tbuckley/cabot-search huggingface dataset:
Dichotomous and stable gamma delta T-cell number and function in healthy individuals
Authors: Lingling Ou, Huaishan Wang, Qin Liu, Jie Zhang, Hezhe Lu, Liangping Luo, Changzheng Shi, Shaoqiang Lin, Liyun Dong, Yeye Guo, Lili Huang, Jinjin Zhu, Xiangfan Yin, Alexander C Huang, Giorgos Karakousis, Lynn Schuchter, Ravi Amaravadi, Cathy Zheng, Yi Fan, Wei Guo, Xiaowei Xu
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Gamma-delta (γδ) T lymphocytes are primed to potently respond to pathogens and transformed cells by recognizing a broad range of antigens. However, adoptive immunotherapy with γδT cells has exhibited mixed treatment responses. Better understanding of γδT cell biology and stratifying healthy donors for allogeneic adoptive therapy is clinically needed to fully realize the therapeutic potential of γδT cells. Methods We examine 98 blood samples from healthy donors and measure their expansion capacity after zoledronate stimulation, and test the migration and cytotoxic effector function of expanded γδT cells in 2D culture, 3D tumor spheroid and patient-derived melanoma organoid assays. Results We find that γδT cell expansion capacity is independent of expansion methods, gender, age and HLA type. Basal γδT cell levels in Peripheral blood mononuclear cell (PBMC) correlate well with their expansion, migration and cytotoxic effector capacity in vitro. Circulating γδT cells with lower expression of PD-1, CTLA-4, Eomes, T-bet and CD69, or higher IFN-γ production expand better. γδT cells with central memory and effector memory phenotypes are significantly more abundant in good expanders. A cut-off level of 0.82% γδT cells in PBMC stratifies good versus poor γδT cell expansion with a sensitivity of 97.78%, specificity of 90.48% and area under the curve of 0.968 in a healthy individual. Donors with higher Vδ2 Index Score in PBMC have greater anti-tumor functions including migratory function and cytotoxicity. Conclusions Our results demonstrate that the interindividual γδT cell functions correlate with their circulating levels in healthy donors. Examination of circulating γδT cell level may be used to select healthy donors to participate in γδT-based immunotherapies.
Genetic screening of children with marrow failure. The role of primary Immunodeficiencies
Authors: Maurizio Miano, Alice Grossi, Gianluca Dell'Orso, Marina Lanciotti, Francesca Fioredda, Elena Palmisani, Tiziana Lanza, Daniela Guardo, Andrea Beccaria, Silvia Ravera, Vanessa Cossu, Paola Terranova, Fiorina Giona, Michelina Santopietro, Enrico Cappelli, Isabella Ceccherini, Carlo Dufour
Journal: American Journal of Hematology (2021)

Abstract The differential diagnosis of marrow failure (MF) is crucial in the diagnostic work‐up, since genetic forms require specific care. We retrospectively studied all patients with single/multi‐lineage MF evaluated in a single‐center to identify the type and incidence of underlying molecular defects. The diepoxybutane test was used to screen Fanconi Anemia. Other congenital MFs have been searched using Sanger and/or Next Generation Sequencing analysis, depending on the available tools over the years. Between 2009–2019, 97 patients (aged 0–32 years‐median 5) with single‐lineage (29%) or multilineage (68%) MF were evaluated. Fifty‐three (54%) and 28 (29%) were diagnosed with acquired and congenital MF, respectively. The remaining 16 (17%), with trilinear (n=9) and monolinear (n=7) MF, were found to have an underlying primary immunodeficiency (PID) and showed clinical and biochemical signs of immune‐dysregulation in 10/16 (62%) and in 14/16 (87%) of cases, respectively. Clinical signs were also found in 22/53 (41%) and 8/28 (28%) patients with idiopathic and classical cMF, respectively. Eight out of 16 PIDs patients were successfully transplanted, four received immunosuppression, two did not require treatment, and the remaining two died. We show that patients with single/multi‐lineage MF may have underlying PIDs in a considerable number of cases and that MF may represent a relevant clinical sign in patients with PIDs, thus widening their clinical phenotype. An accurate immunological work‐up should be performed in all patients with MF, and PID‐related genes should be considered when screening MF in order to identify disorders that may receive targeted treatments and/or appropriate conditioning regimens before transplant.
