PTBP1 crotonylation promotes colorectal cancer progression through alternative splicing-mediated upregulation of the PKM2 gene.

BACKGROUND: Aerobic glycolysis is a tumor cell phenotype and a hallmark in cancer research. The alternative splicing of the pyruvate kinase M (PKM) gene regulates the expressions of PKM1/2 isoforms and the aerobic glycolysis of tumors. Polypyrimidine tract binding protein (PTBP1) is critical in this process; however, its impact and underlying mechanisms in colorectal cancer (CRC) remain unclear. This study aimed to investigate the role of PTBP1 crotonylation in CRC progression. METHODS: The crotonylation levels of PTBP1 in human CRC tissues and cell lines were analyzed using crotonylation proteomics and immunoprecipitation. The main crotonylation sites were identified by immunoprecipitation and immunofluorescent staining. The glycolytic capacities of CRC cells were evaluated by measuring the glucose uptake, lactate production, extracellular acidification rate, and glycolytic proton efflux rate. The role and mechanism of PTBP1 crotonylation in PKM alternative splicing were determined by Western blot, quantitative real-time PCR (RT-qPCR), RNA immunoprecipitation, and immunoprecipitation. The effects of PTBP1 crotonylation on the behaviors of CRC cells and CRC progression were assessed using CCK-8, colony formation, cell invasion, wound healing assays, xenograft model construction, and immunohistochemistry. RESULTS: The crotonylation level of PTBP1 was elevated in human CRC tissues compared to peritumor tissues. In CRC tissues and cells, PTBP1 was mainly crotonylated at K266 (PTBP1 K266-Cr), and lysine acetyltransferase 2B (KAT2B) acted as the crotonyltranferase. PTBP1 K266-Cr promoted glycolysis and lactic acid production, increasing the PKM2/PKM1 ratio in CRC tissues and cells. Mechanistically, PTBP1 K266-Cr enhanced the interaction of PTBP1 with heterogeneous nuclear ribonucleoprotein A1 and A2 (hnRNPA1/2), thus affecting the PKM alternative splicing. PTBP1 K266-Cr facilitated CRC cell proliferation, migration, and metastasis in vitro and in vivo. Pathologically, a high level of PTBP1 K266-Cr was associated with poor prognosis in CRC patients. CONCLUSIONS: Crotonylation of PTBP1 coordinates tumor cell glycolysis and promotes CRC progression by regulating PKM alternative splicing and increasing PKM2 expression.

Circular RNAs in non-alcoholic fatty liver disease: Functions and clinical significance.

Nonalcoholic fatty liver disease (NAFLD), which affects approximately 25% of the global population, is an urgent health issue leading to various metabolic comorbidities. Circular RNAs (circRNAs), covalently closed RNA molecules, are characterized by ubiquity, diversity, stability, and conservatism. Indeed, they participate in various biological processes via distinct mechanisms that could modify the natural history of NAFLD. In this review, we briefly introduce the biogenesis, characteristics, and biological functions of circRNAs. Furthermore, we summarize circRNAs expression profiles in NAFLD by intersecting seven sequencing data sets and describe the cellular roles of circRNAs and their potential advantages as biomarkers of NAFLD. In addition, we emphatically discuss the exosomal non-coding RNA sorting mechanisms and possible functions in recipient cells. Finally, we extensively discuss the potential application of targeting disease-related circRNAs and competing endogenous RNA networks through gain-of-function and loss-of-function approaches in targeted therapy of NAFLD.

Mendelian-randomization study revealed causal relationship between nonalcoholic fatty liver disease and osteoporosis/fractures.

