OBJECTIVE: To investigate the association between long-term exposure to ambient fine particulate matter (PM _2.5) and its constituents and the risk of incident type 2 diabetes mellitus (T2DM), and to examine the modification roles of overweight status. METHODS: This prospective study included 27,507 adults living in rural China. The annual mean residential exposure to PM _2.5 and its constituents was estimated using a satellite-based statistical model. Cox models were used to estimate the risk of T2DM associated with PM _2.5 and its constituents. Stratified analysis quantified the role of overweight status in the association between PM _2.5 constituents and T2DM. RESULTS: Over a median follow-up of 9.4 years, 3,001 new T2DM cases were identified. The hazard ratio ( HR) for a 10 μg/m ³ increase in ambient PM _2.5 was 1.30 (95% confidence interval [ CI]: 1.17, 1.45). Among the constituents, the strongest association was observed with black carbon. Being overweight significantly modified the association between certain constituents and the risk of T2DM. Participants who were overweight and exposed to the highest quartile of PM _2.5 constituents had the highest risk of T2DM ( HR: 2.46, 95% CI: 2.04, 2.97). CONCLUSIONS Our findings indicate that PM _2.5 was associated with an increased risk of T2DM, with black carbon potentially being the primary contributor. Being overweight appeared to enhance the association between PM _2.5 and T2DM. This suggests that controlling both PM _2.5 exposure and overweight status may reduce the burden of T2DM.
Humans ; Diabetes Mellitus, Type 2/chemically induced* ; China/epidemiology* ; Particulate Matter/analysis* ; Overweight/epidemiology* ; Female ; Male ; Middle Aged ; Rural Population ; Air Pollutants/analysis* ; Adult ; Prospective Studies ; Environmental Exposure/adverse effects* ; Aged ; Risk Factors

In this study, doxorubicin (DOX) was used as the model drug, new indocyanine green (IR820) as the photosensitizer, and temperature sensitive liposomes (TSL) as the carrier. H460-NCI photoheat-sensitive liposomes coated with cell membrane of human cell lung cancer (DOX-IR820-TSL@CCM) for highly effective multi-pathway tumor targeting in chemical-photothermal therapy and photodynamic therapy. DOX-IR820-TSL was prepared by reverse evaporation, cancer cell membrane (CCM) was prepared by lysis, crushing and centrifugation, and DOX-IR820-TSL@CCM was prepared by nanomembrane extrusion. The drug-loading conditions of DOX-IR820-TSL were finally determined: the ratio of organic phase to aqueous phase was 4.02, the dosage of dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was 10.04 mg, and the lipid ratio was 0.12, and the significant phase transition temperature (T_m) of DOX-IR820-TSL was 43.05 ℃. The average particle size of DOX-IR820-TSL@CCM was 153.4 nm, the PDI was 0.279, and the zeta potential was -26.2 mV. The transmission electron microscope (TEM) image shows a homogeneous spherical structure and a translucent film layer. Under near-infrared irradiation, the drug release rate reaches 63.98%, which has adjustable photothermal conversion capacity and the ability to generate reactive oxygen species. Through SDS-PAGE electrophoresis, Western blot, cytotoxicity experiments and cell uptake experiments, it was proved that the design of cell membrane coating can well retain CD47, N-cadherin, CD44, CD326 and other related functional proteins, so that DOX-IR820-TSL@CCM has good immune evasion, homologous adhesion and homologous targeting. In this paper, DOX-IR820-TSL@CCM with camouflage properties and tumor targeting properties were successfully prepared, which can be used as a promising synergistic therapeutic diagnostic platform for future lung cancer treatment. All animal research programs have been approved by the Animal Ethics Committee of Heilongjiang University of Chinese Medicine (number: 2022121011).

Acute suppurative thyroiditis(AST) is a rare thyroid disease, mostly caused by infections such as Staphylococcus aureus, and it is difficult to distinguish from subacute thyroiditis(SAT) at the beginning of the disease. Here we report the clinical data of a young male patient who was initially misdiagnosed as SAT, but was clinically diagnosed as AST with DNSIs accompanied by LS. The clinical features and treatment, combined with related literature, aim to enhance clinicians' understanding of this disease.

