Estrogen/Progesterone Receptor Expression and Cancer Antigen 125 Level as Preoperative Predictors to Estimate Lymph Node Metastasis in Endometrioid Endometrial Cancer.

Loss of estrogen receptor/progesterone receptor (ER/PR) in endometrial cancer (EC) is associated with tumor progression and poor outcomes. Elevated pretreatment cancer antigen 125 (CA 125) level is a risk factor for lymph node metastasis (LNM). We evaluated whether the combination of ER/PR expression and CA 125 level could be used as a biomarker to predict LNM. We retrospectively investigated patients with endometrioid EC who underwent complete staging surgery during January 2015 to December 2020. We analyzed ER/PR status using immunohistochemical staining, and quantified its expression using the sum of both ER/PR H-scores. Receiver operating characteristic curves were used to identify optimal cutoff values of H-score and CA 125 levels for predicting LNM. A nomogram for predicting LNM was constructed and validated by bootstrap resampling. In 396 patients, the optimal cutoff values of the ER/PR H-score and CA 125 were 407 (area under the receiver operating characteristic curve: 0.645, P=0.001) and 40 U/mL (area under the receiver operating characteristic curve: 0.762, P<0.001), respectively. Multivariate analysis showed that CA 125 ≥40 UmL (odds ratio: 10.02; 95% CI: 4.74-21.18) and ER/PR H-score <407 (odds ratio: 4.20; 95% CI: 1.55-11.32) were independent predictors. An LNM predictive nomogram was constructed using these 2 variables and our model yielded a negative predictive value and negative likelihood ratio of 98.3% and 0.14, respectively. ER/PR expression with pretreatment CA 125 levels can help estimate LNM risk and aid in decision-making regarding the need for lymphadenectomy in patients with endometrioid EC.

Pretreatment carcinoembryonic antigen combined with cancer antigen-125 for predicting lymph node metastasis in endometrial carcinoma: a retrospective cohort study.

PURPOSE: To investigate whether the cost-effective, pretreatment tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen-125 (CA-125) can be used to predict lymph node metastasis (LNM) in endometrioid-type endometrial cancer (EC) and to develop a predictive model. METHODS: This was a single-center retrospective study of patients with endometrioid-type EC who underwent complete staging surgery between January 2015 and June 2022. We identified the optimal cut-off values of CEA and CA-125 for predicting LNM using receiver operating characteristic (ROC) curves. Stepwise multivariate logistic regression analysis was used to identify independent predictors. A nomogram for predicting LNM was constructed and validated by bootstrap resampling. RESULTS: The optimal cut-off values of CEA and CA-125 were 1.4 ng/mL (area under the ROC curve (AUC) 0.62) and 40 U/mL (AUC 0.75), respectively. Multivariate analysis showed that CEA (odds ratio (OR) 1.94; 95% confidence interval (CI) 1.01-3.74) and CA-125 (OR 8.75; 95% CI 4.42-17.31) were independent predictors of LNM. Our nomogram showed adequate discrimination with a concordance index of 0.78. Calibration curves for the probability of LNM showed optimal agreement between the predicted and actual probabilities. The risk of LNM for markers below the cut-offs was 3.6%. The negative predictive value and negative likelihood ratio were 96.6% and 0.26, respectively, with moderate ability to rule out the possibility of LNM. CONCLUSION: We report a cost-effective method of using pretreatment CEA and CA-125 levels to identify patients with endometrioid-type EC who are at a low risk for LNM, which may guide decision-making regarding aborting lymphadenectomy.

Characteristics of Cancer-Related Fatigue and an Efficient Model to Identify Patients with Gynecological Cancer Seeking Fatigue-Related Management.

