Copy number variations in a Brazilian cohort with autism spectrum disorders highlight the contribution of cell adhesion genes.

Prediction of pathogenicity of rare copy number variations (CNVs), a genomic alteration known to contribute to the etiology of autism spectrum disorder (ASD), represents a serious limitation to interpreting genetic tests, particularly for genetic counseling purposes. Chromosomal microarray analysis (CMA) was conducted in a unique collection of 144 Brazilian individuals with ASD of strong European and African ancestries. Rare CNVs were detected in 39 patients: 41 of unknown significance (VUS), four pathogenic and one likely pathogenic CNVs (clinical yield of 4.1%; 5/122). Based on gene content and recurrence in three large cohorts [a Brazilian neurodevelopmental disorder cohort, the autism MSSNG cohort, and the Canadian-based Centre for Applied Genomics microarray database], this work strengthened the pathogenicity of 14 genes (FAT1, CAMK4, BIRC6, DPP6, CSMD1, CTNNA3, CDH8/CDH11, CDH13, OR1C1, CNTN6, CNTNAP4, FGF2 and PTPRN2) within 14 CNVs. Notably, enrichment of cell adhesion proteins to ASD etiology was identified (p < 0.05), highlighting the importance of these gene families in the etiology of ASD.

Patterns of Care and Outcomes for Non-Metastatic Prostate Cancer in the United States: Results of the CancerMPact® Survey 2018.

PURPOSE: We describe patterns of care and treatment outcomes for non-metastatic PCa (nmPCA), either hormone-sensitive or castration-resistant, in the United States of America (USA) in 2018. METHODS: A survey (CancerMPact®) recruited physicians nationwide to answer an online questionnaire about how they treated patients with nmPCA. Questions covered aspects of treatment at all disease stages. Board-certified urologists and oncologists with at least five years of clinical practice and who treated at least 30 PCa patients monthly were included. RESULTS: The survey included responses from ninety-four physicians with an average of 17.5 years of clinical practice, who had treated a combined average of 4415 patients with nmPCA per month in 2018. Approximately 40% of patients in stage I were managed with either active surveillance or observation/no therapy, decreasing to 20%, 8% and 6% in stages II, III and IV(M0), respectively. Intensity-modulated radiotherapy was favored over other radiotherapy modalities, with rates of use ranging between 60% and 69% depending on disease stage. Leuprolide as monotherapy or in combination with enzalutamide, abiraterone or bicalutamide were the most common systemic treatment options for non-metastatic hormone-sensitive PCa (nmHSPC) patients with the first or second recurrence. Only 16.5% of non-metastatic castration-resistant PCa (nmCRPC) patients did not relapse within five years of initial therapy for nmCRPC. CONCLUSION: While PCa treatment recommendations are rapidly changing due to advances in treatment, we observed great concordance between their most current versions and real-world data treatment patterns reported by US physicians.

Real-world Adherence and Persistence with Bisphosphonate Therapy in Postmenopausal Women: A Systematic Review.

PURPOSE: Bisphosphonate therapy is a well-established and effective treatment for postmenopausal osteoporosis and the prevention of osteoporotic fracture. However, poor adherence to and poor persistence with bisphosphonate therapy may reduce its benefits. Previous studies have documented the poor rates of adherence and persistence among postmenopausal women with osteoporosis. The objective of this systematic literature review was to evaluate adherence, persistence, and the impact of adherence and persistence on fracture risk in postmenopausal women with diagnosed osteoporosis. METHODS: Articles eligible for review included observational studies of the real-world use of bisphosphonates in 23 countries and were identified by using MEDLINE, EMBASE, IMSEAR (Index Medicus for South-East Asia Region), and LILACS (Latin American and Caribbean Health Sciences Database). FINDINGS: We identified and evaluated 10 studies that assessed bisphosphonate adherence by measuring medication possession ratio (MPR), persistence, and/or the impact of adherence and persistence on fracture risk. Mean MPR at 1 year ranged from 54% to 71% in the 3 studies that reported this assessment of adherence, and 40%-85% of patients at 1 year were adherent, defined as an MPR ≥80%, in the 8 studies that reported this end point. At 1 year, rates of persistence ranged from 28% to 74%. Rates of adherence and persistence were highest with agents requiring less frequent administration and typically declined over time. Fracture rates were significantly lower among adherent women with MPRs ≥80% compared with women with MPRs <80%. IMPLICATIONS: Our results show that suboptimal adherence to and persistence with bisphosphonate therapy in postmenopausal women are common and increase the risk of fracture. Additional research is needed to identify and incorporate effective strategies for improving adherence to bisphosphonates in postmenopausal women.

