Bidirectional Genetic Control of Phenotypic Heterogeneity and Its Implication for Cancer Drug Resistance.

Negative genetic regulators of phenotypic heterogeneity, or phenotypic capacitors/stabilizers, elevate population average fitness by limiting deviation from the optimal phenotype and increase the efficacy of natural selection by enhancing the phenotypic differences among genotypes. Stabilizers can presumably be switched off to release phenotypic heterogeneity in the face of extreme or fluctuating environments to ensure population survival. This task could, however, also be achieved by positive genetic regulators of phenotypic heterogeneity, or "phenotypic diversifiers," as shown by recently reported evidence that a bacterial divisome factor enhances antibiotic resistance. We hypothesized that such active creation of phenotypic heterogeneity by diversifiers, which is functionally independent of stabilizers, is more common than previously recognized. Using morphological phenotypic data from 4,718 single-gene knockout strains of Saccharomyces cerevisiae, we systematically identified 324 stabilizers and 160 diversifiers and constructed a bipartite network between these genes and the morphological traits they control. Further analyses showed that, compared with stabilizers, diversifiers tended to be weaker and more promiscuous (regulating more traits) regulators targeting traits unrelated to fitness. Moreover, there is a general division of labor between stabilizers and diversifiers. Finally, by incorporating NCI-60 human cancer cell line anticancer drug screening data, we found that human one-to-one orthologs of yeast diversifiers/stabilizers likely regulate the anticancer drug resistance of human cancer cell lines, suggesting that these orthologs are potential targets for auxiliary treatments. Our study therefore highlights stabilizers and diversifiers as the genetic regulators for the bidirectional control of phenotypic heterogeneity as well as their distinct evolutionary roles and functional independence.

Genome-Wide Analysis of DCL, AGO, and RDR Gene Families in Pepper (Capsicum Annuum L.).

RNA silencing is an evolutionarily conserved mechanism that regulates variety of cellular processes in plants. Argonaute protein (AGO), Dicer-like protein (DCL) and RNA-dependent RNA polymerase (RDR) are critical components of RNA silencing. These efficient and indispensable components of the RNAi pathway have not been identified and characterized in pepper. In this study, we identified 12 CaAGO, 4 CaDCL and 6 CaRDR genes in pepper and compared them with those of Arabidopsis, tobacco, potato and tomato. Detailed phylogenetic analyses revealed that each CaAGO, CaDCL and CaRDR protein family were classified into four clades. The tissue specific expression and respond to abiotic or biotic stress were studied. The real-time quantitative polymerase chain reaction (PCR) results demonstrated that CaAGO2, CaAGO10b, CaDCL2 and CaDCL4 were upregulated with cucumber mosaic virus (CMV), potato virus Y (PVY) and tobacco mosaic virus (TMV) infections, whereas they showed difference expression patterns in response to abiotic stress. In addition, we found that many of the candidate genes were induced by phytohormones and H2O2 treatment. Our results provide useful information for further elucidation of gene silencing pathways and RNAi-mediated host immunity in pepper.

Bone marrow-derived mesenchymal stem cells induced by inflammatory cytokines produce angiogenetic factors and promote prostate cancer growth.

BACKGROUND: Prostate is susceptible to infection and pro-inflammatory agents in a man's whole life. Chronic inflammation might play important roles in the development and progression of prostate cancer. Mesenchymal stem cells (MSCs) are often recruited to the tumor microenvironment due to local inflammation. We have asked whether stimulation of MSCs by pro-inflammatory cytokines could promote prostate tumor growth. The current study investigated the possible involvement of MSCs stimulated by pro-inflammatory cytokines in promotion and angiogenesis of prostate cancer through relative pathway in vitro and in vivo. METHODS: A syngeneic mouse model of C57 was established. The murine prostate cancer cells (RM-1) mixing with MSCs treated with tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) or vehicle were subcutaneously injected into C57 mice. Tumor volume of C57 mouse model was estimated and serum level of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) was test by Enzyme-linked Immunosorbent Assay (ELISA). A hen egg test-chorioallantoic membrane (HET-CAM) assay was applied to test the effect of conditioned media of stimulated MSCs in chorioallantoic membrane angiogenesis. Short interfering RNA (siRNA) knocked down either hypoxia-inducible factor-1alpha (HIF-1α) or nuclear factor-erythroid-2-related factor 2 (NRF2) were employed. mRNA of PDGF and VEGF in MSCs, as well as NRF2 and HIF-1α was test by Real time polymerase chain reaction (PCR) analyses. Protein expression levels of PDGF and VEGF from conditioned medium, NRF2, HIF-1α, as well as PDGF and VEGF in MSCs were detected by Western blot analysis. RESULTS: MSCs treated with TNF-α and IFN-γ promote tumor growth in C57 syngeneic mouse model, correlating with increased serum level of PDGF, VEGF. HET-CAM assay shows the angiogenic effect of conditioned medium of MSCs pre-treated with the pro-inflammatory cytokines. mRNA and protein levels of two pro-angiogenic factors (PDGF and VEGF) and key hypoxia regulators (HIF-1α and NRF2) in MSCs were induced after MSCs' pretreatment. siRNA knockdown either HIF-1α or NRF2 results reduction of PDGF and VEGF expression. CONCLUSIONS: MSCs stimulated by pro-inflammatory cytokines increase the expression of PDGF and VEGF via the NRF2-HIF-1α pathway and accelerate prostate cancer growth in mice.

