Genetic alterations for epithelial ovarian cancer are insufficiently characterized. Previous studies are limited regarding included histologies, gene numbers, copy number variant (CNV) detection, and ...interpretation of pathway alteration patterns of individual patients.
We sequenced 410 genes to analyze mutations and CNV of 82 ovarian carcinomas, including high-grade serous (n = 37), endometrioid (n = 22) and clear cell (n = 23) histologies. Eligibility for targeted therapy was determined for each patient by a pathway-based approach. The analysis covered DNA repair, receptor tyrosine kinase, PI3K/AKT/MTOR, RAS/MAPK, cell cycle, and hedgehog pathways, and included 14 drug targets.
Postulated PARP, MTOR, and CDK4/6 inhibition sensitivity were most common. BRCA1/2 alterations, PTEN loss, and gain of PIK3CA and CCND1 were characteristic for high-grade serous carcinomas. Mutations of ARID1A, PIK3CA, and KRAS, and ERBB2 gain were enriched in the other histologies. PTEN mutations and high tumor mutational burden were characteristic for endometrioid carcinomas. Drug target downstream alterations impaired actionability in all histologies, and many alterations would not have been discovered by key gene mutational analysis. Individual patients often had more than one actionable drug target.
Genetic alterations in ovarian carcinomas are complex and differ among histologies. Our results aid the personalization of therapy and biomarker analysis for clinical studies, and indicate a high potential for combinations of targeted therapies.
For never-smokers (smoked <100 lifetime cigarettes), lung cancer (LC) has emerged as an important issue. We aimed to investigate the effects of prevalence changes in tobacco smoking and particulate ...matter (PM) 2.5 (PM2.5) levels on LC in Taiwan, in relation to contrasting PM2.5 levels, between Northern Taiwan (NT) and Southern Taiwan (ST).
We reviewed 371,084 patients with LC to assess smoking prevalence and correlations between the incidence of adenocarcinoma lung cancer (AdLC) and non-AdLC. Two subsets were selected to assess different AdLC stage trends and the effect of PM2.5 on survival of patients with AdLC.
From 1995 to 2015, the proportion of male adult ever-smokers decreased from 59.4% to 29.9% whereas the female smoking rate remained low (3.2% to 5.3%). AdLC incidence in males and females increased from 9.06 to 23.25 and 7.05 to 24.22 per 100,000 population, respectively. Since 1993, atmospheric visibility in NT improved (from 7.6 to 11.5 km), but deteriorated in ST (from 16.3 to 4.2 km). The annual percent change in AdLC stages IB to IV was 0.3% since 2009 (95% confidence interval CI: -1.9%–2.6%) in NT, and 4.6% since 2007 (95% CI: 3.3%–5.8%) in ST; 53% patients with LC had never smoked. Five-year survival rates for never-smokers, those with EGFR wild-type genes, and female patients with AdLC were 12.6% in NT and 4.5% in ST (hazard ratio: 0.79, 95% CI: 0.70–0.90).
In Taiwan, greater than 50% of patients with LC had never smoked. PM2.5 level changes can affect AdLC incidence and patient survival.
Virus-encoded microRNAs (miRNAs) have been shown to regulate a variety of biological processes involved in viral infection and viral-associated pathogenesis. Epstein-Barr virus (EBV) is a herpesvirus ...implicated in nasopharyngeal carcinoma (NPC) and other human malignancies. EBV-encoded miRNAs were among the first group of viral miRNAs identified. To understand the roles of EBV miRNAs in the pathogenesis of NPC, we utilized deep sequencing technology to characterize the EBV miRNA transcriptome in clinical NPC tissues. We obtained more than 110,000 sequence reads in NPC samples and identified 44 EBV BART miRNAs, including four new mature miRNAs derived from previously identified BART miRNA precursor hairpins. Further analysis revealed extensive sequence variations (isomiRs) of EBV miRNAs, including terminal isomiRs at both the 5' and 3' ends and nucleotide variants. Analysis of EBV genomic sequences indicated that the majority of EBV miRNA nucleotide variants resulted from post-transcriptional modifications. Read counts of individual EBV miRNA in NPC tissue spanned from a few reads to approximately 18,000 reads, confirming the wide expression range of EBV miRNAs. Several EBV miRNAs were expressed at levels similar to highly abundant human miRNAs. Sequence analysis revealed that most of the highly abundant EBV miRNAs share their seed sequences (nucleotides 2-7) with human miRNAs, suggesting that seed sequence content may be an important factor underlying the differential accumulation of BART miRNAs. Interestingly, many of these human miRNAs have been found to be dysregulated in human malignancies, including NPC. These observations not only provide a potential linkage between EBV miRNAs and human malignancy but also suggest a highly coordinated mechanism through which EBV miRNAs may mimic or compete with human miRNAs to affect cellular functions.
