Inhibition of ferroptosis by POLE2 in gastric cancer cells involves the activation of NRF2/GPX4 pathway.

Gastric cancer results in great cancer mortality worldwide, and inducing ferroptosis dramatically improves the malignant phenotypes of gastric cancer. DNA polymerase epsilon subunit 2 (POLE2) plays indispensable roles in tumorigenesis; however, its involvement and molecular basis in ferroptosis and gastric cancer are not clear. Human gastric cancer cells were infected with lentiviral vectors to knock down or overexpress POLE2, and cell ferroptosis was detected. To further validate the involvement of nuclear factor erythroid 2-related factor 2 (NRF2) and glutathione peroxidase 4 (GPX4), lentiviral vectors were used. POLE2 expression was elevated in human gastric cancer cells and tissues and closely correlated with clinicopathological features in gastric cancer patients. POLE2 knockdown was induced, while POLE2 overexpression inhibited ferroptosis of human gastric cancer cells, thereby modulating the malignant phenotypes of gastric cancer. Mechanistic studies revealed that POLE2 overexpression elevated NRF2 expression and activity and subsequently activated GPX4, which then prevented lipid peroxidation and ferroptosis in human gastric cancer cells. In contrast, either NRF2 or GPX4 silence significantly prevented POLE2 overexpression-mediated inductions of cell proliferation, migration, invasion and inhibition of ferroptosis. POLE2 overexpression inhibits ferroptosis in human gastric cancer cells through activating NRF2/GPX4 pathway, and inhibiting POLE2 may be a crucial strategy to treat gastric cancer.

Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Endoscopic Submucosal Dissection Criteria for Differentiated-type Early Gastric Cancer Are Applicable to Mixed-type Differentiated Predominant.

BACKGROUND: There is a lack of sufficient evidence on whether mixed-type differentiated predominant early gastric cancer (MD-EGC) can be treated endoscopically by referring to the criteria for differentiated-type early gastric cancer (EGC). This study aims to evaluate the efficacy of endoscopic submucosal dissection (ESD) in MD-EGC. METHODS: Patients with differentiated-type EGC treated with ESD first from January 2015 to June 2021 were reviewed, including MD-EGC and pure differentiated-type EGC (PD-EGC). Clinical data, including the clinicopathological characteristics, resection outcomes of ESD, and recurrence and survival time, were collected, and the difference between MD-EGC and PD-EGC was tested. RESULTS: A total of 48 patients (48 lesions) with MD-EGC and 850 patients (890 lesions) with PD-EGC were included. Compared with PD-EGC, MD-EGC had a higher submucosal invasion rate (37.5% vs. 13.7%, P<0.001) and lymphatic invasion rate (10.4% vs. 0.4%, P<0.001). The rates of complete resection (70.8% vs. 92.5%, P<0.001) and curative resection (54.2% vs. 87.4%, P<0.001) in MD-EGC were lower than those of PD-EGC. Multivariate analysis revealed that MD-EGC (OR 4.26, 95% CI, 2.22-8.17, P<0.001) was an independent risk factor for noncurative resection. However, when curative resection was achieved, there was no significant difference in the rates of recurrence (P=0.424) between the 2 groups, whether local or metachronous recurrence. Similarly, the rates of survival(P=0.168) were no significant difference. CONCLUSIONS: Despite the greater malignancy and lower endoscopic curative resection rate of MD-EGC, patients who met curative resection had a favorable long-term prognosis.

Licochalcone A inhibits cell growth through the downregulation of the Hippo pathway via PES1 in cholangiocarcinoma cells.

