tbuckley/cabot-search huggingface dataset:
Hyperactive mTORC1 in lung mesenchyme induces endothelial cell dysfunction and pulmonary vascular remodeling
Authors: Susan M. Lin, Ryan Rue, Alexander R. Mukhitov, Akansha Goel, Maria C. Basil, Kseniya Obraztsova, Apoorva Babu, Slaven Crnkovic, Owen A. Ledwell, Laura T. Ferguson, Joseph D. Planer, Ana N. Nottingham, Kanth Swaroop Vanka, Carly J. Smith, Edward Cantu, Grazyna Kwapiszewska, Edward E. Morrisey, Jillian F. Evans, Vera P. Krymskaya
Journal: Journal of Clinical Investigation (2023)

Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations in pulmonary mesenchymal cells resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of LAM patients develops pulmonary vascular remodeling and pulmonary hypertension. Little, however, is known regarding how LAM cells communicate with endothelial cells (ECs) to trigger vascular remodeling. In end-stage LAM lung explants, we identified endothelial cell dysfunction characterized by increased proliferation, migration, defective angiogenesis, and dysmorphic endothelial tube network formation. To model LAM disease, we utilized an mTORC1 gain-of-function mouse model with a Tsc2 knock-out (Tsc2KO) specific to lung mesenchyme (Tbx4LME-CreTsc2fl/fl), similar to the mesenchyme specific genetic alterations seen in human disease. As early as 8 weeks of age, ECs from Tbx4LME-CreTsc2fl/fl mice exhibited marked transcriptomic changes despite absence of morphological changes to the distal lung microvasculature. In contrast, 1 year old Tbx4LME-CreTsc2fl/fl mice spontaneously developed pulmonary vascular remodeling with increased medial thickness. Single cell RNA-sequencing of 1 year old mouse lung identified paracrine ligands originating from Tsc2KO mesenchyme which can signal through receptors in arterial ECs. These ECs had transcriptionally altered genes including those in pathways associated with blood vessel remodeling. The proposed pathophysiologic mesenchymal ligand/ EC receptor crosstalk highlights the importance of an altered mesenchymal-EC axis in LAM and other hyperactive mTORC1-driven diseases. Since ECs in LAM patients and in Tbx4LME-CreTsc2fl/fl mice do not harbor TSC2 mutations, our study demonstrates that constitutively active mTORC1 lung mesenchymal cells orchestrate dysfunctional EC responses which contribute to pulmonary vascular remodeling.
SARS-CoV-2 Rebound With and Without Use of COVID-19 Oral Antivirals
Authors: Dallas J. Smith, Anastasia Lambrou, Pragna Patel
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Early treatment with a first-line therapy (nirmatrelvir/ritonavir [Paxlovid] or remdesivir) or second-line therapy (molnupiravir) prevents hospitalization and death among patients with mildto-moderate COVID-19 who are at risk for severe disease and is recommended by the National Institutes of Health COVID-19 Treatment Guidelines.On May 25, 2023, the Food and Drug Administration approved nirmatrelvir/ritonavir for treatment of adults at high risk for severe disease.Although antiviral therapies are widely available, they are underutilized, possibly because of reports of SARS-CoV-2 rebound after treatment.To enhance current understanding of rebound, CDC reviewed SARS-CoV-2 rebound studies published during February 1, 2020-November 29, 2023.Overall, seven of 23 studies that met inclusion criteria, one randomized trial and six observational studies, compared rebound for persons who received antiviral treatment with that for persons who did not receive antiviral treatment.In four studies, including the randomized trial, no statistically significant difference in rebound rates was identified among persons receiving treatment and those not receiving treatment.Depending on the definition used, the prevalence of rebound varied.No hospitalizations or deaths were reported among outpatients who experienced rebound, because COVID-19 signs and symptoms were mild.Persons receiving antiviral treatment might be at higher risk for rebound compared with persons not receiving treatment because of host factors or treatment-induced viral suppression early in the course of illness.The potential for rebound should not deter clinicians from prescribing lifesaving antiviral treatments when indicated to prevent morbidity and mortality from COVID-19.* https://covid.cdc.gov/covid-data-tracker/#datatracker-home(Accessed December 15, 2023).Although hospitalizations and deaths are currently much lower than they were during the peak of the pandemic, COVID-19 continues to cause substantial morbidity and mortality.As of December 9, 2023, approximately 23,000 hospitalizations per week were reported among patients with COVID-19, with highest rates among persons aged ≥65 years.Currently, health care providers are positioned to mitigate COVID-19 morbidity and mortality with safe and effective vaccines † and early diagnosis and treatment (1). Antiviral TherapeuticsEarly treatment with first-line therapy (nirmatrelvir/ritonavir [Paxlovid] or remdesivir) or second-line therapy (molnupiravir) reduces the prevalence of hospitalization and death among patients with mild-to-moderate COVID-19 who are at risk for severe disease (2-4), and is recommended by the National † https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19vaccines-us.html
Improving Cancer Outcomes Among Unhoused Patients—Lessons From the Veterans Health Administration
Authors: Maria C. Raven
Journal: JAMA Network Open (2023)

