Mismatch repair deficiency and abnormal p53 expression has significant predictive value for progesterone resistance and endometrial tumorigenesis in patients with endometrial atypical hyperplasia receiving fertility-preserving treatment.

OBJECTIVE: This study aimed to evaluate the prognostic ability of mismatch repair deficiency (MMR-d) and abnormal p53 expression (p53abn) in patients with endometrial atypical hyperplasia (EAH) who underwent fertility-preserving treatment. METHODS: This retrospective study evaluated 51 patients with EAH who underwent fertility-sparing treatment. Endometrial biopsy specimens obtained before hormone therapy were collected and used for immunohistochemical staining for MMR and p53 proteins. Response, relapse, and progression rates were assessed based on age, body mass index, diabetes, polycystic ovary syndrome, reproductive history, MMR status, and p53 status. RESULTS: Overall, 11/51 (21.6%) patients had loss of MMR proteins and 6/51 (11.8%) had p53abn. Patients with MMR-d had lower complete response (CR) rates than those with normal staining patients at 12 months after initial treatment (p = 0.049). Patients with MMR-d had significantly higher relapse rates than those with MMR-p at the 1-year follow-ups after achieving CR (p = 0.035). Moreover, patients with MMR-d had a higher incidence of disease progression at 2, 3, and 4 years after fertility-sparing treatment (p = 0.001, p = 0.01 and p = 0.035, respectively). Patients with p53abn had higher relapse rates than those with p53wt at the 1- and 2-year follow-ups after achieving CR (p = 0.047 and p = 0.036, respectively). Moreover, patients with p53abn had a higher incidence of disease progression at 3 and 4 years after fertility-sparing treatment (p = 0.02 and p = 0.049, respectively). CONCLUSIONS: EAH patients with MMR-d and p53abn have a significantly higher risk of disease relapse and progression. Thus, MMR-d and p53abn may be used as predictive biomarkers of progestin resistance and endometrial tumorigenesis in EAH.

Lactobacillus Plantarum Promotes Wound Healing by Inhibiting the NLRP3 Inflammasome and Pyroptosis Activation in Diabetic Foot Wounds.

Objective: Diabetic foot ulcer (DFU) impairs the quality of life of diabetic patients and overburdens healthcare systems and society. It is crucial to comprehend the pathophysiology of DFU and develop effective treatment strategies. The aim of this study was to to evaluate the therapeutic potential of Lactobacillus Plantarum (LP) on wound healing in DFU and to explore the underlying mechanisms. Methods: To investigate the effects of LP on wound healing, human umbilical vein endothelial cells (HUVECs) were treated with advanced glycation end products (AGEs) and used to assess cell viability, migration, and pyroptosis using CCK-8, cell scratch, and flow cytometry. The levels of IL-1ß and IL-18 were measured by ELISA. The expression of NLRP3, caspase-1 p20, and GSDMD-N was detected by Western blot. Additionally, NLRP3 inhibitor MCC950 was used to treat a diabetic rat model established by streptozotocin (STZ). Pearson correlation analysis was performed to analyze the relationship between LP and NLRP3, IL-1ß, IL-18 in ulcer tissue. Results: Our data mechanistically demonstrate that AGEs activate the NLRP3/Caspase-1/GSDMD pathway, leading to an increase in the levels of IL-1ß and IL-18 and ultimately promoting cell pyroptosis. Furthermore, we identified that LP inhibits the effects of AGEs by downregulating NLRP3 inflammasome activity. LP facilitated wound healing in diabetic rats and resulted in decreased protein levels of NLRP3 and its downstream target caspase-1 p20. Finally, we observed a negative correlation between LP and NLRP3, IL-1ß, IL-18 in diabetic foot skin tissue. Conclusion: Our findings uncovered a novel role of LP in diabetic foot wound healing via regulation of the NLRP3 inflammasome, suggesting this link as a therapeutic target. In future research, it would be valuable to explore the signaling cascades involved in LP-mediated inhibition of NLRP3 inflammasome activation.

Negative Pressure Wound Therapy Promotes Wound Healing by Inhibiting Inflammation in Diabetic Foot Wounds: A Role for NOD1 Receptor.

