Inhibition of 14-3-3ε by K50 acetylation activates YAP1 to promote cholangiocarcinoma growth.

14-3-3 proteins are ubiquitous adapters combining with phosphorylated serine/threonine motifs to regulate multiple cellular processes. As a negative regulator, 14-3-3 proteins could sequester the phosphorylated YAP1 in cytoplasm to inhibit its activity. In this study, we identified the K50 acetylation (K50ac) of 14-3-3ε protein and investigated its roles and mechanism in cholangiocarcinoma progression. The NAD (+)-dependent protein deacetylases inhibitor, NAM treatment significantly up-regulated the K50ac of 14-3-3ε. K50R mutation resulted in the decrease of K50ac of 14-3-3ε. The K50ac of 14-3-3ε was reversibly mediated by PCAF acetyltransferase and sirt1 deacetylases. K50ac had no obvious effect on the protein stability of 14-3-3ε, but inhibited the combination of 14-3-3ε with phosphorylated YAP1, which resulted in the activation of YAP1 in cholangiocarcinoma. K50R significantly decreased cholangiocarcinoma cell proliferation in vitro and the growth of tumor xenograft in vivo compared with WT (wild type) 14-3-3ε. The level of K50ac were higher in cholangiocarcinoma tissues accompanied by the accumulation of YAP1 in nuclear than para-carcinoma tissues. Our study revealed the underlying mechanism of K50ac of 14-3-3ε and its roles in cholangiocarcinoma, providing a potential targeting for cholangiocarcinoma therapy.

Spatiotemporal analysis of the morbidity of global Omicron from November 2021 to February 2022.

The Omicron variant was first reported to the World Health Organization (WHO) from South Africa on November 24, 2021; this variant is spreading rapidly worldwide. No study has conducted a spatiotemporal analysis of the morbidity of Omicron infection at the country level; hence, to explore the spatial transmission of the Omicron variant among the 220 countries worldwide, we aimed to the analyze its spatial autocorrelation and to conduct a multiple linear regression to investigate the underlying factors associated with the pandemic. This study was an ecological study. Data on the number of confirmed cases were extracted from the WHO website. The spatiotemporal characteristic was described in a thematic map. The Global Moran Index (Moran's I) was used to detect the spatial autocorrelation, while the local indicators of spatial association (LISA) were used to analyze the local spatial correlation characteristics. The joinpoint regression model was used to explore the change in the trend of the Omicron incidence over time. The association between the morbidity of Omicron and influencing factors were analyzed using multiple linear regression. This study was an ecological study. Data on the number of confirmed cases were extracted from the WHO website. The spatiotemporal characteristic was described in a thematic map. The Global Moran Index (Moran's I) was used to detect the spatial autocorrelation, while the LISA were used to analyze the local spatial correlation characteristics. The joinpoint regression model was used to explore the change in the trend of the Omicron incidence over time. The association between the morbidity of Omicron and influencing factors were analyzed using multiple linear regression. The value of Moran's I was positive (Moran's I = 0.061, Z-score = 3.772, p = 0.007), indicating a spatial correlation of the morbidity of Omicron at the country level. From November 26, 2021 to February 26, 2022; the morbidity showed obvious spatial clustering. Hotspot clustering was observed mostly in Europe (locations in High-High category: 24). Coldspot clustering was observed mostly in Africa and Asia (locations in Low-Low category: 32). The result of joinpoint regression showed an increasing trend from December 21, 2021 to January 26, 2022. Results of the multiple linear regression analysis demonstrated that the morbidity of Omicron was strongly positively correlated with income support (coefficient = 1.905, 95% confidence interval [CI]: 1.354-2.456, p < 0.001) and strongly negatively correlated with close public transport (coefficient = -1.591, 95% CI: -2.461 to -0.721, p = 0.001). Omicron outbreaks exhibited spatial clustering at the country level worldwide; the countries with higher disease morbidity could impact the other countries that are surrounded by and close to it. The locations with High-High clustering category, which referred to the countries with higher disease morbidity, were mainly observed in Europe, and its adjoining country also showed high spatial clustering. The morbidity of Omicron increased from December 21, 2021 to January 26, 2022. The higher morbidity of Omicron was associated with the economic and policy interventions implemented; hence, to deal with the epidemic, the prevention and control measures should be strengthened in all aspects.

