TGF-ß downstream of Smad3 and MAPK signaling antagonistically regulate the viability and partial epithelial-mesenchymal transition of liver progenitor cells.

BACKGROUND: Liver progenitor cells (LPCs) are a subpopulation of cells that contribute to liver regeneration, fibrosis and liver cancer initiation under different circumstances. RESULTS: By performing adenoviral-mediated transfection, CCK-8 analyses, F-actin staining, transwell analyses, luciferase reporter analyses and Western blotting, we observed that TGF-ß promoted cytostasis and partial epithelial-mesenchymal transition (EMT) in LPCs. In addition, we confirmed that TGF-ß activated the Smad and MAPK pathways, including the Erk, JNK and p38 MAPK signaling pathways, and revealed that TGFß-Smad signaling induced growth inhibition and partial EMT, whereas TGFß-MAPK signaling had the opposite effects on LPCs. We further found that the activity of Smad and MAPK signaling downstream of TGF-ß was mutually restricted in LPCs. Mechanistically, we found that TGF-ß activated Smad signaling through serine phosphorylation of both the C-terminal and linker regions of Smad2 and 3 in LPCs. Additionally, TGFß-MAPK signaling inhibited the phosphorylation of Smad3 but not Smad2 at the C-terminus, and it reinforced the linker phosphorylation of Smad3 at T179 and S213. We then found that overexpression of mutated Smad3 at linker phosphorylation sites intensifies TGF-ß-induced cytostasis and EMT, mimicking the effects of MAPK inhibition in LPCs, whereas mutation of Smad3 at the C-terminus caused LPCs to blunt TGF-ß-induced cytostasis and partial EMT. CONCLUSION: These results suggested that TGF-ß downstream of Smad3 and MAPK signaling were mutually antagonistic in regulating the viability and partial EMT of LPCs. This antagonism may help LPCs overcome the cytostatic effect of TGF-ß under fibrotic conditions and maintain partial EMT and progenitor phenotypes.

A combined pre- and intra-operative nomogram in evaluation of degrees of liver cirrhosis predicts post-hepatectomy liver failure: a multicenter prospective study.

Background: Adequate evaluation of degrees of liver cirrhosis is essential in surgical treatment of hepatocellular carcinoma (HCC) patients. The impact of the degrees of cirrhosis on prediction of post-hepatectomy liver failure (PHLF) remains poorly defined. This study aimed to construct and validate a combined pre- and intra-operative nomogram based on the degrees of cirrhosis in predicting PHLF in HCC patients using prospective multi-center's data. Methods: Consecutive HCC patients who underwent hepatectomy between May 18, 2019 and Dec 19, 2020 were enrolled at five tertiary hospitals. Preoperative cirrhotic severity scoring (CSS) and intra-operative direct liver stiffness measurement (DSM) were performed to correlate with the Laennec histopathological grading system. The performances of the pre-operative nomogram and combined pre- and intra-operative nomogram in predicting PHLF were compared with conventional predictive models of PHLF. Results: For 327 patients in this study, histopathological studies showed the rates of HCC patients with no, mild, moderate, and severe cirrhosis were 41.9%, 29.1%, 22.9%, and 6.1%, respectively. Either CSS or DSM was closely correlated with histopathological stages of cirrhosis. Thirty-three (10.1%) patients developed PHLF. The 30- and 90-day mortality rates were 0.9%. Multivariate regression analysis showed four pre-operative variables [HBV-DNA level, ICG-R15, prothrombin time (PT), and CSS], and one intra-operative variable (DSM) to be independent risk factors of PHLF. The pre-operative nomogram was constructed based on these four pre-operative variables together with total bilirubin. The combined pre- and intra-operative nomogram was constructed by adding the intra-operative DSM. The pre-operative nomogram was better than the conventional models in predicting PHLF. The prediction was further improved with the combined pre- and intra-operative nomogram. Conclusions: The combined pre- and intra-operative nomogram further improved prediction of PHLF when compared with the pre-operative nomogram. Trial Registration: Clinicaltrials.gov Identifier: NCT04076631.

Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile.

BACKGROUND: Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells. METHODS: In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059. RESULTS: GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile. CONCLUSION: GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.

The effects of initial and subsequent overweight or obesity on hypertension in the middle age.

The aims of our study were to examine whether initial or subsequent adiposity status had a greater effect on hypertension. We collected data in 1992 and again in 2007 from the same group of 597 individuals in the middle age. The subjects were classified into four groups: individuals with a normal body mass index (BMI) in 1992 and 2007 were in Group I; those with a normal BMI in 1992, but became overweight or obese in 2007 were in Group II; those who were overweight or obese in 1992, but had a normal BMI in 2007 were in Group III; and those who were overweight or obese in 1992 and 2007 were in Group IV. Their demographic data were recorded. The relationship between adiposity status and hypertension was analyzed using logistic regression model. The cumulative incidence of hypertension was 35.5%, 56.3%, 50.0%, and 65.1% for Group I to IV, respectively. Compared with Group I, after adjusted factors, the hazard ratio (HR) was 1.80 for Group II (P = .001), 1.40 for Group III (P = .150), and 2.31 for Group IV (P < .001). Adiposity status in 2007 could predict hypertension (OR = 2.5, P < .001), as opposed to the initial adiposity status (P = .148). Subsequently adiposity status could have major effects on hypertension. Our society is very short of public health resources, particularly in developing countries, we should pay more attention to current adiposity status and encourage middle-aged people to lose weight.

Thermal ablation for hepatic tumors in high-risk locations.

Thermal ablative techniques such as radiofrequency and microwave ablation are minimally invasive and cost-effective approaches that are currently being adopted as alternatives to surgical resection for primary and metastatic liver malignancies. However, they are considered to be relatively contraindicated for tumors in high-risk locations due to technical difficulties and a perceived increased risk of perioperative complications. Several techniques, including artificial ascites, non-touch multibipolar ablation, and laparoscopically assisted ablation, can be used to improve the outcomes of ablation for high-risk tumors. This review aims to provide a comprehensive summary of the techniques currently used to improve thermal ablation outcomes for high-risk liver tumors.

GAS5 promotes cytarabine induced myelosuppression via inhibition of hematopoietic stem cell differentiation.

Cytarabine (Ara-C) is widely used in the induction chemotherapy for acute myeloid leukemia (AML). Association between LncRNA GAS5 genetic polymorphism and the recovery of hematopoietic function after Ara-C-based chemotherapy is observed. This study aimed to identify whether intervention of GAS5 expression and GAS5 genotype affect Ara-C-induced inhibition of hematopoietic stem cells (HSCs) differentiation. In this study, cord blood-derived CD34+ cells were cultured in vitro, and a cell model of myelosuppression was established by treatment of CD34+ cells with Ara-C. The effect of GAS5 overexpression, Ara-C treatment, and GAS5 rs55829688 genotype on the hematopoietic colony-forming ability of CD34+ cells was assessed using methylcellulose-based colony forming unit assay. GAS5 overexpression slowed down the proliferation of cord blood-derived CD34+ cells significantly (p < 0.05) and decreased their ability to form hematopoietic colonies in vitro. Ara-C significantly reduced the hematopoietic colony-forming ability of CD34+ cells in vitro (p < 0.0001), and overexpressing GAS5 further decreased the number of hematopoietic colonies. GAS5 expression was higher in CD34+ cells than in CD34- cells, and positively correlated with GATA1 mRNA expression in CD34+ cells in vitro culture. However, GAS5 genotype had no effect on the total number of hematopoietic colonies formed from cord blood-derived CD34+ cells. In conclusion, our study highlights that GAS5 inhibited the in vitro proliferation and reduced the hematopoietic colony-forming ability of cord blood-derived CD34+ cells, with the most pronounced effect observed on CFU-GEMM formation. GAS5 also enhanced the inhibitory effect of Ara-C on the in vitro hematopoietic ability of CD34+ HSCs.

Risk factors for immediate and delayed cardiogenic shock in patients with ventricular septal rupture after myocardial infarction.

