Roles of blood metabolites in mediating the relationship between vitiligo and autoimmune diseases: Evidence from a Mendelian randomization study.

OBJECTIVE: This study employed Mendelian Randomization (MR) to investigate the causal relationship between genetic susceptibility to vitiligo and the risk of various autoimmune diseases, along with the mediating role of blood metabolites. METHODS: We performed two-sample MR analyses using aggregated genome-wide association studies (GWAS) data on 486 blood metabolites, vitiligo, and nine autoimmune diseases to investigate blood metabolites' causal effects on the susceptibility of vitiligo and the associations of vitiligo with nine autoimmune comorbidities. We also applied multivariable MR to unravel metabolites by which vitiligo influences the pathogenesis of autoimmune diseases. RESULTS: Our findings indicate that vitiligo amplified the risk of several autoimmune diseases, including rheumatoid arthritis (OR 1.17; 95 % CI 1.08-1.27), psoriasis (OR 1.10; 95 % CI 1.04-1.17), type 1 diabetes (OR 1.41; 95 % CI 1.23-1.63), pernicious anemia (OR 1.23; 95 % CI 1.12-1.36), autoimmune hypothyroidism (OR 1.19; 95 % CI 1.11-1.26), alopecia areata (OR 1.22; 95 % CI 1.10-1.35), and autoimmune Addison's disease (OR 1.22; 95 % CI 1.12-1.33). Additionally, our analysis identified correlations with vitiligo for 14 known (nine risk, five protective) and seven uncharacterized serum metabolites. After adjusting for genetically predicted levels of histidine and pyruvate, the associations between vitiligo and these diseases were attenuated. CONCLUSIONS: We substantiated vitiligo's influence on susceptibility to seven autoimmune diseases and conducted a thorough investigation of serum metabolites correlated with vitiligo. Histidine and pyruvate are potential mediators of vitiligo associated with autoimmune diseases.By combining metabolomics with genomics, we provide new perspectives on the etiology of vitiligo and its immune comorbidities.

Revealing the spatial nature of sublattice symmetry.

The sublattice symmetry on a bipartite lattice is commonly regarded as the chiral symmetry in the AIII class of the tenfold Altland-Zirnbauer classification. Here, we reveal the spatial nature of sublattice symmetry and show that this assertion holds only if the periodicity of primitive unit cells agrees with that of the sublattice labeling. In cases where the periodicity does not agree, sublattice symmetry is represented as a glide reflection in energy-momentum space, which inverts energy and simultaneously translates some k by π, leading to substantially different physics. Particularly, it introduces novel constraints on zero modes in semimetals and completely alters the classification table of topological insulators compared to class AIII. Notably, the dimensions corresponding to trivial and nontrivial classifications are switched, and the nontrivial classification becomes Z 2 instead of Z . We have applied these results to several models, including the Hofstadter model both with and without dimerization.

Quercetin Ameliorates Myocardial Injury in Diabetic Rats by Regulating Autophagy and Apoptosis through AMPK/mTOR Signaling Pathway.

A high-glucose environment is involved in the progression of diabetes mellitus (DM). This study aims to explore the regulatory effects of quercetin (QUE) on autophagy and apoptosis after myocardial injury in rats with DM. The type 2 DM rat models were constructed using low-dose streptozotocin (STZ) treatment combined with a high-carbohydrate (HC) diet in vivo. Compared with the control group, the body weight was decreased, whereas blood pressure, blood glucose, and the LVW/BW ratio were increased in the diabetic group. The results showed that the myocardial fibers were disordered in the diabetic group. Moreover, we found that the myocardial collagen fibers, PAS-positive cells, and apoptosis were increased, whereas the mitochondrial structure was destroyed and autophagic vacuoles were significantly reduced in the diabetic group compared with the control group. The expression levels of autophagy-related proteins LC3 and Beclin1 were decreased, whereas the expression levels of P62, Caspae-3, and Bax/Bcl-2 were increased in the diabetic group in vitro and in vivo. Moreover, QUE treatment alleviated the cellular oxidative stress reaction under high-glucose environments. The results of immunoprecipitation (IP) showed that the autophagy protein Beclin1 was bound to Bcl-2, and the binding capacity increased in the HG group, whereas it decreased after QUE treatment, suggesting that QUE inhibited the binding capacity between Beclin1 and Bcl-2, thus leading to the preservation of Beclin1-induced autophagy. In addition, the blood pressure, blood glucose, and cardiac function of rats were improved following QUE treatment. In conclusion, QUE suppressed diabetic myocardial injury and ameliorated cardiac function by regulating myocardial autophagy and inhibition of apoptosis in diabetes through the AMPK/mTOR signaling pathway.