Clinical correlation of cadherin-17 marker with advanced tumor stages and poor prognosis of cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: In this retrospective study, we examined the CA17 tissue expression and analyzed its clinical significance in cholangiocarcinoma (CCA). MATERIALS AND METHODS: Immunohistochemistry was performed to assess CA17 expression on tissue microarrays in a training cohort enrolling 120 CCA patients and a validation cohort comprising 60 CCA patients. Image pro plus was applied to score the staining intensity and expression level of CA17 marker. Kaplan-Meier analysis, Cox's proportional hazards regression, and nomogram were applied to evaluate the prognostic significance of CA17. RESULTS: CA17 cancer biomarker over-expression was significantly observed in CCA compared to their non-tumor counterparts, and positively correlated with aggressive tumor phenotypes, like lymph node metastasis. Meanwhile, patients with high expression of CA17 correlated with worse postoperative overall survival (OS) and recurrence-free survival. Besides, multivariate analysis identified that CA17 expression was an independent prognostic factor for cholangiocarcinoma patients, which indicated that the CA17 could be more efficient than serum CA19-9 in predicting the OS of CCA patients. Notably, the nomogram integrating CA17 expression had better prognostic performance as compared with current TNM staging systems. CONCLUSION: CA17 was an independent adverse prognostic factor for CCA patients' survival, which may serve as a promising prognostic biomarker for CCA patients.

MUC16 C-terminal binding with ALDOC disrupts the ability of ALDOC to sense glucose and promotes gallbladder carcinoma growth.

The MUC16 C-terminal (MUC16c) level is associated with tumor serum CA-125 levels, however, the roles remain unclear in gallbladder carcinoma (GBC). In this study, we found that MUC16c promoted glucose uptake and glycolysis for GBC cell proliferation. Mass spectrometry analysis suggested that MUC16c could combine with aldolase. The ALDOC mRNA and protein are overexpressed in GBC tumors. The IHC results also showed the consistent up-regulation of. ALDOC and MUC16c level in GBC tumor tissues than in peritumor tissues. We determined that MUC16c combining with ALDOC promoted ALDOC protein stability and disrupted the ability of ALDOC sensing glucose deficiency, which activated AMPK pathway and increased GBC cell proliferation. ALDOC knockdown significantly inhibited the glucose uptake and glycolysis induced by MUC16c. Our study established important roles of MUC16c promoting GBC cell glycolysis and proliferation and revealed the underlying mechanism of CA-125-related heavy tumor metabolic burden in GBC.

Multidrug-resistant Staphylococcus aureus nasal carriage among HIV-positive outpatients in Guangzhou, China: Prevalence, risk factors, phenotypic and molecular characteristics.

INTRODUCTION: Data on comprehensive characterization of multidrug-resistant (MDR) Staphylococcus aureus (S. aureus) carriage in human immunodeficiency virus (HIV)-positive patients are limited. The objective of the present study is to determine the prevalence, risk factors, phenotypic and molecular characterization of MDR S. aureus isolated from HIV-positive population. METHODS: A cross-sectional study was conducted to determine the characteristics of MDR S. aureus nasal carriage among HIV-positive outpatients in an HIV clinic from June to August 2017. Nasal swabs and risk factor data of the enrolled HIV-positive outpatients were collected. Phenotypic and molecular characteristics of MDR and non-MDR S. aureus isolates were analyzed. Risk factors for nasal carriage with MDR S. aureus were estimated by logistic regression. The relationship between phenotypic and molecular characteristics of S. aureus isolates was assessed by the correspondence analysis. RESULTS: Overall, 1001 HIV-positive outpatients were included. The prevalence of MDR S. aureus nasal carriage was 15.18% (152/1001), and the proportion of multidrug resistance among S. aureus isolates was 60.08% (152/253). Having a history of respiratory tract infection was the risk factor for MDR S. aureus nasal carriage (adjusted odds ratio = 1.90, 95% confidence interval: 1.25-2.89). Multidrug resistance of S. aureus isolates was in good corresponding relationships with clonal complex (CC)5, CC15, CC59 and CC398. CONCLUSIONS: We found high burden of multidrug resistance among S. aureus isolated from HIV-positive outpatients, particularly in those who had upper respiratory tract infection. Moreover, CC59 and CC398 are highly related to multidrug resistance of S. aureus isolates.

Effects of exposure to low-dose ionizing radiation on changing platelets: a prospective cohort study.

