Clinical and laboratory characteristics of salivary gland ultrasonography-positive patients with primary Sjögren's syndrome.

OBJECTIVE: This study aimed to investigate the clinical and laboratory characteristics of salivary gland ultrasonography (SGUS)-positive patients with primary Sjögren's syndrome (pSS) compared to SGUS-negative patients and to analyse the diagnostic value of SGUS and labial salivary gland biopsy (LSGB) grading in pSS. METHODS: A retrospective analysis of patients admitted to the Affiliated Hospital of Yangzhou University between May 2019 and November 2023 was conducted. According to the OMERACT scoring system, patients with pSS were divided into an SGUS-negative group (score <2) and an SGUS-positive group (score ≥2). The patient's age, gender, clinical symptoms, laboratory parameters and diagnostic examinations were compared and analysed, and Spearman correlation analysis was used to analyse the correlation between SGUS, LSGB and influencing factors. RESULTS: There was no significant difference in dry mouth, dry eyes, tooth loss, fever, joint pain, fatigue, interstitial lung disease or renal tubular acidosis between the two groups, although there were more patients with salivary gland enlargement in the SGUS-positive group (p < 0.05). In terms of high levels of immunoglobulin G (IgG), high levels of rheumatoid factor (RF), anti-nuclear antibody ≥1:320, anti-Sjögren's syndrome A-52KD and anti-Sjögren's syndrome B, the number of cases in the SGUS-positive group was greater than that in the SGUS-negative group (p < 0.05). LSGB samples were graded per the Chisholm-Mason system with significant differences between multiple groups. SGUS score negatively correlated with age and positively correlated with LSGB grade. CONCLUSION: This study showed that the SGUS score positively correlated with LSGB grade in pSS patients and negatively correlated with patient age. Thus, SGUS and LSGB are consistent in the diagnosis of pSS to reflect the degree of salivary gland involvement, and patients who are SGUS positive have high RF and IgG levels, a variety of autoantibodies positive and a tendency toward salivary gland enlargement.

Deep brain stimulation of the subthalamic nucleus increases the risk of sialorrhea in patients with advanced Parkinson's disease.

INTRODUCTION: Sialorrhea is a common neurological manifestation of Parkinson's disease (PD). No specifically designed prospective study has tested the effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) on sialorrhea in patients with advanced PD. We focused on the effect of STN-DBS on the incidence of sialorrhea in patients with PD. METHODS: This multicenter, prospective, non-randomized concurrent clinical trial analyzed the incidence of sialorrhea during long-term follow-up in 170 patients with advanced PD (84 patients with STN-DBS and 86 patients with medication therapy). RESULTS: After STN-DBS, 58.1% of patients presented with sialorrhea (Drooling Rating Scale (DRS) > 5) compared with 39.3% of patients with medication therapy (P < 0.001). STN-DBS stimulation demonstrated a significant increase in DRS and Drooling Severity and Frequency Scale (DSFS) compared with the patients with medication therapy (P < 0.001). At follow-up, the onabotulinumtoxin-A (BTX-A) injection ratio was significantly higher in the STN-DBS group (29.8% vs. 11.9%, P = 0.0057) compared with the patients with medication therapy. CONCLUSIONS: STN-DBS increased the risk of sialorrhea in patients with advanced PD. TRIAL REGISTRATION: clinicaltrials. gov (NCT06090929).

MYB/LINC00092 regulatory axis promotes the progression of papillary thyroid carcinoma.

INTRODUCTION: Thyroid carcinoma is the most frequent malignancy in different endocrine-related tumours. In this study, we demonstrated a long non-coding RNA LINC00092-associated molecular mechanism in promoting the progression of papillary thyroid carcinoma (PTC). MATERIAL AND METHODS: The expression of LINC00092 was analysed in the The Cancer Genome Atlas Thyroid Cancer (TCGA-THCA) patient cohorts and further determined by q-PCR. (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) (MTT) assay, and wound healing assay confirmed the function of LINC00092 in migration and proliferation. Q-ChIP validated the transcriptional target. Luciferase reporter assay validated the miRNA-mRNA target. RESULTS: The analysis in patient cohorts and in PTC TPC-1 cells showed that the expression of LINC00092 was repressed in thyroid carcinoma. In addition, the expression of LINC00092 was negatively associated with the advanced thyroid TNM stages. LINC00092 repressed epithelial-mesenchymal transition (EMT), migration, and proliferation of TPC-1 cells. Interestingly, we identified that MYB, a well-studied tumour promoter, is a transcription factor of LINC00092, thereby the expression of LINC00092 was directly repressed by MYB. Furthermore, miR-4741 was also validated as a direct target of MYB and was induced by MYB. Notably, LINC00092 was repressed by miR-4741 through the direct 3'-untranslational region (3'-UTR) target. Therefore, MYB induced EMT of TPC-1 cells by repressing LINC00092 directly or indirectly via miR-4741. CONCLUSIONS: Our study validated that LINC00092 is a tumour suppressor lncRNA in PTC. MYB directly or indirectly represses LINC00092, which contributes to the PTC progression. MYB, LINC00092, and miR-4741 form a coherent feed forward loop. The axis of MYB-LINC00092 promotes progression of PTC.

