tbuckley/cabot-search huggingface dataset:
Person-Centered Trajectories of Psychopathology From Early Childhood to Late Adolescence
Authors: Colm Healy, Ross Brannigan, Niamh Dooley, Lorna Staines, Helen Keeley, Robert Whelan, Mary Clarke, Stanley Zammit, Ian Kelleher, Mary Cannon
Journal: JAMA Network Open (2022)

The understanding of the development of psychopathology has been hampered by a reliance on cross-sectional data and symptom- or disorder-centered methods. Person-centered methods can accommodate both the problems of comorbidity and the movement between different psychopathological states at different phases of development.To examine the profiles and map the trajectories of psychopathology from early childhood to late adolescence.This cohort study used 2 longitudinal nationally representative community-based cohorts from the Growing Up in Ireland study covering developmental periods from early childhood to late adolescence. Data in this investigation came from children and their families who participated in all waves of cohorts recruited in 2008 (children ages 3, 5, and 9 years) and 1998 (adolescents ages 9, 13, and 17 or 18 years). Both samples were weighted to account for representation and attrition. Latent transition analyses were used to map the trajectories of psychopathology. Data were analyzed between October 2020 and September 2021.Psychopathology was measured using the Strengths and Difficulties Questionnaire at all ages in both samples.A total of 13 546 individuals were included in the analyses. In the child cohort, mean (SD) age was 3.0 [0.01] years; 3852 (51.3%) were male participants. In the adolescent cohort, mean age was 9.0 (0.1) years; 3082 (51.0%) were male participants. Four profiles were identified in both cohorts that could be broadly labeled as no psychopathology (incidence range, 60%-70%), high psychopathology (incidence range, 3%-5%), externalizing problems (incidence range, 15%-25%), and internalizing problems (incidence range, 7%-12%). Transition between the profiles was common in both cohorts, with 3649 of 7507 participants (48.6%) in the child cohort and 2661 of 6039 participants (44.1%) in the adolescent cohort moving into 1 of the 3 psychopathology profiles at some point in development. Transition to the high psychopathology profile was most often preceded by externalizing problems. Approximately 3% to 4% of the sample had persistent psychopathology (child cohort, 203 participants [2.7%]; adolescent cohort, 216 participants [3.6%]). All psychopathology profiles were more common in boys in early life but, by late adolescence, girls were more likely to have internalizing problems. In a cross-cohort comparison at age 9, there were differences in the sex distributions of the profiles between the samples.Using person-centered methods, this study demonstrated that from early life young peoples' experience of psychopathology is dynamic-they can move between different mental health problems; for most children, these problems are transient, but a small proportion (fewer than 5%) have persistent difficulties. In the context of finite resources, optimizing care requires the early identification of those with persistent phenomena.
Hsa-miR-3178/RhoB/PI3K/Akt, a novel signaling pathway regulates ABC transporters to reverse gemcitabine resistance in pancreatic cancer
Authors: Jianyou Gu, Wenjie Huang, Xianxing Wang, Junfeng Zhang, Tian Tao, Yao Zheng, Songsong Liu, Jiali Yang, Zhe-Sheng Chen, Chao-Yun Cai, Jinsui Li, Huaizhi Wang, Yingfang Fan
Journal: Molecular Cancer (2022)