Cancer-related fatigue (CRF) is the most common somatic discomfort in patients with gynecological cancers. CRF is often overlooked; however, it can impair the patients' quality of life considerably. This cross-sectional study aimed to identify the clinical characteristics of CRF in gynecological cancer patients. Questionnaires and the International Classification of Diseases 10th Revision (ICD-10) criteria were used to identify CRF. The enrolled patients were further categorized according to the amount of fatigue-related management received. Of the enrolled 190 patients, 40.0% had endometrial cancer, 28.9% had cervical cancer, and 31.1% had ovarian cancer. On the basis of the ICD-10 diagnostic criteria, 42.6% had non-cancer-related fatigue, 10% had CRF, and 51% had BFI-T questionnaire-based fatigue. Moreover, 77.9% of the study cohort had ever received fatigue-related management. Further analysis showed that patients with endometrial/cervical cancer, International Federation of Gynecology and Obstetrics stage >1, Eastern Cooperative Oncology Group performance status score ≥1, inadequate cancer treatment response, and receiving cancer treatment in the past week had a higher probability of receiving more fatigue-related management. The five-item predictive model developed from these factors may help physicians recognize patients seeking more fatigue-related management more efficiently. This is important as they may suffer from a more profound CRF.

Unveiling the transcriptomic landscape and the potential antagonist feedback mechanisms of TGF-ß superfamily signaling module in bone and osteoporosis.

BACKGROUND: TGF-ß superfamily signaling is indispensable for bone homeostasis. However, the global expression profiles of all the genes that make up this signaling module in bone and bone-related diseases have not yet been well characterized. METHODS: Transcriptomic datasets from human bone marrows, bone marrow-derived mesenchymal stem cells (MSCs) and MSCs of primary osteoporotic patients were used for expression profile analyses. Protein treatments, gene quantification, reporter assay and signaling dissection in MSC lines were used to clarify the interactive regulations and feedback mechanisms between TGF-ß superfamily ligands and antagonists. Ingenuity Pathway Analysis was used for network construction. RESULTS: We identified TGFB1 in the ligand group that carries out SMAD2/3 signaling and BMP8A, BMP8B and BMP2 in the ligand group that conducts SMAD1/5/8 signaling have relatively high expression levels in normal bone marrows and MSCs. Among 16 antagonist genes, the dominantly expressed TGF-ß superfamily ligands induced only NOG, GREM1 and GREM2 via different SMAD pathways in MSCs. These induced antagonist proteins further showed distinct antagonisms to the treated ligands and thus would make up complicated negative feedback networks in bone. We further identified TGF-ß superfamily signaling is enriched in MSCs of primary osteoporosis. Enhanced expression of the genes mediating TGF-ß-mediated SMAD3 signaling and the genes encoding TGF-ß superfamily antagonists served as significant features to osteoporosis. CONCLUSION: Our data for the first time unveiled the transcription landscape of all the genes that make up TGF-ß superfamily signaling module in bone. The feedback mechanisms and regulatory network prediction of antagonists provided novel hints to treat osteoporosis. Video Abstract.

Sofosbuvir-based direct-acting antivirals and changes in cholesterol and low density lipoprotein-cholesterol.

Worsened lipid profiles were observed in chronic hepatitis C (CHC) patients during direct-acting antivirals (DAAs) treatment, among which combination drugs confounded the effect of individual ingredient on lipid. Tenofovir alafenamide (TAF) also worsened lipid profiles in HIV patients. Structural similarity between sofosbuvir (SOF) and TAF prompted us to investigate rapid increase in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in CHC patients treated with SOF-based DAAs. A retrospective study was performed to analyze 487 CHC patients receiving DAAs with SVR12. Relative risks on elevating TC and LDL-C were analyzed by logistic regression to determine SOF-based over non-SOF-based regimens. TC or LDL-C levels at baseline, week-4 and SVR12 were compared by Wilcoxon matched-pairs signed rank test. Week 4 or SVR12 to baseline ratios of serum TC or LDL-C between regimens were compared by Mann-Whitney's test. 487 patients were treated with Harvoni (SOF-based, 206 patients), Epclusa (SOF-based, 124 patients), Maviret (non-SOF-based, 122 patients), or Zepatier (non-SOF-based, 35 patients). At week 4 during drug treatment, Harvoni, Epclusa, and Maviret induced statistically significant elevation of TC and LDL-C, but Zepatier did not. SOF-based regimens had 2.72-fold higher relative risk (RR) causing 10% elevation of TC (95% CI 1.84-4.02, p < 0.001) and 2.04-fold higher RR causing 10% elevation of LDL-C (95% CI 1.39-3.01, p < 0.001) than non-SOF-based DAAs. SOF-based DAAs were associated with significantly larger amplitude of increases in TC and LDL-C than non-SOF-based DAAs during the initial 4 weeks of treatment, but the increases were not sustained to SVR12.

