Risk and incidence of breast cancer in transgender individuals: a systematic review and meta-analysis

AlexandrosSfakianakis shared this article with you from Inoreader Risk and incidence of breast cancer in transgender individuals: a systematic review and meta-analysis via European Journal of Cancer Prevention - Published Ahead-of-Print Background and aims The risk of developing breast cancer in transgender individuals [male-to-female (MtF) or female-to-male (FtM)] is still inadequately quantified. We aimed to evaluate the impact of breast cancer in this population. Methods We conducted a systematic literature search and review using the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines through the PUBMED and SCOPUS databases. We identified six cohort studies (for both populations) plus 35 case reports. Incidence and breast cancer risk quantification were the main outcomes considered. Results FtM individuals had a higher risk of developing breast cancer in comparison to cisgender men [standardized incidence ratio (SIR) = 63.4; 95% confidence interval (CI), 32.2–124.9] but a lower risk than cisgender women (SIR = 0.42; 95% CI, 0.07–2.41). Similarly, MtF individuals were at higher risk of developing breast cancer in comparison to cisgender men (SIR = 22.5; 95% CI, 5.54–91.8) and at lower risk than cisgender women (SIR = 0.30; 95% CI, 0.22–0.42). Conclusion In this systematic study and meta-analysis, we identified that FtM and MtF individuals are at substantially higher risk of developing breast cancer in comparison to cisgender men, though at lower risk than cisgender women. These individuals, in the absence of defined guidelines for breast cancer prevention, should periodically undergo breast or chest examinations. View on Web

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Impact of Exercise and Detraining on Signs of Puberty and Selected Inflammatory Markers in Girls with Precocious Puberty

AlexandrosSfakianakis shared this article with you from Inoreader Impact of Exercise and Detraining on Signs of Puberty and Selected Inflammatory Markers in Girls with Precocious Puberty via Medicine & Science in Sports & Exercise - Published Ahead-of-Print Purpose We examined the effects of aerobic exercise and detraining on adiponectin, resistin, tumor necrosis factor alpha (TNF-α), white blood cell, and pubertal signs (uterine length, ovarian volume, luteinizing hormone (LH), and follicle-stimulating hormone (FSH)) in girls with central precocious puberty (CPP). Methods Thirty girls with CPP (aged 7-9) were randomly divided into CPP and CPP + Exercise (EX) groups. 15 Healthy age-matched girls without precocious puberty participated for comparison with CPP. Subjects in the CPP + Ex group attended 12 weeks of aerobic exercise protocol three sessions a week. In the baseline, after completing the exercise protocol and after 4 weeks of detraining, all the parameters were measured. In the CPP and healthy groups, all the parameters were measured in all three stages. To measure adiponectin, resistin, and TNF-α, the ELISA method was used. LH and FSH were measured by electrochemiluminescence immunoassay. WBC counts were analyzed by an automated blood cell counter. Analysis of Variance with repeated measures test was used to analyze the results. Results CPP girls have lower adiponectin (P = 0.01) and higher TNF-α levels (P = 0.001) than healthy girls. In the CPP + EX group, after 12 weeks, body weight and fat mass decreased, adiponectin increased significantly (P = 0.02). Resistin (P = 0.02), TNF-α (P = 0.02), neutrophils (P = 0.01), and signs of puberty significantly (P View on Web

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Characterization of Hyaluronan Localization in the Developing Mammary Gland and Mammary Tumors

AlexandrosSfakianakis shared this article with you from Inoreader Characterization of Hyaluronan Localization in the Developing Mammary Gland and Mammary Tumors via Journal of Mammary Gland Biology and Neoplasia AbstractThe extracellular matrix (ECM) is biochemically and biomechanically important for the structure and function of the mammary gland, which undergoes vast structural changes throughout pubertal and reproductive development. Although hyaluronan (HA) is a ubiquitous glycosaminoglycan (GAG) of the mammary gland ECM, extensive characterization of HA deposition in the mammary gland is lacking. Understanding physiologic HA metabolism is critical as this tightly controlled system is often hijacked in cancer. In the current studies, we characterize HA regulation throughout mammary gland development to better understand subsequent dysregulation of HA in mammary tumors. Using immunofluorescence (IF) imaging, we demonstrate that organized HA-rich septa exist in the mammary gland stroma throughou... View on Web

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Opening of mitochondrial permeability transition pore in cardiomyocytes: Is ferutinin a suitable tool for its assessment?

