tbuckley/cabot-search huggingface dataset:
Type 2 Diabetes Subgroups, Risk for Complications, and Differential Effects Due to an Intensive Lifestyle Intervention
Authors: Michael P. Bancks, Haiying Chen, Ashok Balasubramanyam, Alain G. Bertoni, Mark A. Espeland, Steven E. Kahn, Scott Pilla, Elizabeth Vaughan, Lynne E. Wagenknecht
Journal: Diabetes Care (2021)

OBJECTIVE We reevaluated the Action for Health in Diabetes (Look AHEAD) intervention, incorporating diabetes subgroups, to identify whether intensive lifestyle intervention (ILI) is associated with differential risk for cardiovascular disease (CVD) by diabetes subgroup. RESEARCH DESIGN AND METHODS In the Look AHEAD trial, 5,145 participants, aged 45–76 years, with type 2 diabetes (T2D) and overweight or obesity were randomly assigned to 10 years of ILI or a control condition of diabetes support and education. The ILI focused on weight loss through decreased caloric intake and increased physical activity. To characterize diabetes subgroups, we applied k-means clustering to data on age of diabetes diagnosis, BMI, waist circumference, and glycated hemoglobin. We examined whether relative intervention effects on the trial’s prespecified CVD outcomes varied among diabetes subgroups. RESULTS We characterized four subgroups related to older age at diabetes onset (42% of sample), poor glucose control (14%), severe obesity (24%), and younger age at diabetes onset (20%). We observed interactions (all P &amp;lt; 0.05) between intervention and diabetes subgroups for three separate composite cardiovascular outcomes. Randomization to ILI was associated with increased risk for each cardiovascular outcome only among the poor-glucose-control subgroup (hazard ratio &amp;gt;1.32). Among the three other diabetes subgroups, ILI was not associated with increased risk for CVD. CONCLUSIONS Among overweight and obese adults with T2D, a lifestyle intervention was associated with differential risk for CVD that was dependent on diabetes subgroup. Diabetes subgroups may be important to identify the patients who would achieve benefit and avoid harm from an ILI.
Innovative color jet 3D printing of levetiracetam personalized paediatric preparations
Authors: Zengming Wang, Xiaolu Han, Ruxin Chen, Jingru Li, Jing Gao, Hui Zhang, Nan Liu, Xiang Gao, Aiping Zheng
Journal: Asian Journal of Pharmaceutical Sciences (2021)

3D printing is a promising technology used in the fabrication of complex oral dosage delivery pharmaceuticals. This study first reports an innovative color jet 3D printing (CJ-3DP) technology to produce colorful cartoon levetiracetam pediatric preparations with high accuracy and reproducibility. For this study, the ideal printing ink consisted of 40% (v/v) isopropanol aqueous solution containing 0.05% (w/w) polyvinylpyrrolidone and 4% (w/w) glycerin, which was satisfied with scale-up of the production. The external and internal spatial structures of the tablets were designed to control the appearance and release, and cartoon tablets with admirable appearances and immediate release characteristics were printed. The dosage model showed a good linear relationship between the model volume and the tablet strength (r > 0.999), which proved the potential of personalized administration. The surface roughness indicated that the appearance of the CJ-3DP tablets was significantly better than the first listed 3D printed drug (SpritamⓇ). Moreover, the scanning electron microscopy and porosity results further showed that the tablets have a structure of loose interior and tight exterior, which could ensure good mechanical properties and rapid dispersion characteristics simultaneously. In conclusion, the innovative CJ-3DP technology can be used to fabricate personalized pediatric preparations for improved compliance. Due to the stable formulation and fabrication process, this technology has the potential in scale-up production.
Single-cell analysis reveals the origins and intrahepatic development of liver-resident IFN-γ-producing γδ T cells
Authors: Yuan Hu, Keke Fang, Yanan Wang, Nan Lu, Haoyu Sun, Cai Zhang
Journal: Cellular and Molecular Immunology (2021)