Objective This study aims to elucidate the structure-activity domain of LBP1C-2 targeting Kvβ.2 through an exploration of the structure-activity relationship.This study may also provide the scientific basis for the development of drug candidate with anti-early-onset dementia activity.Methods After partial acid hydrolysis,various structural fragments were obtained and subjected to monosaccharide composition and molecular weight analysis.Potential target proteins were selected using a protein chip,followed by validation of the targeting specificity of each structural fragment using surface plasmon resonance(SPR)technology.Results Through high-throughput screening using the HuProtTM human protein array,potential target protein Kvβ.2 was identified for LBP1C-2.SPR experiments revealed a strong binding affinity between LBP1C-2 and Kvβ.2 protein,with a binding constant(KD)of 1.9×10-7 M.The various structural fragments of LBP1C-2 exhibited different binding strengths with the target protein Kvβ.2.Among them,the segment LBP1C-2-1I(18.1 k Da)with a molar ratio of rhamose to galecturonic acid of 1:1 showed a binding strength to Kvβ.2 similar to that of the polysaccharide LBP1C-2,with a KD of approximately 3.3×10-7 M.Structural analysis indicates that the structure of LBP1C-2-1I contains 1,2-linked Rha and 1,4-linked GalA which are alternatively linked.The acid-hydrolyzed extracellular portion corresponding to this segment,LBP1C-2-1O may also bind to Kvβ.2.However,compared to other segments,it demonstrated a higher tendency to dissociate from the protein.Knockdown of the KCNAB2 gene(Kvβ.2)in BV2 cells inhibited the uptake of Aβ in BV2 cells,suggesting that protein Kvβ.2 may be a functional protein in the development of Alzheimer's disease.Conclusion LBP1C-2-1I has been identified as the primary active domain through which LBP1C-2 targets Kvβ.2.This suggests that the active domain of LBP1C-2 predominantly resides on the main chain rather than the side chain.This study provides crucial insights for a deeper understanding of the anti-early-onset dementia activity of LBP1C-2 and lays an experimental foundation for the design and development of targeted drugs for anti-early-onset dementia based on Lycium barbarum polysaccharides.

Objective:To explore influencing factors of the self-reported brief life quality satisfaction score(Brief-QoL) in patients with acromegaly and understand the persistent low Brief-QoL scores in cases achieving biochemical remission.Methods:This study included 836 acromegaly patients who were hospitalized at Peking Union Medical College Hospital between January 2012 and December 2020. We retrospectively examined how clinical characteristics, biochemical parameters, comorbidities, and symptoms influenced Brief-QoL. Among patients who achieved biochemical remission, differences in clinical symptoms and comorbidities were analyzed between the high and low quality of life groups.Results:Patients with well-controlled biochemical indicators at the last follow-up had generally high Brief-QoL. However, patients with symptoms such as headaches (47.8% in the low-score group vs 14.9% in the high-score group, P<0.001) and joint pain (69.6% in the low-score group vs 19.0% in the high-score group, P<0.001) had low Brief-QoL despite biochemical remission. Receiving combined treatment(52.4% in the low-score group vs 27.5% in the high-score group, P=0.030) and having comorbid diabetes or hyperlipidemia were significant factors leading to decreased quality of life. Conclusion:Brief-QoL is suitable for follow-up of outpatient patients. Early identification of factors affecting quality of life and timely intervention can facilitate the realization of standardized management.

Objective: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician’s choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. Methods: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/ adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. Results: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1–43.0) months.Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49–1.10) and 0.64 (0.44–0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45–1.02) and 0.61 (0.41–0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3–5, 74% and 72%), respectively. Conclusion Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC.

Objective: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician’s choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. Methods: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/ adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. Results: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1–43.0) months.Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49–1.10) and 0.64 (0.44–0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45–1.02) and 0.61 (0.41–0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3–5, 74% and 72%), respectively. Conclusion Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC.

Objective: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interim analysis, lenvatinib+pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus treatment of physician’s choice chemotherapy (TPC) in patients with previously treated advanced/recurrent endometrial cancer (EC). This exploratory analysis evaluated outcomes in patients enrolled in East Asia at the time of prespecified final analysis. Methods: Women ≥18 years with histologically confirmed advanced, recurrent, or metastatic EC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/ adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks (≤35 cycles) or TPC (doxorubicin or paclitaxel). Primary endpoints were PFS per RECIST v1.1 by blinded independent central review and OS. No alpha was assigned for this subgroup analysis. Results: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78), median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1–43.0) months.Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS (lenvatinib+pembrolizumab vs. TPC) were 0.74 (0.49–1.10) and 0.64 (0.44–0.94) in the mismatch repair proficient (pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45–1.02) and 0.61 (0.41–0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22% with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverse events occurred in 97% and 96% (grade 3–5, 74% and 72%), respectively. Conclusion Lenvatinib+pembrolizumab provided clinically meaningful benefit with manageable safety compared with TPC, supporting its use in East Asian patients with previously treated advanced/recurrent EC.

