Camp-style lifestyle modification program (CAMP) for diabetes prevention among rural women with prior GDM: study protocol for a three-arm cluster hybrid type 2 randomized controlled trial.

BACKGROUND: Intensive lifestyle interventions were effective to reduce the risk of type 2 diabetes mellitus (T2DM) for women with gestational diabetes mellitus (GDM) history. However, reaching these mothers and maintaining participation in lifestyle interventions is suboptimal in real-world settings. Effective, feasible and sustainable new lifestyle interventions are needed. The objectives of this three-arm trial are to (1) compare diabetes risk outcomes of an evidence-based intensive lifestyle modification (ILSM) intervention, a camp-style lifestyle modification program (CAMP) intervention, and usual care among women with GDM history; and (2) evaluate the comparative efficacy of the CAMP versus ILSM intervention on implementation outcomes. METHODS: A three-arm cluster randomized clinical trial (RCT) using a hybrid type 2 implementation design will be conducted in two counties in Hunan province in China. Six towns from each county will be randomly selected and assigned to CAMP, ILSM, and the usual care group (25 women from each of 12 towns, 100 women in each arm). The ILSM includes six biweekly in-person sessions and 3-month telephone health consultations, while the CAMP consists of a 2-day camp-based session and 3-month health consultations via a popular social media platform. Both interventions share the same session content, including six lifestyle skills. Efficacy (T2DM risk score and behavioral, anthropometric, psychosocial, and glycemic variables) and implementation outcomes (recruitment, acceptability, feasibility, fidelity, and cost-effectiveness) will be collected at baseline, 6-month, and 12-month. Pre-planned ANOVA F-test and generalized estimating equations will be included to test time-by-arm interactions. DISCUSSION: The CAMP intervention is expected to have better reach, better attendance, and comparable effectiveness in reducing the risk of T2DM, thus improving postpartum care for GDM in China. The delivery of a concentrated format supplemented with technology-based support may provide an efficient and effective delivery model for implementing maternal health promotion programs in primary care settings. TRIAL REGISTRATION: Registered in the Chinese Clinical Trial Registry (ChiCTR2200058150) on 31st March 2022.

Proportion and risk factors of diabetic retinopathy by stage in less-developed rural areas of Hunan province of China: A multi-site cross-sectional study.

AIMS: To investigate the proportion and risk factors of diabetic retinopathy (DR) by stages in less-developed rural areas in Hunan Province of China. BACKGROUND: DR is common among people with diabetes but not well recognized in less-developed rural areas. There is insufficient evidence on the risk factors of DR by stages, making it challenging to develop targeted prevention and intervention programs for DR in primary care settings. METHODS: A multi-site cross-sectional survey was conducted among people with type 2 diabetes mellitus (T2DM) from four less-developed counties in Hunan Province of China. All participants underwent the screening of DR via digital fundus photography and completed self-reported questionnaires on their socio-demographic and clinical characteristics, diabetes self-efficacy, diabetes self-care behaviors, social support, family function, and health service accessibility. The multinomial logistic regression models were employed to explore the risk factors of DR by stage, which were selected based on the socio-ecological model, literature, and clinical experience. RESULTS: A total of 196 participants were included in this study with an average age of 57.43 ± 10.26. 59.6% (117/196) of the participants were identified as DR, including 37.2% (73/196) non-proliferative DR and 22.4% (44/196) proliferative DR. Compared to the non-DR group, the risk factors of non-proliferative DR and proliferative DR were diabetes duration (OR: 1.10, 95 CI%: 1.04-1.17; OR: 1.14, 95 CI% 1.06-1.22) and self-monitoring of blood glucose (OR: 1.09, 95 CI% 1.01-1.17; OR: 1.11, 95 CI%: 1.02-1.20); the protective factors of non-proliferative DR was accessible complication prevention and management education (OR: 0.37, 95 CI% 0.14-0.94) while the protective factors of proliferative DR were physical activities (OR: 0.89, 95 CI%: 0.80-0.98). Compared to the non-proliferative DR group, the protective factors of proliferative DR were physical activities (OR: 0.89, 95 CI% 0.02-0.89) and family function (OR: 0.84, 95 CI%: 0.04-0.84). CONCLUSION: DR was prevalent among people with T2DM in less-developed rural areas, indicating the need of strengthening DR screening. Risk factors of DR varied by stage while sharing some common factors. Future DR prevention and intervention programs may benefit from improving these factors to reduce the risk of DR by stage.

Exploring the frontiers of sustainable livelihoods research within grassland ecosystem: A scientometric analysis.