BACKGROUND: Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have a higher risk of osteoporosis/fractures; however, the causal relationship remains unclear. METHODS: Publicly available genome-wide association studies (GWASs) were used for Mendelian randomization (MR) analysis. GWASs of NAFLD and fractures were obtained from the FinnGen Consortium. GWASs of bone mineral density (BMD) were derived from a meta-analysis. GWASs of obesity, diabetes, liver function, and serum lipid-related metrics were used to clarify whether the accompanying NAFLD symptoms contributed to fractures. Moreover, two additional GWASs of NAFLD were applied. RESULTS: A causal association was not observed between NAFLD and BMD using GWASs from the FinnGen Consortium. However, a causal relationship between NAFLD and femoral neck-BMD (FN-BMD), a suggestive relationship between fibrosis and FN-BMD, and between NAFLD and osteoporosis were identified in replication GWASs. Genetically proxied body mass index (BMI), high-density lipoprotein (HDL), and hip circumference increased the likelihood of lower limb fractures. The waist-to-hip ratio decreased, whereas glycated hemoglobin (HbA1C) and homeostasis model assessment of ß-cell function (HOMA-B) increased the risk of forearm fractures. Low-density lipoprotein (LDL) reduced, whereas HbA1C increased the incidence of femoral fractures. Alkaline phosphatase (ALP) raised the risk of foot fractures. However, after a multivariate MR analysis (adjusted for BMI), all the relationships became insignificant. CONCLUSIONS: NAFLD caused reduced BMD, and genetically predicted HDL, LDL, HbA1C, HOMA-B, ALP, hip circumference, and waist-to-hip ratio causally increased the risk of fractures. BMI may mediate causal relationships. Larger GWASs are required to verify this finding.

Sigma-1 receptor activation mediates the sustained antidepressant effect of ketamine in mice via increasing BDNF levels.

Sigma-1 receptor (S1R) is a unique multi-tasking chaperone protein in the endoplasmic reticulum. Since S1R agonists exhibit potent antidepressant-like activity, S1R has become a novel target for antidepression therapy. With a rapid and sustained antidepressant effect, ketamine may also interact with S1R. In this study, we investigated whether the antidepressant action of ketamine was related to S1R activation. Depression state was evaluated in the tail suspension test (TST) and a chronic corticosterone (CORT) procedure was used to induce despair-like behavior in mice. The neuronal activities and structural changes of pyramidal neurons in medial prefrontal cortex (mPFC) were assessed using fiber-optic recording and immunofluorescence staining, respectively. We showed that pharmacological manipulation of S1R modulated ketamine-induced behavioral effect. Furthermore, pretreatment with an S1R antagonist BD1047 (3 mg·kg-1·d-1, i.p., for 3 consecutive days) significantly weakened the structural and functional restoration of pyramidal neuron in mPFC caused by ketamine (10 mg·kg-1, i.p., once). Ketamine indirectly triggered the activation of S1R and subsequently increased the level of BDNF. Pretreatment with an S1R agonist SA4503 (1 mg·kg-1·d-1, i.p., for 3 consecutive days) enhanced the sustained antidepressant effect of ketamine, which was eliminated by knockdown of BDNF in mPFC. These results reveal a critical role of S1R in the sustained antidepressant effect of ketamine, and suggest that a combination of ketamine and S1R agonists may be more beneficial for depression patients.

TRAF6 Restricts p53 Mitochondrial Translocation, Apoptosis, and Tumor Suppression.

Mitochondrial p53 is involved in apoptosis and tumor suppression. However, its regulation is not well studied. Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK. Genotoxic stress reduces this ubiquitination in cytosol by S13/T330 phosphorylation-dependent translocation of TRAF6 from cytosol to nucleus, where TRAF6 also facilitates the K63-linked ubiquitination of nuclear p53 and its transactivation by recruiting p300 for p53 acetylation. Functionally, K63-linked ubiquitination of p53 compromised p53-mediated apoptosis and tumor suppression. Colorectal cancer samples with WT p53 reveal that TRAF6 overexpression negatively correlates with apoptosis and predicts poor response to chemotherapy and radiotherapy. Together, our study identifies TRAF6 as a critical gatekeeper to restrict p53 mitochondrial translocation, and such mechanism may contribute to tumor development and drug resistance.

Enantioselective and Regiodivergent Synthesis of Propargyl- and Allenylsilanes through Catalytic Propargylic C-H Deprotonation.

We report a highly enantioselective intermolecular C-H bond silylation catalyzed by a phosphoramidite-ligated iridium catalyst. Under reagent-controlled protocols, propargylsilanes resulting from C(sp3)-H functionalization, as well the regioisomeric and synthetically versatile allenylsilanes, could be obtained with excellent levels of enantioselectivity and good to excellent control of propargyl/allenyl selectivity. In the case of unsymmetrical dialkyl acetylenes, good to excellent selectivity for functionalization at the less-hindered site was also observed. A variety of electrophilic silyl sources (R3SiOTf and R3SiNTf2), either commercial or in situ-generated, were used as the silylation reagents, and a broad range of simple and functionalized alkynes, including aryl alkyl acetylenes, dialkyl acetylenes, 1,3-enynes, and drug derivatives were successfully employed as substrates. Detailed mechanistic experiments and DFT calculations suggest that an η3-propargyl/allenyl Ir intermediate is generated upon π-complexation-assisted deprotonation and undergoes outer-sphere attack by the electrophilic silylating reagent to give propargylic silanes, with the latter step identified as the enantiodetermining step.

