Asparagine Synthetase Marks a Distinct Dependency Threshold for Cardiomyocyte Dedifferentiation.

BACKGROUND: Adult mammalian cardiomyocytes have limited proliferative capacity, but in specifically induced contexts they traverse through cell-cycle reentry, offering the potential for heart regeneration. Endogenous cardiomyocyte proliferation is preceded by cardiomyocyte dedifferentiation (CMDD), wherein adult cardiomyocytes revert to a less matured state that is distinct from the classical myocardial fetal stress gene response associated with heart failure. However, very little is known about CMDD as a defined cardiomyocyte cell state in transition. METHODS: Here, we leveraged 2 models of in vitro cultured adult mouse cardiomyocytes and in vivo adeno-associated virus serotype 9 cardiomyocyte-targeted delivery of reprogramming factors (Oct4, Sox2, Klf4, and Myc) in adult mice to study CMDD. We profiled their transcriptomes using RNA sequencing, in combination with multiple published data sets, with the aim of identifying a common denominator for tracking CMDD. RESULTS: RNA sequencing and integrated analysis identified Asparagine Synthetase (Asns) as a unique molecular marker gene well correlated with CMDD, required for increased asparagine and also for distinct fluxes in other amino acids. Although Asns overexpression in Oct4, Sox2, Klf4, and Myc cardiomyocytes augmented hallmarks of CMDD, Asns deficiency led to defective regeneration in the neonatal mouse myocardial infarction model, increased cell death of cultured adult cardiomyocytes, and reduced cell cycle in Oct4, Sox2, Klf4, and Myc cardiomyocytes, at least in part through disrupting the mammalian target of rapamycin complex 1 pathway. CONCLUSIONS: We discovered a novel gene Asns as both a molecular marker and an essential mediator, marking a distinct threshold that appears in common for at least 4 models of CMDD, and revealing an Asns/mammalian target of rapamycin complex 1 axis dependency for dedifferentiating cardiomyocytes. Further study will be needed to extrapolate and assess its relevance to other cell state transitions as well as in heart regeneration.

Associations of genetic variations in pyroptosis related genes with acute adverse events in postoperative rectal cancer patients receiving concurrent chemoradiotherapy / 中华肿瘤杂志

Objective: This study aims to investigate the associations between genetic variations of pyroptosis pathway related key genes and adverse events (AEs) of postoperative chemoradiotherapy (CRT) in patients with rectal cancer. Methods: DNA was extracted from the peripheral blood which was collected from 347 patients before CRT. Sequenom MassARRAY was used to detect the genotypes of 43 haplotype-tagging single nucleotide polymorphisms (htSNPs) in eight pyroptosis genes, including absent in melanoma 2 (AIM2), caspase-1 (CASP1), caspase-4(CASP4), caspase-5 (CASP5), caspase-11 (CASP11), gasdermin D (GSDMD), gasdermin E (GSDME) and NLR family pyrin domain containing 3 (NLRP3). The associations between 43 htSNPs and AEs were evaluated by the odd ratios (ORs) and 95% confidence intervals (CIs) by unconditional logistic regression models, adjusted for sex, age, clinical stage, tumor grade, Karnofsky performance status (KPS), surgical procedure, and tumor location. Results: Among the 347 patients with rectal cancer underwent concurrent CRT with capecitabine after surgery, a total of 101(29.1%) occurred grade ≥ 2 leukopenia. rs11226565 (OR=0.41, 95% CI: 0.21-0.79, P=0.008), rs579408(OR=1.54, 95% CI: 1.03-2.29, P=0.034) and rs543923 (OR=0.63, 95% CI: 0.41-0.98, P=0.040) were significantly associated with the occurrence of grade ≥ 2 leukopenia. One hundred and fifty-six (45.0%) had grade ≥ 2 diarrhea, two SNPs were significantly associated with the occurrence of grade ≥ diarrhea, including CASP11 rs10880868 (OR=0.55, 95% CI: 0.33-0.91, P=0.020) and GSDME rs2954558 (OR=1.52, 95% CI: 1.01-2.31, P=0.050). In addition, sixty-six cases (19.0%) developed grade ≥2 dermatitis, three SNPs that significantly associated with the risk of grade ≥2 dermatitis included GSDME rs2237314 (OR=0.36, 95% CI: 0.16-0.83, P=0.017), GSDME rs12540919 (OR=0.52, 95% CI: 0.27-0.99, P=0.045) and NLRP3 rs3806268 (OR=1.51, 95% CI: 1.03-2.22, P=0.037). There was no significant difference in the association between other genetic variations and AEs of rectal cancer patients (all P>0.05). Surgical procedure and tumor location had great impacts on the occurrence of grade ≥2 diarrhea and dermatitis (all P<0.01). Conclusion: The genetic variants of CASP4, CASP11, GSDME and NLRP3 are associated with the occurrence of AEs in patients with rectal cancer who received postoperative CRT, suggesting they may be potential genetic markers in predicting the grade of AEs to achieve individualized treatment of rectal cancer.

