tbuckley/cabot-search huggingface dataset:
Single-Cell RNA Profiling of Glomerular Cells Shows Dynamic Changes in Experimental Diabetic Kidney Disease
Authors: Jia Fu, Kemal M. Akat, Zeguo Sun, Weijia Zhang, Detlef Schlondorff, Zhihong Liu, Thomas Tuschl, Kyung Lee, John Cijiang He
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Although transcriptomic profiling of kidney tissues or isolated glomeruli has provided insights into broad changes in the pathogenesis of diabetic kidney disease, the presence of multiple cell types in kidney samples limits what can be discerned about changes in specific types of cells. To better elucidate the mechanisms of early diabetic kidney injury, the authors used single-cell RNA sequencing technology to perform a gene expression analysis of individual kidney glomerular cells of a diabetic mouse model. A comparison of gene expression in normal versus diabetic mouse kidney cells at a single-cell level showed dynamic changes in the pattern of expressed genes. This approach may help identify important factors underlying the pathophysiology of diabetic kidney disease progression and point to potential new therapeutic approaches. Background Recent single-cell RNA sequencing (scRNA-seq) analyses have offered much insight into cell-specific gene expression profiles in normal kidneys. However, in diseased kidneys, understanding of changes in specific cells, particularly glomerular cells, remains limited. Methods To elucidate the glomerular cell–specific gene expression changes in diabetic kidney disease, we performed scRNA-seq analysis of isolated glomerular cells from streptozotocin-induced diabetic endothelial nitric oxide synthase (eNOS)–deficient (eNOS −/− ) mice and control eNOS −/− mice. Results We identified five distinct cell populations, including glomerular endothelial cells, mesangial cells, podocytes, immune cells, and tubular cells. Using scRNA-seq analysis, we confirmed the expression of glomerular cell–specific markers and also identified several new potential markers of glomerular cells. The number of immune cells was significantly higher in diabetic glomeruli compared with control glomeruli, and further cluster analysis showed that these immune cells were predominantly macrophages. Analysis of differential gene expression in endothelial and mesangial cells of diabetic and control mice showed dynamic changes in the pattern of expressed genes, many of which are known to be involved in diabetic kidney disease. Moreover, gene expression analysis showed variable responses of individual cells to diabetic injury. Conclusions Our findings demonstrate the ability of scRNA-seq analysis in isolated glomerular cells from diabetic and control mice to reveal dynamic changes in gene expression in diabetic kidneys, with variable responses of individual cells. Such changes, which might not be apparent in bulk transcriptomic analysis of glomerular cells, may help identify important pathophysiologic factors contributing to the progression of diabetic kidney disease.
Treatment patterns and outcomes for metastatic castration-resistant prostate cancer (mCRPC) in a real-world setting: A retrospective study of greater than 2500 patients.
Authors: Celestia S. Higano, Cora N. Sternberg, Fred Saad, Bertrand F. TOMBAL, Kurt Miller, Jan Kalinovsky, XiaoLong Jiao, Krishna Tangirala, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2019)

256 Background: In the era of expanding therapeutic options for mCRPC, there is a growing need to develop an optimal treatment sequence. This real-world study evaluated treatment patterns and outcomes in mCRPC patients. Methods: This retrospective cohort study used the Flatiron prostate cancer core registry (Jan 2013 to Sep 2017) to assess real-world treatment patterns (lines of therapy and transitions to subsequent lines) and outcomes (overall survival, OS) in patients with mCRPC. Descriptive analysis was performed for treatment patterns, and the Kaplan–Meier method was used to analyze OS. Results: This study comprised 2559 patients with mCRPC who received up to three lines of therapy. 23% of patients did not receive a life-prolonging therapy after the initial diagnosis of mCRPC. In the first-line (1L) setting, abiraterone (Abi, 37%) was the most-prescribed therapy, followed by enzalutamide (Enza, 28%) and docetaxel (15%). In the second line (2L), combination therapies were frequent (17%), with rates similar to taxane-based chemotherapy (docetaxel or cabazitaxel). Enza was the most-common 2L therapy used after Abi, and vice versa. Radium-223 (Ra-223) was prescribed as 1L therapy in 5% and 2L therapy in 9% of patients, either as monotherapy or part of a combination regimen. When Ra-223 was used in the 1L setting, similar proportions of patients received subsequent therapy with Enza (14%), Abi (13%), or chemotherapy (11%). Ra-223 was commonly used in the third line (14%), but less frequently than chemotherapy (36%). After each line, ~50% of patients did not receive a subsequent life-prolonging agent. Overall, 66% of patients used bone health agents at any time (denosumab, 48%; zoledronic acid, 24%). The median OS from the diagnosis of mCRPC was 21 months. Conclusions: This real-world study shows that not all patients with mCRPC received a life-prolonging therapy. Among patients who received an anti-cancer therapy, approximately half did not receive a subsequent life-prolonging therapy. Abi and Enza were the most-common 1L therapies, and their back-to-back use was common despite reported cross-resistance and limited benefit.