Simultaneous Quantification of the 8 Human Herpesviruses in Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Human herpesviruses may cause severe complications after allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of some of these infections on transplant outcomes is still unclear. A prospective survey on the incidence and clinical features of herpesviruses infections after HSCT has not yet been conducted in Brazilian patients, and the impact of these infections on HSCT outcome remains unclear. METHODS: We prospectively analyzed the incidence of infection of the eight human herpesviruses simultaneously in 1 045 peripheral blood samples from 98 allogeneic HSCT recipients. Samples were collected weekly starting at the time of transplant until day +100. All herpesviruses were screened and quantified in plasma by quantitative real-time polymerase chain reaction. Median follow up time was 24 months. RESULTS: The incidences of infection for each herpesvirus were as follows: cytomegalovirus (CMV), 44%; human herpesvirus [HHV] 6, 18%; HHV8, 6%; Epstein-Barr virus, 3%; herpes simplex virus 1, 3%; varicella zoster virus, 3%; HHV7, 2%; and herpes simplex virus 2, 1%. The CMV infection was significantly more frequent among adults and was associated with a higher risk of developing acute graft-versus-host disease. The HHV6 infection was significantly more frequent after umbilical cord blood transplant and was associated with an increased risk of platelet engraftment failure. There was no significant impact of these infections on the other transplant outcomes. CONCLUSIONS: Herpesviruses infections were uncommon after HSCT, except for CMV and HHV6, which, although relatively frequent, had no clinically relevant impact on the outcomes.

Lithium reduces Gsk3b mRNA levels: implications for Alzheimer Disease.

BACKGROUND: There is evidence of increased systemic expression of active GSK3B in Alzheimer's disease patients, which apparently is associated with the formation of senile plaques and neurofibrillary tangles. Due to its central role in the pathogenesis of AD, GSK3B is currently a promising target of the pharmaceutical industry. Whilst trials with specific GSK inhibitors in AD are under way, major attention has been focused on the neuroprotective effects of lithium. Whereas the direct and indirect inhibitory effects of lithium over GSK3 activity have been documented by several groups, its effects over Gsk3 transcription have not yet been addressed. METHODS: We used quantitative PCR to evaluate the transcriptional regulation of Gsk3a and Gsk3b in lithium-treated primary cultures of rat cortical and hippocampal neurons. RESULTS: We found a significant and dose-dependent reduction in the expression of Gsk3b, which was specific to hippocampal cells. This same effect was further confirmed in vivo by measuring Gsk3 expression in different brain regions and in peripheral leukocytes of adult rats treated with lithium. CONCLUSION: Our studies show that LiCl can modulate Gsk3b transcription in vitro and in vivo. This observation suggest new regulatory effects of lithium over Gsk3b, contributing to the better understanding of its mechanisms of action, offering a new and complementary explanation for Gsk3b modulation and reinforcing its potential for the inhibition of key pathological pathways in Alzheimer's disease.

FLT3 internal tandem duplication during myelodysplastic syndrome follow-up: a marker of transformation to acute myeloid leukemia.

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and risk for evolving to acute leukemia. Some molecular abnormalities related to acute myeloid leukemia (AML) transformation have been reported, such as FLT3 (FMS-like tyrosine kinase 3) mutations. FLT3, a member of the class 3 receptor tyrosine kinase family, mediates stem cell proliferation and differentiation, and its mutations, internal tandem duplication (ITD) and Asp835, have been reported in rare MDS patients. We studied FLT3 ITD, prospectively, in 50 MDS patients at diagnosis, at 6 and 12 months follow-up, and at any other time-point if AML transformation was detected. FLT3 ITD was not observed at diagnosis, but during follow-up the mutation was present in 2 of 50 patients (4%). Of these, one case exhibited FLT3 ITD at the end of the 6 months of follow-up in approximately 8% of bone marrow cells; this case evolved into AML at 8 months, at which time FLT3 ITD was present in approximately 85% of bone marrow cells. The other case exhibited FLT3 ITD in 68% of bone marrow cells at 7 months, precisely at the time of AML transformation. Although rare in MDS, FLT3 ITD is associated with a high probability of evolution to AML.

A transcript finishing initiative for closing gaps in the human transcriptome.

We report the results of a transcript finishing initiative, undertaken for the purpose of identifying and characterizing novel human transcripts, in which RT-PCR was used to bridge gaps between paired EST clusters, mapped against the genomic sequence. Each pair of EST clusters selected for experimental validation was designated a transcript finishing unit (TFU). A total of 489 TFUs were selected for validation, and an overall efficiency of 43.1% was achieved. We generated a total of 59,975 bp of transcribed sequences organized into 432 exons, contributing to the definition of the structure of 211 human transcripts. The structure of several transcripts reported here was confirmed during the course of this project, through the generation of their corresponding full-length cDNA sequences. Nevertheless, for 21% of the validated TFUs, a full-length cDNA sequence is not yet available in public databases, and the structure of 69.2% of these TFUs was not correctly predicted by computer programs. The TF strategy provides a significant contribution to the definition of the complete catalog of human genes and transcripts, because it appears to be particularly useful for identification of low abundance transcripts expressed in a restricted set of tissues as well as for the delineation of gene boundaries and alternatively spliced isoforms.