Aquaporin-1 Facilitates Macrophage M1 Polarization by Enhancing Glycolysis Through the Activation of HIF1α in Lipopolysaccharide-Induced Acute Kidney Injury.

This study aimed to investigate how aquaporin 1 (AQP1) modulates hypoxia-inducible factor-1α (HIF1α) to promote glycolysis and drive the M1 polarization of macrophages. Within 12 h post-treatment with LPS to induce acute kidney injury in rats, a significant upregulation of AQP1 and HIF1α protein levels was noted in serum and kidney tissues. This elevation corresponded with a decrease in blood glucose concentrations and an enhancement of glycolytic activity relative to the control group. Furthermore, there was a pronounced reduction in the circulating levels of the anti-inflammatory cytokine IL-10, accompanied by an upregulation in the levels of the pro-inflammatory cytokines IL-6 and TNF-α. The administration of an HIF1α inhibitor reversed these effects, which did not affect the production of AQP1 protein. In cellular assays, AQP1 knockdown mitigated the increase in HIF1α expression induced by LPS. Furthermore, the suppression of HIF1α with PX-478 led to decreased expression levels of Hexokinase 2 (HK2) and Lactate Dehydrogenase A (LDHA), indicating that AQP1 regulates glycolysis through HIF1α. M1 polarization of macrophages was reduced by AQP1 knockdown and was further diminished by the addition of an HIF1α inhibitor. Inhibition of the glycolytic process not only weakened M1 polarization but also promoted M2 polarization, thereby reducing the release of inflammatory cytokines. These findings provide a novel perspective for developing therapeutic strategies that target AQP1 and HIF1α, potentially improving the treatment of sepsis-associated AKI.

Single-Cell Transcriptomic Analysis Reveals Dynamic Cellular Processes in Corneal Epithelium During Wound Healing in Cynomolgus Monkeys.

Purpose: Corneal wounding healing is critical for maintaining clear vision, however, a complete understanding of its dynamic regulatory mechanisms remains elusive. Here, we used single-cell RNA sequencing (scRNA-seq) to analyze the cellular activities and transcriptional changes of corneal limbal epithelial cells at different stages after wound healing in cynomolgus monkeys, which exhibit a closer transcriptomic similarity to humans. Methods: Corneal limbal tissues were collected during uninjured, 1-day and 3-day healing stages, dissociated into single cells, and subjected to scRNA-seq using the 10× Genomics platform. Cell types were clustered by graph-based visualization methods and unbiased computational analysis. Additionally, cell migration assays and immunofluorescent staining were performed on cultured human corneal epithelial cells. Results: We characterized nine cell clusters by scRNA-seq analysis of the cynomolgus monkey corneal epithelium. By comparing heterogeneous transcriptional changes in major cell types during corneal healing, we highlighted the importance of limbal epithelial cells (LEPCs) and basal epithelial cells (BEPCs) in extracellular matrix (ECM) formation and wound healing, as well as suprabasal epithelial cells (SEPCs) in epithelial differentiation during the healing processes. We further identified five different sub-clusters in LEPC, including the transit amplifying cell (TAC) sub-cluster that promotes early healing through the activation of thrombospondin-1 (THBS1) expression. Conclusions: Our study represents the first comprehensive exploration of the detailed transcriptome profile of individual corneal cells during the wound healing process in nonhuman primates. We demonstrate the intricate mechanisms involved in corneal healing and provide a promising avenue for potential therapies in corneal wound healing.

SQLE-a promising prognostic biomarker in cervical cancer: implications for tumor malignant behavior, cholesterol synthesis, epithelial-mesenchymal transition, and immune infiltration.