[Comprehensive Review on Environmental Biogeochemistry of Nonylphenol and Suggestions for the Management of Emerging Contaminants].

In recent years, China's air environment, water environment, and soil environmental quality have been improved, and a "clear water blue sky" has become a normal state. However, as persistent organic pollutants, endocrine-disrupting chemicals, antibiotics, microplastics, and other emerging contaminants are continuously detected in the environment, these emerging contaminants have gradually been attracting wide attention. Nonylphenol, as a typical endocrine disrupting chemical, has also attracted the attention of researchers. The environmental behaviors and exposure levels of nonylphenol in Chinese water bodies were summarized systematically, and the ecological risks caused by nonylphenol were evaluated based on the risk quotient method and joint probability curve method. The results showed that the toxic effects of nonylphenol on aquatic organisms mainly included acute toxicity, growth and development toxicity, and estrogenic effect and reproductive toxicity. Nonylphenol was commonly found in the water bodies of major drainage areas in China, and the average concentration of nonylphenol ranged from 60 to 1000 ng·L-1, with the highest concentration being as high as 4628 ng·L-1. The results of risk assessment based on the risk quotient method and joint probability curve method showed that nonylphenol had certain risks to aquatic life in the major basins of China. Finally, the commonly used nonylphenol treatment, disposal, and risk management and control technologies were summarized, and the international supervision methods of endocrine-disrupting chemicals were compared. Aiming at addressing the problems existing in China's environmental management, targeted policy suggestions were put forward. The research results can provide reference for the management and control of emerging contaminants in China.

An Fc-muted bispecific antibody targeting PD-L1 and 4-1BB induces antitumor immune activity in colorectal cancer without systemic toxicity.

BACKGROUND: Resistance to immune checkpoint inhibitor (ICI) therapy narrows the efficacy of cancer immunotherapy. Although 4-1BB is a promising drug target as a costimulatory molecule of immune cells, no 4-1BB agonist has been given clinical approval because of severe liver toxicity or limited efficacy. Therefore, a safe and efficient immunostimulatory molecule is urgently needed for cancer immunotherapy. METHODS: HK010 was generated by antibody engineering, and the Fab/antigen complex structure was analyzed using crystallography. The affinity and activity of HK010 were detected by multiple in vitro bioassays, including enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), flow cytometry, and luciferase-reporter assays. Humanized mice bearing human PD-L1-expressing MC38 (MC38/hPDL1) or CT26 (CT26/hPDL1) tumor transplants were established to assess the in vivo antitumor activity of HK010. The pharmacokinetics (PK) and toxicity of HK010 were evaluated in cynomolgus monkeys. RESULTS: HK010 was generated as an Fc-muted immunoglobulin (Ig)G4 PD-L1x4-1BB bispecific antibody (BsAb) with a distinguished Fab/antigen complex structure, and maintained a high affinity for human PD-L1 (KD: 2.27 nM) and low affinity for human 4-1BB (KD: 493 nM) to achieve potent PD-1/PD-L1 blockade and appropriate 4-1BB agonism. HK010 exhibited synergistic antitumor activity by blocking the PD-1/PD-L1 signaling pathway and stimulating the 4-1BB signaling pathway simultaneously, and being strictly dependent on the PD-L1 receptor in vitro and in vivo. In particular, when the dose was decreased to 0.3 mg/kg, HK010 still showed a strong antitumor effect in a humanized mouse model bearing MC38/hPDL1 tumors. Strikingly, HK010 treatment enhanced antitumor immunity and induced durable antigen-specific immune memory to prevent rechallenged tumor growth by recruiting CD8+ T cells and other lymphocytes into tumor tissue and activating tumor-infiltrating lymphocytes. Moreover, HK010 not only did not induce nonspecific production of proinflammatory cytokines but was also observed to be well tolerated in cynomolgus monkeys in 5 week repeated-dose (5, 15, or 50 mg/kg) and single-dose (75 or 150 mg/kg) toxicity studies. CONCLUSION: We generated an Fc-muted anti-PD-L1x4-1BB BsAb, HK010, with a distinguished structural interaction with PD-L1 and 4-1BB that exhibits a synergistic antitumor effect by blocking the PD-1/PD-L1 signaling pathway and stimulating the 4-1BB signaling pathway simultaneously. It is strictly dependent on the PD-L1 receptor with no systemic toxicity, which may offer a new option for cancer immunotherapy.