AlexandrosSfakianakis shared this article with you from Inoreader Opening of mitochondrial permeability transition pore in cardiomyocytes: Is ferutinin a suitable tool for its assessment? via Fundamental & Clinical Pharmacology Abstract Mitochondrial permeability transition pore (mPTP) opening is a critical event leading to cell injury during myocardial ischemia-reperfusion but having a reliable cellular model to study the effect of drugs targeting mPTP is an unmet need. This study evaluated whether the Ca2+ electrogenic ionophore ferutinin is a relevant tool to induce mPTP in cardiomyocytes. mPTP opening was monitored using the calcein/cobalt fluorescence technique in adult cardiomyocytes isolated from wild-type and cyclophylin D (CypD) knock-out mice. Concomitantly, the effect of ferutinin was assessed in isolated myocardial mitochondria. Our results confirmed the Ca2+ ionophoric effect of ferutinin in isolated mitochondria and cardiomyocytes. Ferutinin induced all the hallmarks of mPTP opening in cells (loss of calcein, of mitochondrial potential and cell death) but none of them could be inhibited by CypD deletion or cyclosporine A, indicating that mPTP opening was not the major contributor to the effect of fe rutinin. This was confirmed in isolated mitochondria where ferutinin acts by different mechanisms dependent and independent of the mitochondrial membrane potential. At low ferutinin/mitochondria concentration ratio, ferutinin displays protonophoric-like properties, lowering the mitochondrial membrane potential and limiting oxidative phosphorylation without mitochondrial swelling. At high ferutinin/mitochondria ratio, ferutinin induced a sudden Ca2+ independent mitochondrial swelling, which is only partially inhibited by cyclosporine A. Together, these result show that ferutinin is not a suitable tool to investigate CypD-dependent mPTP opening in isolated cardiomyocytes because it possesses other mitochondrial properties such as swelling induction and mitochondrial uncoupling properties which impede its utilization. View on Web

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Complex Ataxia‐Dementia Phenotype in Patients with Digenic TBP/STUB1 Spinocerebellar Ataxia

AlexandrosSfakianakis shared this article with you from Inoreader Complex Ataxia‐Dementia Phenotype in Patients with Digenic TBP/STUB1 Spinocerebellar Ataxia via Movement Disorders Digenic SCA TBP/STUB1 is caused by the concomitant inheritance of an intermediate expansion in TBP gene and a deleterious mutation in STUB1 gene. SCA TBP/STUB1 patients present a complex phenotype including ataxia, chorea, dementia, and diffuse cerebellar and cerebral brain atrophy. Genetic counseling is essential for all family members. ABSTRACT Background and Objectives Spinocerebellar ataxias (SCAs) are autosomal dominant disorders with extensive clinical and genetic heterogeneity. We recently identified a form of SCA transmitted with a digenic pattern of inheritance caused by the concomitant presence of an intermediate-length expansion in TATA-box binding protein gene (TBP 40–46) and a heterozygous pathogenic variant in the Stip1-homologous and U-Box containing protein 1 gene (STUB1). This SCA TBP/STUB1 represents the first example of a cerebellar disorder in which digenic inheritance has been identified. Objectives We studied a large cohort of patients with SCA TBP/STUB1 with the aim of describing specific clinical and neuroimaging features of this distinctive genotype. Methods In this observational study, we recruited 65 affected and unaffected family members from 21 SCA TBP/STUB1 families and from eight families with monogenic SCA17. Their characteristics and phenotypes were compared with those of 33 age-matched controls. Results SCA TBP/STUB1 patients had multi-domain dementia with a more severe impairment in respect to patient carrying only fully expanded SCA17 alleles. Cerebellar volume and thickness of cerebellar cortex were reduced in SCA TBP/STUB1 compared with SCA17 patients (P = 0.03; P = 0.008). Basal ganglia volumes were reduced in both patient groups, as compared with controls, whereas brainstem volumes were significantly reduced in SCA TBP/STUB1 , but not in SCA17 patients. Conclusions The identification of the complex SCA TBP/STUB1 phenotype may impact on diagnosis and genetic counseling in the families with both hereditary and sporadic ataxia. The independent segregation of TBP and STUB1 alleles needs to be considered for recurrence risk and predictive genetic tests. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. View on Web

