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Cardiorenal syndrome type I (CRS I) is defined as the development of acute kidney injury (AKI) following acute decompensated heart failure (ADHF). The clinical significance of endothelial markers in ADHF-associated AKI has yet to be clarified. This study therefore investigated the biological processes linking ADHF and AKI with the aim of determining whether the plasma markers of endothelial injury and activation are associated with AKI in patients with ADHF. The study prospectively recruited 125 consecutive patients admitted to a coronary critical unit due to ADHF. Patients with and without AKI were compared in terms of soluble thrombomodulin (sTM), angiopoietin (Ang)-1 and -2 plasma levels as well as baseline characteristics. Among the study population, 14 (11.2%) patients developed CRS within 7 days after admission. The hemoglobin levels (median [IQR]11.3[10.8-12.6] vs. 13.5 [12.2-15.0] g/dL

RTL1/PEG11, which has been associated with anxiety disorders, is a retrotransposon-derived imprinted gene in the placenta. However, imprinting patterns and functions of RTL1 in the brain have not been well-investigated. We found Rtl1 was paternally, but not maternally, expressed in brain stem, thalamus, and hypothalamus of mice, and imprinting status of RTL1 was maintained in human brain. Paternal Rtl1 knockout (Rtl1m+/p-) mice had higher neonatal death rates due to impaired suckling, and low body weights beginning on embryonic day 16.5. High paternal expression of Rtl1 was detected in the locus coeruleus (LC) and Rtl1m+/p- mice showed an increased delay in time of onset for action potentials and inward currents with decreased neuronal excitability of LC neurons. Importantly, Rtl1m+/p- mice exhibited behaviors associated with anxiety, depression, fear-related learning and memory, social dominance, and low locomotor activity. Taken together, our findings demonstrate RTL1 is imprinted in brain, mediates emotional and social behaviors, and regulates excitability in LC neurons.

Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.

Diabetes mellitus is associated with a high risk of developing gastric cancer (GC). Metformin, which is conventionally used to treat type 2 diabetes, induces AMP-activated protein kinase signaling and suppresses gluconeogenesis. Recent studies have reported that metformin is associated with beneficial effects in cancer prevention and treatment owing to its anti-tumor effects. This makes metformin a potential medication for GC therapy. However, contradicting reports have emerged regarding the efficacy of metformin in reducing the risk of GC. This review summarizes the impact of metformin on mitigating GC risk by analyzing clinical databases. The mechanism underlying the anti-tumor effect of metformin on GC is also discussed.

Background There are few studies demonstrating how the effectiveness of various extents of Non-Pharmaceutical Interventions (NPIs) before and after vaccination periods. The study aimed to demonstrate such an effectiveness in the alteration of the epidemic curves from theory to practice. Methods The empirical data on the daily reported COVID-19 cases were extracted from open source. A computer simulation design in conjunction with the susceptible-exposed-infected-recovered (SEIR) type model was applied to evaluating confinement measures in Italy with adjustment for underreported cases; isolation and quarantine in Taiwan; and NPIs and vaccination in Israel. Results In Italy scenario, the extents of confinement measures were 34% before the end of March and then scaled up to 70% after then. Both figures were reduced to 22-69% after adjusting for underreported cases. Approximately 44% of confinement measures was implemented in the second surge of pandemic in Italy. Fitting the observational data on Taiwan assuming the initial outbreak similar to Wuhan, China, 44% of isolation and quarantine was estimated before 23th March 2020. Isolation and quarantine were scaled up to 90% and at least 60% to contain community-acquired outbreaks from March 24th 2020 onwards. Given 15% monthly vaccination rate from December 2020 in Israel, the effectiveness estimates of reducing the infected toll were 36%, 56%, and 85% for NPIs alone, vaccination alone, and both combined, respectively. Conclusion We demonstrated how various NPIs stamp out and delay the epidemic curve of COVID-19. The optimal implementation of these NPIs has to be planned before wide vaccine uptake worldwide.

Background Toll‐like receptor (TLR)‐7‐associated rhinovirus (RV) activation is involved in the pathogenesis of asthma. Plasmacytoid dendritic cells (pDCs) are the main interferon‐α‐producing cells against viruses. Objective To determine whether asthmatic patients and control subjects differ in terms of interferon‐α expression in pDCs under TLR‐7 or RV stimulation. Methods pDCs were identified in BDCA‐2+ and HLA‐DR+ peripheral blood mononuclear cells. Interferon‐α expression of pDCs was analyzed after TLR‐7 stimulation with or without interleukin 4 (IL‐4)/IL‐13 pretreatment. Interferon‐α expression was also analyzed after RV stimulation over periods of 24, 48, or 96 h with or without IL‐4 pretreatment. RV detection and molecular typing were assayed from throat swabs. Results Following TLR‐7 stimulation, the expression of intracellular interferon‐α was higher in the pDCs of normal subjects than those of asthmatic patients; however, pretreatment with IL‐4 was shown to reduce this effect. After 48‐ and 96‐h RV stimulation, we observed a notable increase in the production of interferon‐α of pDCs in normal subjects but not in asthmatic patients. Baseline interferon‐α expression in pDCs and the incidence of asthma exacerbation to emergency was higher among the 13% of patients identified as rhinovirus+ than among their RV counterparts. Conclusion Our study discovered the response to TLR‐7 stimulation in pDCs was compromised and the sustainability of interferon‐α expression to RV stimulation was reduced in pDCs of asthmatic patients, which provide further evidence of defective innate response and subspeciality to RV infection in asthma. The high exacerbation history founded in RV+ patients agrees with these findings. Further research is required for the modulatory effect of IL‐4 on TLR‐7 stimulated pDCs., Our study discovered the response to TLR‐7 stimulation in pDCs was compromised and the sustainability of interferon‐a expression to RV stimulation was reduced in pDCs of asthmatic patients, which provide further evidence of defective innate response and subspeciality to RV infection in asthma. The high exacerbation history founded in RV+ patients agrees with these findings.

Pseudouridine (Ψ) is an RNA base modification ubiquitously found in many types of RNAs. In humans, the isomerization of uridine is catalyzed by different stand-alone pseudouridine synthases (PUS). Genomic mutations in the human pseudouridine synthase 3 gene (PUS3) have been identified in patients with neurodevelopmental disorders. However, the underlying molecular mechanisms that cause the disease phenotypes remain elusive. Here, we utilize exome sequencing to identify genomic variants that lead to a homozygous amino acid substitution (p.[(Tyr71Cys)];[(Tyr71Cys)]) in human PUS3 of two affected individuals and a compound heterozygous substitution (p.[(Tyr71Cys)];[(Ile299Thr)]) in a third patient. We obtain wild-type and mutated full-length human recombinant PUS3 proteins and characterize the enzymatic activity in vitro. Unexpectedly, we find that the p.Tyr71Cys substitution neither affect tRNA binding nor pseudouridylation activity in vitro, but strongly impair the thermostability profile of PUS3, while the p.Ile299Thr mutation causes protein aggregation. Concomitantly, we observe that the PUS3 protein levels as well as the level of PUS3-dependent Ψ levels are strongly reduced in fibroblasts derived from all three patients. In summary, our results directly illustrate the link between the identified PUS3 variants and reduced Ψ levels in the patient cells, providing a molecular explanation for the observed clinical phenotypes.

BackgroundTreatment responsiveness to corticosteroids is excellent for cryptogenic organizing pneumonia (COP) and sarcoidosis, but suboptimal for idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). We hypothesise that the differential expression of IL-17 contributes to variable corticosteroid sensitivity in different interstitial lung diseases.ObjectiveTo determine the associations among expression of IL-17, glucocorticoid receptor-β and responsiveness to corticosteroid treatment in interstitial lung diseases.MethodsImmunohistochemical (IHC) staining was performed on formalin-fixed paraffin-embedded (FFPE) lung tissues obtained by bronchoscopic, CT-guided or surgical biopsies, and quantified by both cell counting (% positive cells) by individuals and by software IHC Profiler plugin of ImageJ (opacity density score). We studied the effect of IL-17 on corticosteroid sensitivity in human fibroblast MRC5 cell line.ResultsCompared with specimens from patients with COP (n =13) and sarcoidosis (n =13), those from IPF patients (n = 21) had greater GR-β and IL-17 expression and neutrophil infiltration. Radiographic progression after oral corticosteroid treatment was positively correlated with the expression in IL-17 and GR-β/GR-α ratio in all patients (COP, sarcoidosis and IPF) and also within the IPF subgroup only. IL-17 expression level was positively associated with GR-β and GR-β/GR-α ratio. In MRC5 cells, exogenous IL-17 increased the production of collagen I and up-regulated GR-β expression and dexamethasone’s suppressive effect on collagen I production was impaired by IL-17, and silencing IL-17 receptor A gene attenuated the effect of IL-17.ConclusionUp-regulation of GR-β/GR-α ratio by IL-17 could be associated with the relative corticosteroid-insensitivity of IPF.