Hannah C. Decker, MD; Laura A. Graham, PhD; Ashley Titan, MD; Hemal K. Kanzaria, MD, MSc; Mary T. Hawn, MD, MPH; Margot Kushel, MD; Elizabeth Wick, MD
Survival Outcomes and Patterns of Care for Stage II or III Resected Gastric Cancer by Race and Ethnicity
Authors: S. Peter Wu, Sara H. Keshavjee, Sam S. Yoon, Steve Kwon
Journal: JAMA Network Open (2023)

Importance Many multimodality treatment regimens exist for gastric adenocarcinoma, including neoadjuvant vs adjuvant chemotherapy, radiation, or both. Neoadjuvant therapy is recommended in the United States for patients with locally advanced gastric cancer; however, it is unknown whether the outcomes of neoadjuvant therapy are associated with race and ethnicity. Objective To evaluate the differences in outcomes by race and ethnicity of patients with noncardia gastric cancer undergoing surgical procedures with and without neoadjuvant therapy. Design, Setting, and Participants This retrospective cohort study examined the National Cancer Database from the American College of Surgeons for patients with clinical stage II or III gastric adenocarcinoma, excluding gastric cardia tumors, undergoing surgical resection procedures from January 2006 to December 2019. Statistical analysis was performed from December 2021 to May 2023. Exposure Patients were stratified by race and ethnicity, and their outcomes were analyzed for those who received and did not receive neoadjuvant therapy. Main Outcomes and Measures The Cox proportional hazard model was used to compare overall survival (OS) between racial and ethnic groups (Asian, Black, Hispanic, and White) overall and according to receipt of neoadjuvant therapy. Among those who received neoadjuvant therapy, proportional differences in pathological responses were calculated in each group. Results Among a total of 6938 patients in the cohort, 4266 (61.4%) were male; mean (SD) age was 65.9 (12.8) years; 1046 (15.8%) were Asian, 1606 (24.3%) were Black, 1175 (17.8%) were Hispanic, and 3540 (53.6%) were White. Compared with other races and ethnicities, the group of White patients had significantly more who were 65 years or older with more comorbidities. White patients underwent surgical resection procedures alone without neoadjuvant or adjuvant therapy more frequently than other races and ethnicities. Asian and Black patients had the highest proportion of being downstaged or achieving pathological complete response after neoadjuvant therapy. In multivariate models, perioperative chemotherapy was associated with improved OS (HR, 0.79 [95% CI, 0.69-0.90]), whereas number of positive lymph nodes and surgical margins were associated with the largest decreases in OS. Asian and Hispanic race and ethnicity were associated with significantly improved OS compared with Black and White races (eg, Asian patients: HR, 0.64 [95% CI, 0.58-0.72]; and Hispanic patients: HR, 0.77 [95% CI, 0.69-0.85]). Black race was associated with improved OS compared with White race when receiving neoadjuvant therapy (HR, 0.78 [95% CI, 0.67-0.90]). Conclusions and Relevance In this large nationwide cohort study of survival outcomes among patients with resected clinical stage II or III gastric cancer, there were significant differences in response to treatment and OS between different racial and ethnic groups.
Housing Status, Cancer Care, and Associated Outcomes Among US Veterans
Authors: Hannah C. Decker, Laura A. Graham, Ashley Titan, Hemal K. Kanzaria, Mary T. Hawn, Margot Kushel, Elizabeth Wick
Journal: JAMA Network Open (2023)