Molecular mechanism of vasculogenic mimicry
Authors: Caterina A. Laporta, Silvia De Biasi, Stefania Rao, Umberto Fascio, Martin C. Mihm, Claudio Clemente
Journal: Cancer Research (2004)

4944  Vasculogenic mimicry (VM) has stimulated considerable discussion and debate in the literature. In the present paper, we confirm the presence of VM in BL6 murine metastatic cells and human WM115 primary melanoma cells grown subcutaneously in syngeneic or SCID mice, respectively. Both cells show vascular spaces lined only by melanoma cells positive for VE-cadherin and HMB-45, typical markers of endothelial and melanoma cells, respectively. Furthermore, in vitro, human primary WM115 melanoma cells and WM266 metastatic cells as well as murine BL6 metastatic melanoma cells are able to form a pattern of cord like networks resembling endothelial cells; all such cells are positive for VE-cadherin. Furthermore, a positive signal for AQP1, a water channel protein involved in angiogenesis, is found in all the cells grown either in vitro or in vivo. Taken together, our results show that vessels lined by HMB45 positive melanoma cells express VE-cadherin and AQP1. This might facilitate vacuolisation and tube formation. In addition, at least in vitro, our findings show that VM occurs both in primary and metastatic human melanoma cells.
Effect of Granulocyte Colony-Stimulating Factor as a non-invasive regeneration therapy for patients with intractable chronic ischemic heart disease by myocardial perfusion scintigraphy
Authors: Suzuki K, Nagashima K, Arai M, Nishigaki K, Uno Y, Takemura G, Minatoguchi S, Gotoh K, Fujiwara H
Journal: Circulation (2003)
Abstract 16808: Divergent Mature Vascular Smooth Muscle Cell Fates Are Directed by Platelet-Derived Transcriptomic Codes in Aortic Aneurysms
Authors: Tarik HADI, Michele Silvestro, Cristobal Rivera Martinez, Rayan Sleiman Tellaoui, ariadne zias, Bhama Ramkhelawon
Journal: Circulation (2020)

Introduction: Loss of vascular smooth-muscle cells (vSMC) and subsequent defective replenishment of functional vSMC de novo are pathological hallmarks of abdominal aortic aneurysm (AAA). Evidence suggests that clusters of progenitors can be reprogrammed into vSMC lineage following vascular injury. However, the landscape of vSMC precursors and reprograming signatures that determine their fate in AAA is undefined. Hypothesis: We hypothesize that quiescent progenitor pools reside in aorta and undergo spatiotemporal fate decision into mature vSMC in AAA. We speculate that distinct ligand-receptor and transcriptional signals gear their pathogenic trajectories into dysfunctional vSMC in AAA. Methods &amp; Results: Single-cell RNA-sequencing (scRNA-seq) identified vascular progenitor cells (Cd34 + Pdgfrα+) in murine (angiotensin II-induced) and human AAA. Pseudotime analysis tracked two differentiation fates of progenitors into divergent mature vSMC pools characterized by enrichment in contractile cytoskeleton machinery (Acta2 + Myh11 + ) or abnormally supplemented with matrix remodeling genes (Mmp2 + Col8a1 + ). Mmp2 + Col8a1 + clusters were dominant in AAA suggesting pathological reprograming in AAA. Gene regulatory network analysis mapped distinct libraries of upstream transcription factors in each mature vSMC states in AAA. Acta2 + Myh11 + and Mmp2 + Col8a1 + transcriptomes were driven by opposing actions of Pparγ and its repressor Runx1 respectively. Interestingly, cellular interaction analysis revealed that platelet-derived Pdgfβ fueled the phenotypic switch into Mmp2 + Col8a1 + vSMC via its receptor Pdgfrα. Dampening Pdgfrα signaling by systemic platelet depletion repressed Runx1 activation thereby increasing Pparγ transcriptomic activity in progenitors in the aortic wall. This rescued functional regeneration of vSMC (Acta2 + Myh11 + ) with contractile properties consistent with reduced aortic damage and diminished AAA incidence. Conclusions: Our data demonstrate that platelets are novel actors capable of awakening progenitor pools by coding their fate into pathogenic vSMC lineage in AAA. We provide evidence suggesting that strategies aimed at sustaining vSMC contractile destiny could encourage repair of vascular damage in AAA.