STUDY OBJECTIVES: Polysomnography is the gold standard in identifying sleep stages; however, there are discrepancies in how technicians use the standards. Because organizing meetings to evaluate this discrepancy and/or reach a consensus among multiple sleep centers is time-consuming, we developed an artificial intelligence system to efficiently evaluate the reliability and consistency of sleep scoring and hence the sleep center quality. METHODS: An interpretable machine learning algorithm was used to evaluate the interrater reliability (IRR) of sleep stage annotation among sleep centers. The artificial intelligence system was trained to learn raters from 1 hospital and was applied to patients from the same or other hospitals. The results were compared with the experts’ annotation to determine IRR. Intracenter and intercenter assessments were conducted on 679 patients without sleep apnea from 6 sleep centers in Taiwan. Centers with potential quality issues were identified by the estimated IRR. RESULTS: In the intracenter assessment, the median accuracy ranged from 80.3%–83.3%, with the exception of 1 hospital, which had an accuracy of 72.3%. In the intercenter assessment, the median accuracy ranged from 75.7%–83.3% when the 1 hospital was excluded from testing and training. The performance of the proposed method was higher for the N2, awake, and REM sleep stages than for the N1 and N3 stages. The significant IRR discrepancy of the 1 hospital suggested a quality issue. This quality issue was confirmed by the physicians in charge of the 1 hospital. CONCLUSIONS: The proposed artificial intelligence system proved effective in assessing IRR and hence the sleep center quality. CITATION: Liu G-R, Lin T-Y, Wu H-T, et al. Large-scale assessment of consistency in sleep stage scoring rules among multiple sleep centers using an interpretable machine learning algorithm. J Clin Sleep Med. 2021;17(2):159–166.

The novel coronavirus disease 2019 (COVID-19), with first presentation of atypical pneumonia, has spread rapidly from Wuhan, China, on December 12, 2019 to over 200 countries, caused 2 310 572 infected individuals and 158 691 mortalities, updated on April 19, 2020. Many studies have published timely to help global healthcare workers to understand and control the disease. Vulnerable patients with risk factors such as elderly, cardiovascular diseases (eg, hypertension, coronary disease, or cardiomyopathy), diabetes, and chronic kidney disease have worse outcomes after COVID-19 infection. COVID-19 could directly cause cardiovascular injuries such as pericarditis, myocarditis, myocardial infarction, heart failure, arrhythmias, or thromboembolic events, which urge cardiologists to be involved in the frontline to practice. Here, we provide a review of COVID-19 on cardiovascular system to assist clinical cardiologists to better understand the disease and being capable of providing comprehensive medical support.

Numerous sonographic modalities and parameters have been used to diagnose carpal tunnel syndrome (CTS), with varying accuracy. Our umbrella review aimed to summarize the evidence from systematic reviews and meta-analyses regarding the use of ultrasound imaging to diagnose CTS.Systematic reviews and meta-analyses meeting the inclusion criteria were searched in PubMed, Embase, Medline, Web of Science, and Cochrane databases from inception to March 2022. Critical appraisal, data extraction, and synthesis were performed in accordance with the criteria for conducting an umbrella review.Sixteen reviews were included. Three reviews were classified as high quality, one as moderate, four as low, and eight as critically low. The cross-sectional area (CSA) of the median nerve at the carpal tunnel inlet demonstrated the best reliability and diagnostic accuracy among multiple parameters. A cutoff CSA value of 9-10.5 mmSonography is a reliable tool to diagnose CTS, with inlet CSA being the most robust parameter. Sonoelastography and Doppler ultrasound can serve as auxiliary tools to confirm CTS diagnoses. Further studies are needed to expand the use of sonography for diagnosing CTS, especially in the presence of concomitant neuromuscular disease(s).

Uremic pericarditis and pericardial effusion are possible complications among patients with end-stage renal disease. The accumulation of toxic metabolites may contribute to the pathogenesis of uremic pericarditis. Bleeding diathesis in peritoneal dialysis patients raises the risk of hemorrhagic pericardial tamponade, which is a fatal complication of peritoneal dialysis. We report a case of hemorrhagic pericardial tamponade who was non-adherent to peritoneal dialysis with initial presentation of hypotension and syncope. Transthoracic echocardiogram revealed septated, fibrinoid pericardial effusion and right ventricular diastolic compression. A massive bloody pericardial effusion was drained when he underwent the pericardial window procedure. There was a significant improvement both in his clinical condition and in the echocardiogram images after the procedure. Hemorrhagic pericardial tamponade occurs in uremic patients but is rarely seen in those undergoing peritoneal dialysis. Early diagnosis, immediate surgical drainage, and regular follow-up with echocardiography are crucial to achieve better prognoses in future similar clinical scenarios.

In the face of rapid emerging variants of concern (VOCs) with potential of evading immunity from Beta to Omicron and uneven distribution of different vaccine brands, a mix-match strategy has been considered to enhance immunity. However, whether increasing immunogenicity using such a mix-match can lead to high clinical efficacy, particularly when facing Omicron pandemic, still remains elusive without using the traditional phase 3 trial. The aim of this study is to demonstrate how to evaluate correlates of protection (CoP) of the mix-match vaccination.Data on neutralizing antibody (NtAb) titers and clinical efficacy against Wuhan or D614G strains of homologous ChAdOx1 nCov-19 or mRNA-1273 and heterologous vaccination were extracted from previous studies for demonstration. The reductions in NtAb titers of homologous vaccination against Beta, Delta, and Omicron variants were obtained from literatures. A Bayesian inversion method was used to derive CoP from homologous to mix-match vaccine. Findings The predicted efficacy of ChAdOx1 nCov-19 and mRNA-1273 for Wuhan or D614G strains was 93 % (89 %-97 %). Given 8 ∼ 11-fold, 2 ∼ 5.5-fold, and 32.5 ∼ 36-fold reduction of NtAb for Beta, Delta, and Omicron variants compared with D614G, the corresponding predictive efficacy of the mix-match ranged from 75.63 % to 73.87 %, 84.87 % to 81.25 %, and 0.067 % to 0.059 %, respectively. Interpretations While ChAdOx1 nCov-19 and mRNA-1273 used for demonstrating how to timely evaluate CoP for the mix-match vaccine still provides clinical efficacy against Beta and Delta VOCs but it appears ineffective for Omicron variants, which highlights the urgent need for next generation vaccine against Omicron variant.

Peritoneal dissemination is the most frequent metastatic route of ovarian cancer. However, due to the high heterogeneity in ovarian cancer, most conventional studies lack parental tumor controls relevant to metastases and, thus, it is difficult to trace the molecular changes of cancer cells along with the selection by the abdominal microenvironment. Here, we established an in vivo mouse peritoneal dissemination scheme that allowed us to select more aggressive sublines from parental ovarian cancer cells, including A2780 and SKOV‐3. Microarray and gene profiling analyses indicated that autophagy‐related genes were enriched in selected malignant sublines. Detection of LC3‐II, p62 and autophagic puncta demonstrated that these malignant variants were more sensitive to autophagic induction when exposed to diverse stress conditions, such as high cell density, starvation and drug treatment. As compared with parental A2780, the selected variant acquired the ability to grow better under high‐density stress; however, this effect was reversed by addition of autophagic inhibitors or knockdown of ATG5. When analyzing the clinical profiles of autophagy‐related genes identified to be enriched in malignant A2780 variant, 73% of them had prognostic significance for the survival of ovarian cancer patients. Taken together, our findings indicate that an increase in autophagic potency among ovarian cancer cells is crucial for selection of metastatic colonies in the abdominal microenvironment. In addition, the derived autophagic gene profile can not only predict prognosis well but can also be potentially applied to precision medicine for identifying those ovarian cancer patients suitable for taking anti–autophagy cancer drugs.