Lipoprotein a Combined with Fibrinogen as an Independent Predictor of Long-Term Prognosis in Patients with Acute Coronary Syndrome: A Multi-Center Retrospective Study.

Background: Patients with acute coronary syndrome (ACS) still have a high risk of recurrence of major adverse cardiovascular and cerebrovascular events (MACCE). However, there are rare studies on the prediction of MACCE in patients with ACS using lipoprotein a [Lp(a)] combined with fibrinogen. The aim of this study was to analyze the predictive value of Lp(a) combined with fibrinogen for the long-term prognosis of patients with ACS. Methods: 804 patients with ACS admitted to 11 tertiary general hospitals in Chengdu from January 2017 to June 2019 were included in the study. According to the Lp(a) 300 mg/L, patients were assigned to the non-high Lp(a) group and high Lp(a) group. Patients were assigned to the non-high or high fibrinogen groups using the fibrinogen level of 3.08 g/L. Subsequently, patients were divided into group A, B, or C by Lp(a) combined with fibrinogen. The study endpoints were MACCE, including all-cause death, non-fatal myocardial infarction, non-fatal stroke, and revascularization. The incidences of MACCE among groups were compared. Lp(a), fibrinogen, Lp(a) combined with fibrinogen classifications were each added into the basic model to construct three new models. The C-index, net reclassification index (NRI) and integrated discrimination improvement (IDI) of the three new models were then compared. Results: The median follow-up was 16 months. During follow-up, the cumulative incidence of MACCE in group C was significantly higher than that measured in group A and B (p < 0.001). The results of the multivariate Cox regression analysis of MACCE showed that Lp(a) ≥300 mg/L with fibrinogen ≥3.08 g/L was an independent predictor of MACCE. According to the GRACE score and the statistical analyses, the basic model was constructed, which had a C-index of 0.694. The C-index, NRI, and IDI of the new model constructed using the basic model + Lp(a) combined with fibrinogen classification were 0.736, 0.095, and 0.094 respectively. Conclusions: Single Lp(a), single fibrinogen and Lp(a) combined with fibrinogen were independent predictors of MACCE in patients with ACS. The predictive value of Lp(a) combined with fibrinogen in patients with ACS was better than that of single Lp(a) and single fibrinogen.

A humanized 4-1BB-targeting agonistic antibody exerts potent antitumor activity in colorectal cancer without systemic toxicity.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies and the patient survival rate remains unacceptably low. The anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody-based immune checkpoint inhibitors have been added to CRC treatment regimens, however, only a fraction of patients benefits. As an important co-stimulatory molecule, 4-1BB/CD137 is mainly expressed on the surface of immune cells including T and natural killer (NK) cells. Several agonistic molecules targeting 4-1BB have been clinically unsuccessful due to systemic toxicity or weak antitumor effects. We generated a humanized anti-4-1BB IgG4 antibody, HuB6, directed against a unique epitope and hypothesized that it would promote antitumor immunity with high safety. METHODS: The antigen binding specificity, affinity and activity of HuB6 were determined by enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), biolayer interferometry (BLI) and flow cytometry. The antitumor effects were evaluated in humanized mice bearing syngeneic tumors, and possible toxicity was evaluated in humanized mice and cynomolgus monkeys. RESULTS: HuB6 showed high specificity and affinity for a binding epitope distinct from those of other known 4-1BB agonists, including utomilumab and urelumab, and induced CD8 + T, CD4 + T and NK cell stimulation dependent on Fcγ receptor (FcγR) crosslinking. HuB6 inhibited CRC tumor growth in a dose-dependent manner, and the antitumor effect was similar with urelumab and utomilumab in humanized mouse models of syngeneic CRC. Furthermore, HuB6 combined with an anti-PD-L1 antibody significantly inhibited CRC growth in vivo. Additionally, HuB6 induced antitumor immune memory in tumor model mice rechallenged with 4 × 106 tumor cells. Toxicology data for humanized 4-1BB mice and cynomolgus monkeys showed that HuB6 could be tolerated up to a 180 mg/kg dose without systemic toxicity. CONCLUSIONS: This study demonstrated that HuB6 should be a suitable candidate for further clinical development and a potential agent for CRC immunotherapy.