Effects of concurrent chemoradiotherapy with or without Endostar on the regression of retropharyngeal lymph node and prognosis of patients with locally advanced nasopharyngeal carcinoma: a retrospective study.

BACKGROUND AND PURPOSE: To investigate the effect of combining Endostar with concurrent chemoradiotherapy (ECCRT) compared to concurrent chemoradiotherapy (CCRT) on the regression rate of retropharyngeal lymph nodes (RLNs) and the relationship between regression rate of RLNs and prognosis of patients with locally advanced nasopharyngeal carcinoma (LANPC). METHODS: A total of 122 LANPC patients with RLNs metastasis were included. Metastatic RLNs were delineated both before and after treatment slice by slice on the magnetic resonance images cross-section. The regression rate of RLNs, adverse effects (AE) were evaluated. The median regression rate of RLNs was taken as the cut-off value, and the patients were furtherly divided into high regression rate (HRR) group and low regression rate (LRR) group, then survival times were evaluated. RESULTS: The median regression rates of RLNs in the ECCRT and CCRT groups were 81% and 50%, respectively (P < 0.001). There was no statistically significant difference in the incidence of grade 3/4 AEs between the two groups, except for oral mucositis (ECCRT 26.23% vs. CCRT 44.26%, P = 0.037). The 3-year overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and locoregional failure-free survival (LRFFS) rates in the HRR and LRR groups were 85.48% and 86.67% (P = 0.983), 80.65% and 68.33% (P = 0.037), 83.87% and 85% (P = 0.704), 93.55% and 81.67% (P = 0.033), respectively. CONCLUSIONS: Patients in the ECCRT group had higher regression rates of RLNs and lower incidence of severe oral mucositis. Furthermore, patients in the HRR group had a better 3-year PFS and LRFFS rate than those in the LRR group.

Rising incidence of obesity-related cancers among younger adults in China: A population-based analysis (2007-2021).

BACKGROUND: Developing countries face an "obesity epidemic," particularly affecting children and younger adults. While obesity is a known risk factor for 12 types of cancer, primarily affecting older populations, its impact on younger generations is understudied. METHODS: This study analyzed data from a population-based cancer registry covering 14.14 million individuals in China (2007-2021). We compared the incidence of obesity- and non-obesity-related cancers and applied an age-period-cohort model to estimate their impacts. FINDINGS: Among 651,342 cancer cases, 48.47% were obesity related. The age-standardized incidence rates (ASRs) of the 12 obesity-related cancers increased annually by 3.6% (p < 0.001), while ASRs for non-obesity-related cancers remained stable. Obesity-related cancers surged among younger adults, with rates rising across successive generations. The annual percentage of change decreased with age, from 15.28% for ages 25-29 years to 1.55% for ages 60-64 years. The incidence rate ratio for obesity-related cancer was higher in younger generations compared to those born in 1962-1966. We predict that the ASR for obesity-related cancers will nearly double in the next decade. CONCLUSIONS: The rising incidence of obesity-related cancers among young adults poses a significant public health concern. The increasing cancer burden underscores the need for targeted interventions to address the obesity epidemic. FUNDING: This work was supported by the National Natural Science Foundation of China (81930019, 82341076) to J.-K.Y.

Predictive value of DNA methylation in the efficacy of chemotherapy for gastric cancer.

