TRIP6 promotes neural stem cell maintenance through YAP-mediated Sonic Hedgehog activation.

In the adult mammalian brain, new neurons are continuously generated from neural stem cells (NSCs) in the subventricular zone (SVZ)-olfactory bulb (OB) pathway. YAP, a transcriptional co-activator of the Hippo pathway, promotes cell proliferation and inhibits differentiation in embryonic neural progenitors. However, the role of YAP in postnatal NSCs remains unclear. Here, we showed that YAP was present in NSCs of the postnatal mouse SVZ. Forced expression of Yap promoted NSC maintenance and inhibited differentiation, whereas depletion of Yap by RNA interference or conditional knockout led to the decline of NSC maintenance, premature neuronal differentiation, and collapse of neurogenesis. For the molecular mechanism, thyroid hormone receptor-interacting protein 6 (TRIP6) recruited protein phosphatase PP1A to dephosphorylate LATS1/2, therefore inducing YAP nuclear localization and activation. Moreover, TRIP6 promoted NSC maintenance, cell proliferation, and inhibited differentiation through YAP. In addition, YAP regulated the expression of the Sonic Hedgehog (SHH) pathway effector Gli2 and Gli1/2 mediated the effect of YAP on NSC maintenance. Together, our findings demonstrate a novel TRIP6-YAP-SHH axis, which is critical for regulating postnatal neurogenesis in the SVZ-OB pathway.

A comprehensive study of pre-eclampsia in IVF and natural conceptions: clinical phenotypes, perinatal outcomes and neonatal echocardiography.

RESEARCH QUESTION: What differences exist in the phenotypes of pre-eclampsia, perinatal outcomes and neonatal echocardiography between pregnancies conceived naturally and through IVF? DESIGN: Six hundred and ten women diagnosed with pre-eclampsia between January 2002 and December 2022 were included in this study. This research was conducted within the IVF and Maternal-Fetal Medicine Department of Kaohsiung Chang Gung Memorial Hospital, Taiwan. Participants were divided into two groups: those who achieved pregnancy through IVF, and those who conceived naturally. The phenotypes of pre-eclampsia and perinatal outcomes were assessed using a propensity-matched sample (n = 218), along with neonatal echocardiography. RESULTS: After conducting propensity score matching, the natural conception group had a higher prevalence of early-onset pre-eclampsia (53.9% versus 37.7%, P = 0.04) and exhibited more severe features of pre-eclampsia (89.1% versus 69.8%, P = 0.01) compared with the IVF group. Regarding perinatal outcomes, neonates in the IVF group had higher placental weights compared with the natural conception group (580 versus 480 g, P = 0.031). The prevalence of abnormal findings on neonatal echocardiography was similar between the groups. Multivariate analysis showed that greater gestational age at delivery reduced the likelihood of abnormal findings on echocardiography [adjusted risk ratio (aRR) 0.950, P = 0.001], while pregestational diabetes mellitus increased the likelihood of abnormal findings (aRR 1.451, P = 0.044). Septal defects were the most common type of defect, occurring in 16.1% of infants. CONCLUSION: The impact of IVF conception on the severity of pre-eclampsia is not as expected. Neonatal echocardiography revealed a higher prevalence of abnormalities in offspring of women with pre-eclampsia compared with the general population. However, these issues were not linked to the method of conception, suggesting the existence of undisclosed factors that could influence the clinical features and perinatal outcomes of pre-eclampsia.

A singleton pregnancy with placental chorioangioma and hydrops fetalis complicated with mirror syndrome and ritodrine-induced side effects: a case report.

