The opportunities and challenges of the disease-modifying immunotherapy for type 1 diabetes: A systematic review and meta-analysis.

There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00-0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04-0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, -0.07units/kg/day, 95% CI, -0.11 to -0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, -0.11units/kg/day, 95% CI, -0.23 to -0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.

Long Noncoding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 Promotes the Osteoblast Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells by Targeting the microRNA-96/Osterix Axis.

OBJECTIVES: To investigate whether and how the long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) sponges microRNA-96 (miR-96) to achieve the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). METHODS: Protein levels were detected by Western blot. Mineralized bone matrix formation was studied by alizarin red staining. Metastasis-associated lung adenocarcinoma transcript 1, miR-96, and osteogenesis-related Messenger RNA expression was assessed by Quantitative Real-time Polymerase Chain Reaction (qRT-PCR). The interactions between miR-96 and osterix (Osx), MALAT1, and miR-96 were determined by luciferase reporter assay. RESULTS: The expression of MALAT1 was upregulated whereas that of miR-96 was downregulated in osteogenic hBMSCs. In addition, the expression of MALAT1 significantly decreased whereas that of miR-96 increased in the hBMSCs of osteoporosis (OP) patients. qRT-PCR and alizarin red staining assays showed that MALAT1 silencing or miR-96 overexpression inhibits hBMSC osteogenic differentiation and vice versa. overexpression of miR-96 reversed the promotive effect of MALAT1 on the osteogenic differentiation of hBMSCs. Dual luciferase report assay verified that miR-96 is a regulatory target of MALAT1 and that Osx is a gene target of miR-96. CONCLUSIONS: Taken together, the results demonstrate that MALAT1 promotes the osteogenic differentiation of hBMSCs by regulating the miR-96/Osx axis. Our study provides novel mechanistic insights into the critical role of lncRNA MALAT1 as a microRNA sponge in OP patients and sheds new light on lncRNA-directed diagnostics and therapeutics in OP.

Weight reduction and the risk of gallbladder and biliary disease: A systematic review and meta-analysis of randomized clinical trials.

In this meta-analysis, we aim to evaluate the risk of gallbladder and biliary disease of weight management strategies and investigate the association between weight reduction and risk of gallbladder or biliary disease. Randomized controlled trials (RCTs) with a duration of at least 12 weeks that compare antiobesity medications (AOMs) with placebo or bariatric surgery with less intensive weight management strategy were concluded. Weight management strategy was associated with a significant increased risk of gallbladder or biliary disease (OR 1.361, 95% CI 1.147 to 1.614, P < 0.001, I2 = 3.5%), cholelithiasis, cholecystitis, and cholecystectomy compared with placebo or controls. The increased risk of gallbladder or biliary disease was observed both in pharmacotherapies subgroup and bariatric surgery subgroup. With regards of specific pharmacotherapies, an increased risk of gallbladder or biliary disease was observed in trials with glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatments. In addition, trials with indication of obesity and overweight treatment and trials with higher doses showed significant higher risk of gallbladder or biliary disease compared with placebo or controls. In conclusion, weight management strategy was associated with an increased risk of gallbladder or biliary disease when compared with placebo or control groups.

The mutual overlapping impact of stress and infection on mental health problems in adolescents and youths during and after COVID-19 pandemic in China.

