CCL5 promotes the epithelial-mesenchymal transition of circulating tumor cells in renal cancer.

BACKGROUND: Circulating tumor cells (CTCs) are pivotal in tumor metastasis across cancers, yet their specific role in renal cancer remains unclear. METHODS: This study investigated C-C motif chemokine ligand 5 (CCL5)'s tumorigenic impact on renal cancer cells and CTCs using bioinformatics, in vivo, and in vitro experiments. It also assessed renal cancer patients' CTCs prognostic value through Lasso regression and Kaplan-Meier survival curves. RESULTS: Bioinformatics analysis revealed differential genes focusing on cellular adhesion and migration between CTCs and tumor cells. CCL5 exhibited high expression in various CTCs, correlating with poor prognosis in renal cancer. In 786-O-CTCs, CCL5 enhanced malignancy, while in renal cell carcinoma cell line CAKI-2 and 786-O, it promoted epithelial-mesenchymal transition (EMT) via smad2/3, influencing cellular characteristics. The nude mouse model suggested CCL5 increased CTCs and intensified EMT, enhancing lung metastasis. Clinical results shown varying prognostic values for different EMT-typed CTCs, with mesenchymal CTCs having the highest value. CONCLUSIONS: In summary, CCL5 promoted EMT in renal cancer cells and CTCs through smad2/3, enhancing the malignant phenotype and facilitating lung metastasis. Mesenchymal-type CTC-related factors can construct a risk model for renal cancer patients, allowing personalized treatment based on metastatic risk prediction.

A novel immunogenic cell death-related classification indicates the immune landscape and predicts clinical outcome and treatment response in acute myeloid leukemia.

BACKGROUND: Immunogenic cell death (ICD) is closely related to anti-tumor therapy and regulates the tumor microenvironment (TME). This study aims to explore the molecular characteristics of ICD in acute myeloid leukemia (AML) and to analyze the value of ICD-related biomarkers in TME indication, prognosis prediction, and treatment response evaluation in AML. METHODS: Single-sample gene set enrichment analysis was used to calculate the ICD score. LASSO regression was used to construct a prognostic risk score model. We also analyzed differences in clinical characteristics, immune landscape, immunotherapy response, and chemotherapy sensitivity between high-risk and low-risk patients. RESULTS: This study identified two ICD-related subtypes and found significant heterogeneity in clinical prognosis, TME, and immune landscape between different ICD subtypes. Subsequently, a novel ICD-related prognostic risk score model was developed, which accurately predicted the prognosis of AML patients and was validated in nine AML cohorts. Moreover, there were significant correlations between risk scores and clinicopathological factors, somatic mutations, TME characteristics, immune cell infiltration, immunotherapy response, and chemosensitivity. We further validated the model gene expression in a clinically real-world cohort. CONCLUSIONS: The novel ICD-related signatures identified and validated by us can serve as promising biomarkers for predicting clinical outcomes, chemotherapy sensitivity, and immunotherapy response in AML patients, guiding the establishment of personalized and accurate treatment strategies for AML.

Clinical Characteristics of Microcystic Macular Edema in Chronic Primary Angle-Closure Glaucoma and Primary Open-Angle Glaucoma Patients.

INTRODUCTION: This study investigated the clinical characteristics of and risk factors for microcystic macular edema (MME) in patients with chronic primary angle-closure glaucoma (CPACG) and primary open-angle glaucoma (POAG). METHODS: This retrospective observational study included 1,588 eyes from 926 glaucoma inpatients and analyzed the patients' basic demographic information, visual field parameters, macular scans, and peripapillary retinal nerve fiber layer thickness. RESULTS: Our findings were that the incidence rate of MME was 3.97% (34/857) in CPACG and 5.88% (43/731) in POAG. MME was predominantly diagnosed at an advanced stage in CPACG (almost 100%) compared to POAG (93.02%). MME was most frequently involved in the inferior (83.12%) quadrant of the peri-macular region in both CPACG and POAG. Risk factors for MME occurrence in CPACG and POAG included lower visual field mean deviation (OR = 1.14, 95%: CI 1.05-1.24, p = 0.003; OR = 1.14, 95% CI: 1.06-1.21, p < 0.001) and younger age (OR = 0.92, 95% CI: 0.88-0.96, p < 0.001; OR = 0.96, 95% CI: 0.93-0.99, p = 0.003), while female sex (OR = 0.30, 95% CI: 0.11-0.84, p = 0.022) reduced the MME occurrence in POAG. CONCLUSION: MME could develop in both CPACG and POAG patients, occurring earlier in POAG. The inferior peri-macular region is commonly affected. Younger age and poorer visual field are risk factors for MME in glaucoma patients.