Understanding cannabis use in Singapore: profile of users and drug progression

INTRODUCTION@#Cannabis has consistently been the third most commonly abused drug among drug arrestees in Singapore over the past few years. Accordingly, this study aimed to understand the profile of cannabis users in Singapore and explore the effects of cannabis use on drug progression.@*METHODS@#A total of 450 participants who had used cannabis at least once in their lifetime were recruited from the National Addictions Management Service, prisons, the Community Rehabilitation Centre and halfway houses from August 2017 to May 2018. A face-to-face questionnaire was administered and descriptive analyses were conducted.@*RESULTS@#The mean participant age was 40.9 ± 14.51 years, and 93.1% of them were male. The participants generally initiated cannabis use during adolescence, at a mean onset age of 16.5 ± 4.46 years. Most (89.6%) were introduced to cannabis by peers. Approximately half of them (46.9%) had used cannabis before other illicit drugs and 42.1% of them had used heroin as the succeeding drug.@*CONCLUSION@#In Singapore, cannabis use is often initiated during adolescence, largely under peer influence. Cannabis users may progress to other illicit drugs, particularly heroin, later in life.

Knowledge, Attitudes, and Practices of COVID-19 Vaccination among Adults in Singapore: A Cross-Sectional Study.

Public health measures promoting compliance of COVID-19 vaccination requires understanding of knowledge, attitudes, and practices (KAP). This study explored the KAP and risk factors influencing COVID-19 vaccination, including changes in preventive practices before and after vaccination in a high-income country, Singapore. An online cross-sectional study among Singaporeans and permanent residents aged 21 years and older was conducted from July to August 2021. Univariate and multivariable logistic regressions using RStudio version 1.4.1106 was performed to assess associations between demographic factors, KAP, and vaccination status. P values < 0.05 were considered statistically significant. A total of 869 respondents completed the survey. Individuals with higher knowledge (adjusted odds ratio [aOR] = 2.00, P = 0.024), perceived efficacy (aOR = 1.19, P = 0.004), perceived safety (aOR = 1.20, P = 0.005), and willingness to uptake (aOR = 1.55, P < 0.001) scores were more likely to be vaccinated. There was a significant increase in the use of proper handwashing techniques among the vaccinated group before and after vaccinations. The governmental risk communication approaches have been useful in instilling high levels of vaccine knowledge. High levels of good attitudes about and knowledge of COVID-19 vaccination were associated with a high level of vaccination practices. Good perceived vaccine efficacy and confidence in government were also associated with positive vaccine uptake. This study paves the way for more targeted government measures to be implemented to improve vaccination rates of COVID-19 booster vaccines in a high-income country like Singapore.

A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity.