Abstract γδ T cells are heterogeneous lymphocytes located in various tissues. However, a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associated with liver γδ T cells remain largely unsolved. In this study, we performed single-cell RNA sequencing (scRNA-seq) to comprehensively catalog the heterogeneity of γδ T cells derived from murine liver and thymus samples. We revealed the developmental trajectory of γδ T cells and found that the liver contains γδ T cell precursors (pre-γδ T cells). The developmental potential of hepatic γδ T precursor cells was confirmed through in vitro coculture experiments and in vivo adoptive transfer experiments. The adoptive transfer of hematopoietic progenitor Lin − Sca-1 + Mac-1 + (LSM) cells from fetal or adult liver samples to sublethally irradiated recipients resulted in the differentiation of liver LSM cells into pre-γδ T cells and interferon-gamma + (IFN-γ + ) but not interleukin-17a + (IL-17a + ) γδ T cells in the liver. Importantly, thymectomized mouse models showed that IFN-γ-producing γδ T cells could originate from liver LSM cells in a thymus-independent manner. These results suggested that liver hematopoietic progenitor LSM cells were able to differentiate into pre-γδ T cells and functionally mature γδ T cells, which implied that these cells are involved in a distinct developmental pathway independent of thymus-derived γδ T cells.
Abstract PO017: Role of NF-κB and epiregulin in tumor-associated macrophages promoting therapeutic resistance to JAK inhibition
Authors: Aditi S. Bapat, Emily Jesser, Chelsea Lassiter, Kaylee Schwertfeger
Journal: Cancer Research (2021)

Abstract Breast cancer is the second leading cause of cancer-related mortalities in women. Triple-negative is the most lethal type of breast cancer with poorest survival rates. Triple-negative breast cancers do not respond to conventional hormone receptor targeted therapies and thus inhibitors for other overactivated signaling pathways are being investigated. The Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) is an oncogenic transcription factor pathway expressed in tumor and stromal cell populations. Inhibitors of this pathway such as ruxolitinib are being studied for treatment of triple-negative breast cancer but their efficacy in patients is limited. A significant barrier to the success of these inhibitors in the clinic is the lack of information about mechanisms of resistance. Tumor-associated macrophages (TAMs) are important components of the immune-suppressive environment within the tumor and are associated with poor outcome. We found that JAK inhibition in TAMs leads to induction of tumor-promoting genes that mediate therapeutic resistance of the tumor to JAK inhibition. A subset of the activated tumor promoting genes are known transcriptional targets of the NF-κB transcription factor pathway. We hypothesize that JAK inhibition activates tumor-promoting pathways in TAMs through activation of the NF-κB pathway and targeting these tumor-promoting pathways in combination with JAK inhibition will be beneficial over single therapy. We aim to elucidate activation of NF-κB in TAMs, to identify the mechanism of the observed pro-tumor response. In addition, we aim to target epiregulin, an EGFR ligand which was observed to be one of the most significantly upregulated genes in TAMs treated with JAK inhibitor. We hypothesize that targeting effects of macrophage-derived epiregulin in combination with JAK inhibition will overcome macrophage-mediated therapeutic resistance. This work will provide useful information about novel pathways that can be targeted to combat the compensatory negative effects of TAMs on tumor-targeted therapies. The results will also pave the way for development of novel inhibitor combinations targeting the tumor microenvironment in addition to targeting the tumor, and ultimately benefit patients who do not respond to single therapies. Citation Format: Aditi S. Bapat, Emily Jesser, Chelsea Lassiter, Kaylee Schwertfeger. Role of NF-κB and epiregulin in tumor-associated macrophages promoting therapeutic resistance to JAK inhibition [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO017.
Abstract P357: The Association between Sleep and Waist Circumference Varies among Women as a Function of Race and Ethnicity
Authors: Nour Makarem, Ming Liao, Brooke Aggarwal
Journal: Circulation (2017)