Integrative analysis of the prognostic value and immune microenvironment of mitophagy-related signature for multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a fatal malignant tumor in hematology. Mitophagy plays vital roles in the pathogenesis and drug sensitivity of MM. METHODS: We acquired transcriptomic expression data and clinical index of MM patients from NCI public database, and 36 genes involved in mitophagy from the gene set enrichment analysis (GSEA) database. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was conducted to construct a risk score prognostic model. Kaplan-Meier survival analysis and receiver operation characteristic curves (ROC) were conducted to identify the efficiency of prognosis and diagnosis. ESTIMATE algorithm and immune-related single-sample gene set enrichment analysis (ssGSEA) was performed to uncover the level of immune infiltration. QRT-PCR was performed to verify gene expression in clinical samples of MM patients. The sensitivity to chemotherapy drugs was evaluated upon the database of the genomics of drug sensitivity in cancer (GDSC). RESULTS: Fifty mitophagy-related genes were differently expressed in two independent cohorts. Ten out of these genes were identified to be related to MM overall survival (OS) rate. A prognostic risk signature model was built upon on these genes: VDAC1, PINK1, VPS13C, ATG13, and HUWE1, which predicted the survival of MM accurately and stably both in training and validation cohorts. MM patients suffered more adverse prognosis showed more higher risk core. In addition, the risk score was considered as an independent prognostic element for OS of MM patients by multivariate cox regression analysis. Functional pathway enrichment analysis of differentially expressed genes (DEGs) based on risk score showed terms of cell cycle, immune response, mTOR pathway, and MYC targets were obviously enriched. Furthermore, MM patients with higher risk score were observed lower immune scores and lower immune infiltration levels. The results of qRT-PCR verified VDAC1, PINK1, and HUWE1 were dysregulated in new diagnosed MM patients. Finally, further analysis indicated MM patients showed more susceptive to bortezomib, lenalidomide and rapamycin in high-risk group. CONCLUSION: Our research provided a neoteric prognostic model of MM based on mitophagy genes. The immune infiltration level based on risk score paved a better understanding of the participation of mitophagy in MM.

An early-stage primary signet ring cell carcinoma of the colon.

Primary signet ring cell carcinoma of the colorectum is rarely detected at an early stage,here,we present a case with early stage primary signet ring cell carcinoma of the colon, and the patient was treated at an early stage, and the prognosis was well. We also provide endoscopic and histological characteristics of early stage SRCC.

Serum miR-101-3p combined with pepsinogen contributes to the early diagnosis of gastric cancer.

BACKGROUND: This study aimed to explore the diagnostic value of serum miR-101-3p combined with pepsinogen (PG) on early diagnosis of gastric cancer (GC). METHODS: A total of 61 atrophic gastritis (AG) and 86 GC patients, and 50 healthy volunteers were enrolled. The serum expression of miR-101-3p was measured by qRT-PCR. The serum content of carcinoembryonic antigen (CEA) was measured by Electrochemiluminescence immunoassay. The serum contents of PGI and PGII were measured by Enzyme linked immunosorbent assay. The diagnostic value of serum markers on AG and GC was analyzed by receiver operating characteristic (ROC) analysis. RESULTS: The expression of miR-101-3p, the content of PGI and the ratio of PGI/II were significantly decreased, and the content of PGII was significantly increased in AG patients compared with those in normal controls. The changes of the above serum indicators were more obvious in GC patients than those in AG patients. The content of CEA was significantly higher in GC patients than that in AG patients. In addition, the expression of miR-101-3p was negatively associated with the submucosal infiltration in GC patients. MiR-101-3p exhibited high diagnostic value on AG (AUC 0.8493, sensitivity 80.33%, specificity 80%) and GC (AUC 0.8749, sensitivity 72.09%, specificity 86.49%). MiR-101-3p + PGI + PGI/II (AUC 0.856, sensitivity 80.23%, specificity 77.05%) exhibited a high diagnostic value in distinguishing between AG and GC. CONCLUSIONS: MiR-101-3p was a potential diagnostic marker for AG and GC. MiR-101-3p + PGI + PGI/II was effective in distinguishing between AG and GC.