Circulating miRNA signatures: a new challenge in castration-resistant prostate cancer.
Authors: Laura Noto, Maria Picciotto, Monica Currò, Tindara Franchina, Giuseppe Chiofalo, Cristina Del Re, Daniela Caccamo, Riccardo Ientile, Vincenzo Adamo
Journal: Journal of Clinical Oncology (2015)

e16100 Background: The androgen receptor (AR) signaling pathway is involved in the emergence of castration-resistant prostate cancer (CRPC). Novel biomarkers are strongly needed to improve prediction for early detection of CRPC. Accumulating evidence has shown that specific microRNAs (miRNAs) serve key functional roles in prostate cancer (PC) cells. In this study we evaluated the role of miR-141 and miR-21, in PC transition to CRPC. Methods: A total of 24 consecutive patients (pts) affected by PC (12 hormone sensitive prostate cancer-HSPC and 12 CRPC) and 20 sex matched healthy controls were included in this preliminary analysis. The putative miR-141 and miR-21 binding sites were identified by means of common algorithms, validating the involvement of these microRNAs in androgen receptor signaling pathway. miRNAs profiling was performed using Real-Time PCR. P-values < 0.05 were considered statistically significant. Clinical and pathological data were collected. Results: The expression levels of miR-141 were increased by 3.7-fold in serum samples from PC patients in comparison with controls (p = 0.029). In particular, miR-141 levels were increased by 2.4-fold (p > 0.05) and 4.2-fold (p = 0.005) in HSPC and CRPC patients, respectively, compared with controls. Interestingly, the amounts of miR-141 were also found to be 1.9-fold increased in serum samples of CRPC patients when compared to HSPC patients (p = 0.038). miR-21 was also upregulated in serum samples obtained from prostate cancer patients in comparison to those of healthy subjects, but not significantly (1.7-fold, p > 0.05). In addition, no significant differences were observed in the expression levels of miR-21 between HSPC and CRPC patients. A positive correlation was recorded between PSA levels and miR-141 amounts ( p < 0.023). Conclusions: Our preliminary data confirm a potential role for circulating miR-141 in PC and androgen resistance. These preliminary findings support the future potential of miRNAs as early predictor of disease progression and castration resistance for PC. Further validations and investigations will be needed to better define their role as useful serum biomarkers.
The change in the prevalence of wheeze, eczema and rhino‐conjunctivitis among Japanese children: Findings from 3 nationwide cross‐sectional surveys between 2005 and 2015
Authors: Mari Sasaki, Emi Morikawa, Koichi Yoshida, Yuichi Adachi, Hiroshi Odajima, Akira Akasawa
Journal: Allergy (2019)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Abstract P150: Age, Gender and Race Variations in QRS Duration in Patients With Atrial Fibrillation
Authors: Hassan Tahir, Landai Nguyen, Sarina Sachdev, Bassam Omar, G. Mustafa Awan, Christopher Malozzi, Farnoosh Rahimi
Journal: Circulation (2019)

Background: Atrial fibrillation (AF) is associated with increased incidence of congestive heart failure (CHF). While patients with intraventricular conduction delay were shown to have increased risk of atrial fibrillation, recent analysis of a study revealed increased mortality among patients with QRS 90-119 ms and AF. The demographics of QRS duration (QRSD) in AF remain under-studied. Methods: A University-based EKG database was randomly searched for 150 total EKGs: 75 EKGs were with AF; another 75 were with sinus rhythm, as a control group. Demographics, heart rate and QRSD were documented. QRSDs were retrieved from the baseline electrocardiograms of patients included in both groups, and were compared using student’s T test. Further subgroup analyses based on age, gender and race were also performed. Results: The mean QRSD in AF group was 102 ± 22 ms compared to 92 ± 19 ms in SR group (P &lt; 0.05). In patient’s &lt; 65 years of age, QRSD in AF group was 96 ± 12 ms compared to 92 ± 19 ms in SR group (P = NS); however, In patient’s ≥ 65 years of age, QRSD in AF group was 107 ± 26 ms compared to 91 ± 18 ms in SR group (P &lt; 0.05). In males, QRSD in AF group