Background Global transmission from imported cases to domestic cluster infections is often the origin of local community-acquired outbreaks when facing emerging SARS-CoV-2 variants. Objective We aimed to develop new surveillance metrics for alerting emerging community-acquired outbreaks arising from new strains by monitoring the risk of small domestic cluster infections originating from few imported cases of emerging variants. Methods We used Taiwanese COVID-19 weekly data on imported cases, domestic cluster infections, and community-acquired outbreaks. The study period included the D614G strain in February 2020, the Alpha and Delta variants of concern (VOCs) in 2021, and the Omicron BA.1 and BA.2 VOCs in April 2022. The number of cases arising from domestic cluster infection caused by imported cases (Dci/Imc) per week was used as the SARS-CoV-2 strain-dependent surveillance metric for alerting local community-acquired outbreaks. Its upper 95% credible interval was used as the alert threshold for guiding the rapid preparedness of containment measures, including nonpharmaceutical interventions (NPIs), testing, and vaccination. The 2 metrics were estimated by using the Bayesian Monte Carlo Markov Chain method underpinning the directed acyclic graphic diagram constructed by the extra-Poisson (random-effect) regression model. The proposed model was also used to assess the most likely week lag of imported cases prior to the current week of domestic cluster infections. Results A 1-week lag of imported cases prior to the current week of domestic cluster infections was considered optimal. Both metrics of Dci/Imc and the alert threshold varied with SARS-CoV-2 variants and available containment measures. The estimates were 9.54% and 12.59%, respectively, for D614G and increased to 14.14% and 25.10%, respectively, for the Alpha VOC when only NPIs and testing were available. The corresponding figures were 10.01% and 13.32% for the Delta VOC, but reduced to 4.29% and 5.19% for the Omicron VOC when NPIs, testing, and vaccination were available. The rapid preparedness of containment measures guided by the estimated metrics accounted for the lack of community-acquired outbreaks during the D614G period, the early Alpha VOC period, the Delta VOC period, and the Omicron VOC period between BA.1 and BA.2. In contrast, community-acquired outbreaks of the Alpha VOC in mid-May 2021, Omicron BA.1 VOC in January 2022, and Omicron BA.2 VOC from April 2022 onwards, were indicative of the failure to prepare containment measures guided by the alert threshold. Conclusions We developed new surveillance metrics for estimating the risk of domestic cluster infections with increasing imported cases and its alert threshold for community-acquired infections varying with emerging SARS-CoV-2 strains and the availability of containment measures. The use of new surveillance metrics is important in the rapid preparedness of containment measures for averting large-scale community-acquired outbreaks arising from emerging imported SARS-CoV-2 variants.

Prolonged mechanical ventilation (PMV) is associated with poor outcomes and a high economic cost. The association between protein intake and PMV has rarely been investigated in previous studies. This study aimed to investigate the impact of protein intake on weaning from mechanical ventilation. Patients with the PMV (mechanical ventilation ≥6 h/day for ≥21 days) at our hospital between December 2020 and April 2022 were included in this study. Demographic data, nutrition records, laboratory data, weaning conditions, and survival data were retrieved from the patient’s electronic medical records. A total of 172 patients were eligible for analysis. The patients were divided into two groups: weaning success (n = 109) and weaning failure (n = 63). Patients with daily protein intake greater than 1.2 g/kg/day had significant shorter median days of ventilator use than those with less daily protein intake (36.5 vs. 114 days, respectively, p < 0.0001). Daily protein intake ≥1.065 g/kg/day (odds ratio: 4.97, p = 0.033), daily protein intake ≥1.2 g/kg/day (odds ratio: 89.07, p = 0.001), improvement of serum albumin (odds ratio: 3.68, p = 0.027), and BMI (odds ratio: 1.235, p = 0.014) were independent predictor for successful weaning. The serum creatinine level in the 4th week remained similar in patients with daily protein intake either >1.065 g/kg/day or >1.2 g/kg/day (p = 0.5219 and p = 0.7796, respectively). Higher protein intake may have benefits in weaning in patients with PMV and had no negative impact on renal function.

Cannulation in low birth weight (LBW) neonates using larger sheaths could increase the risk of vascular injury. This study investigated the relationship between body weight (BW) and diameter of femoral vessels in LBW neonates and whether BW can be used to predict femoral vessel diameter.The cohort included 100 neonates weighing 2.5 kg (.57-2.42 kg) with a gestational age of 24-39 weeks. Vascular ultrasonography was used to measure diameters of the bilateral femoral arteries (FA) and veins (FV). The cohort was divided into four groups according to weight: group-A, 2-2.49 kg (n = 28); group-B, 1.5-1.99 kg (n = 38); group-C, 1-1.49 kg (n = 21); and group-D, 1 kg (n = 13); or according to BSA: group-A, BSA .16 mThe median vessel diameters (mm) in groups A-D according to weight were FA, 1.96, 1.86, 1.78, and 1.53, and FV, 2.30, 2.28, 2.13, and 1.87, respectively. The median vessel diameters (mm) in groups A-D according to BSA were FA, 1.96, 1.86, 1.76, and 1.53, and FV, 2.30, 2.28, 2.05, and 1.87, respectively. There were positive correlations between BW and femoral vessel diameter (correlation coefficient: .56 and .55 between BW and FA and FV, respectively) (p 0.001), and between BSA and femoral vessel diameter (correlation coefficient: .56 and .55 between BSA and FA and FV, respectively) (p 0.001).BW is a predictor of femoral vessel diameter in LBW newborns. This finding may help to avoid using larger sheath in smaller vessels.

The TGF-β superfamily members and their antagonists comprise an indispensable system that controls mammalian ovarian development in a sophisticated manner. In contrast to a plethora of studies on the ovary-expressed TGF-β superfamily members, knowledge regarding their antagonists, including their expression profiles and antagonism preferences, is still lacking. Using quantitative PCR in rats and transcriptomic dataset comparisons in mice and humans, we set out to characterize the relative expression levels of most antagonists in the mammalian ovary. We found that Twsg1 and Nbl1 are the most abundant BMP antagonists expressed in the rodent and human ovaries, respectively. TWSG1 has been reported to have synergistic action with the chordin subfamily, including CHRD and CHRDL1, the genes of which also showed moderate expression in the mammalian ovary. Therefore, their ovarian expression profiles and antagonisms against the ovary-expressed TGF-β superfamily members were further characterized. Bioactivity tests indicated that TWSG1 alone can directly inhibit the signaling of BMP6 or BMP7. In addition, it can further enhance the antagonizing ability of CHRD towards BMP2, BMP4, BMP7 and GDF5, or CHRDL1's antagonism towards BMP2, BMP4, GDF5 and activin A. In combination with their distinct transcript profiles in ovarian compartments, our findings suggest that TWSG1 may work coordinately with CHRD within theca/interstitial shells and also with CHRDL1 in developing granulosa cells; these interactions would modulate the intraovarian functions of the TGF-β superfamily members, such as the control of progesterone production.

Background Global burden of COVID-19 has not been well studied, disability-adjusted life years(DALYs) and value of statistical life(VSL) metrics were therefore proposed to quantify its impacts on health and economic loss globally. Methods The life expectancy, cases, and death numbers of COVID-19 until 30th April 2021 were retrieved from open data to derive the epidemiological profiles and DALYs (including years of life lost (YLL) and years loss due to disability (YLD)) by four periods. The VSL estimates were estimated by using hedonic wage method(HWM) and contingent valuation method(CVM). The estimate of willingness to pay using CVM was based on the meta-regression mixed model. Machine learning method was used for classification. Results Globally, DALYs (in thousands) due to COVID-19 was tallied as 31,930 from Period I to IV. YLL dominated over YLD. The estimates of VSL were US$591 billion and US$5,135 billion based on HWM and CVM, respectively. The estimate of VSL increased from US$579 billion in Period I to US$2160 billion in Period IV using CVM. The higher the human development index(HDI), the higher the value of DALYs and VSL. However, there exits the disparity even at the same level of HDI. Machine learning analysis categorized eight patterns of global burden of COVID-19 with a large variation from US$0.001 billion to US$691.4 billion. Conclusions Global burden of COVID-19 pandemic resulted in substantial health and value of life loss particularly in developed economies. Classifications of such health and economic loss is informative to early preparation of adequate resource to reduce impacts.