Importance Cancer is a leading cause of death among older people experiencing homelessness. However, the association of housing status with cancer outcomes is not well described. Objective To characterize the diagnosis, treatment, surgical outcomes, and mortality by housing status of patients who receive care from the US Department of Veterans Affairs (VA) health system for colorectal, breast, or lung cancer. Design, Setting, and Participants This retrospective cohort study identified all US veterans diagnosed with lung, colorectal, or breast cancer who received VA care between October 1, 2011, and September 30, 2020. Data analysis was performed from February 13 to May 9, 2023. Exposures Veterans were classified as experiencing homelessness if they had any indicators of homelessness in outpatient visits, clinic reminders, diagnosis codes, or the Homeless Operations Management Evaluation System in the 12 months preceding diagnosis, with no subsequent evidence of stable housing. Main Outcomes and Measures The major outcomes, by cancer type, were as follows: (1) treatment course (eg, stage at diagnosis, time to treatment initiation), (2) surgical outcomes (eg, length of stay, major complications), (3) overall survival by cancer type, and (4) hazard ratios for overall survival in a model adjusted for age at diagnosis, sex, stage at diagnosis, race, ethnicity, marital status, facility location, and comorbidities. Results This study included 109 485 veterans, with a mean (SD) age of 68.5 (9.7) years. Men comprised 92% of the cohort. In terms of race and ethnicity, 18% of veterans were Black, 4% were Hispanic, and 79% were White. A total of 68% of participants had lung cancer, 26% had colorectal cancer, and 6% had breast cancer. There were 5356 veterans (5%) experiencing homelessness, and these individuals more commonly presented with stage IV colorectal cancer than veterans with housing (22% vs 19%; P = .02). Patients experiencing homelessness had longer postoperative lengths of stay for all cancer types, but no differences in other treatment or surgical outcomes were observed. These patients also demonstrated higher rates of all-cause mortality 3 months after diagnosis for lung and colorectal cancers, with adjusted hazard ratios of 1.1 (95% CI, 1.1-1.2) and 1.3 (95% CI, 1.2-1.4) (both P &amp;amp;lt; .001), respectively. Conclusions and Relevance In this large retrospective study of US veterans with cancer, homelessness was associated with later stages at diagnosis for colorectal cancer. Differences in lung and colorectal cancer survival between patients with housing and those experiencing homelessness were present but smaller than observed in other settings. These findings suggest that there may be important systems in the VA that could inform policy to improve oncologic outcomes for patients experiencing homelessness.
Body Core Temperature After Foot Immersion and Neck Cooling in Older Adults Exposed to Extreme Heat
Authors: Robert D. Meade, Emma R. McCourt, James J. McCormick, Pierre Boulay, Ronald J. Sigal, Glen P. Kenny
Journal: JAMA (2023)

This randomized study evaluates the hypothesis that foot immersion in cool water alone or with supplemental neck cooling mitigates increases in core temperature in older adults exposed to environmental conditions simulating deadly heat waves in North America.
Residential Structural Racism and Prevalence of Chronic Health Conditions
Authors: Dinushika Mohottige, Clemontina A. Davenport, Nrupen Bhavsar, Tyler Schappe, Michelle J. Lyn, Pamela Maxson, Fred Johnson, Arrianna M. Planey, Lisa M. McElroy, Virginia Wang, Ashley N. Cabacungan, Patti Ephraim, Paul Lantos, Sarah Peskoe, Joseph Lunyera, Keisha Bentley-Edwards, Clarissa J. Diamantidis, Brian Reich, L. Ebony Boulware
Journal: JAMA Network Open (2023)

Studies elucidating determinants of residential neighborhood-level health inequities are needed.
NADase CD38 is a key determinant of ovarian aging
Authors: Qingling Yang, Wenhui Chen, Luping Cong, Mengchen Wang, Hui Li, Huan Wang, Xiaoyan Luo, Jing Zhu, Xinxin Zeng, Zhenye Zhu, Yining Xu, Min Lei, Yanqing Zhao, Chenlu Wei, Yingpu Sun
Journal: Nature Aging (2023)