A Phase I, Prospective, Randomized, Open-labeled Study to Evaluate the Safety, Tolerability, and Immunogenicity of Booster Dose with MVC-COV1901 or MVC-COV1901(Beta) SARS-CoV-2 Vaccine in Adults

BackgroundThe use of variant-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine as a booster is being evaluated to overcome reduced neutralisation of variants induced by the original SARS-CoV-2 vaccine and waning protection over time. MethodsThis is a phase one, prospective, randomized, and open-labeled trial to study the safety and immunogenicity of a booster dose consisting of a subunit vaccine based on the stabilized prefusion SARS-CoV-2 spike protein, MVC-COV1901 or its Beta version, MVC-COV1901-Beta. One-hundred and seven participants aged [≥]18 and <55 years, who received two or three prior doses of MVC-COV1901 vaccines, were enrolled and were to receive a booster dose of either 15 mcg of MVC-COV1901, 15 mcg or 25 mcg of MVC-COV1901-Beta in 1:1:1 ratio. The primary endpoints were the incidences of adverse events and immunogenicity of the booster dose from Visit 2 (the day of the booster) to Visit 5 (four weeks after the booster). Cellular immunity was also investigated with memory B cell (MBC) and T cell assays. FindingsAdverse reactions after either MVC-COV1901 or MVC-COV1901-Beta booster doses after two or three doses of MVC-COV1901 were comparable and mostly mild and transient. At four weeks after the booster dose, participants with two prior doses of MVC-COV1901 exhibited numerically higher levels of neutralising antibodies against SARS-CoV-2 or Beta variant than participants with three prior doses of MVC-COV1901 regardless of the type of booster used. However, compared to 15 mcg of MVC-COV1901, 25 mcg of MVC-COV1901-Beta significantly improved neutralising antibody titre against Beta variant and BA.4/BA.5 Omicron variant pseudoviruses. The booster dose also significantly increased the proportion of spike-specific MBCs, including those of Beta and Omicron variants. InterpretationMVC-COV1901-Beta can be effectively used as a booster dose against SARS-CoV-2, including the circulating BA.4/BA.5 Omicron variant. FundingMedigen Vaccine Biologics Corporation

Prognostic Value of the Leuko-Glycemic Index in Acute Myocardial Infarction Patients with or without Diabetes.

Purpose: The leuko-glycaemic index (LGI) is an index that combines white blood cell count and blood glucose and could be a marker of systemic inflammatory response syndrome. The prognostic value of the LGI in acute myocardial infarction (AMI) is still unclear. We aimed to investigate the prognostic value of the LGI for short- and long-term prognosis in AMI patients with different diabetic status. Patients and Methods: This was an observational, multicenter study involving 1256 AMI patients admitted in 11 hospitals between March 2014 and June 2019 in Chengdu. White blood cell count and blood glucose were measured on admission. The LGI was calculated by multiplying both values and dividing them by a thousand. Logistic regression was used to explore the predictive value of LGI in in-hospital mortality. Receiver operating characteristic curve was used to determine the optimal cut-off values of the LGI to predict in-hospital mortality. The patients were classified into diabetic and non-diabetic groups and further divided into higher and lower LGI subgroups according to the optimal cut-off values. The endpoints were all-cause mortality during the hospitalization and major adverse cardiovascular and cerebrovascular events (MACCE) during follow-up, including all-cause mortality, non-fatal myocardial infarction, vessel revascularization and non-fatal stroke. Results: LGI was an independent predictor of all-cause mortality during the hospitalization in non-diabetics, but not in diabetics. The optimal cut-off values of diabetics and non-diabetics were 3593 mg/dl. mm3 and 1402 mg/dl. mm3, respectively. Whether diabetics or not, in-hospital mortality was higher in the higher LGI subgroup (p-value < 0.001). And in the follow-up of 15 months (9 months, 22 months), we observed 99 (8.6%), 6 (0.5%), 54 (4.7%) and 29 (2.5%) cases of death, non-fatal MI, revascularization and non-fatal stroke, respectively. The cumulative incidence of MACCE during follow-up was higher in the higher LGI subgroup, both in the diabetics and non-diabetics (p-value < 0.05). In non-diabetics, higher LGI was an independent predictor of MACCE. Conclusion: LGI was an independent predictor for short- and long-term prognosis in AMI patients without diabetes, but had no prognostic value for short- and long-term prognosis of AMI patients with diabetes.

[Tetrahydropalmatine alleviated diabetic neuropathic pain by inhibiting activation of microglia via p38 MAPK signaling pathway].