Overexpression or activation of Yes-associated protein (YAP) is common in cancer cells. Thus, targeting YAP may be a strategy for cancer therapy. Licochalcone A (LicA) is a primary active compound of licorice root and is known to have medicinal effects, such as antioxidant, antibacterial, antiviral, and anticancer effects. However, the anticancer pharmacological mechanism of LicA has not been investigated in cholangiocarcinoma. In this study, we investigated the antiproliferative effect of LicA and the underlying molecular mechanism in HCCC-9810 and RBE human cholangiocarcinoma cells. Our experiments indicated that LicA suppressed the growth of cholangiocarcinoma cells through inactivation of the Hippo pathway. Pescadillo ribosomal biogenesis factor 1 (PES1) was notably upregulated and related to carcinogenesis. We also found that LicA suppressed the expression and nuclear localization of PES1, which was associated with the inhibition of YAP expression and transcriptional activity.

[Study on improvement and mechanism of tableting properties of porous Fagopyri Dibotryis Rhizoma powders].

At present, there are many difficulties in the development and production of traditional Chinese medicine(TCM) tablets. This work aimed to explore the feasibility of improving dissolution difficulty and large dosage of TCM tablets by co-spray drying TCM extract with a small amount of pore-foaming agent ammonium bicarbonate. A series of porous Fagopyri Dibotryis Rhizoma powders were prepared by co-spray drying Fagopyri Dibotryis Rhizoma with different amounts of ammonium bicarbonate, and their powder pro-perties and tablet properties were comparatively investigated. At the same time, Fagopyri Dibotryis Rhizoma commercial tablets and raw material tablets were used as control drugs, the improvement degree of its compressibility and dissolution rate was investigated. The results showed that there were higher porosity, specific surface area and hollow spheroidal particles structure of powders via co-spray drying Fagopyri Dibotryis Rhizoma with NH_4HCO_3. Compared to parent and commercial Fagopyri Dibotryis Rhizoma tablets, the dissolution rates and compressibility of porous Fagopyri Dibotryis Rhizoma tablets were significantly increasing. High compressibility could increase drug loading by reducing excipients in manufacturing of tablets and lower the dose of Fagopyri Dibotryis Rhizoma tablets.

Homocysteine might increase the risk of recurrence in patients presenting with primary cerebral infarction.

PURPOSE: Although hyperhomocysteinemia (Hhcy) is a risk factor for cerebral infarction, its effect on recurrent cerebral infarction is less-defined. We aimed to investigate the association of Hhcy and increased risk of recurrent cerebral infarct. MATERIALS AND METHODS: From 2011 to 2013, we recruited 231 primary cerebral infarct patients that were divided to a Hhcy group (n = 105) and a control group (n = 126) according to plasma homocysteinemia (Hcy) levels exceeding 15 µmol/L. In this prospective study, risk factors such as gender, age, blood lipid and glucose levels, history of diabetes, high blood pressure, smoking habits and plasma Hhcy levels were determined. A three-year follow-up compared differences in cerebral infarction recurrence rates. Statistical analyses identified whether plasma Hhcy levels were an independent risk factor for recurrent cerebral infarction. RESULTS: Triglyceride and low-density lipoprotein (LDL) levels in the Hhcy group were significantly higher than controls, and cerebral infarct recurrence rates in the Hhcy group exceeded control subject rates through the three-year follow-up (p = .021, p = .036 and p = .025). Cox proportional hazards modeling showed that elevated Hhcy levels (hazard ratio [HR] = 3.062, p < .001), increased age (HR = 1.069, p < .01), circulating triglyceride levels (HR = 1.686, p = .048), and relative National Institutes of Health Stroke (NIHSS) score (HR = 1.068, p = .016) were risk factors for recurrent cerebral infarction. CONCLUSIONS: Level of Hhcy was a risk factor for recurrent cerebral infarction. Further, particular demographic and clinical outcomes including age, relative NIHSS scores, and circulating triglyceride levels were markedly associated with the occurrence of cerebral infarction.

An innovative medical consultation model in mainland China.

