tbuckley/cabot-search huggingface dataset:
Abstract P192: Disparities In Stroke And Mortality In Children With Congenital Heart Defects
Authors: Chinwe Ibeh, Amanda Bilski, Melissa Argenio, Gular Mammadli, Matthew Lewis, Marlon S Rosenbaum, Eliza C Miller
Journal: Circulation (2022)

Background: Critical congenital heart defects (CCHD) are a subset of cyanotic lesions that require intervention within the first days to weeks of life for survival. For children born with CCHD, the neonatal period is considered the time of highest risk for stroke and overall poor outcomes. Prior studies have identified racial differences in neonatal outcomes among children with CCHD. Whether these differences persist throughout childhood is unclear. Methods: Using the National Inpatient Sample database, we analyzed all children with CCHD ≤ 18 years hospitalized from 2005-2018. Primary outcome was a composite of incident stroke (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage) and all-cause mortality within strata of ages and years and over the 14-year period of observation. Chi-square tests and multivariable regression were used to assess differences in outcomes. Trends were analyzed adjusting for sex, insurance, and hospital features. Results: A total of 59,438 children with CCHD were hospitalized during the study period: 58% were White (W), 15% Black (B), and 27% Hispanic (H). Overall rate of stroke or death was 4.7% in White children, 6.6% in Black, and 5.6% in Hispanic. Disparities were most pronounced in infancy (Figure; relative differences (RD) compared to White children: 27% (B) and 20% (H), P=0.000) and in early childhood (Figure; RD: 42% (B) and 9% (H), P=0.002). Black and Hispanic children with CCHD had higher rates of stroke and death from 2005-2009 (Figure; RD compared to White children: 24% (B), 22% (H); P = 0.001) and in 2015-2018 (Figure; RD: 21% (B), 18% (H); P = 0.000). These disparities did not change significantly over time in crude or adjusted models (P=0.07, P=0.06). Conclusion: Racial and ethnic disparities in stroke and death among children with CCHD persist after the neonatal period with only modest change in these differences in recent years. Further work identifying the mediators of these disparities is necessary to improve outcomes in this vulnerable pediatric population.
Molecular and Pharmacological Bladder Cancer Therapy Screening: Discovery of Clofarabine as a Highly Active Compound
Authors: Iris E. Ertl, Ursula Lemberger, Dafina Ilijazi, Melanie R. Hassler, Andreas Bruchbacher, Robert Brettner, Hannah Kronabitter, Michael Gutmann, Petra Vician, Gerhard Zeitler, Anna Koren, Charles-Hugues Lardeau, Thomas Mohr, Andrea Haitel, Eva Compérat, André Oszwald, Gabriel Wasinger, Thomas Clozel, Olivier Elemento, Stefan Kubicek, Walter Berger, Shahrokh F. Shariat
Journal: European Urology (2022)

The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need. We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC. A collection of commercially available BC cell lines (n = 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen. Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line. Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patient-derived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n = 12) suffering from both early- and late-stage disease. We further took advantage of another patient-derived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n = 8). The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care. We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment.
Abstract P092: Cell Adhesion Molecules And Incident Hypertension In Black And White Adults: The REasons For Geographic And Racial Differences In Stroke (REGARDS) Study
Authors: Tyler A Harkness, Katherine Wilkinson, Ying Loo, George Howard, Virginia J Howard, Mary Cushman, Neil A Zakai, Katharine L Cheung, Suzanne E Judd, Timothy B Plante
Journal: Circulation (2022)