Tafenoquine and its derivatives as inhibitors for the severe acute respiratory syndrome coronavirus 2.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely affected human lives around the world as well as the global economy. Therefore, effective treatments against COVID-19 are urgently needed. Here, we screened a library containing Food and Drug Administration (FDA)-approved compounds to identify drugs that could target the SARS-CoV-2 main protease (Mpro), which is indispensable for viral protein maturation and regard as an important therapeutic target. We identified antimalarial drug tafenoquine (TFQ), which is approved for radical cure of Plasmodium vivax and malaria prophylaxis, as a top candidate to inhibit Mpro protease activity. The crystal structure of SARS-CoV-2 Mpro in complex with TFQ revealed that TFQ noncovalently bound to and reshaped the substrate-binding pocket of Mpro by altering the loop region (residues 139-144) near the catalytic Cys145, which could block the catalysis of its peptide substrates. We also found that TFQ inhibited human transmembrane protease serine 2 (TMPRSS2). Furthermore, one TFQ derivative, compound 7, showed a better therapeutic index than TFQ on TMPRSS2 and may therefore inhibit the infectibility of SARS-CoV-2, including that of several mutant variants. These results suggest new potential strategies to block infection of SARS-CoV-2 and rising variants.

Concomitant Diseases and Co-contribution on Progression of Liver Stiffness in Patients with Hepatitis B Virus Infection.

BACKGROUND: The association between hepatitis B and concomitant diseases, such as fatty liver, T2DM, MetS, and Hp infection, remains unclear. AIM: The present study was to illustrate the association and explore the co-contribution on abnormal transaminase and progression of liver stiffness. METHODS: A total of 95,998 participants underwent HBsAg screening in West China Hospital from 2014 to 2017. Multivariable logistic regression was used to determine the adjusted odds ratios. RESULTS: The prevalence of HBsAg-positive rate was 8.30% of our included study population. HBsAg positive was associated with negative risk of fatty liver (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.65-0.78, p < 0.001) and MetS (OR 0.74, 95% CI 0.67-0.84, p < 0.001), and with positive risk of Hp infection (OR 1.09, 95% CI 1.02-1.17, p = 0.012) and T2DM (OR 1.18, 95% CI 1.01-1.40, p = 0.043). Besides, HBsAg-positive patients with T2DM had higher risk of elevated ALT (OR 2.09, 95% CI 1.69-2.83, p < 0.001 vs OR 1.59, 95% CI 1.51-1.68, p < 0.001), AST (OR 2.69, 95% CI 1.98-3.65, p < 0.001 vs OR 1.89, 95% CI 1.76-2.02, p < 0.001) than HBV alone. In addition to HBV, T2DM also can increase the risk of liver fibrosis (OR 3.23, 95% CI 1.35-7.71, p = 0.008) and cirrhosis (OR 4.31, 95% CI 1.41-13.20, p = 0.010). CONCLUSION: Hepatitis B patients have a lower risk of fatty liver and MetS, and a higher risk of T2DM and Hp infection. Besides, T2DM might be possibly associated with abnormal liver transaminase and fibrosis progression in HBsAg-positive patients.

Skp2-Mediated RagA Ubiquitination Elicits a Negative Feedback to Prevent Amino-Acid-Dependent mTORC1 Hyperactivation by Recruiting GATOR1.

The regulation of RagA(GTP) is important for amino-acid-induced mTORC1 activation. Although GATOR1 complex has been identified as a negative regulator for mTORC1 by hydrolyzing RagA(GTP), how GATOR1 is recruited to RagA to attenuate mTORC1 signaling remains unclear. Moreover, how mTORC1 signaling is terminated upon amino acid stimulation is also unknown. We show that the recruitment of GATOR1 to RagA is induced by amino acids in an mTORC1-dependent manner. Skp2 E3 ligase drives K63-linked ubiquitination of RagA, which facilitates GATOR1 recruitment and RagA(GTP) hydrolysis, thereby providing a negative feedback loop to attenuate mTORC1 lysosomal recruitment and prevent mTORC1 hyperactivation. We further demonstrate that Skp2 promotes autophagy but inhibits cell size and cilia growth through RagA ubiquitination and mTORC1 inhibition. We thereby propose a negative feedback whereby Skp2-mediated RagA ubiquitination recruits GATOR1 to restrict mTORC1 signaling upon sustained amino acid stimulation, which serves a critical mechanism to maintain proper cellular functions.