Aims: Diabetic foot results in frequent amputation and quality-of-life reduction in diabetes population. These lesions are featured by a prolonged and exaggerated inflammation with a significant impairment in local bacterial invasion. Negative pressure wound therapy (NPWT) attenuates hyperinflammation in the healing of diabetic foot wounds, but the potential mechanism of NPWT down-regulated inflammatory reaction still remains elusive. This study aims to explore the inflammatory signaling involved in the effect of NPWT on diabetic ulcer. Methods: Thirty patients with diabetic foot ulceration were divided into NPWT group (treated with NPWT, n = 10), NPWT + FK565 group (treated with NPWT combined with FK565 which is NOD1 receptor ligand, n = 10) and control group (n = 10). After two weeks treatment, samples were harvested and analyzed by histochemistry for infiltration of inflammatory cells, immunofluorescence stain for NOD1, western blotting for NOD1, RIP2 (Receptor interacting protein 2), IL-1ß, TAK1 (Transforming growth factor-ß-activated kinase1), p65 and real time-PCR for expression of NOD1 and RIP2. Results: NPWT could notably accelerate the diabetic wound healing through alleviating inflammatory reaction. The immunofluorescence analysis results revealed that NOD1 was mainly expressed in the cytoplasm and noticeably decreased after the NPWT treatment. And NPWT obviously decreased both the mRNA and protein level of NOD1 and RIP2. Moreover, The protein expression of IL-1ß, TAK1 and p65 in the NPWT-group were significant decreased. Conclusion: NPWT effectively promotes wound healing by suppressing the wound inflammation in diabetic foot, which is mediated at least in part by suppression of NOD1 receptor.

Inhibition of USP7 suppresses advanced glycation end-induced cell cycle arrest and senescence of human umbilical vein endothelial cells through ubiquitination of p53.

Diabetes mellitus is a n arising public health concern, and diabetic foot is one of the most common complications of diabetes. Current management for diabetic foot cannot reach optimal remission. In this study, we aim to explore the mechanism underlying the pathogenesis of diabetic foot and provide novel strategies for the treatment of diabetic foot. A total of 10 normal skin tissues and 20 diabetic foot ulcer specimens are collected. Cell proliferation is determined by CCK-8 assay. Cell cycle is determined by flow cytometry, and cell senescence is evaluated by ß-galactosidase staining. Co-immunoprecipitation assay is used to explore the interaction between USP7 and p53. Advanced glycation end products (AGEs) are used to establish diabetic cell model, and streptozotocin (STZ) is used to establish diabetic rat model. Our results showed that USP7 expression is increased in diabetic foot ulcer and in human umbilical vein endothelial cells (HUVECs) after treatment with AGEs. Inhibition of USP7 can reduce cell cycle arrest and cell senescence in HUVECs. Moreover, USP7 can interact with p53 and promote its expression through mediating its deubiquitination. Knockdown of p53 can reverse USP7-mediated cell cycle arrest and cell senescence in HUVECs. In diabetic rats, HBX 41108, the specific inhibitor of USP7, can significantly accelerate wound healing. Our study reveals that the inhibition of USP7 can suppress AGEs-induced cell cycle arrest and cell senescence of HUVECs through promoting p53 ubiquitination. USP7 is a potential target for the treatment of diabetic foot ulcers.

MF-094, a potent and selective USP30 inhibitor, accelerates diabetic wound healing by inhibiting the NLRP3 inflammasome.

Diabetes is a prevalent disease worldwide that can result in several complications, including renal failure, blindness, and amputation. Diabetic foot ulcers, which have the characteristics of chronic wounds, are a devastating component of diabetes progression that can lead to lower extremity amputation. In this study, we set out to investigate the mechanisms involved in wound healing of diabetic foot ulcers. The expression of USP30 in skin tissues of patients with diabetic foot ulcers and HSF2 human skin fibroblasts treated with advanced glycation end (AGE) products was detected by qRT-PCR, and CCK-8, cell scratch and ELISA assay were used to detect cell viability, migration and levels of Col I, Col III, MMP-2, MMP-9, IL-1ß and IL-18. The interaction between USP30 and NLRP3 was verified by co-immunoprecipitation and ubiquitination assays. The expression of USP30, NLRP3 and caspase-1 p20 was detected by Western blot. USP30 inhibitor MF-094 was used to treat diabetic rat model established by streptozotocin (STZ). We found that USP30, a deubiquitinase, was upregulated in skin tissues of patients with diabetic foot ulcers compared with normal skin tissues. In vitro, we found that treatment of HSF2 human skin fibroblasts with advanced glycation end (AGE) products, known to contribute to diabetic complications, resulted in suppressed viability and migration of HSF2 cells, as well as increased levels of USP30 mRNA and protein. Functionally, downregulation of USP30 via shRNA-mediated knockdown or treatment with the USP30 inhibitor MF-094, restored viability and migration of AGE-treated HSF2 cells. We identified the NLRP3 inflammasome as a critical target of USP30 in AGE-induced functions. Mechanistically, we demonstrate that USP30 activates the NLRP3 inflammasome by deubiquitinating NLRP3. Finally, we show that inhibition of USP30 via MF-094 treatment facilitated wound healing in diabetic rats and resulted in decreased protein levels of NLRP3 and its downstream target caspase-1 p20, thus establishing the physiological importance of the identified USP30-NLRP3 link. Together, our findings suggest a therapeutic potential for USP30 in diabetic foot ulcers.