was 102 ± 22 ms compared to 89 ± 16 ms in SR group (P &lt; 0.05); however, in females, QRSD in AF group was 94 ± 21 ms compared to 93 ± 20 ms in SR group (P = NS). In white patients, QRSD in AF group was 102 ± 20 ms compared to 90 ± 14 ms in SR group (P &lt; 0.05); however, in black patients, QRSD in AF group was 104 ± 27 ms compared to 94 ± 23 ms in SR group (P = NS). Conclusion: The incidence of AF, approaching 6 million in the US, continues to rise in epidemic proportions, and is expected to double over the next few decades as the population ages. The poor rate control in AF, in addition to the loss of the atrial contraction, are two main factors thought to be responsible for symptoms and development of CHF. In our cohort, we demonstrated a significant association between AF and widened QRSD, previously shown to correlate with poor outcome in AF patients. In age analysis, the development of intraventricular conduction delay (IVCD) was significant only in the elderly with AF, who are known to be at higher risk of CHF. IVCD was also more common in white patients compared to black patients; of interest, white patients have been previously shown to develop CHF at an older age compared to black patients, suggesting that IVCD may play a role in the CHF mechanism in this subgroup with AF. In our cohort, males, but not females, had a significantly wider QRSD in AF compared to control. Our findings shed some light on a potentially new mechanism of added morbidity and mortality in AF patients, with higher prevalence in elderly white males, a subgroup which may benefit from early detection and treatment of AF and CHF. Further studies will help validate our findings in a larger cohort and in patients with CHF diagnosis.
Building a pediatric fertility preservation program.
Authors: Karen Cristly Burns, Christine L. Phillips, Olivia Jaworek, Mary Anne Lenk, Janie Benoit, Lesley Breech
Journal: Journal of Clinical Oncology (2015)

e17546 Background: Pediatric cancer patients are at risk of infertility based on their therapy. Many patients have questions about fertility regardless of risk, yet few pediatric centers have an oncofertility program. Of the 60 centers in the Oncofertility Consortium’s National Physician Collaborative, 9 are pediatric programs. In Sept 2013 we began our current Fertility Consult Service (FCS) model. We discuss risk of infertility and fertility preservation (FP) options. This includes sperm banking (SB) or testicular tissue cryopreservation (TTC) for males; oocyte/embryo freezing, or ovarian tissue cryopreservation (OTC) for females. We identified a Fertility Navigator (FN) to serve as a point of contact and coordinate services. This project looks at the ability of our program to identify patients and provide FP services. Methods: Patients new to the Division of Oncology at CCHMC were eligible. There was no age restriction. Patients were excluded for the following reasons: surgical resection, observation, palliative treatment, Phase I treatment, or second opinion/consult only; previous fertility consult / intervention; family declination. The oncology team care manager notified the FN at the time of diagnosis to initiate the consult. Patients were also identified through weekly oncology team meetings. Once a consult was requested the team saw the patient, reviewed options, and coordinated FP follow-up. Results: From Sept 2013 through Dec 2014 the FCS identified 350 patients new to the Division of Oncology. 183 were ineligible for a fertility consult (34 surgical resection, 50 observation, 22 palliative treatment, 11 Phase I, 49 second opinion, 14 previous consult / intervention, 2 declined, 1 died). Of the 167 eligible patients, 122 (73%) were seen by FCS. Consult rates improved over time. 24 (non-malignant) pre-bone marrow transplant patients were also seen by FCS. A total of 29 patients proceeded with FP (14 SB, 13 OTC, 2 TTC). Conclusions: Our FN-driven model is an effective approach to a Pediatric FCS. Although the number of patients choosing FP is small, this demonstrates the need for fertility counseling in this population. The role of the FCS in pediatric oncology will increase as additional FP options become available for pre-pubertal patients.