Obesity is a potential risk factor for cognitive deficits in the elder humans. Using a high-fat diet (HFD)–induced obese mouse model, we investigated the impacts of HFD on obesity, metabolic and ...stress hormones, learning performance, and hippocampal synaptic plasticity. Both male and female C57BL/6J mice fed with HFD (3 weeks to 9–12 months) gained significantly more weights than the sex-specific control groups. Compared with the obese female mice, the obese males had similar energy intake but developed more weight gains. The obese male mice developed hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hyperleptinemia, but not hypertriglyceridemia. The obese females had less hyperinsulinemia and hypercholesterolemia than the obese males, and no hyperglycemia and hypertriglyceridemia. In the contextual fear conditioning and step-down passive avoidance tasks, the obese male, but not female, mice showed poorer learning performance than their normal counterparts. These learning deficits were not due to sensorimotor impairment as verified by the open-field and hot-plate tests. Although, basal synaptic transmission characteristics (input–output transfer and paired-pulse facilitation (PPF) ratio) were not significantly different between normal and HFD groups, the magnitudes of synaptic plasticity (long-term potentiation (LTP) and long-term depression (LTD)) were lower at the Schaffer collateral-CA1 synapses of the hippocampal slices isolated from the obese male, but not female, mice, as compared with their sex-specific controls. Our results suggest that male mice are more vulnerable than the females to the impacts of HFD on weight gains, metabolic alterations and deficits of learning, and hippocampal synaptic plasticity.
Several reports have indicated that hypoxia, GLI, and connective tissue growth factor (CTGF) contribute to pulmonary fibrosis in idiopathic pulmonary fibrosis. We investigated the participation of ...mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1)/MEK1/ERK1/GLI-1/2 and activator protein-1 (AP-1) signaling in hypoxia-induced CTGF expression in human lung fibroblasts. Hypoxia time-dependently increased CTGF expression, which was attenuated by the small interfering RNA (siRNA) of GLI-1 (GLI-1 siRNA) and GLI-2 (GLI-2 siRNA) in both human lung fibroblast cell line (WI-38) and primary human lung fibroblasts (NHLFs). Moreover, GLI-1 siRNA and GLI-2 siRNA attenuated hypoxia-induced CTGF-luciferase activity, and the treatment of cells with hypoxia induced GLI-1 and GLI-2 translocation. Furthermore, hypoxia-induced CTGF expression was reduced by an MEK inhibitor (PD98059), MEK1 siRNA, ERK inhibitor (U0126), ERK1 siRNA, and MEKK1 siRNA. Both PD98059 and U0126 significantly attenuated hypoxia-induced CTGF-luciferase activity. Hypoxia time-dependently increased MEKK1, ERK, and p38 MAPK phosphorylation. Moreover, SB203580 (a p38 MAPK inhibitor) also apparently inhibited hypoxia-induced CTGF expression. The treatment of cells with hypoxia induced ERK, GLI-1, or GLI-2 complex formation. Hypoxia-induced GLI-1 and GLI-2 translocation into the nucleus was significantly attenuated by U0126. In addition, hypoxia-induced ERK Tyr204 phosphorylation was impeded by MEKK1 siRNA. Moreover, hypoxia-induced CTGF-luciferase activity was attenuated by cells transfected with AP-1 site mutation in a CTGF construct. Exposure to hypoxia caused a time-dependent phosphorylation of c-Jun, but not of c-Fos. Chromatin immunoprecipitation (ChIP) revealed that hypoxia induced the recruitment of c-Jun, GLI-1, and GLI-2 to the AP-1 promoter region of CTGF. Hypoxia-treated cells exhibited an increase in α-smooth muscle actin (α-SMA) and collagen production, which was blocked by GLI-1 siRNA and GLI-2 siRNA. Overall, these data implied that the MEKK1/MEK1/ERK1/GLI-1/GLI-2, and AP-1 pathways mediated hypoxia-induced CTGF expression in human lung fibroblasts. Furthermore, GLI-1 and GLI-2 found to be involved in hypoxia-induced α-SMA and collagen expression.