PURPOSE: The purposes of this paper are two-fold: first, to introduce a new concept of primary care consultation system at a mainland Chinese hospital in response to healthcare reform; and second, to explore the factors associated with change resistance and acceptance from both patients' and medical staff's perspectives. DESIGN/METHODOLOGY/APPROACH: A survey design study, with two questionnaires developed and distributed to patients and medical staff. Convenience and stratified random sampling methods were applied to patient and medical staff samples. FINDINGS: A 5-dimension, 21-item patient questionnaire and a 4-dimension, 16-item staff questionnaire were identified and confirmed, with 1020 patients (91.07 percent) and 202 staff (90.18 percent) as effective survey participants. The results revealed that patient resistance mainly stems from a lack of personal experiences with visiting general practice (GP) and being educated or having lived overseas; while staff resistance came from occupation, education, GP training certificate, and knowledge and experience with specialists. Living in overseas and knowledge of GP concepts, gender and education are associated with resistance of accepting the new practice model for both patients and staff. ORIGINALITY/VALUE: There are few Chinese studies on process reengineering in the medical sector; this is the first study to adopt this medical consultation model and change in patients' consultation culture in Mainland China. Applying organizational change and process reengineering theories to medical and healthcare services not only extends and expands hospital management theory but also allows investigation of modern hospital management practice. The experience from this study can serve as a reference to promote this new consultation model in Chinese healthcare reform.

Engineered Zymomonas mobilis for salt tolerance using EZ-Tn5-based transposon insertion mutagenesis system.

BACKGROUND: The cell growth and ethanol yield of Zymomonas mobilis may be detrimentally affected by salt stress frequently present in some biomass-based fermentation systems, leading to a decrease in the rate of sugar conversion to ethanol or other bioproducts. To address this problem, improving the salt tolerance of Z. mobilis is a desirable way. However, limited progress has been made in development of Z. mobilis with higher salt tolerance for some technical challenges in the past decades. Recently, transposon insertion mutant system has been widely used as a novel genetic tool in many organisms to develop mutant strains. In this study, Tn5-based transposon insertion mutagenesis system firstly used for construction of higher salt tolerance strain in Z. mobilis. RESULTS: Approximately 200 Z. mobilis ZM4 mutants were generated by using Tn5-based transposon mutagenesis system. The mutant strain ZMT2 with improved salt tolerance phenotype was obtained by screening on RM agar plates with additional 1 % NaCl. Strain ZMT2 was confirmed to exhibit better fermentation performance under NaCl stress than wild type of strain ZM4. The transposon insertion was located in ZMO1122 (himA) by genome walking. Discruption of himA gene showed that himA may play an important role in response to salt tolerance in Z. mobils. CONCLUSIONS: The mutant strain ZMT2 with a transposon insertion in himA gene of the genome showed obviously higher sugar conversion rate to ethonal under up to 2 % NaCl stress than did the wild ZM4 strain. Besides, ZMT2 exhibited shared fermentative capabilities with wild ZM4 strain under no or low NaCl stress. This report firstly showed that himA played a role in responding to NaCl stress. Furthermore, the result indicated that Tn5-based transposon mutagenesis system was a feasible tool not only for genetic engineering in Z. mobilis strain improvement, but also in tapping resistent genes.

Lentibacillus amyloliquefaciens sp. nov., a halophilic bacterium isolated from saline sediment sample.

A Gram-stain positive, non-motile, non-sporogenous, aerobic, rod-shaped and halophilic bacterium, designated LAM0015(T), was isolated from a saline sediment sample collected from Yantai City in China. The isolate was found to be able to grow at NaCl concentrations of 5-25 % (w/v) (optimum: 7-12 %), 15-45 °C (optimum: 35 °C) and pH 5.0-9.0 (optimum: 7.0). The major fatty acids were determined to be anteiso-C15:0 and anteiso-C17:0. The predominant respiratory quinone was identified as MK-7. The cell wall peptidoglycan was determined to contain meso-diaminopimelic acid. The polar lipids were found to be diphosphatidyglycerol, phosphatidylglycerol, five phospholipids and one glycolipid. The DNA G+C content was 43.1 mol% as determined by the T m method. Analysis of the 16S rRNA gene sequence indicated that the isolate belongs within the genus Lentibacillus and is closely related to Lentibacillus persicus DSM 22530(T), Lentibacillus salicampi JCM 11462(T) and Lentibacillus jeotgali JCM 15795(T) with 97.3, 96.7 and 96.4 % sequence similarity, respectively. The DNA-DNA hybridization value between LAM0015(T) and L. persicus DSM 22530(T) was 51.2 ± 1.4 %. Based on its phenotypic, phylogenetic and chemotaxonomic characteristics, strain LAM0015(T) is concluded to represent a novel species of the genus Lentibacillus, for which the name Lentibacillus amyloliquefaciens sp. nov. is proposed. The type strain is LAM0015(T) (=ACCC 06401(T) = JCM 19838(T)).