BACKGROUND: Ritodrine hydrochloride is a widely used beta-adrenergic agonist used to stop preterm labor in Taiwan. Many side effects causing maternal morbidity and mortality have been reported. We report a case complicated with ritodrine-induced side effects and mirror syndrome that was associated with placental chorioangioma. CASE PRESENTATION: A 36-year-old singleton pregnant woman at 25 6/7 weeks of gestation, with an undiagnosed placental chorioangioma, underwent tocolysis due to preterm uterine contractions. Her clinical condition deteriorated, attributed to mirror syndrome and adverse events induced by ritodrine. An emergency cesarean section was performed at 27 1/7 weeks of gestation, delivering an infant with generalized subcutaneous edema. A placental tumor measuring 8.5 cm was discovered during the operation, and pathology confirmed chorioangioma. Gradual improvement in her symptoms and laboratory data was observed during the postpartum period. Identifying mirror syndrome and ritodrine-induced side effects poses challenges. Therefore, this case is educational and warrants discussion. CONCLUSION: Our case demonstrates mirror syndrome induced by chorioangioma, which is rare, and ritodrine-induced side effects. The cessation of intravenous ritodrine and delivery are the best methods to treat maternal critical status due to fluid overload.

Modification of Risk for All-cause and Cardiovascular Disease-related Mortality with Changes in the Body Mass Index in Older Individuals: A Population-based Cohort Study.

INTRODUCTION: Existing evidence evaluating the impact of change in body mass index (BMI) on the risk of all-cause and cardiovascular disease (CVD)-related mortality in older people is limited and inconsistent. This population-based cohort study evaluated the association of changes in BMI over time with all-cause and CVD-related mortality in older adults. METHODS: We recruited 55,351 adults aged over 65 years between 2006-2011 from Taipei Elderly Health Examination Program who underwent repeated annual health examinations at 3.2 year-intervals and were followed-up for mortality over 5.5 years. Cox proportional hazard and Fine-Gray sub-distribution hazard models with death from non-CVD causes as the competing risk were used to determine the impact of changes in BMI status on the risk of all-cause or CVD-related mortality, respectively. RESULTS: Over 227,967 person-years of follow-up, 4,054 participants died, including 940 (23.2%) CVD-related deaths. After adjusting for other covariates, >10% decrease of BMI was significantly associated with a higher risk of all-cause (adjusted hazard ratio [AHR]= 1.93; 95% confidence interval [CI]: 1.74-2.13) and CVD-related mortality (AHR= 1.96; 95%CI: 1.60-2.40), compared with stable BMI. Sensitivity analysis showed that a >10% decrease in BMI was significantly associated with a high risk of all-cause and CVD-related mortality in participants with normal weight, underweight, overweight, or obesity at baseline. DISCUSSION/CONCLUSION: Older adults with >10% decrease in BMI are at high risk of all-cause and CVD-related mortality. Our findings suggest that older individuals experiencing a substantial reduction in BMI should undergo a thorough evaluation to minimize the risks associated with mortality.

Label-Free Three-Dimensional Morphological Characterization of Cell Death Using Holographic Tomography.

This study presents a novel label-free approach for characterizing cell death states, eliminating the need for complex molecular labeling that may yield artificial or ambiguous results due to technical limitations in microscope resolution. The proposed holographic tomography technique offers a label-free avenue for capturing precise three-dimensional (3D) refractive index morphologies of cells and directly analyzing cellular parameters like area, height, volume, and nucleus/cytoplasm ratio within the 3D cellular model. We showcase holographic tomography results illustrating various cell death types and elucidate distinctive refractive index correlations with specific cell morphologies complemented by biochemical assays to verify cell death states. These findings hold promise for advancing in situ single cell state identification and diagnosis applications.

Rapid generation of mouse model for emerging infectious disease with the case of severe COVID-19.

Since the pandemic of COVID-19 has intensely struck human society, small animal model for this infectious disease is in urgent need for basic and pharmaceutical research. Although several COVID-19 animal models have been identified, many of them show either minimal or inadequate pathophysiology after SARS-CoV-2 challenge. Here, we describe a new and versatile strategy to rapidly establish a mouse model for emerging infectious diseases in one month by multi-route, multi-serotype transduction with recombinant adeno-associated virus (AAV) vectors expressing viral receptor. In this study, the proposed approach enables profound and enduring systemic expression of SARS-CoV-2-receptor hACE2 in wild-type mice and renders them vulnerable to SARS-CoV-2 infection. Upon virus challenge, generated AAV/hACE2 mice showed pathophysiology closely mimicking the patients with severe COVID-19. The efficacy of a novel therapeutic antibody cocktail RBD-chAbs for COVID-19 was tested and confirmed by using this AAV/hACE2 mouse model, further demonstrating its successful application in drug development.