Although gemcitabine has been considered as the first-line drug for advanced pancreatic cancer (PC), development of resistance to gemcitabine severely limits the effectiveness of this chemotherapy, and the underlying mechanism of gemcitabine resistance remains unclear. Various factors, such as ATP binding cassette (ABC) transporters, microRNAs and their downstream signaling pathways are included in chemoresistance to gemcitabine. This study investigated the potential mechanisms of microRNAs and ABC transporters related signaling pathways for PC resistance to gemcitabine both in vivo and in vitro.Immunohistochemistry and Western blotting were applied to detect the expression of ABC transporters. Molecular docking analysis was performed to explore whether gemcitabine interacted with ABC transporters. Gain-of-function and loss-of-function analyses were performed to investigate the functions of hsa-miR-3178 in vitro and in vivo. Bioinformatics analysis, Western blotting and dual-luciferase reporter assay were used to confirm the downstream regulatory mechanisms of hsa-miR-3178.We found that P-gp, BCRP and MRP1 were highly expressed in gemcitabine-resistant PC tissues and cells. Molecular docking analysis revealed that gemcitabine can bind to the ABC transporters. Hsa-miR-3178 was upregulated in gemcitabine resistance PANC-1 cells as compared to its parental PANC-1 cells. Moreover, we found that hsa-miR-3178 promoted gemcitabine resistance in PC cells. These results were also verified by animal experiments. RhoB was down-regulated in gemcitabine-resistant PC cells and it was a downstream target of hsa-miR-3178. Kaplan-Meier survival curve showed that lower RhoB expression was significantly associated with poor overall survival in PC patients. Rescue assays demonstrated that RhoB could reverse hsa-miR-3178-mediated gemcitabine resistance. Interestingly, hsa-miR-3178 promoted gemcitabine resistance in PC by activating the PI3K/Akt pathway-mediated upregulation of ABC transporters.Our results indicate that hsa-miR-3178 promotes gemcitabine resistance via RhoB/PI3K/Akt signaling pathway-mediated upregulation of ABC transporters. These findings suggest that hsa-miR-3178 could be a novel therapeutic target for overcoming gemcitabine resistance in PC.
Ambient Air Pollutant Exposures and COVID-19 Severity and Mortality in a Cohort of Patients with COVID-19 in Southern California
Authors: Zhanghua Chen, Margo A. Sidell, Brian Z. Huang, Ting Chow, Sandrah P. Eckel, Mayra P. Martinez, Roya Gheissari, Fred Lurmann, Duncan C. Thomas, Frank D. Gilliland, Anny H. Xiang
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Ecological studies have shown air pollution associations with coronavirus disease (COVID-19) outcomes. However, few cohort studies have been conducted. Objectives: To conduct a cohort study investigating the association between air pollution and COVID-19 severity using individual-level data from the electronic medical record. Methods: This cohort included all individuals who received diagnoses of COVID-19 from Kaiser Permanente Southern California between March 1 and August 31, 2020. One-year and 1-month averaged ambient air pollutant (particulate matter ⩽2.5 μm in aerodynamic diameter [PM2.5], NO2, and O3) exposures before COVID-19 diagnosis were estimated on the basis of residential address history. Outcomes included COVID-19–related hospitalizations, intensive respiratory support (IRS), and ICU admissions within 30 days and mortality within 60 days after COVID-19 diagnosis. Covariates included socioeconomic characteristics and comorbidities. Measurements and Main Results: Among 74,915 individuals (mean age, 42.5 years; 54% women; 66% Hispanic), rates of hospitalization, IRS, ICU admission, and mortality were 6.3%, 2.4%, 1.5%, and 1.5%, respectively. Using multipollutant models adjusted for covariates, 1-year PM2.5 and 1-month NO2 average exposures were associated with COVID-19 severity. The odds ratios associated with a 1-SD increase in 1-year PM2.5 (SD, 1.5 μg/m3) were 1.24 (95% confidence interval [CI], 1.16–1.32) for COVID-19–related hospitalization, 1.33 (95% CI, 1.20–1.47) for IRS, and 1.32 (95% CI, 1.16–1.51) for ICU admission; the corresponding odds ratios associated with 1-month NO2 (SD, 3.3 ppb) were 1.12 (95% CI, 1.06–1.17) for hospitalization, 1.18 (95% CI, 1.10–1.27) for IRS, and 1.21 (95% CI, 1.11–1.33) for ICU admission. The hazard ratios for mortality were 1.14 (95% CI, 1.02–1.27) for 1-year PM2.5 and 1.07 (95% CI, 0.98–1.16) for 1-month NO2. No significant interactions with age, sex or ethnicity were observed. Conclusions: Ambient PM2.5 and NO2 exposures may affect COVID-19 severity and mortality.
Synthetic Essentiality of Tryptophan 2,3-Dioxygenase 2 in <i>APC</i>-Mutated Colorectal Cancer
Authors: Rumi Lee, Jiexi Li, Jun Li, Chang-Jiun Wu, Shan Jiang, Wen-Hao Hsu, Deepavali Chakravarti, Peiwen Chen, Kyle A. LaBella, Jing Li, Denise J. Spring, Di Zhao, Y. Alan Wang, Ronald A. DePinho
Journal: Cancer Discovery (2022)