Background: Ventricular septal rupture (VSR) is a serious complication occurring after myocardial infarction (MI). Cardiogenic shock (CS) is a common complication of VSR and an important factor affecting its prognosis. CS can occur in either an immediate or delayed manner after VSR; however, studies on the risk factors associated with immediate or delayed CS are scarce. Methods: We retrospectively studied patients diagnosed with VSR after MI and admitted to the West China Hospital between September 2009 and August 2023. Demographic data, medical history, physical examination results, electrocardiograms, and echocardiographic and hematological data were extracted from electronic medical records or archived records. CS was defined as hypotension (<90 mmHg) and/or the requirement for catecholamines, pulmonary congestion, and signs of end-organ failure. The CS onset time was defined as the time at which catecholamines were initiated. Results: A total of 88 patients with VSR after MI, including 49 males (55.7%), were enrolled. The average age was 70.2 years. Of these patients, 32 (36.4%) who already had CS at the time of VSR discovery were defined as immediate CS, and 28 (31.8%) who developed CS within 2 weeks after VSR discovery were defined as delayed CS. A smaller left ventricular end-diastolic diameter (LVEDD) and VSR discovered after admission were independent risk factors for immediate CS. Elevated heart rate and higher levels of creatine kinase-MB isoenzyme on admission were independent risk factors for delayed CS in patients without immediate CS after VSR. Conclusions: The occurrence of CS in patients with VSR after MI has an evident time course. Thus, an early identification of patients at risk of immediate or delayed CS and optimization of treatment procedures may help improve the prognosis.

Case Report: Durable complete response of metastatic hepatocellular carcinoma with asymptomatic hyperamylasemia to combined immunotherapy of anti-cytotoxic T lymphocyte-associated antigen 4 plus anti-programmed cell death-1 antibodies.

Background: Combined immunotherapy has shown promising results in the treatment of advanced HCC, whereas the priority population that would respond to the combined immunotherapy is still elusive. In addition, HCC with asymptomatic hyperamylasemia was not reported previously. Case presentation: An aged patient was diagnosed as HCC with BCLC stage C (bone metastasis). Notably, this patient showed asymptomatic hyperamylasemia. The patient was then enrolled in a trial evaluating combined immunotherapy of anti-PD-1 antibody sintilimab (IBI308) plus anti-CTLA-4 antibody (IBI310) in advanced HCC. After being treated with combined immunotherapy, this patient rapidly achieved complete response (CR) according to mRECIST criteria or immune partial response (iPR) according to iRECIST criteria and maintain the CR state for more than 12 months. Interestingly, serum levels of amylase and lipase in this patient were reduced after treatment. Conclusion: We reported, for the first time, a case of metastatic HCC with asymptomatic hyperamylasemia, and suggested that HCC patients with asymptomatic hyperamylasemia may benefit from combined immunotherapy of anti-CTLA-4 and PD-1 antibodies.

Nutrient content and resorption efficiency of leaves of broad-leaved trees along altitudes in Wuyi Mountains, China.

To reveal the variation of leaf nutrient utilization strategies with altitude gradient in subtropical mountain broadleaved trees, 44 species of broadleaved trees at different altitudes (1400, 1600 and 1800 m) in Wuyi Mountains were selected to measure nutrient content, stoichiometric ratio, and nutrient resorption efficiency of green and senescent leaves, and analyzed their allometric growth relationships. The results showed that nitrogen (N) and phosphorus (P) contents in green leaves were significantly higher than those in senescent leaves, which increased with the increases of altitude. The average values of phosphorus resorption efficiency (PRE) and nitrogen resorption efficiency (NRE) were 48.3% and 34.9%, respectively. PRE was significantly higher than NRE. There was no significant difference in nutrient resorption efficiency with altitude. NRE had positive isokinetic growth with and mature leaf N content at low altitude (1400 m) and negative allometry growth with senescent leaf N content at high altitude (1800 m). PRE and N and P contents of senescent leaves had negative isokinetic growth at low altitude (1400 m) and negative allometry growth at high altitudes (1600 and 1800 m). PRE-NRE allometric growth index was 0.95 at each altitude. The nutrient contents of green and senescent leaves increased with the increases of altitude, but altitude did not affect nutrient resorption efficiency. Plants preferred to re-absorbed P from senescent leaves. Nutrient resorption efficiency of leaves at high altitude affected the nutrient status of senescent leaves.