It is difficult to draw conclusions about the effect of resistance exercises on information processing speed and inhibitory control from previous studies due to possible underestimations of maximal strength and the lack of information on the intervention programs. To address this issue, a familiarization of resistance exercise was introduced before the strength test, and the repetition-to-fatigue method was used to calculate the 1RM (one repetition max). A two-arm RCT was conducted to evaluate the cognitive effect of resistance exercise. Male adults aged 50–65 years old performed a single bout of multiple joint, structural barbell resistance exercises (back squat, press, and deadlift) with 75% 1RM * 5 repetitions * 3 sets with 2–3 min rest between sets and exercises or a stretching exercise session (active-control intervention). This type of resistance exercise improved the information processing speed measured by Stroop task reaction time (t(23) = − 2.313, p = .030, M = − 16 ms, 95% CI [− 30, − 2]) and decreased the conflict-related neural activity measured by event-related potential N2b in both congruent (t(20) = 2.674, p = .015, M = 2.290 μv, 95% CI [0.504, 4.075]) and incongruent (t(20) = 2.851, p = .018, M = 2.291 μv, 95% CI [0.439, 4.142]) conditions. Resistance exercise significantly improved information processing speed and decrease conflict-related neural activity, but did not change inhibitory control in older adults compared to active control.Trial registration: NCT04534374 (01/09/2020).

BACKGROUND: As Coronavirus disease 2019 (COVID-19) pandemic led to the unprecedent large-scale repeated surges of epidemics worldwide since the end of 2019, data-driven analysis to look into the duration and case load of each episode of outbreak worldwide has been motivated. METHODS: Using open data repository with daily infected, recovered and death cases in the period between March 2020 and April 2021, a descriptive analysis was performed. The susceptible-exposed-infected-recovery model was used to estimate the effective productive number (Rt). The duration taken from Rt > 1 to Rt

To use mammographic tumour features (imaging biomarkers) to identify and investigate breast cancers originating from the terminal ductal lobular units (TDLUs) of the breast in order to overcome the confusion arising from the current histopathology terminology, which calls cancers arising from the TDLUs either "ductal" or "lobular".Prospectively collected data from a randomized controlled mammography screening trial with more than four decades of follow up, and data from the subsequent population-based service screening program in Dalarna County, Sweden, provided the database necessary for studying nonpalpable, primarily screen-detected breast cancer cases in their earliest detectable phases. Large format thick (subgross) and thin section histopathologic images of breast cancers originating from the TDLUs were correlated with their mammographic tumour features (imaging biomarkers) and long-term patient outcome.This systematic correlation indicates that imaging biomarkers can reliably determine the site of origin of breast cancers arising from the terminal ductal lobular units (TDLUs). This breast cancer subgroup has four specific mammographic tumour features: the in situ carcinomas developing from the TDLUs appear as powdery or crushed stone-like calcifications, while the invasive carcinomas appear as stellate/spiculated or circular/oval shaped tumour masses. These features are easily identified with breast imaging, either alone or in combination, unifocal or multifocal. We propose calling breast cancers of TDLU origin acinar adenocarcinoma of the breast (AAB).The era of early detection necessitates rectifying the current, confusing histopathological nomenclature to one that is based on the anatomical site of origin of breast cancers. Invasive cancers originating from the TDLUs are either stellate/spiculated or circular, irrespective of the complex WHO histopathologic terminology. The mortality reduction accomplished by participation in mammography screening is mostly accomplished by identifying and treating the AABs in their non-palpable, early phase. AABs detected when 15 mm diameter with no associated carcinoma originating from the major lactiferous ducts (ductal adenocarcinoma of the breast, DAB) have a good to excellent long-term outcome, irrespective of the current terminology, which tends to lead to overtreatment of these early invasive tumours. The conventionally used prognostic factors, including immunohistochemical biomarkers, fail to identify those 1-14 mm invasive AABs tumours that are eventually fatal. This identification can be made preoperatively by including the characteristic mammographic tumour features, imaging biomarkers, in primary diagnosis, treatment planning, and predicting long-term patient outcome. Forthcoming articles will address breast malignancies originating from structures of the breast other than the TDLUs.

Rationale: The progression of prostate cancer (PCa) to castration-resistant PCa (CRPC) despite continuous androgen deprivation therapy is a major clinical challenge. Over 90% of patients with CRPC exhibit sustained androgen receptor (AR) signaling. KDM4B that removes the repressive mark H3K9me3/2 is a transcriptional activator of AR and has been implicated in the development of CRPC. However, the mechanisms of KDM4B involvement in CRPC remain largely unknown. Here, we sought to demonstrate the molecular pathway mediated by KDM4B in CRPC and to provide proof-of-concept evidence that KDM4B is a potential CRPC target. Methods: CRPC cells (C4-2B or CWR22Rv1) depleted with KDM4B followed by cell proliferation (in vitro and xenograft), microarray, qRT-PCR, Seahorse Flux, and metabolomic analyses were employed to identify the expression and metabolic profiles mediated by KDM4B. Immunoprecipitation was used to determine the KDM4B-c-Myc interaction region. Reporter activity assay and ChIP analysis were used to characterize the KDM4B-c-Myc complex-mediated mechanistic actions. The clinical relevance between KDM4B and c-Myc was determined using UCSC Xena analysis and immunohistochemistry. Results: We showed that KDM4B knockdown impaired CRPC proliferation, switched Warburg to OXPHOS metabolism, and suppressed gene expressions including those targeted by c-Myc. We further demonstrated that KDM4B physically interacted with c-Myc and they were co-recruited to the c-Myc-binding sequence on the promoters of metabolic genes (LDHA, ENO1, and PFK). Importantly, KDM4B and c-Myc synergistically promoted the transactivation of the LDHA promoter in a demethylase-dependent manner. We also provided evidence that KDM4B and c-Myc are co-expressed in PCa tissue and that high expression of both is associated with worse clinical outcome. Conclusions: KDM4B partners with c-Myc and serves as a coactivator of c-Myc to directly enhance c-Myc-mediated metabolism, hence promoting CRPC progression. Targeting KDM4B is thus an alternative therapeutic strategy for advanced prostate cancers driven by c-Myc and AR.

Background The interaction between the pulmonary function and cardiovascular mechanics is a crucial issue, particularly when treating patients with chronic obstructive pulmonary disease (COPD). Synchrogram index is a new parameter that can quantify this interaction and has the potential to apply in COPD patients. Our objective in this study was to characterize cardiorespiratory interactions in terms of cardiorespiratory coupling (CRC) using the synchrogram index of the heart rate and respiratory flow signals in patients with chronic obstructive pulmonary disease. Methods This is a cross-sectional and preliminary data from a prospective study, which examines 55 COPD patients. K-means clustering analysis was applied to cluster COPD patients based on the synchrogram index. Linear regression and multivariable regression analysis were used to determine the correlation between the synchrogram index and the exercise capacity assessed by a six-minute walking test (6MWT). Results The 55 COPD patients were separated into a synchronized group (median 0.89 (0.64–0.97), n = 43) and a desynchronized group (median 0.23 (0.02–0.51), n = 12) based on K-means clustering analysis. Synchrogram index was correlated significantly with six minutes walking distance (r = 0.42, p = 0.001) and distance saturation product (r = 0.41, p = 0.001) assessed by 6MWT, and still was an independent variable by multivariable regression analysis. Conclusion This is the first result studying the heart–lung interaction in terms of cardiorespiratory coupling in COPD patients by the synchrogram index, and COPD patients are clustered into synchronized and desynchronized groups. Cardiorespiratory coupling is associated with exercise capacity in patients with COPD.