BACKGROUND: Cervical cancer, encompassing squamous cell carcinoma and endocervical adenocarcinoma (CESC), presents a considerable risk to the well-being of women. Recent studies have reported that squalene epoxidase (SQLE) is overexpressed in several cancers, which contributes to cancer development. METHODS: RNA sequencing data for SQLE were obtained from The Cancer Genome Atlas. In vitro experiments, including colorimetry, colony formation, Transwell, RT-qPCR, and Western blotting were performed. Furthermore, a transplanted CESC nude mouse model was constructed to validate the tumorigenic activity of SQLE in vivo. Associations among the SQLE expression profiles, differentially expressed genes (DEGs), immune infiltration, and chemosensitivity were examined. The prognostic value of genetic changes and DNA methylation in SQLE were also assessed. RESULTS: SQLE mRNA expression was significantly increased in CESC. ROC analysis revealed the strong diagnostic ability of SQLE toward CESC. Patients with high SQLE expression experienced shorter overall survival. The promotional effects of SQLE on cancer cell proliferation, metastasis, cholesterol synthesis, and EMT were emphasized. DEGs functional enrichment analysis revealed the signaling pathways and biological processes. Notably, a connection existed between the SQLE expression and the presence of immune cells as well as the activation of immune checkpoints. Increased SQLE expressions exhibited increased chemotherapeutic responses. SQLE methylation status was significantly associated with CESC prognosis. CONCLUSION: SQLE significantly affects CESC prognosis, malignant behavior, cholesterol synthesis, EMT, and immune infiltration; thereby offering diagnostic and indicator roles in CESC. Thus, SQLE can be a novel therapeutic target in CESC treatment.

Synthesis and immunotherapy efficacy of a PD-L1 small-molecule inhibitor combined with its 131I-iodide labelled isostructural compound.

Although antibody-based immune checkpoint blockades have been successfully used in antitumor immunotherapy, the low response rate is currently the main problem. In this work, a small-molecule programmed cell death-ligand (PD-L1) inhibitor, LG-12, was developed and radiolabeled with 131I to obtain the chemically and biologically identical radiopharmaceutical [131I]LG-12, which aimed to improve the antitumor effect by combination of LG-12 and [131I]LG-12. LG-12 showed high inhibitory activity to PD-1/PD-L1 interaction. The results of cell uptake and biodistribution studies indicated that [131I]LG-12 could specifically bind to PD-L1 in B16-F10 tumors. It could induce immunogenic cell death and the release of high mobility group box 1 and calreticulin. The combination of [131I]LG-12 and LG-12 could significantly inhibit tumor growth and resulted in enhanced antitumor immune response. This PD-L1 small-molecule inhibitor based combination strategy has great potential for tumor treatment.

CSF and blood glial fibrillary acidic protein for the diagnosis of Alzheimer's disease: A systematic review and meta-analysis.

Recently included in the 2024 new revised diagnostic criteria of Alzheimer's disease (AD), glial fibrillary acidic protein (GFAP) has garnered significant attention. A systematic review and meta-analysis were performed to comprehensively evaluate the diagnostic, differential diagnostic, and prospective diagnostic performance of GFAP in cerebrospinal fluid (CSF) and blood for AD continuum. A literature search using common electronic databases, important websites and historical search way was performed from inception to the beginning of March 2023. The inclusion criteria was studies evaluating the diagnostic accuracy of GFAP in CSF and/or blood for the AD continuum patients, utilizing PET scans, CSF biomarkers and/or clinical criteria. The systematic review and meta-analysis were conducted referring to the Cochrane Handbook. In total, 34 articles were eventually included in the meta-analysis, 29 of which were published within the past three years. Blood GFAP exhibited good diagnostic accuracy across various AD continuum patients, and the summary area under curve for distinguishing PET positive and negative individuals, CSF biomarkers defined positive and negative individuals, clinically diagnosed AD and cognitive unimpaired controls, AD and/or mild cognitive impairment and other neurological diseases, and prospective cases and controls was 0.85[0.81-0.88], 0.77[0.73-0.81], 0.92[0.90-0.94], 0.80[0.77-0.84], and 0.79[0.75-0.82], respectively. Only several studies were recognized to evaluate the diagnostic accuracy of CSF GFAP, which was not as good as that of blood GFAP (paired mixed data: AUC = 0.86 vs. AUC = 0.77), but its accuracy remarkably increased to AUC = 0.91 when combined with other factors like sex, age, and ApoE genotype. In summary, GFAP, particularly in blood, shown good diagnostic, differential diagnostic, and prospective diagnostic accuracy for AD continuum patients, with improved accuracy when used alongside other basic indexes.

Investigation of risk factors for invasive pulmonary aspergillosis among patients with COVID-19.