Background: High C-reactive protein (a nonspecific inflammatory biomarker) is a risk factor for incident hypertension. The role of specific inflammation pathways in hypertension’s origins are unresolved. E-selectin, ICAM-1, and VCAM are cell adhesion molecules expressed by endothelial cells that aid leukocyte adhesion during inflammation. Their association with incident hypertension is unclear. Objective: To determine risk of incident hypertension by level of E-selectin, ICAM-1, and VCAM. Methods: REGARDS enrolled 30,239 Black and White US adults aged ≥45 years from across the continental US in 2003-2006, with a second exam in 2013-2016. The Biomarkers as Mediators of Racial Disparities in Risk Factors (BioMedioR) study included 4,400 REGARDS participants who attended both exams. We excluded participants with hypertension or missing biomarkers of interest at baseline. Hypertension was defined using a 140/90 mm Hg threshold or self-reported use of blood pressure (BP) lowering medications. Modified Poisson regression estimated relative risk (RR) of incident hypertension by baseline E-Selectin, ICAM-1, and VCAM. Results: Among 1,923 normotensive participants (mean [SD] age 71 [8] years, 36% Black race, 51% women) with 9 years median follow up, 37% developed hypertension. Baseline E-selectin and ICAM-1 but not VCAM were higher among Black participants and obese participants. In multivariable adjusted models, higher E-selectin was associated with greater risk of incident hypertension among White but not Black adults (P interaction = 0.05) in all but the final model ( Table ). Higher ICAM-1 and VCAM were not associated with risk of hypertension in any model. Conclusion: In a prospective study of Black and White US adults, E-selectin was associated with incident hypertension among White adults except when adjusting for medical comorbidities, including baseline systolic BP. Modification of E-selectin through behavioral interventions or medical therapies might be tested to lower risk of hypertension development.
A Novel Synthetic Lethal Approach to Target <i>MYC</i>-Driven Cancers
Authors: Roman M. Chabanon, Sophie Postel-Vinay
Journal: Cancer Research (2022)

The MYC proto-oncogene family encompasses three related transcription factors (MYC, MYCL, and MYCN), which are master regulators of cellular programs orchestrating multiple hallmarks of cancer, including proliferation, metabolism, invasiveness, and immune surveillance. MYC activation is one of the most frequent alterations in cancer, induced by genetic, epigenetic, or posttranslational alterations of MYC itself, or of MYC-related proteins or pathways. Sun and colleagues found a unique function of the rate-limiting nucleotide synthesis enzyme CTP synthase 1 (CTPS1) in the survival of MYC-driven cancer cells. They further identified a novel synthetic lethal strategy to combat MYC-driven cancers by combining CTPS1 inhibitors with ataxia telangiectasia and Rad3-related protein inhibitors, which exploits the inherent vulnerability of MYC-driven tumors to nucleotide shortage and DNA replication stress. These findings open novel therapeutic avenues for targeting the traditionally “undruggable” MYC-driven cancers, which represent one of the highest unmet clinical needs in cancer. See related article by Sun et al. p. 1013
Losartan ameliorates TGF-β1–induced CFTR dysfunction and improves correction by cystic fibrosis modulator therapies
Authors: Michael D. Kim, Charles D. Bengtson, Makoto Yoshida, Asef J. Niloy, John S. Dennis, Nathalie Baumlin, Matthias Salathe
Journal: Journal of Clinical Investigation (2022)

Highly effective modulator therapies dramatically improve the prognosis for those with cystic fibrosis (CF). The triple combination of elexacaftor, tezacaftor, and ivacaftor (ETI) benefits many, but not all, of those with the most common F508del mutation in the CF transmembrane conductance regulator (CFTR). Here, we showed that poor sweat chloride concentration responses and lung function improvements upon initiation of ETI were associated with elevated levels of active TGF-β1 in the upper airway. Furthermore, TGF-β1 impaired the function of ETI-corrected F508del-CFTR, thereby increasing airway surface liquid (ASL) absorption rates and inducing mucus hyperconcentration in primary CF bronchial epithelial cells in vitro. TGF-β1 not only decreased CFTR mRNA, but was also associated with increases in the mRNA expression of TNFA and COX2 and TNF-α protein. Losartan improved TGF-β1-mediated inhibition of ETI-corrected F508del-CFTR function and reduced TNFA and COX2 mRNA and TNF-α protein expression. This likely occurred by improving correction of mutant CFTR rather than increasing its mRNA (without an effect on potentiation), thereby reversing the negative effects of TGF-β1 and improving ASL hydration in the CF airway epithelium in vitro. Importantly, these effects were independent of type 1 angiotensin II receptor inhibition.
FDG PET/CT in Isolated Thoracic Vertebral Rosai-Dorfman Disease
Authors: Qian Zhao, Yushu Bai, Aisheng Dong, Changjing Zuo
Journal: Clinical Nuclear Medicine (2021)