Background: Gastric cancer (GC) is one of the most common causes of cancer-related death. Drug resistance in chemotherapy often occurs in patients with GC, leading to tumor recurrence and poor survival. DNA methylation is closely related to the development of cancer. Methods: To investigate the role of DNA methylation in chemotherapy resistance in GC patients, we conducted a comprehensive analysis using DNA methylation data and survival information obtained from The Cancer Genome Atlas. Univariate Cox analysis was performed to screen for differential DNA methylation of chemotherapy response in patients who did and did not receive chemotherapy. Multivariate Cox analysis was then performed to identify the independent prognostic genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were used to explore the biological function of the signature genes. Results: Patients receiving adjuvant chemotherapy for GC survived longer. 308 differentially methylated genes were demonstrated to be associated with prognosis. Six genes were optimally chosed for establisehing the risk model, including C6orf222, CCNL1, CREBZF, GCKR, TFCP2, and VIPR2. It was constructed based on the DNA methylation levels of these six genes: risk score = 0.47123374*C6orf222 + 9.53554803*CCNL1 + 10.40234138* CREBZF + 0.07611856* GCKR + 18.87661557*TFCP2 - 0.46396254* VIPR2. According to the risk score, patients receiving chemotherapy were divided into high- and low-risk groups, and the prognosis of the two groups was compared. The high-risk group had a shorter survival; however, this association was not present in patients without chemotherapy. The accuracy and predictive efficacy of the risk score in predicting the 1-, 3-, and 5-year survival of patients was evaluated with the receiver operating characteristic curve. In patients receiving chemotherapy, the area under the curve of the risk score for 1-, 3-, and 5-year survival was 0.841, 0.72, and 0.734, respectively. In patients who did not receive chemotherapy, the area under the curve was 0.406, 0.585, and 0.585, respectively. A nomogram model was constructed based on the risk score and clinical indicators. The model showed good consistency in the predicted probabilities and actual probabilities. Gene Ontology functional enrichment of these candidate methylated genes showed the following molecular functions: RNA binding, protein binding, mRNA binding, and nucleic acid binding; that they were mediated mainly through the following cell components: nuclear speck, nucleoplasm, nucleus, catalytic step 2 spliceosome, and the transcription factor AP-1 complex; and that they were involved in the following biological processes: mRNA processing, mRNA splicing, and RNA polymerase II promoter transcription. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment results revealed that the signaling pathways mainly enriched were transcriptional misregulation in cancer, spliceosome, and the IL-17 signaling pathway. Conclusion: Our work identifies a six DNA methylated expression signature as a promising biomarker of chemo-resistance in GC, which provides new insights into the development of new strategies to overcome chemo-resistance in GC.

A retrospective cohort study on the efficacy and safety for combination therapy of immunotherapy, targeted agent, and chemotherapy versus immunochemotherapy or chemotherapy alone in the first-line treatment of advanced biliary tract carcinoma.

Background: A paucity of effective treatment for biliary tract carcinoma (BTC) has necessitated the investigation into new therapies. As combinations of targeted therapy with immunotherapy are well-established in hepatocellular carcinoma, the GEMOX chemotherapy (gemcitabine and oxaliplatin) is the standard treatment for BTC. This study aimed to evaluate the efficacy and safety of immunotherapy in combination with targeted agent and chemotherapy in advanced BTC. Methods: Patients who were pathologically identified advanced BTC and had received gemcitabine-based chemotherapy alone or in combination with anlotinib, and/or anti-programmed cell death protein-1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors such as camrelizumab as first-line treatment were retrospectively screened from The First Affiliated Hospital of Guangxi Medical University from February 2018 to August 2021. The outcomes included objective response rate (ORR), median overall survival (OS), and median progressive-free survival (PFS). Adverse events (AEs) were assessed according to the NCI-CTCAE v. 4.03. Patients were followed up weekly. Results: A total of 35 patients were enrolled in this study: 11 patients treated with PD-1/PD-L1 inhibitor plus anlotinib and gemcitabine (arm A), 12 patients with the GEMOX combined with PD-1/PD-L1 inhibitor (arm B), and 12 patients with GEMOX (arm C). With a median follow-up time of 31.9 months (range, 23.8-39.7 months), the median OS was 16.8 months [95% confidence interval (CI): 7.0-not reached], 11.8 months (95% CI: 7.2-31.7 months), and 11.6 months (95% CI: 7.3-18.0 months) in arms A, B, and C, respectively (P=0.298). The median PFS was 16.8 months (95% CI: 7.0-NR), 6.0 months (95% CI: 5.1-8.7 months), and 6.3 months (95% CI: 4.6-7.0 months) in arms A, B, and C, respectively. The ORR were 63.6% in arm A, 33.3% in arm B, and 25.0% in arm C. AEs of all grades occurred in 33 (94.3%) patients. Grade 3-4 AEs in all patients included neutrophil count decrease (14.3%), aspartate aminotransferase increase (8.6%), alanine aminotransferase increase (8.6%), fatigue (5.7%), and blood bilirubin increase (5.7%). Conclusions: Anti-PD-1/PD-L1 immunotherapy in combination with anlotinib and gemcitabine showed promising efficacy and an acceptable safety profile for the BTC patients included in this study.