Malaria persists as a major health problem due to the spread of drug resistance and the lack of effective vaccines. DNA gyrase is a well-validated and extremely effective therapeutic target in bacteria, and it is also known to be present in the apicoplast of malarial species, including Plasmodium falciparum. This raises the possibility that it could be a useful target for novel antimalarials. To date, characterization and screening of this gyrase have been hampered by difficulties in cloning and purification of the GyrA subunit, which is necessary together with GyrB for reconstitution of the holoenzyme. To overcome this, we employed a library of compounds with specificity for P. falciparum GyrB and assessed them in activity tests utilizing P. falciparum GyrB together with Escherichia coli GyrA to reconstitute a functional hybrid enzyme. Two inhibitory compounds were identified that preferentially inhibited the supercoiling activity of the hybrid enzyme over the E. coli enzyme. Of these, purpurogallin (PPG) was found to disrupt DNA binding to the hybrid gyrase complex and thus reduce the DNA-induced ATP hydrolysis of the enzyme. Binding studies indicated that PPG showed higher-affinity binding to P. falciparum GyrB than to the E. coli protein. We suggest that PPG achieves its inhibitory effect on gyrase through interaction with P. falciparum GyrB leading to disruption of DNA binding and, consequently, reduction of DNA-induced ATPase activity. The compound also showed an inhibitory effect against the malaria parasite in vitro and may be of interest for further development as an antimalarial agent.

Background Postoperative positive pressure lung expansion is associated with decreased pulmonary complications and improved clinical outcomes. The aim of the present study was to compare the differences in post-operative pulmonary complications and clinical outcomes between two groups of study subjects who underwent cardiac surgery; one included subjects who received mechanical insufflation-exsufflation (MI-E) and the other included subjects who received intermittent positive pressure breathing (IPPB) therapy. Methods This retrospective study included 51 subjects, who underwent cardiac surgery in an intensive care unit of a tertiary hospital during the time period from June 2017 to February 2018. After liberation from mechanical ventilation, the subjects received lung expansion therapy by means of two types of positive pressure devices, MI-E (n = 21) or IPPB (n = 30). The pulmonary complications, lung function, and clinical outcomes were compared between the two groups. Results Subjects in both groups displayed similar baseline characteristics and underwent similar types of surgical procedures. Compared to subjects who received non-oscillatory therapy, those who received MI-E therapy had higher post-operative force vital capacity (58.4 ± 4.74% vs. 46.0 ± 3.70%, p = 0.042), forced expiratory volume in one second (62.4 ± 5.23% vs. 46.8 ± 3.83%, p = 0.017), and peak flow rate (67.1 ± 5.53 L vs. 55.7 ± 4.44 L p = 0.111). However, the incidence of chest pain was higher in the MI-E group (n = 13, 61.9%) than in the IPPB group (n = 4, 16.7%; odds ratio, 0.123, 95% confidence interval, 0.03–0.45; p = 0.002). The length of hospital and ICU stay, development of atelectasis, pneumonia, and pleural effusion were similar in both the groups. Conclusion Both IPPB and MI-E therapies have similar effects on preventing post-operative complications in cardiac surgery patients. However, compared to IPPB therapy, MI-E therapy was associated with better-preserved pulmonary function and higher incidence of chest pain.

Few studies quantify a cascade of dynamic transitions on the detailed components of metabolic syndrome (MetS) and subsequent progressions to cardiovascular disease (CVD) and its death. A total of 47,495 subjects repeatedly attending a community-based integrated screening program in Taiwan were recruited. The refined MetS-related classification (RMRC) in relation to five criteria of MetS was defined as free of metabolic disorder (FMD, none of any criteria), mild metabolic disorder (MMD, 1–2 criteria) and MetS. A multistate Markov model was used for modelling such a multistate process. The estimated progression rate from FMD to MMD was 44.82% (95% CI 42.95–46.70%) whereas the regression rate was estimated as 29.11% (95% CI 27.77–30.45%). The progression rate from MMD to MetS was estimated as 6.15% (95% CI 5.89–6.42%). The estimated annual incidence rates of CVD increased with the severity of RMRC, being 1.62% (95% CI 1.46–1.79%) for FMD, 4.74% (95% CI 4.52–4.96%) for MMD, to 20.22% (95% CI 19.52–20.92%) for MetS. The estimated hazard rate of CVD death was 6.1 (95% CI 4.6–7.7) per thousand. Elucidating the dynamics of MetS-related transition and quantifying the incidence and prognosis of CVD provide a new insight into the design and the evaluation of intervention programs for CVD.

The aim of this study was to develop a simplified screening questionnaire to detect the existence of severe obstructive sleep apnea (OSA) in chronic obstructive pulmonary disease (COPD) patients to reduce mortality and hospitalization rates. Seventy-seven stable Asian COPD patients aged 69.2 ± 11.5 years were retrospectively analyzed into the development group. The simplified screening questionnaire was developed from factors identified from sleep surveys and demographic data to predict severe OSA. Receiver operating characteristic (ROC) curve analysis was used to validate the simplified screening questionnaire. Data from another 78 stable COPD patients were used for validation. The apnea-hypopnea index was similar between the development and validation groups (26.3 ± 21.9 and 27.6 ± 21.1, respectively). After logistic regression analysis in the development group, snoring, body mass index ≥27.5 kg/m2, witnessed apnea and coronary artery disease were incorporated into the screening questionnaire to predict OSA. When this questionnaire was applied to the validation group, the results were similar. The simplified screening questionnaire developed is useful in identifying severe OSA in COPD patients.

The tautomeric pair of garcinielliptone FC (GFC) is a novel tautomeric pair of polyprenyl benzophenonoid isolated from the pericarps of Garcinia subelliptica Merr. (G. subelliptica, Clusiaceae), a tree with abundant sources of polyphenols. Our previous report demonstrated that GFC induced apoptosis on various types of human cancer cell lines including chemoresistant human colorectal cancer HT-29 cells. In the present study, we observed that many autophagy-related genes in GFC-treated HT-29 cells were up- and down-regulated using a cDNA microarray containing oncogenes and kinase genes. GFC-induced autophagy of HT-29 cells was confirmed by observing the formation of acidic vesicular organelles, LC3 puncta, and double-membrane autophagic vesicles using flow cytometry, confocal microscopy, and transmission electron microscopy, respectively. Inhibition of AKT/mTOR/P70S6K signaling as well as formation of Atg5-Atg12 and PI3K/Beclin-1 complexes were observed using Western blot. Administration of autophagy inhibitor (3-methyladenine and shRNA Atg5) and apoptosis inhibitor Z-VAD showed that the GFC-induced autophagy was cytotoxic form and GFC-induced apoptosis enhanced GFC-induced autophagy. Our data suggest the involvement of autophagy and apoptosis in GFC-induced anticancer mechanisms of human colorectal cancer.