Grassland degradation has become a global social-ecological problem, which seriously limits the sustainability of indigenous people's livelihoods. Bibliometrics, a type of analysis based on the Science Citation Index-Expanded (SCI-E), was therefore performed to explore the research trends and focus areas of studies on sustainable livelihoods (SLs). We conducted an in-depth analysis of 489 research publications and their 25,144 references from 1991 to 2020. The results show that only few papers have been published, but the number of countries and research institutions involved shows an overall imbalance. We identified eight main clusters based on keyword co-occurrence, these being studies the content of which is an important representation of current research directions in this topic. The document co-citation analysis revealed 10 research clusters, representing the frontiers of research. Clusters included the following topics: NPP (Net Primary Productivity) dynamics, global change, ecological restoration, risk indicators, livelihood strategies, smallholder systems, drought relief, sustainable land management and common pool resources. We reviewed and interpreted these clusters in depth with a view to provide an up-to-date account of the dynamics of this research. As the first scientometric evaluation of research on sustainable livelihoods in grassland ecosystems, this study provides several theoretical and practical implications for global poverty eradication research, which are of great scientific value for global sustainable development.

Biological and sociocultural determinants of increased blood pressure among women with a history of gestational diabetes mellitus in rural China: a retrospective cohort study.

OBJECTIVES: Gestational diabetes mellitus (GDM) increases the risk of hypertension and cardiovascular events among mothers later in life. This risk has not been well recognised by healthcare professionals in rural China. Our objectives were to (1) describe the proportion of rural women with increased blood pressure and a history of GDM; and (2) explore the biological and sociocultural factors associated with increased blood pressure. DESIGN: A retrospective cohort study using data from a cross-sectional survey. SETTING: Data were collected in two county-level hospitals in the central south of China between November 2017 and June 2018. PARTICIPANTS: Postpartum women aged >18 years with a history of GDM (N=397). METHODS: Biological and sociocultural variables were examined. We used bivariate analyses to examine the associations between time since delivery and 2-hour postload glucose, and logistic regression to determine the biological and sociocultural factors associated with increased postpartum blood pressure. RESULTS: Approximately 20% (n=78) of women had increased blood pressure, defined as a systolic blood pressure ≥130 mm Hg and/or a diastolic blood pressure ≥85 mm Hg. The biological factors of advanced age, family history of hypertension and abnormal 2-hour postload plasma glucose levels were positively associated with increased blood pressure (p<0.05). General self-efficacy was the only sociocultural factor negatively associated with increased blood pressure (p<0.05). CONCLUSIONS: One in five rural Chinese postpartum women with a history of GDM were found to have increased blood pressure. Biological and sociocultural factors were associated with increased postpartum blood pressure; women with lower general self-efficacy were more likely to have increased blood pressure. Disseminating knowledge about the high risk of developing increased blood pressure among women with prior GDM in rural China is indicated. Diabetes prevention programmes could consider adding general self-efficacy promotion strategies in this population.

Factors Associated with Adherence to Self-Monitoring of Blood Glucose Among Young People with Type 1 Diabetes in China: A Cross-Sectional Study.

BACKGROUND: Self-monitoring of blood glucose (SMBG) plays a crucial role in the maintenance of glycemic control in young people with type 1 diabetes mellitus (T1DM), but most of them do not perform SMBG as recommended. Few studies comprehensively explored factors that correlate with adherence to SMBG among this population on the basis of a framework. Hence, the aims of this study were to describe adherence to SMBG among young people with T1DM in China and explore its associating factors according to the Self and Family Management (SFM) framework. METHODS: A cross-sectional study was conducted on young people with T1DM in Hunan Province of China from July to August 2020. Based on the SFM framework, self-reported questionnaires were organized for the collection of data on adherence to SMBG, socio-demographic and clinical factors, resources, health care system, and personal factors. Factors associated with adherence to SMBG were determined through multivariate logistic regression analysis. RESULTS: A total of 165 young people were invited, of which 122 (73.9%) completed the questionnaires. The mean age was 12.41 years (SD = 3.18), and the proportion of young people who adhered to SMBG was 53.3%. Multivariate logistic regression analysis revealed that children aged 8-12 years (OR = 0.188, P = 0.002), from two-parent families (OR = 0.232, P = 0.019), and with better personal factors (eg, with more information of SMBG, OR = 1.072, P = 0.020; lower diabetes-related worry, OR = 0.917, P = 0.031; higher level of pain during SMBG, OR = 1.852, P = 0.001), had better adherence to SMBG. CONCLUSION: Nearly half of the young people with T1DM were not adherent to SMBG in China. Clinicians need to pay more attention to adolescents from single-parent families with regard to their adherence to SMBG. Providing management strategies of SMBG, including delivering SMBG-related information, decreasing diabetes-related worry, and relieving pain related to SMBG, may improve adherence.

