Sommerlarsen7042
Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2,650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity assays (MTT), global gene expression analysis, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo. selleck chemicals llc Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC.
To identify determinants associated with insulin resistance and to assess the association between insulin resistance and cardiovascular events, vascular interventions and mortality in people with type 1 diabetes at high risk of cardiovascular disease .
Prospective cohort study.
195 people with type 1 diabetes from the Secondary Manifestations of ARTerial disease (SMART) cohort were included. Insulin resistance was quantified by the estimated glucose disposal rate (eGDR) with higher eGDR levels indicating higher insulin sensitivity (i.e. lower eGDR levels indicating higher insulin resistance). Linear regression models were used to evaluate determinants associated with eGDR. The effect of eGDR on cardiovascular events, cardiovascular events or vascular interventions (combined endpoint) and on all-cause mortality was analysed using Cox proportional hazards models adjusted for confounders.
In 195 individuals (median follow-up 12.9 years, IQR 6.7-17.0), a total of 25 cardiovascular events, 26 vascular interventions and 27 deaths were observed. High eGDR as a marker for preserved insulin sensitivity was independently associated with a lower risk of cardiovascular events (HR 0.75; 95%CI 0.61-0.91), a lower risk of cardiovascular events and vascular interventions (HR 0.74; 95%CI 0.63-0.87), and a lower risk of all-cause mortality (HR 0.81; 95%CI 0.67-0.98).
Insulin resistance as measured by eGDR is an additional risk factor for cardiovascular disease in individuals with type 1 diabetes. Modification of insulin resistance by lifestyle interventions or pharmacological treatment could be a viable therapeutic target to lower the risk of cardiovascular disease.
Insulin resistance as measured by eGDR is an additional risk factor for cardiovascular disease in individuals with type 1 diabetes. Modification of insulin resistance by lifestyle interventions or pharmacological treatment could be a viable therapeutic target to lower the risk of cardiovascular disease.
Pituitary adenoma (PA) is one of the three major components of multiple endocrine neoplasia type 1 (MEN1). Recent studies have suggested that MEN1-associated PAs are less aggressive than initially estimated. We propose an analysis of the outcome of PAs with standard of care treatment in a nationwide cohort of MEN1 patients.
Retrospective observational nationwide cohort study using the MEN1 patient registry from the French Group of Endocrine Tumours (GTE).
The GTE database population consists of 1,435 patients with MEN1. This analysis focused on 551 patients recruited after 2000 with at least 3 years of follow-up. The study outcome was tumour progression of PA defined by an increase in Hardy classification (HC) during follow-up according to referring physician regular reports.
Among 551 MEN1 patients (index and related), 202 (36.7%) had PA, with 114 (56.4%) diagnosed by MEN1-related screening. PAs were defined according to HC as microadenoma (grade I) in 117 cases (57.9%), macroadenoma in 59 (29.2%) with 20 HC grade II and 39 HC grade III-IV and unspecified in 26 (12.8%). They were prolactinomas in 92 cases (45.5%) and non-secreting in 73 (36.1%). After a median follow-up of 3 years among the 137 patients with HC grades I-II, 4 patients (2.9%) presented tumour progression.
PAs in patients with MEN1 are less aggressive than previously thought. Tumour progression is rare with standard of care monitoring and treatment, especially in related patients who mostly present non-secreting microadenoma. MRI monitoring for asymptomatic MEN1 patients should be reduced accordingly.
PAs in patients with MEN1 are less aggressive than previously thought. Tumour progression is rare with standard of care monitoring and treatment, especially in related patients who mostly present non-secreting microadenoma. MRI monitoring for asymptomatic MEN1 patients should be reduced accordingly.
Triglyceride glycemic (TyG) index is a novel tool for assessing insulin resistance (IR). Recently, TyG index as a potential biomarker for gestational diabetes mellitus (GDM) has been studied, but its performance is yet inconclusive. Thus, we performed this systemic review and meta-analysis to evaluate the performance of TyG index in predicting GDM.
Studies published before March 1st, 2021 with comparison of TyG index between GDM patients and healthy controls were retrieved from multiple databases (PubMed, Web of Science, The Cochrane Library and Embase). The mean difference (MD) of TyG index in GDM patients and healthy controls were pooled using random-effect models.