AIMS: Cardiotoxicity leading to heart failure (HF) is a growing problem in many cancer survivors. As specific treatment strategies are not available, RNA discovery pipelines were employed and a new and powerful circular RNA (circRNA)-based therapy was developed for the treatment of doxorubicin-induced HF. METHODS AND RESULTS: The circRNA sequencing was applied and the highly species-conserved circRNA insulin receptor (Circ-INSR) was identified, which participates in HF processes, including those provoked by cardiotoxic anti-cancer treatments. Chemotherapy-provoked cardiotoxicity leads to the down-regulation of Circ-INSR in rodents and patients, which mechanistically contributes to cardiomyocyte cell death, cardiac dysfunction, and mitochondrial damage. In contrast, Circ-INSR overexpression prevented doxorubicin-mediated cardiotoxicity in both rodent and human cardiomyocytes in vitro and in a mouse model of chronic doxorubicin cardiotoxicity. Breast cancer type 1 susceptibility protein (Brca1) was identified as a regulator of Circ-INSR expression. Detailed transcriptomic and proteomic analyses revealed that Circ-INSR regulates apoptotic and metabolic pathways in cardiomyocytes. Circ-INSR physically interacts with the single-stranded DNA-binding protein (SSBP1) mediating its cardioprotective effects under doxorubicin stress. Importantly, in vitro transcribed and circularized Circ-INSR mimics also protected against doxorubicin-induced cardiotoxicity. CONCLUSION: Circ-INSR is a highly conserved non-coding RNA which is down-regulated during cardiotoxicity and cardiac remodelling. Adeno-associated virus and circRNA mimics-based Circ-INSR overexpression prevent and reverse doxorubicin-mediated cardiomyocyte death and improve cardiac function. The results of this study highlight a novel and translationally important Circ-INSR-based therapeutic approach for doxorubicin-induced cardiac dysfunction.

Modeling Susceptibility to Cardiotoxicity in Cancer Therapy Using Human iPSC-Derived Cardiac Cells and Systems Biology.

The development of human-induced pluripotent stem cell-derived cardiac cell types has created a new paradigm in assessing drug-induced cardiotoxicity. Advances in genomics and epigenomics have also implicated several genomic loci and biological pathways that may contribute to susceptibility to cancer therapies. In this review, we first provide a brief overview of the cardiotoxicity associated with chemotherapy. We then provide a detailed summary of systems biology approaches being applied to elucidate potential molecular mechanisms involved in cardiotoxicity. Finally, we discuss combining systems biology approaches with iPSC technology to help discover molecular mechanisms associated with cardiotoxicity.

Non-Hermitian Edge Burst.

We unveil an unexpected non-Hermitian phenomenon, dubbed edge burst, in non-Hermitian quantum dynamics. Specifically, in a class of non-Hermitian quantum walk in periodic lattices with open boundary condition, an exceptionally large portion of loss occurs at the system boundary. The physical origin of this edge burst is found to be an interplay between two unique non-Hermitian phenomena: non-Hermitian skin effect and imaginary gap closing. Furthermore, we establish a universal bulk-edge scaling relation underlying the non-Hermitian edge burst. Our predictions are experimentally accessible in various non-Hermitian systems including quantum-optical and cold-atom platforms.

The Association of Obstructive Sleep Apnea With Breast Cancer Incidence and Mortality: A Systematic Review and Meta-analysis / 한국유방암학회지