Abstract Isolated osseous Rosai-Dorfman disease is rare. We describe FDG PET/CT findings of solitary thoracic vertebral Rosai-Dorfman disease without extraosseous involvement. The vertebral lesion caused osteolytic destruction of the vertebral body and showed intense FDG uptake.
PREVALENCE AND CHARACTERISTICS OF ABNORMALITIES ON CARDIAC MRI IN PRIMARY CARE FOLLOWING RECOVERY FROM ACUTE SARS-COV-2 INFECTION AND CORRELATION WITH MARKERS OF IMMUNITY AND COAGULATION: PRIMARY RESULTS OF THE SETANTA STUDY
Authors: Roisin Colleran, Roger J. Byrne, Andrea Cradock, Darach O'Ciardha, Shane McKeogh, Nial Blake, Hannah Wilson, Ahmed Mansur, James Bisset, Amy Carswell, Carmen Farrelly, Laurna McGovern, Margret Hannan, Maria Fitzgibbon, James O'Donnell, Himanshu Rai, Robert A. Byrne
Journal: Journal of the American College of Cardiology (2022)
Abstract P138: Post-partum Maternal Vascular Function Is Reduced In Preeclampsia And Preterm Births: A Pilot Study
Authors: Janessa Snippen, Eleanor Saffian, Nicole L Lohr, Jennifer McIntosh, Jacquelyn P Kulinski
Journal: Circulation (2022)

Introduction: Women with a history of preeclampsia (PreE) or preterm (PreT) birth are at elevated risk of future hypertension, ischemic heart disease, and stroke. Mechanisms for this increased risk are unknown. Flow-mediated dilation of the brachial artery (FMD) is an established surrogate for cardiovascular risk. Hypothesis: In this pilot study, we hypothesize that maternal vascular dysfunction associated with PreE is reversible, and the extent of recovery is predicated on specific maternal characteristics. Methods: In this prospective study, subjects were recruited to three groups: PreE with delivery at 27-34 weeks; PreT delivery at 27-34 weeks without preeclampsia; and healthy controls at 39-40 weeks. Vascular function (FMD), nutrition (validated questionnaire), and physical activity (accelerometers) data were collected at 1-2 days post-partum and 3 months. Results: Fourteen subjects were enrolled (mean age 32±6 years). Systolic blood pressure was higher for PreE subjects (average 131±6) compared to controls (109 ± 9, p=0.004) and PreT (110±8, p=0.008) at visit 1. This difference resolved at visit 2. Though non-significant, FMD (mean±SE) was higher in controls compared to PreE and PreT groups at visit 1 (7.7%±0.8 v. 7.4%±0.7 and 6.9%±1.0, Figure 1). FMD remains depressed at 3 months, but subject follow-up was impacted by the Covid 19 pandemic. Alternate Healthy Eating Index scores were non-significantly higher in the PreT group than PreE and controls. PreT subjects were less sedentary and more physically active (higher moderate-vigorous physical activity, higher total steps). Conclusions: Maternal FMD is reduced immediately post-partum in PreE and PreT births. The PreT group had lower FMD despite better nutrition and physical activity scores. This is a pilot study, and we are not powered for significance. Data from our small cohort support the ability to collect meaningful data in these understudied populations which could inform future studies of long-term cardiovascular risk.
Abstract 10685: Right Ventricular-Pulmonary Arterial Coupling in Heart Failure Patients with Secondary Mitral Regurgitation: Analysis from the COAPT Trial
Authors: Michael I Brener, Paul Grayburn, Joann Lindenfeld, Daniel Burkhoff, Mengdan Liu, Zhipeng Zhou, Maria Alu, Diego A Medvedofsky, Federico M Asch, Neil J Weissman, Jeroen J Bax, William T Abraham, Michael Mack, Gregg W Stone, Rebecca T Hahn
Journal: Circulation (2021)