Paenibacillus vini sp. nov., isolated from alcohol fermentation pit mud in Sichuan Province, China.

A novel facultatively anaerobic bacterial strain, designated LAM0504(T), was isolated from a pit mud of Luzhou flavour liquor alcohol fermentation in Sichuan Province, China. Cells of strain LAM0504(T) were observed to be Gram-stain negative, spore-forming, rod shaped and motile by means of peritrichous flagella. Strain LAM0504(T) was found to be able to grow at 20-48 °C (optimum: 30 °C), pH 5.0-9.0 (optimum: 7.0) and 0-3 % NaCl (w/v) (optimum: 1.0 %). The 16S rRNA gene sequence similarity analysis showed that strain LAM0504(T) was most closely related to Paenibacillus konsisdensis JCM 14798(T), Fontibacillus phaseoli LMG 27589(T) and Paenibacillus motobuensis JCM 12774(T), with 97.0, 96.8 and 96.7 % sequence similarity, respectively. The DNA-DNA hybridization value between strain LAM0504(T) and P. konsisdensis JCM 14798(T) was 53.3 ± 1.2 %. The genomic DNA G+C content of strain LAM0504(T) was 43.0 mol% as determined by the Tm method. The major fatty acids of strain LAM0504(T) were identified as anteiso-C15:0, C16:0 and iso-C15:0. The cell-wall peptidoglycan was found to contain meso-diaminopimelic acid. The predominant menaquinone was identified as MK-7. The major polar lipids were found to be diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, two unidentified phospholipids, two unidentified glycolipids and three unidentified lipids. On the basis of its physiological and phylogenetic characteristics, strain LAM0504(T) is concluded to represent a novel species of the genus Paenibacillus, for which the name Paenibacillus vini sp. nov. is proposed. The type strain is LAM0504(T) (=ACCC 06420(T) = JCM 19842(T)).

N-Directed, Radical Relay Enantioconvergent Sulfinylation of Distal C(sp3)-H Bonds via Cobalt Catalysis.

Cobalt-catalyzed enantioconvergent cross-coupling of C(sp3)-H bonds with in situ-generated sulfenate anions is achieved to access chiral sulfoxides, which are found in the structures of many biologically active agents. The more challenging aliphatic C-H bonds as well as sterically hindered substrates containing tertiary C-H bonds could also be tolerated well. Mechanistic studies indicate that the transformation could undergo a CoIIS(O)R-mediated single-electron transfer with N-fluorocarboxamides, followed by a 1,5-hydrogen atom transfer and then a pivotal organocobalt(IV)-controlled enantioselective cross-coupling process. This novel asymmetric radical reaction for C-S bond construction could open a new door for the synthesis of sulfur-centered chiral compounds.

Association of IL­6 and MMP­3 gene polymorphisms with adolescent idiopathic scoliosis: A systematic review and meta­analysis.

