tbuckley/cabot-search huggingface dataset:
Simultaneous Targeting of NQO1 and SOD1 Eradicates Breast Cancer Stem Cells via Mitochondrial Futile Redox Cycling
Authors: Ming Luo, Na Shen, Li Shang, Zeng Fang, Ying Xin, Yuxi Ma, Min Du, Yuan Yuan, Chenchen Hu, Yun Tang, Jing Huang, Wei Wei, Myung Ryul Lee, Paul J. Hergenrother, Max S. Wicha
Journal: Cancer Research (2024)

Abstract Triple negative breast cancer (TNBC) contains the highest proportion of cancer stem-like cells (CSCs), which display intrinsic resistance to currently available cancer therapies. This therapeutic resistance is partially mediated by an antioxidant defense coordinated by the transcription factor NRF2 and its downstream targets including NQO1. Here, we identified the antioxidant enzymes NQO1 and SOD1 as therapeutic vulnerabilities of ALDH+ epithelial-like CSCs and CD24-/loCD44+/hi mesenchymal-like CSCs in TNBC. Effective targeting of these CSC states was achieved by utilizing IB-DNQ, a potent and specific NQO1-bioactivatable futile redox cycling molecule, which generated large amounts of reactive oxygen species (ROS) including superoxide and hydrogen peroxide. Furthermore, the CSC killing effect was specifically enhanced by genetic or pharmacological inhibition of SOD1, a copper-containing superoxide dismutase highly expressed in TNBC. Mechanistically, a significant portion of NQO1 resided in the mitochondrial intermembrane space, catalyzing futile redox cycling from IB-DNQ to generate high levels of mitochondrial superoxide, and SOD1 inhibition markedly potentiated this effect resulting in mitochondrial oxidative injury, cytochrome c release, and activation of the caspase 3-mediated apoptotic pathway. Treatment with IB-DNQ alone or together with SOD1 inhibition effectively suppressed tumor growth, metastasis, and tumor-initiating potential in xenograft models of TNBC expressing different levels of NQO1. This futile oxidant-generating strategy, which targets CSCs across the epithelial-mesenchymal continuum, could be a promising therapeutic approach for treating TNBC patients.
Neuroendocrine Differentiation in Prostate Cancer Requires ASCL1
Authors: Kathia E. Rodarte, Shaked Nir Heyman, Lei Guo, Lydia Flores, Trisha K. Savage, Juan Villarreal, Su Deng, Lin Xu, Rajal B. Shah, Trudy G. Oliver, Jane E. Johnson
Journal: Cancer Research (2024)

Abstract Most patients with prostate adenocarcinoma develop resistance to therapies targeting the androgen receptor (AR). Consequently, a portion of these patients develop AR-independent neuroendocrine prostate cancer (NEPC), a rapidly progressing cancer with limited therapies and poor survival outcomes. Current research to understand the progression to NEPC suggests a model of lineage plasticity whereby AR-dependent luminal-like tumors progress towards an AR-independent NEPC state. Genetic analysis of human NEPC identified frequent loss of RB1 and TP53, and the loss of both genes in experimental models mediates the transition to a neuroendocrine lineage. Transcriptomics studies have shown that lineage transcription factors ASCL1 and NEUROD1 are present in NEPC. In this study, we modeled the progression of prostate adenocarcinoma to NEPC by establishing prostate organoids and subsequently generating subcutaneous allograft tumors from genetically-engineered mouse models harboring Cre-induced loss of Rb1 and Trp53 with Myc overexpression (RPM). These tumors were heterogeneous and displayed adenocarcinoma, squamous, and neuroendocrine features. ASCL1 and NEUROD1 were expressed within neuroendocrine-defined regions, with ASCL1 being predominant. Genetic loss of Ascl1 in this model did not decrease tumor incidence, growth, or metastasis; however, there was a notable decrease in neuroendocrine identity and an increase in basal-like identity. This study provides an in vivo model to study progression to NEPC and establishes the requirement for ASCL1 in driving neuroendocrine differentiation in prostate cancer.
Postprandial metabolomics analysis reveals disordered serotonin metabolism in post-bariatric hypoglycemia
Authors: Rafael Ferraz-Bannitz, Berkcan Ozturk, Cameron J Cummings, Vissarion Efthymiou, Pilar Casanova Querol, Lindsay Poulos, Hanna J Wang, Valerie Navarrete, Hamayle Saeed, Christopher M Mulla, Hui Pan, Jonathan M Dreyfuss, Donald C Simonson, Darleen A Sandoval, Mary-Elizabeth Patti
Journal: Journal of Clinical Investigation (2024)

