ABSTRACT
BACKGROUND: Previous studies have shown that peptides encoded by noncoding RNAs (ncRNAs) can be used as peptide drugs to alleviate diseases. We found that microRNA-31 (miR-31) is involved in the regulation of hypertension and that the peptide miPEP31, which is encoded by the primary transcript of miR-31 (pri-miR-31), can inhibit miR-31 expression. However, the role and mechanism of miPEP31 in hypertension have not been elucidated. METHODS: miPEP31 expression was determined by western blot analysis. miPEP31-deficient mice (miPEP31-/-) were used, and synthetic miPEP31 was injected into Ang II-induced hypertensive mice. Blood pressure was monitored through the tail-cuff method. Histological staining was used to evaluate renal damage. Regulatory T (Treg) cells were assessed by flow cytometry. Differentially expressed genes were analysed through RNA sequencing. The transcription factors were predicted by JASPAR. Luciferase reporter and electrophoretic mobility shift assays (EMSAs) were used to determine the effect of pri-miR-31 on the promoter activity of miPEP31. Images were taken to track the entry of miPEP31 into the cell. RESULTS: miPEP31 is endogenously expressed in target organs and cells related to hypertension. miPEP31 deficiency exacerbated but exogenous miPEP31 administration mitigated the Ang II-induced systolic blood pressure (SBP) elevation, renal impairment and Treg cell decreases in the kidney. Moreover, miPEP31 deletion increased the expression of genes related to Ang II-induced renal fibrosis. miPEP31 inhibited the transcription of miR-31 and promoted Treg differentiation by occupying the Cebpα binding site. The minimal functional domain of miPEP31 was identified and shown to regulate miR-31. CONCLUSION: miPEP31 was identified as a potential therapeutic peptide for treating hypertension by promoting Treg cell differentiation in vivo. Mechanistically, we found that miPEP31 acted as a transcriptional repressor to specifically inhibit miR-31 transcription by competitively occupying the Cebpα binding site in the pri-miR-31 promoter. Our study highlights the significant therapeutic effect of miPEP31 on hypertension and provides novel insight into the role and mechanism of miPEPs.
Subject(s)
Angiotensin II , Blood Pressure , Disease Models, Animal , Hypertension , Kidney , Mice, Inbred C57BL , Mice, Knockout , MicroRNAs , Promoter Regions, Genetic , T-Lymphocytes, Regulatory , Animals , MicroRNAs/metabolism , MicroRNAs/genetics , Hypertension/chemically induced , Hypertension/metabolism , Hypertension/physiopathology , Hypertension/genetics , Binding Sites , Blood Pressure/drug effects , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/metabolism , T-Lymphocytes, Regulatory/immunology , Kidney/metabolism , Kidney/pathology , Male , Mice , Gene Expression Regulation , Signal Transduction , CCAAT-Enhancer-Binding Proteins/metabolism , CCAAT-Enhancer-Binding Proteins/genetics , Antihypertensive Agents/pharmacology , HumansABSTRACT
AIM: To determine the association of the presence of diabetes and, among persons with diabetes, the age at type 2 diabetes mellitus (T2DM) onset, BMI and the interactive effect with the subsequent thyroid cancer risk. MATERIALS AND METHODS: We conducted a population register-based longitudinal cohort study in Shanghai, including 428 568 persons with new-onset T2DM matched with the general population. The risk of thyroid cancer among subgroups was calculated based on standardized incidence ratio (SIR), hazard ratio (HR) and Cox proportional hazards models. RESULTS: In total, 1142 thyroid cancer cases were identified during 8 years of follow-up, with an incidence rate of 59.01/100 000 person-years and a higher risk (SIR = 1.21) compared with the general population. The earlier age at T2DM onset and higher BMI were associated with an increasing risk of thyroid cancer independently (onset age <50, SIR: 1.46; BMI ≥30.0 kg/m2, SIR: 1.93), with the highest risk in patients with both BMI ≥30.0 kg/m2 and onset age <50 years (SIR = 3.91, HR = 3.04). Among patients with T2DM onset age <60 years, SIR increased with higher BMI, while there were no trends when onset age ≥60 years. Among patients with BMI ≥25.0 kg/m2, SIR increased with an earlier onset age, whereas no trends were shown in the BMI <24.9 kg/m2 groups. Obese (BMI ≥30.0 kg/m2) patients had a significantly higher HR of thyroid cancer only when T2DM onset age <60 years. CONCLUSIONS: Both earlier age of T2DM onset (<50 years) and higher BMI (≥30 kg/m2) contributed to the higher risk of thyroid cancer. Patients with young-onset T2DM and obesity are considered more vulnerable to thyroid cancer development.