Purpose@#Emerging evidence from animal models suggests that intermittent hypoxia due to obstructive sleep apnea (OSA) is a risk factor for breast cancer. Despite their biological plausibility, human epidemiological studies have reported conflicting results. Therefore, we conducted a meta-analysis to delineate this relationship. @*Methods@#We searched the PubMed, Embase, Scopus, and Cochrane Library databases for eligible studies from inception until June 6, 2021. Two reviewers selected randomized trials or observational studies reporting the association between OSA and breast cancer incidence compared with those without OSA. Two reviewers extracted relevant data and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and Newcastle-Ottawa Scale (NOS). We pooled the maximally covariate-adjusted hazard ratios (HRs) using a random-effects inverse varianceweighted meta-analysis and performed pre-specified subgroup analyses. @*Results@#We included six studies out of 1,707 records, comprising a combined cohort of 5,165,200 patients. All studies used the International Classification of Diseases codes to classify OSA and breast cancer. OSA patients had a 36% increased breast cancer risk (HR, 1.36; 95% confidence interval [CI], 1.03–1.80; N = 6, I 2 = 96%) compared to those without OSA. Most studies adjusted for confounders, such as age, sex, obesity, diabetes mellitus, alcohol use, and hypertension. Subgroup analyses for studies with (1) multivariate adjustment and (2) at least five years of follow-up yielded HRs of 1.35 (95% CI, 0.98–1.87; N = 5, I 2 = 96%) and 1.57 (95% CI, 1.14–2.18; N = 4; I 2 = 90%), respectively. One Mendelian randomization study suggested a causal relationship, with a two-fold increase in the odds of breast cancer in patients with OSA. @*Conclusion@#This meta-analysis suggested that OSA is a risk factor for breast cancer. Future studies should explore the dose-response relationship between OSA and breast cancer, and whether treatment may mitigate breast cancer risk or progression.

Roles of lncRNA MAGI2-AS3 in human cancers.

Long noncoding RNAs (lncRNAs) are noncoding RNAs more than 200 nucleotides in length. A growing number of reports indicate that lncRNAs play a key role in multiple cancers by serving as oncogenes or tumor suppressor genes. MAGI2 antisense RNA 3 (MAGI2-AS3) is ubiquitously expressed in human cancers, and the level of MAGI2-AS3 expression is associated with the progression and prognosis of cancers. Moreover, dysregulation of MAGI2-AS3 has been found to regulate cancer cell proliferation, cell death, invasion and metastasis and treatment resistance by serving as a competing endogenous RNA (ceRNA), epigenomic regulator, and transcriptional regulator. Moreover, increasing evidence shows that MAGI2-AS3 may be a potential biomarker for cancer prognosis and a potential target for cancer therapy. In this review, we summarize current research on the functions, mechanisms and clinical significance of the lncRNA MAGI2-AS3 in cancer development.

Preliminary application and efficacy analysis of transumbilical single-incision plus one port robotic total mesorectal excision / 中华胃肠外科杂志

Objective: To investigate the feasibility of transumbilical single-incision plus one port (SIPOP) robotic total mesorectal excision. Methods: Clinical data of a 70-year-old male patient with BMI 22.1 kg/m(2) who successfully underwent transumbilical single-incision plus 1 port robotic total mesorectal resection of upper rectal cancer at the General Surgery Department of Daping Hospital of Army Military Medical University on September 18, 2019 were retrospectively analyzed. Preoperative colonoscopy revealed that the distance of upper rectal cancer to anal edge was 14 cm, and the tumor size was 2.5 cm×1.5 cm×1 cm. Pathological result confirmed rectal moderately differentiated adenocarcinoma. The preoperative abdominal CT showed thickened bowel-wall of upper rectum and the blurred perirectal fat, suggesting tumor infiltration. Results: The operation was successful. There were no conversion to laparotomy or abdominal auxiliary incision, and the mesorectum of the specimen was intact. The operation time was 165 minutes, the blood loss was about 20 ml, and there were no complications such as injury to peripheral organs. Postoperative pathology showed ulcerative moderately differentiated adenocarcinoma of the upper rectum with TNM stage IVA (T4N2b). The postoperative recovery was smooth. Patient ambulated on the 1st day, the catheter was removed on the 7th day, and discharged from the hospital on the 8th day. Conclusion: The transumbilical SIPOP robotic total mesorectal excision is safe, effective and feasible.