Bariatric surgery is a potent therapeutic approach for obesity and type 2 diabetes but can be complicated by post-bariatric hypoglycemia (PBH). PBH typically occurs 1 to 3 hours after meals, in association with exaggerated postprandial levels of incretins and insulin.
A six-year study in a real-world population reveals an increased incidence of dyslipidemia during COVID-19
Authors: Valentina Trimarco, Raffaele Izzo, Stanislovas S Jankauskas, Mario Fordellone, Giuseppe Signoriello, Maria Virginia Manzi, Maria Lembo, Paola Gallo, Giovanni Esposito, Roberto Piccinocchi, Francesco Rozza, Carmine Morisco, Pasquale Mone, Gaetano Piccinocchi, Fahimeh Varzideh, Bruno Trimarco, Gaetano Santulli
Journal: Journal of Clinical Investigation (2024)

Recent studies conducted in COVID-19 survivors suggest that SARS-CoV-2 infection is associated with an increased risk of dyslipidemia. However, it remains unclear whether this augmented risk is confirmed in the general population and how this phenomenon is impacting the overall burden of cardiometabolic diseases.
Uterine cyclin A2 deficient mice as a model of female early pregnancy loss
Authors: Fatimah Aljubran, Katelyn Schumacher, Amanda Graham, Sumedha Gunewardena, Courtney Marsh, Michael Lydic, Kristin Holoch, Warren B Nothnick
Journal: Journal of Clinical Investigation (2024)

Proper action of the female sex steroids, 17β-estradiol (E2) and progesterone (P4) on endometrium is essential for fertility. Beyond its role in regulating the cell cycle, cyclin A2 (CCNA2) also mediates E2 and P4 signaling in vitro, but a potential role in modulating steroid action for proper endometrial tissue development and function is unknown. To fill this gap in our knowledge, we examined human endometrial tissue from fertile and infertile women for CCNA2 expression and correlated this with pregnancy outcome. Functional assessment of CCNA2 was validated in vivo using a conditional Ccna2 uterine deficient mouse model while in vitro function was assessed using human cell culture models. We found that CCNA2 expression was significantly reduced in endometrial tissue, specifically the stromal cells, from women undergoing in vitro fertilization who failed to achieve pregnancy. Conditional deletion of Ccna2 from mouse uterine tissue resulted in an inability to achieve pregnancy which appears to be due to alterations in the process of decidualization, which was confirmed using in vitro models. From these studies, we conclude that CCNA2 expression during the proliferative/regenerative stage of the menstrual cycle acts as a safeguard allowing for proper steroid responsiveness, decidualization and pregnancy. When CCNA2 expression levels are insufficient there is impaired endometrial responsiveness, aberrant decidualization and loss of pregnancy.
Endothelial metabolic control of insulin sensitivity through resident macrophages
Authors: Jing Zhang, Kim Anker Sjøberg, Songlin Gong, Tongtong Wang, Fengqi Li, Andrew Kuo, Stephan Durot, Adam Majcher, Raphaela Ardicoglu, Thibaut Desgeorges, Charlotte Greta Mann, Ines Soro Arnáiz, Gillian Fitzgerald, Paola Gilardoni, E Dale Abel, Shigeyuki Kon, Danyvid Olivares-Villagómez, Nicola Zamboni, Christian Wolfrum, Thorsten Hornemann, Raphael Morscher, Nathalie Tisch, Bart Ghesquière, Manfred Kopf, Erik A Richter, Katrien De Bock
Journal: Cell Metabolism (2024)
Kidney Outcomes Following Angiotensin Receptor-Neprilysin Inhibitor vs Angiotensin-Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Therapy for Thrombotic Microangiopathy
Authors: Jianbo Li, Qinghua Liu, Xingji Lian, Shicong Yang, Rong Lian, Wenchuan Li, Jianwen Yu, Fengxian Huang, Wenfang Chen, Feng He, Wei Chen
Journal: JAMA Network Open (2024)