Association between Covid-19 vaccination and incidence of type 1 diabetes in China: Evidence from 14.14 million registered residents between 2007 and 2021.

AIMS: Reports have suggested that COVID-19 vaccination may cause Type 1 diabetes (T1D), particularly fulminant T1D (FT1D). This study aimed to investigate the incidence of T1D in a general population of China, where>90% of the people have received three injections of inactivated SARS-Cov-2 vaccines in 2021. METHODS: A population-based registry of T1D was performed using data from the Beijing Municipal Health Commission Information Center. Annual incidence rates were calculated by age group and gender, and annual percentage changes were assessed using Joinpoint regression. RESULTS: The study included 14.14 million registered residents, and 7,697 people with newly diagnosed T1D were identified from 2007 to 2021. T1D incidence increased from 2.77 in 2007 to 3.84 per 100,000 persons in 2021. However, T1D incidence was stable from 2019 to 2021, and the incidence rate did not increase when people were vaccinated in January-December 2021. The incidence of FT1D did not increase from 2015 to 2021. CONCLUSIONS: The findings suggest that COVID-19 vaccination did not increase the onset of T1D or have a significant impact on T1D pathogenesis, at least not on a large scale.

[Hospitalization rates for coronary heart disease from 2007 to 2009 in Beijing].

OBJECTIVE: To examine the distribution and trends of hospitalization rates for coronary heart disease (CHD) from 2007 to 2009 in Beijing. METHODS: We calculated hospitalization rates for CHD using data from Beijing Hospital Discharge Information System. Information of census registered population in Beijing was obtained from Beijing Municipal Bureau of Statistics. CHD includes acute myocardial infarction, unstable angina and other forms of CHD. Age-standardized hospitalization rates for CHD per 100 000 population aged 25 years or more were calculated. RESULTS: During 2007 - 2009, a total of 248 049 patients aged 25 years or more hospitalized in Beijing with the primary discharge diagnosis of CHD were enrolled, of whom 73.7% were permanent registered Beijing citizens. The average hospitalization rate for CHD in 2007 - 2009 was 651.2/100 000 for the permanent residences in Beijing (741.2/100 000 in men, 560.9/100 000 in women). The highest average hospitalization rate (671.9/100 000) was seen in exurban area compared to other areas in Beijing. The average hospitalization rate for acute myocardial infarction, unstable angina, and other CHD was 126.4/100 000, 226.4/100 000 and 298.4/100 000, respectively. The hospitalization rate for CHD increased 18.1% from 2007 to 2009 (from 598.1/100 000 to 706.5/100 000). The same trend was seen in women (20.2%) and men (16.6%). The hospitalization rates of CHD in the urban, suburban, and exurban areas of Beijing all increased in the three years, and the greatest increase (36.6%) was found in exurban area. Hospitalization rates of acute myocardial infarction and unstable angina increased 24.5% and 55.3%, respectively, in the three years, while hospitalization rates of other CHD decreased 5.7%. CONCLUSIONS: The hospitalization rate of CHD is higher in men than in women in Beijing. The hospitalization rates for CHD increased from the observation period, especially in those living in exurban area. Awareness of the magnitudes and trends of CHD hospitalization rates is of great importance in evaluating the burden of cardiovascular disease, allocating and utilizing health care resources, and estimating the health insurance for Beijing.

[Surveillance on the incidence of acute coronary events in the permanent residents of Beijing aged 25 years and more from 2007 to 2009].

