Cohort profile for the Tongji Cardiovascular Health Study: a prospective multiomics cohort study.

PURPOSE: The Tongji Cardiovascular Health Study aimed to further explore the onset and progression mechanisms of cardiovascular disease (CVD) through a combination of traditional cohort studies and multiomics analysis, including genomics, metabolomics and metagenomics. STUDY DESIGN AND PARTICIPANTS: This study included participants aged 20-70 years old from the Geriatric Health Management Centre of Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology. After enrollment, each participant underwent a comprehensive series of traditional and novel cardiovascular risk factor assessments at baseline, including questionnaires, physical examinations, laboratory tests, cardiovascular health assessments and biological sample collection for subsequent multiomics analysis (whole genome sequencing, metabolomics study from blood samples and metagenomics study from stool samples). A biennial follow-up will be performed for 10 years to collect the information above and the outcome data. FINDINGS TO DATE: A total of 2601 participants were recruited in this study (73.4% men), with a mean age of 51.5±11.5 years. The most common risk factor is overweight or obesity (54.8%), followed by hypertension (39.7%), hyperlipidaemia (32.4%), current smoking (23.9%) and diabetes (12.3%). Overall, 13.1% and 48.7% of men and women, respectively, did not have any of the CVD risk factors (hypertension, hyperlipidaemia, diabetes, cigarette smoking and overweight or obesity). Additionally, multiomics analyses of a subsample of the participants (n=938) are currently ongoing. FUTURE PLANS: With the progress of the cohort follow-up work, it is expected to provide unique multidimensional and longitudinal data on cardiovascular health in China.

A deep learning system for predicting time to progression of diabetic retinopathy.

Diabetic retinopathy (DR) is the leading cause of preventable blindness worldwide. The risk of DR progression is highly variable among different individuals, making it difficult to predict risk and personalize screening intervals. We developed and validated a deep learning system (DeepDR Plus) to predict time to DR progression within 5 years solely from fundus images. First, we used 717,308 fundus images from 179,327 participants with diabetes to pretrain the system. Subsequently, we trained and validated the system with a multiethnic dataset comprising 118,868 images from 29,868 participants with diabetes. For predicting time to DR progression, the system achieved concordance indexes of 0.754-0.846 and integrated Brier scores of 0.153-0.241 for all times up to 5 years. Furthermore, we validated the system in real-world cohorts of participants with diabetes. The integration with clinical workflow could potentially extend the mean screening interval from 12 months to 31.97 months, and the percentage of participants recommended to be screened at 1-5 years was 30.62%, 20.00%, 19.63%, 11.85% and 17.89%, respectively, while delayed detection of progression to vision-threatening DR was 0.18%. Altogether, the DeepDR Plus system could predict individualized risk and time to DR progression over 5 years, potentially allowing personalized screening intervals.

Lower BCL11B expression is associated with adverse clinical outcome for patients with myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is an aggressive and genetically heterogeneous disease with poor prognosis. Cellular immune disorder is a common characteristic of this disease and is thought to be related to clinical outcome. Alterations in T cell clonal expansion and T cell dysfunction has been detected in MDS patients. Little is known about whether there are immune biomarkers to evaluate the T cell alterations with clinical outcome. Previous studies have demonstrated that B-cell leukemia/lymphoma 11B (BCL11B) plays an important role in regulating T cell development and proliferation. In this study, the prognostic value of BCL11B for MDS patients was explored by analyzing RNA-seq data from 270 patients in two datasets in the Gene Expression Omnibus (GEO) database and real-time quantitative PCR data (qRT-PCR) of 31 bone marrow (BM) samples of MDS and 6 BM samples of patients with MDS progress to secondary acute myeloid leukemia (sAML) from our clinical center. The results demonstrated that BCL11B is significantly down-regulated in MDS patients as compared with healthy individuals (HIs). Importantly, lower BCL11B expression was found in MDS patients who were of high/very high risk, older than 60 y, or male and patients with sAML. Furthermore, low BCL11B expression appeared to be associated with poor overall survival (OS) for MDS patients, though the data were not yet significant enough at this point. In addition, BCL11B low-expressing MDS patients had shorter restricted mean survival time (RMST) than those with high BCL11B expression. Interestingly, BCL11B positively correlated with naive and activated memory CD4 + T cells, CD8 + T cells, and the T cell receptor complex genes CD3E and CD3G, but it negatively correlated with regulatory T cells (Treg). Additionally, co-occurrence of low BCL11B expression and CD3E and CD3G was associated with poor OS and shorter RMST. In conclusion, lower BCL11B expression in BM samples of MDS patients was associated with adverse clinical outcome.