COVID-19 associated pulmonary aspergillosis (CAPA) had been reported, and raised concern about this secondary infection due to the high mortality. This study aimed to investigate the risk factors for CAPA. The enrolled 114 COVID-19 patients were further divided into CAPA group and non-CAPA group. Demographic characteristics, underlying diseases, laboratory parameters and therapeutic schedule between the two groups were compared to identify the independent risk factors for CAPA by univariate analysis and multivariable logistic regression analysis. Sensitivity and specificity of independent risk factors were confirmed by receiver operating characteristic (ROC) curve analysis. Univariate analysis showed that renal transplant, IL-6 and CRP levels, decreased CD4 + T cell and CD8 + T cell, duration of antibiotics therapy, and prolonged mechanical ventilation were risk factors for development of CAPA. These factors were further analyzed by multivariable logistic regression analysis and the results indicated that elevated IL-6 level, decreased CD4 + T cell and prolonged mechanical ventilation could be recognized as independent risk factors for CAPA in COVID-19 patients. Identification of these risk factors is essential to initiate antifungal therapy as soon as possible to improve outcome of patients with CAPA.

High-Intensity Interval Training Mitigates Sarcopenia and Suppresses the Myoblast Senescence Regulator EEF1E1.

BACKGROUND: The optimal exercise regimen for alleviating sarcopenia remains uncertain. This study aimed to investigate the efficacy of high-intensity interval training (HIIT) over moderate-intensity continuous training (MICT) in ameliorating sarcopenia. METHODS: We conducted a randomized crossover trial to evaluate plasma proteomic reactions to acute HIIT (four 4-min high-intensity intervals at 70% maximal capacity alternating with 4 min at 30%) versus MICT (constant 50% maximal capacity) in inactive adults. We explored the relationship between a HIIT-specific protein relative to MICT, identified via comparative proteomic analysis, eukaryotic translation elongation factor 1 epsilon 1 (EEF1E1) and sarcopenia in a paired case-control study of elderly individuals (aged over 65). Young (3 months old) and aged (20 months old) mice were randomized to sedentary, HIIT and MICT groups (five sessions/week for 4 weeks; n = 8 for each group). Measurements included skeletal muscle index, hand grip strength, expression of atrophic markers Atrogin1 and MuRF1 and differentiation markers MyoD, myogenin and MyHC-II via western blotting. We examined the impact of EEF1E1 siRNA and recombinant protein on D-galactose-induced myoblast senescence, measuring senescence-associated ß-galactosidase and markers like p21 and p53. RESULTS: The crossover trial, including 10 sedentary adults (32 years old, IQR 31-32) demonstrated significant alterations in the abundance of 21 plasma proteins after HIIT compared with MICT. In the paired case-control study of 84 older adults (84 years old, IQR 69-81; 52% female), EEF1E1 was significantly increased in those with sarcopenia compared to those without (14.68 [95%CI, 2.02-27.34] pg/mL, p = 0.03) and was associated with skeletal muscle index (R2 = 0.51, p < 0.001) and hand grip strength (R2 = 0.54, p < 0.001). In the preclinical study, aged mice exhibited higher EEF1E1 mRNA and protein levels in skeletal muscle compared to young mice, accompanied by a lower muscle mass and strength, increased cellular senescence and protein degradation markers and reduced muscle differentiation efficiency (all p < 0.05). HIIT reduced EEF1E1 expression and mitigated age-related muscle decline and atrophy in aged mice more effectively than MICT. Notably, EEF1E1 downregulation via siRNA significantly counteracted D-galactose-induced myoblast senescence as evidenced by reduced markers of muscle protein degradation and improved muscle differentiation efficiency (all p < 0.05). Conversely, treatments that increased EEF1E1 levels accelerated the senescence process (p < 0.05). Further exploration indicated that the decrease in EEF1E1 was associated with increased SIRT1 level and enhanced autophagy. CONCLUSIONS: This study highlights the potential of HIIT as a promising approach to prevent and treat sarcopenia while also highlighting EEF1E1 as a potential intervention target.

Ultrasound Diagnosis of Bilateral Primary Breast Burkitt Lymphoma in a 28-Year-Old Lactating Patient: A Case Report.