Prolonged sitting time links to subclinical atherosclerosis.

BACKGROUND: This study investigates the association between daily sitting time and subclinical atherosclerosis by using coronary computed tomography angiography (CCTA). METHODS: The study enrolled 203 subjects (age 57.6 ± 8.8 years) who underwent CCTA at annual medical checkups. Sitting time was categorized as < 5 hours/day (short), 5 to 9 hours/day (moderate) and ≥10 hours/d (long). We analyzed the coronary calcium score, plaque characteristics, and severity of coronary artery stenosis, including the segment involvement score (SIS) and segment stenosis score (SSS). RESULTS: Subjects with longer sitting times tended to be male gender and have lower levels of high-density lipoprotein cholesterol (p for trend < 0.05). In addition, those with longer sitting time had higher SIS (1.2 ± 1.5 vs. 1.6 ± 2.1 vs. 2.3 ± 2.0 for short, moderate, and long sitting time, respectively) (p for trend = 0.015) and SSS (1.4 ± 2.0 vs. 1.9 ± 2.7 vs. 2.7 ± 2.6) (p for trend = 0.015), suggesting longer sitting time-correlated with the severity of coronary atherosclerosis. When considering the coronary plaque patterns, subjects with shorter sitting time (<5 hours/d) tended to have more calcified plaque and subjects with longer sitting time (≥10 hours/d) had more mixed plaque (p for trend = 0.018). After adjusting for age, gender, comorbidities, body mass index, and lipid profiles, increased sitting time was independently associated with the presence of mixed plaque, suggesting longer sitting time may be associated with higher risk of the formation of vulnerable plaque. CONCLUSION: Longer sitting time was linked to the severity of subclinical atherosclerosis and the presence of high-risk vulnerable plaque in the general population.

Effect of sofosbuvir-based DAAs on changes in lower-density lipoprotein in HCV patients: a systematic review and meta-analysis.

BACKGROUND: Previous studies reported worsened lipid profiles in patients infected with hepatitis C virus (HCV) during direct-acting antivirals (DAAs) treatment. This study aimed to investigate the effect of sofosbuvir (SOF)-based DAAs on changes in low-density lipoprotein (LDL) in HCV patients. METHODS: A systematic review of articles published before 31 May 2021 was conducted by searching MEDLINE, Cochrane Library, EMBASE, and CINAHL Plus. Eligible studies were those comparing SOF-based DAAs and non-SOF DAAs for HCV patients and providing numerical data for changes in LDL. Risk of Bias in Non-randomized Studies- of Interventions was used for assessing risk of bias, and meta-analysis was performed for changes in LDL. RESULTS: Six studies comprising 1248 patients were included, 848 patients treated with SOF-based DAAs and 400 patients with non-SOF DAAs vs. SOF-based DAAs group had significantly greater increases in LDL from baseline to week 4 than non-SOF DAAs group (P = 0.001). However, changes in LDL from baseline to the end of treatment (P = 0.060), to post-treatment week 12 (P = 0.263), and to post-treatment week 24 (P = 0.319) did not significantly differ between the two groups. Further comparison of SOF/ledipasvir with asunaprevir/daclatasvir revealed a similar trend in changes in LDL. CONCLUSIONS: For HCV patients, SOF-based DAA regimens were associated with rapid and significant increases in LDL during the initial 4 weeks of treatment, and the changes did not sustain after the end of treatment. Potential mechanism might be related to the phosphoramidate side chain of SOF.