OBJECTIVE: To survey the incidence of acute coronary events and its trend in three years, and explore the distribution of the incidence across Beijing residents aged 25 years and more from 2007 to 2009. METHODS: The present study incorporated and linked the routinely collected data from the Hospital Discharge Information System and Cause of Death Register System in Beijing, estimated the incidence of acute coronary events, and analyzed the distribution of the incidence across gender, age groups and regions. Acute coronary event was defined as non-fatal myocardial infarction and death from coronary heart disease. Numbers of residents by age, gender and area were obtained from the Beijing Statistics Bureau. RESULTS: A total of 68 390 acute coronary events were identified among permanent residents of Beijing aged 25 years and more from 2007 to 2009. The age-standardized incidence was 166.4 per 100 000 people in overall population, with 218.5 in males and 115.2 in females. The age-standardized incidence was 144.3, 154.7, and 195.8 per 100 000 people in urban, suburban, and exurban area, respectively. The incidence was the highest in Huairou district (263.8 per 100 000), while was the lowest in Haidian district (121.5 per 100 000). The age-standardized incidence was 158.4, 169.4, and 171.2 per 100 000 in 2007, 2008, and 2009, respectively. The age-standardized incidence increased by 8.1% in 2009 compared to 2007, increase in men (11.1%) was greater than in women (2.5%). The incidence increased significantly with age in each year. The incidence raised by 30.3% in 2009 compared to 2007 for men aged 35 - 44 years. In 2009, the incidence was 146.7, 155.9, and 207.4 per 100 000 people in urban, suburban, and exurban area, respectively. The rates increased by 3.2% in both urban and suburban areas, and 16.4% in exurban areas in 2009 compared to 2007. CONCLUSION: The incidence of acute coronary events increased from 2007 to 2009 among the permanent residents of Beijing aged 25 years and over, especially in young men, and people living in the exurban areas.

Speckle Noise Algorithm-Based Ultrasound Imaging in Evaluating the Therapeutic Effect of Blood Purification on Children with Kidney Failure and Analysis of Its Correlation with Serum Inflammatory Factor Levels.

The study focused on the therapeutic effect of clinical treatment on urinary calculi with kidney failure and its relationship with the serum inflammatory factor levels. 90 children with melamine urinary calculi were selected as research subjects. Of them, 52 cases were in group 1 (nonrenal failure), and 38 cases were in group 2 (combined with renal failure). In addition, 35 hospitalized children with no history of melamine-contaminated milk feeding during the same period were used as healthy controls. They all underwent ultrasound imaging examination based on the speckle noise algorithm, and the prognosis was analyzed. It was found that the peak signal-to-noise ratio (PSNR), structural similarity (SSIM), and local edge preservation index (EPI) of the algorithm in this study were significantly greater than other algorithms (P < 0.05). The admission age of the children in group 1 was significantly younger than that of group 2, the bilateral stone rate was significantly higher than that in group 2, and the difference was statistically significant (P < 0.05). Of the 52 children in group 1, the stone disappeared in 25 cases after treatment, the stone was reduced in 20 cases, and the stone remained unchanged in 7 cases. The total effective rate of treatment was 88.46%. Of the 38 cases in group 2, the stone disappeared in 22 cases after treatment, the stone was reduced in 12 cases, and the stone remained unchanged in 4 cases. The total effective rate of treatment was 89.47%. No difference was noted in blood urea nitrogen (BUN), blood creatinine (Cr), TNF-α, and C-reactive protein (CRP) levels in group 1, group 2, and the healthy control group (P > 0.05). Hence, the denoising algorithm in this study has better denoising effects on ultrasound images than traditional algorithms, with higher definition and less noise and artifacts. The clinical treatment of children with urinary calculi and renal failure is highly effective, the renal function and serum inflammatory factor levels return to the normal range, and the inflammatory response is weakened.

Advances in postoperative adjuvant therapy for primary liver cancer.

Hepatocellular carcinoma (HCC) is a highly heterogeneous, invasive, and conventional chemotherapy-insensitive tumor with unique biological characteristics. The main methods for the radical treatment of HCC are surgical resection or liver transplantation. However, recurrence rates are as high as 50% and 70% at 3 and 5 years after liver resection, respectively, and even in Milan-eligible recipients, the recurrence rate is approximately 20% at 5 years after liver transplantation. Therefore, reducing the postoperative recurrence rate is key to improving the overall outcome of liver cancer. This review discusses the risk factors for recurrence in patients with HCC radical surgical resection and adjuvant treatment options that may reduce the risk of recurrence and improve overall survival, including local adjuvant therapy (e.g., transcatheter arterial chemoembolization), adjuvant systemic therapy (e.g., molecular targeted agents and immunotherapy), and other adjuvant therapies (e.g., antiviral and herbal therapy). Finally, potential research directions that may change the paradigm of adjuvant therapy for HCC are analyzed.

Efficacy and Safety of First-Line Chemotherapies for Patients With Advanced Biliary Tract Carcinoma: A Systematic Review and Network Meta-Analysis.