Objective:To study the characteristics of vaginal microbiota in pregnant women with premature rupture of membranes (PROM) and to establish prediction models for PROM.Methods:This study involved 35 women with preterm premature rupture of membranes (PPROM), 180 with term premature rupture of membranes (TPROM) and 255 term birth cases without premature rupture of membranes (TBWPROM, control group). The V3-V4 hypervariable region sequences in the vaginal samples collected at 16-28 weeks of gestation were detected by 16S rRNA gene next-generation sequencing. The differences in Alpha and Beta diversity, and the attributes and metabolic function prediction of each recognized species among the three groups were analyzed. Subsequently, a random forest model was used to establish the prediction models for PROM using vaginal microbiota species and environmental risk factors.Results:Compared with the control group, the Alpha diversity of the PPROM group was higher (Observed features, P=0.022; Faith_pd index, P=0.024) and Beta diversity was also significantly different (Unweighted UniFrac, P=0.010; Jaccard index, P=0.008). In PPROM cases, Megasphaera genomosp. typeⅠ was significantly increased ( P=0.017) and Lactobacillus mulieris was significantly decreased ( P=0.003). In the patients with TPROM, Megasphaera was significantly increased ( P=0.009) and Lactobacillus mulieris was significantly decreased ( P=0.002). In terms of functional pathways, sulfur oxidation ( P=0.021), methanogenesis from acetate ( P=0.036), L-histidine biosynthesis ( P=0.009), adenosylcobalamin biosynthesis ( P=0.041) and fucose degradation ( P=0.001) were significantly increased in patients with PPROM; L-histidine biosynthesis ( P<0.001) and fucose degradation ( P=0.030) were significantly increased in patients with TPROM. The prediction models were established using the random forest model with vaginal microbiota species and environmental risk factors and the prediction model for PPROM performed well [AUC: 0.739 (95%CI: 0.609-0.869), sensitivity: 0.928, specificity: 0.659, positive predictive value: 0.750, negative predictive value: 0.906], which had a certain reference value. Conclusions:Vaginal microbiota might be related to the development and progression of PROM. Studying the differences in vaginal microbiota might provide a new idea for the prevention and treatment of PROM. Functional prediction provided a direction for further research on the mechanism of PROM. The established prediction model could prevent the occurrence of PPROM and promote maternal and infant health.

PURPOSE: This study aims to elucidate the electrotaxis response of alveolar epithelial cells (AECs) in direct-current electric fields (EFs), explore the impact of EFs on the cell fate of AECs, and lay the foundation for future exploitation of EFs for the treatment of acute lung injury. METHODS: AECs were extracted from rat lung tissues using magnetic-activated cell sorting. To elucidate the electrotaxis responses of AECs, different voltages of EFs (0, 50, 100, and 200 mV/mm) were applied to two types of AECs, respectively. Cell migrations were recorded and trajectories were pooled to better demonstrate cellular activities through graphs. Cell directionality was calculated as the cosine value of the angle formed by the EF vector and cell migration. To further demonstrate the impact of EFs on the pulmonary tissue, the human bronchial epithelial cells transformed with Ad12-SV40 2B (BEAS-2B cells) were obtained and experimented under the same conditions as AECs. To determine the influence on cell fate, cells underwent electric stimulation were collected to perform Western blot analysis. RESULTS: The successful separation and culturing of AECs were confirmed through immunofluorescence staining. Compared with the control, AECs in EFs demonstrated a significant directionality in a voltage-dependent way. In general, type Ⅰ alveolar epithelial cells migrated faster than type Ⅱ alveolar epithelial cells, and under EFs, these two types of cells exhibited different response threshold. For type Ⅱ alveolar epithelial cells, only EFs at 200 mV/mm resulted a significant difference to the velocity, whereas for, EFs at both 100 mV/mm and 200 mV/mm gave rise to a significant difference. Western blotting suggested that EFs led to an increased expression of a AKT and myeloid leukemia 1 and a decreased expression of Bcl-2-associated X protein and Bcl-2-like protein 11. CONCLUSION EFs could guide and accelerate the directional migration of AECs and exert antiapoptotic effects, which indicated that EFs are important biophysical signals in the re-epithelialization of alveolar epithelium in lung injury.
Humans ; Rats ; Animals ; Alveolar Epithelial Cells ; Lung ; Lung Injury ; Cell Movement/physiology*