Background: Waist circumference (WC) is an established predictor of global 10-y risk for cardiovascular disease (CVD). Sleep duration and quality have also been associated with CVD risk. The association between sleep and WC and how it may vary among racially/ethnically diverse women has not been fully established. Hypothesis: We assessed the hypothesis that sufficient sleep duration (≥6 h), good sleep quality, and lower insomnia severity would be associated with reduced WC and that associations would vary by race/ethnicity. Methods: Participants were English or Spanish speaking females (n=50), aged 20-79y, recruited as visitors of patients or members of the community surrounding an urban medical center, as part of the American Heart Association Go Red for Women Strategically Focused Research Network. Sleep duration and quality were assessed using the Pittsburgh Sleep Quality Index, and insomnia was assessed using the Insomnia Severity Index (ISI). Anthropometric measures were obtained by trained personnel. A standardized health questionnaire was used to obtain medical and demographic data. Linear regression models were used to evaluate cross-sectional associations between sleep patterns and WC in the overall sample and stratified by race/ethnicity. Results: The mean age of the sample was 41±18y and 56% (28 of 50) were racial/ethnic minorities. The mean body mass index (BMI) was 26.0±4.5 kg/m 2 and half of women had a BMI ≥25 kg/m 2 . One third were current/former smokers, 36% (18 of 50) were postmenopausal and 60% (30 of 50) reported a history of chronic disease. In the overall sample, a sleep duration of &lt;6 versus ≥6 h was associated with higher WC in univariate (beta(SE)=4.90(1.44), p=.001) and multivariable models adjusted for age, race/ethnicity, education, marital status, menopausal status and history of chronic disease (beta(SE): 4.38(1.76), p=.02). In analyses stratified by race/ethnicity, null associations between sleep duration and WC were observed for non-Hispanic whites in univariate (beta(SE)=3.30(2.19), p=.15) and multivariable-adjusted models (beta(SE)=0.97(2.68), p=.72). However, among racial/ethnic minorities, a sleep duration &lt;6 versus ≥6 h was associated with higher WC in both univariate (beta(SE)=5.65(1.07), p=.01) and multivariable-adjusted models (beta(SE)=6.68(2.12), p=.01). In general, the mean WC among minority women who slept &lt;6 versus ≥6 h was 41.1 versus 35.5 inches (p=.03). Sleep quality and ISI were not significantly associated with WC. Conclusions: In this diverse sample of women, sleeping for ≥6 h/night had a protective impact on WC, particularly among minority women. These preliminary findings suggest that minority women with insufficient sleep may be particularly prone to central adiposity, thereby predisposing them to increased CVD risk. Analyses are ongoing to confirm these results in a larger sample.
Addressing financial toxicity in urologic oncology patients.
Authors: Divya Ahuja Parikh, Sandy Srinivas, Elizabeth Kerr, Manali I. Patel
Journal: Journal of Clinical Oncology (2021)

170 Background: Financial toxicity, or the financial burden related to cancer care, is a source of distress for urologic oncology patients. This study aimed to address financial toxicity among prostate, kidney and bladder cancer patients and test the feasibility of a lay-health worker (LHW) and social work (SW) driven intervention. Methods: LHW assessed financial burden in urologic oncology patients with advanced cancer who presented for return visits at a single academic center. The LHW collected responses to three statements on a Likert scale – “I worry about the financial problems I will have in the future because of my illness or treatment”, “My cancer or treatment has reduced satisfaction with my present financial situation”, and “I feel financially stressed”. Patients who responded, “Very much” (4) or “Quite a bit” (3) to all statements were offered a one-on-one consultation with a trained SW. The SW provided personalized recommendations after review of patients' financial information, insurance status, and out of pocket costs. SW referred patients to appropriate support services including those offered by the hospital, government, nonprofits and private corporations. Pre-specified outcomes included pre/post-intervention financial toxicity and patient satisfaction with the intervention. Results: 145 patients (67%) agreed to be screened for financial toxicity by the LHW. Most participants were White (n = 100, 69%), male (n = 130, 90%), married (n = 104, 72%) and with incomes &gt; $100,000 (n = 111, 77%). The majority had prostate cancer (n = 87, 60%), followed by kidney cancer (n = 36, 25%) and bladder cancer (n = 22, 15%). 12% (n = 26) responded “I worry about the financial problems I will have in the future because of my illness or treatment”, “Very much” or “Quite a bit”. 14% (n = 20) responded “My cancer or treatment has reduced satisfaction with my present financial situation”, “Very much” or “Quite a bit”. 12% (n = 17) reported “I feel financially stressed”, “Very much” or “Quite a bit”. A total of 14 patients were eligible for the intervention and were referred for a one-on-one SW consultation. Post-intervention results indicated excellent patient satisfaction with the intervention and a significant improvement in financial toxicity. 100% of patients reported the SW “provided financial resources that were beneficial to me”, and 78% (n = 11) had a decrease in financial toxicity score post-intervention (average decrease = -1, p = 0.05038). Conclusions: In this single institution study of prostate, kidney and bladder cancer patients with overall low baseline financial burden a LHW and SW driven intervention was feasible and effective in reducing financial toxicity.
Increased day‐to‐day fluctuations in exhaled breath profiles after a rhinovirus challenge in asthma
Authors: Ariana Lammers, Paul Brinkman, Louwrina H. te Nijenhuis, Rianne de Vries, Yennece W. F. Dagelet, Erik Duijvelaar, Binbin Xu, Mahmoud I. Abdel‐Aziz, Susanne J. Vijverberg, Anne H. Neerincx, Urs Frey, Rene Lutter, Anke H. Maitland‐van der Zee, Peter J. Sterk, Anirban Sinha
Journal: Allergy (2021)