Primary breast Burkitt lymphoma (PB-BL) is an exceedingly rare form of primary breast lymphoma. Ultrasonography is the preferred modality for diagnosing breast diseases; however, the ultrasonic features of Burkitt lymphoma have rarely been reported. Herein, we report a case of ultrasonically diagnosed bilateral PB-BL in a lactating patient and present a literature review. A 28-year-old female patient experienced bilateral breast engorgement starting more than a month after childbirth. At three months postpartum, the patient experienced extreme bilateral breast engorgement, with the skin appearing dark purple and jaundiced. Based on the imaging diagnosis, pathological, immunohistochemical, and molecular biological findings, she was diagnosed with Burkitt lymphoma involves bilateral breasts, right adrenal glands, uterus, and multiple bones. After 4 cycles of combination chemotherapy, the tumor basically disappeared, and then after autologous stem cell transplantation and one cycle of combination chemotherapy, the patient is generally in good condition and is under follow-up. We found that the ultrasonic characteristics of PB-BL are different from those of common breast cancer or lactation mastitis. PB-BL lesions are often multiple, large masses, and even involve the whole breast. The characteristic reticular structures are common in lesions, and irregular hyperechoic masses can be seen around it. The mass has abundant peripheral and internal blood flow signals, but internal calcification and attenuated posterior echoes of masses are rarely observed. Thus, the ultrasonic features of breast Burkitt lymphoma are somewhat specific and understanding these features is conducive to its early identification.

Water-soluble vitamins stability by robust liquid chromatography-mass spectrometry.

INTRODUCTION: The measurement of water-soluble vitamins is essential to diagnose and monitor various vitamin deficiencies. Establishing stability limits for these vitamins is crucial to ensure accurate laboratory testing. This study aimed to assess the stability of commonly measured water-soluble vitamins under different storage conditions to improve the accuracy of water-soluble vitamin measurement. METHODS: The stabilities of thiamine, riboflavin, nicotinamide, pantothenic acid, pyridoxic acid and pyridoxal, biotin, 5-methyltetrahydrofolic acid (5-MTHF), and ascorbic acid were measured using liquid chromatography-tandem mass spectrometry. We investigated three pre-analytical factors: the effect of different temperatures and time durations on serum stability, variation between serum and plasma samples, and the impact of transferring samples to an ice bath before serum separation. We evaluated stability based on differences from the baseline. RESULTS: Thiamine, pyridoxal, and ascorbic acid in serum exhibited instability at room temperature and 2-8℃. Riboflavin and 5-MTHF in serum were only stable for up to 48 and 72 h at 2-8℃. However, when stored at -20℃, all water-soluble vitamins remained stable for up to 72 h, whereas at -80℃, stability was maintained for up to 7 days. All vitamins in whole blood, except nicotinamide, were stable for up to 2-4 h when stored in an ice bath. CONCLUSIONS: Water-soluble vitamins, such as thiamine, riboflavin, pyridoxal, and ascorbic acid, are unstable at room temperature and 2-8℃. All vitamins were stable for up to 7 days and stored at -80℃. The ice bath improved the stability of whole blood samples before centrifugation. Thus, laboratories should ensure appropriate storage conditions to maintain pre-analytical quality for vitamin measurements.

Limosilactobacillus Regulating Microbial Communities to Overcome the Hydrolysis Bottleneck with Efficient One-Step Co-Production of H2 and CH4.

The efficient co-production of H2 and CH4 via anaerobic digestion (AD) requires separate stages, as it cannot yet be achieved in one step. Lactic acid bacteria (LAB) (Limosilactobacillus) release H2 and acetate by enhancing hydrolysis, potentially increasing CH4 production with simultaneous H2 accumulation. This study investigated the enhanced effect of one-step co-production of H2 and CH4 in AD by LAB and elucidated its enhancement mechanisms. The results showed that 236.3 times increase in H2 production and 7.1 times increase in CH4 production are achieved, resulting in profits of 469.39 USD. Model substrates lignocellulosic straw, sodium acetate, and H2 confirmes LAB work on the hydrolysis stage and subsequent sustainable volatile fatty acid production during the first 6 days of AD. In this stage, the enrichment of Limosilactobacillus carrying bglB and xynB, the glycolysis pathway, and the high activity of protease, acetate kinase, and [FeFe] hydrogenase, jointly achieved rapid acetate and H2 accumulation, driving hydrogenotrophic methanogenesis dominated. From day 7 to 24, with enriched Methanosarcina, and increased methenyltetrahydromethanopterin hydrogenase activity, continuously produced acetate led to the mainly acetoclastic methanogenesis shift from hydrogenotrophic methanogenesis. The power generation capacity of LAB-enhanced AD is 333.33 times that of China's 24,000 m3 biogas plant.

Lysosomal TFEB-TRPML1 Axis in Astrocytes Modulates Depressive-like Behaviors.

