DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T cells.

We demonstrate that DNA hypomethylating agent (HMA) treatment can directly modulate the anti-tumor response and effector function of CD8+ T cells. In vivo HMA treatment promotes CD8+ T cell tumor infiltration and suppresses tumor growth via CD8+ T cell-dependent activity. Ex vivo, HMAs enhance primary human CD8+ T cell activation markers, effector cytokine production, and anti-tumor cytolytic activity. Epigenomic and transcriptomic profiling shows that HMAs vastly regulate T cell activation-related transcriptional networks, culminating with over-activation of NFATc1 short isoforms. Mechanistically, demethylation of an intragenic CpG island immediately downstream to the 3' UTR of the short isoform was associated with antisense transcription and alternative polyadenylation of NFATc1 short isoforms. High-dimensional single-cell mass cytometry analyses reveal a selective effect of HMAs on a subset of human CD8+ T cell subpopulations, increasing both the number and abundance of a granzyme Bhigh, perforinhigh effector subpopulation. Overall, our findings support the use of HMAs as a therapeutic strategy to boost anti-tumor immune response.

Epigenetic therapy induces transcription of inverted SINEs and ADAR1 dependency.

Cancer therapies that target epigenetic repressors can mediate their effects by activating retroelements within the human genome. Retroelement transcripts can form double-stranded RNA (dsRNA) that activates the MDA5 pattern recognition receptor1-6. This state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses7,8. However, the clinical efficacy of epigenetic therapies has been limited. To find targets that would synergize with the viral mimicry response, we sought to identify the immunogenic retroelements that are activated by epigenetic therapies. Here we show that intronic and intergenic SINE elements, specifically inverted-repeat Alus, are the major source of drug-induced immunogenic dsRNA. These inverted-repeat Alus are frequently located downstream of 'orphan' CpG islands9. In mammals, the ADAR1 enzyme targets and destabilizes inverted-repeat Alu dsRNA10, which prevents activation of the MDA5 receptor11. We found that ADAR1 establishes a negative-feedback loop, restricting the viral mimicry response to epigenetic therapy. Depletion of ADAR1 in patient-derived cancer cells potentiates the efficacy of epigenetic therapy, restraining tumour growth and reducing cancer initiation. Therefore, epigenetic therapies trigger viral mimicry by inducing a subset of inverted-repeats Alus, leading to an ADAR1 dependency. Our findings suggest that combining epigenetic therapies with ADAR1 inhibitors represents a promising strategy for cancer treatment.

Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia.

Progression to aggressive secondary acute myeloid leukaemia (sAML) poses a significant challenge in the management of myeloproliferative neoplasms (MPNs). Since the physiopathology of MPN is closely linked to the activation of interferon (IFN) signalling and that AML initiation and aggressiveness is driven by leukaemia stem cells (LSCs), we investigated these pathways in MPN to sAML progression. We found that high IFN signalling correlated with low LSC signalling in MPN and AML samples, while MPN progression and AML transformation were characterized by decreased IFN signalling and increased LSC signature. A high LSC to IFN expression ratio in MPN patients was associated with adverse clinical prognosis and higher colony forming potential. Moreover, treatment with hypomethylating agents (HMAs) activates the IFN signalling pathway in MPN cells by inducing a viral mimicry response. This response is characterized by double-stranded RNA (dsRNA) formation and MDA5/RIG-I activation. The HMA-induced IFN response leads to a reduction in LSC signature, resulting in decreased stemness. These findings reveal the frequent evasion of viral mimicry during MPN-to-sAML progression, establish the LSC-to-IFN expression ratio as a progression biomarker, and suggests that HMAs treatment can lead to haematological response in murine models by re-activating dsRNA-associated IFN signalling.

Metformin use and preeclampsia risk in women with diabetes: a two-country cohort analysis.