Early detection/prediction of flare-ups in asthma, commonly triggered by viruses, would enable timely treatment. Previous studies on exhaled breath analysis by electronic nose (eNose) technology could discriminate between stable and unstable episodes of asthma, using single/few time-points. To investigate its monitoring properties during these episodes, we examined day-to-day fluctuations in exhaled breath profiles, before and after a rhinovirus-16 (RV16) challenge, in healthy and asthmatic adults.In this proof-of-concept study, 12 atopic asthmatic and 12 non-atopic healthy adults were prospectively followed thrice weekly, 60 days before, and 30 days after a RV16 challenge. Exhaled breath profiles were detected using an eNose, consisting of 7 different sensors. Per sensor, individual means were calculated using pre-challenge visits. Absolute deviations (|%|) from this baseline were derived for all visits. Within-group comparisons were tested with Mann-Whitney U tests and receiver operating characteristic (ROC) analysis. Finally, Spearman's correlations between the total change in eNose deviations and fractional exhaled nitric oxide (FeNO), cold-like symptoms, and pro-inflammatory cytokines were examined.Both groups had significantly increased eNose fluctuations post-challenge, which in asthma started 1 day post-challenge, before the onset of symptoms. Discrimination between pre- and post-challenge reached an area under the ROC curve of 0.82 (95% CI = 0.65-0.99) in healthy and 0.97 (95% CI = 0.91-1.00) in asthmatic adults. The total change in eNose deviations moderately correlated with IL-8 and TNFα (ρ ≈ .50-0.60) in asthmatics.Electronic nose fluctuations rapidly increase after a RV16 challenge, with distinct differences between healthy and asthmatic adults, suggesting that this technology could be useful in monitoring virus-driven unstable episodes in asthma.
Abstract 16416: Associations of NT-proBNP and High Sensitivity Cardiac Troponin T Concentrations With 6-year Changes in Left Ventricular Structure and Function in Older Adults: The Atherosclerosis Risk in Community (ARIC) Study
Authors: Peder L Myhre, Brian Claggett, Christie M Ballantyne, Elizabeth Selvin, Kunihiro Matsushita, Dalane W Kitzman, Suma H Konety, Thomas Mosley, Amil M Shah
Journal: Circulation (2020)