Subject(s)
Age of Onset , Body Mass Index , Diabetes Mellitus, Type 2 , Thyroid Neoplasms , Humans , Thyroid Neoplasms/epidemiology , Thyroid Neoplasms/etiology , China/epidemiology , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/complications , Male , Female , Middle Aged , Adult , Longitudinal Studies , Risk Factors , Incidence , Aged , Cohort Studies , Obesity/complications , Obesity/epidemiology , Proportional Hazards ModelsABSTRACT
In recent years, the incidence of diabetes has been increasing rapidly, posing a serious threat to human health. Diabetic cardiomyopathy (DCM) is characterized by cardiomyocyte hypertrophy, myocardial fibrosis, apoptosis, ventricular remodeling, and cardiac dysfunction in individuals with diabetes, ultimately leading to heart failure and mortality. However, the underlying mechanisms contributing to DCM remain incompletely understood. With advancements in molecular biology technology, accumulating evidence has shown that numerous non-coding RNAs (ncRNAs) crucial roles in the development and progression of DCM. This review aims to summarize recent studies on the involvement of three types of ncRNAs (micro RNA, long ncRNA and circular RNA) in the pathophysiology of DCM, with the goal of providing innovative strategies for the prevention and treatment of DCM.
Subject(s)
Diabetic Cardiomyopathies , RNA, Circular , RNA, Long Noncoding , Humans , Diabetic Cardiomyopathies/genetics , Diabetic Cardiomyopathies/physiopathology , Diabetic Cardiomyopathies/metabolism , Animals , RNA, Circular/genetics , RNA, Circular/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Gene Expression Regulation , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Signal Transduction , Myocardium/pathology , Myocardium/metabolismABSTRACT
BACKGROUND: While liver cancer stem cells (CSCs) play a crucial role in hepatocellular carcinoma (HCC) initiation, progression, recurrence, and treatment resistance, the mechanism underlying liver CSC self-renewal remains elusive. We aim to characterize the role of Methyltransferase 16 (METTL16), a recently identified RNA N6-methyladenosine (m6A) methyltransferase, in HCC development/maintenance, CSC stemness, as well as normal hepatogenesis. METHODS: Liver-specific Mettl16 conditional KO (cKO) mice were generated to assess its role in HCC pathogenesis and normal hepatogenesis. Hydrodynamic tail-vein injection (HDTVi)-induced de novo hepatocarcinogenesis and xenograft models were utilized to determine the role of METTL16 in HCC initiation and progression. A limiting dilution assay was utilized to evaluate CSC frequency. Functionally essential targets were revealed via integrative analysis of multi-omics data, including RNA-seq, RNA immunoprecipitation (RIP)-seq, and ribosome profiling. RESULTS: METTL16 is highly expressed in liver CSCs and its depletion dramatically decreased CSC frequency in vitro and in vivo. Mettl16 KO significantly attenuated HCC initiation and progression, yet only slightly influenced normal hepatogenesis. Mechanistic studies, including high-throughput sequencing, unveiled METTL16 as a key regulator of ribosomal RNA (rRNA) maturation and mRNA translation and identified eukaryotic translation initiation factor 3 subunit a (eIF3a) transcript as a bona-fide target of METTL16 in HCC. In addition, the functionally essential regions of METTL16 were revealed by CRISPR gene tiling scan, which will pave the way for the development of potential inhibitor(s). CONCLUSIONS: Our findings highlight the crucial oncogenic role of METTL16 in promoting HCC pathogenesis and enhancing liver CSC self-renewal through augmenting mRNA translation efficiency.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Neoplastic Stem Cells , Animals , Humans , Mice , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Self Renewal/genetics , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Methyltransferases/genetics , Methyltransferases/metabolism , Neoplastic Stem Cells/pathology , Protein Biosynthesis , Ribosomes/metabolism , RNAABSTRACT