BACKGROUND: Metformin is a hypoglycaemic medication that has been proposed to treat or prevent preeclampsia. Combining national birth data from Scotland and Sweden, we investigated whether metformin used during pregnancy was associated with an altered risk of developing a hypertensive disorder of pregnancy. METHODS: We utilised data from two population-based cohorts: Scotland (2012-2018) and Sweden (2007-2019). Nulliparous women with gestational diabetes or type 2 diabetes who had birth outcome data linked with medications prescribed during pregnancy were included. The association between metformin prescription and hypertensive disorders of pregnancy was characterised using inverse probability weighted regression analysis, adjusting for variables that predict metformin use and potential confounders. Adverse neonatal outcomes were included as secondary outcomes. Results from both countries were then combined in a meta-analysis using a random effects model. RESULTS: The Scottish cohort included 3859 women with gestational diabetes or type 2 diabetes. Of these women, 30.8% (n = 1187) received at least one metformin prescription during pregnancy. For Sweden, 7771 women with gestational diabetes were included where 19.3% (1498) used metformin during pregnancy. Metformin prescription was not associated with an altered risk of any hypertensive disorder of pregnancy (Scotland adjusted relative risk (aRR) 0.88 [95% confidence interval (CI) 0.66-1.19]; Sweden aRR 1.08 [95% CI 0.86-1.37]) or preeclampsia (Scotland aRR 1.02 [95% CI 0.66-1.60]; Sweden aRR 1.00 [95% CI 0.72-1.39]). Combining adjusted results in a meta-analysis produced similar findings, with a pooled RR of 0.98 (95% CI 0.79-1.18) for any hypertensive disorder and RR 1.01 ([95% CI 0.73-1.28]) for preeclampsia. For neonatal outcomes, metformin was associated with a reduced risk of birthweight > 4500 g in Scotland (aRR 0.39 [95% CI 0.21-0.71]) but not in Sweden. There was no association between metformin and preterm birth or birthweight < 3rd or < 10th percentiles. Pooling results from both countries, metformin was not associated with adverse neonatal outcomes, including preterm birth (RR 1.00 [95% CI 0.89-1.13]), and birthweight < 10th percentile (RR 0.82 [95% CI 0.60-1.13]) or < 3rd percentile (RR 0.78 [95% CI 0.41-1.48]). CONCLUSIONS: In this two-country analysis, metformin use in pregnancy among women with diabetes was not associated with an altered risk of developing any hypertensive disorder of pregnancy. In the combined meta-analysis, metformin was not associated with an altered risk of adverse neonatal outcomes.

PRMT inhibition induces a viral mimicry response in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors.

Metformin in pregnancy and childhood neurodevelopmental outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to examine the impact of maternal metformin use during pregnancy on offspring neurodevelopmental outcomes. DATA SOURCES: MEDLINE, Embase, and Web of Science (Core Collection) were searched from inception until July 1, 2023. STUDY ELIGIBILITY CRITERIA: Studies of women who received treatment with metformin at any stage of pregnancy for any indication with neurodevelopmental data available for their offspring were included. Studies without a control group were excluded. Randomized controlled trials, case-control, cohort, and cross-sectional studies were included in the review. METHODS: Studies were screened for inclusion and data were extracted independently by 2 reviewers. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale for nonrandomized studies, and the Risk of Bias 2 tool for randomized trials. RESULTS: A total of 7 studies met the inclusion criteria, including a combined cohort of 14,042 children with 7641 children who were exposed and followed for up to 14 years of age. Metformin use during pregnancy was not associated with neurodevelopmental delay in infancy (relative risk, 1.09; 95% confidence interval, 0.54-2.17; 3 studies; 9668 children) or at ages 3 to 5 years (relative risk, 0.90; 95% confidence interval, 0.56-1.45; 2 studies; 6118 children). When compared with unexposed peers, metformin use during pregnancy was not associated with altered motor scores (mean difference, 0.30; 95% confidence interval, -1.15 to 1.74; 3 studies; 714 children) or cognitive scores (mean difference, -0.45; 95% confidence interval, -1.45 to 0.55; 4 studies; 734 children). Studies that were included were of high quality and deemed to be at low risk of bias. CONCLUSION: In utero exposure to metformin does not seem to be associated with adverse neurodevelopmental outcomes in children up to the age of 14 years. These findings provide reassurance to clinicians and pregnant women considering metformin use during pregnancy.

Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BACKGROUND: Imperfect adherence is a major barrier to effective primaquine radical cure of Plasmodium vivax. This study investigated the effect of reduced adherence on the risk of P. vivax recurrence. METHODS: Efficacy studies of patients with uncomplicated P. vivax malaria, including a treatment arm with daily primaquine, published between January 1999 and March 2020 were identified. Individual patient data from eligible studies were pooled using standardized methodology. Adherence to primaquine was inferred from i) the percentage of supervised doses and ii) the total mg/kg dose received compared to the target total mg/kg dose per protocol. The effect of adherence to primaquine on the incidence of P. vivax recurrence between days 7 and 90 was investigated by Cox regression analysis. RESULTS: Of 82 eligible studies, 32 were available including 6917 patients from 18 countries. For adherence assessed by percentage of supervised primaquine, 2790 patients (40.3%) had poor adherence (≤ 50%) and 4127 (59.7%) had complete adherence. The risk of recurrence by day 90 was 14.0% [95% confidence interval: 12.1-16.1] in patients with poor adherence compared to 5.8% [5.0-6.7] following full adherence; p = 0.014. After controlling for age, sex, baseline parasitaemia, and total primaquine dose per protocol, the rate of the first recurrence was higher following poor adherence compared to patients with full adherence (adjusted hazard ratio (AHR) = 2.3 [1.8-2.9]). When adherence was quantified by total mg/kg dose received among 3706 patients, 347 (9.4%) had poor adherence, 88 (2.4%) had moderate adherence, and 3271 (88.2%) had complete adherence to treatment. The risks of recurrence by day 90 were 8.2% [4.3-15.2] in patients with poor adherence and 4.9% [4.1-5.8] in patients with full adherence; p < 0.001. CONCLUSION: Reduced adherence, including less supervision, increases the risk of vivax recurrence.

Trends of Diabetes Mortality in Iran at National and Sub-National Levels from 1990 to 2015 and Its Association with Socioeconomic Factors.

Background: Following global commitments to prevent and control non-communicable diseases, we sought to estimate national and sub-national trends in diabetes mortality in Iran and assess its association with socioeconomic factors. Methods: In a systematic analytical study, to assess the correlation between diabetes mortality and socioeconomic factors, we used data obtained from the Death Registration System (DRS), the Spatio-temporal model and Gaussian Process Regression (GPR) levels and the diabetes mortality trends, which were estimated by sex, age and year at national and sub-national levels from 1990 to 2015. Results: Between the years 1990 and 2015, the age-standardized diabetes mortality rate (per 100,000) increased from 3.40 (95% UI: 2.33 to 4.99) to 7.72 (95% UI: 5.51 to 10.78) in males and from 4.66 (95% UI: 3.23 to 6.76) to 10.38 (95% UI: 7.54 to 14.23) in females. In 1990, the difference between the highest age-standardized diabetes mortality rate among males was 3.88 times greater than the lowest (5.97 vs. 1.54), and in 2015 this difference was 3.96 times greater (14.65 vs. 3.70). This provincial difference was higher among females and was 5.13 times greater in 1990 (8.41 vs. 1.64) and 5.04 times greater in 2015 (19.87 vs. 3.94). The rate of diabetes mortality rose with urbanization yet declined with an increase in wealth and years of schooling as the main socio-economic factors. Conclusion: The rising trend of diabetes mortality rate at the national level and the sub-national disparities associated with socioeconomic status in Iran warrant the implementation of specific interventions recommended by the '25 by 25' goal.

Introducing an efficient sampling method for national surveys with limited sample sizes: application to a national study to determine quality and cost of healthcare.