Introduction: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) improve prediction of incident heart failure (HF) and are cross-sectionally associated with left ventricular (LV) remodeling, but their associations with changes in cardiac structure and function are unclear. Hypothesis: Concentrations of NT-proBNP and hs-cTnT associate with 6-year change in cardiac structure in older adults. Methods: We studied 1,916 participants aged 67-88 in the ARIC Study free of overt cardiovascular disease at baseline (study Visit 5; 2011-13). We quantified the associations of baseline NT-proBNP and hs-cTnT with subsequent changes in LV structure and systolic and diastolic function assessed by echocardiography over a median of 6.6 (IQR 6.1-7.0) years using multivariable linear regression and restricted cubic spline models. Models adjusted for demographics, systolic blood pressure, heart rate, body mass index, diabetes, hypertension, kidney function, and the baseline echocardiographic value of interest at Visit 5. Results: Mean age was 75±4 years, 60% were female, 23% were black, median hs-cTnT was 9 (IQR 6-13) ng/L and NT-proBNP was 88 (50-157) ng/L at Visit 5. In adjusted models, higher hs-cTnT was modestly associated with 6-year increase in LV wall thickness (p=0.02) but not with changes in LV function. In contrast, higher NT-proBNP at Visit 5 was associated with 6-year increase in LV mass, decline in LV systolic function (ejection fraction, longitudinal and circumferential strain), and worsening of diastolic function (left atrium volume, E/e’, tricuspid regurgitation peak velocity) (all p&lt;0.01, Figure ). These associations were non-linear. Conclusions: Higher NT-proBNP, but not hs-cTnT, concentrations are associated with greater declines in LV systolic and diastolic function over ~6 years in late life.
Three-dimensional decellularized tumor extracellular matrices with different stiffness as bioengineered tumor scaffolds
Authors: Yonggang Lv, Hongjun Wang, Gui Li, Boyuan Zhao
Journal: Bioactive Materials (2021)

In the three-dimensional (3D) tumor microenvironment, matrix stiffness is associated with the regulation of tumor cells behaviors. In vitro tumor models with appropriate matrix stiffness are urgently desired. Herein, we prepare 3D decellularized extracellular matrix (DECM) scaffolds with different stiffness to mimic the microenvironment of human breast tumor tissue, especially the matrix stiffness, components and structure of ECM. Furthermore, the effects of matrix stiffness on the drug resistance of human breast cancer cells are explored with these developed scaffolds as case studies. Our results confirm that DECM scaffolds with diverse stiffness can be generated by tumor cells with different lysyl oxidase (LOX) expression levels, while the barely intact structure and major components of the ECM are maintained without cells. This versatile 3D tumor model with suitable stiffness can be used as a bioengineered tumor scaffold to investigate the role of the microenvironment in tumor progression and to screen drugs prior to clinical use to a certain extent.
Co-encapsulation of Cas9 mRNA and guide RNA in polyplex micelles enables genome editing in mouse brain
Authors: Saed Abbasi, Satoshi Uchida, Kazuko Toh, Theofilus A. Tockary, Anjaneyulu Dirisala, Kotaro Hayashi, Shigeto Fukushima, Kazunori Kataoka
Journal: Journal of Controlled Release (2021)
Comprehensive Molecular Characterization and Response to Therapy in Fumarate Hydratase–Deficient Renal Cell Carcinoma
Authors: Jack P. Gleeson, Ines Nikolovski, Renzo Dinatale, Mark Zucker, Andrea Knezevic, Sujata Patil, Yasser Ged, Ritesh R. Kotecha, Natalie Shapnik, Samuel Murray, Paul Russo, Jonathan Coleman, Chung Han Lee, Zsofia K. Stadler, A. Ari Hakimi, Darren R. Feldman, Robert J. Motzer, Ed Reznik, Martin H. Voss, Ying-Bei Chen, Maria I. Carlo
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Fumarate hydratase–deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking. Experimental Design: We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic FH mutation plus IHC evidence of FH loss, were included. Results: A total of 28 of 32 included patients (median age 46; range, 20–74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic FH germline variant. Five (16%) were negative for germline FH mutations; all had biallelic somatic FH loss. Somatic NGS (31/32 patients) revealed co-occurring NF2 mutation most frequently (n = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; P &amp;lt; 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; P = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n = 18, ORR 44%), VEGF monotherapy (n = 15, ORR 20%), checkpoint inhibitor therapy (n = 8, ORR 0%), and mTOR monotherapy (n = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3–33.8] and 8.7 months (95% CI: 4.8–12.3), respectively. Conclusions: Although most FH-RCC tumors are due to germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.