The pathogenesis of adolescent idiopathic scoliosis (AIS) remains unclear. It has been found that interleukin-6 (IL-6) rs1800795 locus and matrix metalloproteinase-3 (MMP-3) rs3025058 locus gene polymorphisms may be associated with AIS susceptibility, which has been controversial and needs to be further confirmed by updated meta-analysis. The aim of the present study was to investigate the association of MMP-3 rs3025058 and IL-6 rs1800795 single nucleotide polymorphisms (SNPs) with susceptibility to AIS. All relevant articles that met the criteria were retrieved and included, and the publication dates were limited from January 2005 to December 2023. The allele frequencies and different genotype frequencies of IL-6 rs1800795 and MMP-3 rs3025058 loci in each study were extracted and statistically analyzed by ReviewManager 5.4 software, and the odds ratio (OR) and 95% confidence interval (95% CI) of different genetic models were calculated. The results of the meta-analysis showed that there was no significant association between the gene polymorphism of IL-6 rs1800795 locus and the pathogenesis of AIS. The allele 5A and genotype 5A5A of MMP-3 rs3025058 SNP were associated with AIS susceptibility (5A vs. 6A, OR=1.18; 95% CI, 1.04-1.33; 5A5A vs. 6A6A, OR=1.65; 95% CI, 1.23-2.21; and 5A5A vs. 5A6A + 6A6A, OR=1.54; 95% CI, 1.19-1.99). Results of subgroup analysis revealed that the allele 5A and genotype 5A5A of MMP-3 rs3025058 SNP were associated with AIS susceptibility in the Caucasian population, and the susceptibility of AIS was associated with the genotype 5A5A of MMP-3 rs3025058 SNP in an Asian population. There was no significant association between the gene polymorphism of IL-6 rs1800795 locus and the pathogenesis of AIS, while the allele 5A of MMP-3 rs3025058 locus was associated with the susceptibility to AIS, especially in the Caucasian population.

Overexpression of a novel chrysanthemum Cys2/His2-type zinc finger protein gene DgZFP3 confers drought tolerance in tobacco.

A drought stress-responsive Cys2/His2-type zinc finger protein gene DgZFP3 was previously isolated (Liu et al., Afr J Biotechnol 11:7781-7788, 2012b) from chrysanthemum. To assess roles of DgZFP3 in plant drought stress responses, we performed gain-of-function experiment. The DgZFP3-overexpression tobacco plants showed significant drought tolerance over the wild type (WT). The transgenic lines exhibited less accumulation of H2O2 under drought stress, more accumulation of proline and greater activities of peroxidase (POD) and superoxide dismutase than the WT under both control conditions and drought stress. In addition, there was greater up-regulation of the ROS-related enzyme genes (NtSOD and NtPOD) and stress-related genes (NtLEA5 and NtDREB) in transgenic lines under normal or drought conditons. Thus DgZFP3 probably plays a positive regulatory role in drought stress response and has the potential to be utilized in transgenic breeding to improve drought stress tolerance in plants.

[Effects of arbuscular mycorrhizal fungi on terpenoids in Isodon adenantha].

OBJECTIVE: To observe the effects of Arbuscular Mycorrhizal (AM) fungi on terpenoids in Isodon adenantha. METHODS: Three different treated plant groups were divided as followings: indoor inoculation with AM fungi, non-inoculation with AM fungi, and outdoor natural growth, the effects of AM fungi on the major terpenoids in Isodon adenantha were evaluated. RESULTS: AM fungi had little influence on the content of terpenoids in underground part of Isodon adenantha, but they showed great impact on the content of terpenoids in the aerial part of the plant. CONCLUSION: The content of terpenoids in the aerial part of Isodon adenantha is positively correlated with AM fungi.

ANGPTL2 aggravates LPS-induced septic cardiomyopathy via NLRP3-mediated inflammasome in a DUSP1-dependent pathway.