BACKGROUND: It is unclear about the mutual impact of COVID-19 related psychological stress and infection on mental health of adolescent and youth students. This study aimed to explore the mutual impact of COVID-19 related psychological stress and infection on mental health problems among students. METHODS: This study was conducted from December 14, 2022 to February 28, 2023 in Sichuan, China. Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, PTSD Checklist for DSM-5, Insomnia Severity Index, and Internet Addiction Test were used. Participants were grouped by COVID-19 infection and psychological stress level. The differences among groups were compared, and logistic regression analysis was used to investigate risk factors for depression, anxiety, PTSD and insomnia among groups. RESULTS: Of 90,118 participants, 82,873 (92.0 %) finished the questionnaires and were included in the study. Of 82,873 participants, 33,314 (40.2 %) reported to be infected with COVID-19. Participants had depression symptoms (38.1 %), anxiety symptoms (31.8 %), PTSD (33.9 %), insomnia (34.0 %), and internet addiction (60.3 %). Compared with participants uninfected with low psychological stress level, the risk for symptoms of depression, anxiety, PTSD and insomnia increased by 9.6 %, 12.3 %, 6.6 %, and 12.0 % in participants infected with low psychological stress level (p < 0.001), 106.8 %, 125.9 %, 125.2 %, and 95.7 % in participants uninfected with high psychological stress level (p < 0.001), and 147.3 %, 161.1 %, 158.7 %, and 141.0 % in participants infected with high psychological stress level (p < 0.001). LIMITATION: This study is a cross-sectional design, and no causal associations should be inferred. Infection status was based on self-report of participants with infectious symptoms. CONCLUSION: COVID-19 related psychological stress and infection per se have mutually overlapping impacts on mental health problems among students. Further health policies and psychosocial interventions should be developed to reduce mutually overlapping impact and improve the long-term mental health among students.

Cadherin-16 inhibits thyroid carcinoma cell proliferation and invasion.

Cadherin-16 (CDH16), a member of the cadherin family of adhesion molecules, serves an important role in the formation and maintenance of the thyroid follicular lumen. Decreased expression of CDH16 has been reported to be associated with tumor stage in papillary thyroid cancer (PTC); however, previous analyses have been limited and the biological role of CDH16 in different subtypes of TC is unknown. To investigate the role of CDH16 in the occurrence and development of TC, bioinformatic analysis of three TC subtypes (PTC, follicular cell-derived TC and anaplastic TC) was performed using an extended data set from the Gene Expression Omnibus database, with additional confirmation using data from The Cancer Genome Atlas, as well as biopsies from 35 patients with PTC and TC or follicular cell lines. According to the dataset analysis, CDH16 was downregulated in PTC and follicular cell-derived and anaplastic TC; the downregulation in PTC was independent of DNA copy number variation. Furthermore, low expression levels of CDH16 were significantly correlated with tumor size, lymph node metastasis status and disease stage in 35 patients with PTC. Gene Set Enrichment Analysis suggested that CDH16 participated in DNA replication and cell adhesion pathways. To evaluate CDH16 activity, CDH16 was overexpressed in TC-derived BCPAP cells. CDH16 overexpression inhibited cell proliferation, migration and invasion and induced apoptosis by downregulating proteins associated with DNA replication and cell adhesion. These results support the identification of CDH16 as a valuable target for TC prognosis and therapy and, to the best of our knowledge, represent the first direct demonstration of its mechanistic role in TC.

ZNF703 is Overexpressed in Papillary Thyroid Carcinoma Tissues and Mediates K1 Cell Proliferation.

Zinc finger protein 703 (ZNF703), a member of the NET family of transcription factors, has recently emerged as an important player in the development of several types of cancers, though its role in papillary thyroid cancer (PTC) has not been characterized. We investigated the expression of ZNF703, its association with the most common genetic mutation in PTC, BRAF V600E, and its potential use as a therapeutic target. Real-time PCR, immunohistochemical staining, and western blot analysis of ZNF703 expression were performed for 36 cases of PTC and corresponding normal thyroid tissues. ZNF703 mRNA and protein expression was found to be significantly higher in PTC compared to normal thyroid tissues (P < 0.05). Furthermore, expression was associated with the tumor size, lymph node metastasis, and advanced disease stage. Immunohistochemical results showed that there was no correlation between ZNF703 protein levels and BRAF V600E mutation. The human PTC cell line K1, which has a BRAF V600E mutation, was selected for further investigation. Using small interfering RNA (siRNA), ZNF703 was shown to contribute to the proliferation, apoptosis, and invasion of K1 cells. ZNF703-siRNA downregulated E2F1 and MMP9 protein expression and enhanced the expression of p27 protein (P < 0.05), but had no effects on BRAF V600E protein levels. These results suggest that ZNF703 may be of potential use as a new marker for PTC prognosis and therapy that functions independent of BRAF V600E expression.

Silencing of zinc finger protein 703 inhibits medullary thyroid carcinoma cell proliferation in vitro and in vivo.