NOTCH3-targeted antibody drug conjugates regress tumors by inducing apoptosis in receptor cells and through transendocytosis into ligand cells
Authors: Kenneth G. Geles, Yijie Gao, Andreas Giannakou, Latha Sridharan, Ting-Ting Yamin, Jing Zhang, Riyez Karim, Joel Bard, Nicole Piche-Nicholas, Manoj Charati, Andreas Maderna, Judy Lucas, Jonathon Golas, Magali Guffroy, Steven Pirie-Shepherd, Marc Roy, Jessie Qian, Tania Franks, Wenyan Zhong, Christopher J. O’Donnell, Lioudmila Tchistiakova, Hans-Peter Gerber, Puja Sapra
Journal: Cell Reports Medicine (2021)

Aberrant NOTCH3 signaling and overexpression is oncogenic, associated with cancer stem cells and drug resistance, yet therapeutic targeting remains elusive. Here, we develop NOTCH3-targeted antibody drug conjugates (NOTCH3-ADCs) by bioconjugation of an auristatin microtubule inhibitor through a protease cleavable linker to two antibodies with differential abilities to inhibit signaling. The signaling inhibitory antibody rapidly induces ligand-independent receptor clustering and internalization through both caveolin and clathrin-mediated pathways. The non-inhibitory antibody also efficiently endocytoses via clathrin without inducing receptor clustering but with slower lysosomal co-localization kinetics. In addition, DLL4 ligand binding to the NOTCH3 receptor mediates transendocytosis of NOTCH3-ADCs into ligand-expressing cells. NOTCH3-ADCs internalize into receptor and ligand cells independent of signaling and induce cell death in both cell types representing an atypical mechanism of ADC cytotoxicity. Treatment of xenografts with NOTCH3-ADCs leads to sustained tumor regressions, outperforms standard-of-care chemotherapy, and allows targeting of tumors that overexpress NOTCH3 independent of signaling inhibition.