Angiopoietin-like protein 2 (ANGPTL2) was implicated in various cardiovascular diseases; however, its role in lipopolysaccharide (LPS)-related septic cardiomyopathy remains unclear. Herein, mice were exposed to LPS to generate septic cardiomyopathy, and adeno-associated viral vector was employed to overexpress ANGPTL2 in the myocardium. Besides, mice were treated with adenoviral vector to knock down ANGPTL2 in hearts. ANGPTL2 expressions in hearts and cardiomyocytes were upregulated by LPS challenge. ANGPTL2 overexpression aggravated, while ANGPTL2 silence ameliorated LPS-associated cardiac impairment and inflammation. Mechanically, we found that ANGPTL2 activated NLRP3 inflammasome via suppressing DUSP1 signaling, and NLRP3 knockdown abrogated the detrimental role of ANGPTL2 in aggravating LPS-induced cardiac inflammation. Furthermore, DUSP1 overexpression significantly inhibited ANGPTL2-mediated NLRP3 activation, and subsequently improved LPS-related cardiac dysfunction. In summary, ANGPTL2 exacerbated septic cardiomyopathy via activating NLRP3-mediated inflammation in a DUSP1-dependent manner, and our study uncovered a promising therapeutic target in preventing septic cardiomyopathy.

CNIH4 governs cervical cancer progression through reducing ferroptosis.

Cervical cancer is one of the most leading causes of cancer death worldwide, and ferroptosis is implicated in the progression of cervical cancer. Cornichon family AMPA receptor auxiliary protein 4 (CNIH4) is involved in the progression of various human cancers; however, its function in cervical cancer remains unclear. The present study aims to investigate the role and mechanism of CNIH4 in cervical cancer using gain- and loss-of-function studies in vitro. SiHa and CaSki cells were infected with lentiviral vectors to manipulate the expression of CNIH4 in vitro, and cell viability, migration, invasion as well as ferroptosis were evaluated. Transcriptome sequencing analysis was performed to further validate the mechanism through which CNIH4 regulated the progression of cervical cancer. The expression of CNIH4 was upregulated in human cervical cancer tissues and cells, and strongly correlated with the decreases in overall survival and disease free survival rates of cervical cancer patients. CNIH4 silence inhibited, while CNIH4 overexpression facilitated the survival of human cervical cancer cells. Mechanistically, CNIH4 elevated solute carrier family 7 member 11 (SLC7A11)-mediated cystine import, and subsequently increased intracellular glutathione synthesis and glutathione peroxidase 4 activity, thereby inhibiting ferroptosis of human cervical cancer cells. SLC7A11 silence significantly abolished CNIH4-mediated inhibition of ferroptosis in cervical cancer cells in vitro. Our study for the first time reveals that CNIH4 inhibits ferroptosis of human cervical cancer cells through upregulating SLC7A11, defining CNIH4 as an attractive therapeutic and prognostic target for cervical cancer.

Duration of SARS-CoV-2 Serum-Neutralizing Antibodies Against SARS-CoV-2 Dependent on the Individual.

We investigated the persistence of SARS-CoV-2-specific neutralizing antibodies in serum (CoV-2-SNAb) against the "WH-Human 1" coronavirus in 57 convalescent persons from January 2020 to January 2021. The CoV-2-SNAb response against authentic "WH-Human 1" showed a significant (p < 0.01) neutralizing high effect (≥95%) in the following manner: by 94.7% neutralization for up to 6 months, by 73.1% for up to 8 months, and by 31.7% for up to 10 months in correlation with a significant decrease in the concentration of the virus determined by SARS-CoV-2 spike protein extracellular domain and spike-receptor-binding domain (S-RBD). There was neutralizing effect (<95%) when the S-RBD optical density (OD) value was more than 1.0, showing a suitable threshold of S-RBD = 1.0 (antibody-tittering, OD). However, in some convalescent persons, no neutralizing effect (<95%) was observed although the SARS-CoV-2-specific neutralizing antibodies were bound to the S-RBD (OD >1.0). The neutralization of the virus in these cases may not involve S-RBD, but rather B- and T cell memory responses in overall immunity, using the threshold value (OD = 1.0) of S-RBD as a simple and effective method to determine the neutralization effect of the antibody efficacy and use of vaccination in combination with a standard pseudovirus neutralizing assay. We suggest that convalescent persons should contact their physicians 6-month postinfection to test the function of their serum neutralizing antibodies and determine whether administering a SARS-CoV-2 vaccine is necessary to prevent the development of severe illness in the future.