Zinc finger protein 703 (ZNF703) is a new member of the zinc finger protein family of transcription factors that plays an important role during embryogenesis in metazoans. The overexpression of ZNF703 contributes to tumorigenesis and progression of a number of malignancies by activating the Akt/mammalian target of rapamycin (mTOR) signaling pathway. This pathway is activated in medullary thyroid cancer (MTC), but its mechanism of action is not yet fully understood. The aim of the present study was to examine the role of ZNF703 and its association with Akt/mTOR activation in MTC. The present study used the phosphorylation of Akt1 protein at serine 473 (pAkt473) as an indicator of signaling activation. Immunohistochemistry (IHC) staining and western blot analyses were performed in order to examine the expression of ZNF703 in 34 cases of MTC and 12 cases of corresponding normal thyroid tissues. ZNF703 expression in MTC was significantly higher compared with the corresponding normal thyroid tissues (P<0.05). Furthermore, expression of ZNF703 was associated with tumor size, lymph node metastasis and advanced stage of disease. IHC also demonstrated that the level of ZNF703 was positively correlated with p-Akt473 in the 34 cases of MTC. The human MTC cell line TT was selected for further investigation as TT cells exhibit Akt/mTOR activation. The biological effects of silencing ZNF703 in TT cells on proliferation and apoptosis, both in vitro and in vivo were investigated in the present study. ZNF703 silencing inhibited the proliferation of TT cells in vitro and inhibited xenograft tumor growth in vivo. These effects were accompanied by the substantial decrease of pAkt473 and the induction of p53 protein. These results demonstrate that ZNF703 may play a relevant role in MTC due to its association with the Akt/mTOR signaling pathway.

MicroRNA­16/VEGFR2/p38/NF­κB signaling pathway regulates cell growth of human pituitary neoplasms.

The association of microRNA (miRNA) with tumor has gradually become an active medical research field, since its discovery in 1993. The aim of the present study was to clarify how microRNA­16 expression affects the proliferation and survival of pituitary tumor, revealing its potential mechanism. MicroRNA­16 expression of pituitary tumor patients was observably declined, compared with the normal group. A high expression of microRNA­16 showed longer survival in pituitary tumor patients, compared to a low expression of microRNA­16 in pituitary tumor patients. MicroRNA­16 upregulation effectively decreased cell proliferation and induced apoptosis in HP75 cells. MicroRNA­16 overexpression effectively induced p27, Bax protein expression and caspase­3/8 activities, and suppressed phosphorylation-(p)-p38, NF­κB, MMP­9 and VEGFR2 protein expression in HP75 cells. After VEGFR2 suppression, the effects of microRNA­16 overexpression on cell proliferation and apoptosis were significantly inhibited in HP75 cells. Moreover, the effects of microRNA­16 overexpression on p27, Bax protein expression and caspase­3/8 activities were significantly decreased in HP75 cells after p38 suppression. VEGFR2 or NF­κB suppression reduced the effects of microRNA­16 overexpression on p­p38, NF­κB, MMP­9 and VEGFR2 protein expression inhibition in HP75 cells. Our results suggest that microRNA­16 expression affects the proliferation and angiogenesis of pituitary cancer through the VEGFR2/p38/NF­κB signaling pathway.

Efficacy and safety of tangshen formula on patients with type 2 diabetic kidney disease: a multicenter double-blinded randomized placebo-controlled trial.