BACKGROUND: At present, chemotherapy is still the primary treatment for advanced biliary tract carcinoma, but it is challenging to balance the efficacy and side effects. Network meta-analysis (NMA) is a better way to identify the protocol, and the advantage is that it can be combined with direct and indirect evidence to judge the best treatment regimens. Therefore, we conducted NMA on the searched randomized controlled trials (RCTs). METHODS: NMA was conducted regarding the searched RCTs by comparing progression-free survival (PFS), overall survival (OS), objective remission rates (ORRs), and adverse events (AEs) of different chemotherapy protocols. RESULTS: We screened 24 studies that met the inclusion criteria for further analysis. Compared with other regimens, the best supportive care (BSC) or FUFA protocol has a worse OS. Folfox4, GEMOX+erlotinib, and C+GEMOX can improve patients' PFS compared with BSC. Patients receiving GP+cediranib protocol have higher ORRs. There was reduced neutropenia grade ≥3 when adopting GP+cediranib, GS, C+GEMOX, RAM+GP, and MER+GP than when using FUFA protocol. The probability of vomiting of XELOX is lower than that of GEM+XELOX. There is a lower diarrhea incidence of XELOX than that of GEMOX+erlotinib. The results of cluster grade analysis illustrated that GEMOX+erlotinib owned a higher ORR and a higher surface under the cumulative ranking (SUCRA) of neutropenia and vomiting but also had a lower SUCRA of diarrhea and fatigue. Meanwhile, both GEMOX and C+GEMOX have a better ORR and a higher AE SUCRA. CONCLUSION: The NMA demonstrated that chemotherapy combined with targeted therapy has better efficacy and lower incidence of AEs than chemotherapy alone.

Incidence of Type 1 Diabetes May Be Underestimated in the Chinese Population: Evidence From 21.7 Million People Between 2007 and 2017.

OBJECTIVE: Previous reports of the annual incidence of type 1 diabetes (T1D) in China were conducted using retrospective hospital cases, which may not reflect the reality. This longitudinal study estimated T1D incidence in a Chinese population of 21.7 million from 2007 to 2017. RESEARCH DESIGN AND METHODS: A population-based registry of T1D was performed by the Beijing Municipal Health Commission Information Center. Annual incidence and 95% CIs were calculated by age group and sex. The association of sex with T1D incidence and predicted new cases of T1D were assessed using Poisson regression models. Annual percentage change and average annual percentage of change were assessed using Joinpoint regression. RESULTS: Overall, there were 6,875 individuals who developed T1D from 2007 to 2017 in this population. T1D incidence (/100,000 persons) (95% CI) significantly increased from 2.72 (2.51, 2.93) in 2007 to 3.60 (3.38, 3.78) in 2017 (P < 0.001). The T1D onset peak was in the 10-14-year-old age group. While no significant trend was found in the 0-14- and 15-29-year-old age groups, T1D incidence markedly increased from 1.87 to 3.52 in the ≥30-year-old age group (P < 0.05). The prevalence of diabetic ketoacidosis at diagnosis was highest in the 0-4-year-old age group. We predicted new cases of T1D will increase 1.57-fold over the next decade. CONCLUSIONS: T1D incidence in this large Chinese population is higher than has been reported previously. From 2007 to 2017, although the incidence peak was in the 10-14-year age group, the T1D incidence increased sharply in adults but not in youth.

Identification of high expression profiles of miR-31-5p and its vital role in lung squamous cell carcinoma: a survey based on qRT-PCR and bioinformatics analysis.

BACKGROUND: The function of miR-31-5p in lung squamous cell carcinoma (LUSC) remains unclear, therefore, a systematic study was performed for the clinical significance and molecular mechanism of miR-31-5p in LUSC. METHODS: Quantitative real-time reverse transcription PCR (qRT-PCR) was utilized to test the expression level of miR-31-5p in 88 LUSC tissue samples and their matching normal tissues. Data from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were also utilized to confirm the expression level and clinical value of miR-31-5p in LUSC. The potential target genes of miR-31-5p were predicted by several online predicted software. Gene ontology (GO), protein-protein interaction (PPI) and pathway analysis were utilized to investigate the underlying molecular mechanism of miR-31-5p in LUSC. RESULTS: The result from qRT-PCR found that there was significant difference of miR-31-5p between LUSC and normal tissues (P<0.001). Meanwhile, Data from TCGA also showed a higher expression of miR-31-5p in LUSC tissues than that in the normal tissues (P<0.001). on the basis of the data of GEO database, five GEO datasets indicated that the expression of miR-31-5p in LUSC tissues was significantly higher than that in normal lung tissues, include GSE51858 (P=0.025), GSE74190 (P<0.000), GSE16025 (P=0.031), GSE25508 (P=0.0.01), and GSE47525 (P=0.049). Moreover, in consideration of the meta-analysis, 1,012 clinical specimens were systematically analyzed via meta-analysis, clinical specimens were systematically analyzed via meta-analysis, and the results showed that the expression of miR-31-5p in LUSC was significantly higher than in the adjacent lung tissues (SMD =0, CI: 1.08-1.45, Z=13.30, P=0.000). In addition, result from GO and pathway analyses showed that potential target genes of miR-31-5p were significantly associated with 20 GO terms and 5 pathways, such as signal transduction, transmembrane receptor protein tyrosine kinase activity, plasma membrane and Rap1 signaling pathway. Meanwhile, we also found thatmiR-31-5p target genes were related to the Rap1 signaling pathway, Oxytocin signaling pathway and Proteoglycans in cancer. Furthermore, six hub genes were identified from PPI and three hub genes, including ADCY6, ADCY9 and EGFR, proved to coexist in the Rap1 signaling pathway, oxytocin signaling pathway and Melanogenesis simultaneously. CONCLUSIONS: According to what has been discussed above, we speculated that miR-31-5p may play a vital role in the occurrence and development of LUSC.