Metformin induction of heat shock factor 1 activation and the mitochondrial unfolded protein response alleviate cardiac remodeling in spontaneously hypertensive rats.

Heart failure and cardiac remodeling are both characterized by mitochondrial dysfunction. Healthy mitochondria are required for adequate contractile activity and appropriate regulation of cell survival. In the mammalian heart, enhancement of the mitochondrial unfolded protein response (UPRmt) is cardioprotective under pressure overload conditions. We explored the UPRmt and the underlying regulatory mechanism in terms of hypertension-induced cardiac remodeling and the cardioprotective effect of metformin. Male spontaneously hypertensive rats and angiotensin II-treated neonatal rat cardiomyocytes were used to induce cardiac hypertrophy. The results showed that hypertension induced the formation of aberrant mitochondria, characterized by a reduced mtDNA/nDNA ratio and swelling, as well as lower levels of mitochondrial complexes I to V and inhibition of the expression of one protein subunit of each of complexes I to IV. Such changes eventually enlarged cardiomyocytes and increased cardiac fibrosis. Metformin treatment increased the mtDNA/nDNA ratio and regulated the UPRmt, as indicated by increased expression of activating transcription factor 5, Lon protease 1, and heat shock protein 60, and decreased expression of C/EBP homologous protein. Thus, metformin improved mitochondrial ultrastructure and function in spontaneously hypertensive rats. In vitro analyses revealed that metformin reduced the high levels of angiotensin II-induced mitochondrial reactive oxygen species in such animals and stimulated nuclear translocation of heat shock factor 1 (HSF1). Moreover, HSF1 small-interfering RNA reduced the metformin-mediated improvements in mitochondrial morphology and the UPRmt by suppressing hypertrophic signals and cardiomyocyte apoptosis. These results suggest that HSF1/UPRmt signaling contributes to the beneficial effects of metformin. Metformin-mediated targeting of mitochondrial protein homeostasis and modulation of HSF1 levels have potential therapeutic implications in terms of cardiac remodeling.

Roseburia intestinalis Supplementation Could Reverse the Learning and Memory Impairment and m6A Methylation Modification Decrease Caused by 27-Hydroxycholesterol in Mice.

The abnormality in N6-methyladenosine (m6A) methylation is involved in the course of Alzheimer's disease (AD), while the intervention of 27-Hydroxycholesterol (27-OHC) can affect the m6A methylation modification in the brain cortex. Disordered gut microbiota is a key link in 27-OHC leading to cognitive impairment, and further studies have found that the abundance of Roseburia intestinalis in the gut is significantly reduced under the intervention of 27-OHC. This study aims to investigate the association of 27-OHC, Roseburia intestinalis in the gut, and brain m6A modification in the learning and memory ability injury. In this study, 9-month-old male C57BL/6J mice were treated with antibiotic cocktails for 6 weeks to sweep the intestinal flora, followed by 27-OHC or normal saline subcutaneous injection, and then Roseburia intestinalis or normal saline gavage were applied to the mouse. The 27-OHC level in the brain, the gut barrier function, the m6A modification in the brain, and the memory ability were measured. From the results, we observed that 27-OHC impairs the gut barrier function, causing a disturbance in the expression of m6A methylation-related enzymes and reducing the m6A methylation modification level in the brain cortex, and finally leads to learning and memory impairment. However, Roseburia intestinalis supplementation could reverse the negative effects mentioned above. This study suggests that 27-OHC-induced learning and memory impairment might be linked to brain m6A methylation modification disturbance, while Roseburia intestinalis, as a probiotic with great potential, could reverse the damage caused by 27-OHC. This research could help reveal the mechanism of 27-OHC-induced neural damage and provide important scientific evidence for the future use of Roseburia intestinalis in neuroprotection.

Construction and validation of a neovascular glaucoma nomogram in patients with diabetic retinopathy after pars plana vitrectomy.