Expression profiling of ovarian BMP antagonists reveals the potential interaction between TWSG1 and the chordin subfamily in the ovary.

The TGF-ß 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-ß 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-ß 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-ß superfamily members, such as the control of progesterone production.

Maternal Obesity Related to High Fat Diet Induces Placenta Remodeling and Gut Microbiome Shaping That Are Responsible for Fetal Liver Lipid Dysmetabolism.

Background: Maternal obesity in utero may affect fetal development and cause metabolic problems during childhood and even adulthood. Diet-induced maternal obesity can impair gut barrier integrity and change the gut microbiome, which may contribute to adverse placental adaptations and increase the obesity risk in offspring. However, the mechanism through which maternal obesity causes offspring metabolic disorder must be identified. Methods: Eight-week-old female rats received a control diet or high-fat (HF) diet for 11 weeks before conception and during gestation. The placentas were collected on gestational day 21 before offspring delivery. Placental tissues, gut microbiome, and short-chain fatty acids of dams and fetal liver tissues were studied. Results: Maternal HF diet and obesity altered the placental structure and metabolism-related transcriptome and decreased G protein-coupled receptor 43 expression. HF diet and obesity also changed the gut microbiome composition and serum propionate level of dams. The fetal liver exhibited steatosis, enhanced oxidative stress, and increased expression of acetyl-CoA carboxylase 1 and lipoprotein lipase with changes in maternal HF diet and obesity. Conclusions: Maternal HF diet and obesity shape gut microbiota and remodel the placenta of dams, resulting in lipid dysmetabolism of the fetal liver, which may ultimately contribute to the programming of offspring obesity.

Human bone morphogenetic protein 8A promotes expansion and prevents apoptosis of cumulus cells in vitro.

Cumulus expansion is essential for ovulation and oocyte maturation in mammals. Previous studies suggest that this process requires certain cumulus expansion enabling factors, induced by LH surge, that activate SMAD signaling locally. However, their identities remain uncertain. Using a superovulated rat model, we showed that Bmp8 transcripts were abundant in cumulus cell-oocyte complexes (COCs) and their levels can be further induced during ovulation. By analyzing human COC-related transcriptomic datasets, BMP8 transcripts in cumulus cells were also found to be significantly elevated along with the maturation status and developmental competence of enclosed oocytes. In cultured rat COCs, treatment with recombinant BMP8A protein activated both SMAD1/5/8 and SMAD2/3 pathways; the resulting SMAD2/3 signaling induced COC expansion as well as the expression of COC expansion-related genes, whereas the resulting SMAD2/3 and SMAD1/5/8 activations were both required for protecting expanded cumulus cells from apoptosis. Taken together, our data demonstrated that addition of BMP8 protein in the in vitro rat COC cultures not only promotes cumulus expansion but also sustains survival of expanded cumulus cells via different SMAD downstreams. With these capabilities, BMP8 may have clinical applications to ameliorate the fertilizability and subsequent developmental competence of the enclosed oocytes when doing in vitro COC maturation.

The association of the steatosis severity in fatty liver disease with coronary plaque pattern in general population.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is commonly observed in patients with cardiovascular disease (CVD). However, whether the steatosis severity of NAFLD is independently associated with coronary artery atherosclerosis is still controversial. METHODS: Consecutive Taiwanese individuals (1502) who received coronary computed tomography angiography (CCTA) and abdominal sonography as part of a general routine health evaluation were enrolled. The association between steatosis severity, coronary atherosclerosis involvement and various plaque patterns were analysed. RESULTS: Compared with non-steatosis, NAFLD subjects had more cardiovascular risk factors that correlated with the severity of steatosis (P for the trend <.05). The presence of atherosclerotic plaques correlated with the severity of steatosis (none: 53%, mild: 64.1%, and moderate to severe: 66.9%; P for the trend <.001). Parameters of coronary atherosclerosis, including atheroma burden obstructive score (ABOS), segment involvement score (SIS) and segment stenosis score (SSS), were higher in the moderate to severe steatosis group. After adjusting for major confounding factors, the severity of steatosis still correlated with the mixed plaque pattern (P = .043). Subgroup analysis of the risk of the presence of overall coronary and mixed plaques showed a significant association with increasing severity of steatosis, especially among these who were <65 years old, male, without metabolic syndrome, and with lower low-density lipoprotein choleseterol values. CONCLUSION: In this general population, steatosis severity of NAFLD is associated with coronary artery atherosclerosis burden. Furthermore, steatosis severity correlated with the risk of the presence of coronary plaques, especially high-risk plaques, and was independent of traditional risk factors.