Lysosomes are important cellular structures for human health as centers for recycling, signaling, metabolism and stress adaptation. However, the potential role of lysosomes in stress-related emotions has long been overlooked. Here, it is found that lysosomal morphology in astrocytes is altered in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social defeat stress. A screen of lysosome-related genes revealed that the expression of the mucolipin 1 gene (Mcoln1; protein: mucolipin TRP channel 1) is decreased in susceptible mice and depressed patients. Astrocyte-specific knockout of mucolipin TRP channel 1 (TRPML1) induced depressive-like behaviors by inhibiting lysosomal exocytosis-mediated adenosine 5'-triphosphate (ATP) release. Furthermore, this stress response of astrocytic lysosomes is mediated by the transcription factor EB (TFEB), and overexpression of TRPML1 rescued depressive-like behaviors induced by astrocyte-specific knockout of TFEB. Collectively, these findings reveal a lysosomal stress-sensing signaling pathway contributing to the development of depression and identify the lysosome as a potential target organelle for antidepressants.

Pre-analytical stability and physiological fluctuations affect plasma steroid hormone outcomes: A real-world study.

Since steroids are crucial for diagnosing endocrine disorders, the lack of research on factors that affect hormone levels makes interpreting the results difficult. Our study aims to assess the stability of the pre-analytical procedure and the impact of hormonal physiological fluctuations using real-world data. The datasets were created using 12,418 records from individuals whose steroid hormone measurements were taken in our laboratory between September 2019 and March 2024. 22 steroid hormones in plasma by a well-validated liquid chromatography tandem mass spectrometry method were measured. After normalization transformation, outlier removal, and z-score normalization, generalized additive models were constructed to evaluate preanalytic stability and age, sex, and sample time-dependent hormonal fluctuations. Most hormones exhibit significant variability with age, particularly steroid hormone precursors, sex hormones, and certain corticosteroids such as aldosterone. 18-hydroxycortisol, 18-oxocortisol. Sex hormones varied between males and females. Levels of certain hormones, including cortisol, cortisone, 11-deoxycortisol, 18-hydroxycortisol, 18-oxocortisol, corticosterone, aldosterone, estrone, testosterone, dihydrotestosterone, dehydroepiandrosterone sulfate, 11-ketotestosterone, and 11-hydroxytestosterone, fluctuated with sampling time. Moreover, levels of pregnenolone and progesterone decreased within 1 hour of sampling, with pregnenolone becoming unstable with storage time at 4 degrees after centrifugation, while other hormone levels remained relatively stable for a short period of time without or after centrifugation of the sample. This is the first instance real-world data has been used to assess the pre-analytic stability of plasma hormones and to evaluate the impact of physiological factors on steroid hormones.

Preclinical Evaluation of a PSMA Aptamer-Based Bifunctional PET and Fluorescent Probe.

Prostate cancer is the most prevalent malignant tumor affecting male individuals worldwide. The accurate early detection of prostate cancer is crucial to preventing unnecessary diagnosis and subsequent excessive treatment. Prostate-specific membrane antigen (PSMA) has emerged as a promising biomarker for the diagnosis of prostate cancer. In this study, a dual-modality imaging probe utilizing aptamer technology was developed for positron emission tomography/near-infrared fluorescence (PET/NIRF) imaging, and the specificity and sensitivity of the probe toward PSMA were evaluated both in vitro and in vivo. The probe precursor NOTA-PSMA-Cy5 was synthesized via automated solid-phase oligonucleotide synthesis. Subsequently, the PET/NIRF dual-modality probe [68Ga]Ga-NOTA-PSMA-Cy5 was successfully prepared and exhibited favorable fluorescence properties and stability in vitro. The binding specificity of [68Ga]Ga-NOTA-PSMA-Cy5 to PSMA was assessed through flow cytometry, fluorescence imaging, and cellular uptake experiments in LNCaP cells and PC-3 cells. In vivo PET/NIRF imaging studies demonstrated the sensitive and specific binding of [68Ga]Ga-NOTA-PSMA-Cy5 to PSMA. Overall, the PET/NIRF dual-modality probe [68Ga]Ga-NOTA-PSMA-Cy5 shows promise for the diagnosis of prostate cancer and for the fluorescence-guided identification of PSMA-positive cancer lesions during surgical procedures.

Activity Prediction Modeling Based on a Combination of Growth Differentiation Factor 15 and Serum Biomarker Levels in Dermatomyositis and Polymyositis.