Upregulation of PD-L1 by SARS-CoV-2 promotes immune evasion.

Patients with severe COVID-19 often suffer from lymphopenia, which is linked to T-cell sequestration, cytokine storm, and mortality. However, it remains largely unknown how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces lymphopenia. Here, we studied the transcriptomic profile and epigenomic alterations involved in cytokine production by SARS-CoV-2-infected cells. We adopted a reverse time-order gene coexpression network approach to analyze time-series RNA-sequencing data, revealing epigenetic modifications at the late stage of viral egress. Furthermore, we identified SARS-CoV-2-activated nuclear factor-κB (NF-κB) and interferon regulatory factor 1 (IRF1) pathways contributing to viral infection and COVID-19 severity through epigenetic analysis of H3K4me3 chromatin immunoprecipitation sequencing. Cross-referencing our transcriptomic and epigenomic data sets revealed that coupling NF-κB and IRF1 pathways mediate programmed death ligand-1 (PD-L1) immunosuppressive programs. Interestingly, we observed higher PD-L1 expression in Omicron-infected cells than SARS-CoV-2 infected cells. Blocking PD-L1 at an early stage of virally-infected AAV-hACE2 mice significantly recovered lymphocyte counts and lowered inflammatory cytokine levels. Our findings indicate that targeting the SARS-CoV-2-mediated NF-κB and IRF1-PD-L1 axis may represent an alternative strategy to reduce COVID-19 severity.

Association between vegetarian diet and gouty arthritis: A retrospective cohort study.

BACKGROUND AND AIMS: A vegetarian diet is rich in vegetables, fruits, and soy products. Although vegetarian diet is beneficial for improving the health outcomes such as body mass index, metabolic syndrome, cardiovascular disease, and mortality rate, the association between a vegetarian diet and gout incidence is not well known. METHODS AND RESULTS: We linked the MJ Health Survey Data and MJ Biodata 2000 with the National Health Insurance Research Database (NHIRD) and the National Registration of Death (2000-2018). Information on the diet was collected from the MJ Health Survey Data, and the incidence of gouty arthritis was confirmed using the NHIRD. The Kaplan-Meier survival curve and log-rank test were used to compare the differences between vegetarian and non-vegetarian participants. Cox regression models were used to estimate the risk of the incidence of gouty arthritis. Among 76,972 participants, 37,297 (48.46%) were men, 2488 (3.23%) were vegetarians and the mean age was 41.65 ± 14.13 years. The mean baseline uric acid level was 6.14 ± 1.65 mg/dL. A total of 16,897 participants developed gouty arthritis, including 16,447 (22.08%) non-vegetarians and 450 (18.9%) vegetarians over a mean follow-up of 19 years. Significant differences were observed in the Kaplan-Meier survival curves between vegetarians and non-vegetarians (log-rank p < 0.001). Vegetarians had a significantly decreased incidence of gouty arthritis compared with non-vegetarians (hazard ratio = 0.87, 95% confidence interval = 0.78-0.98, p = 0.02) after adjusting for potential confounders. CONCLUSION: People with a vegetarian diet had a significantly decreased risk of developing gouty arthritis compared with non-vegetarians in Taiwan.

Interventions to improve the sleep of nurses: A systematic review.

Nurses are at a high risk for short sleep duration and poor sleep quality due to irregular work schedules and high occupational stress. Considering the effect of nurses' sleep on the safety and health of themselves and their patients, it is important to promote healthy sleep for nurses. We sought to synthesize the published experimental and quasi-experimental studies that address interventions to improve sleep in nurses. A systematic search was conducted for studies published in English up until May 15, 2023, using the databases PubMed, CINAHL, Academic Search Ultimate, and PsycINFO. In total, 38 articles were included, covering 22 experimental and 16 quasi-experimental studies with sample sizes ranging from 9 to 207. Studies were assessed using the Cochrane Risk of Bias tool and considered as low to medium quality. Thirty-six of the 38 studies reported positive findings for at least one sleep outcome. Intervention types included aroma therapy, dietary supplements, cognitive behavioral therapy, light therapy, mind-body therapy, sleep education, exercise, napping, shift schedule modification, and multicomponent intervention, all of which showed moderate effectiveness in promoting sleep outcomes of nurses. Comparing and contrasting studies on specific interventions for improving sleep in nurses is sparse and often equivocal. With the variations of research methodology and outcome measures, it is difficult to make a conclusion about each intervention's effectiveness on specific sleep outcomes. Additional high-quality research, including randomized controlled trials, is needed to evaluate strategies for improving sleep in this unique, safety-sensitive occupational group.