BACKGROUND: Numerous studies have concentrated on high-dose radiation exposed accidentally or through therapy, and few involve low-dose occupational exposure, to investigate the correlation between low-dose ionizing radiation and changing hematological parameters among medical workers. METHODS: Using a prospective cohort study design, we collected health examination reports and personal dose monitoring data from medical workers and used Poisson regression and restricted cubic spline models to assess the correlation between changing hematological parameters and cumulative radiation dose and determine the dose-response relationship. RESULTS: We observed that changing platelet of 1265 medical workers followed up was statistically different among the cumulative dose groups (P = 0.010). Although the linear trend tested was not statistically significant (Ptrend = 0.258), the non-linear trend tested was statistically significant (Pnon-linear = 0.007). Overall, there was a correlation between changing platelets and cumulative radiation dose (a change of ßa 0.008 × 109/L during biennially after adjusting for gender, age at baseline, service at baseline, occupation, medical level, and smoking habits; 95% confidence interval [CI] = 0.003,0.014 × 109/L). Moreover, we also found positive first and then negative dose-response relationships between cumulative radiation dose and changing platelets by restricted cubic spline models, while there were negative patterns of the baseline service not less than 10 years (- 0.015 × 109/L, 95% CI = - 0.024, - 0.007 × 109/L) and radiation nurses(- 0.033 × 109/L, 95% CI = - 0.049, - 0.016 × 109/L). CONCLUSION: We concluded that although the exposure dose was below the limit, medical workers exposed to low-dose ionizing radiation for a short period of time might have increased first and then decreased platelets, and there was a dose-response relationship between the cumulative radiation dose and platelets changing.

Methicillin-Resistant Coagulase-Negative Staphylococci Carriage is a Protective Factor of Methicillin-Resistant Staphylococcus Aureus Nasal Colonization in HIV-Infected Patients: A Cross-Sectional Study.

BACKGROUND: Methicillin-resistant coagulase-negative Staphylococci (MRCoNS) is regarded as the repository of mecA gene for methicillin-resistant Staphylococcus aureus (MRSA) and may develop methicillin-susceptible Staphylococcus aureus (MSSA) to MRSA. Therefore, we aimed to explore whether MRCoNS carriage is a risk factor of MRSA colonization. Phenotypic characteristics were performed to further assess the associations between MRSA and MRCoNS. METHODS: This cross-sectional study was conducted in Guangzhou, China. Participants completed a questionnaire and provided a nasal swab for further analysis. The risk factors of MRSA colonization were analyzed using nonconditional logistic regression models. The phenotypic characteristics between MRSA and MRCoNS were compared by Chi-square test. RESULTS: Among the 1001 HIV-infected patients, a total of 119 (11.89%) participants were positive for MRSA, and 34.45% (41/119) of all MRSA carriers were positive for MRCoNS. We found MRCoNS carriage was a protective factor of MRSA colonization (adjusted odds ratio = 0.59, 95% confidence interval: 0.38-0.91). A significant difference in the proportions of antibiotic resistance between MRSA and MRCoNS isolates was found except for penicillin, clindamycin, tetracycline, and teicoplanin. The main STs and CC types of MRSA isolates in this population were ST188 (15.1%) and CC59 (17.6%), respectively. CONCLUSIONS: HIV-infected patients remain a highly vulnerable population for MRSA colonization. Though who carried MRCoNS is less likely to have MRSA colonization, similarity of some antibiotic resistance between MRSA and MRCoNS was found in this study. Regular surveillance on the colonization and antibiotic patterns of MRSA and MRCoNS is still necessary.

Clinical Characteristics and Prognostic Factors of Patients with Intrahepatic Cholangiocarcinoma with Fever: A Propensity Score Matching Analysis.