Inactivation of adenomatous polyposis coli (APC) is common across many cancer types and serves as a critical initiating event in most sporadic colorectal cancers. APC deficiency activates WNT signaling, which remains an elusive target for cancer therapy, prompting us to apply the synthetic essentiality framework to identify druggable vulnerabilities for APC-deficient cancers. Tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient colorectal cancer. Mechanistically, APC deficiency results in the TCF4/β-catenin-mediated upregulation of TDO2 gene transcription. TDO2 in turn activates the Kyn-AhR pathway, which increases glycolysis to drive anabolic cancer cell growth and CXCL5 secretion to recruit macrophages into the tumor microenvironment. Therapeutically, APC-deficient colorectal cancer models were susceptible to TDO2 depletion or pharmacologic inhibition, which impaired cancer cell proliferation and enhanced antitumor immune profiles. Thus, APC deficiency activates a TCF4-TDO2-AhR-CXCL5 circuit that affects multiple cancer hallmarks via autonomous and nonautonomous mechanisms and illuminates a genotype-specific vulnerability in colorectal cancer. This study identifies critical effectors in the maintenance of APC-deficient colorectal cancer and demonstrates the relationship between APC/WNT pathway and kynurenine pathway signaling. It further determines the tumor-associated macrophage biology in APC-deficient colorectal cancer, informing genotype-specific therapeutic targets and the use of TDO2 inhibitors. This article is highlighted in the In This Issue feature, p. 1599.
Cardiovascular Risk Factors Mediate the Long-Term Maternal Risk Associated With Hypertensive Disorders of Pregnancy
Authors: Jennifer J. Stuart, Lauren J. Tanz, Eric B. Rimm, Donna Spiegelman, Stacey A. Missmer, Kenneth J. Mukamal, Kathryn M. Rexrode, Janet W. Rich-Edwards
Journal: Journal of the American College of Cardiology (2022)

Hypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia, are associated with an increased risk of CVD. The purpose of this study was to evaluate associations between HDP and long-term CVD and identify the proportion of the association mediated by established CVD risk factors. Parous participants without CVD in the Nurses' Health Study II (n = 60,379) were followed for incident CVD from first birth through 2017. Cox proportional hazards models estimated HRs and 95% CIs for the relationship between HDP and CVD, adjusting for potential confounders, including prepregnancy body mass index, smoking, and parental history of CVD. To evaluate the proportion of the association jointly accounted for by chronic hypertension, hypercholesterolemia, type 2 diabetes, and changes in body mass index, we used the difference method. Women with HDP in first pregnancy had a 63% higher rate of CVD (95% CI: 1.37-1.94) compared with women with normotensive pregnancies. This association was mediated by established CVD risk factors (proportion mediated = 64%). The increased rate of CVD was higher for preeclampsia (HR: 1.72; 95% CI: 1.42-2.10) than gestational hypertension (HR: 1.41; 95% CI: 1.03-1.93). Established CVD risk factors accounted for 57% of the increased rate of CVD for preeclampsia but 84% for gestational hypertension (both P < 0.0001). Established CVD risk factors arising after pregnancy explained most (84%) of the increased risk of CVD conferred by gestational hypertension and 57% of the risk among women with preeclampsia. Screening for chronic hypertension, hypercholesterolemia, type 2 diabetes, and overweight/obesity after pregnancy may be especially helpful in CVD prevention among women with a history of HDP.
Progressive Parkinsonism With Features of Mitochondrial Disease
Authors: Tjerk J. Lagrand, Mehri Salari, Alexander C. Lehn
Journal: JAMA Neurology (2022)