Genomic landscape of DNA repair genes in cancer: Mutation and copy number variation (CNV) frequencies.
Authors: Jonathan Anker, Young Kwang Chae
Journal: Journal of Clinical Oncology (2015)

2557 Background: DNA repair genes are frequently mutated in cancer, with different cancers linked to specific repair pathways. However, much remains unknown, including whether these mutations drive cancer or are a result of the disease. We have reviewed genome sequencing data of tumor samples to identify DNA repair genes that are frequently mutated or display high CNV. Methods: We created a comprehensive list of DNA repair genes and indirectly involved caretaker genes. The mutation and CNV frequencies of these genes were recorded from the COSMIC database (cancer.sanger.ac.uk). Results: Of the 193 genes analyzed, 24 had a mutation frequency of greater than 1.0% across all cancers. Table 1 lists the 10 genes most frequently mutated (overall and by common cancer types; n > 19,778 for each gene overall) or with CNVs (n > 4,118 for each gene). Colorectal, skin, lung, and breast cancer were most associated with DNA repair mutations. There was an inverse correlation as genes with a high CNV gain displayed a low CNV loss frequency, and vice versa (p < 0.001). Conclusions: Multiple DNA repair pathways were affected in each cancer type. Interestingly, genes with high frequency CNVs were either predominantly CNV gain or loss, but not both, providing evidence that these are functional alterations. This study provides comprehensive lists of candidate genes to be further studied as biomarkers for genomic instability or novel therapeutic targets. Table 1: Direct (bold) and indirect DNA repair genes most frequently mutated or with CNV gain or loss in cancer. Overall % Lung % Breast % CRC % Skin % CNV gain % CNV loss % TP53 26.9 TP53 33.0 TP53 22.9 TP53 43.7 TP53 24.5 RRM2B 7.0 NEIL2 2.3 MLL3 4.3 MLL3 10.1 MLL3 6.8 ATM 22.5 MLL3 12.0 RECQL4 6.8 WRN 2.1 ATM 4.2 ATM 4.7 ATM 2.3 MSH6 12.0 ATM 7.0 RAD54B 6.0 FANCB 1.5 DNA-PKcs 2.1 POLQ 4.7 CENPE 1.9 DNA-PKcs 11.8 POLQ 6.6 NBS1 6.0 POLI 1.2 BRCA2 2.1 DNA-PKcs 3.9 BRCA1 1.9 MLL3 11.7 BRCA2 5.9 SPO11 5.0 RPA4 1.1 BAP1 2.0 FANCM 3.5 BRCA2 1.7 BRCA2 11.1 TP53BP1 5.7 RFC4 4.3 TREX2 1.0 POLQ 1.7 CENPE 3.1 TP53BP1 1.6 MLH1 10.1 ATR 5.6 RAD1 4.2 CETN2 0.9 ATR 1.6 BRCA2 3.0 POLE 1.5 LIG1 9.6 DNA-PKcs 5.3 RNF168 4.2 UBE2A 0.9 MSH6 1.6 SHPRH 2.8 DNA-PKcs 1.5 ATR 8.5 FANCP 5.2 POLB 4.1 APEX2 0.8 CHEK2 1.5 MDC1 2.7 ATR 1.5 MSH2 8.1 POLE 4.7 CDK12 4.0 FAN1 0.7
Abstract P350: Psychological Resilience and CVD-related Health Behaviors: a Cross-sectional Analysis of the Women’s Health Initiative Extension Study
Authors: Sparkle Springfield
Journal: Circulation (2019)

Introduction: Psychological resilience (resilience), defined as the self-reported ability to bounce back from stress by the Brief Resilience Scale (BRS), has been associated with CVD-related health behaviors. However, the evidence is limited in ethnically diverse older populations. This study investigates the association between self-reported resilience and CVD-related health behaviors (smoking status, sleep, recreational physical activity, and diet quality) in women aged 62+ years of age. Hypothesis: Higher levels self-reported resilience will be positively associated with CVD-related health behaviors after adjustment for age, race-ethnicity, and stressful life events (SLE). Methods and Materials: A cross-sectional secondary analysis was conducted on 77,395 women aged 62-85+ [African American (N=4475, 5.8%), White (N=69,448, 89.7%), Latina (N=1891, 2.4%), and Asian or Pacific Islander (N=1581, 2.0%)] who enrolled in the second Women’s Health Initiative Extension Study. Resilience was measured by a short version of the Brief Resilience Scale for assessing the Ability to Bounce Back and divided into 3 levels for descriptive analyses (i.e., low, normal, and high resilience). Multiple regression was used to evaluate the association between levels of resilience and each CVD-related health behavior. Smoking status and sleep were modeled as binary while recreational physical activity and diet quality (as measured by the