BACKGROUND: Patients with intrahepatic cholangiocarcinoma (ICC) rarely present fever as the initial symptom. We aimed to identify clinical characteristics and prognostic factors for these feverish patients. SUBJECTS, MATERIALS, AND METHODS: This study retrospectively reviewed 31 patients with ICC with fever (≥38.0°C) treated at our hospital between January 2002 and December 2014. A propensity score was used to match patients with and without fever at a ratio of 1:2. RESULTS: Patients with ICC with fever had higher serum γ-glutamyl transferase and carcinoembryonic antigen levels, larger tumors, poorer tumor differentiation, and worse prognosis (all p < .05) than those without fever. This was supported by propensity score matching (PSM) analysis. Univariate and multivariate analyses indicated that microvascular invasion, hilar lymph node metastasis, and temperature ≥ 38.6°C were related to prognosis. Patients with ICC with fever had higher levels of leucocytes, neutrophils, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in peripheral blood before and after PSM analysis. Body temperature positively correlated with leucocytes (r = 0.599, p < .001), neutrophils (r = 0.644, p < .001), NLR (r = 0.681, p < .001), and PLR (r = 0.457, p = .010). CONCLUSION: Patients with ICC with fever ≥38.0°C and ≥38.6°C had poor and extremely poor prognosis, respectively. Radical surgical treatment may improve the prognosis of patients with ICC with fever <38.6°C. However, systemic therapy (e.g., anti-inflammatory and immune therapy) may be preferable to surgery for these patients with fever ≥38.6°C. IMPLICATIONS FOR PRACTICE: Patients with intrahepatic cholangiocarcinoma (ICC) with fever (≥38.0°C) as the initial symptom are extremely rare. Because their symptoms are similar to those of liver abscess, diagnosis is challenging, and most of these patients are already at an advanced stage at the time of diagnosis. Patients with ICC with fever had different clinical characteristics and worse prognosis than those without fever. The prognosis of those with temperature <38.6°C would be improved by timely surgical intervention. Those with fever ≥38.6°C had an extremely dismal outcome, although they all received radical surgical treatment. New therapeutic strategies are needed to improve survival for patients with ICC with temperature ≥38.6°C.

PLAC8 overexpression correlates with PD-L1 upregulation and acquired resistance to chemotherapies in gallbladder carcinoma.

Gallbladder carcinoma (GBC) is always diagnosed at an advanced stage, and patients often miss the opportunity for surgery. Gemcitabine (GEM) and platinum-based drugs, including oxaliplatin (OXA), are mainstays of chemotherapy. However, drug resistance causes treatment failure. Hence, salvage mechanisms are critical to improve outcomes. This study revealed the positive correlation between placenta-specific protein 8 (PLAC8) overexpression and PD-L1 overexpression in GBC. Given the roles of PLAC8 and PD-L1 in chemotherapy resistance, GEM-resistant and OXA-resistant cell lines (SGC966GR and SGC966OR, respectively) were established to test whether and how PLAC8 and PD-L1 function in chemotherapy resistance. Drug-insensitive SGC966GR and SGC966OR cells upregulated MRP and MDR1 and had high expression of PLAC8. PLAC8 blockade using siRNA reversed chemotherapy resistance and downregulated MRP and MDR1 in SGC966GR and SGC966OR cells, suggesting that PLAC8 mediates chemotherapy resistance in GBC. Consistent with the increased mRNA levels of PD-L1 after the acquisition of resistance, PLAC8 knockdown reduced PD-L1 mRNA expression in SGC966GR and SGC966OR cells. In conclusion, PLAC8 overexpression in GBC patients positively correlated with PD-L1 expression. PLAC8 conferred resistance to GEM and OXA by upregulating PD-L1 expression, and PLAC8 or PD-L1 blockade may have potential for overcoming chemotherapy resistance, providing therapeutic options for chemotherapy-refractory GBC patients.

Sphere-forming culture enriches liver cancer stem cells and reveals Stearoyl-CoA desaturase 1 as a potential therapeutic target.

BACKGROUNDS: The role of sphere-forming culture in enriching subpopulations with stem-cell properties in hepatocellular carcinoma (HCC) is unclear. The present study investigates its value in enriching cancer stem cells (CSCs) subpopulations and the mechanism by which HCC CSCs are maintained. METHODS: HCC cell lines and fresh primary tumor cells were cultured in serum-free and ultra-low attachment conditions to allow formation of HCC spheres. In vitro and in vivo experiments were performed to evaluate CSC characteristics. Expression levels of CSC-related genes were assessed by qRT-PCR and the correlation between sphere formation and clinical characteristics was investigated. Finally, gene expression profiling was performed to explore the molecular mechanism underlying HCC CSC maintenance. RESULTS: We found that both cell lines and primary tumor cells formed spheres. HCC spheres possessed the capacity for self-renewal, proliferation, drug resistance, and contained different subpopulations of CSCs. Of interest, 500 sphere-forming Huh7 cells or 200 primary tumor cells could generate tumors in immunodeficient animals. Sphere formation correlated with size, multiple tumors, satellite lesions, and advanced stage. Further investigation identified that the PPARα-SCD1 axis plays an important role in maintenance of the CSC properties of HCC sphere cells by promoting nuclear accumulation of ß-Catenin. Inhibition of SCD1 interfered with sphere formation, down-regulated expression of CSC-related markers, and reduced ß-Catenin nuclear accumulation. CONCLUSIONS: Sphere-forming culture can effectively enrich subpopulations with stem-cell properties, which are maintained through activation of the PPARα-SCD1 axis. Therefore, we suggest that targeting the SCD1-related CSC machinery might provide a novel insight into HCC treatment.

