 25 publicly available metagenomic study populations for various health conditions (n=5792). Both microbiome-based models had a high prediction accuracy on a German validation population (n=76). Several faecal PDAC marker species were detectable in pancreatic tumour and non-tumour tissue using 16S rRNA sequencing and fluorescence in situ hybridisation.Taken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible.
Examining allostatic load, neighborhood socioeconomic status, symptom burden and mortality in multiple myeloma patients
Authors: Samilia Obeng-Gyasi, Noah Graham, Shaji Kumar, Ju-Whei Lee, Susanna Jacobus, Matthias Weiss, David Cella, Fengmin Zhao, Edward H. Ip, Nathaniel O’Connell, Fangxin Hong, Devin J. Peipert, IIana. F. Gareen, Lava R. Timsina, Robert Gray, Lynne I. Wagner, Ruth C. Carlos
Journal: Blood Cancer Journal (2022)

Abstract The objective of this study is to examine the association between neighborhood socioeconomic status (nSES) and baseline allostatic load (AL) and clinical trial endpoints in patients enrolled in the E1A11 therapeutic trial in multiple myeloma (MM). Study endpoints were symptom burden (pain, fatigue, and bother) at baseline and 5.5 months, non-completion of induction therapy, overall survival (OS) and progression-free survival (PFS). Multivariable logistic and Cox regression examined associations between nSES, AL and patient outcomes. A 1-unit increase in baseline AL was associated with greater odds of high fatigue at baseline (adjusted OR [95% CI] = 1.21 [1.08–1.36]) and a worse OS (adjusted hazard ratio, [95% CI] = 1.21 [1.06–1.37]). High nSES was associated with worse baseline bother (middle OR = 4.22 [1.11–16.09] and high 4.49 [1.16–17.43]) compared to low nSES. There was no association between AL or nSES and symptom burden at 5.5 months, non-completion of induction therapy or PFS. Additionally, there was no association between nSES and OS. AL may have utility as a predictive marker for OS among patients with MM and may allow individualization of treatment. Future studies should standardize and validate AL patients with MM.
The RNA helicase DHX15 is a critical regulator of natural killer-cell homeostasis and functions
Authors: Guangchuan Wang, Xiang Xiao, Yixuan Wang, Xiufeng Chu, Yaling Dou, Laurie J. Minze, Rafik M. Ghobrial, Zhiqiang Zhang, Xian C. Li
Journal: Cellular and Molecular Immunology (2022)
Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring
Authors: Maarten J. Wensink, Ying Lu, Lu Tian, Gary M. Shaw, Silvia Rizzi, Tina Kold Jensen, Elisabeth R. Mathiesen, Niels E. Skakkebæk, Rune Lindahl-Jacobsen, Michael L. Eisenberg
Journal: Annals of Internal Medicine (2022)

Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown.
An anti-PD-1–GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy
Authors: Sarah Chan, Nicole Belmar, Sun Ho, Bryan Rogers, Marcia Stickler, Michelle Graham, Eileen Lee, Ninian Tran, Dong Zhang, Priyanka Gupta, Mien Sho, Tracy MacDonough, Andrew Woolley, Han Kim, Hong Zhang, Wei Liu, Pingping Zheng, Zoltan Dezso, Kyle Halliwill, Michele Ceccarelli, Susan Rhodes, Archana Thakur, Charles M. Forsyth, Mengli Xiong, Siu Sze Tan, Ramesh Iyer, Marc Lake, Enrico Digiammarino, Li Zhou, Lance Bigelow, Kenton Longenecker, Russell A. Judge, Cassie Liu, Max Trumble, Jonathan P. Remis, Melvin Fox, Belinda Cairns, Yoshiko Akamatsu, Diane Hollenbaugh, Fiona Harding, Hamsell M. Alvarez
Journal: Nature Cancer (2022)

Abstract Costimulatory receptors such as glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR) play key roles in regulating the effector functions of T cells. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect, which may be due to suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies. Here we show a bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (GITR-L) that induces PD-1-dependent and FcγR-independent GITR clustering, resulting in enhanced activation, proliferation and memory differentiation of primed antigen-specific GITR + PD-1 + T cells. The anti-PD-1–GITR-L bispecific is a PD-1-directed GITR-L construct that demonstrated dose-dependent, immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models, with a dose-dependent correlation between target saturation and Ki67 and TIGIT upregulation on memory T cells. Anti-PD-1–GITR-L thus represents a bispecific approach to directing GITR agonism for cancer immunotherapy.