AIMS: Growth differentiation factor 15 (GDF15) plays an important role in multiple inflammatory disorders. We aimed to analyze serum GDF15 levels in adult patients with idiopathic inflammatory myopathies (IIMs). METHODS: Serum GDF15 levels were measured in 179 adult patients with IIMs and 76 healthy controls (HCs). The association between GDF15 levels and disease variables was analyzed using Spearman's rank correlation. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminatory ability of GDF15 and the GDF15-to-lymphocyte ratio (GLR). Machine learning methods were applied to build predictive models. RESULTS: GDF15 levels and GLR were significantly elevated in patients with adult IIMs than in HCs. Compared with patients in remission, both GDF15 and GLR were significantly higher in myositis patients in an active phase. GDF15 levels correlated positively with myositis disease activity indices and negatively correlated with lymphocyte and platelet counts. ROC curve analysis revealed that GDF15 levels and GLR outperformed muscle enzymes and distinguished well between patients with active disease and those in remission. Furthermore, even in the normal muscle enzyme group, GDF15 levels and GLR were also well-distinguished between patients with active disease and those in remission. Using machine learning, a logistic regression model of GDF15 combined with creatine kinase and lymphocyte count was constructed and had a reliable predictive value for disease activity. CONCLUSIONS: GDF15, particularly GLR, was significantly correlated with disease activity in adult patients with IIMs. They could serve as useful biochemical markers for evaluating disease activity, monitoring disease progression, and guiding treatment in adult patients with IIMs.

Healthy Dietary Pattern Improves Cognitive Function in Elderly Persons With Periodontitis: A Cross-Sectional Study of NHANES.

AIM: Cognitive decline is thought to be more prevalent in elderly persons with periodontitis. Greater adherence to Healthy Eating Index (HEI)-2015 has been reported to improve cognitive function in the elderly population. However, whether the benefits of HEI-2015 on cognitive function apply to elderly patients with periodontitis remains unknown. METHODS: This is a cross-sectional study based on the National Health and Nutrition Examination Survey (NHANES). The data were extracted from database 2011-2014. Cognitive function was measured through the Consortium to Establish a Registry for Alzheimer's Disease battery for immediate recall (CERAD-WL) and delayed recall (CERAD-DR), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). The data of HEI-2015 were acquired from 24-hour dietary recalls. Weighted linear regression models were performed to investigate the association between HEI-2015 and cognitive function in elderly patients with periodontitis. The associations were further investigated in subgroups of sex, cardiovascular disease status, and depression status. RESULTS: A total of 1862 participants were included, and 1223 of them had periodontitis. Periodontitis was negatively associated with cognitive function (ß = -0.45; 95% confidence interval [CI], -0.87 to -0.03). No statistically significant relationship was observed between HEI-2015 and cognitive function (ß = 0.33; 95% CI, -0.02 to 0.69). Low HEI-2015 score was associated with high odds of cognitive decline in patients with periodontitis (ß = -0.73; 95% CI, -1.25 to -0.21; P for trend = .01). Higher HEI-2015 was related to the lower incidence of cognitive function decline in patients with periodontitis who were female (ß = -0.53; 95% CI, -1.03 to -0.03), had a socioeconomic status from 0 to 3 (ß = -0.55; 95% CI, -1.00 to -0.09), did not have cardiovascular disease (ß = -0.60; 95% CI, -1.14 to -0.05), and did not have depression (ß = -0.57; 95% CI, -1.11 to -0.03). CONCLUSIONS: Greater HEI-2015 adherence may improve cognitive function amongst elderly patients with periodontitis. Further studies are needed to investigate this putative association in elderly persons with periodontitis.

ADH4-a potential prognostic marker for hepatocellular carcinoma with possible immune-related implications.