The association of growth differentiation factor 5 rs143383 gene polymorphism with osteoarthritis: a systematic review and meta-analysis.

BACKGROUND: Osteoarthritis (OA) is caused by a complex set of pathophysiological factors. The genetic factors involved in the occurrence and progress of the disease have been widely discussed by scholars. It was found that growth differentiation factor 5 (GDF5) gene polymorphisms may be linked to OA susceptibility, which has been controversial and needs to be further confirmed by an updated meta-analysis. OBJECTIVES: We examined the association between GDF5 rs143383 single nucleotide polymorphism (SNP) and OA susceptibility. METHODS: All relevant articles that met the criteria are retrieved and included, and the search deadline is June 2022. The allele frequencies and different genotype frequencies of GDF5 rs143383 loci in each study were extracted and statistically analyzed by R4.1.3 software, and the different genetic models were analyzed based on their odds ratio (OR) and 95% confidence interval (CI). RESULTS: The meta-analysis explained that GDF5 rs143383 SNP was crucial correlated with OA in all patients with OA of knee, hip and hand. The codominant gene model in the whole crowd (OR = 1.17, 95% CI 1.07-1.27, P < 0.01) enlightened that OA was vitally associated with GDF5 gene polymorphism. At the same time, we did a subgroup analysis based on ethnicity. The codominant gene model (OR = 1.31, 95% CI 1.12-1.53, P < 0.01) in Asian population, the codominant homozygote model (OR = 1.28, 95% CI 1.14-1.43), codominant heterozygote gene model (OR = 1.12, 95% CI 1.01-1.23, P = 0.02), and dominant gene model (OR = 1.19, 95% CI 1.09-1.31, P < 0.01) in Caucasian are analyzed by subgroup analysis. It means that there is a momentous relationship between the GDF5rs143383 gene polymorphism and OA, especially among Caucasians. In addition, we also discussed different types of OA separately and discover that the GDF5rs143383 gene polymorphism was relevant for knee osteoarthritis (KOA) and hand osteoarthritis, and it was more significant in the Caucasian population. But due to the high heterogeneity in hip osteoarthritis, it could not be accurately concluded. Furthermore, we also analyzed the osteoarthritis of different genders and found that the GDF5 rs143383 SNP was associated with both men and women and was still significant in the Caucasian population. CONCLUSION: We found a close association between osteoarthritis and GDF5rs143383SNP in this study. From the analysis of each group, we got the same conclusion in KOA and hand OA, but which need further verification in hip OA. Considering gender, we found a close relationship between GDF5 rs143383 SNP and OA of the knee, hip and hand, both for men and women. This conclusion is more obvious in Caucasian people.

A Prediction Model Based on the Risk Factors Associated with Pathological Upgrading in Patients with Early-Stage Gastric Neoplasms Diagnosed by Endoscopic Forceps Biopsy.

Background/Aims: The discrepancies between the diagnosis of preoperative endoscopic forceps biopsy (EFB) and endoscopic submucosal dissection (ESD) in patients with early gastric neoplasm (EGN) exist objectively. Among them, pathological upgrading directly influences the accuracy and appropriateness of clinical decisions. The aims of this study were to investigate the risk factors for the discrepancies, with a particular focus on pathological upgrading and to establish a prediction model for estimating the risk of pathological upgrading after EFB. Methods: We retrospectively collected the records of 978 patients who underwent ESD from December 1, 2017 to July 31, 2021 and who had a final histopathology determination of EGN. A nomogram to predict the risk of pathological upgrading was constructed after analyzing subgroup differences among the 901 lesions enrolled. Results: The ratio of pathological upgrading was 510 of 953 (53.5%). Clinical, laboratorial and endoscopic characteristics were analyzed using univariable and binary multivariable logistic regression analyses. A nomogram was constructed by including age, history of chronic atrophic gastritis, symptoms of digestive system, blood high density lipoprotein concentration, macroscopic type, pathological diagnosis of EFB, uneven surface, remarkable redness, and lesion size. The C-statistics were 0.804 (95% confidence interval, 0.774 to 0.834) and 0.748 (95% confidence interval, 0.664 to 0.832) in the training and validation set, respectively. We also built an online webserver based on the proposed nomogram for convenient clinical use. Conclusions: The clinical value of identifying the preoperative diagnosis of EGN lesions is limited when using EFB separately. We have developed a nomogram that can predict the probability of pathological upgrading with good calibration and discrimination value.