BACKGROUND: Sampling a small number of participants from an entire country is not straightforward. In this case, researchers reluctantly sample from a single setting or few settings, which limits the generalizability of findings. Therefore, there is a need to design efficient sampling method for small sample size surveys that can produce generalizable results at the country level. METHODS: Data comprised of twenty proxy variables to measure health services demands, structures, and outcomes of 413 districts of Iran. We used two data mining methods (hierarchical clustering method (HCM) and model-based clustering method (MCM)) to create homogenous groups of districts, i.e., strata based on these variables. We compared the internal and stability validity of the methods by statistical indices. An expert group checked the face validity of the methods, particularly regarding the total number of strata and the combination of districts in each stratum. The efficiency of selected method, which is measured by the inverse of variance, was compared with a simple random sampling (SRS) through simulation. The sampling design was tested in a national study in Iran, which aimed to evaluate the quality and costs of medical care for eight selected diseases by only recruiting 300 participants per disease at the country level. RESULTS: MCM and HCM divided the districts into eight and two clusters, respectively. The measures of internal and stability validity showed that clusters created by MCM were more separated, compact, and stable, thus forming our optimum strata. The probability of death from stroke, chronic obstructive pulmonary disease, and in-hospital mortality rate were the most important indicators that distinguished the eight strata. Based on the simulation results, MCM increased the efficiency of the sampling design up to 1.7 times compared to SRS. CONCLUSIONS: The use of data mining improved the efficiency of sampling up to 1.7 times greater than SRS and markedly reduced the number of strata to eight in the entire country. The proposed sampling design also identified key variables that could be used to classify districts in Iran for sampling from these target populations in the future studies.

Trends in the drowning mortality rate in Iran.

OBJECTIVE: The WHO estimates the global incidence of death by drowning to be about 300 000 cases per year. The objective of this study was to estimate the trend in mortality due to drowning in all provinces of Iran in all age groups and both genders from 1990 to 2015. STUDY DESIGN: The National and Subnational Burden of Diseases (NASBOD) project is a comprehensive project in Iran. It is based on the Global Burden of Disease study and includes novel methods to estimate the burden of diseases in Iran. METHODS: This study used the results of the mortality rate due to drowning as part of NASBOD and investigated the causes behind the mortality rates. The data set recorded mortality rates by 19 age groups and two genders with the corresponding subnational pattern during the time period from 1990 to 2015. RESULTS: The drowning mortality rate decreased in Iran from 1990 to 2015. From 1990 to 2015, the annual percentage change for males and females was -5.28% and -10.73%, respectively. There were 56 184 male and 21 589 female fatalities during the study period. The highest number of deaths was seen in 1993 with 4459, and the lowest number of fatalities was observed in 2015 with 903 deaths. CONCLUSION: Our data showed a decline in drowning mortality in Iran from 1990 to 2015, but the rates and declines varied by province. Our findings are of great importance to health officials and authorities in order to further reduce the burden of drowning.

Insight into blood pressure targets for universal coverage of hypertension services in Iran: the 2017 ACC/AHA versus JNC 8 hypertension guidelines.