OBJECTIVE: Diabetes presenting at a younger age has a more aggressive nature. We aimed to explore the association of age at type 2 diabetes mellitus (T2DM) diagnosis with subsequent cancer incidence in a large Chinese population. RESEARCH DESIGN AND METHODS: The prospective population-based longitudinal cohort included 428,568 newly diagnosed T2DM patients from 2011 to 2018. Participants were divided into six groups according to their age at diagnosis: 20-54, 55-59, 60-64, 65-69, 70-74, and ≥75 years. The incidence of overall and 14 site-specific cancers was compared with the Shanghai general population including 100,649,346 person-years. RESULTS: A total of 18,853 and 582,643 overall cancer cases were recorded in the T2DM cohort and the general population. The age-standardized rate of overall cancer in T2DM patients was 501 (95% CI: 491, 511) per 100,000 person-years, and the standardized incidence ratio (SIR) was 1.10 (1.09, 1.12). Younger age at T2DM diagnosis was associated with higher incidence of overall and site-specific cancers. SIRs for overall cancer with T2DM diagnosis at ages 20-54, 55-59, 60-64, 65-69, 70-74, and ≥75 years were 1.48 (1.41, 1.54), 1.30 (1.25, 1.35), 1.19 (1.15, 1.23), 1.16 (1.12, 1.20), 1.06 (1.02, 1.10), and 0.86 (0.84, 0.89), respectively. Similar trends were observed for site-specific cancers, including respiratory, colorectum, stomach, liver, pancreatic, bladder, central nervous system, kidney, and gallbladder cancer and lymphoma among both males and females. CONCLUSIONS: Our findings highlight the necessity of stratifying management for T2DM according to age of diagnosis. As with a range of vascular outcomes, age-standardized cancer risks are greater in earlier compared with later onset T2DM.
Subject(s)
Diabetes Mellitus, Type 2 , Neoplasms , Male , Female , Humans , Child, Preschool , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/epidemiology , Incidence , Risk Factors , Prospective Studies , China/epidemiology , Neoplasms/diagnosis , Neoplasms/epidemiologyABSTRACT
To explore whether granulosa cell (GC)-derived exosomes (GC-Exos) and follicular fluid-derived exosomes (FF-Exos) have functional similarities in follicle development and to establish relevant experiments to validate whether GC-Exos could serve as a potential substitute for follicular fluid-derived exosomes to improve folliculogenesis. GC-Exos were characterized. MicroRNA (miRNA) profiles of exosomes from human GCs and follicular fluid were analyzed in depth. The signature was associated with folliculogenesis, such as phosphatidylinositol 3 kinases-protein kinase B signal pathway, mammalian target of rapamycin signal pathway, mitogen-activated protein kinase signal pathway, Wnt signal pathway, and cyclic adenosine monophosphate signal pathway. A total of five prominent miRNAs were found to regulate the above five signaling pathways. These miRNAs include miRNA-486-5p, miRNA-10b-5p, miRNA-100-5p, miRNA-99a-5p, and miRNA-21-5p. The exosomes from GCs and follicular fluid were investigated to explore the effect on folliculogenesis by injecting exosomes into older mice. The proportion of follicles at each stage is counted to help us understand folliculogenesis. Exosomes derived from GCs were isolated successfully. miRNA profiles demonstrated a remarkable overlap between the miRNA profiles of FF-Exos and GC-Exos. The shared miRNA signature exhibited a positive influence on follicle development and activation. Furthermore, exosomes derived from GCs and follicular fluid promoted folliculogenesis in older female mice. Exosomes derived from GCs had similar miRNA profiles and follicle-promoting functions as follicular fluid exosomes. Consequently, GC-Exos are promising for replacing FF-Exos and developing new commercial reagents to improve female fertility.