BACKGROUND: Persons with diabetes are at high risk of developing diabetic kidney disease (DKD), which is associated with high morbidity and mortality. Current drug therapies for DKD, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are not entirely satisfactory. This study aimed to evaluate the additional benefit and safety of the Chinese herbal granule Tangshen Formula (TSF) in treating DKD. METHODS: The study was designed as a six-center randomized, double-blind, placebo-controlled trial. From April 2007 through December 2009, 180 patients with DKD were enrolled. In addition to conventional treatment with ACEIs or ARBs, 122 participants were randomly assigned to receive TSF and 58 participants to receive placebo for 24 weeks. Primary outcome was urinary protein level, measured by urinary albumin excretion rate (UAER) for participants with microalbuminuria, 24-hour urinary protein (24h UP) for participants with macroalbuminuria. Secondary outcomes included renal function, serum lipids, quality of life, symptoms, and adverse events. FINDINGS: After 24 weeks of treatment, no statistically significant difference in UAER (TSF -19.53 µg/min compared with placebo -7.01 µg/min, with a mean difference of -12.52 µg/min; 95%CI, -68.67 to 43.63, P = 0.696) was found between TSF and placebo groups. However, TSF displayed a statistically significant decrease in 24h UP (TSF-0.21 g compared with placebo 0.36 g, with a mean difference of -0.57g; 95%CI, -1.05 to -0.09, P = 0.024). Estimated glomerular filtration rate (eGFR) was improved in both patients with microalbuminuria and macroalbuminuria, with a mean difference of 15.51 ml/min/1.73 m2 (95%CI, 3.71 to 27.31), 9.01 ml/min/1.73 m2 (95%CI, -0.10 to 18.13), respectively. Other secondary outcomes showed no statistically significant difference between groups or in the incidence of adverse events. CONCLUSIONS: Based on conventional treatments, TSF appears to provide additional benefits compared with placebo in decreasing proteinuria and improving eGFR in DKD patients with macroalbuminuria. Nevertheless, further study is needed to evaluate TSF treating patients with microalbuminuria. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-10000843.

[The relationship of angiotensin I-converting enzyme gene polymorphism with diabetic retinopathy and diabetes myocardial infarction].

OBJECTIVE: To investigate the relationship of angiotensin I-converting enzyme (ACE) gene polymorphism to diabetic retinopathy and diabetes myocardial infarction. METHODS: ACE insertion/deletion(I/D) polymorphism was determined by PCR. RESULTS: No evidence showed that ACE gene was associated with diabetic retinopathy. By comparison of the type 2 diabetes patients with myocardial infarction versus those without-myocardial infarction, it was found that the frequencies of homozygote DD (41.2% versus 33.2%) and of allele D (64.7% versus 55.0%) increased remarkably; the difference was statistically significant (P<0.05). CONCLUSION: Allele D(RR=1.50) and genotype DD(RR=1.33) seemed to be a genetic risk factor for type 2 diabetes myocardial infarction.

TPX2 overexpression in medullary thyroid carcinoma mediates TT cell proliferation.

TPX2 (targeting protein for xenopus kinesin-like protein 2), a microtubule-associated protein, plays an important role in the formation of the mitotic spindle. Abnormal expression of TPX2 in various types of malignant tumors has been reported, but less is known for medullary thyroid cancer (MTC). We investigated the expression of TPX2 in human MTC tissues and its potential use as a therapeutic target. Immunohistochemical analysis of TPX2 expression was performed for 32 cases of MTC and 8 cases of normal thyroid. TPX2 expression was found to be significantly higher in MTC compared to normal thyroid tissues (P < 0.05), and to be associated with tumor size, lymph node metastasis, and advanced disease stage. The cellular effects of TPX2 knockdown, including cell proliferation, apoptosis, cell cycle diffusions, and mitotic gene expression were investigated using small interfering RNA (siRNA). TPX2-siRNA caused G1 and G2-phase cell cycle arrest, inhibited cell proliferation, and induced apoptosis. TPX2-siRNA also downregulated Aurora-A and cyclinB1 protein expression in MTC cells and enhanced the expression of p53 protein (P < 0.05). These results suggest that TPX2 may be of potential use as a new marker for MTC prognosis and therapy.

Clinical significance of mannose-binding lectin expression in thyroid carcinoma tissues.