CircRNA-PI4KB Induces Hepatic Lipid Deposition in Non-Alcoholic Fatty Liver Disease by Transporting miRNA-122 to Extra-Hepatocytes.

Ectopic fat deposition in the liver, known as non-alcoholic fatty liver disease (NAFLD), affects up to 30% of the worldwide population. miRNA-122, the most abundant liver-specific miRNA, protects hepatic steatosis and inhibits cholesterol and fatty acid synthesis in NAFLD. Previously, we have shown that compared with its expression in healthy controls, miRNA-122 decreased in the liver tissue but gradually increased in the serum of patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, suggesting that miRNA-122 could have been transported to the serum. Here, we aimed to confirm and unravel the mechanism of transportation of miRNA-122 to extra-hepatocytes. Our findings showed a decrease in the intra-hepatocyte miRNA-122 and an increase in the extra-hepatocyte (medium level) miRNA-122, suggesting the miRNA-122 "escaped" from the intra-hepatocyte due to an increased extra-hepatocyte excretion. Using bioinformatics tools, we showed that miRNA-122 binds to circPI4KB, which was further validated by an RNA pull-down and luciferase reporter assay. The levels of circPI4KB in intra- and extra-hepatocytes corresponded to that of miRNA-122, and the overexpression of circPI4KB increased the miRNA-122 in extra-hepatocytes, consequently accomplishing a decreased protective role of miRNA-122 in inhibiting the lipid deposition. The present study provides a new explanation for the pathogenesis of the hepatic lipid deposition in NAFLD.

Allicin Alleviated LPS-Induced Mastitis via the TLR4/NF-κB Signaling Pathway in Bovine Mammary Epithelial Cells.

Dairy farming is the most important economic activity in animal husbandry. Mastitis is the most common disease in dairy cattle and has a significant impact on milk quality and yield. The natural extract allicin, which is the main active ingredient of the sulfur-containing organic compounds in garlic, has anti-inflammatory, anticancer, antioxidant, and antibacterial properties; however, the specific mechanism underlying its effect on mastitis in dairy cows needs to be determined. Therefore, in this study, whether allicin can reduce lipopolysaccharide (LPS)-induced inflammation in the mammary epithelium of dairy cows was investigated. A cellular model of mammary inflammation was established by pretreating bovine mammary epithelial cells (MAC-T) with 10 µg/mL LPS, and the cultures were then treated with varying concentrations of allicin (0, 1, 2.5, 5, and 7.5 µM) added to the culture medium. MAC-T cells were examined using RT-qPCR and Western blotting to determine the effect of allicin. Subsequently, the level of phosphorylated nuclear factor kappa-B (NF-κB) was measured to further explore the mechanism underlying the effect of allicin on bovine mammary epithelial cell inflammation. Treatment with 2.5 µM allicin considerably decreased the LPS-induced increase in the levels of the inflammatory cytokines interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) and inhibited activation of the NOD-like receptor protein 3 (NLRP3) inflammasome in cow mammary epithelial cells. Further research revealed that allicin also inhibited the phosphorylation of inhibitors of nuclear factor kappa-B-α (IκB-α) and NF-κB p65. In mice, LPS-induced mastitis was also ameliorated by allicin. Therefore, we hypothesize that allicin alleviated LPS-induced inflammation in the mammary epithelial cells of cows probably by affecting the TLR4/NF-κB signaling pathway. Allicin will likely become an alternative to antibiotics for the treatment of mastitis in cows.

Solubility Determination and Comprehensive Analysis of the New Heat-Resistant Energetic Material TNBP.