A man aged 44 years presented with progressive parkinsonism and poor levodopa response. His medical history included unexplained sensory hearing loss, hyperlipidemia, osteoarthritis, and walking difficulty with frequent falls. What is your diagnosis?
Reply to Frederic Panthier, Alba Sierra, and Olivier Traxer’s Letter to the Editor re: Øyvind Ulvik, Mathias Sørstrand Æsøy, Patrick Juliebø-Jones, Peder Gjengstø, Christian Beisland. Thulium Fibre Laser Versus Holmium:YAG for Ureteroscopic Lithotripsy: Outcomes from a Prospective Randomised Clinical Trial. Eur Urol. 2022;82:73–9
Authors: Øyvind Ulvik, Mathias Sørstrand Æsøy, Patrick Juliebø-Jones, Peder Gjengstø, Christian Beisland
Journal: European Urology (2022)
Disruption of Prostaglandin E2 Signaling in Cancer-Associated Fibroblasts Limits Mammary Carcinoma Growth but Promotes Metastasis
Authors: Eiman Elwakeel, Mirko Brüggemann, Jessica Wagih, Olga Lityagina, Mohammed A.F. Elewa, Yingying Han, Timo Frömel, Rüdiger Popp, Adele M. Nicolas, Yannick Schreiber, Elise Gradhand, Dominique Thomas, Rolf Nüsing, Julia Steinmetz-Späh, Rajkumar Savai, Emmanouil Fokas, Ingrid Fleming, Florian R. Greten, Kathi Zarnack, Bernhard Brüne, Andreas Weigert
Journal: Cancer Research (2022)

Abstract The activation and differentiation of cancer-associated fibroblasts (CAF) are involved in tumor progression. Here, we show that the tumor-promoting lipid mediator prostaglandin E2 (PGE2) plays a paradoxical role in CAF activation and tumor progression. Restricting PGE2 signaling via knockout of microsomal prostaglandin E synthase-1 (mPGES-1) in PyMT mice or of the prostanoid E receptor 3 (EP3) in CAFs stunted mammary carcinoma growth associated with strong CAF proliferation. CAF proliferation upon EP3 inhibition required p38 MAPK signaling. Mechanistically, TGFβ–activated kinase-like protein (TAK1L), which was identified as a negative regulator of p38 MAPK activation, was decreased following ablation of mPGES-1 or EP3. In contrast with its effects on primary tumor growth, disruption of PGE2 signaling in CAFs induced epithelial-to-mesenchymal transition in cancer organoids and promoted metastasis in mice. Moreover, TAK1L expression in CAFs was associated with decreased CAF activation, reduced metastasis, and prolonged survival in human breast cancer. These data characterize a new pathway of regulating inflammatory CAF activation, which affects breast cancer progression. Significance: The inflammatory lipid prostaglandin E2 suppresses cancer-associated fibroblast expansion and activation to limit primary mammary tumor growth while promoting metastasis.
Spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals
Authors: Andrea Brizzi, Charles Whittaker, Luciana M. S. Servo, Iwona Hawryluk, Carlos A. Prete, William M. de Souza, Renato S. Aguiar, Leonardo J. T. Araujo, Leonardo S. Bastos, Alexandra Blenkinsop, Lewis F. Buss, Darlan Candido, Marcia C. Castro, Silvia F. Costa, Julio Croda, Andreza Aruska de Souza Santos, Christopher Dye, Seth Flaxman, Paula L. C. Fonseca, Victor E. V. Geddes, Bernardo Gutierrez, Philippe Lemey, Anna S. Levin, Thomas Mellan, Diego M. Bonfim, Xenia Miscouridou, Swapnil Mishra, Mélodie Monod, Filipe R. R. Moreira, Bruce Nelson, Rafael H. M. Pereira, Otavio Ranzani, Ricardo P. Schnekenberg, Elizaveta Semenova, Raphael Sonabend, Renan P. Souza, Xiaoyue Xi, Ester C. Sabino, Nuno R. Faria, Samir Bhatt, Oliver Ratmann
Journal: Nature Medicine (2022)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Gamma variant of concern has spread rapidly across Brazil since late 2020, causing substantial infection and death waves. Here we used individual-level patient records after hospitalization with suspected or confirmed coronavirus disease 2019 (COVID-19) between 20 January 2020 and 26 July 2021 to document temporary, sweeping shocks in hospital fatality rates that followed the spread of Gamma across 14 state capitals, during which typically more than half of hospitalized patients aged 70 years and older died. We show that such extensive shocks in COVID-19 in-hospital fatality rates also existed before the detection of Gamma. Using a Bayesian fatality rate model, we found that the geographic and temporal fluctuations in Brazil's COVID-19 in-hospital fatality rates were primarily associated with geographic inequities and shortages in healthcare capacity. We estimate that approximately half of the COVID-19 deaths in hospitals in the 14 cities could have been avoided without pre-pandemic geographic inequities and without pandemic healthcare pressure. Our results suggest that investments in healthcare resources, healthcare optimization and pandemic preparedness are critical to minimize population-wide mortality and morbidity caused by highly transmissible and deadly pathogens such as SARS-CoV-2, especially in low- and middle-income countries.
Phosphatidylserine Synthase PTDSS1 Shapes the Tumor Lipidome to Maintain Tumor-Promoting Inflammation
Authors: Divya Sekar, Christina Dillmann, Evelyn Sirait-Fischer, Annika F. Fink, Aleksandra Zivkovic, Natalie Baum, Elisabeth Strack, Stephan Klatt, Sven Zukunft, Stefan Wallner, Arnaud Descot, Catherine Olesch, Priscila da Silva, Andreas von Knethen, Tobias Schmid, Sabine Grösch, Rajkumar Savai, Nerea Ferreirós, Ingrid Fleming, Sourav Ghosh, Carla V. Rothlin, Holger Stark, Hind Medyouf, Bernhard Brüne, Andreas Weigert
Journal: Cancer Research (2022)

