Background: The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications. Methods: We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants. Results: Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; Pmeta=7.6×10-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; Pmeta=3.1×10-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals. Conclusion Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.

Background: The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications. Methods: We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants. Results: Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; Pmeta=7.6×10-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; Pmeta=3.1×10-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals. Conclusion Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.

Background: The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications. Methods: We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants. Results: Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; Pmeta=7.6×10-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; Pmeta=3.1×10-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals. Conclusion Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.

Background: The genetic basis for hyperglycaemia in pregnancy remain unclear. This study aimed to uncover the genetic determinants of gestational diabetes mellitus (GDM) and investigate their applications. Methods: We performed a meta-analysis of genome-wide association studies (GWAS) for GDM in Chinese women (464 cases and 1,217 controls), followed by de novo replications in an independent Chinese cohort (564 cases and 572 controls) and in silico replication in European (12,332 cases and 131,109 controls) and multi-ethnic populations (5,485 cases and 347,856 controls). A polygenic risk score (PRS) was derived based on the identified variants. Results: Using the genome-wide scan and candidate gene approaches, we identified four susceptibility loci for GDM. These included three previously reported loci for GDM and type 2 diabetes mellitus (T2DM) at MTNR1B (rs7945617, odds ratio [OR], 1.64; 95% confidence interval [CI],1.38 to 1.96]), CDKAL1 (rs7754840, OR, 1.33; 95% CI, 1.13 to 1.58), and INS-IGF2-KCNQ1 (rs2237897, OR, 1.48; 95% CI, 1.23 to 1.79), as well as a novel genome-wide significant locus near TBR1-SLC4A10 (rs117781972, OR, 2.05; 95% CI, 1.61 to 2.62; Pmeta=7.6×10-9), which has not been previously reported in GWAS for T2DM or glycaemic traits. Moreover, we found that women with a high PRS (top quintile) had over threefold (95% CI, 2.30 to 4.09; Pmeta=3.1×10-14) and 71% (95% CI, 1.08 to 2.71; P=0.0220) higher risk for GDM and abnormal glucose tolerance post-pregnancy, respectively, compared to other individuals. Conclusion Our results indicate that the genetic architecture of glucose metabolism exhibits both similarities and differences between the pregnant and non-pregnant states. Integrating genetic information can facilitate identification of pregnant women at a higher risk of developing GDM or later diabetes.

G protein-coupled receptors (GPCRs) are significant drug targets, but their potential in cancer therapy remains underexplored. Conventional GPCR agonists or antagonists have shown limited effectiveness in cancer treatment, necessitating new GPCR-targeting strategies for more effective therapies. This study discovers that Yersinia pestis LcrV, a crucial linker protein for plague infection, acts as a biased agonist of a GPCR, the formyl peptide receptor 1 (FPR1). The LcrV protein induces unique conformational changes in FPR1, resulting in G proteins being activated in a distinctive state without subunit dissociation. This leads to a biased signaling profile characterized by cyclic adenosine monophosphate (cAMP) responses and β-arrestin2 recruitment, but not calcium mobilization. In FPR1-expressing triple-negative breast cancer (TNBC) cells, LcrV bi-directionally modulates intracellular signaling pathways, downregulating extracellular signal-regulated kinases (ERK1/2) and Akt pathways while upregulating Jun N-terminal kinase (JNK) and p38 pathways. This dual modulation results in cell cycle arrest and the inhibition of TNBC cell proliferation. In TNBC xenograft mouse models, long-term LcrV treatment inhibits tumor growth more effectively than a conventional FPR1 antagonist. Additionally, LcrV treatment reprograms tumor cells by reducing stemness-associated proteins OCT4 and c-MYC. Our findings highlight the potential of biased GPCR agonists as a novel GPCR-targeting strategy for cancer treatment.

Background/Aims: Gastric intestinal metaplasia (GIM), a common precancerous lesion of gastric cancer, can be caused by bile acid reflux. GATA binding protein 4 (GATA4) is an intestinal transcription factor involved in the progression of gastric cancer. However, the expression and regulation of GATA4 in GIM has not been clarified. Methods: The expression of GATA4 in bile acid-induced cell models and human specimens was examined. The transcriptional regulation of GATA4 was investigated by chromatin immunoprecipitation and luciferase reporter gene analysis. An animal model of duodenogastric reflux was used to confirm the regulation of GATA4 and its target genes by bile acids. Results: GATA4 expression was elevated in bile acid-induced GIM and human specimens.GATA4 bound to the promoter of mucin 2 (MUC2) and stimulate its transcription. GATA4 and MUC2 expression was positively correlated in GIM tissues. Nuclear transcription factor-κB activation was required for the upregulation of GATA4 and MUC2 in bile acid-induced GIM cell models. GATA4 and caudal-related homeobox 2 (CDX2) reciprocally transactivated each other to drive the transcription of MUC2. In chenodeoxycholic acid-treated mice, MUC2, CDX2, GATA4, p50, and p65 expression levels were increased in the gastric mucosa. Conclusions GATA4 is upregulated and can form a positive feedback loop with CDX2 to transactivate MUC2 in GIM. NF-κB signaling is involved in the upregulation of GATA4 by chenodeoxycholic acid.