Midterm results of coronary artery bypass graft surgery after synchronous or staged carotid revascularization.

OBJECTIVE: In the absence of randomized trials, the optimal approach to managing coexisting severe carotid and coronary diseases remains controversial. The aim of this study was to present the midterm follow-up results of patients who received a coronary artery bypass graft (CABG) after carotid revascularization and to compare the risk-adjusted outcomes of two approaches to carotid revascularization in the CABG population in a single center. METHODS: From January 2011 to December 2016, 245 patients underwent carotid revascularization within 90 days before CABG in Fuwai Hospital, including 32 who received combined carotid endarterectomy (CEA) and CABG (CEA-CABG), 208 who received staged carotid artery stenting (CAS) before CABG (CAS before CABG), and 5 who underwent a hybrid procedure of carotid stenting and coronary surgery (combined CAS-CABG). The primary composite end points were all-cause death, stroke, and myocardial infarction (MI). Therefore, the multivariable logistic regression analyses and propensity score-adjusted multiphase hazard function model were used to analyze the association between the types of revascularization, complications, and risk-adjusted mortality. RESULTS: One patient (3.13%) died 6 months after the CABG surgery in the combined CEA-CABG group. In the staged CAS group, 9 patients (4.33%) died after CABG surgery, including 3, 2, and 4 patients who died within 30 days, 1 year, and after 1 year (mean time after CABG surgery, 39 months; adjusted odds ratio [OR], 2.188; 95% confidence interval [CI], 0.251-19.093; P = .479), respectively. Stroke was observed in three patients (9.38%) in the combined CEA group and in 12 patients (5.77%) in the staged CAS group (OR, 0.625; 95% CI, 0.133-2.935; P = .552). The rates of MI were 6.25% and 7.21% for the combined and staged groups, respectively (adjusted OR, 1.249; 95% CI, 0.250-6.324; P = .787). In addition, composite events occurred in five (15.63%) and 33 patients (15.87%) in the combined and staged groups, respectively (adjusted OR, 1.362, 95% CI, 0.455-4.077; P = .581). No statistically significant differences were observed in the overall midterm incidences of mortality, stroke, MI, and composite events. CONCLUSIONS: Carotid revascularization is a safe and effective treatment for patients with concomitant carotid and cardiac disease. Combined CEA-CABG and staged CAS-CABG are associated with similar risks of mortality, stroke, or MI in the midterm outcomes.

Modifying spin current filtering and magnetoresistance in a molecular spintronic device.

The zigzag edged graphene nanoribbon (ZGNR) is excellent for spintronics devices, and many efforts have been made to investigate its properties such as spin filtering, rectification and magnetoresistance. Here we propose a molecular spintronic transport device based on two ZGNR electrodes connected with a dibenzo[a,c]dibenzo[5,6:7,8]quinoxalino[2,3-i]phenazine (DDQP) molecule. By performing first-principles electron transport computations, we found an enhanced spin polarized current-voltage curve, giant spin filter efficiency, magnetoresistance and rectification ratio properties of the device compared to its all-carbon molecular analogue. Our systematic investigation suggests the vital role played in spin polarized electron transport by nitrogen atoms in DDQP, the ZGNR probe's width and terminal geometry, especially the increased spin filter efficiency with higher ZGNR width.

[Analysis of urine cadmium and blood cadmium of workers before and after the cadmium dust control].

OBJECTIVE: To analyze the urinary cadmium, blood cadmium and urinary beta2-MG of workers in a zinc powder processing plant before and after the cadmium dust control, and to explore the effects of dust control on the prevention and treatment of cadmium hazards. METHODS: The on-site occupational hazard survey was used to investigate the changes of urine cadmium, blood cadmium and beta3-MG of 84 workers exposed to cadmium before and after the treatment by self-control analysis for evaluating the effects of dust control measures in a zinc powder processing plant. RESULTS: After treatment of the cadmium dust, the geometric mean of zinc dust in the workplace significantly decreased from 3.38 mg/m3 to 2.22 mg/m3 (P < 0.01). The geometric mean concentration of blood cadmium [(2.19 +/- 1.19) microg/L] and urine cadmium [(1.96 +/- 0.74) microg/g Cr] before treatment were significantly higher than those of one year [(1.63 +/- 0.83) microg/L] and [(1.25 +/- 0.83) microg/g Cr] and two years [(1.36 +/- 0.95) microg/L] and [(0.94 +/- 0.72) microg/g Cr] after the cadmium dust control (P < 0.01), respectively. The positive correlations analysis between urine cadmium and blood cadmium concentration of one and two years before and after the cadmium dust treatment implied that there was significant difference (r = 0.466, P < 0.01). CONCLUSION: Dust treatment could reduce the impact of low concentration cadmium on the urine cadmium and blood cadmium concentrations of the workers exposed to cadmium, and effectively prevent the cadmium poisoning.