Neuropathic pain is one of the common complications of diabetes. Tetrahydropalmatine(THP) is a main active component of Corydalis Rhizoma with excellent anti-inflammatory and pain-alleviating properties. This study aims to investigate the therapeutic effect of THP on diabetic neuropathic pain(DNP) and the underlying mechanism. High-fat and high-sugar diet(4 weeks) and streptozotocin(STZ, 35 mg·kg~(-1), single intraperitoneal injection) were employed to induce type-2 DNP in rats. Moreover, lipopolysaccharide(LPS) was used to induce the activation of BV2 microglia in vitro to establish an inflammatory cellular model. Fasting blood glucose(FBG) was measured by a blood glucose meter. Mechanical withdrawal threshold(MWT) was assessed with von Frey filaments, and thermal withdrawal latency(TWL) with hot plate apparatus. The protein expression levels of OX42, inducible nitric oxide synthase(iNOS), CD206, p38, and p-p38 were determined by Western blot, the fluorescence expression levels of OX42 and p-p38 in the dorsal horn of the rat spinal cord by immunofluorescence, the mRNA content of p38 and OX42 in rat spinal cord tissue by qRT-PCR, and levels of nitric oxide(NO), interleukin-1ß(IL-1ß), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), interleukin-10(IL-10), and serum fasting insulin(FINS) by enzyme-linked immunosorbent assay(ELISA). RESULTS:: showed that the mo-del group demonstrated significant decrease in MWT and TWL, with pain symptoms. THP significantly improved the MWT and TWL of DNP rats, inhibited the activation of microglia and p38 MAPK signaling pathway in rat spinal cord, and ameliorated its inflammatory response. Meanwhile, THP promoted the change of LPS-induced BV2 microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, suppressed the activation of the p38 MAPK signaling pathway, decreased the expression levels of inflammatory factors NO, IL-1ß, IL-6, and TNF-α, and increased the expression level of anti-inflammatory factor IL-10. The findings suggested that THP can significantly ameliorate the pain symptoms of DNP rats possibly by inhibiting the inflammatory response caused by M1 polarization of microglia via the p38 MAPK pathway.

Elevated lipoprotein(a) levels as an independent predictor of long-term recurrent events in patients with acute coronary syndrome: an observational, retrospective cohort study.

BACKGROUND: Whether lipoprotein(a) [Lp(a)] is associated with recurrent cardiovascular events (RCVEs) still remains controversial. The present study aimed to investigate the prognostic value of Lp(a) for long-term RCVEs and each component of it in people with acute coronary syndrome (ACS). METHODS: This multicenter, observational and retrospective study enrolled 765 ACS patients at 11 hospitals in Chengdu from January 2014 to June 2019. Patients were assigned to low-Lp(a) group [Lp(a) < 30 mg/dl] and high-Lp(a) group [Lp(a) ≥ 30 mg/dl]. The primary and secondary endpoints were defined as RCVEs and their elements, including all-cause death, nonfatal myocardial infarction (MI), nonfatal stroke and unplanned revascularization. RESULTS: Over a median 17-month follow-up, 113 (14.8%) patients presented with RCVEs were reported, among which we observed 57 (7.5%) all-cause deaths, 22 (2.9%) cases of nonfatal stroke, 13 (1.7%) cases of nonfatal MI and 33 (4.3%) cases of unplanned revascularization. The incidences of RCVEs and revascularization in the high-Lp(a) group were significantly higher than those in the low-Lp(a) group ( P < 0.05), whereas rates of all-cause death, nonfatal stroke and nonfatal MI were not statistically different ( P > 0.05). Kaplan-Meier analysis also revealed the same trend. Multivariate Cox proportional hazards analysis showed that 1-SD increase of Lp(a) was independently associated with both the primary endpoint event [hazard ratio (HR), 1.285 per 1-SD; 95% confidence interval (CI), 1.112-1.484; P < 0.001] and revascularization (HR, 1.588 per 1-SD; 95% CI, 1.305-1.932; P < 0.001), but not with the other secondary events. CONCLUSION: Increased Lp(a) is an independent predictor of RCVEs and unplanned revascularization in patients with ACS.

miR-576-5p Promotes the Proliferation of Papillary Thyroid Carcinoma through the MAPK4-AKT Pathway.