BACKGROUND: Neovascular glaucoma (NVG) is likely to occur after pars plana vitrectomy (PPV) for diabetic retinopathy (DR) in some patients, thus reducing the expected benefit. Understanding the risk factors for NVG occurrence and building effective risk prediction models are currently required for clinical research. AIM: To develop a visual risk profile model to explore factors influencing DR after surgery. METHODS: We retrospectively selected 151 patients with DR undergoing PPV. The patients were divided into the NVG (NVG occurrence) and No-NVG (No NVG occurrence) groups according to the occurrence of NVG within 6 months after surgery. Independent risk factors for postoperative NVG were screened by logistic regression. A nomogram prediction model was established using R software, and the model's prediction accuracy was verified internally and externally, involving the receiver operator characteristic curve and correction curve. RESULTS: After importing the data into a logistic regression model, we concluded that a posterior capsular defect, preoperative vascular endothelial growth factor ≥ 302.90 pg/mL, glycosylated hemoglobin ≥ 9.05%, aqueous fluid interleukin 6 (IL-6) ≥ 53.27 pg/mL, and aqueous fluid IL-10 ≥ 9.11 pg/mL were independent risk factors for postoperative NVG in patients with DR (P < 0.05). A nomogram model was established based on the aforementioned independent risk factors, and a computer simulation repeated sampling method was used to internally and externally verify the nomogram model. The area under the curve (AUC), sensitivity, and specificity of the model were 0.962 [95% confidence interval (95%CI): 0.932-0.991], 91.5%, and 82.3%, respectively. The AUC, sensitivity, and specificity of the external validation were 0.878 (95%CI: 0.746-0.982), 66.7%, and 95.7%, respectively. CONCLUSION: A nomogram constructed based on the risk factors for postoperative NVG in patients with DR has a high prediction accuracy. This study can help formulate relevant preventive and treatment measures.

Image-based remote evaluation of PASI scores with psoriasis by the YOLO-v4 algorithm.

As a chronic relapsing disease, psoriasis is characterized by widespread skin lesions. The Psoriasis Area and Severity Index (PASI) is the most frequently utilized tool for evaluating the severity of psoriasis in clinical practice. Nevertheless, long-term monitoring and precise evaluation pose difficulties for dermatologists and patients, which is time-consuming, subjective and prone to evaluation bias. To develop a deep learning system with high accuracy and speed to assist PASI evaluation, we collected 2657 high-quality images from 1486 psoriasis patients, and images were segmented and annotated. Then, we utilized the YOLO-v4 algorithm to establish the model via four modules, we also conducted a human-computer comparison through quadratic weighted Kappa (QWK) coefficients and intra-class correlation coefficients (ICC). The YOLO-v4 algorithm was selected for model training and optimization compared with the YOLOv3, RetinaNet, EfficientDet and Faster_rcnn. The model evaluation results of mean average precision (mAP) for various lesion features were as follows: erythema, mAP = 0.903; scale, mAP = 0.908; and induration, mAP = 0.882. In addition, the results of human-computer comparison also showed a median consistency for the skin lesion severity and an excellent consistency for the area and PASI score. Finally, an intelligent PASI app was established for remote disease assessment and course management, with a pleasurable agreement with dermatologists. Taken together, we proposed an intelligent PASI app based on the image YOLO-v4 algorithm that can assist dermatologists in long-term and objective PASI scoring, shedding light on similar clinical assessments that can be assisted by computers in a time-saving and objective manner.

Dietary Inflammatory Index and Cognitive Function: Findings from a Cross-Sectional Study in Obese Chinese Township Population from 45 to 75 Years.

