Control of adult neurogenesis by programmed cell death in the mammalian brain

The presence of neural stem cells (NSCs) and the production of new neurons in the adult brain have received great attention from scientists and the public because of implications to brain plasticity and their potential use for treating currently incurable brain diseases. Adult neurogenesis is controlled at multiple levels, including proliferation, differentiation, migration, and programmed cell death (PCD). Among these, PCD is the last and most prominent process for regulating the final number of mature neurons integrated into neural circuits. PCD can be classified into apoptosis, necrosis, and autophagic cell death and emerging evidence suggests that all three may be important modes of cell death in neural stem/progenitor cells. However, the molecular mechanisms that regulate PCD and thereby impact the intricate balance between self-renewal, proliferation, and differentiation during adult neurogenesis are not well understood. In this comprehensive review, we focus on the extent, mechanism, and biological significance of PCD for the control of adult neurogenesis in the mammalian brain. The role of intrinsic and extrinsic factors in the regulation of PCD at the molecular and systems levels is also discussed. Adult neurogenesis is a dynamic process, and the signals for differentiation, proliferation, and death of neural progenitor/stem cells are closely interrelated. A better understanding of how adult neurogenesis is influenced by PCD will help lead to important insights relevant to brain health and diseases. © 2016 Ryu et al.1

Short Term Effects of Repetitive Transcranial Magnetic Stimulation in Patients with Catastrophic Intractable Tinnitus: Preliminary Report

ObjectivesThe short-term effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) in the patients with catastrophic and intractable tinnitus were investigated.MethodsFifteen participants were recruited among patients with catastrophic intractable tinnitus to receive 1 Hz rTMS treatment. Tinnitus severity was assessed before rTMS and directly after sham or real rTMS using the tinnitus handicap inventory (THI) and visual analog scale (VAS).ResultsThere was no statistical difference in the THI score before and after sham stimulation. However, after 5 replications of real rTMS there was statistically significant reduction in THI score. Eight patients showed a decrease of more than 10 in THI score. Patients who showed a vast change in THI score after rTMS also showed a large decrease in their VAS score (r=0.879, P<0.001). Duration of tinnitus and change of THI score showed statistically significant moderate negative correlation (r=-0.637, P=0.011). But in case of VAS, there was no significant difference between VAS and duration of tinnitus.ConclusionAmong total 15 patients with catastrophic intractable chronic tinnitus, eight patients showed some improvement in symptoms after 1 Hz rTMS. rTMS can be considered management modality for intractable tinnitus even with distress as severe as catastrophic stage

Clinical implementation of whole-genome array CGH as a first-tier test in 5080 pre and postnatal cases

<p>Abstract</p> <p>Background</p> <p>Array comparative genomic hybridization (CGH) is currently the most powerful method for detecting chromosomal alterations in pre and postnatal clinical cases. In this study, we developed a BAC based array CGH analysis platform for detecting whole genome DNA copy number changes including specific micro deletion and duplication chromosomal disorders. Additionally, we report our experience with the clinical implementation of our array CGH analysis platform. Array CGH was performed on 5080 pre and postnatal clinical samples from patients referred with a variety of clinical phenotypes.</p> <p>Results</p> <p>A total of 4073 prenatal cases (4033 amniotic fluid and 40 chorionic villi specimens) and 1007 postnatal cases (407 peripheral blood and 600 cord blood) were studied with complete concordance between array CGH, karyotype and fluorescence <it>in situ </it>hybridization results. Among 75 positive prenatal cases with DNA copy number variations, 60 had an aneuploidy, seven had a deletion, and eight had a duplication. Among 39 positive postnatal cases samples, five had an aneuploidy, 23 had a deletion, and 11 had a duplication.</p> <p>Conclusions</p> <p>This study demonstrates the utility of using our newly developed whole-genome array CGH as first-tier test in 5080 pre and postnatal cases. Array CGH has increased the ability to detect segmental deletion and duplication in patients with variable clinical features and is becoming a more powerful tool in pre and postnatal diagnostics.</p

Clinical Approaches for Understanding the Expression Levels of Pattern Recognition Receptors in Otitis Media with Effusion

Objectives. Bacterial infections in the normally sterile environment of the middle ear cavity usually trigger host immune response, whereby the innate immune system plays a dominant role as the host’s first line of defense. We evaluated the expression levels of Toll-like receptors (TLRs)-2,-4,-5,-9, and nucleotide-binding oligomerization domain-containing proteins (NODs)-1 and-2, all of which are related to bacterial infection in pediatric patients with otitis media with effusion (OME). Methods. The study sample consisted of 46 pediatric patients with OME, all of whom had ventilation tubes inserted. The expression levels of TLR-2,-4,-5,-9, NOD-1 and-2 mRNA in middle ear effusion were assessed by polymerase chain reaction (PCR). Difference of pattern recognition receptors (PRRs) expression level by presence of bacteria, ventilation tube insertion rate, and effusion fluid character was assessed. Results. All effusion fluid samples collected from patients with OME showed expression of TLR-2,-4,-5,-9, NOD-1, and-2 mRNA by PCR. However, we found no differences among expression levels of PRRs in relation to characteristics of exudates, presence of bacteria, or frequencies of ventilation tube insertion (P&gt;0.05). Conclusion. Our findings suggest that exudates of OME patients show PRR expressions that are related to the innate immune response regardless of the characteristics of effusion fluid, presence of bacteria in exudates, or frequency o