Importance Thrombotic microangiopathy (TMA) on kidney biopsy is a pattern of endothelial injury commonly seen in malignant hypertension (mHTN), but treatment strategies are not well established. Objective To evaluate the kidney outcomes of angiotensin receptor-neprilysin inhibitor (ARNI), specifically sacubitril/valsartan, vs angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy for patients with mHTN-associated TMA. Design, Setting, and Participants This single-center cohort study enrolled consecutive patients in China diagnosed with mHTN-associated TMA through kidney biopsy from January 2008 to June 2023. Follow-up was conducted until the conclusion of the study period. Data were analyzed in September 2023. Exposures Treatment with sacubitril/valsartan or ACEI/ARBs during hospitalization and after discharge. Main Outcomes and Measures The primary outcome was a composite of kidney recovery: a 50% decrease in serum creatinine level, decrease in serum creatinine levels to the reference range, or kidney survival free from dialysis for more than 1 month. The secondary and tertiary outcomes were a 15% increase in the estimated glomerular filtration rate (eGFR) relative to baseline and kidney survival free from dialysis, respectively. Propensity score matching (PSM) and Cox proportional hazards regression analysis were used to evaluate the association between sacubitril/valsartan and ACEI/ARB therapy with kidney recovery outcomes. Results Among the 217 patients (mean [SD] age, 35.9 [8.8] years; 188 men [86.6%]) included in the study, 66 (30.4%) received sacubitril/valsartan and 151 (69.6%) received ACEI/ARBs at baseline. Sacubitril/valsartan treatment was associated with shorter time to the primary outcome compared with ACEI/ARB treatment (20 of 63 [31.7%] vs 38 of 117 [32.5%]; adjusted hazard ratio [aHR], 1.85; 95% CI, 1.05-3.23). Sacubitril/valsartan treatment was independently associated with shorter time to a 15% increase in eGFR (15 of 46 [32.6%] vs 46 of 83 [55.4%]; aHR, 2.13; 95% CI, 1.09-4.17) and kidney survival free from dialysis (11 of 23 [47.8%] vs 16 of 57 [28.1%]; aHR, 2.63; 95% CI, 1.15-5.88) compared with ACEI/ARB treatment. These differences remained significant in the PSM comparison. Conclusions and Relevance In this cohort study, sacubitril/valsartan treatment was associated with a potential kidney function benefit in patients with mHTN-associated TMA compared with ACEI/ARB treatment. The findings suggested that sacubitril/valsartan could be a superior therapeutic approach for managing this serious condition in terms of kidney recovery.
Mortality and Function After Widowhood Among Older Adults With Dementia, Cancer, or Organ Failure
Authors: Rebecca Rodin, Alexander K. Smith, Edie Espejo, Siqi Gan, W. John Boscardin, Lauren J. Hunt, Katherine A. Ornstein, R. Sean Morrison
Journal: JAMA Network Open (2024)

Importance The widowhood effect, in which mortality increases and function decreases in the period following spousal death, may be heightened in older adults with functional impairment and serious illnesses, such as cancer, dementia, or organ failure, who are highly reliant on others, particularly spouses, for support. Yet there are limited data on widowhood among people with these conditions. Objective To determine the association of widowhood with function and mortality among older adults with dementia, cancer, or organ failure. Design, Setting, and Participants This longitudinal cohort study used population-based, nationally representative data from the Health and Retirement Study database linked to Medicare claims from 2008 to 2018. Participants were married or partnered community-dwelling adults aged 65 years and older with and without cancer, organ failure, or dementia and functional impairment (function score &amp;amp;lt;9 of 11 points), matched on widowhood event and with follow-up until death or disenrollment. Analyses were conducted from September 2021 to May 2024. Exposure Widowhood. Main Outcomes and Measures Function score (range 0-11 points; 1 point for independence with each activity of daily living [ADL] or instrumental activity of daily living [IADL]; higher score indicates better function) and 1-year mortality. Results Among 13 824 participants (mean [SD] age, 70.1 [5.5] years; 6416 [46.4%] female; mean [SD] baseline function score, 10.2 [1.6] points; 1-year mortality: 0.4%) included, 5732 experienced widowhood. There were 319 matched pairs of people with dementia, 1738 matched pairs without dementia, 95 matched pairs with cancer, 2637 matched pairs without cancer, 85 matched pairs with organ failure, and 2705 matched pairs without organ failure. Compared with participants without these illnesses, widowhood was associated with a decline in function immediately following widowhood for people with cancer (change, −1.17 [95% CI, −2.10 to −0.23] points) or dementia (change, −1.00 [95% CI, −1.52 to −0.48] points) but not organ failure (change, −0.84 [95% CI, −1.69 to 0.00] points). Widowhood was also associated with increased 1-year mortality among people with cancer (hazard ratio [HR], 1.08 [95% CI, 1.04 to 1.13]) or dementia (HR, 1.14 [95% CI, 1.02 to 1.27]) but not organ failure (HR, 1.02 [95% CI, 0.98 to 1.06]). Conclusions and Relevance This cohort study found that widowhood was associated with increased functional decline and increased mortality in older adults with functional impairment and dementia or cancer. These findings suggest that persons with these conditions with high caregiver burden may experience a greater widowhood effect.
Automated Analysis of Stereotypical Movements in Videos of Children With Autism Spectrum Disorder
Authors: Tal Barami, Liora Manelis-Baram, Hadas Kaiser, Michal Ilan, Aviv Slobodkin, Ofri Hadashi, Dor Hadad, Danel Waissengreen, Tanya Nitzan, Idan Menashe, Analya Michaelovsky, Michal Begin, Ditza A. Zachor, Yair Sadaka, Judah Koler, Dikla Zagdon, Gal Meiri, Omri Azencot, Andrei Sharf, Ilan Dinstein
Journal: JAMA Network Open (2024)

