Background.
The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear.
Methods.
We assessed the hormonal and hematologic responses to testosterone administration in a ...clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months.
Results.
The 7%–10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range.
Conclusions.
Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis.
The standard treatment for metastatic prostate cancer, androgen deprivation therapy (ADT), is designed to suppress androgen receptor (AR) activity. However, men invariably progress to ...castration-resistant prostate cancer (CRPC), and AR reactivation contributes to progression in most cases. To identify mechanisms that may drive CRPC, we examined a VCaP prostate cancer xenograft model as tumors progressed from initial androgen sensitivity prior to castration to castration resistance and then on to relapse after combined therapy with further AR-targeted drugs (abiraterone plus enzalutamide). AR activity persisted in castration-resistant and abiraterone/enzalutamide-resistant xenografts and was associated with increased expression of the AR gene and the AR-V7 splice variant. We then assessed expression of individual AR-regulated genes to identify those that persisted, thereby contributing to tumor growth, versus those that decreased and may therefore exhibit tumor suppressor activities. The most significantly decreased AR target gene was dipeptidyl peptidase 4
, which encodes a membrane-anchored protein that cleaves dipeptides from multiple growth factors, resulting in their increased degradation. DPP4 mRNA and protein were also decreased in clinical CRPC cases, and inhibition of DPP4 with sitagliptin enhanced the growth of prostate cancer xenografts following castration. Significantly, DPP4 inhibitors are frequently used to treat type 2 diabetes as they increase insulin secretion. Together, these results implicate DPP4 as an AR-regulated tumor suppressor gene whose loss enhances growth factor activity and suggest that treatment with DPP4 inhibitors may accelerate emergence of resistance to ADT.
These findings identify DPP4 as an AR-stimulated tumor suppressor gene that is downregulated during progression to castration-resistant prostate cancer, warning that treatment with DPP4 inhibitors, commonly used to treat type 2 diabetes, may accelerate prostate cancer progression following androgen deprivation therapy.
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Different driver mutations and/or chromosomal aberrations and dysregulated signaling interactions between leukemia cells and the immune microenvironment have been implicated in the development of ...T-cell acute lymphoblastic leukemia (T-ALL). To better understand changes in the bone marrow microenvironment and signaling pathways in pediatric T-ALL, bone marrows collected at diagnosis (Dx) and end of induction therapy (EOI) from 11 patients at a single center were profiled by single cell transcriptomics (10 Dx, 5 paired EOI, 1 relapse). T-ALL blasts were identified by comparison with healthy bone marrow cells. T-ALL blast-associated gene signature included SOX4, STMN1, JUN, HES4, CDK6, ARMH1 among the most significantly overexpressed genes, some of which are associated with poor prognosis in children with T-ALL. Transcriptome profiles of the blast cells exhibited significant inter-patient heterogeneity. Post induction therapy expression profiles of the immune cells revealed significant changes. Residual blast cells in MRD+ EOI samples exhibited significant upregulation (P < 0.01) of PD-1 and RhoGDI signaling pathways. Differences in cellular communication were noted in the presence of residual disease in T cell and hematopoietic stem cell compartments in the bone marrow. Together, these studies generate new insights and expand our understanding of the bone marrow landscape in pediatric T-ALL.
Abstract
Acute myeloid leukemia (AML) microenvironment exhibits cellular and molecular differences among various subtypes. Here, we utilize single-cell RNA sequencing (scRNA-seq) to analyze pediatric ...AML bone marrow (BM) samples from diagnosis (Dx), end of induction (EOI), and relapse timepoints. Analysis of Dx, EOI scRNA-seq, and TARGET AML RNA-seq datasets reveals an AML blasts-associated 7-gene signature (
CLEC11A, PRAME, AZU1, NREP, ARMH1, C1QBP, TRH
), which we validate on independent datasets. The analysis reveals distinct clusters of Dx relapse- and continuous complete remission (CCR)-associated AML-blasts with differential expression of genes associated with survival. At Dx, relapse-associated samples have more exhausted T cells while CCR-associated samples have more inflammatory M1 macrophages. Post-therapy EOI residual blasts overexpress fatty acid oxidation, tumor growth, and stemness genes. Also, a post-therapy T-cell cluster associated with relapse samples exhibits downregulation of MHC Class I and T-cell regulatory genes. Altogether, this study deeply characterizes pediatric AML relapse- and CCR-associated samples to provide insights into the BM microenvironment landscape.