OBJECTIVE: This study aims to explore ADH4 expression in hepatocellular carcinoma (HCC), its prognostic impact, and its immune correlation to provide novel insights into HCC prognostication and treatment. METHODS: HCC prognostic marker genes were rigorously selected using GEO database, Lasso regression, GEPIA, Kaplan-Meier and pROC analyses. The expression of interested markers (ADH4, DNASE1L3, RDH16, LCAT, HGFAC) in HCC and adjacent tissues was assessed by Immunohistochemistry (IHC). We observed that ADH4 exhibited low expression levels in liver cancer tissues and high expression levels in normal liver tissues. However, the remaining four genes did not manifest any statistically significant differences between hepatocellular carcinoma (HCC) tissue and adjacent non-cancerous tissue. Consequently, ADH4 became the primary focus of our research. ADH4 expression was validated by signed-rank tests and unpaired Wilcoxon rank sum tests across pan-cancer and HCC datasets. Clinical significance and associations with clinicopathological variables were determined using Kaplan-Meier, logistic regression and Cox analyses on TCGA data. The ADH4-related immune responses were explored by Spearman correlation analysis using TIMER2 data. CD68, CD4, and CD19 protein levels were confirmed by IHC in HCC and non-cancerous tissues. RESULTS: ADH4 showed significant downregulation in various cancers, particularly in HCC. Moreover, low ADH4 expression was associated with clinicopathological variables and served as an independent prognostic marker for HCC patients. Additionally, ADH4 affects a variety of biochemical functions and may influence cancer development, prognosis, and treatment by binding to immune cells. Furthermore, at the immune level, the low expression pattern of ADH4 is TME-specific, indicating that ADH4 has the potential to be used as a target for cancer immunotherapy. CONCLUSION: This study highlights the diagnostic, prognostic and immunomodulatory roles of ADH4 in HCC. ADH4 could serve as a valuable biomarker for HCC diagnosis and prognosis, as well as a potential target for immunotherapeutic interventions.

Loss of monopolar spindle-binding protein 3B expression promotes colorectal cancer invasiveness by activation of target of rapamycin kinase/autophagy signaling.

BACKGROUND: Monopolar spindle-binding protein 3B (MOB3B) functions as a signal transducer and altered MOB3B expression is associated with the development of human cancers. AIM: To investigate the role of MOB3B in colorectal cancer (CRC). METHODS: This study collected 102 CRC tissue samples for immunohistochemical detection of MOB3B expression for association with CRC prognosis. After overexpression and knockdown of MOB3B expression were induced in CRC cell lines, changes in cell viability, migration, invasion, and gene expression were assayed. Tumor cell autophagy was detected using transmission electron microscopy, while nude mouse xenograft experiments were performed to confirm the in-vitro results. RESULTS: MOB3B expression was reduced in CRC vs normal tissues and loss of MOB3B expression was associated with poor CRC prognosis. Overexpression of MOB3B protein in vitro attenuated the cell viability as well as the migration and invasion capacities of CRC cells, whereas knockdown of MOB3B expression had the opposite effects in CRC cells. At the molecular level, microtubule-associated protein light chain 3 II/I expression was elevated, whereas the expression of matrix metalloproteinase (MMP)2, MMP9, sequestosome 1, and phosphorylated mechanistic target of rapamycin kinase (mTOR) was downregulated in MOB3B-overexpressing RKO cells. In contrast, the opposite results were observed in tumor cells with MOB3B knockdown. The nude mouse data confirmed these in-vitro findings, i.e., MOB3B expression suppressed CRC cell xenograft growth, whereas knockdown of MOB3B expression promoted the growth of CRC cell xenografts. CONCLUSION: Loss of MOB3B expression promotes CRC development and malignant behaviors, suggesting a potential tumor suppressive role of MOB3B in CRC by inhibition of mTOR/autophagy signaling.

Intravenous patient-controlled analgesia with esketamine improves early depressive symptoms in patients with postherpetic neuralgia: a single-center retrospective cohort study.