Background/Aims: Cancer stem cells (CSCs) are believed to drive tumor development and metastasis. Activin and hepatocyte growth factor (HGF) are important cytokines with the ability to induce cancer stemness. However, the effect of activin and HGF combination treatment on CSCs is still unclear. Methods: In this study, we sequentially treated colorectal cancer cells with activin and HGF and examined CSC marker expression, self-renewal, tumorigenesis, and metastasis. The roles of forkhead box M1 (FOXM1) and sex-determining region Y-box 2 (SOX2), two stemness-related transcription factors, in activin/HGF-induced aggressive phenotype were explored. Results: Activin and HGF treatment increased the expression of CSC markers and enhanced sphere formation in colorectal cancer cells. The tumorigenic and metastatic capacities of colorectal cancer cells were enhanced upon activin and HGF treatment. Activin and HGF treatment preferentially promoted stemness and metastasis of CD133 + subpopulations sorted from colorectal cancer cells. FOXM1 was upregulated by activin and HGF treatment, and the knockdown of FOXM1 blocked activin/HGF-induced stemness, tumorigenesis, and metastasis of colorectal cancer cells.Similarly, SOX2 was silencing impaired sphere formation of activin/HGF-treated colorectal cancers. Overexpression of SOX2 rescued the stem cell-like phenotype in FOXM1-depleted colorectal cancer cells with activin and HGF treatment. Additionally, the inhibition of FOXM1 via thiostrepton suppressed activin/HGF-induced stemness, tumorigenesis and metastasis. Conclusions Sequential treatment with activin and HGF promotes colorectal cancer stemness and metastasis through activation of the FOXM1/SOX2 signaling. FOXM1 could be a potential target for the treatment of colorectal cancer metastasis.

OBJECTIVE: To preliminarily explore the applicable scenarios of an intraoral camera to assist oral anatomical landmarks recognition, so as to improve the clinical diagnosis and treatment mode, cultivate the concept of caring for patients, strengthen doctor-patient communication, assist experts to teach, and improve the clinical diagnosis and efficacy rate. METHODS: A new type of an intraoral camera was applied in the recognition of oral anatomy landmarks and four application scenarios were developed, namely: (1) clinical diagnosis and treatment scenarios, in which doctors used intraoral camera to conduct a comprehensive examination of patients in the mouth and take videos and photos; (2) doctor-patient communication scenarios, when the doctor told the patient about the treatment plan, the video or photo taken by the intraoral camera was displayed to the patient; (3) expert teaching scenarios, when the expert used an intraoral camera to teach in the patient's mouth, and the young doctor learned oral anatomical signs on the projection screen, with the study of theoretical lessons; (4) difficult case recording scenarios, in the process of clinical diagnosis and treatment, when encountering difficult cases, you could use intraoral camera to record and take photos for young doctors to discuss, and experts to comment and guide. RESULTS: The application of intraoral camera could: (1) improve the clinical diagnosis and treatment mode and raise the clinical diagnosis and efficacy rate; (2) stimulate young doctors' interest in learning, use intraoral camera in assessments, and skillfully combine theoretical knowledge of anatomical landmarks with clinical practice, so as to improve the teaching effect; (3) cultivate, through self or mutual use, the concept of caring for patients and reinforce the importance of gentle operation; (4) strengthen doctor-patient communication. Doctors could communicate with patients more visually, so that the patients could better understand their own situation, and strengthen the patients' trust in the doctors. CONCLUSION Intraoral camera can assist oral clinical diagnosis and treatment, such as the recognition of oral anatomical landmarks. It plays a certain role in promoting the improvement of clinical diagnosis and treatment mode, stimulating learning interest, cultivating the concept of caring for patients, and enhancing doctor-patient communication.
Humans ; Physician-Patient Relations ; Physicians ; Communication ; Mouth ; Learning

Animals ; Mice ; Corticotropin-Releasing Hormone/metabolism* ; Neurons/metabolism* ; Brain/metabolism*

Non-puerperal mastitis(NPM)is a group of chronic inflammatory diseases with breast pain,lumps,abscesses and sinus tracts/fistulas as the main clinical manifestations,which is easily confused with breast cancer or other benign breast diseases.NPM always leads to a long treatment cycle and high recurrence rate,which may cause a large economic and psychological burden to patients.At present,the etiology and pathogenesis of NPM are still unclear,but it has a certain correlation with immune abnormality,bacterial infection,hormone disorder and other factors.Although several diagnostic methods available,the diagnosis of NPM relies on histopathological examination mainly.The treatment methods of the disease include observation and follow-up,pharmacotherapy,surgical treatment,etc.,but there is still no unified standard for specific treatment timing and treatment selection.In view of the controversy over etiology and treatment selection of NPM,this paper comprehensively summarizes the latest research progress in disease characteristics,clinical diagnosis and treatment of NPM based on domestic and foreign literature,aiming to provide reference and inspiration for the selection of reasonable clinical diagnosis and treatment.