Changes in physical activity and adiposity with all-cause, cardiovascular disease, and cancer mortality.

BACKGROUND: The relationship between joint changes in physical activity and adiposity with mortality is not well understood. We examined the association of changes in these two established risk factors with all-cause (ACM), cardiovascular disease (CVD), and cancer mortality. METHODS: We used longitudinal data from Taiwan's MJ Cohort, comprising 116,228 general population adults recruited from 1998-2013 with repeated measures 4.6 y (2.5) apart and followed up for mortality for 11.9 y (3.5). Physical activity, body mass index (BMI), waist circumference (WC), and body fat percentage (BF%) groups and changes were based on public health and clinical guidelines. RESULTS: Compared to stable-insufficient physical activity, increasing physical activity from any baseline level was associated with lower ACM (HR [95%CI]): 0.85 [0.74, 0.96]) and CVD mortality (0.72 [0.55, 0.93]) risk. This was approximately equal to meeting physical activity guidelines at both timepoints (eg: 0.71 [0.58, 0.88] for CVD mortality). Compared to stable-overweight/moderate adiposity, decreasing adiposity level attenuated but did not offset mortality risk for all three outcomes (eg: BMI = 0.95 [0.76, 1.16] for CVD mortality). Only maintaining a healthy adiposity level at both timepoints offset mortality risk (BMI = 0.75 [0.61, 0.89]) for CVD mortality). In the joint changes analyses, lower mortality risk was a consequence of increases in physical activity across adiposity change groups (eg: WC decrease = 0.57 [0.48, 0.67]; WC stability = 0.73 [0.66, 0.80], WC increase = 0.83 [0.72, 0.97] for ACM). Decreasing adiposity attenuated the negative associations of decreased physical activity (BF% = 1.13 [0.95, 1.35] for ACM). CONCLUSIONS: We found a lower risk for ACM, CVD, and cancer mortality from increasing physical activity and an attenuation from decreasing adiposity regardless of baseline levels. The beneficial associations of joint changes were primarily driven by physical activity, suggesting lower mortality risk may be more immediate through physical activity improvements compared to adiposity improvements alone.

HSPA4 Is a Biomarker of Placenta Accreta and Enhances the Angiogenesis Ability of Vessel Endothelial Cells.

Placenta accreta spectrum (PAS) accounts for 7% of maternal mortality and is associated with intraoperative and postoperative morbidity caused by massive blood loss, infection, and adjacent organ damage. The aims of this study were to identify the protein biomarkers of PAS and to further explore their pathogenetic roles in PAS. For this purpose, we collected five placentas from pregnant subjects with PAS complications and another five placentas from normal pregnancy (NP) cases. Then, we enriched protein samples by specifically isolating the trophoblast villous, deeply invading into the uterine muscle layer in the PAS patients. Next, fluorescence-based two-dimensional difference gel electrophoresis (2D-DIGE) and MALDI-TOF/MS were used to identify the proteins differentially abundant between PAS and NP placenta tissues. As a result, nineteen spots were determined as differentially abundant proteins, ten and nine of which were more abundant in PAS and NP placenta tissues, respectively. Then, specific validation with western blot assay and immunohisto/cytochemistry (IHC) assay confirmed that heat shock 70 kDa protein 4 (HSPA4) and chorionic somatomammotropin hormone (CSH) were PAS protein biomarkers. Further tube formation assays demonstrated that HSPA4 promoted the in vitro angiogenesis ability of vessel endothelial cells, which is consistent with the in vivo scenario of PAS complications. In this study, we not only identified PAS protein biomarkers but also connected the promoted angiogenesis with placenta invasion, investigating the pathogenetic mechanism of PAS.