Precipitating factors causing hyperbilirubinemia during chronic hepatitis C treatment with paritaprevir/ritonavir/ombitasvir and dasabuvir.

BACKGROUND: Hepatic decompensation is a fatal on-treatment side effect during chronic hepatitis C treatment with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD). Prompt bilirubin testing can reveal hepatic failure in susceptible patients, and clinical parameters precipitating early elevation of bilirubin can warn clinicians to avoid PrOD prescription. METHODS: This retrospective study included 169 Hepatitis C virus (HCV)-genotype 1b patients who underwent a 12-week course of PrOD with or without ribavirin. Laboratory data underwent χ analysis with Fisher's exact test to determine the precipitating factors causing hyperbilirubinemia in patients who had received 1 week of treatment. RESULTS: Sustained viral response was achieved in 164 patients (97.0%). Total bilirubin was ≥2 mg/dL (21.3%) in 36 patients after 1 week of treatment. Pretreatment white blood cell (WBC) <4500/µL and platelet <100,000/µL correlated with total bilirubin ≥2 mg/dL (relative risk [RR]: 21.64, 95% CI: 5.23-89.64, p < 0.001) after 1 week of treatment. Pretreatment platelet ≥100 000/µL and WBC <4500/µL correlated with direct bilirubin ≥0.45 mg/dL (RR: 6.56, 95% CI: 1.42-30.38, p = 0.016) and indirect bilirubin ≥0.6 mg/dL (RR: 4.77, 95% CI: 1.03-22.15, p = 0.046). Pretreatment platelet <100,000/µL with F3/F4 fibrosis correlated with first week total bilirubin ≥2 mg/dL (RR: 3.57, 95% CI: 1.35-9.09, p = 0.010). CONCLUSION: PrOD is an effective antiviral regimen for HCV genotype 1b patients. Total bilirubin ≥2 mg/dL after 1 week of treatment serves as an early warning of irreversible progression toward hepatic decompensation, and the current study provides a guide by which to monitor chronic hepatitis C patients undergoing PrOD treatment.

Factor analysis for the clustering of cardiometabolic risk factors and sedentary behavior, a cross-sectional study.

BACKGROUND: Few studies have reported on the clustering pattern of CVD risk factors, including sedentary behavior, systemic inflammation, and cadiometabolic components in the general population. OBJECTIVE: We aimed to explore the clustering pattern of CVD risk factors using exploratory factor analysis to investigate the underlying relationships between various CVD risk factors. METHODS: A total of 5606 subjects (3157 male, 51.5±11.7 y/o) were enrolled, and 14 cardiovascular risk factors were analyzed in an exploratory group (n = 3926) and a validation group (n = 1676), including sedentary behaviors. RESULTS: Five factor clusters were identified to explain 69.4% of the total variance, including adiposity (BMI, TG, HDL, UA, and HsCRP; 21.3%), lipids (total cholesterol and LDL-cholesterol; 14.0%), blood pressure (SBP and DBP; 13.3%), glucose (HbA1C, fasting glucose; 12.9%), and sedentary behavior (MET and sitting time; 8.0%). The inflammation biomarker HsCRP was clustered with only adiposity factors and not with other cardiometabolic risk factors, and the clustering pattern was verified in the validation group. CONCLUSION: This study confirmed the clustering structure of cardiometabolic risk factors in the general population, including sedentary behavior. HsCRP was clustered with adiposity factors, while physical inactivity and sedentary behavior were clustered with each other.