Background and Objective: Cognitive dysfunction is highly prevalent in obese people, and food is a key factor in obesity, and dietary inflammatory index (DII) can reflect whether diet has anti-inflammatory or pro-inflammatory potential. In addition, dietary fatty acid consumption is linked to inflammation, obesity, and cognitive impairment. Erythrocyte membrane fatty acids can reflect dietary fatty acid intake. Our hypothesis was that erythrocyte membrane fatty acids might have a significant impact on the relationship between DII and cognition in obese individuals, and we designed experiments to test the hypothesis. Methods: In three villages in Beijing, we collected 579 respondents from individuals 45 to 75 years old and categorized them by body mass index. The Montreal Cognitive Assessment (MoCA) score and DII score was calculated and gas chromatography was used to measure the proportion of erythrocyte membrane fatty acids. The relationship between the DII score and cognition was examined using multiple linear regression and binary logistic regression. Mediation analysis can help to understand the causal chain between variables, deeply explore the internal relationship and mechanism of action between variables. So a multiple chain mediation model was developed to investigate the mediating factors between the DII score and cognitive association. Results: According to adjusted linear regression, higher DII scores were linked to lower MoCA scores in the obese group. The negative correlation between DII score and cognitive function score remains in binary linear regression. We discovered through mediation analysis that erythrocyte membrane fatty acids mediate the detrimental link between DII and cognitive function in obese individuals. Conclusion: We propose that higher DII scores in obese people are associated with a decline in cognitive function. In addition, this effect might be mediated via the fatty acids in the erythrocyte membrane.

m6A RNA methylation: The latent string-puller in fibrosis.

Fibrosis is a pathological phenomenon characterized by the aberrant accumulation of extracellular matrix (ECM) in tissues. Fibrosis is a universally age-related disease involving that many organs and is the final stage of many chronic inflammatory diseases, which often threaten the patient's health. Undoubtedly, fibrosis has become a serious economic and health burden worldwide, However, the pathogenesis of fibrosis is complex. Further, the key molecules still remain to be unraveled. Hence, so far, there have been no effective treatments designed against the key targets of fibrosis. The methylation modification on the nitrogen atom at position 6 of adenine (m6A) is the most common mRNA modification in mammals. There is increasing evidence that m6A is actively involved in the pathogenesis of fibrosis. This review aims to highlight m6A-associated mechanisms and functions in several organic fibrosis, which implies that m6A is universal and critical for fibrosis and summarize the outlook of m6A in the treatment of fibrosis. This may light up the unknown aspects of this condition for researchers interested to explore fibrosis further.

Complement C1q/C3-CR3 signaling pathway mediates abnormal microglial phagocytosis of synapses in a mouse model of depression.

BACKGROUND: Both functional brain imaging studies and autopsy reports have indicated the presence of synaptic loss in the brains of depressed patients. The activated microglia may dysfunctionally engulf neuronal synapses, leading to synaptic loss and behavioral impairments in depression. However, the mechanisms of microglial-synaptic interaction under depressive conditions remain unclear. METHODS: We utilized lipopolysaccharide (LPS) to induce a mouse model of depression, examining the effects of LPS on behaviors, synapses, microglia, microglial phagocytosis of synapses, and the C1q/C3-CR3 complement signaling pathway. Additionally, a C1q neutralizing antibody was employed to inhibit the C1q/C3-CR3 signaling pathway and assess its impact on microglial phagocytosis of synapses and behaviors in the mice. RESULTS: LPS administration resulted in depressive and anxiety-like behaviors, synaptic loss, and abnormal microglial phagocytosis of synapses in the hippocampal dentate gyrus (DG) of mice. We found that the C1q/C3-CR3 signaling pathway plays a crucial role in this abnormal microglial activity. Treatment with the C1q neutralizing antibody moderated the C1q/C3-CR3 pathway, leading to a decrease in abnormal microglial phagocytosis, reduced synaptic loss, and improved behavioral impairments in the mice. CONCLUSIONS: The study suggests that the C1q/C3-CR3 complement signaling pathway, which mediates abnormal microglial phagocytosis of synapses, presents a novel potential therapeutic target for depression treatment.

Multi-omics study reveals different pathogenesis of the generation of skin lesions in SLE and IDLE patients.