An altered lipidome in tumors may affect not only tumor cells themselves but also their microenvironment. In this study, a lipidomics screen reveals increased amounts of phosphatidylserine (PS), particularly ether-PS (ePS), in murine mammary tumors compared with normal tissue. PS was produced by phosphatidylserine synthase 1 (PTDSS1), and depletion of Ptdss1 from tumor cells in mice reduced ePS levels accompanied by stunted tumor growth and decreased tumor-associated macrophage (TAM) abundance. Ptdss1-deficient tumor cells exposed less PS during apoptosis, which was recognized by the PS receptor MERTK. Mammary tumors in macrophage-specific Mertk-/- mice showed similarly suppressed growth and reduced TAM infiltration. Transcriptomic profiles of TAMs from Ptdss1-knockdown tumors and Mertk-/- TAMs revealed that macrophage proliferation was reduced when the Ptdss1/Mertk pathway was targeted. Moreover, PTDSS1 expression correlated positively with TAM abundance but negatively with breast carcinoma patient survival. PTDSS1 thus may be a target to modify tumor-promoting inflammation.This study shows that inhibiting the production of ether-phosphatidylserine by targeting phosphatidylserine synthase PTDSS1 limits tumor-associated macrophage expansion and breast tumor growth.
Reassessing the health impacts of trade and investment agreements: a systematic review of quantitative studies, 2016–20
Authors: Pepita Barlow, Rujuta Sanap, Amandine Garde, L Alan Winters, Mzwandile A Mabhala, Anne-Marie Thow
Journal: The Lancet Planetary Health (2022)