HEI-2005) were modeled as continuous outcomes. Results: Of the 77,395 women, those with high resilience were younger and less likely to have had SLE. African American women were the most likely to self-report high resilience (48.6%; n=2174), followed by White (45.5%; n=31584), and then Asian or Pacific Islander (43.3%; n=684) and Latina women (43.3%; n=819). After controlling for age, race-ethnicity, and SLE, there was a negative association between self-reported resilience and current smoking status (OR=0.92; 95%; CI:0.87-0.97), and a positive association between 7-9 hours of sleep per night (OR=1.20; CI: 1.17-1.22). Linear regression analysis showed a positive association between self-reported resilience and both recreational physical activity (β= + 0.45; CI: 0.42-0.49) and HEI-2005 (β= + 0.60; CI: 0.51-0.69). Conclusions: Resilience is associated with better CVD-related health behaviors in older ethnically diverse women. These findings warrant further investigation into whether assessing and potentially intervening to improve resilience could help to increase the effectiveness of lifestyle interventions.
Comparison of the Impact of Pre-Transplant Co-Morbidity Scores on Allogeneic Hematopoietic Stem Cell Transplant Outcomes
Authors: Mohammed A. Marei, Eshetu G Atenafu, Arjun Law, Wilson Lam, Rajat Kumar, Santhosh Thyagu, Auro Viswabandya, Dennis Dong Hwan Kim, Jeff H. Lipton, Hans A. Messner, Fotios V. Michelis
Journal: Blood (2018)
Abstract P068: Associations Between Taste and Smell Alterations and Diabetes-Related Comorbidities Among US Adults: The National Health and Nutrition Examination Surveys 2011-2014
Authors: Jing Li, Yiqing Song
Journal: Circulation (2019)

There is evidence that taste and smell dysfunctions may be associated with type 2 diabetes. Due to sparse data, it remains unclear to what extent taste and smell impairment is related to diabetic complications. We thus aimed to examine the associations between smell and taste alterations and diabetes/prediabetes with and without comorbidities by utilizing the nationally representative data from the National Health and Nutrition Examination Survey (NHANES) collected between 2011 and 2014. Analyses were conducted on 7,027 participants aged 40 to 80 years, of whom 2609 were healthy people, 2625 pre-diabetic patients, and 1793 diabetic patients. Either taste or smell disorder was, respectively, defined as at least one adverse alteration through self-reported questions. Crude prevalence of taste and smell disorders among healthy population, diabetic/prediabetic patients with and without comorbidities were calculated. Weighted logistic regression analyses were performed to examine the associations between declined ability of taste, smell senses and diabetes/prediabetes with and without comorbidities, including cancer, cardiovascular disease, chronic kidney disease, neuropathy, and retinopathy. The multivariate-adjusted models controlled for age, sex, race, BMI, education, cigarette smoking, alcohol intake, and family history of diabetes. Compared to healthy people (prevalence was 15.5% for taste and 19.4% for smell impairment), prediabetic/diabetic patients without comorbidities (taste: 19.2%; smell: 21.1%), and prediabetic/diabetic patients with comorbidities (taste: 22.8%; smell: 28.0%) had higher prevalence of diminished capacity in taste and smell. After adjustment for confounders in our models, significant associations remained between taste and smell impairment and prediabetes/diabetes with comorbidities (taste: OR 1.79, 95% CI (1.31, 2.45); smell: OR 1.52, 95%CI (1.17, 1.97)), but not without comorbidities versus healthy people (taste: OR 1.15, 95% CI (0.85, 1.54); smell: OR 1.10, 95% CI(0.89, 1.37)), and were not modified by age, sex, and race. Furthermore, we conducted sensitivity analyses for individual comorbidities and found that cardiovascular disease and neuropathy were consistently associated with reduced ability in both taste and smell. In conclusion, our results from national data indicate that taste and smell alterations may be possible predictors of the presence and progression of prediabetes/diabetes.