KS is a prevalent tumor associated with infections with two distinct viruses, KSHV and HIV. Since KSHV and HIV infect distinct cell types, the virus-virus interaction associated with KS formation has focused on secretory factors. HIV Tat is a well-known RNA binding protein secreted by HIV. Here, we revealed LINC00313, an lncRNA upregulated during KSHV lytic reactivation, as a novel HIV Tat-interacting lncRNA that potentially mediates HIV-KSHV interactions. We found that LINC00313 can repress endothelial cell angiogenesis-related properties potentially by interacting with chromatin remodeling complex PRC2 and downregulation of cell migration-regulating genes. An interaction between HIV Tat and LINC00313 contributed to the dissociation of PRC2 from LINC00313 and the disinhibition of LINC00313-induced repression of cell motility. Given that lncRNAs are emerging as key players in tissue physiology and disease progression, including cancer, the mechanism identified in this study may help decipher the mechanisms underlying KS pathogenesis induced by HIV and KSHV coinfection., Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma (KS), an AIDS-defining cancer with abnormal angiogenesis. The high incidence of KS in human immunodeficiency virus (HIV)-infected AIDS patients has been ascribed to an interaction between HIV type 1 (HIV-1) and KSHV, focusing on secretory proteins. The HIV-1 secreted protein HIV Tat has been found to synergize with KSHV lytic proteins to induce angiogenesis. However, the impact and underlying mechanisms of HIV Tat in KSHV-infected endothelial cells undergoing viral lytic reactivation remain unclear. Here, we identified LINC00313 as a novel KSHV reactivation-activated long noncoding RNA (lncRNA) that interacts with HIV Tat. We found that LINC00313 overexpression inhibits cell migration, invasion, and tube formation, and this suppressive effect was relieved by HIV Tat. In addition, LINC00313 bound to polycomb repressive complex 2 (PRC2) complex components, and this interaction was disrupted by HIV Tat, suggesting that LINC00313 may mediate transcription repression through recruitment of PRC2 and that HIV Tat alleviates repression through disruption of this association. This notion was further supported by bioinformatics analysis of transcriptome profiles in LINC00313 overexpression combined with HIV Tat treatment. Ingenuity Pathway Analysis (IPA) showed that LINC00313 overexpression negatively regulates cell movement and migration pathways, and enrichment of these pathways was absent in the presence of HIV Tat. Collectively, our results illustrate that an angiogenic repressive lncRNA, LINC00313, which is upregulated during KSHV reactivation, interacts with HIV Tat to promote endothelial cell motility. These results demonstrate that an lncRNA serves as a novel connector in HIV-KSHV interactions. IMPORTANCE KS is a prevalent tumor associated with infections with two distinct viruses, KSHV and HIV. Since KSHV and HIV infect distinct cell types, the virus-virus interaction associated with KS formation has focused on secretory factors. HIV Tat is a well-known RNA binding protein secreted by HIV. Here, we revealed LINC00313, an lncRNA upregulated during KSHV lytic reactivation, as a novel HIV Tat-interacting lncRNA that potentially mediates HIV-KSHV interactions. We found that LINC00313 can repress endothelial cell angiogenesis-related properties potentially by interacting with chromatin remodeling complex PRC2 and downregulation of cell migration-regulating genes. An interaction between HIV Tat and LINC00313 contributed to the dissociation of PRC2 from LINC00313 and the disinhibition of LINC00313-induced repression of cell motility. Given that lncRNAs are emerging as key players in tissue physiology and disease progression, including cancer, the mechanism identified in this study may help decipher the mechanisms underlying KS pathogenesis induced by HIV and KSHV coinfection.

Algae produce the largest amount of oxygen on earth and are invaluable for human nutrition and biomedicine, as well as for the chemical industry, energy production and agriculture. The mechanisms by which algae can detect and respond to changes in their environments can rely on membrane receptors, including TRP ion channels. Here we present a 3.5-Å resolution cryo-EM structure of the transient receptor potential (TRP) channel crTRP1 from the alga Chlamydomonas reinhardtii that opens in response to increased temperature and is positively regulated by the membrane lipid PIP2. The structure of crTRP1 significantly deviates from the structures of other TRP channels and has a unique 2-fold symmetrical rose-shape architecture with elbow domains and ankyrin repeat domains submerged and dipping into the membrane, respectively. Our study provides a structure of a TRP channel from a micro-organism and a structural framework for better understanding algae biology and TRP channel evolution., Transient receptor potential (TRP) channels are ubiquitous occurring cation-selective sensory ion channels that respond to various stimuli. Here the authors characterize crTRP1 from the alga Chlamydomonas reinhardtii, present its 3.5 Å cryo-EM structure and show that crTRP1 opens in response to increased temperature and is positively regulated by the membrane lipid PIP2.

IntroductionPositive fluid balance is a prognostic factor for mortality in patients with sepsis; however, the association between cumulated fluid balance (CFB) and sepsis-induced multi-organ dysfunction syndrome (MODS) has yet to be elucidated. In this study, we sought to determine whether CFB is correlated with MODS and mortality in cases of septic shock.MethodsThe study retrospectively recruited patients with septic shock from the intensive care unit of a tertiary care hospital. Multiple organ dysfunction syndrome (MODS) was identified as sequential organ failure assessment (SOFA) score ≥ 2 in more than one organ system. The CFB is the sum of all daily intake and output. An independent t-test, single and multivariate logistic regression, the receiver operating characteristic (ROC) curves, and the Pearson correlation coefficient were used to determine whether a relationship exists between CFB and the development of MODS and mortality.ResultsAmong the 104 patients enrolled in the study, 58 (55.8%) survived more than 28 days, and 73 (70.2%) developed MODS on day 3. The values of CFB in the first 24 hours and 72 hours after diagnosis of septic shock in patients with MODS were higher than these in patients without MODS (1086.6 ± 176.3 vs. 325.5 ± 205.7 ml, p = 0.013 and 2408 ± 361 vs. 873.1 ± 489 ml, p < 0.0001). In a multivariate logistic regression, the independent factors associated with the development of MODS on day 3 were APACHE II score at ICU admission (27.6 ± 7.6 in patients with MODS vs. 20.5 ± 6.4 in those without; O.R. 1.18; 95% C.1 I. 1.08-1.30; p < 0.001), disseminated intravascular coagulopathy (DIC) (n = 28; 38.4% vs. n = 2; 6.5%; O.R. 23.67; 95% C.I. 3.58-156.5; p = 0.001), and CFB in the first 72 hours (72-hr CFB) > median (1767.50ml) (n = 41; 56.2% vs. n = 11; 35.5%; O.R. 3.67; 95% C.I., 1.18-11.40; p = 0.024). Moreover, a multivariate logistic regression also identified neoplasm (n = 25; 54.3% vs. n = 17; 29.3%; O.R. 3.45; 95% C.I. 1.23-10.0; p = 0.019) and 72-hr CFB > median (n = 30; 65.2% vs. n = 21; 36.2%; O.R. 4.13; 95% C.I. 1.34-12.66; p = 0.013) as independent factors associated with 28-day mortality. 72-hr CFB values were strongly correlated with the SOFA score (r = 0.445, p < 0.0001). The area under the ROC curve revealed that 72-hr CFB has good discriminative power in associating the development of MODS (0.644, p = 0.002) and predicting subsequent 28-day mortality (0.704, p < 0.0001).Conclusions72-hr CFB appears to be correlated with the likelihood of developing MODS and mortality in patients with septic shock. Thus, it appears that 72-hr CFB could perhaps be used as an indicator for MODS and a predictor for mortality in those patients.

Aflatoxins are carcinogenic secondary metabolites of fungi that contaminate many staple crops and foods. Aflatoxin contamination is a worldwide problem, especially in developing countries, posing health hazards, e.g., causing aflatoxicosis and hepatocellular carcinoma, and even death. Biological solutions for aflatoxin detoxification are environmentally friendly and a cheaper alternative than chemical methods. The aims of the current study were to investigate: (1) the ability of MSMEG_5998, an aflatoxin-degrading F420H2-dependent reductase from Mycobacterium smegmatis, to degrade aflatoxin B1 (AFB1) and reduce AFB1-caused damage in HepG2 cell culture model, and (2) whether a thioredoxin (Trx) linkage of MSMEG_5998 enhanced the enzyme activity. We show that Trx-linked MSMEG_5998 degraded 63% AFB1 and native MSMEG_5998 degraded 31% after 4 h at 22 &deg, C, indicating that the Trx-linked enzyme had a better AFB1-degrading ability. In a HepG2 cell culture model, Trx-linked MSMEG_5998 reduced DNA damage and p53-mediated apoptosis caused by AFB1 to a greater extent than the native enzyme. These findings suggest that Trx-linked MSMEG_5998 could potentially be developed to protect the liver from AFB1 damage, or as a candidate protein to reduce AFB1-related toxicity in animals.

Elp3, the catalytic subunit of the eukaryotic Elongator complex, is a lysine acetyltransferase that acetylates the C5 position of wobble-base uridines (U34) in transfer RNAs (tRNAs). This Elongator-dependent RNA acetylation of anticodon bases affects the ribosomal translation elongation rates and directly links acetyl-CoA metabolism to both protein synthesis rates and the proteome integrity. Of note, several human diseases, including various cancers and neurodegenerative disorders, correlate with the dysregulation of Elongator’s tRNA modification activity. In this review, we focus on recent findings regarding the structure of Elp3 and the role of acetyl-CoA during its unique modification reaction.