OBJECTIVE: Patients with Postherpetic Neuralgia (PHN) often exhibit depressive-like symptoms, significantly impacting their quality of life. Esketamine, known for its analgesic properties, has also been recognized for its rapid antidepressant effects. However, its efficacy in the treatment of PHN requires further exploration. This study aims to evaluate the impact of intravenous patient-controlled analgesia(PICA) with esketamine on depressive mood in PHN patients. METHODS: This retrospective study analyzed PHN patients hospitalized and treated at the affiliated hospital of Southwest Medical University from June 2021 to March 2023. Patients were divided into the esketamine group (E group) and the sufentanil group (S group) based on their treatment regimens. Primary outcomes included pain numerical rating scale(NRS), depression patient health questionaire-9(PHQ-9), and anxiety generalized anxiety disorder-7(GAD-7) scores measured before treatment, and at 3 days, 7 days, 1 month, 2 months, and 3 months post-treatment. RESULTS: A total of 83 patients were included in the analysis. Before treatment, there were no statistically significant differences in pain NRS, depression PHQ-9, and anxiety GAD-7 scores between the two groups (P > 0.05). Compared to before treatment, significant reductions in pain NRS scores were observed at all post-treatment time points in both groups (P < 0.05), with no differences between groups (P > 0.05). The E group exhibited significantly lower depression PHQ-9 scores than the S group at 3 days and 7 days post-treatment (P < 0.05), but no significant differences were observed at 1 month, 2 months, and 3 months (P > 0.05). Anxiety GAD-7 scores were significantly lower in the E group compared to the S group at 3 days, 7 days post-treatment (P < 0.05), with no statistical differences at 1 month, 2 months, and 3 months post-treatment (P > 0.05). CONCLUSION: Both PICA with esketamine and sufentanil alleviated pain equally in PHN patients. However, PICA with esketamine specifically improved early symptoms of anxiety and depression.

Associations of alcohol and tobacco use with psychotic, depressive and developmental disorders revealed via multimodal neuroimaging.

People affected by psychotic, depressive and developmental disorders are at a higher risk for alcohol and tobacco use. However, the further associations between alcohol/tobacco use and symptoms/cognition in these disorders remain unexplored. We identified multimodal brain networks involving alcohol use (n = 707) and tobacco use (n = 281) via supervised multimodal fusion and evaluated if these networks affected symptoms and cognition in people with psychotic (schizophrenia/schizoaffective disorder/bipolar, n = 178/134/143), depressive (major depressive disorder, n = 260) and developmental (autism spectrum disorder/attention deficit hyperactivity disorder, n = 421/346) disorders. Alcohol and tobacco use scores were used as references to guide functional and structural imaging fusion to identify alcohol/tobacco use associated multimodal patterns. Correlation analyses between the extracted brain features and symptoms or cognition were performed to evaluate the relationships between alcohol/tobacco use with symptoms/cognition in 6 psychiatric disorders. Results showed that (1) the default mode network (DMN) and salience network (SN) were associated with alcohol use, whereas the DMN and fronto-limbic network (FLN) were associated with tobacco use; (2) the DMN and fronto-basal ganglia (FBG) related to alcohol/tobacco use were correlated with symptom and cognition in psychosis; (3) the middle temporal cortex related to alcohol/tobacco use was associated with cognition in depression; (4) the DMN related to alcohol/tobacco use was related to symptom, whereas the SN and limbic system (LB) were related to cognition in developmental disorders. In summary, alcohol and tobacco use were associated with structural and functional abnormalities in DMN, SN and FLN and had significant associations with cognition and symptoms in psychotic, depressive and developmental disorders likely via different brain networks. Further understanding of these relationships may assist clinicians in the development of future approaches to improve symptoms and cognition among psychotic, depressive and developmental disorders.

Targeted delivery of activatable 131I-radiopharmaceutical for sustained radiotherapy with improved pharmacokinetics.

Targeted radionuclide therapy (TRT) is an effective treatment for tumors. Self-condensation strategies can enhance the retention of radionuclides in tumors and enhance the anti-tumor effect. Considering legumain is overexpressed in multiple types of human cancers, a 131I-labeled radiopharmaceutical ([131I]MAAN) based on the self-condensation reaction between 2-cyanobenzothiazole (CBT) and cysteine (Cys) was developed by us recently for treating legumain-overexpressed tumors. However, liver enrichment limits its application. In this study, a new radiopharmaceutical [131I]IM(HE)3AAN was designed and synthesized by introducing a hydrophilic peptide sequence His-Glu-His-Glu-His-Glu ((HE)3) into [131I]MAAN to optimize the pharmacokinetics. Upon activation by legumain under a reducing environment, hydrophilic [131I]IM(HE)3AAN could react with its precursor to form heterologous dimer [131I]H-Dimer that is highly hydrophobic. Cerenkov imaging revealed that [131I]IM(HE)3AAN displayed superior tumor selectivity and longer tumor retention time as compared with [131I]MAAN, with a significant reduction in the liver uptake. After an 18-day treatment with [131I]IM(HE)3AAN, the tumor proliferation was obviously inhibited, while no obvious injury was observed in the normal organs. These findings suggest that [131I]IM(HE)3AAN could serve as a promising drug candidate for treating legumain-overexpressed tumors.