Coronary Dilatation and Endothelial Inflammation in Neonates Born to Mothers with Preeclampsia.

OBJECTIVES: To investigate the cardiovascular features and endothelium in neonates born to mothers with preeclampsia. STUDY DESIGN: In this combined observational cohort and case-control study, neonates born to mothers with normotension and mothers with preeclampsia were recruited at a neonatal intensive care unit of a tertiary medical center. Cardiovascular measurements by echocardiography and the clinical measures upon admission were analyzed. Vascular cell adhesion molecule-1 expression in umbilical arteries and in in vitro endothelial cell stimulation with plasma were examined. Continuous data were compared using nonparametric analysis, and their relationships were analyzed using linear regression. Binary logistic regression was performed in the model of adjustment of birth body weight and for multivariate analysis. RESULTS: In the cohort, almost all cardiovascular segments positively correlated to birth weight. Notably, neonates (n = 65) of mothers with preeclampsia had significantly larger coronary arteries at birth than neonates of mothers with normotension (n = 404) (median size of left main coronary artery 1.36 mm versus 1.08 mm, p <0.001; median size of right coronary artery, RCA 1.25 mm versus 1.0 mm, p <0.001). The size of the right coronary artery positively correlated to the maternal antepartum diastolic blood pressure (r = 0.298, P = .018) and was associated with in-hospital death (P < .001). Meanwhile, endothelial vascular cell adhesion molecule-1 expression was significantly increased in the umbilical arteries of the preeclamptic group and following preeclamptic cord-plasma stimulation. The latter also correlated with their relative coronary sizes. CONCLUSIONS: Neonates of mothers with preeclampsia had distinctive coronary dilatation at birth. Coronary size might be useful as a severity index of neonatal endothelial inflammation as a result of maternal preeclampsia.

Whether to transfer mosaic embryos: a cytogenetic view of true mosaicism by amniocentesis.

RESEARCH QUESTION: Preimplantation genetic testing for aneuploidies has increasingly been employed for embryo selection, resulting in a recent surge in mosaic embryos. According to the cytogenetic results, which types of mosaic embryo survive early pregnancy, progress to the second trimester and finally result in a live birth? DESIGN: This study evaluated 30,587 pregnant women undergoing amniocentesis from January 2004 to March 2020 at the cytogenic centre of Kaohsiung Chang Gung Memorial Hospital. Samples from amniocentesis were cultured using the in-situ method. The types and distribution of level III chromosomal mosaicism (two or more cells with the same abnormality in two or more colonies and both culture dishes, clinically referred to as 'true mosaicism') were retrospectively reviewed. RESULTS: Among the 30,587 women, 78 cases (0.26%) of level III chromosomal mosaicism were identified. The types of chromosomal mosaicism were classified as sex chromosome mosaicism (SCM), autosomal chromosome mosaicism (ACM) and marker chromosome mosaicism (MCM), with SCM, ACM and MCM accounting for 58.97%, 32.05% and 8.97% of cases, respectively. The most common mosaic cell lines were monosomy X and trisomy 21. The most common mosaic cell line progressing to live birth was monosomy X. CONCLUSIONS: Mosaic monosomy X and trisomy 21 are the most common cell lines of true mosaicism determined by amniocentesis. Monosomy X mosaicism is the most common cell line in live births. For women considering the transfer of these types of mosaic embryo in a circumstance where euploid embryos are unavailable, clinicians should provide careful prenatal counselling, detailed ultrasonography and amniocentesis.

A dose response relationship between accelerometer assessed daily steps and depressive symptoms in older adults: a two-year cohort study.