To improve the crystal quality of 4,8-bis(2,4,6-trinitrophenyl)difurazolo [3,4-b:3',4'-e] pyrazine (TNBP), the solubility of TNBP in organic solvents (six pure and four mixed solvents) was determined by the laser monitoring technique from 293.15 to 353.15 K. The results showed that the solubility was positively correlated with the increase in the experimental temperature and the main solvent content, except for the co-solvent phenomenon in the DMSO + ethyl acetate solvent mixture. To explain the dissolution behavior of TNBP, the KAT-SER model was analyzed for pure solvent systems, and it was found that hydrogen bonding alkalinity and self-cohesiveness were the main influencing factors. The free energy of solvation and radial distribution function of TNBP in mixed solvents were also obtained by molecular dynamics simulation, and the effect of solute-solvent and solvent-solvent interactions on the solubility trend was analyzed. The experimental data were correlated using three empirical equations (van't Hoff equation, modified Apelblat equation, and λh equation), and the deviation analysis showed the good applicability of the modified Apelblat model. Furthermore, the dissolution of TNBP was heat-absorbing and not spontaneous, according to the thermodynamic characteristics estimated by the van't Hoff equation.

Thermal Behaviors and Interaction Mechanism of Ammonium Dinitramide with Nitrocellulose.

The initial interaction mechanism is very important for the design and safety of nano-scale composite energetic materials composed of ammonium dinitramide (ADN) and nitrocellulose (NC). The thermal behaviors of ADN, NC and an NC/ADN mixture under different conditions were studied by using differential scanning calorimetry (DSC) with sealed crucibles, an accelerating rate calorimeter (ARC), a self-developed gas pressure measurement instrument and a DSC-thermogravimetry (TG)-quadrupole mass spectroscopy (MS)-Fourier transform infrared spectroscopy (FTIR) combined technique. The results show that the exothermic peak temperature of the NC/ADN mixture shifted forward greatly in both open and closed circumstances compared to those of NC or ADN. After 585.5 min under quasi-adiabatic conditions, the NC/ADN mixture stepped into the self-heating stage at 106.4 °C, which was much less than the initial temperatures of NC or ADN. The significant reduction in net pressure increment of NC, ADN and the NC/ADN mixture under vacuum indicates that ADN initiated the interaction of NC with ADN. Compared to gas products of NC or ADN, two new kinds of oxidative gases O2 and HNO2 appeared for the NC/ADN mixture, while NH3 and aldehyde disappeared. The mixing of NC with ADN did not change the initial decomposition pathway of either, but NC made ADN more inclined to decompose into N2O, which resulted in the formation of oxidative gases O2 and HNO2. The thermal decomposition of ADN dominated the initial thermal decomposition stage of the NC/ADN mixture, followed by the oxidation of NC and the cation of ADN.

[Arsenic speciation and valence].

As arsenic widely exists in nature and has been used in the pharmaceutical preparations, the traditional Chinese medicine(TCM) with arsenic include realgar(As_2S_2 or As_4S_4), orpiment(As_2S_3), and white arsenic(As_2O_3). Among the above representative medicine, the TCM compound formulas with realgar are utilized extensively. Just in Chinese Pharmacopoeia(2020 edition), there are 37 Chinese patent medicines including realgar. The traditional element analysis focuses on the detection of the total amount of elements, which neglects the study on the speciation and valence of elements. The activity, toxicity, bioavailability, and metabolic pathways of arsenic in vivo are closely related to the existence of its form, and different forms of arsenic have different effects on organisms. Therefore, the study on the speciation and valence of arsenic is of great importance for arsenic-containing TCMs and their compound formulas. This paper reviewed four aspects of the speciation and valence of arsenic, including property, absorption and metabolism, toxicity, and analytical assay.

[Varieties systematization and standards status analysis of fermented Chinese medicine].

Fermented Chinese medicine has long been used. Amid the advance for preservation of experience, the connotation of fermented Chinese medicine has been enriched and improved. However, fermented Chinese medicine prescriptions generally contain a lot of medicinals. The fermentation process is complicated and the conventional fermentation conditions fail to be strictly controlled. In addition, the judgment of the fermentation end point is highly subjective. As a result, quality of fermented Chinese medicine is of great difference among regions and unstable. At the moment, the quality standards of fermented Chinese medicine are generally outdated and different among regions, with simple quality control methods and lacking objective safe fermentation-specific evaluation indictors. It is difficult to comprehensively evaluate and control the quality of fermented medicine. These problems have aroused concern in the industry and also affected the clinical application of fermented Chinese medicine. This article summarized and analyzed the application, quality standards, and the modernization of fermentation technology and quality control methods of fermented Chinese medicine and proposed suggestions for improving the quality standards of the medicine, with a view to improving the overall quality of it.