Objectives: We sought to determine the prognostic impact of right ventricular (RV) function characterized by RV-pulmonary arterial (PA) coupling in heart failure (HF) patients with severe secondary mitral regurgitation (SMR) enrolled in the COAPT trial. Background: RV contractile function and PA pressures influence outcomes in patients with SMR, but the impact of RV-PA coupling in patients randomized to transcatheter edge-to-edge repair (TEER) versus guideline-directed medical therapy (GDMT) has not been examined. Methods: We assessed RV-PA coupling by the ratio of RV free wall longitudinal strain (FWLS) derived from speckle-tracking echocardiography (STE) and non-invasively measured RV systolic pressure (RVSP). Advanced RV-PA uncoupling was defined by RVFWLS/RVSP ≤0.5. The primary endpoint was a composite of all-cause mortality or HF hospitalization at 24-month follow-up. Results: A total of 372 patients underwent STE, among whom 70.2% had advanced RV-PA uncoupling. By multivariable analysis, advanced RV-PA uncoupling was strongly associated with an increased risk for the primary 24-month endpoint of death or HF hospitalization (HR 1.87, 95% CI 1.31-2.66, p=0.0005). A similar association was present for all-cause mortality alone (HR 2.57, 95% CI 1.54-4.29, p=0.0003). The impact of RV-PA uncoupling was consistent in patients randomized to TEER and GDMT alone. TEER improved 2-year outcomes both in patients with (48.0% vs. 74.8%, HR 0.51, 95% CI 0.37-0.71) and without (28.8% vs. 47.8%, HR 0.51, 95% CI 0.27-0.97) advanced RV-PA uncoupling (pinteraction=0.98). Conclusions: In the COAPT trial, advanced RV-PA uncoupling was a powerful predictor of 2-year adverse outcomes ( Figure 1 ), reinforcing the importance of RV dysfunction in patients with HF.
Folliculin impairs breast tumor growth by repressing TFE3-dependent induction of the Warburg effect and angiogenesis
Authors: Leeanna El-Houjeiri, Marco Biondini, Mathieu Paquette, Helen Kuasne, Alain Pacis, Morag Park, Peter M. Siegel, Arnim Pause
Journal: Journal of Clinical Investigation (2021)

Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The folliculin (FLCN) tumor suppressor complex (FLCN, FNIP1, FNIP2) is implicated in the regulation of energy homeostasis via 2 metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here, we revealed that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers, including poor-prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared with the luminal, less aggressive subtypes. FLCN loss in luminal breast cancer promoted tumor growth through TFE3 activation and subsequent induction of several pathways, including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN-deficient cells was dictated by the activation of the PGC-1α/HIF-1α pathway, which we showed to be TFE3 dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Conversely, FLCN overexpression in invasive basal-like breast cancer models attenuated TFE3 nuclear localization, TFE3-dependent transcriptional activity, and tumor growth. These findings support a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.
Olaparib Maintenance Monotherapy in Asian Patients with Platinum-Sensitive Relapsed Ovarian Cancer: Phase III Trial (L-MOCA)
Authors: Qinglei Gao, Jianqing Zhu, Weidong Zhao, Yi Huang, Ruifang An, Hong Zheng, Pengpeng Qu, Li Wang, Qi Zhou, Danbo Wang, Ge Lou, Jing Wang, Ke Wang, John Low, Beihua Kong, Abdul Malik Rozita, Lim Chun Sen, Rutie Yin, Xing Xie, Jihong Liu, Wei Sun, Jingya Su, Chunyi Zhang, Rongyu Zang, Ding Ma
Journal: Clinical Cancer Research (2022)