[Comparison of the Effects of ILO and LLO in Helping Listeria Adhere, Invade Cell and Intracellularly Multiply].

OBJECTIVE: To study the primary function of ivanolysin O (ILO) and Listeriolysin O (LLO) and compare the effects of these two hemolysins in helping bacteria adhere, invade cell and intracellularly multiply. METHODS: The targeting plasmids carrying the upstream and downstream sequences of i-hly and lacZ gene sequence or hly gene sequence were constructed. Then two recombinant strains, the ILO deletion strain LIΔi-hly::lacZ and LLO compensative expressing strain LIΔi-hly::hly, were constructed by plasmid targeting recombinant technique. The adhesive and invasive ability of LIΔi-hly::hly, LI and LIΔi-hly::lacZ were evaluated in HepG2 cells, and their intracellular multiplication abilities were evaluated in RAW264.7 macrophages. RESULTS: Genome sequences of the recombinant strains were as expected. The adhesive rate of LIΔi-hly::i-hly LI and LIΔi-hly::lacZ were (3.43±0.82)%, (3.43±1.59)% and (3.41±1.12)% respectively, and the invasive rate were (1.74±0.46)%, (1.22±0.75)% and (1.39±0.46)% respectively. Difference in adhesive and invasive rates showed no significance. Among three strains, LIΔi-hly::lacZ showed the lowest intracellular proliferation rate, and LIΔi-hly::hly possessed the highest intracellular proliferation rate in RAW264.7 macrophages. CONCLUSION: The intracellular multiplication ability of LI is related to ILO. Deletion of ILO induces a distinct decrease in intracellular multiplication for LI. Compared with ILO, LLO shows a stronger ability in helping the bacteria escape from the phagosome into the host cell cytosol.

Analgesic and physiological effect of electroacupuncture combined with epidural lidocaine in goats.

OBJECTIVE: To investigate physiological and antinociceptive effects of electroacupuncture (EA) with lidocaine epidural nerve block in goats. STUDY DESIGN: Prospective experimental trial. ANIMALS: Forty-eight hybrid male goats weighing 27 ± 2 kg. METHODS: The goats were randomly assigned to six groups: L2.2, epidural lidocaine (2.2 mg kg-1); L4.4, epidural lidocaine (4.4 mg kg-1); EA; EA-L1.1, EA with epidural lidocaine (1.1 mg kg-1); EA-L2.2, EA with epidural lidocaine (2.2 mg kg-1); and EA-L4.4, EA with epidural lidocaine (4.4 mg kg-1). EA was administered for 120 minutes. Epidural lidocaine was administered 25 minutes after EA started. Nociceptive thresholds of flank and thigh regions, abdominal muscle tone, mean arterial pressure (MAP), heart rate (HR), respiratory frequency (fR) and rectal temperature were recorded at 30, 60, 90, 120, 150 and 180 minutes. RESULTS: Lidocaine dose-dependently increased nociceptive thresholds. There were no differences in nociceptive thresholds between L4.4 and EA from 30 to 120 minutes. The threshold in EA-L2.2 was lower than in EA-L4.4 from 30 to 120 minutes, but higher than in EA-L1.1 from 30 to 150 minutes or in L4.4 from 30 to 180 minutes. The abdominal muscle tone in EA-L2.2 was higher at 30 minutes, but lower at 90 and 120 minutes than at 0 minutes. There were no differences in muscle tone between L4.4 and L2.2 or EA-L4.4, and between any two of the three EA-lidocaine groups from 0 to 180 minutes. The fR and HR decreased in L4.4 at 60 and 90 minutes compared with 0 minutes. No differences in fR, HR, MAP and temperature among the groups occurred from 30 to 180 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: EA combined with 2.2 mg kg-1 epidural lidocaine provides better antinociceptive effect than 4.4 mg kg-1 epidural lidocaine alone in goats. EA provided antinociception and allowed a decrease in epidural lidocaine dose.