Current multistep methods utilized for preparing and cryopreserving single-cell suspensions from blood samples for single-cell RNA sequencing (scRNA-seq) are time-consuming, requiring trained ...personnel and special equipment, so limiting their clinical adoption. We developed a method, Simple prEservatioN of Single cElls (SENSE), for single-step cryopreservation of whole blood (WB) along with granulocyte depletion during single-cell assay, to generate high quality single-cell profiles (SCP).
WB was cryopreserved using the SENSE method and peripheral blood mononuclear cells (PBMCs) were isolated and cryopreserved using the traditional density-gradient method (PBMC method) from the same blood sample (n=6). The SCPs obtained from both methods were processed using a similar pipeline and quality control parameters. Further, entropy calculation, differential gene expression, and cellular communication analysis were performed to compare cell types and subtypes from both methods.
Highly viable (86.3 ± 1.51%) single-cell suspensions (22,353 cells) were obtained from the six WB samples cryopreserved using the SENSE method. In-depth characterization of the scRNA-seq datasets from the samples processed with the SENSE method yielded high-quality profiles of lymphoid and myeloid cell types which were in concordance with the profiles obtained with classical multistep PBMC method processed samples. Additionally, the SENSE method cryopreserved samples exhibited significantly higher T-cell enrichment, enabling deeper characterization of T-cell subtypes. Overall, the SENSE and PBMC methods processed samples exhibited transcriptional, and cellular communication network level similarities across cell types with no batch effect except in myeloid lineage cells.
Comparative analysis of scRNA-seq datasets obtained with the two cryopreservation methods i.e., SENSE and PBMC methods, yielded similar cellular and molecular profiles, confirming the suitability of the former method's incorporation in clinics/labs for cryopreserving and obtaining high-quality single-cells for conducting critical translational research.
Self-care activities are the cornerstone of diabetes care that ensures patients participation to achieve optimal glycemic control and to prevent complications.
The aim of this study is to find the ...level of self-care activities among diabetics aged ≥20 years residing in a resettlement colony in East Delhi and its association with sociodemographic factors, disease, and treatment profile.
Using cross-sectional survey, 168 known diabetic patients were selected from Nand Nagri, a resettlement colony in East Delhi. Data were collected using Hindi translation of revised version-Summary of Diabetic Self Care Activities along with a pretested semi-open-ended questionnaire. Self-care was assessed on six parameters as follows: (a) general diet, (b) specific diet, (c) exercise, (d) blood sugar testing, (e) foot-care, and (f) smoking. The study period was from November 2014 to April 2016.
Nearly 35.1% of respondents belonged to 60-69 years age group. About 52.4% of respondents were female. Fifty-two diabetics (31%) reported having practised diet control on all 7 days in the past 1 week. Nearly 39.3% of patients did not perform any physical activity. The blood test was not practised by 92.3% of respondents. Foot-care was practised by only 19% of patients. There was a significant association between general diet among diabetics with family support (P = 0.020), place of diagnosis (P = 0.033), and treatment funds (P = 0.017). The exercise score among diabetics who were below the poverty line was higher than those above poverty line (P = 0.029). Younger age (P = 0.005) and treatment with insulin (P = 0.008) were positively associated with blood glucose testing. The foot-care practice was better in patients aware of complications and foot-care practices (P < 0.001).
Self-care activities among diabetic patients were very poor. Self-management educational programs at hospitals along with information, education, and communication activities at the community level and one-to-one counseling are recommended.
Insertion of foreign objects into the rectum is a well-described phenomenon and not an uncommon referral to the general surgeon on call. Although usually not life-threatening, there can be ...consequences following migration of the object or perforation of the large bowel. This study looks at the incidence of removal of foreign objects from the rectum over the last decade and the financial burden it presents to the NHS.
Hospital Episode Statistics for 2010-2019 were used to calculate the number of rectal foreign bodies that required removal in hospital. Data for age groups and genders have been compared.
A total of 3,500 rectal foreign bodies were removed over the course of 9 years. Males accounted for 85.1% of rectal foreign bodies whilst 14.9% were females. This equates to 348 bed-days per annum. Admission peaks were observed in the second and fifth decades of life.
This study shows that the incidence of rectal foreign bodies is higher in men and has been increasing over the period studied. Most foreign bodies can be removed trans-anally with the use of anaesthesia, with only a small proportion of patients requiring hospital stay over 24 hours (mean length of stay = 24 hours). Nearly 400 rectal foreign body removals are performed each year with an annual cost of £338,819, illustrating the effect this has on NHS resources.