Effect of umbilical moxibustion on phlegm damp constitution and intestinal flora / 中国针灸

OBJECTIVE@#To observe the effect of umbilical moxibustion on phlegm damp constitution and intestinal flora, and explore the mechanism of umbilical moxibustion in improving phlegm damp constitution.@*METHODS@#A total of 60 subjects with phlegm damp constitution were randomly divided into an observation group and a control group, 30 cases in each group. The control group was given TCM health guidance, such as diet and exercise; on the basis of the control group, umbilical moxibustion was applied in the observation group, 7 moxa cones each time, 2 times a week for 8 weeks. Before and after intervention, the indexes (transformation score of phlegm damp constitution, body mass, body mass index [BMI], waist circumference, hip circumference, heart rate and blood pressure) related to phlegm damp constitution were recorded in the two groups. The intestinal flora was detected with 16S rDNA sequencing technology in the two groups.@*RESULTS@#After intervention, the transformation score of phlegm damp constitution, body mass, BMI, waist circumference and hip circumference were decreased compared before intervention in the observation group (@*CONCLUSION@#Umbilical moxibustion may reshape the intestinal flora by up-regulating the relative abundance of

Metformin inhibits pancreatic cancer metastasis caused by SMAD4 deficiency and consequent HNF4G upregulation

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis due to limited therapeutic options. This study examines the roles of genome-wide association study identified PDAC-associated genes as therapeutic targets. We have identified HNF4G gene whose silencing most effectively repressed PDAC cell invasiveness. HNF4G overexpression is induced by the deficiency of transcriptional factor and tumor suppressor SMAD4. Increased HNF4G are correlated with SMAD4 deficiency in PDAC tumor samples and associated with metastasis and poor survival time in xenograft animal model and in patients with PDAC (log-rank P = 0.036; HR = 1.60, 95% CI = 1.03-2.47). We have found that Metformin suppresses HNF4G activity via AMPK-mediated phosphorylation-coupled ubiquitination degradation and inhibits in vitro invasion and in vivo metastasis of PDAC cells with SMAD4 deficiency. Furthermore, Metformin treatment significantly improve clinical outcomes and survival in patients with SMAD4-deficient PDAC (log-rank P = 0.022; HR = 0.31, 95% CI = 0.14-0.68) but not in patients with SMAD4-normal PDAC. Pathway analysis shows that HNF4G may act in PDAC through the cell-cell junction pathway. These results indicate that SMAD4 deficiency-induced overexpression of HNF4G plays a critical oncogenic role in PDAC progression and metastasis but may form a druggable target for Metformin treatment.

Construction and Identification of Leukemia Cell Line Stably Expressing CD123 and CLL-1 / 中国实验血液学杂志

OBJECTIVE@#To construct an acute myeloid leukemia cell line stably expressing CD123-CLL1 so as to provide an "in vitro" model for studying the role of CD123 and CLL-1 in leukemia and the treatment targeting CD123 and CLL-1.@*METHODS@#The recombinant plasmid of lentivirus was constructed by synthesizing CD123 and CLL-1 sequences and PCR homologous recombination. The lentivirus vector was packaged by three-plasmid packaging system. After collecting the supernatant of lentivirus, the virus titer was determined by quantitative PCR. K562 leukemia cells were collected and transtected with virus supernatant. Leukemia cell line stably expressing the target gene were screened by purinomycin. The expression levels of CD123 and CLL-1 were detected by RT-PCR and flow cytometry.@*RESULTS@#The lentiviral vector was successfully constructed, and identified by agarose gel electrophoresis and gene sequencing, then the virus titer of the supernatant was up to 5.81×10@*CONCLUSION@#Lentiviral vector expressing CD123-CLL1 has been successfully constructed, and K562 leukemia cell line stably expressing CD123 and CLL-1 has been successfully obtained.