Lupus erythematosus (LE) is a heterogeneous, antibody-mediated autoimmune disease. Isolate discoid LE (IDLE) and systematic LE (SLE) are traditionally regarded as the two ends of the spectrum, ranging from skin-limited damage to life-threatening multi-organ involvement. Both belong to LE, but IDLE and SLE differ in appearance of skin lesions, autoantibody panels, pathological changes, treatments, and immunopathogenesis. Is discoid lupus truly a form of LE or is it a completely separate entity? This question has not been fully elucidated. We compared the clinical data of IDLE and SLE from our center, applied multi-omics technology, such as immune repertoire sequencing, high-resolution HLA alleles sequencing and multi-spectrum pathological system to explore cellular and molecular phenotypes in skin and peripheral blood from LE patients. Based on the data from 136 LE patients from 8 hospitals in China, we observed higher damage scores and fewer LE specific autoantibodies in IDLE than SLE patients, more uCDR3 sharing between PBMCs and skin lesion from SLE than IDLE patients, elevated diversity of V-J recombination in IDLE skin lesion and SLE PBMCs, increased SHM frequency and class switch ratio in IDLE skin lesion, decreased SHM frequency but increased class switch ratio in SLE PBMCs, HLA-DRB1*03:01:01:01, HLA-B*58:01:01:01, HLA-C*03:02:02:01, and HLA-DQB1*02:01:01:01 positively associated with SLE patients, and expanded Tfh-like cells with ectopic germinal center structures in IDLE skin lesions. These findings suggest a significant difference in the immunopathogenesis of skin lesions between SLE and IDLE patients. SLE is a B cell-predominate systemic immune disorder, while IDLE appears limited to the skin. Our findings provide novel insights into the pathogenesis of IDLE and other types of LE, which may direct more accurate diagnosis and novel therapeutic strategies.

Increased miR-3074-5p expression promotes M1 polarization and pyroptosis of macrophages via ERα/NLRP3 pathway and induces adverse pregnancy outcomes in mice.

Decidual macrophages (dMϕs) play critical roles in regulation of immune-microhomeostasis at maternal-fetal interface during pregnancy, but the underlying molecular mechanisms are still unclear. In this study, it was found that litter size and fetal weight were significantly reduced, whereas the rate of embryo resorption was increased in miR-3074-5p knock-in (3074-KI) pregnant mice, compared to that of wild-type (WT) pregnant mice. Plasma levels of pro-inflammatory cytokines in 3074-KI pregnant mice were also significantly elevated compared to WT pregnant mice at GD7.5. The quantity of M1-Mϕs in uterine tissues of 3074-KI pregnant mice was significantly increased compared to WT pregnant mice at GD13.5. Estrogen receptor-α (ERα) was validated to be a target of miR-3074-5p. Either miR-3074-5p overexpression or ERα knockdown promoted transcriptional activity of NF-κB/p65, induced M1-polarization and pyroptosis of THP1-derived Mϕs, accompanied with increased intracellular levels of cleaved Caspase-1, cleaved IL-1ß, NLRP3, cleaved GSDMD and ASC aggregation. Furthermore, ERα could not only bind to NLRP3 or ASC directly, but also inhibit the interaction between NLRP3 and ASC. The endometrial miR-3074-5p expression level at the middle secretory stage of repeated implantation failure (RIF) patients was significantly decreased compared to that of control fertile women. These data indicated that miR-3074-5p could promote M1 polarization and pyroptosis of Mϕs via activation of NLRP3 inflammasome by targeting ERα, and the dysregulation of miR-3074-5p expression in dMϕs might damage the embryo implantation and placentation by interfering with inflammatory microenvironment at the maternal-fetal interface during early pregnancy.

Redoxhigh phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma.

Metabolism reprogramming within the tumor microenvironment (TME) can have a profound impact on immune cells. Identifying the association between metabolic phenotypes and immune cells in lung adenocarcinoma (LUAD) may reveal mechanisms of resistance to immune checkpoint inhibitors (ICIs). Metabolic phenotypes were classified by expression of metabolic genes. Somatic mutations and transcriptomic features were compared across the different metabolic phenotypes. The metabolic phenotype of LUAD is predominantly determined by reductase-oxidative activity and is divided into two categories: redoxhigh LUAD and redoxlow LUAD. Genetically, redoxhigh LUAD is mainly driven by mutations in KEAP1, STK11, NRF2, or SMARCA4. These mutations are more prevalent in redoxhigh LUAD (72.5%) compared to redoxlow LUAD (17.4%), whereas EGFR mutations are more common in redoxlow LUAD (19.0% vs. 0.7%). Single-cell RNA profiling of pre-treatment and post-treatment samples from patients receiving neoadjuvant chemoimmunotherapy revealed that tissue-resident memory CD8+ T cells are responders to ICIs. However, these cells are significantly reduced in redoxhigh LUAD. The redoxhigh phenotype is primarily attributed to tumor cells and is positively associated with mTORC1 signaling. LUAD with the redoxhigh phenotype demonstrates a lower response rate (39.1% vs. 70.8%, p = 0.001), shorter progression-free survival (3.3 vs. 14.6 months, p = 0.004), and overall survival (12.1 vs. 31.2 months, p = 0.022) when treated with ICIs. The redoxhigh phenotype in LUAD is predominantly driven by mutations in KEAP1, STK11, NRF2, and SMARCA4. This phenotype diminishes the number of tissue-resident memory CD8+ T cells and attenuates the efficacy of ICIs.