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LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease

AlexandrosSfakianakis shared this article with you from Inoreader LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease via Movement Disorders Abstract Background Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD). Objective The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the potent, selective, CNS-penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants and patients with PD. Methods Two randomized, double-blind, placebo-controlled studies were completed. The phase 1 study (DNLI-C-0001) evaluated single and multiple doses of BIIB122 for up to 28 days in healthy participants. The phase 1b study (DNLI-C-0003) evaluated BIIB122 for 28 days in patients with mild to moderate PD. The primary objectives were to investigate the safety, tolerability, and plasma pharmacokinetics of BIIB122. Pharmacodynamic outcomes included peripheral and central target inhibition and lysosomal pathway engagement biomarkers. Results A total of 186/184 healthy participants (146/145 BIIB122, 40/39 placebo) and 36/36 patients (26/26 BIIB122, 10/10 placebo) were randomized/treated in the phase 1 and phase 1b studies, respectively. In both studies, BIIB122 was generally well tolerated; no serious adverse events were reported, and the majority of treatment-emergent adverse events were mild. BIIB122 cerebrospinal fluid/unbound plasma concentration ratio was ~1 (range, 0.7–1.8). Dose-dependent median reductions from baseline were observed in whole-blood phosphorylated serine 935 LRRK2 (≤98%), peripheral blood mononuclear cell phosphorylated threonine 73 pRab10 (≤93%), cerebrospinal fluid total LRRK2 (≤50%), and urine bis (monoacylglycerol) phosphate (≤74%). Conclusions At generally safe and well-tolerated doses, BIIB122 achieved substantial peripheral LRRK2 kinase inhibition and modulation of lysosomal pathways downstream of LRRK2, with evidence of CNS distribution and target inhibition. These studies support continued investigation of LRRK2 inhibition with BIIB122 for the treatment of PD. © 2023 Denali Therapeutics Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. View on Web

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LRRK2 Quantification in Cerebrospinal Fluid of Patients with Parkinson's Disease and Atypical Parkinsonian Syndromes

AlexandrosSfakianakis shared this article with you from Inoreader LRRK2 Quantification in Cerebrospinal Fluid of Patients with Parkinson's Disease and Atypical Parkinsonian Syndromes via Movement Disorders Abstract Background The alteration of leucine-rich repeat kinase 2 (LRRK2) kinase activity is thought to be involved in Parkinson's disease (PD) pathogenesis beyond familiar cases, and LRRK2 inhibitors are currently under investigation. Preliminary data suggest a relationship between LRRK2 alteration and cognitive impairment in PD. Objective To investigate cerebrospinal fluid (CSF) LRRK2 levels in PD and other parkinsonian disorders, also correlating them with cognitive impairment. Methods In this study, we retrospectively investigated by means of a novel highly sensitive immunoassay the levels of total and phosphorylated (pS1292) LRRK2 in CSF of cognitively unimpaired PD (n = 55), PD with mild cognitive impairment (n = 49), PD with dementia (n = 18), dementia with Lewy bodies (n = 12), atypical parkinsonian syndromes (n = 35), and neurological controls (n = 30). Results Total and pS1292 LRRK2 levels were significantly higher in PD with dementia with respect to PD with mild cognitive impairment and PD, and also showed a correlation with cognitive performances. Conclusions The tested immunoassay may represent a reliable method for assessing CSF LRRK2 levels. The results appear to confirm an association of LRRK2 alteration with cognitive impairment in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. View on Web

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