Application of Serum Annexin A3 in Diagnosis, Outcome Prediction and Therapeutic Response Evaluation for Patients with Hepatocellular Carcinoma.

PURPOSE: Annexin A3 (ANXA3) could induce progression of hepatocellular carcinoma (HCC) via promoting stem cell traits of CD133-positive cells. Moreover, serum ANXA3 showed preliminary diagnostic potential, however further validation was required. Meanwhile, the prognostic value of ANXA3 remained elusive. The present study aimed to validate diagnostic performance and further systematically investigate the prognostic value of serum ANXA3. METHODS: Serum ANXA3 of 368 HCC patients was determined by enzyme-linked immunosorbent assay (ELISA); 295 of these patients underwent resection and 73 underwent transcatheter arterial chemoembolization (TACE). Diagnostic performance of ANXA3 was evaluated by receiver operating characteristic (ROC) analysis, and the prognostic value was evaluated by Cox regression and Kaplan-Meier analysis. To evaluate the relationship between serum ANXA3 and circulating CD133 mRNA-positive tumor cells (CD133mRNA+ CTCs), real-time polymerase chain reaction was conducted in 69 patients who underwent resection. RESULTS: Serum ANXA3 provided greater diagnostic performance than α-fetoprotein (area under the curve [AUC] 0.869 vs. 0.782), especially in early diagnosis (AUC 0.852 vs. 0.757) and discriminating HCC from patients at risk (0.832 vs. 0.736). Pretreatment ANXA3 was an independent predictor of tumor recurrence (hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26-2.76, p = 0.002)/progression (HR 1.88, 95% CI 1.04-3.43, p = 0.038) and survival (resectable: HR 2.26, 95% CI 1.44-3.56, p = 0.001; unresectable: HR 2.08, 95% CI 1.10-4.05, p = 0.025), and retained its performance in low-recurrence-risk subgroups. Specifically, dynamic changes of ANXA3-positive status was associated with worse prognosis. ANXA3 was positively correlated with CD133mRNA+ CTCs (r = 0.601, p < 0.001). In patients with detectable CD133mRNA+ CTC, high ANXA3 was positively associated with a higher risk of recurrence and shorter overall survival. CONCLUSIONS: Serum ANXA3 shows promise as a biomarker for diagnosis, outcome prediction, and therapeutic response evaluation in patients with HCC.

Longer duration of the Pringle maneuver is associated with hepatocellular carcinoma recurrence following curative resection.

OBJECTIVES: To evaluate the effect of Pringle maneuver time on tumor recurrence following liver resection in patients with hepatocellular carcinoma (HCC). METHODS: In this single-center study, we retrospectively evaluated the effect of Pringle maneuver time on HCC recurrence over a 10-year period from 1999 to 2008 using a Cox regression analysis. RESULTS: This study enrolled a total of 2,368 patients. A Pringle maneuver time of 15 min was associated with HCC recurrence (log likelihood ratio test, P = 0.001). A Pringle maneuver time less than 15 min was not a significant risk factor for HCC recurrence (hazard ratio, HR = 0.97, P = 0.708). However, a Pringle maneuver time greater than 15 min was an independent predictor of HCC recurrence (HR = 1.41, P < 0.001). The patients who underwent the Pringle maneuver for over 15 min had lower overall survival (OS) and recurrence-free survival (RFS) than did those who either did not undergo the maneuver or underwent the maneuver for less than 15 min (both P < 0.001). CONCLUSIONS: These results suggest that a longer duration of the Pringle maneuver increases the risk of tumor recurrence in patients with HCC. However, a shorter duration of the Pringle maneuver decreases this risk. J. Surg. Oncol. 2016;114:112-118. © 2016 Wiley Periodicals, Inc.