To ensure a high level of health protection, governments must ensure that health and trade policy objectives are aligned. We conducted a systematic review of the health impacts of trade policies, including trade and investment agreements (TIAs), to provide a timely overview of this field. We systematically reviewed studies evaluating the health impacts of trade policies published between Jan 19, 2016, and July 10, 2020. Included studies were quantitative studies evaluating the impact of TIAs and trade policies on health determinants or outcomes. We evaluated methodological quality and performed a narrative synthesis. 21 of 28 067 articles identified via searches met our criteria. Methodologically strong studies found reduced child mortality, deteriorating worker health, rising supplies of sugar, ultra-processed food, tobacco, and alcohol supplies, and increased drug overdoses following trade reforms, compared with the time periods before trade reform. However, associations varied substantially across contexts and socioeconomic characteristics. Our findings show that trade policies, including TIAs, have diverse effects on health and health determinants. These effects vary substantially across contexts and socioeconomic groups. Governments seeking to adopt healthy trade policies should consider these updated findings to ensure that opportunities for health improvement are leveraged and widely shared, while harms are avoided, especially among vulnerable groups.
A Short Isoform of Spermatogenic Enzyme GAPDHS Functions as a Metabolic Switch and Limits Metastasis in Melanoma
Authors: Jennifer G. Gill, Samantha N. Leef, Vijayashree Ramesh, Misty S. Martin-Sandoval, Aparna D. Rao, Lindsey West, Sarah Muh, Wen Gu, Zhiyu Zhao, Gregory A. Hosler, Travis W. Vandergriff, Alison B. Durham, Thomas P. Mathews, Arin B. Aurora
Journal: Cancer Research (2022)

Despite being the leading cause of cancer deaths, metastasis remains a poorly understood process. To identify novel regulators of metastasis in melanoma, we performed a large-scale RNA sequencing screen of 48 samples from patient-derived xenograft (PDX) subcutaneous melanomas and their associated metastases. In comparison with primary tumors, expression of glycolytic genes was frequently decreased in metastases, whereas expression of some tricarboxylic acid (TCA) cycle genes was increased in metastases. Consistent with these transcriptional changes, melanoma metastases underwent a metabolic switch characterized by decreased levels of glycolytic metabolites and increased abundance of TCA cycle metabolites. A short isoform of glyceraldehyde-3-phosphate dehydrogenase, spermatogenic (GAPDHS) lacking the N-terminal domain suppressed metastasis and regulated this metabolic switch. GAPDHS was downregulated in metastatic nodules from PDX models as well as in human patients. Overexpression of GAPDHS was sufficient to block melanoma metastasis, whereas its inhibition promoted metastasis, decreased glycolysis, and increased levels of certain TCA cycle metabolites and their derivatives including citrate, fumarate, malate, and aspartate. Isotope tracing studies indicated that GAPDHS mediates this shift through changes in pyruvate carboxylase activity and aspartate synthesis, both metabolic pathways critical for cancer survival and metastasis. Together, these data identify a short isoform of GAPDHS that limits melanoma metastasis and regulates central carbon metabolism.This study characterizes metabolic changes during cancer metastasis and identifies GAPDHS as a novel regulator of these processes in melanoma cells.
Racial and Ethnic Disparities in Estimated Excess Mortality From External Causes in the US, March to December 2020
Authors: Ruijia Chen, Hélène E. Aschmann, Yea-Hung Chen, M. Maria Glymour, Kirsten Bibbins-Domingo, Andrew C. Stokes, Mathew V. Kiang
Journal: JAMA Internal Medicine (2022)

The COVID-19 Pandemic and Racial and Ethnic Disparities in Estimated Excess Mortality From External Causes
Cost-effectiveness of the Self-Help Plus Intervention for Adult Syrian Refugees Hosted in Turkey
Authors: A-La Park, Tamara Waldmann, Markus Kösters, Federico Tedeschi, Michela Nosè, Giovanni Ostuzzi, Marianna Purgato, Giulia Turrini, Maritta Välimäki, Tella Lantta, Minna Anttila, Johannes Wancata, Fabian Friedrich, Ceren Acartürk, Zeynep İlkkursun, Ersin Uygun, Sevde Eskici, Pim Cuijpers, Marit Sijbrandij, Ross G. White, Mariana Popa, Kenneth Carswell, Teresa Au, Reinhold Kilian, Corrado Barbui
Journal: JAMA Network Open (2022)

The cost-effectiveness of the Self-Help Plus (SH+) program, a group-based, guided, self-help psychological intervention developed by the World Health Organization for people affected by adversity, is unclear.