Summary Endocrine disease frequently interrupts sexual function, and sexual dysfunction may signal serious endocrine disease. Diabetic autonomic neuropathy and endothelial dysfunction impair erectile ...function, and phosphodiesterase inhibition produces only moderate benefit. The effect of diabetes on women's sexual function is complex: the most consistent finding is a correlation between sexual dysfunction and depression. Reductions in testosterone level in men are associated with low sexual desire and reduced nocturnal erections and ejaculate volume, all of which improve with testosterone supplementation. The age-dependent decline in testosterone production in men is not associated with precise sexual symptoms, and supplementation has not been shown to produce sexual benefit. In women, sexual dysfunction has not been associated with serum testosterone, but this may be confounded by limitations of assays at low concentrations and by the greater importance of intracellular production of testosterone in women than in men. Testosterone supplementation after menopause does improve some aspects of sexual function in women, but long-term outcome data are needed. More research on the sexual effects of abnormal adrenal and thyroid function, hyperprolactinaemia, and metabolic syndrome should also be prioritised. We have good data on local management of the genital consequences of oestrogen lack, but need to better understand the potential role of systemic oestrogen supplementation from menopause onwards in sexually symptomatic women.
Millions of patients suffer from major depressive disorder (MDD), but many do not respond to selective serotonin reuptake inhibitor (SSRI) therapy. We used a pharmacometabolomics-informed ...pharmacogenomics research strategy to identify genes associated with metabolites that were related to SSRI response. Specifically, 306 MDD patients were treated with citalopram or escitalopram and blood was drawn at baseline, 4 and 8 weeks for blood drug levels, genome-wide single nucleotide polymorphism (SNP) genotyping and metabolomic analyses. SSRI treatment decreased plasma serotonin concentrations (P<0.0001). Baseline and plasma serotonin concentration changes were associated with clinical outcomes (P<0.05). Therefore, baseline and serotonin concentration changes were used as phenotypes for genome-wide association studies (GWAS). GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant (P=7.84E-09) SNP cluster on chromosome four 5' of TSPAN5 and a cluster across ERICH3 on chromosome one (P=9.28E-08) that were also observed during GWAS for change in serotonin at 4 (P=5.6E-08 and P=7.54E-07, respectively) and 8 weeks (P=1.25E-06 and P=3.99E-07, respectively). The SNPs on chromosome four were expression quantitative trait loci for TSPAN5. Knockdown (KD) and overexpression (OE) of TSPAN5 in a neuroblastoma cell line significantly altered the expression of serotonin pathway genes (TPH1, TPH2, DDC and MAOA). Chromosome one SNPs included two ERICH3 nonsynonymous SNPs that resulted in accelerated proteasome-mediated degradation. In addition, ERICH3 and TSPAN5 KD and OE altered media serotonin concentrations. Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may have a role in SSRI treatment outcomes.
Background: To improve breastfeeding practices, many interventions have been studied at various critical contact points. Our study aimed to improve exclusive breastfeeding by integrating a limited ...number of counselling sessions with routine immunization visits. Objective: To find out the effect of one-to-one counselling on six months of exclusive breastfeeding among infants attending immunization clinic. Methodology: An open-labelled, randomised controlled trial was conducted from September 2022 in the Immunization clinic at the Urban Health Training Centre of Dept of Community Medicine, UCMS, at Ghazipur, New Delhi. Mother-Child dyads visiting the clinic (child between 1 ½ to 3 ½ months) were recruited for the study based on certain appropriate inclusion and exclusion criteria. One-to-one counselling on breastfeeding and complementary feeding were provided, respectively, in the first visit (at the time of Pentavalent 1 or 2 vaccination,) and the second visit (at the time of Pentavalent 3 vaccination) to the intervention group. The control group received routine care. In the follow-up visit at 9 months for measles vaccination, a final assessment was done for both the groups. Analysis was done based on Intention to treat and per protocol approaches. Results: 92 Mother-child dyads were recruited in the study, of which 46 were randomized each in the intervention and control group. 6 were lost to follow-up on the second visit and 13 on the third (follow-up) visit. At the first visit, 56.5% of the mothers in the intervention group and 63% of mothers in the control group were exclusively breastfeeding. The proportion of mothers who exclusively breastfed their infant till six months of age were 65.2% in the intervention and 39.1% in the control group with an OR of 2.92(1.25, 6.81). Conclusion: One-to-one counselling at an immunization clinic has an effect on increasing rates of exclusive breastfeeding for 6 months.
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