Chloroflexus aurantiacus acetyl-CoA carboxylase evolves fused biotin carboxylase and biotin carboxyl carrier protein to complete carboxylation activity.

Acetyl-CoA carboxylases (ACCs) convert acetyl-CoA to malonyl-CoA, a key step in fatty acid biosynthesis and autotrophic carbon fixation pathways. Three functionally distinct components, biotin carboxylase (BC), biotin carboxyl carrier protein (BCCP), and carboxyltransferase (CT), are either separated or partially fused in different combinations, forming heteromeric ACCs. However, an ACC with fused BC-BCCP and separate CT has not been identified, leaving its catalytic mechanism unclear. Here, we identify two BC isoforms (BC1 and BC2) from Chloroflexus aurantiacus, a filamentous anoxygenic phototroph that employs 3-hydroxypropionate (3-HP) bi-cycle rather than Calvin cycle for autotrophic carbon fixation. We reveal that BC1 possesses fused BC and BCCP domains, where BCCP could be biotinylated by E. coli or C. aurantiacus BirA on Lys553 residue. Crystal structures of BC1 and BC2 at 3.2 Å and 3.0 Å resolutions, respectively, further reveal a tetramer of two BC1-BC homodimers, and a BC2 homodimer, all exhibiting similar BC architectures. The two BC1-BC homodimers are connected by an eight-stranded ß-barrel of the partially resolved BCCP domain. Disruption of ß-barrel results in dissociation of the tetramer into dimers in solution and decreased biotin carboxylase activity. Biotinylation of the BCCP domain further promotes BC1 and CTß-CTα interactions to form an enzymatically active ACC, which converts acetyl-CoA to malonyl-CoA in vitro and produces 3-HP via co-expression with a recombinant malonyl-CoA reductase in E. coli cells. This study revealed a heteromeric ACC that evolves fused BC-BCCP but separate CTα and CTß to complete ACC activity.IMPORTANCEAcetyl-CoA carboxylase (ACC) catalyzes the rate-limiting step in fatty acid biosynthesis and autotrophic carbon fixation pathways across a wide range of organisms, making them attractive targets for drug discovery against various infections and diseases. Although structural studies on homomeric ACCs, which consist of a single protein with three subunits, have revealed the "swing domain model" where the biotin carboxyl carrier protein (BCCP) domain translocates between biotin carboxylase (BC) and carboxyltransferase (CT) active sites to facilitate the reaction, our understanding of the subunit composition and catalytic mechanism in heteromeric ACCs remains limited. Here, we identify a novel ACC from an ancient anoxygenic photosynthetic bacterium Chloroflexus aurantiacus, it evolves fused BC and BCCP domain, but separate CT components to form an enzymatically active ACC, which converts acetyl-CoA to malonyl-CoA in vitro and produces 3-hydroxypropionate (3-HP) via co-expression with recombinant malonyl-CoA reductase in E. coli cells. These findings expand the diversity and molecular evolution of heteromeric ACCs and provide a structural basis for potential applications in 3-HP biosynthesis.

Fasting-induced RNF152 resensitizes gallbladder cancer cells to gemcitabine by inhibiting mTORC1-mediated glycolysis.

Abnormal mTORC1 activation by the lysosomal Ragulator complex has been implicated in cancer and glycolytic metabolism associated with drug resistance. Fasting upregulates RNF152 and mediates the metabolic status of cells. We report that RNF152 regulates mTORC1 signaling by targeting a Ragulator subunit, p18, and attenuates gemcitabine resistance in gallbladder cancer (GBC). We detected levels of RNF152 and p18 in tissues and undertook mechanistic studies using activators, inhibitors, and lentivirus transfections. RNF152 levels were significantly lower in GBC than in adjacent non-cancer tissues. Fasting impairs glycolysis, induces gemcitabine sensitivity, and upregulates RNF152 expression. RNF152 overexpression increases the sensitivity of GBC cells to gemcitabine, whereas silencing RNF152 has the opposite effect. Fasting-induced RNF152 ubiquitinates p18, resulting in proteasomal degradation. RNF152 deficiency increases the lysosomal localization of p18 and increases mTORC1 activity, to promote glycolysis and decrease gemcitabine sensitivity. RNF152 suppresses mTORC1 activity to inhibit glycolysis and enhance gemcitabine sensitivity in GBC.