Biological and cellular interleukin-6 (IL-6)-related therapies have been used to treat severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure, which prompted further ...exploration of the role of IL-6 in human umbilical cord mesenchymal stem cell (hUCMSC) therapy. Peripheral blood mononuclear cells (PBMCs) were responders cocultured with hUCMSCs or exogenous IL-6. A PBMC suppression assay was used to analyze the anti-inflammatory effects via MTT assay. The IL-6 concentration in the supernatant was measured using ELISA. The correlation between the anti-inflammatory effect of hUCMSCs and IL-6 levels and the relevant roles of IL-6 and IL-6 mRNA expression was analyzed using the MetaCore functional network constructed from gene microarray data. The location of IL-6 and IL-6 receptor (IL-6R) expression was further evaluated. We reported that hUCMSCs did not initially exert any inhibitory effect on PHA-stimulated proliferation; however, a potent inhibitory effect on PHA-stimulated proliferation was observed, and the IL-6 concentration reached approximately 1000 ng/mL after 72 hours. Exogenous 1000 ng/mL IL-6 inhibited PHA-stimulated inflammation but less so than hUCMSCs. The inhibitory effects of hUCMSCs on PHA-stimulated PBMCs disappeared after adding an IL-6 neutralizing antibody or pretreatment with tocilizumab (TCZ), an IL-6R antagonist. hUCMSCs exert excellent anti-inflammatory effects by inducing higher IL-6 levels, which is different from TCZ. High concentration of IL-6 cytokine secretion plays an important role in the anti-inflammatory effect of hUCMSC therapy. Initial hUCMSC therapy, followed by TCZ, seems to optimize the therapeutic potential to treat COVID-19-related acute respiratory distress syndrome (ARDS).
Early recognition and prevention comprise the first ring of the Chain of Survival for in-hospital cardiac arrest (IHCA). We previously developed and internally validated an emergency department (ED) ...triage tool, Emergency Department In-hospital Cardiac Arrest Score (EDICAS), for predicting ED-based IHCA. We aimed to externally validate this novel tool in another ED population. This retrospective cohort study used electronic clinical warehouse data from a tertiary medical center with approximately 130,000 ED visits per year. We retrieved data from 268,208 ED visits over a 2-year period. We selected one ED visit per person and excluded out-of-hospital cardiac arrest or children. Patient demographics and computerized triage information were retrieved, and the EDICAS was calculated to predict the ED-based IHCA. A total of 145,557 adult ED patients were included. Of them, 240 (0.16%) developed IHCA. The EDICAS showed excellent discrimination with an area under the receiver operating characteristic (AUROC) of 0.88. The AUROC of the EDICAS outperformed those of other early warning scores (0.80 for Modified Early Warning Score MEWS and 0.83 for Rapid Emergency Medicine Score REMS) in the same ED population. An EDICAS of 6 or above (i.e., high-risk patients) corresponded to a sensitivity of 33%, a specificity of 97%, and a positive likelihood ratio of 12.2. In conclusion, we externally validated a tool for predicting imminent IHCA in the ED and demonstrated its superior performance over other early warning scores. The real-world impact of the EDICAS warning system with appropriate interventions would require a future prospective study.