Importance Stereotypical motor movements (SMMs) are a form of restricted and repetitive behavior, which is a core symptom of autism spectrum disorder (ASD). Current quantification of SMM severity is extremely limited, with studies relying on coarse and subjective caregiver reports or laborious manual annotation of short video recordings. Objective To assess the utility of a new open-source AI algorithm that can analyze extensive video recordings of children and automatically identify segments with heterogeneous SMMs, thereby enabling their direct and objective quantification. Design, Setting, and Participants This retrospective cohort study included 241 children (aged 1.4 to 8.0 years) with ASD. Video recordings of 319 behavioral assessments carried out at the Azrieli National Centre for Autism and Neurodevelopment Research in Israel between 2017 and 2021 were extracted. Behavioral assessments included cognitive, language, and autism diagnostic observation schedule, 2nd edition (ADOS-2) assessments. Data were analyzed from October 2020 to May 2024. Exposures Each assessment was recorded with 2 to 4 cameras, yielding 580 hours of video footage. Within these extensive video recordings, manual annotators identified 7352 video segments containing heterogeneous SMMs performed by different children (21.14 hours of video). Main outcomes and measures A pose estimation algorithm was used to extract skeletal representations of all individuals in each video frame and was trained an object detection algorithm to identify the child in each video. The skeletal representation of the child was then used to train an SMM recognition algorithm using a 3 dimensional convolutional neural network. Data from 220 children were used for training and data from the remaining 21 children were used for testing. Results Among 319 behavioral assessment recordings from 241 children (172 [78%] male; mean [SD] age, 3.97 [1.30] years), the algorithm accurately detected 92.53% (95% CI, 81.09%-95.10%) of manually annotated SMMs in our test data with 66.82% (95% CI, 55.28%-72.05%) precision. Overall number and duration of algorithm-identified SMMs per child were highly correlated with manually annotated number and duration of SMMs ( r = 0.8; 95% CI, 0.67-0.93; P &amp;amp;lt; .001; and r = 0.88; 95% CI, 0.74-0.96; P &amp;amp;lt; .001, respectively). Conclusions and relevance This study suggests the ability of an algorithm to identify a highly diverse range of SMMs and quantify them with high accuracy, enabling objective and direct estimation of SMM severity in individual children with ASD.
Cervical Cancer Incidence in the US-Affiliated Pacific Islands
Authors: Sameer V. Gopalani, Jin Qin, Janos Baksa, Trevor D. Thompson, Mona Saraiya, Virginia Senkomago, Paran Pordell, Youngju Jeong, Neal A. Palafox, Martina Reichhardt, Lee E. Buenconsejo-Lum
Journal: JAMA Oncology (2024)