Microplastics are detected in human gallstones and have the ability to form large cholesterol-microplastic heteroaggregates.

Ubiquitous pollution due to microplastics through the food chain is a major cause of various deleterious effects on the human health. The aim of this study was to determine the existence of microplastics and the internal mechanism of microplastics as accelerators of cholelithiasis. Gallstones were collected from 16 patients after cholecystectomy, and microplastics in the gallstones were detected through laser direct infrared and pyrolysis gas chromatographymass spectrometry examinations. Mice model of gallstone were constructed with or without different diameters of microplastic (0.5, 5 and 50 µm). The affinity between microplastic and cholesterol or bilirubin was tested by co-culturing and qualified using molecular dynamics simulations. Finally, altered gut microbiota among the groups were identified using 16 s rRNA sequencing. The presence of microplastics in the gallstones of all the patients were confirmed. Microplastic content was significantly higher in younger chololithiasis patients (age<50 years). Mice fed a high-cholesterol diet with microplastic drinks showed more severe chololithiasis. In terms of the mechanism, microplastics showed a higher affinity for cholesterol than for bilirubin. Significant alterations in the gut microbiota have also been identified after microplastic intake in mice. Our study revealed the presence of microplastics in human gallstones, showcasing their potential to aggravate chololithiasis by forming large cholesterol-microplastic heteroaggregates and altering the gut microbiota.

Whole-genome sequencing analysis of Klebsiella aerogenes among men who have sex with men in Guangzhou, China.

Klebsiella aerogenes is a common infectious bacterium that poses a threat to human health. Nevertheless, there are limited data on the population structure, genetic diversity, and pathogenicity of K. aerogenes, especially among men who have sex with men (MSM). The present study aimed to clarify the sequence types (STs), clonal complexes (CCs), resistance genes, and virulence factors of popular strains. Multilocus sequence typing was used to describe the population structure of K. aerogenes. The Virulence Factor Database and Comprehensive Antibiotic Resistance Database were used to assess the virulence and resistance profiles. In this study, next-generation sequencing was performed on nasal swabs specimens collected in an HIV Voluntary Counseling Testing outpatient department in Guangzhou, China, from April to August 2019. The identification results showed that a total of 258 K. aerogenes isolates were collected from 911 participants. We found that the isolates were most resistant to furantoin (89.53%, 231/258) and ampicillin (89.15%, 230/258), followed by imipenem (24.81%, 64/258) and cefotaxime (18.22%, 47/258). The most common STs in carbapenem-resistant K. aerogenes were ST4, ST93, and ST14. The population has at least 14 CCs, including several novel ones identified in this study (CC11-CC16). The main mechanism of drug resistance genes was antibiotic efflux. Based on the presence of the iron carrier production genes irp and ybt, we identified two clusters according to virulence profiles. In cluster A, CC3 and CC4 carry the clb operator encoding the toxin. Increased monitoring is needed for the three main ST type strains carried by MSM. The main clone group CC4 has a large number of toxin genes, and it spreads among MSM. Caution is needed to prevent further spread of this clone group in this population. In sum, our results may provide a foundation for the development of new therapeutic and surveillance strategies for treating MSM.

FANCI serve as a prognostic biomarker correlated with immune infiltrates in skin cutaneous melanoma.

Background: As a member of tumor, Skin cutaneous melanoma (SKCM) poses a serious threat to people's health because of its strong malignancy. Unfortunately, effective treatment methods for SKCM remain lacking. FANCI plays a vital role in the occurrence and metastasis of various tumor types. However, its regulatory role in SKCM is unclear. The purpose of this study was to explore the association of FANCI with SKCM. Methods: This study investigated the expression of FANCI in GSE46517, GSE15605, and GSE114445 from the Gene Expression Omnibus database and The Cancer Genome Atlas (TCGA)-SKCM datasets using the package "limma" or "DESeq2" in R environment and also investigated the prognostic significance of FANCI by utilizing the GEPIA database. Additionally, our research made use of real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC) staining to verify FANCI expression between SKCM and normal tissues and developed the knockdown of FANCI in A375 and A875 cells to further analyze the function of FANCI. Finally, this study analyzed the correlation of FANCI and tumor-infiltrating immune cells by CIBERSORT, ESTIMATE, and ssGSEA algorithms. Results: The FANCI level was increasing in SKCM tissues from GSE46517, GSE15605, GSE114445, and TCGA-SKCM. However, high FANCI expression correlated with poor overall survival. The RT-qPCR and IHC confirmed the accuracy of bioinformatics. Knocking down FANCI suppresses A375 and A875 cell proliferation, migration, and invasion. FANCI could be involved in the immunological milieu of SKCM by regulating immune responses and infiltrating numerous immune cells, particularly neutrophils, CD8+ T cells, and B cells. Furthermore, patients with SKCM who have a high FANCI expression level are reported to exhibit immunosuppression, whereas those with a low FANCI expression level are more likely to experience positive outcomes from immunotherapy. Conclusions: The increased FANCI expression in SKCM can be a prognostic biomarker. Knockdown FANCI can reduce the occurrence and progression of SKCM. The FANCI expression provides a foundation for predicting the immune status and treatment of SKCM.