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It is of great practical significance to identify service blind area, scientifically select park construction areas, and clarify the priority of parks' construction based on the co-ordination of supply-demand evaluation. With the urban parks within the Taiyuan Ring Expressway as the research subjects, we estimated the accessibility range and the service pressure of each park by using the application programming interface of Gaode map route planning and point of interest data to characterize their supply and demand levels. We identified the service blind areas of parks by overlay analysis, and used the location-allocation (LA) model to purposefully supply park green space. Results showed that the accessibility coverage rates of the parks by walking and bicycling within 15 minutes were 35.6% and 71.7%, respectively, indicating insufficient supply capacity of parks. The areas with large potential demand for park green space in Taiyuan were mainly concentrated in the business district of Qinxian-Changfeng Street and the Shuangta business district within Dongzhong ring road, which existed the obviously invisible blind areas. Finally, we proposed new park green space site selection proposal based on LA model. Optimization results indicated that the coverage rates of walking and bicycling within 15 minutes increased to 46.7% and 81.0%, respectively, and that the service pressure of parks was relieved. We combined the leisure demands of urban residents and the distribution of urban parks by utilizing network big data, which could promote the scientific nature and accuracy of the optimizing site selection and provide scientific method and theory basis for urban park construction.

International experts consensus guidelines on robotic liver resection in 2023.

The robotic liver resection (RLR) has been increasingly applied in recent years and its benefits shown in some aspects owing to the technical advancement of robotic surgical system, however, controversies still exist. Based on the foundation of the previous consensus statement, this new consensus document aimed to update clinical recommendations and provide guidance to improve the outcomes of RLR clinical practice. The guideline steering group and guideline expert group were formed by 29 international experts of liver surgery and evidence-based medicine (EBM). Relevant literature was reviewed and analyzed by the evidence evaluation group. According to the WHO Handbook for Guideline Development, the Guidance Principles of Development and Amendment of the Guidelines for Clinical Diagnosis and Treatment in China 2022, a total of 14 recommendations were generated. Among them were 8 recommendations formulated by the GRADE method, and the remaining 6 recommendations were formulated based on literature review and experts' opinion due to insufficient EBM results. This international experts consensus guideline offered guidance for the safe and effective clinical practice and the research direction of RLR in future.

Comparison of Dural Puncture Epidural, Epidural and Combined Spinal-Epidural Anesthesia for Cesarean Delivery: A Randomized Controlled Trial.

Purpose: Catheter-based techniques such as combined spinal-epidural (CSE) anesthesia which are sometimes indicated for obstetric anesthesia have a complex mechanism of action. The application of the dural puncture epidural (DPE) anesthesia for cesarean section (CS) has not been well investigated. The present study compared the relatively novel DPE technique with epidural (EA) and CSE anesthesia. Patients and Methods: We randomly assigned 150 parturients who underwent elective CS to receive DPE, EA or CSE anesthesia. The primary outcome was the onset of sensory anesthesia to the T5 dermatome assessed using the Cox proportional hazards model. Secondary outcomes included median time to sensory block, quality of block, patient and surgeon satisfaction, APGAR scores and other side effects. Results: For DPE anesthesia versus EA anesthesia, the onset of anesthesia was faster (hazard ratio 2.47 [95% CI 1.56 to 3.90], adjusted P < 0.001) and the median time to surgical level was shorter (16 [IQR 14-18] min versus 19 [15.5-21] min, adjusted P < 0.001); the incidence of intraoperative pain was lower (7/48 versus 17/47, adjusted P = 0.046) and the median patient satisfaction score was higher (9 [IQR 9-10] versus 8 [8-9.5], adjusted P = 0.004). In the CSE group, the onset of anesthesia was faster than in the other two but the incidence of hypotension was higher (P < 0.001) and the phenylephrine requirement was greater (P < 0.001). Conclusion: DPE anesthesia had a faster onset and better quality of block than EA anesthesia and provided less influence to maternal hemodynamic parameters than CSE anesthesia for CS. These results suggest that the dural puncture plays a significant role in enhancing the effectiveness of epidural top-ups during CSE anesthesia and indicates enlightenment that contributes to the satisfaction of anesthetic effect in DPE technique labor analgesia transferred to CS.