Early echocardiographic signs of diastolic dysfunction predict acute kidney injury in cirrhotic patients.

BACKGROUND: Cardiovascular dysfunction in cirrhotic patients affects survival and the development of cirrhotic complications. We aimed to evaluate potential echocardiographic parameters to predict mortality and acute kidney injury (AKI) in cirrhotic patients. METHODS: A total of 103 cirrhotic patients who underwent echocardiography between February 2009 and August 2016 in Taipei Veterans General Hospital were retrospectively enrolled. Cardiac function was evaluated using transthoracic two-dimensional echocardiography with tissue Doppler imaging. Cox hazard regression analysis was used for assessing predictors for 1-year mortality and AKI within 1 year. RESULTS: Baseline echocardiographic parameters were similar between survivors (n = 92) and nonsurvivors (n = 11). Lower serum levels of albumin, as well as higher albumin-bilirubin (ALBI) scores, Child-Pugh scores, and model for end-stage liver disease scores were observed in nonsurvivors. Cox proportional hazard regression analysis revealed Child-Pugh score as the only predictor of 1-year mortality. Baseline serum creatinine (Cr) > 1.5 mg/dL, total bilirubin > 2 mg/dL, and a higher E/e' ratio predict occurrence of AKI within 1 year. Among patients with serum Cr < 1.5 mg/dL, an increased atrial filling velocity and higher ALBI scores predict AKI occurrence within 1 year. CONCLUSION: Severity of underlying liver disease but not echocardiographic parameters predicts 1-year mortality in cirrhosis. Early echocardiographic signs of diastolic dysfunction and higher ALBI scores may predict development of AKI in cirrhotic patients with serum Cr < 1.5 mg/dL.

Hemoglobin A1C Levels are Independently Associated with the Risk of Coronary Atherosclerotic Plaques in Patients without Diabetes: A Cross-Sectional Study.

AIM: Coronary atherosclerotic plaques can be detected in asymptomatic subjects and are related to low-density lipoprotein cholesterol (LDL) levels in patients with coronary artery disease. However, researchers have not yet determined the associations between various plaque characteristics and other lipid parameters, such as HDL-C and TG levels, in low-risk populations. METHODS: One thousand sixty-four non-diabetic subjects (age, 57.86±9.73 years; 752 males) who underwent coronary computed tomography angiography (CCTA) were enrolled and the severity and patterns of atherosclerotic plaques were analyzed. RESULTS: Statin use was reported by 25% of the study population, and subjects with greater coronary plaque involvement (segment involvement score, SIS) were older and had a higher body mass index (BMI), blood pressure, unfavorable lipid profiles and comorbidities. After adjusting for comorbidities, only age (ß=0.085, p＜0.001), the male gender (ß=1.384, p＜0.001), BMI (ß=0.055, p=0.019) and HbA1C levels (ß=0.894, p＜0.001) were independent factors predicting the greater coronary plaque involvement in non-diabetic subjects. In the analysis of significantly different (＞50%) stenosis plaque patterns, age (OR: 1.082, 95% CI: 10.47-1.118) and a former smoking status (OR: 2.061, 95% CI: 1.013-4.193) were independently associated with calcified plaques. For partial calcified (mixed type) plaques, only age (OR: 1.085, 95% CI: 1.052-1.119), the male gender (OR: 7.082, 95% CI: 2.638-19.018), HbA1C levels (OR: 2.074, 95% CI: 1.036-4.151), and current smoking status (OR: 1.848, 95% CI: 1.089-3.138) were independently associated with the risk of the presence of significant stenosis in mixed plaques. CONCLUSIONS: A higher HbA1c levels is independently associated with the presence and severity of coronary artery atherosclerosis in non-diabetic subjects, even when LDL-C levels are tightly controlled.