Subject(s)
Exosomes , Granulosa Cells , MicroRNAs , Ovarian Follicle , Animals , Female , Humans , Mice , Exosomes/genetics , Exosomes/metabolism , Follicular Fluid/metabolism , Granulosa Cells/metabolism , MicroRNAs/genetics , Ovarian Follicle/metabolism , Signal TransductionABSTRACT
BACKGROUND: This study aimed to investigate the risks of all-cause and cardiovascular mortality associated with blood pressure (BP) levels of 130-139/80-89 mmHg in Chinese adults with different glucose metabolism, during a long-term follow-up of over 20 years. METHODS: A prospective population-based cohort of 2,132 adults in Shanghai was established in 2002 and followed for 21 years. The association between BP categories and mortality was assessed, and the risk was further analyzed using multiple Cox regression analysis by combining BP and blood glucose categories. RESULTS: The final analysis included 2,004 participants, with 397 all-cause and 166 cardiovascular mortality. The incidence of all-cause and cardiovascular mortality per 1,000 person-years for different BP categories were as follows: BP < 130/80 mmHg (4.5 and 1.3), 130-139/80-89 mmHg (7.7 and 2.9), and ≥ 140/90 mmHg or treated groups (19.9 and 8.7), respectively. After adjusting for age, sex, and other factors, BP ≥ 140/90 mmHg was significantly associated with a higher risk of mortality across different blood glucose categories. However, using BP < 130/80 mmHg and normoglycemia as the reference, a BP of 130-139/80-89 mmHg was significantly associated with higher risks of all-cause (hazard ratio 3.30 [95% confidence interval 1.48-7.38], P < 0.01) and cardiovascular mortality (9.60 [1.93-47.7], P < 0.01) in diabetes, but not in those with normoglycemia or prediabetes. CONCLUSIONS: BP of 130-139/80-89 mmHg may lead to a significantly higher risk of all-cause and cardiovascular mortality in Chinese adults with diabetes, but not in those with normoglycemia or prediabetes. This suggests that the targeted BP for people with diabetes should be < 130-139/80-89 mmHg.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus , Hypertension , Prediabetic State , Adult , Humans , Blood Pressure , Hypertension/epidemiology , Prediabetic State/complications , Cardiovascular Diseases/epidemiology , Blood Glucose/metabolism , Prospective Studies , China/epidemiology , Diabetes Mellitus/epidemiology , Risk FactorsABSTRACT
AIMS: The study aimed to investigate the relationship between cumulative HbA1c exposure and cardiovascular events in patients with type 2 diabetes (T2D). METHODS: This study included 9307 participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Cumulative HbA1c exposure was calculated as the area under the curve during exposure time. RESULTS: After adjusting for covariates, a 1-SD increase in cumulative HbA1c exposure was significantly associated with a higher risk of the primary outcome (HR 1.32, 95 % CI: 1.22-1.43, P < 0.001), all-cause mortality (HR 1.33, 95 % CI: 1.21-1.46, P < 0.001), and cardiovascular death (HR 1.45, 95 % CI: 1.27-1.67, P < 0.001). These associations were independent of baseline HbA1c and the first HbA1c level after enrollment. Cross-tabulation analysis showed that participants in the intensive-therapy group with high baseline HbA1c and cumulative HbA1c exposure had a significantly higher risk of primary outcome, all-cause mortality and cardiovascular death. CONCLUSIONS: Higher cumulative HbA1c exposure was significantly associated with an increased risk of the primary outcome, all-cause mortality and cardiovascular death among T2D patients. Patients with T2D should strive for stable glycemic control to reduce their risk of cardiovascular events, and that those with high baseline HbA1c may require more intensive therapy to achieve this goal.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Humans , Blood Glucose , Cardiovascular Diseases/etiology , Cardiovascular Diseases/complications , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Glycated Hemoglobin , Heart Disease Risk Factors , Risk FactorsABSTRACT
TET2 is recurrently mutated in acute myeloid leukemia (AML) and its deficiency promotes leukemogenesis (driven by aggressive oncogenic mutations) and enhances leukemia stem cell (LSC) self-renewal. However, the underlying cellular/molecular mechanisms have yet to be fully understood. Here, we show that Tet2 deficiency significantly facilitates leukemogenesis in various AML models (mediated by aggressive or less aggressive mutations) through promoting homing of LSCs into bone marrow (BM) niche to increase their self-renewal/proliferation. TET2 deficiency in AML blast cells increases expression of Tetraspanin 13 (TSPAN13) and thereby activates the CXCR4/CXCL12 signaling, leading to increased homing/migration of LSCs into BM niche. Mechanistically, TET2 deficiency results in the accumulation of methyl-5-cytosine (m5C) modification in TSPAN13 mRNA; YBX1 specifically recognizes the m5C modification and increases the stability and expression of TSPAN13 transcripts. Collectively, our studies reveal the functional importance of TET2 in leukemogenesis, leukemic blast cell migration/homing, and LSC self-renewal as an mRNA m5C demethylase.