Shexiang Baoxin Pill treats acute myocardial infarction by promoting angiogenesis via GDF15-TRPV4 signaling.

Angiogenesis has been considered a pivotal strategy for treating ischemic heart disease. One possible approach, the Shexiang Baoxin Pill (MUSKARDIA), has been noted to promote angiogenesis, but its underlying mechanism is still largely unknown. We aimed to determine the effects of MUSKARDIA on acute myocardial infarction (AMI), as well as the underlying mechanistic bases. AMI was induced in rats, using left anterior descending coronary arterial occlusion, and either 6 (low) or 12 (high-dose) mg/kg/day of MUSKARDIA was administered for 56 days. We found that MUSKARDIA improved cardiac function and counteracted against adverse remodeling among AMI rats, which most likely is due to it promoting angiogenesis. Transcriptome analysis by RNA-sequencing found that MUSKARDIA up-regulated cardiac pro-angiogenic genes, particularly growth differentiation factor 15 (GDF15), which was confirmed by RT-qPCR. This up-regulation was also correlated with elevated serum GDF15 levels. In vitro analyses with human umbilical vein endothelial cells found that increased GDF15, stimulated by MUSKARDIA, resulted in enhanced cell migration, proliferation, and tubular formation, all of which were reversed after GDF15 knockdown using a lentiviral vector. Gene Ontology, as well as Kyoto Genes and Genomes enrichment analyses identified calcium signaling pathway as a major contributor to these outcomes, which was verified by Western blot and Cal-590 AM loading showing that transient receptor potential cation channel subfamily V member 4 protein (TRPV4) and intracellular Ca2+ levels increased in accordance with MUSKARDIA-induced GDF15 up-regulation, and decreased with GDF15 knock-down. Therefore, MUSKARDIA may exert its cardioprotective effects via stimulating the GDF15/TRPV4/calcium signaling/angiogenesis axis.

Scientific Hepatectomy for Hepatocellular Carcinoma.

With advances in imaging technology and surgical instruments, hepatectomy can be perfectly performed with technical precision for hepatocellular carcinoma (HCC). However, the 5-year tumor recurrence rates remain greater than 70%. Thus, the strategy for hepatectomy needs to be reappraised based on insights of scientific advances. Scientific evidence has suggested that the main causes of recurrence after hepatectomy for HCC are mainly related to underlying cirrhosis and the vascular spread of tumor cells that basically cannot be eradicated by hepatectomy. Liver transplantation and systemic therapy could be the solution to prevent postoperative recurrence in this regard. Therefore, determining the severity of liver cirrhosis for choosing the appropriate surgical modality, such as liver transplantation or hepatectomy, for HCC and integrating newly emerging immune-related adjuvant and/or neoadjuvant therapy into the strategy of hepatectomy for HCC have become new aspects of exploration to optimize the strategy of hepatectomy. In this new area, hepatectomy for HCC has evolved from a pure technical concept emphasizing anatomic resection into a scientific concept embracing technical considerations and scientific advances in underlying liver cirrhosis, vascular invasion, and systemic therapy. By introducing the concept of scientific hepatectomy, the indications, timing, and surgical techniques of hepatectomy will be further scientifically optimized for individual patients, and recurrence rates will be decreased and long-term survival will be further prolonged.

Correlation between immune-related adverse events and long-term outcomes in pembrolizumab-treated patients with unresectable hepatocellular carcinoma: A retrospective study.