[Effects of Panax notoginseng saponins on long-term potentiation in the CA1 region of the rat hippocampus].

Panax notoginseng saponins (PNS) are very important extracts from roots of medicinal herb Sanchi Ginseng which is highly regarded in China for its therapeutic ability to meliorate blood-circulation, anti-anoxia, improve memory, and anti-caducity effects. In this study, we used blind whole-cell voltage-clamp recordings to detect the effects of PNS on long-term potentiation (LTP) in the CA1 region of the hippocampus, and investigated the electrophysiological mechanisms underlying potentiating effects of PNS on learning and memory. Wistar rats (3-4 weeks) were decapitated and hippocampal slices (400 microm thick) were cut coronally. Excitatory postsynaptic currents (EPSCs) were recorded by patch clamp technique in whole-cell configuration. The Schaffer collateral/commissural pathway was stimulated by high frequency stimulation (HFS: 100 Hz) pulses to induce LTP. The findings showed that 0.1 - 0.4 g x L(-1) PNS significantly depressed the amplitude of EPSCs (P < 0.05) and had no facilitative effects on LTP of pyramidal neurons located in the CA1 region. PNS in the concentrations of 0.04 - 0.05 g x L(-1) did not appreciably affect the amplitude of EPSCs (P > 0.05) but markedly increased the amplitude of LTP (P < 0.05). In conclusion, 0.04 - 0.05 g x L(-1) PNS could facilitate LTP in the CA1 region of the rat hippocampus and it is reasonable to suggest that this action may contribute to its potentiating effects on learning and memory.

Transcriptomic Analysis Implies That GA Regulates Sex Expression via Ethylene-Dependent and Ethylene-Independent Pathways in Cucumber (Cucumis sativus L.).

Sex differentiation of flower buds is an important developmental process that directly affects fruit yield of cucumber (Cucumis sativus L.). Plant hormones, such as gibberellins (GAs) and ethylene can promote development of male and female flowers, respectively, however, the regulatory mechanisms of GA-induced male flower formation and potential involvement of ethylene in this process still remain unknown. In this study, to unravel the genes and gene networks involved in GA-regulated cucumber sexual development, we performed high throughout RNA-Seq analyses that compared the transcriptomes of shoot tips between GA3 treated and untreated gynoecious cucumber plants. Results showed that GA3 application markedly induced male flowers but decreased ethylene production in shoot tips. Furthermore, the transcript levels of M (CsACS2) gene, ethylene receptor CsETR1 and some ethylene-responsive transcription factors were dramatically changed after GA3 treatment, suggesting a potential involvement of ethylene in GA-regulated sex expression of cucumber. Interestingly, GA3 down-regulated transcript of a C-class floral homeotic gene, CAG2, indicating that GA may also influence cucumber sex determination through an ethylene-independent process. These results suggest a novel model for hormone-mediated sex differentiation and provide a theoretical basis for further dissection of the regulatory mechanism of male flower formation in cucumber. Statement: We reveal that GA can regulate sex expression of cucumber via an ethylene-dependent manner, and the M (CsACS2), CsETR1, and ERFs are probably involved in this process. Moreover, CAG2, a C-class floral homeotic gene, may also participate in GA-modulated cucumber sex determination, but this pathway is ethylene-independent.

CaRDR1, an RNA-Dependent RNA Polymerase Plays a Positive Role in Pepper Resistance against TMV.