Norovirus Infection and Histo-blood Group Antigens in Children Hospitalized with Diarrhea in Lulong and Chenzhou in China.

Norovirus (NoV) is a pathogen that commonly causes viral diarrhea in children. Studies indicate that NoV recognizes human histo-blood group antigens (HBGAs) as cell attachment factors. In order to explore the correlation between of NoV infection and HBGAs, a cross-sectional study was conducted in children less than five years old who were hospitalized with diarrhea in two areas of China between November 2014 and February 2015. Of the paired stool and saliva samples taken from 424 children, NoV was detected in 24 (6%) children, with viral genotypes GII.3 (n=5), GII.4 (n=14), GII.12 (n=1), and GII.17 (n=4). All of the individuals having NoV infection were either secretors (Lea-b+/Lex-y+) or partial secretors (Lea+b+/Lex+y+) except one GII.3 infection of a non-secretor (Lea+b-/Lex+y-). These results suggest that secretor positive is associated with NoV infection, although non-secretors are not absolutely protected from NoV infection.

Changes in spectral characteristics and copper (II)-binding of dissolved organic matter in leachate from different water-treatment processes.

The aim of the present study was to investigate the fluorescence properties of dissolved organic matter (DOM) from four leachate samples, which were disposed by regulating tank (RTK), anaerobic treatment (ATT), oxidation ditch (ODH), and membrane bioreactor and to assess their binding capacities and stability constants by Cu(II). The results showed that five fluorescent peaks, including three humic-like peaks (peaks A, C, and E) and two protein-like peaks (peaks B and D), were identified. Most fluorescent components can be degraded after ODH. Fluorescence-quenching titration showed that the modified Stern-Volmer model can be used to fit the quenching data and calculate conditional stability constants (log K) and the % of fluorophores (f %) between DOM and Cu(II). DOM-Cu(II) complexes had relatively high log K values in the RTK and ATT disposals. After the ODH-treatment process, log K values showed a marked decrease. The f % values of protein-like materials were evidently greater than those of humic-like substances. The results showed the impact of the water treatment on the metal-binding ability of various fractions.

Immunoinformatics Design and In Vivo Immunogenicity Evaluation of a Conserved CTL Multi-Epitope Vaccine Targeting HPV16 E5, E6, and E7 Proteins.

Human papillomavirus type 16 (HPV16) infection is responsible for more than 50% of global cervical cancer cases. The development of a vaccine based on cytotoxic T-lymphocyte (CTL) epitopes is a promising strategy for eliminating pre-existing HPV infections and treating patients with cervical cancer. In this study, an immunoinformatics approach was used to predict HLA-I-restricted CTL epitopes in HPV16 E5, E6, and E7 proteins, and a set of conserved CTL epitopes co-restricted by human/murine MHCs was screened and characterized, with the set containing three E5, four E6, and four E7 epitopes. Subsequently, the immunogenicity of the epitope combination was assessed in mice, and the anti-tumor effects of the multi-epitope peptide vaccine E5E6E7pep11 and the recombinant protein vaccine CTB-Epi11E567 were evaluated in the TC-1 mouse tumor model. The results demonstrated that mixed epitope peptides could induce antigen-specific IFN-γ secretion in mice. Prophylactic immunization with E5E6E7pep11 and CTB-Epi11E567 was found to provide 100% protection against tumor growth in mice. Moreover, both types of the multi-epitope vaccine significantly inhibited tumor growth and prolonged mouse survival. In conclusion, in this study, a multi-epitope vaccine targeting HPV16 E5, E6, and E7 proteins was successfully designed and evaluated, demonstrating potential immunogenicity and anti-tumor effects and providing a promising strategy for immunotherapy against HPV-associated tumors.

The Macular Pigment Optical Density (MPOD) Decrease in Chinese Primary Angle Closure Glaucoma Using the One-Wavelength Reflectometry Method.