Your height affects your health: genetic determinants and health-related outcomes in Taiwan.

BACKGROUND: Height is an important anthropometric measurement and is associated with many health-related outcomes. Genome-wide association studies (GWASs) have identified hundreds of genetic loci associated with height, mainly in individuals of European ancestry. METHODS: We performed genome-wide association analyses and replicated previously reported GWAS-determined single nucleotide polymorphisms (SNPs) in the Taiwanese Han population (Taiwan Biobank; n = 67,452). A genetic instrument composed of 251 SNPs was selected from our GWAS, based on height and replication results as the best-fit polygenic risk score (PRS), in accordance with the clumping and p-value threshold method. We also examined the association between genetically determined height (PRS251) and measured height (phenotype). We performed observational (phenotype) and genetic PRS251 association analyses of height and health-related outcomes. RESULTS: GWAS identified 6843 SNPs in 89 genomic regions with genome-wide significance, including 18 novel loci. These were the most strongly associated genetic loci (EFEMP1, DIS3L2, ZBTB38, LCORL, HMGA1, CS, and GDF5) previously reported to play a role in height. There was a positive association between PRS251 and measured height (p < 0.001). Of the 14 traits and 49 diseases analyzed, we observed significant associations of measured and genetically determined height with only eight traits (p < 0.05/[14 + 49]). Height was positively associated with body weight, waist circumference, and hip circumference but negatively associated with body mass index, waist-hip ratio, body fat, total cholesterol, and low-density lipoprotein cholesterol (p < 0.05/[14 + 49]). CONCLUSIONS: This study contributes to the understanding of the genetic features of height and health-related outcomes in individuals of Han Chinese ancestry in Taiwan.

Two-year immune effect differences between the 0-1-2-month and 0-1-6-month HBV vaccination schedule in adults.

BACKGROUND: The short-term 0-1-2-month hepatitis B virus (HBV) vaccination schedule was previously implemented in the adult population; however, its long-term immune effect remains unclear. The present study aimed to investigate (1) the 2-month and 2-year immune effects of HBV vaccination and (2) the compliance rate between the 0-1-2-month and 0-1-6-month vaccination schedules in adults. METHOD: A total of 1281 subjects tested for hepatitis B surface antigen HBsAg(-) and hepatitis B surface antibody (anti-HBs)(-) were recruited. Participants from two distant counties were inoculated with the hepatitis B yeast vaccine at 10 µg per dose, with vaccination schedules of 0, 1, and 2 months (n = 606) and 0, 1, and 6 months (n = 675); sequential follow-up was performed at 2 months and 2 years after the 3rd injection. RESULTS: There were no significant differences in the anti-HBs seroconversion rates between the those in the 0-1-2-month and 0-1-6-month vaccination schedule groups at 2 months (91.96% vs. 89.42%, p = 0.229) and 2 years (81.06% vs. 77.14%, p = 0.217). The quantitative anti-HBs level in those in the 0-1-2-month vaccination schedule group was not different from that in those in the 0-1-6-month vaccination schedule group at 2 months (anti-HBs1) (342.12 ± 378.42 mIU/ml vs. 392.38 ± 391.96 mIU/ml, p = 0.062), but it was higher at 2 years (anti-HBs2) (198.37 ± 286.44 mIU/ml vs. 155.65 ± 271.73 mIU/ml, p = 0.048). According to the subgroup analysis, the 0-1-2-month vaccination schedule induced better maintenance (p = 0.041) and longer reinforcement (p = 0.019) than the 0-1-6 vaccination schedule. The 0-1-2-month vaccination schedule group also had a higher 3rd injection completion rate (89.49% vs. 84.49%, p = 0.010). CONCLUSION: The 0-1-2-month vaccination schedule was associated with a similar short-term immune effect and might induce better long-term immune memory and a higher completion rate in the adult population. Trial registration None.

Predicting progression to severe COVID-19 using the PAINT score.