Use of Circulating Tumor DNA for the Clinical Management of Metastatic Castration-Resistant Prostate Cancer: A Multicenter, Real-World Study
Authors: Baijun Dong, Liancheng Fan, Bin Yang, Wei Chen, Yonghong Li, Kaijie Wu, Fengbo Zhang, Haiying Dong, Huihua Cheng, Jiahua Pan, Yinjie Zhu, Chenfei Chi, Liang Dong, Jianjun Sha, Lei Li, Xudong Yao, Wei Xue
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: This study aimed to describe the aberrations of DNA damage repair genes and other important driving genes in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating tumor (ctDNA) sequencing and to evaluate the associations between the clinical outcomes of multiple therapies and key genomic alterations in mCRPC, especially DNA damage repair genes. Patients and Methods: A total of 292 Chinese patients with mCRPC enrolled from 8 centers. Multigene targeted sequencing was performed on 306 ctDNA samples and 23 matched tumor biopsies. The frequency of genomic alterations were compared with the Stand Up to Cancer–Prostate Cancer Foundation (SU2C-PCF) cohort. The Kaplan-Meier method was used to evaluate progression-free survival (PFS) following standard systemic treatments for mCRPC. Cox regression analyses were performed to determine prognostic factors associated with PFS resulting from treatments for mCRPC. Results: In total, 33 of 36 (91.7%) mutations were found consistently between ctDNA and paired biopsy samples. The most common recurrent genomic alterations were found in AR (34.6%), TP53 (19.5%), CDK12 (15.4%), BRCA2 (13%), and RB1 (5.8%). The frequency of CDK12 alterations (15.4%) in our cohort was significantly higher than that in Western populations (5%–7%). AR amplification and TP53 and/or RB1 alterations were associated with resistance to abiraterone or docetaxel. Patients with a CDK12 defect showed rapid disease progression after abiraterone treatment. However, the clinical outcome after docetaxel treatment was similar between patients with and without CDK12 defects. In multivariate Cox regression analysis, a CDK12 defect was significantly associated with inferior PFS after abiraterone treatment. Patients with a BRCA2 defect showed marked response to both PARP inhibitors and platinum-based chemotherapy. Conclusions: Our study explored the genomic landscape of Chinese patients with mCRPC at different treatment stages using minimally invasive methods and evaluated the clinical implications of the driver genomic alterations on patients’ response to the most widely used therapies for mCRPC. We observed a significantly higher alteration frequency of CDK12 in our cohort compared with the SU2C-PCF cohort.
Abstract P029: Non-high Density Lipoprotein Is A Residual Risk For The Progression Of Endothelial Dysfunction In Patients With Well Controlled Low-density Lipoprotein Cholesterol: Multicenter Prospective Study FMDJ Study
Authors: Chisa Matsumoto, Hirofumi Tomiyama, Taishiro Chikamori
Journal: Circulation (2021)

Introduction: Recently, several guidelines suggest the usefulness of non-high density lipoprotein cholesterol (non-HDLC) as a secondary treatment target for CVD prevention, next to low-density lipoprotein cholesterol (LDLC). However, its effect on endothelial dysfunction have not been fully clarified. The objective of this multicenter-prospective-observational study, FMD-J Study, is to evaluate whether non-HDLC is a residual risk for the progression of endothelial dysfunction in patients with hypertension. Hypothesis: Non-HDLC is a residual risk for the progression of endothelial dysfunction in patients with hypertension. Methods: 633 treated hypertensive patients (mean age 62±9 years) in the FMD-J study were followed for 3 years. Endothelial function was evaluated by the change of flow mediated vasodilation (FMD). Multivariate regression analysis adjusted for established coronary heart disease (CHD) risk factors (sex, age, BMI, systolic blood pressure, heart rate, fasting blood glucose, high density lipoprotein cholesterol, baseline FMD, current smoking, treatment of diabetes, and treatment of dyslipidemia) was performed to evaluate whether LDLC and non-HDLC were associated with the change of FMD. We also performed secondary analysis to evaluate whether non-HDLC is associated with progression of endothelial dysfunction in patients with well controlled LDLC level according to their CHD risk. CHD risk was evaluated by Suita score, which is established risk score to assess the 10-year risk of CHD for the Japanese population. (High-risk: 56≦Suita score, Mid-risk: 41≦Suita score≦55, Low-risk: Suita score≦40) Target controlled LDLC levels according to CHD risk were defined as follows; High-risk: LDLC&lt;70 mg/dl, Mid-risk: LDLC&lt;100 mg/dl, Low-risk: LDLC&lt;70 mg/dl. Results: Mean change of FMD after 3 years was 0.07±2.97% and mean Suita score was 46.4±8.9. Overall, both higher LDLC and non-HDLC was significantly associated with impairment of FMD. (Adjusted 1SD increase of LDLC; β: -0.26±0.11, P=0.02, Adjusted 1SD increase of non-HDLC; β: -0.25±0.11, P=0.03 ). In secondary analysis, 97 patients’ LDLC reached target LDLC level according to CHD risk. Among LDLC controlled group, higher non-HDLC was significantly associated with impairment of FMD. (Adjusted 1SD increase of non-HDLC; β: -0.75±0.13, P=0.02). However, among 536 patients whose LDLC did not reach target LDLC value, non-HDLC was not associated with the change pf FMD. (Adjusted 1SD increase of non-HDLC; β: -0.15±0.12, P=0.20). Conclusions: Non-HDLC may be a residual risk for the progression of endothelial dysfunction in patients with hypertension, especially in hypertensive patients with well controlled LDLC.