Simultaneous improvement to solubility and bioavailability of active natural compound isosteviol using cyclodextrin metal-organic frameworks

Cyclodextrin metal-organic framework (CD-MOF) as a highly porous supramolecular carrier could be one of the solutions to the insolubility of isosteviol (STV). The solubility of STV was lower than 20.00 ng/mL at pH 1.0 and pH 4.5, whilst its solubility increased to 20,074.30 ng/mL at pH 6.8 and 129.58 ng/mL in water with a significant pH-dependence. The

Effects of sodium arsenite and arsenic metabolites on the expression of linear and circular RNA of Nup107 in A549 cells / 中国职业医学

OBJECTIVE: To explore the effect of sodium arsenite and arsenic metabolites monomethylarsenic acid(MMA) and dimethylarsenic acid(DMA)on the expression of linear and circularRNAs of nucleoporin 107(Nup107) in human lung adenocarcinoma A549 cells. METHODS: i) The A549 cells in logarithmic phase were treated with 0, 30, 60, 90 μmol/L sodium arsenite for 48 hours. ii)The A549 cells in logarithmic phase were treated with 90 μmol/L sodium arsenite, MMA and DMA for 48 hours, the control group received no treatment. After culturing, the relative expression of linear RNA and circular RNA(circRNA) of Nup107 was detected by real-time quantitative polymerase chain reaction. RESULTS: i) The relative expression of linear RNA of Nup107 decreased and four circRNA isomers such as hsa＿circ＿0003599, hsa＿circ＿0027477, hsa＿circ＿0027478 and hsa＿circ＿0027479 increased with the increase of sodium arsenite dose(all P<0.01), showing a dose-effect relationship. In the 90 μmol/L sodium arsenite stimulated group, the relative expression of linear RNA of Lin-Nup107 decreased, and the four circRNA isomers increased compared with the control group in the A549 cells(all P<0.01). ii) The relative expression of Lin-Nup107 increased in the MMA and DMA stimulated groups and decreased in the sodium arsenite stimulated group compared with the control group in the A549 cells(all P<0.05). The relative expression of Lin-Nup107 decreased in the sodium arsenite stimulated group compared with the MMA and DMA stimulated groups in the A549 cells(all P<0.05). The relative expressions of hsa＿circ＿0003599, hsa＿circ＿0027478, hsa＿circ＿0027479 in the sodium arsenite stimulated group were higher than that in the MMA and DMA stimulated groups as well as the control group(all P<0.05).The relative expressions of hsa＿circ＿0027479 in the DMA stimulated group was lower than that in the control group(P<0.05). CONCLUSION: Sodium arsenite can induce the down-regulation of linear RNA and the up-regulation of circRNA of Nup107 in a dose-dependent manner. The metabolites of arsenic MMA and DMA can induce the overexpression of linear RNA of Nup107, however, they had no obvious effect on the circRNA of Nup107 in A549 cells.

A cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients.

ObjectiveTo determine the clinical outcomes of older COVID-19 patients who received DMB compared to those who did not. We hypothesized that fewer patients administered DMB would require oxygen therapy and/or intensive care support than those who did not. MethodologyCohort observational study of all consecutive hospitalized COVID-19 patients aged 50 and above in a tertiary academic hospital who received DMB compared to a recent cohort who did not. Patients were administered oral vitamin D3 1000 IU OD, magnesium 150mg OD and vitamin B12 500mcg OD (DMB) upon admission if they did not require oxygen therapy. Primary outcome was deterioration post-DMB administration leading to any form of oxygen therapy and/or intensive care support. ResultsBetween 15 January and 15 April 2020, 43 consecutive COVID-19 patients aged [≥]50 were identified. 17 patients received DMB and 26 patients did not. Baseline demographic characteristics between the two groups was significantly different in age. In univariate analysis, age and hypertension showed significant influence on outcome while DMB retained protective significance after adjusting for age or hypertension separately in multivariate analysis. Fewer DMB patients than controls required initiation of oxygen therapy during their hospitalization (17.6% vs 61.5%, P=0.006). DMB exposure was associated with odds ratios of 0.13 (95% CI: 0.03 - 0.59) and 0.20 (95% CI: 0.04 - 0.93) for oxygen therapy and/or intensive care support on univariate and multivariate analyses respectively. ConclusionsDMB combination in older COVID-19 patients was associated with a significant reduction in proportion of patients with clinical deterioration requiring oxygen support and/or intensive care support. This study supports further larger randomized control trials to ascertain the full benefit of DMB in ameliorating COVID-19 severity.