OBJECTIVES: One of the major challenges in treating patients with coronavirus disease 2019 (COVID-19) is predicting the severity of disease. We aimed to develop a new score for predicting progression from mild/moderate to severe COVID-19. METHODS: A total of 239 hospitalized patients with COVID-19 from two medical centers in China between February 6 and April 6, 2020 were retrospectively included. The prognostic abilities of variables, including clinical data and laboratory findings from the electronic medical records of each hospital, were analysed using the Cox proportional hazards model and Kaplan-Meier methods. A prognostic score was developed to predict progression from mild/moderate to severe COVID-19. RESULTS: Among the 239 patients, 216 (90.38%) patients had mild/moderate disease, and 23 (9.62%) progressed to severe disease. After adjusting for multiple confounding factors, pulmonary disease, age > 75, IgM, CD16+/CD56+ NK cells and aspartate aminotransferase were independent predictors of progression to severe COVID-19. Based on these five factors, a new predictive score (the 'PAINT score') was established and showed a high predictive value (C-index = 0.91, 0.902 ± 0.021, p < 0.001). The PAINT score was validated using a nomogram, bootstrap analysis, calibration curves, decision curves and clinical impact curves, all of which confirmed its high predictive value. CONCLUSIONS: The PAINT score for progression from mild/moderate to severe COVID-19 may be helpful in identifying patients at high risk of progression.

Determinants of suboptimal immune recovery among a Chinese Yi ethnicity population with sustained HIV suppression.

OBJECTIVES: Despite sustained viral suppression with effective antiretroviral therapy (ART), HIV-infected patients with suboptimal immune recovery are still at high risk of both non-AIDS-related and AIDS-related events. The aim of this study was to investigate determinants potentially associated with suboptimal CD4 + T cell count recovery during free ART with sustained viral suppression among an HIV-infected Yi ethnicity population in Liangshan Prefecture, an area in China with high HIV prevalence. METHODS: This retrospective study included HIV-infected Yi adults (≥ 18 years and baseline CD4 + T cell count less than 500 cells/µL) for whom ART supported by National Free Antiretroviral Treatment Program was initiated between January 2015 and December 2018 in Zhaojue County, Liangshan Prefecture. Virological suppression (viral load < 50 copies/mL) was achieved within 12 months after ART initiation, and sustained virological suppression was maintained. Multivariate log-binomial regression analysis was used to assess determinants of suboptimal immune recovery. RESULTS: There were 140 female and 137 male patients in this study, with a mean age of 36.57 ± 7.63 years. Most of the Yi patients were infected through IDU (48.7%) or heterosexual contact (49.8%), and the anti-HCV antibody prevalence was high (43.7%, 121/277). Of the 277 patients with a mean ART duration of 3.77 ± 1.21 years, complete immune recovery occurred in only 32.9%. The baseline CD4 + T cell count in patients with suboptimal and intermediate immune recovery was 248.64 ± 108.10 and 288.59 ± 108.86 cells/µL, respectively, which was much lower than the baseline 320.02 ± 123.65 cells/µL in patients who achieved complete immune recovery (p < 0.001). Multivariable analysis demonstrated that low pre-ART CD4 + cell count and coinfection with HCV were associated with immune recovery of the HIV patients. CONCLUSIONS: Our study suggests that for HIV-infected Yi patients in Liangshan Prefecture, prompt ART initiation after diagnosis of HIV infection should be applied, and curative HCV treatment should be given to patients with HCV/HIV coinfection to improve the immunological effectiveness of ART. Trial registration None.

Minimal change disease associated with gastrointestinal stromal tumor accompanied by significantly elevated serum IgE level: a case report.

BACKGROUND: Minimal change disease (MCD) is a common cause of the nephrotic syndrome. Several studies have shown an increased incidence of cancer in patients with MCD. However, there are no reports on the association between MCD and gastrointestinal stromal tumor (GIST). CASE PRESENTATION: We report a case of a 66-year-old female with severe nephrotic syndrome and concomitant duodenal GIST. Immunoglobulin test showed a significant increase of IgE levels. The diagnosis of renal histopathology was MCD with subacute tubulointerstitial injury. The combination of preoperative Imatinib mesylate chemotherapy and tumor excision was accompanied by significant remission of proteinuria, and IgE level decreasing, without immunosuppressivetherapy. CONCLUSIONS: It is the first case report that MCD was associated with GIST and elevated IgE level. Clinically, in patients with elevated IgE level associated with nephrotic syndrome, the possibility of tumor must be taken into account when allergic factors are excluded.