Abstract 070: Community-based, Cluster Randomized Controlled Trial Increases Physical Activity In Diverse, Low Income Older Adults Over 2-year Period
Authors: Katie Crist, Fatima Tuz Zahra, Kelsie M Full, Marta M Jankowska, Loki Natarajan
Journal: Circulation (2021)

Objective: Older adults are the least active population group in the U.S. Low income and ethnically diverse communities have fewer physical activity (PA) related resources and facilities, which contributes to lower PA levels and disparities in cardiovascular (CVD) risk factors and disease outcomes. This study assessed the hypothesis that low income and diverse older adults participating in the multilevel Peer Empowerment Program 4 Physical Activity (PEP4PA) would increase moderate-to-vigorous PA (MVPA), improve blood pressure (BP), perceived quality of life (PQoL), and depressive symptoms to a greater extent than older adults receiving usual senior center programming. Methods: In a cluster-randomized controlled trial (RCT) in 12 senior centers, 476 older adults (mean age 71.4 years, 76% female, 60% low income, 38% minority) were assigned to a PA intervention (n=267) or control (n=209) condition. The peer-led intervention included individual self-monitoring and counseling, group walks and social support, and community advocacy to improve walking conditions. Outcomes included minutes of MVPA per day (7-day accelerometer), systolic and diastolic BP (automatic cuff), PQoL (PQoL-20) and depressive symptoms (CES-D 10) at baseline, 6, 12, 18 and 24 months. To account for multiple measurement days and clustering of participants within senior centers, mixed effects regression models with random effects estimated the intervention effects on all outcomes between groups over time. Models were adjusted for imbalanced baseline covariates. A three-way interaction term assessed whether intervention effects differed by income status. Results: Compared to the control group, intervention participants significantly increased MVPA from baseline at 6, 12, 18 and 24 months by 8, 11, 9 and 9 minutes/day respectively (p&lt;0.001), with increases remaining statistically significant across the 2-year period. The intervention group significantly increased mean PQoL scores from 7.2 at baseline to 7.6 (p&lt;0.001), 7.8 (p=0.008) and 7.7 (p&lt;0.001) at 12, 18 and 24 months, compared to control participants. No significant effects were observed for BP or depressive symptoms. Low income participants decreased minutes of MVPA, compared to higher income participants, at 12 and 24 months (β=-7.9, p=0.008 and β=-10.8, p=0.001). Conclusions: The multilevel RCT achieved sustained increases in MVPA and QoL in a diverse cohort of older adults across 2 years of follow up. The peer-led, community-based intervention provides a sustainable model to improve health behaviors related to CVD in an at-risk and often difficult to reach aging population. Further exploration is needed to understand what components of the intervention may be modified to address the differential effects by income status.