Structural characterization of an acid polysaccharide from Pinellia ternata and its induction effect on apoptosis of Hep G2 cells.

In the present study, a polysaccharide fraction (PTP) was isolated and purified from the tubers of Pinellia ternata. We researched its structure and anti-tumor activity, and further studied its molecular mechanism of inducing apoptosis of Hep G2 cells. The results indicated that PTP was an acid heteropolysaccharide and the average molecular weight of PTP identified by HPGPC was 3.06 × 106 Da. Ion chromatography (IC) determined that PTP was mainly composed of Ara:Gal:Glu:Man:GlcA:GalA in a molar ratio of 6.98:16.56:7.25:2.04:1:4.16. Combined with the results of FT-IR and NMR spectroscopy, it was found that PTP is a pyranose containing α-configuration and ß-configuration, mainly consist of ß-D-Gal, α-D-Glu, α-D-Ara and ß-D-Man. By analyzing the results of MTT, cell cycle, Annexin V-FITC/PI double staining and cell morphology observation, we concluded that PTP induced dose-dependent apoptosis of Hep G2 cells via S phase arrest. In addition, mitochondrial membrane potential detection and Western blot further indicated that PTP was capable of inducing apoptosis in Hep G2 cells through an endogenous mitochondria-mediated apoptotic pathway.

Comparison of gastrointestinal adverse events with different doses of metformin in the treatment of elderly people with type 2 diabetes.

WHAT IS KNOWN AND OBJECTIVE: Gastrointestinal discomfort is the most common adverse event of metformin treatment for type 2 diabetes, especially in elderly patients. The aim of this study was to compare gastrointestinal adverse events resulting from different doses of metformin used for the treatment of elderly people with type 2 diabetes. METHODS: A total of 361 elderly patients with newly diagnosed diabetes were randomly divided into three groups: metformin 1000 mg/d (N = 120), metformin 1500 mg/d (N = 121) and metformin 2000 mg/d (N = 120). Glycaemic control and gastrointestinal adverse events (abdominal pain, diarrhoea, nausea, vomiting, bloating and anorexia) were assessed and compared among the three groups after 12 weeks of treatment. RESULTS AND DISCUSSION: At baseline, there was no significant difference in gastrointestinal symptoms among the three groups. After 12 weeks of treatment with metformin, the change in HbA1c level was -0.7%, -0.9% and -1.0% for the 1000 mg/d, 1500 mg/d and 2000 mg/d groups, respectively (P < .0001). There was no significant difference in gastrointestinal adverse events among the three groups after treatment with metformin. In total, 62 people (17.2%) could not tolerate the adverse effects of metformin, and most of them stopped treatment in the first 4 weeks. Logistic regression analysis shows that female sex (OR = 2.660, 95%CI 1.692-4.183, P < .0001) and the concurrent use of organic cation transporter 1-inhibiting drugs (OR = 1.874, 95%CI 1.076-3.265, P = .027) are independent risk factors for adverse events. WHAT IS NEW AND CONCLUSIONS: Our data demonstrate that metformin doses of 1000 mg/d-2000 mg/d have similar adverse events but that 2000 mg/d of metformin yields the best glycaemic control in elderly people with diabetes. If elderly people can tolerate 1000 mg/d of metformin, we could gradually increase the dose to 2000 mg/d to achieve better glycaemic control.