Subject(s)
Dioxygenases , Leukemia, Myeloid, Acute , Humans , RNA, Messenger/genetics , RNA, Messenger/metabolism , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Bone Marrow/metabolism , Carcinogenesis/metabolism , Stem Cells/metabolism , Demethylation , Neoplastic Stem Cells/metabolism , Tetraspanins/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Dioxygenases/metabolismABSTRACT
INTRODUCTION: Blood glucose monitoring was vitally important in diabetic kidney disease (DKD) patients for preventing complications and improving survival rates. The associations between glycemic variability and blood biochemical indicators were underestimated in patients with DKD undergoing hemodialysis. Therefore, we primarily aimed to investigate the glycemic variability and 1-year risk of cardiovascular disease events in diabetic hemodialysis patients. And we secondarily aimed to explore the association between glycemic variability and blood biochemical indicators. METHODS: In total, 27 patients were included in the final analysis. Continuous glucose monitoring (CGM) was used to evaluate glucose variability for 14 days. Patients were divided into two groups by the cutoff level of time in range (TIR; >70% or ≤70%). The three-point major adverse cardiovascular event (3P MACE) was recorded within 1 year. RESULTS: After 1 year of follow-up, 4 patients in the high-TIR group and 3 patients in the low-TIR group had 3p MACE. Higher low blood glucose index (LBGI) level in diabetic hemodialysis patients increased the risk of 3p MACE outcomes (HR = 2.37, p = 0.018). And the level of albumin was positively associated with LBGI (ß = 0.51, p = 0.036). The plasma levels of albumin, glycosylated hemoglobin, and hemoglobin were positively associated with other CGM parameters. CONCLUSION: LBGI during 14 days was positively associated with the risk of cardiovascular events in diabetic hemodialysis patients.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Hypoglycemia , Humans , Blood Glucose/analysis , Blood Glucose Self-Monitoring , Hypoglycemia/complications , Renal Dialysis/adverse effects , Glucose , Albumins , Cardiovascular Diseases/complicationsABSTRACT
AIMS: We investigated the associations between time in target range (TTR) of blood pressure (BP) and cardiovascular outcomes in patients with diabetes. METHODS: 4651 participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) BP trial were included in the present study. The diastolic BP target range was defined as 70 to 80 mm Hg, and the systolic as 120 to 140 mm Hg and 110 to 130 mm Hg for the standard and intensive therapy, respectively. RESULTS: After adjusting for covariates, 1-SD increase of diastolic TTR was significantly associated with lower risks of primary outcome (HR 0.82, 95% CI: 0.74-0.91, P < 0.001; HR 0.86, 95% CI: 0.77-0.95, P = 0.0044, as well as nonfatal myocardial infarction (HR 0.79, 95% CI: 0.69-0.91, P < 0.001). Meanwhile, systolic TTR was significantly associated with various cardiovascular outcomes (P ≤ 0.016) in fully-adjusted models. The diastolic TTR sustained significance in myocardial infarction when systolic blood pressure average was higher than 120 mm Hg. CONCLUSIONS: In patients with diabetes, TTR of diastolic and systolic BP was independently associated with lower risks of major outcomes. The diastolic BP within the optimal target range was considerably important for reducing the risk of myocardial infarction, even when systolic BP was under stable control.
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BACKGROUND: Quarantine due to the COVID-19 pandemic may have created great psychological stress among vulnerable populations. We aimed to investigate the prevalence of anxiety and explore the association between physical activities (PA) and anxiety risk in people with non-communicable diseases during the period of COVID-19 lockdown. METHODS: We conducted a cross-sectional telephone survey from February 25 to April 20, 2020, the period of COVID-19 lockdown in Shanghai. Up to 8000 patients with type 2 diabetes and/or hypertension were selected using multi-stage cluster random sampling. PA level was measured based on the International Physical Activity Questionnaire using Metabolic Equivalent for Task scores, while symptoms of anxiety were assessed by the 7-item Generalized Anxiety Disorder scale. Multiple logistic regression analyses were performed to evaluate the associations of type and level of PA with the risk of anxiety. RESULTS: Of a total 4877 eligible patients, 2602 (53.4%) reported with anxiety, and 2463 (50.5%), 123 (2.5%) and 16 (0.3%) reported with mild, moderate, and severe anxiety. The prevalence of anxiety was higher in the females, the elders, non-smokers, non-drinkers, and patients with diabetes, and the associations of anxiety with sex, age, smoking, drinking and diagnosis of diabetes were significant. A significant negative association was observed for housework activities (OR 0.53, 95%CI: [0.45, 0.63], p < 0.001) and trip activities (OR 0.55, 95%CI: [0.48, 0.63], p < 0.001) with anxiety, but no significant was found for exercise activities (OR 1.06, 95%CI: [0.94, 1.20], p = 0.321). Compared with patients with a low PA level, those with a moderate (OR 0.53, 95%CI: [0.44, 0.64], p < 0.001) or a high PA level (OR 0.51, 95%CI: [0.43, 0.51], p < 0.001) had a lower prevalence of anxiety. CONCLUSION: This study demonstrates a higher prevalence of anxiety in patients with hypertension, diabetes, or both during the COVID-19 lockdown. The negative associations of housework and trip activities with anxiety highlight the potential benefit of PA among patients with non-communicable diseases.
Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Noncommunicable Diseases , Female , Humans , Aged , COVID-19/epidemiology , Cross-Sectional Studies , Diabetes Mellitus, Type 2/epidemiology , SARS-CoV-2 , Prevalence , Pandemics , Noncommunicable Diseases/epidemiology , Depression/epidemiology , China/epidemiology , Communicable Disease Control , Anxiety/epidemiology , Anxiety/diagnosis , ExerciseABSTRACT
Background: The aim of the study is to estimate the incidence of pancreatic cancer among individuals with new-onset type 2 Diabetes (T2DM) and evaluate the relationship of pancreatic cancer risk with age at diabetes onset and diabetes duration. Methods: This longitudinal cohort study included 428,362 new-onset T2DM patients in Shanghai and Mendelian randomization (MR) in the east-Asian population were used to investigate the association. Incidence rates of pancreatic cancer in all patients and by subgroups were calculated and compared to the general population. Findings: A total of 1056 incident pancreatic cancer cases were identified during eight consecutive years of follow-up. The overall pancreatic cancer annual incidence rate was 55·28/100,000 person years in T2DM patients, higher than that in the general population, with a standardized incidence ratio (SIR) of 1·54 (95% confidence interval [CI], 1·45-1·64). The incidence of pancreatic cancer increased with age and a significantly higher incidence was observed in the older groups with T2DM. However, the relative pancreatic cancer risk was inversely related to age of T2DM onset, and a higher SIR of 5·73 (95%CI, 4·49-7·22) was observed in the 20-54 years old group. The risk of pancreatic cancer was elevated at any diabetes duration. Fasting blood glucose ≥10·0 mmol/L was associated with increased risk of pancreatic cancer. MR analysis indicated a positive association between T2DM and pancreatic cancer risk. Interpretation: Efforts toward early and close follow-up programs, especially in individuals with young-onset T2DM, and the improvement of glucose control might represent effective strategies for improving the detection and results of treatment of pancreatic cancer. Funding: Chinese National Natural Science Foundation.
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Introduction: The risks associated with non-albuminuric chronic kidney disease (CKD) have been investigated in diabetes mellitus but not in hypertensive patients. The objective of this study was to investigate the risks associated with non-albuminuric CKD in treated hypertensive patients in the Systolic Blood Pressure Intervention Trial (SPRINT) population. Methods: Based on baseline albuminuria status (urine albumin/creatinine ratio [UACR], ≥30 or <30 mg/g) and the levels of estimated glomerular filtration rate ([eGFR], ≥60, 45-59, or <45 mL/min/1.73 m2), participants were classified into six subgroups to assess the risks associated with the primary outcome and mortality. The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or mortality from cardiovascular causes. Results: During a median follow-up of 3.26 years in 8,866 hypertensive patients, there were 352 deaths and 547 participants with the primary outcome. In adjusted Cox regression analysis using non-CKD and non-albuminuria (eGFR ≥60 mL/min/1.73 m2 combined with UACR <30 mg/g) as reference, albuminuria whether combined with CKD or not, showed significantly higher risk of both primary outcome and all-cause mortality in the total population. Whereas, non-albuminuria only combined with eGFR <45 mL/min/1.73 m2 showed significantly higher risk of both primary outcome and all-cause mortality in the intensive-therapy group. Discussion: Non-albuminuric CKD did have higher risk of all-cause and CVD mortality only if the eGFR <45 mL/min/1.73 m2. Increased albuminuria conferred higher risk of primary outcome and all-cause mortality irrespective the levels of eGFR. Clinical trial registration: ClinicalTrials.gov, number: NCT01206062.