Background: MicroRNA-576-5p (miR-576-5p) plays an important role in different human cancers. However, the biological function of miR-576-5p in papillary thyroid carcinoma (PTC) is still unclear. In this study, we explored the function and specific role of miR-576-5p in PTC. Methods: Expression levels of miR-576-5p in PTC patient tissues and cell lines were determined by reverse transcription-quantitative polymerase chain reaction (qRT‒PCR). Cell counting using cell counting kit-8 (CCK-8), wound healing, and Transwell assays were performed to evaluate the effect of miR-576-5p on the proliferation, migration, and invasion of TPC-1 cells. Expression levels of mitogen-activated protein kinase 4 (MAPK4) and phosphorylation levels of protein kinase B (AKT), extracellular regulated protein kinase (ERK), and P38 mitogen-activated protein kinase (P38) were detected by western blotting or immunohistochemistry (IHC). Results: The expression level of miR-576-5p in PTC tissues and TPC-1 cells was significantly increased. In vitro, overexpression of miR-576-5p promoted the proliferation, migration, and invasion of TPC-1 cells. In addition, MAPK4 was highly expressed in PTC tissues, and miR-576-5p could upregulate the expression of MAPK4. Interestingly, MAPK4 knockdown reversed cell proliferation but not migration and invasion in TPC-1 cells after miR-576-5p was overexpressed. Moreover, overexpression of miR-576-5p induced activation of the AKT pathway in TPC-1 cells, and MAPK4 gene knockout reversed this AKT pathway activation. Conclusion: In this study, we found that miR-576-5p was significantly overexpressed in PTC tissues and TPC-1 cells. In addition, miR-576-5p promoted the proliferation of TPC-1 cells by enhancing expression of MAPK4 and activating the AKT pathway.

CREB3 Transactivates lncRNA ZFAS1 to Promote Papillary Thyroid Carcinoma Metastasis by Modulating miR-373-3p/MMP3 Regulatory Axis.

The incidence rate of thyroid carcinoma ranks ninth among human malignancies, and it accounts for the most frequent malignancy in endocrine-related tumors. This study aimed to investigate the role of long noncoding RNA (lncRNA) ZFAS1 in the metastasis of papillary thyroid carcinoma (PTC) and the potential molecular mechanisms. Both ZFAS1 and MMP3 were highly expressed in thyroid carcinoma and PTC cell, as measured by the q-PCR and TCGA database. In addition, ZFAS1 induced TPC-1 metastasis through inducing the epithelial-mesenchymal transition (EMT) process. Besides, ZFAS1 knockdown by siRNA induced miR-373-3p expression and reduced MMP3 expression, as quantified by q-PCR and Western blotting. According to the luciferase assay, both ZFAS1 and MMP3 were classified as the direct targets of miR-373-3p. However, MMP3 itself did not affect ZFAS1. Using the online prediction tool, CREB3 was predicted as the transcription factor (TF) of ZFAS1 that contained two binding sites on its promoter region, and CREB3 was positively correlated with ZFAS1 in thyroid carcinoma cohorts. Results from the dual-luciferase assay and ChIP-qPCR indicated that both the two binding sites were essential for the transcription of ZFAS1. In conclusion, CREB3 activated lncRNA ZFAS1 at the transcriptional level to promote PTC metastasis by modulating miR-373-3p/MMP3.

Aberrant expression of five miRNAs in papillary thyroid carcinomas.

BACKGROUND: The miRNAs play critical roles in the progression of various tumors. Our study aimed to screen and identify miRNAs to investigate their diagnostic and prognostic value for papillary thyroid carcinoma (PTC). METHODS: miRNAs were evaluated in PTC (n = 30) tissues, A-PTC (n = 30), benign nodules (n = 35) and A-benign nodules (n = 35). The expression levels of five miRNAs were quantified using real-time, quantitative PCR. ROC analysis was used to evaluate the miRNA diagnostic value. RESULTS: The expression of miR-1296-5p, miR-1301-3p, and miR-532-5p was significantly downregulated (p = 0.0001, p = 0.0006, p = 0.0024, respectively), while miR-551b-3p and miR-455-3p were significantly upregulated in PTC tissues compared to A-PTC tissues (p = 0.0005, p = 0.0046, respectively). Interestingly, the expression of miR-1296-5p was downregulated, while miR-551b-3p and miR-455-3p were upregulated in the A-PTC group compared to the A-benign group. Moreover, the miR-1296-5p expression level was associated with tumor size, the number of foci and the TNM stage; the miR-455-3p expression level was correlated with patient age, tumor size, and TNM stage; and the miR-532-5p expression level was correlated with patient age, lymph node metastasis and TNM stage correspondingly. ROC analysis revealed that the AUCs for miR-1301-3p, miR-1296-5p, miR-455-3p, miR-532-5p, and miR-551b-3p were 0.773, 0.790, 0.783, 0.744, and 0.650, respectively. CONCLUSIONS: Our results indicated that miR-1296-5p, miR-1301-3p, miR-532-5p, miR-551b-3p, and miR-455-3p are aberrantly expressed in papillary thyroid carcinomas and correlated with clinicopathological features. ROC curve analysis indicated that these five miRNAs have a potential diagnostic value. Consequently, we speculate that the five altered miRNAs may serve as potential diagnostic and prognostic biomarkers for PTC.