IDO-competent-DCs induced by IFN-γ attenuate acute rejection in rat liver transplantation.

PURPOSE: We established a stable rat model of liver transplantation using Sprague-Dawley rats and Wistar rats in order to investigate the role of the IDO gene in acute rejection after rat liver transplantation. METHODS: IDO gene expression and IDO enzyme activity were quantified in liver syngeneic grafts and allografts using microdialysis-HPLC. Liver allografts were evaluated for IDO expression by histopathology. We measured liver function-related biomarkers in liver allografts which were re-infused with untreated or IFN-γ-treated dendritic cells (DCs). RESULTS: We found a significant increase in IDO gene expression and IDO enzyme activity in liver allografts compared the sham and syngeneic graft groups. There was a significant correlation between the number of IDO-positive cells and severity of acute rejection. IDO gene expression and enzyme activity was upregulated in the IFN-γ-treated DC group within 7 days after transplantation compared to the untreated DC group and survival rates were significantly improved. CONCLUSIONS: Our results suggested that IDO gene expression correlates with the severity of acute rejection and that IFN-γ-induced IDO-positive DCs may attenuate acute rejection and catalyze local tryptophan metabolism via IDO enzyme expression, leading to immune tolerance after liver transplantation.

Dose-Response Effects of Low-Dose Ionizing Radiation on Blood Parameters in Industrial Irradiation Workers.

While previous studies have focused on the health effects of occupational exposure of radiations on medical radiation workers, few have analyzed the dose-response relationship between low radiation doses and changes in blood parameters. Even fewer studies have been conducted on industrial worker populations. Using a prospective cohort study design, this study collected health examination reports and personal dose monitoring data from 705 industrial irradiation workers who underwent regular physical examinations at Dongguan Sixth People's Hospital. The dose-response effects of low-dose ionizing radiation on blood parameters were assessed using a generalized linear model and restricted cubic spline model. Red blood cell counts decreased then increased, before decreasing again with increasing ionizing radiation. This was in contrast to the curve of the total platelet count after irradiation. Additionally, a radiation dose of 2.904 mSv was the turning point for the nonlinear curve of hemoglobin count changes. In conclusion, long-term, low-dose ionizing radiation affects blood cell levels in industrial irradiation workers. There is a nonlinear dose-response relationship between red blood cell, platelet, and hemoglobin counts and the cumulative radiation dose. These findings should alert radiation workers to seek preventive medical treatment before the occurrence of any serious hematopoietic disease.

ERBB2 S310F mutation independently activates PI3K/AKT and MAPK pathways through homodimers to contribute gallbladder carcinoma growth.

Genomic instability and mutability are a prominent character of tumor. The whole-exosome sequence reveals that ERBB2 mutations are the representative mutations of gallbladder carcinoma, which takes potential targets for gallbladder carcinoma therapy. However, the roles of ERBB2 mutations are unclear in gallbladder carcinoma. We identified S310F mutation is the hottest mutation of ERBB2 mutations from TCGA PanCancer Altas data with 10,967 samples and our previous study with 157 gallbladder carcinoma samples. S310F mutation located in ERBB2 extracellular domain, promoted ERBB2 homodimerization and consequent auto-phosphorylation to activate the downstream PI3K/AKT and MAPK pathways, which was independent on ERBB1, ERBB3, and ERBB4. ERBB2 S310F mutation up-regulated aerobic glycolysis and promoted gallbladder carcinoma growth. Our study reveals the roles of ERBB2 S310F mutation, which is beneficial to ERBB2 S310F mutant gallbladder carcinoma therapy.