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Purpose: The purpose of this study was to assess the surgical outcomes of patients with primary aldosteronism when surgery was based only on CT finding of unilateral adenoma without adrenal vein sampling (AVS). Methods: This is a retrospective review of the records of patients who had undergone retroperitoneal laparoscopic adrenalectomy for primary aldosteronism based on CT scan finding of unilateral adenoma and had a follow-up of at least 6-12 months from January 2012 to December 2020 in a single center; decision for adrenalectomy was based on CT scan, and AVS was not used. The clinical and biochemical outcomes were accessed using the standardized primary aldosteronism surgical outcome (PASO) criteria. Patient's demographics and preoperative factors were analyzed to assess for independent predictor of surgical success. Results: According to the PASO criteria, 172 patients finally enrolled in the training dataset, and 20 patients enrolled in the validation dataset. In the training dataset, complete clinical success was achieved in 71 patients (41.3%), partial success in 87 (50.6%), and absent success in 14 (8.1%). Biochemical outcomes showed that 151 patients (87.8%) were completely cured, 14 patients (8.1%) got a partial biochemical success, and an absent biochemical success was found in seven patients (4.1%). Multivariate logistic regression analysis showed that age, body mass index (BMI), tumor size, mean arterial pressure (MAP), and serum potassium were the most independent factors for incomplete biochemical success. Based on the results of statistical analysis, our study constructed a nomogram prognostic evaluation model for patients after unilateral primary aldosterone surgery. Conclusions: Laparoscopic adrenalectomy for patients with primary aldosteronism base on CT scan finding of a unilateral adenoma without AVS had a high rate of complete biochemical cure at 12 months. Risk factors for incomplete biochemical success include age, BMI, tumor size, MAP, and serum potassium. Our study constructed a nomogram prognostic evaluation model for patients after unilateral primary aldosterone surgery. The nomogram accurately and reliably predicted the incomplete biochemical success.
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Ovarian cancer (OC) has the greatest mortality rate among gynecological cancers, with a five-year survival rate of <50%. Contemporary adjuvant chemotherapy mostly fails in the case of OCs that are refractory, metastatic, recurrent, and drug-resistant. Emerging ultrasound (US)-mediated technologies show remarkable promise in overcoming these challenges. Absorption of US waves by the tissue results in the generation of heat due to its thermal effect causing increased diffusion of drugs from the carriers and triggering sonoporation by increasing the permeability of the cancer cells. Certain frequencies of US waves could also produce a cavitation effect on drug-filled microbubbles (MBs, phospholipid bilayers) thereby generating shear force and acoustic streaming that could assist drug release from the MBs, and promote the permeability of the cell membrane. A new class of nanoparticles that carry therapeutic agents and are guided by US contrast agents for precision delivery to the site of the ovarian tumor has been developed. Phase-shifting of nanoparticles by US sonication has also been engineered to enhance the drug delivery to the ovarian tumor site. These technologies have been used for targeting the ovarian cancer stem cells and protein moieties that are particularly elevated in OCs including luteinizing hormone-releasing hormone, folic acid receptor, and vascular endothelial growth factor. When compared to healthy ovarian tissue, the homeostatic parameters at the tissue microenvironment including pH, oxygen levels, and glucose metabolism differ significantly in ovarian tumors. US-based technologies have been developed to take advantage of these tumor-specific alterations for precision drug delivery. Preclinical efficacy of US-based targeting of currently used clinical chemotherapies presented in this review has the potential for rapid human translation, especially for formulations that use all substances that are deemed to be generally safe by the U.S. Food and Drug Administration.