BACKGROUND: Although immune checkpoint inhibitor (ICI) therapy has improved the prognosis of unresectable hepatocellular carcinoma (HCC), it has also resulted in unique immune-related adverse events (irAEs). The relationship between irAE and treatment outcomes in ICI-treated unresectable HCC patients remains unknown. AIM: To elucidate the correlation between immune-related toxic effects and prognosis in patients with unresectable HCC treated with pembrolizumab. METHODS: From March 2019 to February 2021, a total of 190 unresectable HCC (Barcelona Clinic Liver Cancer C) patients receiving pembrolizumab treatment were retrospectively reviewed. Overall survival (OS) was the primary endpoint, while objective response rate (ORR), disease control rate (DCR), and time to progression (TTP) were secondary evaluation indexes. We assessed demographics, irAEs, and outcomes by retrospective review. RESULTS: One hundred and forty-three males and 47 females were included in the study. The ORR and DCR were 12.1% (23/190) and 52.1% (99/190), respectively. The median OS was 376 d [95% confidence interval (CI): 340-411 d] and the median TTP was 98 d (95%CI: 75-124 d). The overall incidence of treatment-related adverse events was 72.6% (138/190) and 10.0% of them were severe irAEs (grade ≥ 3). Child-Pugh B class, portal vein tumor thrombus, extrahepatic metastasis, and hypothyroidism were the independent risk factors for survival. Patients with hypothyroidism showed a longer OS [517 d (95%CI: 423-562) vs 431 d (95%CI: 412-485), P = 0.011] and TTP [125 d (95%CI: 89-154) vs 87 d (95%CI: 61-98), P = 0.004] than those without irAEs. CONCLUSION: Pembrolizumab-treated patients with unresectable HCC who experienced hypothyroidism have promising ORR and durable response. Hypothyroidism, an irAE, may be used as a clinical evaluation parameter of response to ICIs in unresectable HCC.

A Co-Expressed Natural Antisense RNA FCER1A-AS Controls IgE-Dependent Immunity by Promoting Expression of FcεRIα.

As the α-subunit of the high-affinity receptor for the Fc portion of immunoglobulin E (FcεRIα), FcεRIα plays a central role in IgE-mediated allergic disorders and in the immunity and immunopathology of some parasitic infections. FcεRIα is specifically expressed on basophils and mast cells, but the mechanism that controls FcεRIα expression in these cells is poorly understood. In this study, we found that the natural antisense transcript (NAT) of FcεRIα (FCER1A-AS) is co-expressed with the sense transcript (FCER1A-S) in both interleukin (IL)-3-induced FcεRIα-expressing cells and in the high FcεRIα-expressing cell line MC/9. When FCER1A-AS is selectively knocked down by the CRISPR/RfxCas13d (CasRx) approach in MC/9 cells, the expression of both FCER1A-S mRNA and proteins is markedly decreased. Furthermore, FCER1A-AS deficiency was also found to be associated with a lack of FCER1A-S expression in vivo. Correspondingly, homozygous mice deficient in FCER1A-AS demonstrated a similar phenotype to FCER1A knockout mice in Schistosoma japonicum infection and in IgE-FcεRIα-mediated cutaneous anaphylaxis. Thus, we uncovered a novel pathway for the control of FcεRIα expression by its co-expressed natural antisense transcript. IMPORTANCE FcεRIα is responsible for high-affinity binding with the Fc portion of IgE, which is critical for IgE-dependent disease responses such as allergy responses and anti-parasite immunity. FcεRIα is expressed on a few cell types, including mast cells and basophils. Although the expression of FcεRIα is known to be promoted by the IL-3-GATA-2 pathway during its differentiation, the mechanism by which FcεRIα expression is maintained remains unknown. In this study, we discovered that a natural antisense transcript, FCER1A-AS, is co-expressed with the sense transcript. The presence of FCER1A-AS is essential for sense transcript expression in mast cells and basophils, but not for the differentiation of these cells through cis-regulation. Like FcεRIα knockout mice, mice lacking FCER1A-AS also exhibit reduced survival after Schistosoma japonicum infection and a lack of IgE-mediated cutaneous anaphylaxis. Thus, a novel pathway for regulating IgE-mediated allergic diseases through noncoding RNAs has been revealed.