Improvement of dielectric properties and energy storage performance in sandwich-structured P(VDF-CTFE) composites with low content of GO nanosheets.

Polymer-based dielectric capacitors play a notable part in the practical application of energy storage devices. Graphene oxide (GO) nanosheets can improve the dielectric properties of polymer-based composites. However, the breakdown strength will greatly reduce with the increase of GO content. Hence, the construction of sandwich structure can enhance the breakdown strength without reducing the dielectric constant. Herein, single-layered and sandwich-structured poly(vinylidene fluoride-co-chlorotrifluoroethylene) (P(VDF-CTFE)) nanocomposites with low content of GO nanosheets (<1.0 wt%) are prepared via employing a straightforward casting method. Compared with the single-layered composites and pure P(VDF-CTFE), the sandwich-structured composites exhibit comprehensively better performance compared. The sandwich-structured composite with 0.4 wt% GO nanosheets show an excellent dielectric constant of 13.6 (at 1 kHz) and an outstanding discharged energy density of 8.25 J cm-3at 3400 kV cm-1. These results demonstrate that the growth of the dielectric properties is owing to 2D GO nanosheets and the enhancement of breakdown strength due to the sandwich structure. The results from finite element simulation provide theoretical support for the design of high energy density composites.

Effect of regional cooperative rescue systems based on chest pain centers for patients with acute myocardial infarction in a first-tier city in China.

Given the increasing burden of acute myocardial infarction (AMI) in China, regional cooperative rescue systems have been constructed based on chest pain centers (CPCs). This study evaluated the effects of these regional cooperative rescue systems on reperfusion time and prognosis of AMI patients. This study included 1937 AMI patients, divided into two groups according to the date of admission, group A (July 2017-June 2018) and group B (July 2018-June 2019). Reperfusion time, the fatality rate for any cause during hospitalization, and the incidence of major adverse cardiovascular and cerebrovascular events (MACCE) in the 6 months following discharge were compared between the two groups. The proportion of patients treated within the guideline goals for first medical contact to balloon (FMC-to-B) time showed improvement from 40.7% in group A to 50.4% in group B (P = 0.005). The fatality rate for any cause (5.5% vs. 8.0%, P = 0.026) during hospitalization was lower in the B group compared to the A group. Multivariate logistic regression analysis revealed that the fatality rate for any cause (OR 0.614, 95% CI 0.411-0.918, P = 0.017) was significantly lower in group B compared with group A. No significant differences were detected between the two groups for the incidence of MACCE and death for any cause at 6 months using the log-rank test and multivariate Cox regression analysis. The improvement of regional cooperative rescue systems shortened system delays and reduced in-hospital deaths. Although the system has resulted in some substantial improvements, additional improvement is needed.

Frequency of ST-segment elevation myocardial infarction, non-ST-segment myocardial infarction, and unstable angina: results from a Southwest Chinese Registry.

The burden of cardiovascular disease is predicted to escalate in developing countries. The aim of this study is to assess the characteristics, management strategies and outcomes of the patients with acute coronary syndrome (ACS) who were admitted to hospitals under the chest pain center mode in southwest P. R. China. Adults hospitalized with a diagnosis of ACS were enrolled in the retrospective, observational registry between January 2017 and June 2019 at 11 hospitals in Chengdu, P. R. China. The collected data included the patients' baseline characteristics, clinical management and in-hospital outcomes. After Statistical analysis, (1) A total of 2857 patients with ACS, among which 1482 have ST-segment elevation myocardial infarction (STEMI), 681 have non-STEMI (NSTEMI) and 694 have unstable angina (UA) were enrolled in the study. (2) 61.3% of the ACS patients received reperfusion therapy. More patients with STEMI underwent percutaneous coronary intervention (PCI) compared with NSTEMI/UA patients (80.6% vs. 38.8%, P < 0.001), while thrombolytics were administered in only 1.8% of STEMI patients. (3) The median time from symptoms to hospital was 190 min (IQR 94-468) in STEMI, 283 min (IQR 112-1084) in NSTEMI and 337 min (IQR 97-2220) in UA (P < 0.001), and the door-to-balloon time for primary PCI (pPCI) was 85 min (IQR 55-121) in STEMI. (4) The in-hospital outcomes for STEMI patients included death (8.1%) and acute heart failure (22.6%), while the outcomes for those with NSTEMI and UA were better: death (4.0% and 0.9%, P < 0.001) and acute heart failure (15.3% and 9.9%, P < 0.001). (5) Antiplatelet drugs, lipid-lowering drugs, ß-blockers and angiotensin-converting enzyme inhibitors (ACEI) /angiotensin receptor blockers (ARB) were used in about 98.3%, 95.0%, 67.7% and 54.3% of the ACS patients, respectively. Therefore, the management capacity in Chengdu has relatively increased compared with previous studies, but important gaps still exist compared with developed countries, especially regarding the management of the NSTEMI/UA patients.