ObjectivesThe role of faecal haemoglobin as a colorectal cancer screening tool has been demonstrated. However, the association between the faecal haemoglobin concentration and the risk of cardiovascular disease events and deaths is still unclear.DesignCohort study design.SettingPopulation-based organised integrated service screening in Keelung City, TaiwanParticipantsA total of 33 355 healthy individuals aged over 40 years who were free of cardiovascular disease at study entry were followed up.Main outcomes and measuresNewly diagnosed cardiovascular disease events and deaths.ResultsAfter a median follow-up of 2.39 years, a total of 2768 participants developed cardiovascular events, and after a median follow-up of 8.43 years, 317 cases of cardiovascular deaths occurred. The risk of cardiovascular disease increased with baseline faecal haemoglobin in a dose–response manner, yielding a significant elevated risk of cardiovascular disease in parallel with the incremental concentration of faecal haemoglobin (adjusted HRs=1.04, 1.10, 1.40 and 1.23 for faecal haemoglobin concentrations of 1–19, 20–49, 50–99 and ≥100 ng/mL, trend test, pConclusionsOur data support that faecal haemoglobin concentrations may be associated with the risk of cardiovascular diseases. The biological mechanisms underlying the role of faecal haemoglobin as health outcomes should be investigated.

Activating mutations in

Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF). This repair capacity is overwhelmed when cytosolic THF hyperaccumulates in the absence of mitochondrially produced formate, leading to THF degradation. Unexpectedly, we also find that the classic antifolate methotrexate, by inhibiting its well-known target DHFR, causes even more extensive folate degradation in nearly all tested cancer cell lines. These findings shed light on designfeatures of folate metabolism, provide a biochemical basis for clinically observed folate deficiency in QDPR-deficient patients, and reveal a hitherto unknown and unexplored cellular effect of methotrexate.

Capnography involves the measurement of end-tidal CO2 (EtCO2) values to detect hypoventilation in patients undergoing sedation. In a previous study, we reported that initiating a flexible bronchoscopy (FB) examination only after detecting signs of hypoventilation could reduce the risk of hypoxemia without compromising the tolerance of the patient for this type of intervention. We hypothesize that hypoventilation status could be determined with greater precision by combining thoracic impedance-based respiratory signals, RESP, and EtCO2 signals obtained from a nasal-oral cannula. Retrospective analysis was conducted on RESP and EtCO2 waveforms obtained from patients during the induction of sedation using propofol for bronchoscopic examination in a previous study. EtCO2 waveforms associated with hypoventilation were then compared with RESP patterns, patient variables, and sedation outcomes. Signals suitable for analysis were obtained from 44 subjects, 42 of whom presented indications of hypoventilation, as determined by EtCO2 waveforms. Two subtypes of hypoventilation were identified by RESP: central-predominant (n = 22, flat line RESP pattern) and non-central-predominant (n = 20, RESP pattern indicative of respiratory effort with upper airway collapse). Compared to cases of non-central-predominant hypoventilation, those presenting central-predominant hypoventilation during induction were associated with a lower propofol dose (40.2 ± 18.3 vs. 60.8 ± 26.1 mg, p = 0.009), a lower effect site concentration of propofol (2.02 ± 0.33 vs. 2.38 ± 0.44 µg/ml, p = 0.01), more rapid induction (146.1 ± 105.5 vs. 260.9 ± 156.2 s, p = 0.01), and lower total propofol dosage (96.6 ± 41.7 vs. 130.6 ± 53.4 mg, p = 0.04). Hypoventilation status (as revealed by EtCO2 levels) could be further classified by RESP into central-predominant or non-central-predominant types. It appears that patients with central-predominant hypoventilation are more sensitive to propofol during the induction of sedation. RESP values could be used to tailor sedation management specifically to individual patients.

Neuromedin U (NMU) was originally named based on its strong uterine contractile activity, but little is known regarding its signaling/functions in utero. We identified that NMU and one of its receptors, NMUR2, are not only present in normal uterine endometrium but also co-expressed in endometrial cancer tissues, where the NMU level is correlated with the malignant grades and survival of patients. Cell-based assays further confirmed that NMU signaling can promote cell motility and proliferation of endometrial cancer cells derived from grade II tumors. Activation of NMU pathway in these endometrial cancer cells is required in order to sustain expression of various adhesion molecules, such as CD44 and integrin alpha1, as well as production of their corresponding extracellular matrix ligands, hyaluronan and collagen IV; it also increased the activity of SRC and its downstream proteins RHOA and RAC1. Thus, it is concluded that NMU pathway positively controls the adhesion signaling-SRC-Rho GTPase axis in the tested endometrial cancer cells and that changes in cell motility and proliferation can occur when there is manipulation of NMU signaling in these cells either in vitro or in vivo. Intriguingly, this novel mechanism also explains how NMU signaling promotes the EGFR-driven and TGFβ receptor-driven mesenchymal transitions. Through the above axis, NMU signaling not only can promote malignancy of the tested endometrial cancer cells directly, but also helps these cells to become more sensitive to niche growth factors in their microenvironment.

MicroRNA-21 is dysregulated in many cancers and fibrotic diseases. Since miR-21 suppresses several tumor suppressor and anti-apoptotic genes, it is considered a cancer therapeutic target. Antisense oligonucleotides are commonly used to inhibit a miRNA; however, blocking miRNA function via an antagomir is temporary, often only achieves a partial knock-down, and may be complicated by off-target effects. Here, we used transcription activator-like effector nucleases (TALENs) to disrupt miR-21 in cancerous cells. Individual deletion clones were screened and isolated without drug selection. Sequencing and quantitative RT-PCR identified clones with no miR-21 expression. The loss of miR-21 led to subtle but global increases of mRNAs containing miR-21 target sequences. Cells without miR-21 became more sensitive to cisplatin and less transformed in culture and in mouse xenografts. In addition to the increase of PDCD4 and PTEN protein, mRNAs for COL4A1, JAG1, SERPINB5/Maspin, SMAD7, and TGFBI - all are miR-21 targets and involved in TGFβ and fibrosis regulation - were significantly upregulated in miR-21 knockout cells. Gene ontology and pathway analysis suggested that cell-environment interactions involving extracellular matrix can be an important miR-21 pathogenic mechanism. The study also demonstrates the value of using TALEN-mediated microRNA gene disruption in human pathobiological studies.

Three-dimensional (3D) collagen type II-hyaluronan (HA) composite scaffolds (CII-HA) which mimics the extracellular environment of natural cartilage were fabricated in this study. Rheological measurements demonstrated that the incorporation of HA increased the compression modulus of the scaffolds. An initial in vitro evaluation showed that scaffolds seeded with porcine chondrocytes formed cartilaginous-like tissue after 8 weeks, and HA functioned to promote the growth of chondrocytes into scaffolds. Placenta-derived multipotent cells (PDMC) and gingival fibroblasts (GF) were seeded on tissue culture polystyrene (TCPS), CII-HA films, and small intestinal submucosa (SIS) sheets for comparing their chondrogenesis differentiation potentials with those of adipose-derived adult stem cells (ADAS) and bone marrow-derived mesenchymal stem cells (BMSC). Among different cells, PDMC showed the greatest chondrogenic differentiation potential on both CII-HA films and SIS sheets upon TGF-β3 induction, followed by GF. This was evidenced by the up-regulation of chondrogenic genes (Sox9, aggrecan, and collagen type II), which was not observed for cells grown on TCPS. This finding suggested the essential role of substrate materials in the chondrogenic differentiation of PDMC and GF. Neocartilage formation was more obvious in both PDMC and GF cells plated on CII-HA composite scaffolds vs. 8-layer SIS at 28 days in vitro. Finally, implantation of PDMC/CII-HA constructs into NOD-SCID mice confirmed the formation of tissue-engineered cartilage in vivo.

A simple and fast method based on magnetic nanoparticles (MNPs) and capillary zone electrophoresis (CZE) with laser-induced fluorescence (LIF) detection was developed for the detection of C-reactive protein (CRP). To optimize the CZE conditions, several factors including buffer compositions, buffer ionic strength, buffer pH, applied voltage and capillary temperature have been examined. The optimal separation buffer selected was a 30 mM sodium phosphate (PB) buffer, pH 8.0. The optimal CE applied voltage and temperature selected were 20 kV and 35 °C, respectively. The CZE profile of the MNP-1°Ab-CRP-2°Ab/FITC bioconjugates showed good reproducibility. One major peak was observed for the MNP bioconjugates. The quantitative analysis also showed good results. The coefficient of variation (CV%) for the major peak area was 8.7%, and the CV% for the major peak migration time was 2.5%. The linear range for CRP analysis was 10–150 μg/mL, and the concentration limit of detection (LOD) was 9.2 μg/mL. Non-specific interactions between bovine serum albumin (BSA) and the system can be prevented by including 10% (v/v) of human plasma in the binding buffers. The CE/LIF method might be helpful for analyzing high concentrations of CRP in a patient's plasma after an acute-phase inflammation. This new method demonstrated the possibility of using MNPs and CE/LIF for the detection of proteins, and provided information for the establishment of appropriate CE conditions.