Prognostic value of preoperative circulating tumor cells for hepatocellular carcinoma with portal vein tumor thrombosis: A propensity score analysis.

PURPOSE: The role of circulating tumor cells (CTCs) in hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is not fully understood. METHODS: In this retrospective analysis, we included 316 HCC patients who underwent hepatectomy and preoperative CTC detection. We selected 41 pairs of matched HCC patients with and without PVTT using propensity score matching (PSM) analysis. We compared the preoperative CTC counts in patients from both the full cohort and the PSM model. We also analyzed their associations with disease-free survival (DFS) and overall survival (OS). RESULTS: Before and after PSM analysis, the preoperative CTC counts in the HCC with PVTT group were substantially higher than in the HCC without PVTT group. In both the full cohort of patients and the PSM model, patients with CTC ≥ 2 had significantly shorter OS and DFS than patients with CTC < 2. The outcomes of HCC patients with PVTT could be well differentiated by preoperative CTC levels. HCC patients with CTC ≥ 2 had noticeably shorter OS (9.9 months vs. 24.6 months, P = 0.0003) and DFS (6.0 months vs. 12.3 months, P = 0.0041) than those with CTC < 2. Moreover, preoperative CTC ≥ 2 remained an independent predictor in all groups' multivariate analysis. CONCLUSION: We discovered a link between preoperative CTC counts and the occurrence of PVTT and confirmed the prognostic significance of preoperative CTC in HCC patients with PVTT. These findings suggest that preoperative CTC counts have the potential to assist in identifying patients with HCC and PVTT who may benefit from surgery.

Postprandial glucagon-like peptide 1 secretion is associated with urinary albumin excretion in newly diagnosed type 2 diabetes patients.

BACKGROUND: Microalbuminuria is an early and informative marker of diabetic nephropathy. Our study found that microalbuminuria developed in patients with newly diagnosed type 2 diabetes mellitus (T2DM). AIM: To investigate the association between glucagon-like peptide 1 (GLP-1) and microalbuminuria in newly diagnosed T2DM patients. METHODS: In total, 760 patients were recruited for this cross-sectional study. The GLP-1 levels during a standard meal test and urinary albumin-creatinine ratio (UACR) were determined. RESULTS: Patients with microalbuminuria exhibited lower GLP-1 levels at 30 min and 120 min during a standard meal test than patients with normal albuminuria (30 min GLP-1, 16.7 ± 13.3 pmol vs 19.9 ± 15.6 pmol, P = 0.007; 120 min GLP-1, 16.0 ± 14.1 pmol vs 18.4 ± 13.8 pmol, P = 0.037). The corresponding area under the curve for active GLP-1 (AUCGLP-1) was also lower in microalbuminuria patients (2257, 1585 to 3506 vs 2896, 1763 to 4726, pmol × min, P = 0.003). Postprandial GLP-1 levels at 30 min and 120 min and AUCGLP-1 were negatively correlated with the UACR (r = 0.159, r = 0.132, r = 0.206, respectively, P < 0.001). The prevalence of microalbuminuria in patients with newly diagnosed T2DM was 21.7%, which decreased with increasing quartiles of AUCGLP-1 levels (27.4%, 25.3%, 18.9% and 15.8%). After logistic regression analysis adjusted for sex, age, hemoglobin A1c, body mass index, systolic blood pressure, estimated glomerular filtration rate, homeostasis model assessment of insulin resistance, AUCglucose and AUCglucagon, patients in quartile 4 of the AUCGLP-1 presented a lower risk of microalbuminuria compared with the patients in quartile 1 (odds ratio = 0.547, 95% confidence interval: 0.325-0.920, P = 0.01). A consistent association was also found between 30 min GLP-1 or 120 min GLP-1 and microalbuminuria. CONCLUSION: Postprandial GLP-1 levels were independently associated with microalbuminuria in newly diagnosed Chinese T2DM patients.

CD80 DNA methylation and single-nucleotide polymorphism associated with clopidogrel response: a whole-genome DNA methylation analysis in acute coronary syndrome.