Abstract 17084: Nuclear Smooth Muscle α-actin Participates in Chromatin Remodeling at Smooth Muscle Contractile Gene Promoters
Authors: Callie Kwartler, Shuangtao Ma, Caroline Kernell, Xue-yan Duan, Charis Wang, Jiyuan Chen, Xuetong Shen, Dianna M Milewicz
Journal: Circulation (2020)

Actin genes encode for cytoskeletal proteins that polymerize to function in cellular motility, adhesion, and contraction. In mammalian cells, ubiquitously expressed β-actin also moves into the nucleus and associates with chromatin remodeling complexes, however a nuclear function of muscle-specific α-actins has not been previously assessed. We hypothesized that smooth muscle α-actin (SMA) plays a role in chromatin remodeling during the differentiation of smooth muscle cells (SMCs) to enable cell fate specification of SMCs. In explanted SMCs from human and mouse ascending aortas, cell fractionation and 2D gel electrophoresis identify both SMA and β-actin in the nuclear lysates. Nuclear SMA but not β-actin accumulates with SMC differentiation driven by serum starvation and transforming growth factor-β1 treatment. SMA accumulates into the nucleus early in the differentiation of SMCs from neural crest progenitor cells, prior to cytosolic accumulation. Immunoprecipitation studies show that SMA binds specifically to the INO80 and the SWI/SNF chromatin remodeling complexes, and this binding increases with SMC differentiation. Chromatin immunoprecipitation reveals that SMA is bound to the promoters of SMC-specific genes, including Acta2 , Cnn1, and Myh11 and that SMA is enriched over β-actin at these promoters with SMC differentiation. Finally, overexpression of SMA tagged with a nuclear localization sequence (NLS) in multiple cell types increases expression of SMC markers, whereas NLS-tagged β-actin localizes to the nucleus to the same extent but does not increase SMC marker expression in any cell type. Finally, we assessed whether skeletal muscle α-actin (SKA) and cardiac muscle α-actin (CMA) may play a similar role in skeletal and cardiac muscle cells. Both SKA and CMA translocate into the nucleus. CMA accumulates into the nucleus early in the differentiation of cardiomyocytes from pluripotent stem cells. Immunoprecipitation reveals that SKA binds to the SWI/SNF complex in differentiated C2C12 myotube cell cultures. These data support that nuclear SMA enriches with and participates in SMC differentiation, and suggest a potential nuclear role for other muscle specific α-actins in developing muscle cells.
Abstract P122: Cardiovascular Fat And Cognitive Function Among Perimenopausal Women: The Study Of Women’s Health Across The Nation Cardiovascular Fat And Heart Ancillary Studies
Authors: Meiyuzhen Qi, Matthew Budoff, Imke Janssen, Kelly Shields, Emma Barinas-Mitchell, Samar R El Khoudary
Journal: Circulation (2021)

Objective: Women experienced disproportionated prevalence of dementia and higher risk of cardiovascular disease (CVD) after menopause. Cardiovascular fat (CF) which is associated with CVD may impact cognitive function through vascular pathology. Perimenopausal women had more CF compared with pre/early perimenopausal women. However, research on the association between CF volume, density and cognitive function among perimenopausal women is limited. We aimed to assess associations of CF volume and density with future cognitive function among midlife women. Design: Midlife women with measures of CF volume and density along with cognitive function measured 1.46 (SD=0.68) years later were evaluated. Computed tomographic scans were used to quantify volume and density of total heart adipose tissue (TAT), EAT, and perivascular adipose tissue (PVAT) of the descending aorta. Digit span backward test, East Boston memory test, and symbol digit modalities test were used to test working memory, verbal episodic memory, and processing speed, respectively. The relationship between each CF measurement and each cognitive function metric was assessed separately with linear regression models. Final models included age, education level, race, menopausal status, waist hip ratio, number of cognitive tests conducted before the included test, and fat density for corresponding fat volume or fat volume for corresponding fat density. Results: Three hundred and eighty-five women (mean age of 50.6 (SD=2.4) years old; 29.2% post-menopausal) were included. In the final models (Table), higher EAT and TAT density were significantly associated with a higher processing speed and immediate episodic memory, respectively. However, there was a significant negative association between PVAT density and working memory. Conclusion: Our findings suggest an association between CF radio-density and future cognitive function in midlife women, which may differ by cardiovascular fat location (heart vs. vasculature).