PURPOSE: The objective of this study was to observe the macular pigment optical density (MPOD) and the relationship between MPOD and retinal thickness in Chinese primary angle-closure glaucoma (PACG) patients by the one-wavelength reflectometry method. METHODS: This study was a prospective comparative observational study, including 39 eyes from 39 PACG patients (15 men and 24 women, mean age 61.89 ± 12.30) and 41 eyes from 41 controls (20 men and 21 women, mean age 63.24 ± 14.02). We measured the MPOD 7-degree area by the one-wavelength reflectometry method and analyzed both the max and mean optical density (OD). The central retinal thickness (CRT) and the total thickness of the macular ganglion cell layer (GCL), and inner plexiform layer (IPL)were measured by spectral-domain-optical coherence tomography (SD-OCT). Statistical methods such as Shapiro-Wilk test, Fisher's exact test, chi-square test, two independent samples test and Spearman's correlation coefficient were used to observe the differences in the MPOD between normal subjects and PACG patients and the correlation between the MPOD and retinal thickness. RESULTS: The max optical density (Max OD) (PACG group: 0.302 ± 0.067d.u, control group: 0.372 ± 0.059d.u., p < .001) and mean optical density (Mean OD) (PACG group: 0.124 ± 0.035d.u., control group: 0.141 ± 0.028d.u., p < 0.05) were significantly reduced in PACG patients compared with control subjects. Significant decreases in GCL + IPL thickness (PACG group: 74.71 ± 39.56 µm, control group:113.61 ± 8.14 µm, p < 0.001) and CRT (PACG group: 254.49 ± 41.47 µm, control group:329.10 ± 18.57 µm, p < 0.001) were also observed in PACG eyes. There was no statistically significant correlation between the MPOD and GCL + IPL thickness (p = .639, p = .828). CONCLUSIONS: MPOD was significantly lower in Chinese PACG patients than in the control group, potentially due to thinning of the GCL + IPL thickness. This study provides insights for the pathophysiology, assessment of PACG and potential guidance for lifestyle modifications.

In this study, we measured the MPOD values of Chinese PACG patients for the first time using the one-wavelength reflectance method and clarified that the MPOD of PACG patients was significantly lower than that of the normal group. This study provides insights for the pathophysiology, assessment of PACG and potential guidance for lifestyle modifications.

Mechanistic insights into the role of probiotics in modulating immune cells in ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a persistent inflammatory disorder that affects the gastrointestinal tract, mainly the colon, which is defined by inflammatory responses and the formation of ulcers. Probiotics have been shown to directly impact various immune cells, including dendritic cells (DCs), macrophages, natural killer (NK) cells, and T and B cells. By interacting with cell surface receptors, they regulate immune cell activity, produce metabolites that influence immune responses, and control the release of cytokines and chemokines. METHODS: This article is a comprehensive review wherein we conducted an exhaustive search across published literature, utilizing reputable databases like PubMed and Web of Science. Our focus centered on pertinent keywords, such as "UC," 'DSS," "TNBS," "immune cells," and "inflammatory cytokines," to compile the most current insights regarding the therapeutic potential of probiotics in managing UC. RESULTS: This overview aims to provide readers with a comprehensive understanding of the effects of probiotics on immune cells in relation to UC. Probiotics have a crucial role in promoting the proliferation of regulatory T cells (Tregs), which are necessary for preserving immunological homeostasis and regulating inflammatory responses. They also decrease the activation of pro-inflammatory cells like T helper 1 (Th1) and Th17 cells, contributing to UC development. Thus, probiotics significantly impact both direct and indirect pathways of immune cell regulation in UC, promoting Treg differentiation, inhibiting pro-inflammatory cell activation, and regulating cytokine and chemokine release. CONCLUSION: Probiotics demonstrate significant potential in modulating the immune reactions in UC. Their capacity to modulate different immune cells and inflammation-related processes makes them a promising therapeutic approach for managing UC. However, further studies are warranted to optimize their use and fully elucidate the molecular mechanisms underlying their beneficial effects in UC treatment.