BACKGROUND: We compared the prevalence, awareness, treatment, and control of hypertension in Iran based on two hypertension guidelines; the 2017 ACC/AHA -with an aggressive blood pressure target of 130/80 mmHg- and the commonly used JNC8 guideline cut-off of 140/90 mmHg. We shed light on the implications of the 2017 ACC/AHA for population subgroups and high-risk individuals who were eligible for non-pharmacologic and pharmacologic therapies. METHODS: Data was obtained from the Iran national STEPS 2016 study. Participants included 27,738 adults aged ≥25 years as a representative sample of Iranians. Regression models of survey design were used to examine the determinants of prevalence, awareness, treatment, and control of hypertension. RESULTS: The prevalence of hypertension based on JNC8 was 29.9% (95% CI: 29.2-30.6), which soared to 53.7% (52.9-54.4) based on the 2017 ACC/AHA. The percentage of awareness, treatment, and control were 59.2% (58.0-60.3), 80.2% (78.9-81.4), and 39.1% (37.4-40.7) based on JNC8, which dropped to 37.1% (36.2-38.0), 71.3% (69.9-72.7), and 19.6% (18.3-21.0), respectively, by applying the 2017 ACC/AHA. Based on the new guideline, adults aged 25-34 years had the largest increase in prevalence (from 7.3 to 30.7%). They also had the lowest awareness and treatment rate, contrary to the highest control rate (36.5%) between age groups. Compared with JNC8, based on the 2017 ACC/AHA, 24, 15, 17, and 11% more individuals with dyslipidaemia, high triglycerides, diabetes, and cardiovascular disease events, respectively, fell into the hypertensive category. Yet, based on the 2017 ACC/AHA, 68.2% of individuals falling into the hypertensive category were eligible for receiving pharmacologic therapy (versus 95.7% in JNC8). LDL cholesterol< 130 mg/dL, sufficient physical activity (Metabolic Equivalents≥600/week), and Body Mass Index were found to change blood pressure by - 3.56(- 4.38, - 2.74), - 2.04(- 2.58, - 1.50), and 0.48(0.42, 0.53) mmHg, respectively. CONCLUSIONS: Switching from JNC8 to 2017 ACC/AHA sharply increased the prevalence and drastically decreased the awareness, treatment, and control in Iran. Based on the 2017 ACC/AHA, more young adults and those with chronic comorbidities fell into the hypertensive category; these individuals might benefit from earlier interventions such as lifestyle modifications. The low control rate among individuals receiving treatment warrants a critical review of hypertension services.

Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies.

Histone deacetylase (HDAC) inhibitors (HDACis) have demonstrated activity in hematological and solid malignancies. Vorinostat, romidepsin, belinostat, and panobinostat are Food and Drug Administration-approved for hematological malignancies and inhibit class II and/or class I HDACs, including HDAC1, 2, 3, and 6. We combined genetic and pharmacological approaches to investigate whether suppression of individual or multiple Hdacs phenocopied broad-acting HDACis in 3 genetically distinct leukemias and lymphomas. Individual Hdacs were depleted in murine acute myeloid leukemias (MLL-AF9;Nras(G12D); PML-RARα acute promyelocytic leukemia [APL] cells) and Eµ-Myc lymphoma in vitro and in vivo. Strikingly, Hdac3-depleted cells were selected against in competitive assays for all 3 tumor types. Decreased proliferation following Hdac3 knockdown was not prevented by BCL-2 overexpression, caspase inhibition, or knockout of Cdkn1a in Eµ-Myc lymphoma, and depletion of Hdac3 in vivo significantly reduced tumor burden. Interestingly, APL cells depleted of Hdac3 demonstrated a more differentiated phenotype. Consistent with these genetic studies, the HDAC3 inhibitor RGFP966 reduced proliferation of Eµ-Myc lymphoma and induced differentiation in APL. Genetic codepletion of Hdac1 with Hdac2 was pro-apoptotic in Eµ-Myc lymphoma in vitro and in vivo and was phenocopied by the HDAC1/2-specific agent RGFP233. This study demonstrates the importance of HDAC3 for the proliferation of leukemia and lymphoma cells, suggesting that HDAC3-selective inhibitors could prove useful for the treatment of hematological malignancies. Moreover, our results demonstrate that codepletion of Hdac1 with Hdac2 mediates a robust pro-apoptotic response. Our integrated genetic and pharmacological approach provides important insights into the individual or combinations of HDACs that could be prioritized for targeting in a range of hematological malignancies.

ADAR1: from basic mechanisms to inhibitors.