Assessment of causal association between the socio-economic status and osteoporosis and fractures: a bidirectional Mendelian randomization study in European population.

BACKGROUND: The relationship between socio-economic status and bone-related diseases is attracting increasing attention. Therefore, a bidirectional Mendelian randomization (MR) analysis was performed in this study. METHODS: Genetic data on factors associated with socio-economic status (average total household income before tax, years of schooling completed and Townsend Deprivation Index at recruitment), femoral neck bone mineral density (FN-BMD), heel bone mineral density (eBMD), osteoporosis, and five different sites of fracture (spine, femur, lower leg-ankle, foot, and wrist-hand fractures) were derived from genome-wide association summary statistics of European ancestry. The inverse variance weighted method was employed to obtain the causal estimates, complemented by alternative MR techniques, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Furthermore, sensitivity analyses, and multivariable MR was performed to enhance the robustness of our findings. RESULTS: A higher educational attainment was associated with an increased level of eBMD (beta:0.06, 95% CI:0.01-0.10, P = 7.24 × 10-3), and decreased risk of osteoporosis (OR:0.78, 95% CI:0.65-0.94, P = 8.49 × 10-3), spine fracture (OR:0.76, 95% CI:0.66-0.88, P = 2.94 × 10-4), femur fracture (OR:0.78, 95% CI:0.67-0.91, P = 1.33 × 10-3), lower leg-ankle fracture (OR:0.79, 95% CI:0.70-0.88, P = 2.05 × 10-5), foot fracture (OR:0.78, 95% CI:0.66-0.93, P = 5.92 × 10-3) and wrist-hand fracture (OR:0.83, 95% CI:0.73-0.95, P = 7.15 × 10-3). Further, material deprivation seemed to harm the spine fracture (OR:2.63, 95% CI:1.43-4.85, P = 1.91 × 10-3). A higher level of FN-BMD positively affected increased household income (beta:0.03, 95% CI:0.01-0.04, P = 6.78 × 10-3). All these estimates were adjusted for body mass index (BMI), type 2 diabetes, smoking initiation, and frequency of alcohol intake. CONCLUSIONS: The Mendelian randomization analyses show that higher educational levels is associated with higher eBMD, reduced risk of osteoporosis and fractures, while material deprivation is positively related to spine fracture. Enhanced FN-BMD correlates with increased household income. These findings offer valuable insights into the formulation of health guidelines and policy development.

We conducted stratified analyses to explore the causal links between socio-economic status and osteoporosis and various fractures and observed that education significantly reduced risk of osteoporosis and lower eBMD. It also lowered the risks of fractures of spine, femur, lower leg-ankle, foot, and wrist-hand, while material deprivation exhibited positive associations with spine fracture risk. Bidirectional MR analysis showed that an elevated score of FN-BMD was associated with a higher income level. Our study shows the importance of conducting routine BMD estimations and osteoporosis screening, to enhance knowledge and awareness among individuals to promote bone health and prevent fractures.

Is postmastectomy radiotherapy necessary for breast cancer patients with clinically node-positive downstaging to ypN0 after neoadjuvant chemotherapy?