Importance The World Health Organization has called for eliminating cervical cancer as a public health problem. Accurate and up-to-date estimates of population-based cervical cancer incidence are essential for monitoring progress toward elimination and informing local cancer control strategies, but these estimates are lacking for the US-Affiliated Pacific Islands (USAPI). Objective To calculate age-standardized incidence rates for cervical cancer in the 6 USAPI and compare these rates with rates in the US (50 states and the District of Columbia). Design, Setting, and Participants This cross-sectional study used population-based data from the Pacific Regional Central Cancer Registry for women aged 20 years or older who were diagnosed with invasive cervical cancer from January 1, 2007, to December 31, 2020. The registry comprises data on all cervical cancers from the USAPI, which include 3 US territories (American Samoa, Commonwealth of the Northern Mariana Islands, and Guam) and 3 freely associated states (Federated States of Micronesia [FSM], Republic of the Marshall Islands [RMI], and Republic of Palau). Data were analyzed from July 10, 2023, to November 28, 2023. Main Outcomes and Measures The main outcome was age-standardized cervical cancer incidence rates, stratified by age, stage, and histologic code for the USAPI using population estimates from 3 different sources (US Census Bureau International Database, United Nations Population Division, and Pacific Data Hub). Rate ratios were calculated to compare incidence rates between the USAPI and the US. Results From 2007 to 2020, 409 cases of cervical cancer were diagnosed in the USAPI (median age at diagnosis, 46.0 years [25th-75th percentile, 39.0-55.0 years]), with an age-standardized incidence rate ranging from 21.7 (95% CI, 19.6-23.9) to 22.1 (95% CI, 20.0-24.4) per 100 000 women, depending on the population estimate. Incidence rates were highest in RMI, ranging from 58.1 (95% CI, 48.0-69.7) to 83.4 (95% CI, 68.3-101.0) per 100 000 women, followed by FSM, ranging from 28.7 (95% CI, 23.4-34.9) to 29.8 (95% CI, 24.3-36.3) per 100 000 women. Compared with the US, incidence rates were highest in RMI (rate ratio, 5.7 [95% CI, 4.7-6.8] to 8.2 [95% CI, 6.7-9.9]) and FSM (rate ratio; 2.8; 95% CI, 2.3-3.4). Of all cases in the USAPI, 213 (68.2%) were diagnosed at a late stage. Conclusions and Relevance In this cross-sectional study, cervical cancer remained a major public health issue in some USAPI, with RMI reporting the highest incidence rates. The findings suggest that improvements in human papillomavirus vaccination and cancer screening coverage through efforts tailored to the unique geographic, sociocultural, economic, and health care landscape of the USAPI may reduce the burden of cervical cancer.
Hospitalization Trends for Airway Infections and In-Hospital Complications in Cleft Lip and Palate
Authors: Rahel Laager, Claudia Gregoriano, Stephanie Hauser, Henrik Koehler, Philipp Schuetz, Beat Mueller, Alexander Kutz
Journal: JAMA Network Open (2024)

Importance Cleft lip or palate is a prevalent birth defect, occurring in approximately 1 to 2 per 1000 newborns and often necessitating numerous hospitalizations. Specific rates of hospitalization and complication are underexplored. Objective To assess the rates of airway infection–associated hospitalization, overall hospital admissions, in-hospital complications, and mortality among children with a cleft lip or palate. Design, Setting, and Participants This nationwide, population-based cohort study used in-hospital claims data from the Federal Statistical Office in Switzerland between 2012 and 2021. Participants included newborns with complete birth records born in a Swiss hospital. Data were analyzed from March to November 2023. Exposure Prevalent diagnosis of a cleft lip or palate at birth. Main Outcomes and Measures Outcomes of interest were monthly hospitalization rates for airway infections and any cause during the first 2 years of life in newborns with cleft lip or palate. In-hospital outcomes and mortality outcomes were also assessed, stratified by age and modality of surgical intervention. Results Of 857 806 newborns included, 1197 (0.1%) had a cleft lip and/or palate, including 170 (14.2%) with a cleft lip only, 493 (41.2%) with a cleft palate only, and 534 (44.6%) with cleft lip and palate. Newborns with cleft lip or palate were more likely to be male (55.8% vs 51.4%), with lower birth weight (mean [SD] weight, 3135.6 [650.8] g vs 3284.7 [560.7] g) and height (mean [SD] height, 48.6 [3.8] cm vs 49.3 [3.2] cm). During the 2-year follow-up, children with a cleft lip or palate showed higher incidence rate ratios (IRRs) for hospitalizations due to airway infections (IRR, 2.33 [95% CI, 1.98-2.73]) and for any reason (IRR, 3.72 [95% CI, 3.49-3.97]) compared with controls. Additionally, children with cleft lip or palate had a substantial increase in odds of mortality (odds ratio [OR], 17.97 [95% CI, 11.84-27.29]) and various complications, including the need for intubation (OR, 2.37 [95% CI, 1.95-2.87]), extracorporeal membrane oxygenation (OR, 2.89 [95% CI, 1.81-4.63]), cardiopulmonary resuscitation (OR, 3.25 [95% CI, 2.21-4.78]), and respiratory support (OR, 1.94 [95% CI, 1.64-2.29]). Conclusions and Relevance In this nationwide cohort study, the presence of cleft lip or palate was associated with increased hospitalization rates for respiratory infections and other causes, as well as poorer in-hospital outcomes and greater resource use.