First-in-Human Trial of a Recombinant Stabilized Prefusion SARS-CoV-2 Spike Protein Vaccine with Adjuvant of Aluminum Hydroxide and CpG 1018

DesignThis is a phase 1, dose-escalation open-label trial to evaluate the safety and immunogenicity of MVC-COV1901, a recombinant stabilized prefusion SARS-CoV-2 spike (S-2P) protein vaccine with adjuvant of aluminum hydroxide and CpG 1018. MethodsWe enrolled 45 healthy adults from 20 to 49 years of age to be administered with two vaccinations of MVC-COV1901 in a low dose (LD), middle dose (MD), and high dose (HD) of spike protein at 28 days apart. There were 15 participants in each dose group, and all of them were followed up for 28 days after the second vaccination at the time of interim analysis. Adverse events (AEs) and laboratory data were recorded for safety evaluation. Blood samples were collected for wild-type SARS-CoV-2 and pseudovirus neutralization assays as well as SARS-CoV-2 spike-specific immunoglobulin G (IgG) at various times. Overall, the study duration will be 7 months. ResultsSolicited events were mostly mild and similar in the participants of all three dose groups. No subject experienced fever. There were no serious nor adverse events of special interest at the time point of this interim report. After the second vaccination, the SARS-CoV-2 spike specific IgG titers increased with peak geometric mean titers at 7178.245 (LD), 7746.086 (MD), and 11220.58 (HD), respectively. Serum neutralizing activity was detected by two methods in all participants of MD and HD groups, with geometric mean values generally comparable to those of a panel of control convalescent serum specimens. All of the participants in the MD and HD groups were seroconverted after the second vaccination. ConclusionsThe MVC-COV1901 vaccine is safe and elicits remarkable immune responses especially in the MD and HD groups. Trial RegistrationClinicalTrials.gov NCT 04487210

Evaluating the neutralizing ability of a CpG-adjuvanted S-2P subunit vaccine against SARS-CoV-2 Variants of Concern

Vaccination is currently the best weapon to control the COVID-19 pandemic. However, an alarming number of novel variants termed Variants of Concern (VoC) were found to harbor mutations that diminished the neutralizing capacity of antibodies elicited by the vaccines. We have investigated the neutralizing titers of antibodies from sera of humans and rats immunized with the MVC-COV1901 vaccine against pseudoviruses coated with the wildtype, D614G, B.1.1.7, or B.1.351 spike proteins. Rats vaccinated with two doses of adjuvanted S-2P retained neutralization activities against the B.1.351 variant, albeit with a slight reduction compared to wildtype. Phase 1 vaccinated subjects showed more reduced neutralization abilities against the B.1.351 variant. The study is among the first, to our knowledge, to demonstrate dose-dependent neutralizing responses against VoCs, particularly against B.1.351, from different doses of antigen in a clinical trial for a subunit protein COVID-19 vaccine. The appearance of vaccine escape variants is a growing concern facing many current COVID-19 vaccines and therapeutics. Strategies should be adopted against the ever-changing nature of these variants. The observations of this study grant us valuable insight into preemptive strikes against current and future variants.

New 3-O-substituted xanthone derivatives as promising acetylcholinesterase inhibitors.

A new series of 3-O-substituted xanthone derivatives were synthesised and evaluated for their anti-cholinergic activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results indicated that the xanthone derivatives possessed good AChE inhibitory activity with eleven of them (5, 8, 11, 17, 19, 21-23, 26-28) exhibited significant effects with the IC50 values ranged 0.88 to 1.28 µM. The AChE enzyme kinetic study of 3-(4-phenylbutoxy)-9H-xanthen-9-one (23) and ethyl 2-((9-oxo-9H-xanthen-3-yl)oxy)acetate (28) showed a mixed inhibition mechanism. Molecular docking study showed that 23 binds to the active site of AChE and interacts via extensive π-π stacking with the indole and phenol side chains of Trp86 and Tyr337, besides the hydrogen bonding with the hydration site and π-π interaction with the phenol side chain of Y72. This study revealed that 3-O-alkoxyl substituted xanthone derivatives are potential lead structures, especially 23 and 28 which can be further developed into potent AChE inhibitors.