Adenosine deaminase acting on RNA 1 (ADAR1) converts adenosine to inosine in double-stranded RNA (dsRNA) molecules, a process known as A-to-I editing. ADAR1 deficiency in humans and mice results in profound inflammatory diseases characterised by the spontaneous induction of innate immunity. In cells lacking ADAR1, unedited RNAs activate RNA sensors. These include melanoma differentiation-associated gene 5 (MDA5) that induces the expression of cytokines, particularly type I interferons (IFNs), protein kinase R (PKR), oligoadenylate synthase (OAS), and Z-DNA/RNA binding protein 1 (ZBP1). Immunogenic RNAs 'defused' by ADAR1 may include transcripts from repetitive elements and other long duplex RNAs. Here, we review these recent fundamental discoveries and discuss implications for human diseases. Some tumours depend on ADAR1 to escape immune surveillance, opening the possibility of unleashing anticancer therapies with ADAR1 inhibitors.

Validation of the self-reported diagnosis of diabetes mellitus, hypercholesterolemia, and hypertension in Iran; STEPS 2016.

Purpose: As a part of STEPwise approach to risk factor Surveillance (STEPS) study, our aim was to evaluate the validity of the self-reported diagnosis of diabetes (DM), hypertension (HTN), and hypercholesterolemia (Hyper-Chol) in the Iranian population. Methods: Using systematic proportional to size cluster sampling, 27,232 participants were included in our study. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) to assess the validity of self-reported diagnoses. Furthermore, logistic regression was employed to examine the relationship between the validity of self-reported diagnoses and sociodemographic and lifestyle factors. All analyses were performed using STATA version 14. Results: The PPV for self-report of DM, HTN, and Hyper-Chol were estimated to be 69%, 74% and 80%, and NPV measured up to 95%, 84%, and 50%, respectively. Positive/negative self-reports were more accurate among older (younger) individuals. Age had a negative correlation with the validity of self-reported Hyper-Chol but a positive correlation with the validity of self-reported DM and hypertension HTN. Additionally, an increase in BMI was associated with an increase/decrease in PPV and a decrease/increase in NPV across all diseases. Conclusion: Self-report studies hold value in situations where direct in-person interaction is not feasible, either due to prohibitive costs or restrictions imposed by infectious diseases (COVID-19). Self-report surveys are valuable tools in studying the epidemiology of diseases; however, the type of the disease, the study purpose, either finding sick people or healthy people, the age subgroups, and socioeconomic status should be taken into consideration.

Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer.

Viral mimicry describes the immune response induced by endogenous stimuli such as double-stranded RNA (dsRNA) from endogenous retroelements. Activation of viral mimicry has the potential to kill cancer cells or augment anti-tumor immune responses. Here, we systematically identify mechanisms of viral mimicry adaptation associated with cancer cell dependencies. Among the top hits is the RNA decay protein XRN1 as an essential gene for the survival of a subset of cancer cell lines. XRN1 dependency is mediated by mitochondrial antiviral signaling protein and protein kinase R activation and is associated with higher levels of cytosolic dsRNA, higher levels of a subset of Alus capable of forming dsRNA, and higher interferon-stimulated gene expression, indicating that cells die due to induction of viral mimicry. Furthermore, dsRNA-inducing drugs such as 5-aza-2'-deoxycytidine and palbociclib can generate a synthetic dependency on XRN1 in cells initially resistant to XRN1 knockout. These results indicate that XRN1 is a promising target for future cancer therapeutics.

Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways.

Inactivating mutations in SMARCB1 confer an oncogenic dependency on EZH2 in atypical teratoid rhabdoid tumors (ATRTs), but the underlying mechanism has not been fully elucidated. We found that the sensitivity of ATRTs to EZH2 inhibition (EZH2i) is associated with the viral mimicry response. Unlike other epigenetic therapies targeting transcriptional repressors, EZH2i-induced viral mimicry is not triggered by cryptic transcription of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a feedforward loop whereby these activated ISGs may reinforce dsRNA formation and viral mimicry. EZH2i also upregulates the expression of full-length LINE-1s, leading to genomic instability and cGAS/STING signaling in a process dependent on reverse transcriptase activity. Co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.

In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions.

Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR-Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential dropout effects in vitro and in vivo. MEN1 knockout in multiple solid cancer types does not impact cell proliferation in vitro but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, MEN1 knockout redistributes MLL1 chromatin occupancy, increasing H3K4me3 at repetitive genomic regions, activating double-stranded RNA expression and increasing neutrophil and CD8+ T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin-MLL interaction reduces tumor growth in a CD8+ T cell-dependent manner. These findings reveal tumor microenvironment-dependent oncogenic and tumor-suppressive functions of MEN1 and provide a rationale for targeting MEN1 in solid cancers.

The levels and trends of diabetes prevalence at national and sub-national levels in Iran (1990 - 2016).

Background: The increasing trends in Diabetes prevalence and its attributed burden emphasized as an important issue that needs serious and urgent attention, all over the word. We estimated the mean Fasting Plasma Glucose (FPG) and the prevalence of Diabetes in aged 25 years or older Iranian adults, by sex, age, province, and year through the time period of 1990 to 2016. Methods: In order to access the most comprehensive relevant data at the same time the systematic data searched added to the data of 5 national surveys and 7 sub-national population based investigations. Two round of modeling, including the Age-Spatio-Temporal and Gaussian Process Regression were used for estimation of mean FPG trend and uncertainties. To estimate Diabetes estimations in target groups, a crosswalk model was applies to the FPG estimates. The model reiterated separately for women and men. All of estimations standardized based on the Iran national census population of 2016 by year, age groups and sexes at national and sub-national levels. Results: In 2016, the number of the diabetic population was 4.43 (3.93-4.99) million (2.38 million women). Between 1990 and 2016, the age-standardized mean of FPG increased from 84.69 mg/dl (79.8-89.8) to 100.5 mg/dl (97.9-103.3) in women and from 82.7 mg/dl (78.3-87.5) to 98.8 mg/dl (96.2-101.4) in men. Simultaneously, with considerable difference, the Diabetes prevalence, has increased from 6.1% (4.7-7.8) to 9.8% (8.7-11.1) in women and from 5.0% 18 (3.8-6.3) to 8.1% (7.2-9.2) in men (75% attributed to population growth). Considering the geographical patterns, the greatest increment in the prevalence of Diabetes detected in the northwestern and the central provinces. Conclusion: Significant increasing trends of Diabetes led to alarming threat, which can make the strategies and goals of our prevention programs out of control. We should plan for more effective communicative interventions for prevention and management of Diabetes, to be designed, implemented and monitored based on the updated scientific evidence. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01197-2.

The levels and trends of metabolic risk factors in the elderly population at the national and sub-national scale in Iran from 1990 to 2016.

Purpose: Describing the trends of metabolic risk factors (MRFs) in the elderly population. Methods: We used modeled data from previous comprehensive systematic reviews for MRFs among adults aged ≥ 60 years. Two stages of age-specific Spatio-temporal modeling and Gaussian process regression were used to estimate the mean of MRFs. We used crosswalk modeling to estimate the prevalence of elevated and raised Total cholesterol (TC), overweight/obesity and obesity, hypertension, and diabetes. Estimates were analyzed based on combinations of sex, age, year, and province from 1990 to 2016. Results: Comparing prevalence estimates from 2016 with those of 1990, in the elderly population, the age-standardized prevalence of overweight/obesity, obesity, diabetes, and hypertension increased, conversely, the prevalence of hypercholesteremia decreased. The prevalence of hypertension increased about 141.5% and 129.9% in men and women respectively. The age-standardized prevalence of diabetes increased about 109.5% in females, and 116.0% in males. Prevalence of elevated TC at the national level decreased to 67.4% (64.1-70.4) in women and to 51.1% (47.5-54.8) in men. These findings were almost shown across provinces. In general, the northern and western provinces had the highest prevalence of overweight/obesity in women in 2016. Conclusion: The rising prevalence of most MRFs, as well as the greater prevalence and mean of all MRFs in women, necessitate effective public health policies to reduce the burden of non-communicable diseases and run preventive programs. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01297-z.