Attenuation of Wnt/ß-catenin signaling in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Current studies have suggested that the pathobiology of drug-mediated SJS/TEN involves a dysregulation of cellular immunity with overwhelming activation of cytotoxic T lymphocytes. The canonical Wnt signaling pathway plays important roles in T cell development and activation, which may provide potential avenues for alleviating dysregulated immunity in SJS/TEN. In this study, we aimed to assess the implication of Wnt signaling in drug-reactive T cells in SJS/TEN. We showed downregulation of Wnt signaling components, including T cell factor 1 (TCF-1)/lymphoid enhancer binding factor 1 (LEF-1) transcription factors, in SJS/TEN patients, suggesting that canonical Wnt signaling is regulated during cytotoxic T cell responses in SJS/TEN. Further analyses demonstrated that engagement of the T cell receptor by antigen encounter and treatment of a prognostic marker of SJS/TEN, IL-15, in vitro led to the downregulation of LEF-1 and TCF-1 expression in CD8+ T cells. Enhancement of Wnt signaling by adding the Wnt activators attenuated ex vivo activation of drug-specific T cells from SJS/TEN patients, indicating a functional involvement of Wnt signaling in the pathomechanism of SJS/TEN. These findings provide additional insight into the immunopathogenesis and therapeutic intervention of this devastating condition.

Human BMP8A suppresses luteinization of rat granulosa cells via the SMAD1/5/8 pathway.

Bone morphogenetic proteins (BMPs) are known to play an indispensable role in preventing the precocious luteinization of granulosa cells within growing ovarian follicles. In this study, we found that the transcripts of BMP8 genes are enriched in the ovaries of humans and rodents. When analyzing transcriptomic datasets obtained from human mature granulosa cells, we further found that the BMP8 transcripts not only show the highest abundance among the searchable BMP-related ligands but also decrease significantly in women of advanced age or women with polycystic ovarian syndrome. The correlation between the BMP8 levels in granulosa cells and the decline in ovarian function in these subjects suggests that BMP8 protein may be involved in the regulation of granulosa cell function(s). Using a rat model, we demonstrated that human BMP8A protein activates the SMAD1/5/8 and the SMAD2/3 pathways simultaneously in both immature and mature granulosa cells. Furthermore, the expression of potential type I and type II receptors used by BMP8 in rat granulosa cells was characterized. We found that BMP8A treatment can significantly inhibit gonadotropin-induced progesterone production and steroidogenesis-related gene expression in granulosa cells. Pathway dissection using receptor inhibitors further revealed that such inhibitory effects occur specifically through the BMP8-activated SMAD1/5/8, but not SMAD2/3, pathway. Taken together, considering its abundance and possible functions in granulosa cells, we suggest that BMP8 may act as a novel luteinization inhibitor in growing follicles.

Spirometric reference values in heathy Chinese adults in Taiwan: The secular changes and comparison with other Asian populations.

BACKGROUND/PURPOSE: Although the lung function test has played an important role in respiratory care for a long time, valid spirometry reference values in the Chinese population in Taiwan remain to be elucidated. METHODS: 2963 healthy Taiwanese subjects aged 21 to 88 years (1765 males, 59.6%) from February 2015 to February 2017 were enrolled. The subjects attempted to meet the 2005 American Thoracic Society (ATS) and the European Respiratory Society (ERS) guidelines when performing forced expiratory spirograms. We would like to establish the spirometry predictive equations for forced expiratory volume (FEV1), forced vital capacity (FVC), FEV1/FVC, and lower limit of normal (LLN) in Taiwan and compare with other Asian populations. RESULTS: We established the spirometry predictive equations using a linear model for the entire population, using age and height as independent variables, which best predicted all spirometry parameters for sea level and highland subjects. We found that the values of FEV1 and FVC for the Taiwanese subjects in our study were systematically lower than those reported in South Korea, Japan, and China, but higher than the values in Yang's 1993 and Pan's 1997 Taiwan study. CONCLUSION: This study addressed the up-to-date spirometry reference equations and values for a healthy adult Chinese population in Taiwan.