Background: Dual antiplatelet therapy with clopidogrel and aspirin is the primary treatment for patients who undergo percutaneous coronary intervention. However, the interindividual difference in clopidogrel response is remarkable, and high on-treatment platelet reactivity (HTPR) can increase the risk of thrombotic events after percutaneous coronary intervention. Objective: We studied novel accessible factors that possibly affect clopidogrel response in DNA methylation. Methods: Methylation 850K bead chips were used to detect DNA methylation levels. The platelet reactivity index (PRI) was determined in 330 subjects with acute coronary syndrome (ACS) after administration of clopidogrel 300 mg loading dose or at least 5 days of 75 mg daily maintenance dose. Results: Overall, 32 discovery samples showed extreme clopidogrel response: 16 with HTPR (PRI > 75%) and 16 with non-HTPR (PRI < 26%). Overall, 61 differential methylation loci (DMLs) were observed between the 2 groups. Most were in the open sea and intergenic regions in the genome. In the validation stage, HTPR showed a lower level of CD80_cg06300880 methylation. Carriers of rs34394661 AA genotype, a CpG-single-nucleotide polymorphism at the CD80_cg06300880 locus, showed an increased odds for HTPR (overall odds ratio of patients with ACS = 7.31, 95% CI: 1.69-31.59, P = .008; non-ST elevation myocardial infarction-ACS: odds ratio = 12.69, 95% CI: 1.68-96.08, P = .01) and decreased CD80_cg06300880 methylation (P < .0001). Multivariate regression analysis showed that both CYP2C19 poor metabolizers and CD80_rs34394661 AA (P = .009) genotype were associated with higher odds for HTPR in the overall samples. In contrast, CD80_cg06300880 methylation (P = .002) caused lower odds for HTPR in patients with non-ST elevation myocardial infarction-ACS. Conclusion: CD80_cg06300880 and CpG-single-nucleotide polymorphism rs34394661 could be independent predictors of HTPR with clopidogrel therapy.

HBcAb positivity increases the risk of postoperative complications after extended hemihepatectomy for hilar cholangiocarcinoma.

BACKGROUND: Hepatitis B core antibody (HBcAb) positivity is considered a prior hepatitis B virus (HBV) infection. However, little is known about the effect of HBcAb positivity on surgical safety for hilar cholangiocarcinoma (hCCA). The present study aims to investigate the role of HBcAb positivity on postoperative complications of hCCA. METHODS: A retrospective analysis was performed on the status of HBcAb positivity, liver fibrosis, perioperative surgical complications, and long-term outcomes of hCCA patients with Hepatitis B surface antigen (HBsAg) negativity who underwent surgical treatment in Tongji Hospital from April 2012 to September 2019. RESULTS: HBcAb positivity with negative HBsAg occurs in 137 hCCA patients (63.1%). A total of 99 hCCA patients with negative HBsAg underwent extended hemihepatectomy, of whom 69 (69.7%) and 30 (30.3%) were HBcAb-positive and HBcAb-negative, respectively. Significant fibrosis was detected in 63.8% of the patients with HBcAb-positive, which was markedly higher than those with HBcAb-negative (36.7%) (p = 0.016). The postoperative complications and 90-day mortality rates were 37.4% (37/99) and 8.1% (8/99), respectively. The incidence of postoperative complications in HBcAb-positive patients (44.9%) was significantly higher than that in HBcAb-negative patients (20.0%) (p = 0.018). All the patients who died within 30-day after surgery were HBcAb-positive. Multivariate analysis showed that the independent risk factors for complications were HBcAb positivity, preoperative cholangitis, portal occlusion >15 min, and significant fibrosis. There were no significant differences in recurrence-free survival (RFS) and overall survival (OS) between HBcAb-positive and HBcAb-negative patients (p = 0.642 and p = 0.400, respectively). CONCLUSIONS: HBcAb positivity is a common phenomenon in hCCA patients from China, a country with highly prevalent HBcAb positivity. The status of HBcAb-positive markedly increases the incidence of postoperative complications after extended hemihepatectomy for hCCA patients.