Differentiation of TyG index between patients with GDM and controls showed significant results. Overall, there is a four-fold increase in TyG index in GDM patients compared with controls (MD 0.22, 95%CI 0.07 - 0.36, p = 0.003; I2 = 71%, p = 0.009). In subgroup analyses according to gestational time, TyG index in the second trimester predicted GDM with low heterogeneity (MD 0.26, 95%CI 0.15 - 0.37, p < 0.001; I2 = 0%, p = 0.54), while no such correlation was found in the first trimester.
TyG index, especially in the second trimester, could be a promising biomarker for predicting GDM.
TyG index, especially in the second trimester, could be a promising biomarker for predicting GDM.Hypopituitarism tends to occur in large pituitary adenomas. However, similar tumors could present with strikingly different hormonal deficiencies. In this study, we looked at MRI characteristics in non-functioning pituitary adenomas (NFPA), which could predict secondary adrenal insufficiency (SAI) and central hypothyroidism (CHT). We reviewed the files of patients with NFPA attending our clinic. Tumor size, invasiveness, MR-signal intensity, and gadolinium enhancement in preoperative MRI were recorded along with documented presurgical hypopituitarism profile. Logistic regression was used to predict SAI, CHT or both (SAI/CHT) based on MRI and demographic parameters. Receiver operating characteristic curves were used to determine their diagnostic utility. 121 patients were included. Older age (P=0.021), male sex (P=0.043), stalk deviation (P3.2 cm3 the sensitivity was around 90-92% for detecting SAI/CHT. Only vertical height was significantly associated with any one or more pituitary hormonal deficit (P=0.001). In conclusion, adenoma size, independent of the measurement used, remains the best predictor of SAI/CHT in NFPA. Dynamic testing to rule out SAI is probably indicated in adenomas larger than 18 mm vertical height, 23 mm largest diameter and 3.2cm3 adenoma volume.
The experience of infertility and its treatment engenders considerable stress and is often described as an emotional rollercoaster. A mobile health (mHealth) app may be a novel solution to address the psychoeducational and psychosocial support needs of fertility patients because of its potential to reduce stress and increase patient empowerment. There are a few fertility-related apps that provide information and support to both men and women undergoing fertility treatment; however, none have documented their development and evaluation process.
This study aims to describe the development and evaluation process of a bilingual mHealth app, Infotility, designed to meet the psychoeducational and psychosocial support needs of men and women undergoing fertility treatment.
To develop the Infotility app, we adhered to the Medical Research Council guidelines for the development and evaluation of complex interventions. First, we conducted literature reviews and needs assessment surveys of fertility patients and hear rating of 3.43 (SD 0.75), with a total possible score and star rating of 5.00.
By documenting the systematic development and evaluation of the mHealth app for men and women undergoing fertility treatment, this paper can facilitate the replication of the study intervention and the development of similar mHealth apps.
By documenting the systematic development and evaluation of the mHealth app for men and women undergoing fertility treatment, this paper can facilitate the replication of the study intervention and the development of similar mHealth apps.
Recent falls prevention guidelines recommend early routine fall risk assessment among older persons.
The purpose of this study was to develop a Falls Screening Mobile App (FallSA), determine its acceptance, concurrent validity, test-retest reliability, discriminative ability, and predictive validity as a self-screening tool to identify fall risk among Malaysian older persons.
FallSA acceptance was tested among 15 participants (mean age 65.93 [SD 7.42] years); its validity and reliability among 91 participants (mean age 67.34 [SD 5.97] years); discriminative ability and predictive validity among 610 participants (mean age 71.78 [SD 4.70] years). Acceptance of FallSA was assessed using a questionnaire, and it was validated against a comprehensive fall risk assessment tool, the Physiological Profile Assessment (PPA). Participants used FallSA to test their fall risk repeatedly twice within an hour. Its discriminative ability and predictive validity were determined by comparing participant fall risk scores b in the use of FallSA to self-screen for falls and thereafter to seek early prevention intervention.
These results suggest that FallSA is a valid and reliable fall risk self-screening tool. Further studies are required to empower and engage older persons or care givers in the use of FallSA to self-screen for falls and thereafter to seek early prevention intervention.