HLA-A*0201-restricted CD8+ T-cell epitopes identified in dengue viruses.

BACKGROUND: All four dengue virus (DV) serotypes (D1V, D2V, D3V and D4V) can cause a series of disorders, ranging from mild dengue fever (DF) to severe dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Previous studies have revealed that DV serotype-specific CD8(+) T cells are involved in controlling DV infection. Serotype cross-reactive CD8(+) T-cells may contribute to the immunopathogenesis of DHF/DSS. The aim of the study was to identify HLA-A*0201-binding peptides from four DV serotypes. We then examined their immunogenicity in vivo and cross-reactivity within heterologous peptides. METHODS: D1V-derived candidate CD8(+) T-cell epitopes were synthesized and evaluated for their affinity to the HLA-A*0201 molecule. Variant peptides representing heterologous D2V, D3V, D4V serotypes were synthesized. The immunogenicity of the high-affinity peptides were evaluated in HLA-A*0201 transgenic mice. RESULTS: Of the seven D1V-derived candidate epitopes [D1V-NS4a(56-64)(MLLALIAVL), D1V-C(46-54)(LVMAFMAFL), D1V-NS4b(562-570)(LLATSIFKL), D1V-NS2a(169-177)(AMVLSIVSL), D1V-NS4a(140-148)(GLLFMILTV), D1V-NS2a(144-152)(QLWAALLSL) and D1V-NS4b(183-191)(LLMRTTWAL)], three peptides [D1V-NS4a(140-148), D1V-NS2a(144-152) and D1V-NS4b(183-191)] had a high affinity for HLA-A*0201 molecules. Moreover, their variant peptides for D2V, D3V and D4V [D2V-NS4a(140-148)(AILTVVAAT), D3V-NS4a(140-148)(GILTLAAIV), D4V-NS4a(140-148)(TILTIIGLI), D2V-NS2a(144-152)(QLAVTIMAI), D3V-NS2a(144-152)(QLWTALVSL), D4V-NS2a(143-151)(QVGTLALSL), D2V-NS4b(182-190)(LMMRTTWAL), D3V-NS4b(182-190) (LLMRTSWAL) and D4V-NS4b(179-187)(LLMRTTWAF)] also had a high affinity for HLA-A*0201 molecules. Furthermore, CD8+ T cells directed to these twelve peptides were induced in HLA-A*0201 transgenic mice following immunization with these peptides. Additionally, cross-reactivity within four peptides (D1V-NS4b(183-191), D2V-NS4b(182-190), D3V-NS4b(182-190) and D4V-NS4b(179-187)) was observed. CONCLUSIONS: Two novel serotype-specific HLA-A*0201-restricted CD8(+) T-cell epitopes (NS4a(140-148) and NS2a(144-152)) and one cross-reactive HLA-A*0201-restricted CD8(+) T-cell epitopes which is similar to a previously identified epitope were identified in D1V-D4V. Combining prediction algorithms and HLA transgenic mice is an effective strategy to identify HLA-restricted epitopes. Serotype-specific epitopes would be used to determine the protective role of serotype-specific CD8(+) T cells, while cross-reactive epitopes may provide assistance in exploring the role of serotype cross-reactive CD8(+) T cells in the immunopathogenesis of DHF/DSS.