Integrated analysis and validation of the TRIM28-H2AX-CDK4 diagnostic model assists to predict the progression of HCC.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality in the world. However, identifying key genes that can be exploited for the effective diagnosis and management of HCC remains difficult. The study aims to examine the prognostic and diagnostic value of TRIM28-H2AX-CDK4 axis in HCC. Analysis in TCGA, GSEA and Gene expression profiling interactive analysis online tools were performed to explore the expression profiles of TRIM28, H2AX and CDK4. Data demonstrating the correlation between TRIM28 expression levels and immune infiltration states or the expression of genes associated with immune checkpoints genes were exacted from TCGA and TIMER. Genetic alteration and enrichment analysis were performed using the cBioPortal and GEPIA2 tools. Finally, the expression of these proteins in HCC was then examined and validated in an independent cohort using immunohistochemistry. TRIM28 alteration exhibited co-occurrence instead of mutual exclusivity with a large number of immune checkpoint components and tumor-infiltrating immune cells, especially B cells, were found to serve roles in patients with HCC with different TRIM28 expression levels. Higher expression levels of TRIM28, H2AX and CDK4 were associated with a poorer prognosis and recurrence in patients with HCC according to TCGA, which was validated further in an independent cohort of patients with HCC. Area under curve revealed the superior predictive power of applying this three-gene signatures in this validation cohort. The diagnostic model based on this TRIM28-H2AX-CDK4 signature is efficient and provides a novel strategy for the clinical management of HCC.

Paracentral Acute Middle Maculopathy Following Acute Primary Angle Closure and Acute Primary Angle Closure Glaucoma.

Purpose: To report the prevalence, clinical characteristics and risk factors for paracentral acute middle maculopathy (PAMM) following acute primary angle closure (APAC) and acute primary angle closure glaucoma (APACG). Methods: This retrospective study consecutively recruited patients diagnosed with APAC or APACG. Based on the spectral domain optical coherence tomography characteristics, PAMM eyes were divided into three stages. Characteristics of different stages such as the time from symptoms to treatment (TST), retinal thickness and BCVA improvement were analyzed. The risk factors of PAMM were evaluated by binary logistic regression models. Results: A total of 781 eyes of 781 APAC or APACG patients were included, and PAMM was found in 22 (2.9%) of them. Stage III eyes had a significantly longer TST than stage I eyes (P = 0.008) while exhibiting significantly thinner retinal thicknesses (P < 0.0001). The BCVA improvement was significantly worse in the eyes treated in stage III than in those treated in stage I (P = 0.008). Older age, longer axial length and without type 2 diabetes were associated with a lower risk of incident PAMM (OR = 0.95, P = 0.028; OR = 0.52, P = 0.019; OR = 3.92, P = 0.022). Conclusion: PAMM can be secondary to APAC or APACG at a rate of 2.9%. Different visual outcomes were observed in patients who received the intervention at different stages of PAMM. Younger patients with a shorter axial length and type 2 diabetes were found to be more susceptible to PAMM.

Protein phosphatase 2A-B55ß mediated mitochondrial p-GPX4 dephosphorylation promoted sorafenib-induced ferroptosis in hepatocellular carcinoma via regulating p53 retrograde signaling.

Rationale: As a key endogenous negative regulator of ferroptosis, glutathione peroxidase 4 (GPX4) can regulate its antioxidant function through multiple post-translational modification pathways. However, the effects of the phosphorylation/dephosphorylation status of GPX4 on the regulation of inducible ferroptosis in hepatocellular carcinoma (HCC) remain unclear. Methods: To investigate the effects and molecular mechanism of GPX4 phosphorylation/dephosphorylation modification on ferroptosis in HCC cells. Sorafenib (Sora) was used to establish the ferroptosis model in HCC cells in vitro. Using the site-directed mutagenesis method, we generated the mimic GPX4 phosphorylation or dephosphorylation HCC cell lines at specific serine sites of GPX4. The effects of GPX4 phosphorylation/dephosphorylation modification on ferroptosis in HCC cells were examined. The interrelationships among GPX4, p53, and protein phosphatase 2A-B55ß subunit (PP2A-B55ß) were also explored. To explore the synergistic anti-tumor effects of PP2A activation on Sora-administered HCC, we established PP2A-B55ß overexpression xenograft tumors in a nude mice model in vivo. Results: In the Sora-induced ferroptosis model of HCC in vitro, decreased levels of cytoplasmic and mitochondrial GPX4, mitochondrial dysfunction, and enhanced p53 retrograde signaling occurred under Sora treatment. Further, we found that mitochondrial p53 retrograded remarkably into the nucleus and aggravated Sora-induced ferroptosis. The phosphorylation status of GPX4 at the serine 2 site (GPX4Ser2) revealed that mitochondrial p-GPX4Ser2 dephosphorylation was positively associated with ferroptosis, and the mechanism might be related to mitochondrial p53 retrograding into the nucleus. In HCC cells overexpressing PP2A-B55ß, it was found that PP2A-B55ß directly interacted with mitochondrial GPX4 and promoted Sora-induced ferroptosis in HCC. Further, PP2A-B55ß reduced the interaction between mitochondrial GPX4 and p53, leading to mitochondrial p53 retrograding into the nucleus. Moreover, it was confirmed that PP2A-B55ß enhanced the ferroptosis-mediated tumor growth inhibition and mitochondrial p53 retrograde signaling in the Sora-treated HCC xenograft tumors. Conclusion: Our data uncovered that the PP2A-B55ß/p-GPX4Ser2/p53 axis was a novel regulatory pathway of Sora-induced ferroptosis. Mitochondrial p-GPX4Ser2 dephosphorylation triggered ferroptosis via inducing mitochondrial p53 retrograding into the nucleus, and PP2A-B55ß was an upstream signal modulator responsible for mitochondrial p-GPX4Ser2 dephosphorylation. Our findings might serve as a potential theranostic strategy to enhance the efficacy of Sora in HCC treatment through the targeted intervention of p-GPX4 dephosphorylation via PP2A-B55ß activation.