The molecular underpinnings of seromucinous borderline tumor (SMBT) – an uncommon ovarian epithelial neoplasm characterized by association with endometriosis, frequent bilateral ovarian involvement, ...and occasional progression to invasive carcinoma – remain poorly understood. Here, we sought to comprehensively characterize the mutational landscape of SMBT and elucidate the clonal relationship between bilateral ovarian SMBTs. We also compared the mutational profiles between SMBTs and concurrent invasive carcinomas. Formalin-fixed, paraffin-embedded tissue specimens were retrieved from 28 patients diagnosed with SMBT. Massively parallel sequencing of 409 cancer-related genes was conducted to identify somatic mutations in 33 SMBT samples and four concurrent invasive carcinoma specimens. TERT promoter mutations were assessed by Sanger sequencing, whereas immunohistochemistry was used as a surrogate tool for detecting deletions or epigenetic silencing of relevant tumor suppressor genes. Twenty-six (92.9%) of the 28 patients were diagnosed with stage I SMBTs. Seven (25%) cases showed bilateral ovarian involvement and 13 (46%) had concomitant endometriosis. Concurrent ovarian carcinomas were identified in three patients, whereas one case had a synchronous endometrial carcinoma. Somatic mutations in the KRAS, PIK3CA, and ARID1A genes were identified in 100, 60.7, and 14.3% of SMBT samples, respectively. In contrast, TERT promoter mutations and DNA mismatch repair deficiencies were absent. Sequencing of paired specimens from patients with bilateral SMBT revealed the presence of at least two shared somatic mutations, suggestive of a clonal relationship. Similarly, we identified shared somatic mutations between SMBT samples and concurrent ovarian carcinoma specimens. Taken together, these findings demonstrated a distinct mutational landscape of SMBT in which (1) KRAS is invariably mutated, (2) PIK3CA is frequently mutated, and (3) TERT promoter mutations and DNA mismatch repair deficiencies are absent. Our findings represent the first extensive characterization of this rare ovarian neoplasm, with potential implications for disease classification and molecular diagnostics.
This brief presents a low-power processor using Photoplethysmography (PPG) for real-time biometric identification (ID) and heart rate (HR) estimation. The proposed processor features a low-power, ...highly-integrated solution by using the algorithm-hardware co-design approach with the proposed compact neural-network topology, model compression flow, and efficient hardware architecture. A prototype chip fabricated in the 180 nm CMOS process occupies an area of 5.80 mm. Measurement results show that the proposed design can operate at 320 KHz and realize simultaneous ID and HR estimation with state-of-the-art prediction performances while consuming 427.0 μW at 1 V. This represents 8.6x, 4.1x, and 32x performance improvements in area, power, and latency, respectively, when compared to the previous works.
To investigate whether the effects of sodium bicarbonate (SB) during cardiopulmonary resuscitation (CPR) would be influenced by blood pH and administration timing. Adult patients experiencing ...in-hospital cardiac arrest (IHCA) from 2006 to 2015 were retrospectively screened. Early intra-arrest blood gas data were obtained within 10 min of CPR. Multivariable logistic regression analysis and generalised additive models were used for effect estimation and data exploration, respectively. A total of 1060 patients were included. Only 59 patients demonstrated favourable neurological status at hospital discharge. Blood pH ≤ 7.18 was inversely associated with favourable neurological outcome (odds ratio OR, 0.24; 95% confidence interval CI, 0.11-0.52; p value < 0.001) while SB use was not. In the interaction analysis for favourable neurological outcome, significant interactions were noted between SB use and time to SB (SB use × time to SB ≥ 20 min; OR 6.16; 95% CI 1.42-26.75; p value = 0.02). In the interaction analysis for survival to hospital discharge, significant interactions were noted between SB use and blood pH (Non-SB use × blood pH > 7.18; OR 1.56; 95% CI 1.01-2.41; p value = 0.05). SB should not be empirically administered for patients with IHCA since its effects may be influenced by blood pH and administration timing.
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