RNA silencing functions as a major natural antiviral defense mechanism in plants. RNA-dependent RNA polymerases (RDRs) that catalyze the synthesis of double-stranded RNAs, are considered as a fundamental element in RNA silencing pathways. In Arabidopsis thaliana, RDR1, 2 and 6 play important roles in anti-viral RNA silencing. Expression of RDR1 can be elevated following plant treatment with defense hormones and virus infection. RDR1 has been studied in several crop species, but not in pepper (Capsicum annuum L.). Here, a RDR1 gene was isolated from Capsicum annuum L., designated as CaRDR1. The full-length cDNA of CaRDR1 was 3,351 bp, encoding a 1,116-amino acid protein, which contains conserved regions, such as the most remarkable motif DLDGD. The transcripts of CaRDR1 could be induced by salicylic acid (SA), abscisic acid (ABA), H2O2, and tobacco mosaic virus (TMV). Silencing of CaRDR1 in pepper resulted in increased susceptibility to TMV as evident by severe symptom, increased of TMV-CP transcript, higher malondialdehyde (MDA) content and lower antioxidant enzymes activities compared with that of control plants. CaRDR1-overexpressing in Nicotiana benthamiana showed mild disease symptom and reduced TMV-CP transcripts than that of empty vector (EV) following TMV inoculation. The RNA silencing related genes, including NbAGO2, NbDCL2, NbDCL3, and NbDCL4 elevated expression in overexpressed plants. Alternative oxidase (AOX), the terminal oxidase of the cyanide (CN)-resistant alternative respiratory pathway, catalyze oxygen-dependent oxidation of ubiquinol in plants. It has an important function in plant defense against TMV. In addition, CaRDR1 overexpression promoted the expression of NbAOX1a and NbAOX1b. In conclusion, these results suggest that CaRDR1 plays a positive role in TMV resistance by regulating antioxidant enzymes activities and RNA silencing-related genes expression to suppress the replication and movement of TMV.

MicroRNA-148a Acts as a Tumor Suppressor in Osteosarcoma via Targeting Rho-Associated Coiled-Coil Kinase.

MicroRNAs (miRs) have been demonstrated to be involved in the development and progression of osteosarcoma (OS), but the molecular mechanism still remains to be fully investigated. The present study investigated the function of miR-148a in OS, as well as its underlying mechanism. Our data showed that miR-148a was significantly downregulated in OS tissues compared to their matched adjacent normal tissues, and also in OS cell lines compared to normal human osteoblast cells. Low expression of miR-148a was significantly associated with tumor progression and a poor prognosis for OS patients. Rho-associated coiled-coil kinase 1 (ROCK1) was then identified as a target of miR-148a in Saos-2 and U2OS cells, and the expression of ROCK1 was significantly increased in OS tissues and cell lines. Moreover, the protein expression of ROCK1 was markedly reduced in miR-148a-overexpressing Saos-2 and U2OS cells, but significantly increased in miR-148a-downregulated Saos-2 and U2OS cells. Further investigation indicated that miR-148a had a suppressive effect on the proliferative, migratory, and invasive capacities of Saos-2 and U2OS cells. Moreover, overexpression of ROCK1 attenuated the inhibitory effects of miR-148a upregulation on the malignant phenotypes of Saos-2 and U2OS cells. In addition, overexpression of miR-148a significantly inhibited the tumor growth of U2OS cells in nude mice. Taken together, these data demonstrate that miR-148a acts as a tumor suppressor in OS, at least partly, via targeting ROCK1. Therefore, the miR-148a/ROCK1 axis may become a potential therapeutic target for OS.

The role of mesenchymal stem cells in promoting the transformation of androgen-dependent human prostate cancer cells into androgen-independent manner.

Mesenchymal stem cells (MSCs) play an important role in the development of human prostate cancer (PCa). However, the role of MSCs in the transformation of androgen-dependent human PCa cells into androgen-independent manner has been poorly understood. In this study, we investigated the underlying mechanism of MSCs in promoting PCa cells from androgen-dependent into androgen-independent manner. Firstly, we demonstrated that MSCs could affect the transformation of androgen-dependent human PCa cells into androgen-independent manner in vivo and in vitro. Then we found a substantial expression of TGF-ß in MSCs. TGF-ß blockade could significantly inhibit the promotive function of MSCs in PCa cells. Besides that, we also demonstrated androgen might inhibit the expression of TGF-ß in MSCs. Furthermore, we found that either overexpression of SSEA-4 or the number of SSEA-4 positive MSCs in PCa tissues was associated with a shorter cancer-free survival interval (CFSI) and a worse overall survival (OS). Our results suggest that androgen blockade treatment in clinical PCa therapy may elicit the expression of TGF-ß in MSCs, which will result in the transformation of androgen-dependent human PCa cells into androgen-independent manner.