Abstract Purpose: In patients with platinum-sensitive relapsed (PSR) ovarian cancer, olaparib maintenance monotherapy significantly improves progression-free survival (PFS) versus placebo. However, evidence in the Asian population is lacking. This is the first study to evaluate olaparib efficacy and tolerability exclusively in Asian patients with PSR ovarian cancer. Patients and Methods: Considering the limited placebo effect and significant clinical benefit of olaparib in previous trials, and the rapid approval of olaparib in China, this phase III study was designed as an open-label, single-arm trial. Patients with high-grade epithelial PSR ovarian cancer were enrolled from country-wide clinical centers across China and Malaysia. Patients received oral olaparib (300 mg) twice daily until disease progression or unacceptable toxicity. Primary endpoint was median PFS (mPFS). Primary analysis of PFS using the Kaplan–Meier method was performed when data reached 60% maturity (clinicaltrials.gov NCT03534453). Results: Between 2018 and 2020, 225 patients were enrolled, and 224 received olaparib; 35.7% had received ≥3 lines of chemotherapy, 35.3% had achieved complete response to their last line of platinum-based chemotherapy, and 41.1% had a platinum-free interval ≤12 months. At primary data cut-off (December 25, 2020), overall mPFS was 16.1 months; mPFS was 21.2 and 11.0 months in BRCA-mutated and wild-type BRCA subgroups, respectively. Adverse events (AE) occurred in 99.1% of patients (grade ≥3, 48.7%); 9.4% discontinued therapy due to treatment-related AEs. Conclusions: Olaparib maintenance therapy was highly effective and well tolerated in Asian patients with PSR ovarian cancer, regardless of BRCA status. This study highlights the promising efficacy of olaparib in this Asian population. See related commentary by Nicum and Blagden, p. 2201
SER-109, an Oral Microbiome Therapy for Recurrent <i>Clostridioides difficile</i> Infection
Authors: Paul Feuerstadt, Thomas J. Louie, Bret Lashner, Elaine E.L. Wang, Liyang Diao, Jessica A. Bryant, Matthew Sims, Colleen S. Kraft, Stuart H. Cohen, Charles S. Berenson, Louis Y. Korman, Christopher B. Ford, Kevin D. Litcofsky, Mary-Jane Lombardo, Jennifer R. Wortman, Henry Wu, John G. Auniņš, Christopher W.J. McChalicher, Jonathan A. Winkler, Barbara H. McGovern, Michele Trucksis, Matthew R. Henn, Lisa von Moltke
Journal: New England Journal of Medicine (2022)

Current therapies for recurrent Clostridioides difficile infection do not address the disrupted microbiome, which supports C. difficile spore germination into toxin-producing bacteria. SER-109 is an investigational microbiome therapeutic composed of purified Firmicutes spores for the treatment of recurrent C. difficile infection.We conducted a phase 3, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of C. difficile infection (inclusive of the qualifying acute episode) received SER-109 or placebo (four capsules daily for 3 days) after standard-of-care antibiotic treatment. The primary efficacy objective was to show superiority of SER-109 as compared with placebo in reducing the risk of C. difficile infection recurrence up to 8 weeks after treatment. Diagnosis by toxin testing was performed at trial entry, and randomization was stratified according to age and antibiotic agent received. Analyses of safety, microbiome engraftment, and metabolites were also performed.Among the 281 patients screened, 182 were enrolled. The percentage of patients with recurrence of C. difficile infection was 12% in the SER-109 group and 40% in the placebo group (relative risk, 0.32; 95% confidence interval [CI], 0.18 to 0.58; P<0.001 for a relative risk of <1.0; P<0.001 for a relative risk of <0.833). SER-109 led to less frequent recurrence than placebo in analyses stratified according to age stratum (relative risk, 0.24 [95% CI, 0.07 to 0.78] for patients <65 years of age and 0.36 [95% CI, 0.18 to 0.72] for those ≥65 years) and antibiotic received (relative risk, 0.41 [95% CI, 0.22 to 0.79] with vancomycin and 0.09 [95% CI, 0.01 to 0.63] with fidaxomicin). Most adverse events were mild to moderate and were gastrointestinal in nature, with similar numbers in the two groups. SER-109 dose species were detected as early as week 1 and were associated with bile-acid profiles that are known to inhibit C. difficile spore germination.In patients with symptom resolution of C. difficile infection after treatment with standard-of-care antibiotics, oral administration of SER-109 was superior to placebo in reducing the risk of recurrent infection. The observed safety profile of SER-109 was similar to that of placebo. (Funded by Seres Therapeutics; ECOSPOR III ClinicalTrials.gov number, NCT03183128.).
Risk of severe COVID-19 from the Delta and Omicron variants in relation to vaccination status, sex, age and comorbidities – surveillance results from southern Sweden, July 2021 to January 2022
Authors: Fredrik Kahn, Carl Bonander, Mahnaz Moghaddassi, Magnus Rasmussen, Ulf Malmqvist, Malin Inghammar, Jonas Björk
Journal: Eurosurveillance (2022)

We compared the risk of severe COVID-19 during two periods 2021 and 2022 when Delta and Omicron, respectively, were the dominating virus variants in Scania county, Sweden. We adjusted for differences in sex, age, comorbidities, prior infection and vaccination. Risk of severe disease from Omicron was markedly lower among vaccinated cases. It was also lower among the unvaccinated but remained high (> 5%) for older people and middle-aged men with two or more comorbidities. Efforts to increase vaccination uptake should continue.