Pegylated liposomal mitoxantrone is more therapeutically active than mitoxantrone in L1210 ascitic tumor and exhibits dose-dependent activity saturation effect.

Our previous studies have proved that encapsulation of mitoxantrone into pegylated SUVs (plm60-s) could enhance its antineoplastic efficacy (Li et al., 2008b). However, why plm60-s is more therapeutically active than free mitoxantrone (MIT), and whether pharmacokinetics and activity of plm60-s exhibits dose-dependency are left unknown. In studies with L1210 ascitic tumor-bearing mice in which the dose of MIT was elevated from 2 to 8mg/kg, a saturation of antineoplastic efficacy was observed after plm60-s, and not after free MIT therapy. Total MIT concentrations in plasma, liver and ascitic fluids after plm60-s increased linearly with escalated doses. The released MIT concentrations in ascitic fluid increased continuously before reaching the peak at a dose of 6mg/kg and then decreased. In vitro release experiments using ascitic fluid as release medium revealed that at high concentrations of plm60-s the release of drug was inhibited. At a dose of 4mg/kg, the areas under the curve (AUC) of released MIT in ascitic fluid after plm60-s were higher than those after free MIT, which might be responsible for the enhanced efficacy of plm60-s. These observations may be used to choose a dose regimen of plm60-s to ensure optimal efficacy and to expound the reasons why plm60-s was more therapeutically active.

Accelerated blood clearance of pegylated liposomal topotecan: influence of polyethylene glycol grafting density and animal species.

Upon repeated administration, empty pegylated liposomes lose long-circulating characteristics, referred to as accelerated blood clearance (ABC) phenomenon. However, pegylated liposomal cytotoxic drug formulations could not elicit the phenomenon. In the study, it was found that repeated injection of pegylated liposomal topotecan could induce ABC phenomenon in Wistar rats, beagle dogs, and mice, which might be associated with the formation of empty liposomes in circulation because of the rapid drug release rate. In rats, the 9% polyethylene glycol (PEG) formulation induced more severe ABC phenomenon than 3% PEG formulation despite the similar anti-PEG immunoglobulin M (IgM) levels following the first dose. Antibody neutralization experiments revealed that high PEG formulation was easily neutralized by IgM. Repeated administration of 3% PEG formulation in dogs could result in more severe ABC phenomenon. It seems that slow infusion was liable to cause ABC phenomenon. In all animal species, considerable intraindividual variability of IgM levels could be observed. Our observations may have important implications for the development, evaluation, and therapeutic use of pegylated liposomal cytotoxic drug formulations because using the current drug loading technology, most of the cytotoxic drugs could not be stably loaded in liposomes and rapid drug leakage from liposomes might occur in circulation.

Sulfosalicylate mediates improved vinorelbine loading into LUVs and antineoplastic effects.

Liposomal vinorelbine formulation is desirable, as it might improve the therapeutic activity of vinorelbine. However, because of its lipophilic and membrane-permeable properties, vinorelbine is hard to be formulated into liposomes using conventional drug-loading technologies. To improve vinorelbine retention, ammonium salts of several anionic agents were employed to prepare liposomal vinorelbine formulations. It was found that 5-sulfosalicylate (5ssa) could form stable complexes with vinorelbine and stabilize entrapped vinorelbine. The resultant vesicles had an in vitro release t(1/2) of ~12.49 hours in NH(3)-containing media, which is longer than those of sulfate and phytate vesicles (~0.57 hours). The circulation half-life of vinorelbine after the injection of 5ssa vesicles into normal mice was ~13.01 hours, accounting for ~2-fold increase relative to that of sulfate vesicles. Improved drug retention correlated with enhanced antitumor efficacy. In the RM-1/c57 model, 5ssa vesicles were more efficacious than sulfate vesicles (P < 0.05). In RM-1/BDF1 and Lewis lung cancer/c57 models, antitumor efficacy was also considerably improved after vinorelbine encapsulation into 5ssa vesicles. For instance, in the RM/BDF1 model, liposomal vinorelbine was at least 4-fold more therapeutically active than free vinorelbine. Our results demonstrated that 5ssa could stabilize vinorelbine relative to other anions, resulting in the formulation with improved drug retention and efficacy. Improved vinorelbine retention might be associated with the formation of insoluble precipitate, which could be proved by precipitation study and decreased drug-release rate at a high D/L ratio.