OBJECTIVES: this study investigated the prospective associations of accelerometer assessed daily steps with subsequent depressive symptoms in older adults. METHODS: a 2-year prospective study was performed in the community. A total of 285 older adults ≥65 years (mean age = 74.5) attended the baseline assessment in 2012. The second wave of assessment was carried out in 2014 including 274 (96.1%) participants. Daily step counts were measured with a triaxial accelerometer (ActiGraph GT3X+), and participants were divided into three categories (<3,500, 3,500-6,999 and ≥ 7,000 steps/day). The 15-item Geriatric Depression Scale was used to measure depressive symptoms. Negative binomial regression models with multivariable adjustment for covariates (baseline depressive symptoms, accelerometer wear time, age, gender, education, chronic disease, activities of daily living) were conducted to examine the association between daily steps and subsequent depressive symptoms. RESULTS: each 1,000-step increase in daily walking was linearly associated with a reduced rate of subsequent depressive symptoms (rate ratio [RR] = 0.95, 95% confidence interval [CI] = 0.92-0.98). Participants with daily step count in 3,500-6,999 (RR = 0.84, 95% CI = 0.70-0.99) and ≥7,000 steps (RR = 0.71, 95% CI = 0.55-0.92) per day had fewer depressive symptoms at follow-up. Sensitivity analyses assessing confounding and reverse causation provided further support for the stability of our findings. CONCLUSION: older adults engaging in more daily steps had fewer depressive symptoms after 2 years. Even as few as 3,500-6,999 steps a day was associated with a protecting effect. Accumulating ≥7,000 steps a day could provide the greatest protection against depressive symptoms.

Association of body mass index with all-cause mortality in the elderly population of Taiwan: A prospective cohort study.

BACKGROUND AND AIMS: The nutritional status of the elderly is different from that of young people. Body composition changes as people age, for example, fat mass increases, muscle mass decreases, and body fat distribution is changed. We aimed to investigate the association of body mass index (BMI) with cause-specific mortality in the elderly population. METHODS AND RESULTS: The data of annual health examination for the older citizens (≥65 years old) from 2006 to 2011 in Taipei City Hospital were used. Information on baseline demographics, lifestyle behaviors, medical, and drug usage were collected by a self-administered questionnaire. Cause-specific mortality was ascertained from the National Registration of Death. Individuals were followed up until death or December 31, 2012, whichever was earlier. Univariable and multivariable Cox proportional hazard analyses were applied to investigate the association between BMI and all-cause mortality. Among 81,221 older people included in the analysis, 42,602 (52.45%) were men. The mean age was 73.85 ± 6.32 years. Among the 81,221 participants, 3398 (4.18%) were underweight, 36,476 (44.91%) were normal weight, 25,708 (31.65%) were overweight, and 15,639 (19.25%) were obese. Those in the BMI category 27 ≤ BMI<28 kg/m2 had the lowest all-cause mortality risk. The BMI of lowest cause-specific mortality was between 27 kg/m2 and 28 kg/m2 in infection mortality, between 28 kg/m2 and 29 kg/m2 in circulation mortality, between 29 kg/m2 and 30 kg/m2 in respiratory mortality, and between 31 kg/m2 and 32 kg/m2 in cancer mortality. CONCLUSIONS: The current study found a J-shaped relation between BMI and cause-specific mortality in the elderly population of Taiwan.

Association between teeth loss and nasogastric tube feeding dependency in older adults from Taiwan: a retrospective cohort study.