Abstract The ovary ages earlier than most other tissues, yet the underlying mechanisms remain elusive. Here a comprehensive analysis of transcriptomic landscapes in different organs in young and middle-aged mice revealed that the ovaries showed earlier expression of age-associated genes, identifying increased NADase CD38 expression and decreased NAD + levels in the ovary of middle-aged mice. Bulk and single-cell RNA sequencing revealed that CD38 deletion mitigated ovarian aging, preserving fertility and follicle reserve in aged mice by countering age-related gene expression changes and intercellular communication alterations. Mechanistically, the earlier onset of inflammation induced higher expression levels of CD38 and decreased NAD + levels in the ovary, thereby accelerating ovarian aging. Consistently, pharmacological inhibition of CD38 enhanced fertility in middle-aged mice. Our findings revealed the mechanisms underlying the earlier aging of the ovary relative to other organs, providing a potential therapeutic target for ameliorating age-related female infertility.
Mapping global new-onset, worsening, and resolution of diabetes following partial pancreatectomy: A systematic review and meta-analysis
Authors: Junlun Wei, Yiran Ou, Jiaoting Chen, Zhicheng Yu, Zhenghao Wang, Ke Wang, Dujiang Yang, Yun Gao, Yong Liu, Jiaye Liu, Xiaofeng Zheng
Journal: International Journal of Surgery (2023)

Background and aims: Partial pancreatectomy, commonly used for chronic pancreatitis, or pancreatic lesions, has diverse impacts on endocrine and metabolism system. The study aims to determine the global prevalence of new-onset, worsening, and resolution of diabetes following partial pancreatectomy. Methods: The authors searched PubMed, Embase, Web of Science, and Cochrane Library from inception to October, 2023. DerSimonian-Laird random-effects model with Logit transformation was used. Sensitivity analysis, meta-regression, and subgroup analysis were employed to investigate determinants of the prevalence of new-onset diabetes. Results: A total of 82 studies involving 13 257 patients were included. The overall prevalence of new-onset diabetes after partial pancreatectomy was 17.1%. Univariate meta-regression indicated that study size was the cause of heterogeneity. Multivariable analysis suggested that income of country or area had the highest predictor importance (49.7%). For subgroup analysis, the prevalence of new-onset diabetes varied from 7.6% (France, 95% CI: 4.3–13.0) to 38.0% (UK, 95% CI: 28.2–48.8, P &lt;0.01) across different countries. Patients with surgical indications for chronic pancreatitis exhibited a higher prevalence (30.7%, 95% CI: 21.8–41.3) than those with pancreatic lesions (16.4%, 95% CI: 14.3–18.7, P &lt;0.01). The type of surgical procedure also influenced the prevalence, with distal pancreatectomy having the highest prevalence (23.7%, 95% CI: 22.2–25.3, P &lt;0.01). Moreover, the prevalence of worsening and resolution of preoperative diabetes was 41.1 and 25.8%, respectively. Conclusions: Postoperative diabetes has a relatively high prevalence in patients undergoing partial pancreatectomy, which calls for attention and dedicated action from primary care physicians, specialists, and health policy makers alike.
AGO2 Protects Against Diabetic Cardiomyopathy by Activating Mitochondrial Gene Translation
Authors: Jiabing Zhan, Kunying Jin, Rong Xie, Jiahui Fan, Yuyan Tang, Chen Chen, Huaping Li, Dao Wen Wang
Journal: Circulation (2023)

Diabetes is associated with cardiovascular complications. microRNAs translocate into subcellular organelles to modify genes involved in diabetic cardiomyopathy. However, functional properties of subcellular AGO2 (Argonaute2), a core member of miRNA machinery, remain elusive.
ENGEP: advancing spatial transcriptomics with accurate unmeasured gene expression prediction
Authors: Shi-Tong Yang, Xiao-Fei Zhang
Journal: Genome biology (2023)