Mannose-binding lectin (MBL) plays an important role in the host defence against pathogens and carcinogenesis. This study aimed to analyze differential expression of MBL protein in thyroid cancer tissues and then to investigate the effects of rhMBL in thyroid cancer cells. Tissue specimens from 45 thyroid carcinoma patients and 45 adenoma patients were recruited for immunohistochemical analysis of MBL expression. Cell viability, apoptosis, RT-PCR and Western blot assays were used to detect changes in tumor cell viability, apoptosis, and gene expression, respectively, after treatment of thyroid cancer cells with rhMBL. MBL was differentially expressed in papillary thyroid carcinoma, adenoma, and the distant normal tissues (0.322 ± 0.008, 0.227 ± 0.003, and 0.113 ± 0.003, respectively, P < 0.05). MBL expression was associated with the advanced disease stage, histological grade, or lymph node metastasis in cancer patients (P < 0.05). Moreover, rhMBL treatment of thyroid cancer cells reduced tumor cell viability but induced apoptosis in a dose- and time-dependent manner. rhMBL treatment also downregulated Bcl2 protein expression in thyroid cancer cells (P < 0.05). In addition, expression p53 protein was increased in thyroid cancer cells after rhMBL treatment (P < 0.05). The data from the current study demonstrate that MBL overexpression is associated with advanced thyroid carcinomas, and rhMBL treatment significantly reduced viability but induced apoptosis of thyroid cancer cell lines. Further studies will clarify whether overexpressed MBL in thyroid cancer tissues is functional.

CCNG2 suppressor biological effects on thyroid cancer cell through promotion of CDK2 degradation.

This study aimed to analyze the expression and clinical significance of cyclin G2 (CCNG2) in thyroid carcinoma and the biological effects of CCNG2 overexpression in a cell line. Immunohistochemistry and Western blotting were used to analyze CCNG2 protein expression in 63 cases of thyroid cancer and normal tissues to allow the relationship with clinical factors to be assessed. CCNG2 lentiviral and empty vectors were transfected into the thyroid cancer K1 cell line. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were applied to detect the mRNA and protein levels of CCNG2. MTT assay and cell cycle were also conducted to assess the influence of up-regulated expression of CCNG2 on K1 cell biology. The level of CCNG2 protein expression was found to be significantly lower in thyroid cancer tissue than normal tissues (P<0.05). Western blot: The relative amount of CCNG2 protein in thyroid cancer tissue was respectively found to be significantly lower than in normal tissues (P<0.05), correlating with lymph node metastasis, clinic stage and histological grade (P<0.05), but not gender, age or tumor size (P>0.05). Loss of CCNG2 expression correlated significantly with poor overall survival time on Kaplan-Meier analysis (P<0.05). The results for biological functions showed that K1 cell transfected CCNG2 had a lower survival fraction, a greater percentage in the G0/G1 phases, and lower cyclin-dependent kinase 2 (CDK2) protein expression compared with K1 cells non-transfected with CCNG2 (P<0.05). CCNG2 expression decreased in thyroid cancer and correlated significantly lymph node metastasis, clinic stage, histological grade and poor overall survival, suggesting that CCNG2 may play important roles as a negative regulator in thyroid cancer K1 cells by promoting degradation of CDK2.

Association between manganese superoxide dismutase gene polymorphism and breast cancer risk: a meta-analysis of 17,842 subjects.

The aim of this meta-analysis was to explore the association between the manganese superoxide dismutase (MnSOD) gene polymorphism and breast cancer risk, and to investigate the interaction of this gene polymorphism with known risk factors for breast cancer. Crude odds ratios (ORs) with 95% confidence intervals (CIs) for breast cancer risk associated with co-dominant models [valine/alanine (Val/Ala) vs. Val/Val, Ala/Ala vs. Val/Val], a dominant model (Val/Ala + Ala/Ala vs. Val/Val) and a recessive model (Ala/Ala vs. Val/Ala + Val/Val) were statistically estimated. This meta­analysis included 8,102 breast cancer cases and 9,740 controls from 14 published case-control studies. The data revealed no significant association between the MnSOD polymorphism and the risk of developing breast cancer. However, upon subgroup analyses, the risk was significantly increased in premenopausal women with the dominant model of the MnSOD gene polymorphism (OR, 1.15; 95% CI, 1.01-1.31). Statistically significant increased risks were also identified in women with the MnSOD genotypes containing the Ala allele who had a tobacco smoking history (OR, 1.17; 95% CI, 1.02-1.34), a higher body mass index (OR, 1.26; 95% CI, 1.02-1.56) or who used oral contraceptives (OR, 1.98; 95% CI, 1.34-2.93). By contrast, there was no significant association between breast cancer risk and alcohol consumption and ethnicity. This meta­analysis demonstrated no statistically significant association between the MnSOD gene polymorphism and breast cancer susceptibility, except in premenopausal women with certain unhealthy lifestyle habbits.