We evaluated the antioxidant, antibacterial, and anti-inflammatory activities of honey made from different floral sources, including the medicinal herb Bidens pilosa, fruit trees, Dimocarpus longan, Litchi chinensis, and Citrus maxima, the Taiwanese endemic plant Aglaia formosana, and a multifloral forest. The total phenolic and flavonoid contents of the honey made from B. pilosa were significantly higher than those of the other honeys. The honey from B. pilosa also had significantly greater scavenging activities for 1,1-diphenyl-2-picrylhydrazyl (DPPH·) and hydroxyl radical, and substantially more reducing power. In addition, the honey from B. pilosa showed greater antibacterial activity against gram-positive and gram-negative bacteria. However, B. pilosa honey showed little inhibitory activity against IL-8 secretion, whereas the other honeys did. These findings suggest that the levels of antioxidant and antibacterial activities are attributable to the total phenolic and flavonoid contents of honeys, while the IL-8 inhibition is attributable to components other than phenols.

Gonadotropin signaling plays an indispensable role in ovarian cancer progression. We previously have demonstrated that thyrostimulin and thyroid-stimulating hormone receptor (TSHR), the most ancient glycoprotein hormone and receptor pair that evolved much earlier than the gonadotropin systems, co-exist in the ovary. However, whether thyrostimulin-driven TSHR activation contributes to ovarian cancer progression in a similar way to gonadotropin receptors has never been explored. In this study, we first found that TSHR is expressed in both rat normal ovarian surface epithelium and human epithelial ovarian cancers (EOCs). Using human NIH:OVCAR-3 as a cell model, we demonstrated that thyrostimulin promotes EOC cell proliferation as strongly as gonadotropins. Thyrostimulin treatment not only activated adenylyl cyclase and the subsequent PKA, MEK-ERK1/2 and PI3K-AKT signal cascades, but also trans-activated EGFR signaling. Signaling dissection using diverse inhibitors indicated that EOC cell proliferation driven by thyrostimulin-TSHR signaling is PKA independent, but does require the involvement of the MEK-ERK and PI3K-AKT signal cascades, which are activated mainly via the trans-activation of EGFR. Thus, not only have we proved that this ancient glycoprotein hormone system is involved in NIH:OVCAR-3 cell proliferation for the first time, but also that it may possibly become a novel oncotarget when studying ovarian cancer.

Rationale: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T-cell immunity in tumor-bearing hosts. Their clinical relevance remains unclear.Objectives: To identify subtypes of myeloid-derived suppressor cells in patients with non–small cell lung cancer (NSCLC) and their clinical relevance.Methods: CD11b+CD14− and CD11b+CD14+ cells, determined and phenotyped by fluorescence-activated cell sorter analysis, in the peripheral blood mononuclear cells (PBMCs) of treatment-naive patients with advanced NSCLC were correlated with clinical data. T-cell activation in response to CD3/CD28 costimulation was determined by carboxy-fluorescein diacetate succinimidyl ester (CFSE) staining and ELISA analysis of IFN-γ. The percentage of CD11b+CD14+S100A9+ cells in PBMCs was correlated with and tested as a predictor for treatment response in a cohort of patients prospectively receiving first-line cisplatin-based chemotherapy.Measurements and Main Results: Patients with NSCLC...

Supporting InformationABSTRACT: We previously reported that the anticancer activity of abotanical compound 10′(Z),13′(E),15′(E)-heptadecatrienylhydroquinone[HQ17(3)] was attributed to topoisomerase (Topo) IIα poisoning andthe induction of oxidative damage. HQ17(3) irreversibly inhibits Topo IIαactivity in vitro and is more cytotoxic in leukemia HL-60 cells than inTopo IIα-deficient variant HL-60/MX2 cells, which suggests that Topo IIαis a cellular target of HQ17(3). This study further characterizes themolecular mechanisms of the anticancer activity of HQ17(3). Proteomicanalyses indicated that HQ17(3) reacted with Cys-427, Cys-733, and Cys-997 of recombinant Topo IIα in vitro, whereas it reacted with Cys-427 ofcellular Topo IIα in Huh7 hepatoma cells. The modification of HQ17(3)inhibited Topo IIα catalytic activity, increased the Topo IIα-DNA cleavagecomplex, and caused the accumulation of DNA breakage. In Huh7 cells, HQ17(3) treatment caused prompt inhibition of DNAsynthesis and consequently induced the expression of DNA damage-related genes DDIT3, GADD45A, and GADD45G. Topo IIαinhibition, apoptosis, and oxidative stress were found to account for cytotoxicity caused by HQ17(3). Pretreatment of Huh7 cellswith N-acetylcysteine (NAC) partially attenuated mitochondrial membrane damage, DNA breakage, and caspase activation.However, NAC pretreatment did not diminish HQ17(3)-induced cell death. These results suggest that the anticancer activity ofHQ17(3) is attributed significantly to Topo IIα poisoning. The structural feature of HQ17(3) can be used as a model for thedesign of Topo IIα inhibitors and anticancer drugs.

Our study investigated whether tumor-associated macrophages (TAMs) in advanced non-small cell lung cancer (NSCLC) are related to treatment response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and may be a predictor of survival. Of 206 advanced NSCLC patients treated (first-line) with an EGFR-TKI at the study hospital from 2006 to 2009, 107 with adequate specimens for assessing CD68 immunohistochemistry as a marker of TAMs were assessed. After EGFR-TKI treatment, response was observed in 55 (51%) patients, and the median follow-up period was 13.5 months. Most TAMs were located in the tumor stroma (>95%) and positively costained with the M2 marker CD163. TAM counts were significantly higher in patients with progressive disease than in those without (p < 0.0001), a trend that remained in patients with known EGFR mutation status (n = 59) and those with wild-type EGFR (n = 20). High TAM counts, among other factors (e.g., wild-type EGFR), were significantly related to poor progression-free survival (PFS) and overall survival (OS) (all p < 0.0001 for TAMs). Multivariate Cox analyses showed that high TAM counts and EGFR mutations were both independent factors associated with PFS [odds ratio (OR), 8.0; 95% confidence interval (CI), 2.87-22.4; p = 0.0001 and OR, 0.03; 95% CI, 0.003-0.31; p = 0.003, respectively] and OS (OR, 2.641; 95% CI, 1.08-6.5; p = 0.03 and OR, 0.14; 95% CI, 0.03-0.56; p = 0.006, respectively). TAMs are related to treatment response irrespective of EGFR mutation and can independently predict survival in advanced NSCLC treated with an EGFR-TKI.

Defective or imbalanced expression of spliceosomal factors has been linked to human disease; however, how a defective spliceosome affects intron-containing gene transcripts in human cells is largely unknown. DEAH-box protein DHX16 is a human orthologue of Saccharomyces cerevisiae spliceosomal protein Prp2, an RNA-dependent ATPase that activates the spliceosome before the first catalytic step of splicing. Yeast prp2 mutants accumulate unspliced RNAs from the vast majority of intron-containing genes. Here we used a genomic tiling microarray to screen transcripts from four chromosomes in human cells expressing a dominant negative DHX16 mutant and identified a number of gene transcripts that retained their introns. The mutant protein also affected gene transcripts that are sensitive to pladienolide, an SF3b inhibitor. The unspliced RNAs were retained in the nucleus, and block of nonsense-mediated decay did not affect their accumulation. Thus, a perturbation of human PRP2/DHX16 results in accumulation of unspliced transcripts, similar to the outcome in yeast prp2 mutants. The results further suggest that mutant DHX16/hPRP2 causes a defective spliceosome to retain unspliced gene transcripts in the nuclei of human cells.