Linking transcriptional and genetic tumor heterogeneity through allele analysis of single-cell RNA-seq data

Characterization of intratumoral heterogeneity is critical to cancer therapy, as the presence of phenotypically diverse cell populations commonly fuels relapse and resistance to treatment. Although genetic variation is a well-studied source of intratumoral heterogeneity, the functional impact of most genetic alterations remains unclear. Even less understood is the relative importance of other factors influencing heterogeneity, such as epigenetic state or tumor microenvironment. To investigate the relationship between genetic and transcriptional heterogeneity in a context of cancer progression, we devised a computational approach called HoneyBADGER to identify copy number variation and loss of heterozygosity in individual cells from single-cell RNA-sequencing data. By integrating allele and normalized expression information, HoneyBADGER is able to identify and infer the presence of subclone-specific alterations in individual cells and reconstruct the underlying subclonal architecture. By examining several tumor types, we show that HoneyBADGER is effective at identifying deletions, amplifications, and copy-neutral loss-of-heterozygosity events and is capable of robustly identifying subclonal focal alterations as small as 10 megabases. We further apply HoneyBADGER to analyze single cells from a progressive multiple myeloma patient to identify major genetic subclones that exhibit distinct transcriptional signatures relevant to cancer progression. Other prominent transcriptional subpopulations within these tumors did not line up with the genetic subclonal structure and were likely driven by alternative, nonclonal mechanisms. These results highlight the need for integrative analysis to understand the molecular and phenotypic heterogeneity in cancer

Development and Verification of Time-Series Deep Learning for Drug-Induced Liver Injury Detection in Patients Taking Angiotensin II Receptor Blockers: A Multicenter Distributed Research Network Approach

Objectives The objective of this study was to develop and validate a multicenter-based, multi-model, time-series deep learning model for predicting drug-induced liver injury (DILI) in patients taking angiotensin receptor blockers (ARBs). The study leveraged a national-level multicenter approach, utilizing electronic health records (EHRs) from six hospitals in Korea. Methods A retrospective cohort analysis was conducted using EHRs from six hospitals in Korea, comprising a total of 10,852 patients whose data were converted to the Common Data Model. The study assessed the incidence rate of DILI among patients taking ARBs and compared it to a control group. Temporal patterns of important variables were analyzed using an interpretable time-series model. Results The overall incidence rate of DILI among patients taking ARBs was found to be 1.09%. The incidence rates varied for each specific ARB drug and institution, with valsartan having the highest rate (1.24%) and olmesartan having the lowest rate (0.83%). The DILI prediction models showed varying performance, measured by the average area under the receiver operating characteristic curve, with telmisartan (0.93), losartan (0.92), and irbesartan (0.90) exhibiting higher classification performance. The aggregated attention scores from the models highlighted the importance of variables such as hematocrit, albumin, prothrombin time, and lymphocytes in predicting DILI. Conclusions Implementing a multicenter-based time-series classification model provided evidence that could be valuable to clinicians regarding temporal patterns associated with DILI in ARB users. This information supports informed decisions regarding appropriate drug use and treatment strategies

The diagnostic value of circulating tumor DNA in hepatitis B virus induced hepatocellular carcinoma: a systematic review and meta-analysis

Background/Aim New biomarkers are urgently needed to aid in the diagnosis of early stage hepatocellular carcinoma (HCC). We performed a meta-analysis on the diagnostic utility of circulating tumor DNA (ctDNA) levels in patients with hepatitis B virus-induced HCC. Methods We retrieved relevant articles from PubMed, Embase, and the Cochrane Library up to February 8, 2022. Two subgroups were defined; one subset of studies analyzed the ctDNA methylation status, and the other subset combined tumor markers and ctDNA assays. Pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristic curve (AUC) were analyzed. Results Nine articles including 2,161 participants were included. The overall SEN and SPE were 0.705 (95% confidence interval [CI], 0.629-0.771) and 0.833 (95% CI, 0.769-0.882), respectively. The DOR, PLR, and NLR were 11.759 (95% CI, 7.982-17.322), 4.285 (95% CI, 3.098-5.925), and 0.336 (0.301-0.366), respectively. The ctDNA assay subset exhibited an AUC of 0.835. The AUC of the combined tumor marker and ctDNA assay was 0.848, with an SEN of 0.761 (95% CI, 0.659-0.839) and an SPE of 0.828 (95% CI, 0.692-0.911). Conclusions Circulating tumor DNA has promising diagnostic potential for HCC. It can serve as an auxiliary tool for HCC screening and detection, especially when combined with tumor markers