PURPOSE: The significance of postmastectomy radiotherapy (PMRT) in breast cancer patients who initially have clinically node-positive (cN +) status but achieve downstaging to ypN0 following neoadjuvant chemotherapy (NAC) remains uncertain. This study aims to assess the impact of PMRT in this patient subset. METHODS: Patients were enrolled from West China Hospital, Sichuan University from 2008 to 2019. Overall survival (OS), Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and breast cancer-specific survival (BCSS) were estimated using the Kaplan-Meier method and assessed with the log-rank test. The impact of PMRT was further analyzed by the Cox proportional hazards model. Propensity score matching (PSM) was performed to reduce the selection bias. RESULTS: Of the 333 eligible patients, 189 (56.8%) received PMRT, and 144 (43.2%) did not. At a median follow-up period of 71 months, the five-year LRFS, DMFS, BCSS, and OS rates were 99.1%, 93.4%, 96.4%, and 94.3% for the entire cohort, respectively. Additionally, the 5-year LRFS, DMFS, BCSS, and OS rates were 98.9%, 93.8%, 96.7%, and 94.5% with PMRT and 99.2%, 91.3%, 94.9%, and 92.0% without PMRT, respectively (all p-values not statistically significant). After multivariate analysis, PMRT was not a significant risk factor for any of the endpoints. When further stratified by stage, PMRT did not show any survival benefit for patients with stage II-III diseases. CONCLUSION: In the context of comprehensive treatments, PMRT might be exempted in ypN0 breast cancer patients. Further large-scale, randomized controlled studies are required to investigate the significance of PMRT in this patient subset.

Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Shell Modulation of Hollow Metal Sulfide Nanocomposite for Stable Potassium Storage at Room and High Temperature.

The large size of K-ion makes the pursuit of stable high-capacity anodes for K-ion batteries (KIBs) a formidable challenge, particularly for high temperature KIBs as the electrode instability becomes more aggravated with temperature climbing. Herein, we demonstrate that a hollow ZnS@C nanocomposite (h-ZnS@C) with a precise shell modulation can resist electrode disintegration to enable stable high-capacity potassium storage at room and high temperature. Based on a model electrode, we identify an interesting structure-function correlation of the h-ZnS@C: with an increase in the shell thickness, the cyclability increases while the rate and capacity decreases, shedding light on the design of high-performance h-ZnS@C anodes via engineering the shell thickness. Typically, the h-ZnS@C anode with a shell thickness of 60 nm can deliver an impressive comprehensive performance at room temperature; the h-ZnS@C with shell thickness increasing to 75 nm can achieve an extraordinary stability (88.6% capacity retention over 450 cycles) with a high capacity (450 mAh g-1) and a superb rate even at an extreme temperature of 60 ℃, which is much superior than those reported anodes. This contribution envisions new perspectives on rational design of functional metal sulfides composite toward high-performance KIBs with insights into the significant structure-function correlation.

Peptide Inhibitor Targeting the Extraterminal Domain in BRD4 Potently Suppresses Breast Cancer Both In Vitro and In Vivo.

BRD4 is associated with a variety of human diseases, including breast cancer. The crucial roles of amino-terminal bromodomains (BDs) of BRD4 in binding with acetylated histones to regulate oncogene expression make them promising drug targets. However, adverse events impede the development of the BD inhibitors. BRD4 adopts an extraterminal (ET) domain, which recruits proteins to drive oncogene expression. We discovered a peptide inhibitor PiET targeting the ET domain to disrupt BRD4/JMJD6 interaction, a protein complex critical in oncogene expression and breast cancer. The cell-permeable form of PiET, TAT-PiET, and PROTAC-modified TAT-PiET, TAT-PiET-PROTAC, potently inhibits the expression of BRD4/JMJD6 target genes and breast cancer cell growth. Combination therapy with TAT-PiET/TAT-PiET-PROTAC and JQ1, iJMJD6, or Fulvestrant exhibits synergistic effects. TAT-PiET or TAT-PiET-PROTAC treatment overcomes endocrine therapy resistance in ERα-positive breast cancer cells. Taken together, we demonstrated that targeting the ET domain is effective in suppressing breast cancer, providing a therapeutic avenue in the clinic.

Green one-step synthesis of N-doped carbon quantum dots for fluorescent detection of lemon yellow in soft drinks.

A new fluorescent sensor for the determination of lemon yellow was developed based on nitrogen-doped carbon quantum dots (N-CQDs), which were prepared via a hydrothermal method with dried pomelo peel and L-tyrosine. The N-CQDs exhibited the blue fluorescence with a quantum yield of 28 %. The sensing principle of N-CQDs was quenched by lemon yellow via static quenching. The potential interfering substances showed no influence on the detection of lemon yellow. The limit of detection was 0.023 mg/L and lower than that of national standard. Furthermore, the synthesized N-CQDs have been successfully applied to the measurement of lemon yellow in real samples. Hence, the N-CQDs would be a promising sensor in food analysis.