Abstract Imaging-based spatial transcriptomics techniques provide valuable spatial and gene expression information at single-cell resolution. However, their current capability is restricted to profiling a limited number of genes per sample, resulting in most of the transcriptome remaining unmeasured. To overcome this challenge, we develop ENGEP, an ensemble learning-based tool that predicts unmeasured gene expression in spatial transcriptomics data by using multiple single-cell RNA sequencing datasets as references. ENGEP outperforms current state-of-the-art tools and brings biological insight by accurately predicting unmeasured genes. ENGEP has exceptional efficiency in terms of runtime and memory usage, making it scalable for analyzing large datasets.
The SNP rs460089 in the gene promoter of the drug transporter OCTN1 has prognostic value for treatment-free remission in chronic myeloid leukemia patients treated with imatinib
Authors: Katerina Machova Polakova, Ali Albeer, Vaclava Polivkova, Monika Krutska, Katerina Vlcanova, Nikola Curik, Alice Fabarius, Hana Klamova, Birgit Spiess, Cornelius F. Waller, Tim H. Brümmendorf, Jolanta Dengler, Volker Kunzmann, Andreas Burchert, Petra Belohlavkova, Satu Mustjoki, Edgar Faber, Jiri Mayer, Daniela Zackova, Panayiotis Panayiotidis, Johan Richter, Henrik Hjorth-Hansen, Magdalena Kamińska, Magdalena Płonka, Elżbieta Szczepanek, Monika Szarejko, Grażyna Bober, Iwona Hus, Olga Grzybowska-Izydorczyk, Ewa Wasilewska, Edyta Paczkowska, Joanna Niesiobędzka-Krężel, Krzysztof Giannopoulos, Francois X. Mahon, Tomasz Sacha, Susanne Saußele, Markus Pfirrmann
Journal: Leukemia (2023)

Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60-82%) compared to patients with GG (51%, 95% CI: 41-61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.
Dielectrophoretic Capture of Cancer‐Derived Small‐Extracellular‐Vesicle‐Bound Janus Nanoparticles via Lectin–Glycan Interaction
Authors: Yonghyun Choi, Kubra Akyildiz, Jihyun Seong, Yangwoo Lee, Eunseo Jeong, Jin‐seok Park, Don Haeng Lee, Kyobum Kim, Hyung‐Jun Koo, Jonghoon Choi
Journal: Advanced Healthcare Materials (2023)

Abstract Glycosylation is closely related to cellular metabolism and disease progression. In particular, glycan levels in cancer cells and tissues increase during cancer progression. This upregulation of glycosylation in cancer cells may provide a basis for the development of new biomarkers for the targeting and diagnosis of specific cancers. Here, they developed a detection technology for pancreatic cancer cell‐derived small extracellular vesicles (PC‐sEVs) based on lectin–glycan interactions. Lectins specific for sialic acids are conjugated to Janus nanoparticles to induce interactions with PC‐sEVs in a dielectrophoretic (DEP) system. PC‐sEVs are selectively bound to the lectin‐conjugated Janus nanoparticles (lectin–JNPs) with an affinity comparable to that of conventionally used carbohydrate antigen 19‐9 (CA19‐9) antibodies. Furthermore, sEVs‐bound Lectin–JNPs (sEVs‐Lec‐JNPs) are manipulated between two electrodes to which an AC signal is applied for DEP capture. In addition, the proposed DEP system can be used to trap the sEVs–Lec–JNP on the electrodes. Their results, which are confirmed by lectin–JNPs using the proposed DEP system followed by target gene analysis, provide a basis for the development of a new early diagnostic marker based on the glycan characteristics of PC‐sEVs. In turn, these novel detection methods could overcome the shortcomings of commercially available pancreatic cancer detection techniques.
Effective medications can work only in patients who take them: Implications for post‐acute heart failure care
Authors: Gad Cotter, Beth A. Davison, Kirkwood F. Adams, Andrew P. Ambrosy, Lina Atabaeva, Craig J. Beavers, Ankeet S. Bhatt, Michael M. Givertz, Justin L. Grodin, Anuradha Lala, Mikhail Novosadov, George G. Sokos, Koji Takagi, John R. Teerlink, Deepak L. Bhatt
Journal: European Journal of Heart Failure (2023)
Myeloid neoplasm occurrence during stable molecular remission of NPM1-mutated AML: are we facing secondary disease or AML relapse?
Authors: Carlotta Giupponi, Diego Bertoli, Erika Borlenghi, Chiara Cattaneo, Tatiana Zollner, Lorenzo Masina, Samuele Bagnasco, Elisa Cerqui, Francesca Federico, Chiara Pagani, Silvana Archetti, Duilio Brugnoni, Giuseppe Rossi, Alessandra Tucci
Journal: Blood Cancer Journal (2023)