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Background: Controlled attenuation parameter (CAP) without the guidance of the grey scale sonogram was a classic method in the quantitative evaluation of liver steatosis, it is recommended by international guidelines. Our study aimed to compare the diagnostic efficiency of a new real-time visual liver steatosis analysis (LiSA) versus CAP in chronic hepatitis B patients with liver steatosis. Methods: Patients were enrolled who underwent liver biopsy and received both LiSA (Hepatus, Mindray, probe LFP5-1U/s, China) and CAP (FibroScan502, Echosens, probe M, France) measurement simultaneously in our hospital from November 2018 to December 2019. The obtained values were both expressed as dB/m. Based on the liver fat content validated by liver biopsy, these patients were divided into the S0 group (fat content <5%) and S1 group (fat content ≥5%). The efficiency of the LiSA and CAP value in the diagnosis of liver steatosis was evaluated. Independent factors influencing the LiSA value were predicted by correlation analysis and multiple linear regression analysis. Results: A total of 151 patients were included in the analysis according to the exclusion criteria from 304 enrolled liver biopsy chronic hepatitis B (CHB) patients. Both LiSA and CAP successfully differentiated the S0 group from the S1 group. Receiver operating characteristic (ROC) curves showed that both LiSA and CAP had good diagnostic performance [area under the ROC curve area under the curve (AUC) >0.7] in evaluating liver steatosis, while there was no significant difference between the 2 methods (AUC 0.825 vs. 0.798, P=0.067). Using the optimal cutoff point, the specificity and sensitivity of LiSA in diagnosing liver steatosis were 89.18% and 79.16%, respectively. The specificity and sensitivity of CAP in diagnosing liver steatosis were 87.20% and 76.31%, respectively. Conclusions: Both LiSA and CAP are efficient for evaluating liver steatosis noninvasively.
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BACKGROUND: Current guidelines for dyslipidemia management recommend that the LDL-C goal be lower than 70 mg/dL. The present study investigated the prognostic significance of visit-to-visit variability in LDL-C, and minimum and maximum LDL-C during follow-up in diabetes mellitus. METHODS: The risk of outcomes in relation to visit-to-visit LDL-C variability was investigated in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial. LDL-C variability indices were coefficient of variation (CV), variability independent of the mean (VIM), and average real variability (ARV). Multivariable Cox proportional hazards models were employed to estimate the adjusted hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Compared with the placebo group (n=2667), the fenofibrate therapy group (n=2673) had a significantly (P<0.01) lower mean plasma triglyceride (152.5 vs. 178.6 mg/dL), and total cholesterol (158.3 vs.162.9 mg/dL) but a similar mean LDL-C during follow-up (88.2 vs. 88.6 mg/dL, P>0.05). All three variability indices were associated with primary outcome, total mortality and cardiovascular mortality both in the total population and in the fenofibrate therapy group but only with primary outcome in the placebo group. The minimum LDL-C but not the maximum during follow-up was significantly associated with various outcomes in the total population, fenofibrate therapy and placebo group. The minimum LDL-C during follow-up ≥70 mg/dL was associated with an increased risk for various outcomes. CONCLUSIONS: Visit-to-visit variability in LDL-C was a strong predictor of outcomes, independent of mean LDL-C. Patients with LDL-C controlled to less than 70 mg/dL during follow-up might have a benign prognosis. ClinicalTrials.gov number: NCT00000620.
Subject(s)
Cholesterol, LDL/blood , Diabetes Mellitus, Type 2/blood , Cholesterol/blood , Coronary Disease/diagnosis , Coronary Disease/mortality , Coronary Disease/prevention & control , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/mortality , Dyslipidemias/drug therapy , Female , Fenofibrate/therapeutic use , Humans , Hypolipidemic Agents/therapeutic use , Male , Middle Aged , Prognosis , Proportional Hazards Models , Time Factors , Triglycerides/bloodABSTRACT
Following the publication of this paper, the authors contacted the Editorial Office to request that the article be retracted on account of an inability to obtain consistent results after having repeated the experiments portrayed in Figs. 1B and 3B. Independently, it was drawn to the Editor's attention that certain of the western blotting data shown in these figures were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that these other articles were under consideration for publication at the same time as the above article was submitted for publication to Molecular Medicine Reports, the Editor has agreed to the authors' request that this article should be retracted from the Journal. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 12: 753759, 2015; DOI: 10.3892/mmr.2015.3425].
ABSTRACT
Following the publication of the above article, the authors have requested that it be retracted. They alerted the Editorial Office to the fact that the same data, albeit with a different view, had been selected to show the 'CON' and 'NC' experiments for the colonyformation assays featured in Fig. 6. The Editor has agreed to the authors' request that the paper be retracted. All the authors agree to this retraction, and apologize for any inconvenience caused. [the original article was published in Molecular Medicine Reports 11: 5966, 2015; DOI: 10.3892/mmr.2014.2732].