BACKGROUND: To examine the association between teeth loss and nasogastric tube feeding dependency in older people. METHODS: The National Health Interview Survey (NHIS) 2005, 2009, and 2013 in Taiwan. Participants were selected by a multistage stratified sampling method and baseline characteristics, including socioeconomic status and health habits, were obtained by well-trained interviewers. The NHIS was linked with the National Health Insurance research database 2000-2016 and the National Deaths Dataset, which contains all the medical information of ambulatory and inpatient care. Cox regression was used to examine the association between the number of teeth lost and nasogastric tube feeding dependency. RESULTS: There were 6165 adults older than 65 years old enrolled in the analysis, with 2959 male (48%) and the mean (SD) age was 73.95(6.46) years old. The mean follow-up duration was 6.5(3.3) years. Regarding the teeth loss categories, 1660 (26.93%), 2123 (34.44%), and 2382 (38.64%) of participants were categorized as having no teeth loss, loss of 1-9 teeth, and loss of 10-28 teeth, respectively. During 39,962 person-years of follow-up, new-onset nasogastric feeding dependency was recognized in 220(13.25%), 256(12.06%), and 461(19.35%) participants who were categorized as having no teeth loss, loss of 1-9 teeth, and loss of 10-28 teeth, respectively. Kaplan-Meier curves demonstrated significant findings (Log-rank P < 0.01). After potential confounders were adjusted, compared with those without teeth loss, older adults who had lost 10-28 teeth had significantly increased risks of occurrence nasogastric feeding dependency (AHR, 1.31; 95% CI, 1.05-1.62; p-value = 0.02). Furthermore, a significant dose-response relation between the number of teeth lost and increased risk of nasogastric feeding was found (p for trend< 0.01). CONCLUSIONS: Older adults who had lost 10-28 teeth had a significantly increased risk of nasogastric tube feeding dependency. Early identification of the oral disease is crucial for the prevention of the occurrence of teeth loss and the following nutrition problems, which would reduce risk of nasogastric tube feeding dependency.

MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1.

BACKGROUND & AIMS: Inhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice. METHODS: We tested the effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell line HCA-1 and in immune-competent and immunodeficient mice with subcutaneous tumors grown from this cell line. Tumors were collected from mice and tumor cells were analyzed by time-of-flight mass cytometry. We used short hairpin RNAs to weaken expression of MET in Hep3B, SK-HEP-1, HA59T, and HA22T liver cancer cell lines and analyzed cells by immunoblot, immunofluorescence, and immunoprecipitation assays. Mass spectrometry was used to assess interactions between MET and glycogen synthase kinase 3ß (GSK3B), and GSK3B phosphorylation, in liver cancer cell lines. C57/BL6 mice with orthotopic tumors grown from Hep1-6 cells were given combinations of capmatinib or tivantinib and antibodies against programmed cell death 1 (PDCD1; also called PD1); tumors were collected and analyzed by immunofluorescence. We analyzed 268 HCCsamples in a tissue microarray by immunohistochemistry. RESULTS: Exposure of liver cancer cell lines to MET inhibitors increased their expression of PD ligand 1 (PDL1) and inactivated cocultured T cells. MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. In orthotopic tumors grown in immune-competent mice, MET inhibitors decreased the antitumor activity of T cells. However, addition of anti-PD1 decreased orthotopic tumor growth and prolonged survival of mice compared with anti-PD1 or MET inhibitors alone. Tissue microarray analysis of HCC samples showed an inverse correlation between levels of MET and PDL1 and a positive correlation between levels of MET and phosphorylated GSK3B. CONCLUSIONS: In studies of liver cancer cell lines and mice with orthotopic tumors, MET mediated phosphorylation and activated GSK3B, leading to decreased expression of PDL1. Combined with a MET inhibitor, anti-PD1 and anti-PDL1 produced additive effect to slow growth of HCCs in mice.

Levels of sex steroid hormones and their receptors in women with preeclampsia.

BACKGROUND: Pregnant women have high serum concentrations of sex steroid hormones, which are major regulators of paracrine and autocrine responses for many maternal and placental functions. The main purpose of this study was to compare patients with preeclampsia and patients with uncomplicated pregnancies in terms of serum steroid hormones (estradiol [E2], progesterone [P4], dehydroepiandrosterone sulfate [DHEAS], and testosterone [T]) throughout pregnancy and the levels of cord blood and placental steroid receptors during the third trimester. METHODS: Quantitative real-time reverse transcription PCR, western blotting, and immunohistochemistry were used to determine the levels of steroid hormones in the serum and cord blood and the placental levels of estrogen receptor-α (ERα), ERß, androgen receptor (AR), and progesterone receptor (PR). RESULTS: There were 45 women in the uncomplicated pregnancy group and 30 women in the preeclampsia group. Serum levels of T were greater and serum levels of E2 were reduced in the preeclampsia group, but the two groups had similar levels of P4 and DHEAS during the third trimester. Cord blood had a decreased level of DHEAS in the preeclampsia group, but the two groups had similar levels of P4, E2, and T. The two groups had similar placental mRNA levels of ERα, ERß, AR, and PR, but the preeclampsia group had a higher level of ERß protein and a lower level of ERα protein. Immunohistochemistry indicated that the preeclampsia group had a greater level of ERß in the nucleus and cytoplasm of syncytiotrophoblasts and stromal cells. CONCLUSIONS: Women with preeclampsia had lower levels of steroid hormones, estrogen, and ERα but higher levels of T and ERß. These molecules may have roles in the pathogenesis of preeclampsia.