Instrument Context Relevance Evaluation, Translation, and Psychometric Testing of the Diabetes Eating Problem Survey-Revised (DEPS-R) among People with Type 1 Diabetes in China.

BACKGROUND: People with type 1 diabetes are susceptible to disordered eating behaviors. The American Diabetes Association recommends using the Diabetes Eating Problem Survey-Revised (DEPS-R) to screen them. There is no validated diabetes-specific screening measure in China. The objectives were to adapt DEPS-R into Mandarin Chinese and to test its psychometric properties among youths and adults with type 1 diabetes in China, respectively. METHODS: This study was conducted in two phases. Phase 1 included context relevance evaluation and instrument translation. Phase 2 was psychometric testing of reliability and construct validity among 89 youths (8~17 years old) and 61 adults with type 1 diabetes. RESULT: The Context Relevance Index and Translation Validity Index of this instrument were good. Strong internal consistency reliability correlations and convergent validity were demonstrated among youths and adults. DISCUSSION: The Chinese version of the DEPS-R is a valid and reliable tool for screening disordered eating behaviors in Chinese youths and adults with type 1 diabetes. The Context Relevance Index is advocated to evaluate the difference between the context in which an instrument was originally developed and the target context.

A potent CBP/p300-Snail interaction inhibitor suppresses tumor growth and metastasis in wild-type p53-expressing cancer.

The zinc finger transcription factor Snail is aberrantly activated in many human cancers and associated with poor prognosis. Therefore, targeting Snail is expected to exert therapeutic benefit in patients with cancer. However, Snail has traditionally been considered "undruggable," and no effective pharmacological inhibitors have been identified. Here, we found a small-molecule compound CYD19 that forms a high-affinity interaction with the evolutionarily conserved arginine-174 pocket of Snail protein. In aggressive cancer cells, CYD19 binds to Snail and thus disrupts Snail's interaction with CREB-binding protein (CBP)/p300, which consequently impairs CBP/p300-mediated Snail acetylation and then promotes its degradation through the ubiquitin-proteasome pathway. Moreover, CYD19 restores Snail-dependent repression of wild-type p53, thus reducing tumor growth and survival in vitro and in vivo. In addition, CYD19 reverses Snail-mediated epithelial-mesenchymal transition (EMT) and impairs EMT-associated tumor invasion and metastasis. Our findings demonstrate that pharmacologically targeting Snail by CYD19 may exert potent therapeutic effects in patients with cancer.

Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis.

Recent interest in the control of bone metabolism has focused on a specialized subset of CD31hiendomucinhi vessels, which are reported to couple angiogenesis with osteogenesis. However, the underlying mechanisms that link these processes together remain largely undefined. Here we show that the zinc-finger transcription factor ZEB1 is predominantly expressed in CD31hiendomucinhi endothelium in human and mouse bone. Endothelial cell-specific deletion of ZEB1 in mice impairs CD31hiendomucinhi vessel formation in the bone, resulting in reduced osteogenesis. Mechanistically, ZEB1 deletion reduces histone acetylation on Dll4 and Notch1 promoters, thereby epigenetically suppressing Notch signaling, a critical pathway that controls bone angiogenesis and osteogenesis. ZEB1 expression in skeletal endothelium declines in osteoporotic mice and humans. Administration of Zeb1-packaged liposomes in osteoporotic mice restores impaired Notch activity in skeletal endothelium, thereby promoting angiogenesis-dependent osteogenesis and ameliorating bone loss. Pharmacological reversal of the low ZEB1/Notch signaling may exert therapeutic benefit in osteoporotic patients by promoting angiogenesis-dependent bone formation.

Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies.

Current antiangiogenic therapy is limited by its cytostatic property, scarce drug delivery to the tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a tumor endothelium-enriched zinc-finger transcription factor, during tumor progression. We discovered that the patients who had lung adenocarcinomas with high ZEB1 expression in tumor endothelium had increased prevalence of metastases and markedly reduced overall survival after the diagnosis of lung cancer. Endothelial ZEB1 deletion in tumor-bearing mice diminished tumor angiogenesis while eliciting persistent tumor vascular normalization by epigenetically repressing TGF-ß signaling. This consequently led to improved blood and oxygen perfusion, enhanced chemotherapy delivery and immune effector cell infiltration, and reduced tumor growth and metastasis. Moreover, targeting vascular ZEB1 remarkably potentiated the anticancer activity of nontoxic low-dose cisplatin. Treatment with low-dose anti-programmed cell death protein 1 (anti-PD-1) antibody elicited tumor regression and markedly extended survival in ZEB1-deleted mice, conferring long-term protective anticancer immunity. Collectively, we demonstrated that inactivation of endothelial ZEB1 may offer alternative opportunities for cancer therapy with minimal side effects. Targeting endothelium-derived ZEB1 in combination with conventional chemotherapy or immune checkpoint blockade therapy may yield a potent and superior anticancer effect.