Prevalence and Associated Factors of Depression, Anxiety and Insomnia Symptoms Among Patients Receiving Ophthalmic Consultation Online During the COVID-2019 Pandemic.

Objective: This study aims to assess the prevalence and associated factors of depression, anxiety and insomnia symptoms among patients undergoing ophthalmic consultation online during the coronavirus disease 2019 (COVID-2019) pandemic. Methods: We reviewed the data of patients who received online ophthalmic consultations during the lockdown period from February to August 2020, and an online survey was conducted among them. We collected the respondents' demographic data and their attitudes toward the online consultation, assessed the depression, anxiety and insomnia symptoms and estimated associated factors by logistic regression analysis. Results: The online service provided 425 consultations during the COVID-19 lockdown period. Of these eligible subjects, 139 patients responded to an invitation to participant in the study (105/75.5% were females, and 40/28.8% were health care workers). More than half of the participants reported that they trusted and were satisfied with the online consultation (109/78.4% and 82/59%, respectively). Fifty-two (37.4%), 32 (23.0%), and 53 (38.1%) patients showed symptoms of depression, anxiety, and insomnia, respectively. Depression was found to be significantly more common in health care workers (P = 0.019) and those who were basically satisfied with online consultation (P = 0.024). Anxiety was more common among participants who had used electronics for a long time (P = 0.038). Binary logistic regression showed health care work as a risk factor for depressive symptoms (odds ratio [OR]: 2.424; 95% CI: 1.143-5.143; P = 0.021). Conclusion: Psychological distress is highly prevalent among patients who were involved in online consultation for ocular manifestations during the COVID-19 lockdown period. In the context of a major public health event, ophthalmologists should focus not only on ocular symptoms but also on the mental health of their patients, and appropriate psychological support should be given.

Prognostic value of circulating tumor cells and immune-inflammatory cells in patients with renal cell carcinoma.

PURPOSE: The relationships among circulating tumor cells (CTCs), inflammatory cells, and platelets in patients with renal cell carcinoma (RCC) are not transparent. We evaluated the correlations among CTCs, blood inflammatory cells, and platelets in patients with RCC and their prognostic value for metastasis-free survival. METHODS: CTC and typical tumor cell chip data were collected and analyzed by the GEO database. The baseline data, survival data, CTCs data, and blood test results were statistically analyzed. RESULTS: Bioinformatics analysis showed that the function of the differentially expressed genes between CTCs and normal tumor cells mainly involved platelets and immune inflammation. A total of 82 patients whose follow-up time was 3 to 68 months were included in the analysis. Clinical data of the patients confirmed that there is a correlation between platelets and mesenchymal CTCs. Simultaneously, there was a correlation between immune inflammatory cells and platelets. The univariate Cox proportional hazards model indicated that staging, mesenchymal CTCs, and the monocyte-to-neutrophil ratio (MNR) had prognostic value. The multivariate Cox proportional hazards model indicated that staging and the MNR had prognostic value and high accuracy. CONCLUSIONS: Bioinformatics analysis showed that CTCs were related to platelets and immune-inflammatory cells. Furthermore, the clinical data confirmed that platelets were correlated with mesenchymal CTCs and immune-inflammatory cells in the blood. By using mesenchymal CTCs, the MNR, or staging respectively, it is possible to predict the risk of postoperative metastasis in RCC patients. As a compound prognostic factor, staging, and the MNR can provide more convenient and accurate condition monitoring.