Association of exercise with all-cause mortality in older Taipei residents.

BACKGROUND: Human life expectancy has increased rapidly in recent decades. Regular exercise can promote health, but the effect of exercise on mortality is not yet well understood. OBJECTIVE: To investigate the association of exercise with mortality in the older people. METHODS: We used data from annual health check-ups of the older citizens of Taipei in 2006. Participants were interviewed by trained nurses using a structured questionnaire to collect data on demographics and lifestyle behaviours. Overnight fasting blood was collected for measuring blood glucose, liver and renal function and lipid profiles. Exercise frequency was categorised into no exercise, 1-2 times in a week and more than 3-5 times in a week. All-cause mortality was ascertained from the National Registration of Death. All participants were followed up until death or December 312012, whichever came first. Kaplan-Meier curves and Cox proportional hazard analysis were used to investigate the association between exercise and all-cause mortality. RESULTS: In total, 42,047 older people were analysed; 22,838 (54.32%) were male and with a mean (SD) age of 74.58 (6.32) years. Kaplan-Meier curves of all-cause mortality stratified by exercise frequency demonstrated significant findings (Log-rank P < 0.01). Multivariate Cox regression analysis showed that older people with higher exercise levels had a significantly decreased risk of mortality (moderate exercise HR = 0.74, 95% CI: 0.68-0.81, high exercise HR = 0.65, 95% CI: 0.59-0.70) after adjusting for potential confounders, with a significant trend (P for trend<0.01). CONCLUSIONS: Older people with increased exercise levels had a significantly decreased risk of all-cause mortality.

Antigen Analysis of Pre-Eclamptic Plasma Antibodies Using Escherichia Coli Proteome Chips.

Pre-eclampsia is one of the main causes of perinatal mortality and morbidity. Many biomarkers for diagnosing pre-eclampsia have been found but most have low accuracy. Therefore, a potential marker that can detect pre-eclampsia with high accuracy is required. Infection has been reported as a cause of pre-eclampsia. In recent years, protein microarray chips have been recognized as a strong and robust tool for profiling antibodies for infection diagnoses. The purpose of the present study was to profile antibodies in the human plasma of healthy and pre-eclamptic pregnancies to identify suitable biomarkers. In this study, an Escherichia coli chip was probed with samples from 29 individuals (16 pre-eclamptic women and 13 healthy pregnant women) to profile plasma antibodies. Bioinformatics tools were used to analyze the results, discover conserved motifs, compare against the entire human proteome, and perform protein functional analysis. An antibody classifier was identified using k-top scoring pairs and additional samples for a blinded test were collected. The findings indicated that compared with the healthy women, the pre-eclamptic women exhibited 108 and 130 differentially immunogenic proteins against human immunoglobulins G and M, respectively. In addition, pre-eclamptic women developed more immunoglobulin G but less immunoglobulin M against bacterial surface proteins compared with healthy women. The k-top scoring pairs identified five pairs of immunogenic proteins as classifiers with a high accuracy of 90% in the blind test. [AG] [ISV] GV [AE] L [LF] and [IV] [IV] RI [AG] [AD] E were the consensus motifs observed in immunogenic proteins in the immunoglobulin G and immunoglobulin M of pre-eclamptic women, respectively, whereas GA [AG] [AL] L [LF] and [SRY] [IQML] [ILV] [ILV] [ACG] GI [GH] [AEF] [AK] [ATY] [RG] N [IV] were observed in the immunoglobulins G and immunoglobulin M of healthy women, respectively.