A ZEB1/p53 signaling axis in stromal fibroblasts promotes mammary epithelial tumours.

Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours. However, the role of stromal ZEB1 in tumour progression remains unexplored. In this study, while interrogating human databases, we uncover a remarkable decrease in relapse-free survival of breast cancer patients expressing high ZEB1 levels in the stroma. Using a mouse model of breast cancer, we show that ZEB1 inactivation in stromal fibroblasts suppresses tumour initiation, progression and metastasis. We associate this with reduced extracellular matrix remodeling, immune cell infiltration and decreased angiogenesis. ZEB1 deletion in stromal fibroblasts increases acetylation, expression and recruitment of p53 to FGF2/7, VEGF and IL6 promoters, thereby reducing their production and secretion into the surrounding stroma. Importantly, p53 ablation in ZEB1 stroma-deleted mammary tumours sufficiently recovers the impaired cancer growth and progression. Our findings identify the ZEB1/p53 axis as a stroma-specific signaling pathway that promotes mammary epithelial tumours.

LW106, a novel indoleamine 2,3-dioxygenase 1 inhibitor, suppresses tumour progression by limiting stroma-immune crosstalk and cancer stem cell enrichment in tumour micro-environment.

BACKGROUND AND PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1) is emerging as an important new therapeutic target for treatment of malignant tumours characterized by dysregulated tryptophan metabolism. However, the antitumour efficacy of existing small-molecule inhibitors of IDO1 is still unsatisfactory and the underlying mechanism remains largely undefined. Hence, we discovered a novel potent small-molecule inhibitor of IDO1, LW106, and studied its antitumour effects and the underlying mechanisms in two tumour models. EXPERIMENTAL APPROACH: C57BL6 mice, athymic nude mice or Ido1-/- mice were inoculated with IDO1-expressing and -nonexpressing tumour cells and treated with vehicle, epacadostat or increasing doses of LW106. Xenografted tumours, plasma, spleens and other vital organs were harvested and subjected to kynurenine/tryptophan measurement and flow cytometric, histological and immunohistochemical analyses. KEY RESULTS: LW106 dose-dependently inhibited the outgrowth of xenografted tumours that were inoculated in C57BL6 mice but not nude mice or Ido1-/- mice, showing a stronger antitumour efficacy than epacadostat, an existing IDO1 inhibitor. LW106 substantially elevated intratumoural infiltration of proliferative Teff cells, while reducing recruitment of proliferative Treg cells and non-haematopoietic stromal cells such as endothelial cells and cancer-associated fibroblasts. LW106 treatment resulted in a reduced subpopulation of cancer stem cells (CSCs) in xenografted tumours in which fewer proliferative/invasive tumour cells and more apoptotic tumour cells were observed. CONCLUSIONS AND IMPLICATIONS: LW106 inhibits tumour outgrowth by limiting stroma-immune crosstalk and CSC enrichment in the tumour micro-environment. LW106 has potential as a immunotherapeutic agent for use in combination with immune checkpoint inhibitors and (or) chemotherapeutic drugs for cancer treatment.

Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer.

The zinc-finger transcription factor Snail1 is inappropriately expressed in breast cancer and associated with poor prognosis. While interrogating human databases, we uncovered marked decreases in relapse-free survival of breast cancer patients expressing high Snail1 levels in tandem with wild-type, but not mutant, p53. Using a Snail1 conditional knockout model of mouse breast cancer that maintains wild-type p53, we find that Snail1 plays an essential role in tumour progression by controlling the expansion and activity of tumour-initiating cells in preneoplastic glands and established tumours, whereas it is not required for normal mammary development. Growth and survival of preneoplastic as well as neoplastic mammary epithelial cells is dependent on the formation of a Snail1/HDAC1/p53 tri-molecular complex that deacetylates active p53, thereby promoting its proteasomal degradation. Our findings identify Snail1 as a molecular bypass that suppresses the anti-proliferative and pro-apoptotic effects exerted by wild-type p53 in breast cancer.