Mitochondrial redox-driven mitofusin 2 S-glutathionylation promotes neuronal necroptosis via disrupting ER-mitochondria crosstalk in cadmium-induced neurotoxicity.

Reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and mitochondrial dysfunction are known to affect the structural and functional damage in the neural system. Cadmium (Cd) is an environmental contaminant that is widely found in numerous environmental matrices and exhibits potential neurotoxic risk. However, it remains unclear how mitochondrial redox status induces, and whether Cd destabilizes, the ER-mitochondria crosstalk to have a toxic effect on the nervous system. Herein, in our present study, bioinformatics analysis revealed an important role of protein interaction and mitochondrial machinery in brain samples from Alzheimer's disease (AD) patients. Furthermore, we established a neurotoxicity model in vivo and in vitro induced by cadmium chloride (CdCl2). We demonstrated that CdCl2 exposure disrupts the balance in mitochondrial redox represented by enhanced mitochondrial ROS (mitoROS) levels, which enhance mitofusin 2 (Mfn2) S-glutathionylation and interrupt the mitochondria-associated ER membranes (MAMs) for crosstalk between the ER and mitochondria to induce neuronal necroptosis. Mechanistically, it was shown that CdCl2 exposure significantly enhances the mitochondria-associated degradation (MAD) of Mfn2 via S-glutathionylation, which inhibits Mfn2 localization to the MAMs and subsequently leads to the formation of the RIPK1-RIPK3-p-MLKL complex (a key component of the necrosome) at MAMs, to promote neuronal necroptosis. Furthermore, the glutaredoxin 1 (Grx1) catalyzed and Mfn2 overexpression restored S-glu-Mfn2, MAMs perturbation, necrosome formation, and necroptosis in neurons induced by CdCl2 exposure in vitro. Moreover, the intervention with antioxidants to reduce mitochondrial redox, such as N-acetyl-l-cysteine (NAC) and mitochondria-targeted antioxidant Mito-TEMPO, reduced the S-glutathionylation of Mfn2 involved in the antagonism of CdCl2-induced necroptosis and neurotoxicity in vivo and in vitro. Taken together, our results are the first time to demonstrate that S-glutathionylation of Mfn2 promotes neuronal necroptosis via disruption of ER-mitochondria crosstalk in CdCl2-induced neurotoxicity, providing the novel mechanistic insight into how hazardous chemical-induced adverse effects in various organs and tissues could be interpreted by intraorganellar pathways under the control of MAMs components in neurons.

Consequences of cps mutation of Klebsiella pneumoniae on 1,3-propanediol fermentation.

The filtration in 1,3-propanediol (1,3-PD) downstream process is influenced by the large amounts of capsular polysaccharides (CPS) produced by Klebsiella pneumoniae CGMCC 1.6366. The morphological and fermentation properties were investigated with the CPS-deficient mutant K. pneumoniae CGMCC 1.6366 CPS. Similar biomass was obtained with CGMCC 1.6366, and the mutant strain in batch cultures indicating the cell growth was slightly inhibited by CPS defection. The viscosity of fermentation broth by mutant strain decreased by 27.45%. The flux with ceramic membrane filter was enhanced from 168.12 to 303.6 l h(-1) m(-2), exhibiting the great importance for downstream processing of 1,3-PD fermentation. The products spectrum of mutant isolate changed remarkably regarding to the concentration of fermentation products. The synthesis of important 1,3-PD and 2,3-butanediol was enhanced from 9.73 and 4.06 g l(-1) to 10.37 and 4.77 g l(-1) in batch cultures. The noncapsuled K. pneumoniae provided higher 1,3-PD yield of 0.54 mol mol(-1) than that of encapsuled wild parent in batch cultures. The fed-batch fermentation of mutant strain resulted in 1,3-PD concentration, yield, and productivity of 78.13 g l(-1), 0.53 mol mol(-1), and 1.95 g l(-1) h(-1), respectively.