[Research and development strategy of new traditional Chinese medicine drugs for syndromes based on human use experience].

Chinese drug registration laws and regulations have always reserved a place for the new traditional Chinese medicine(TCM) drugs for syndromes, but so far no such new drugs have been approved for registration. This paper expounded on the relevant policies, regulations, and technologies of new TCM drugs for syndromes in China and pointed out that the application of the animal model of TCM syndromes to carry out pharmacodynamics research and clinical efficacy evaluation criteria of TCM syndromes were the main technical difficulties in the research and development of new TCM drugs for syndromes. Not all syndromes are suitable for developing new drugs, and the indications for new TCM drugs should be constant syndromes. Among the three research and development models of simple syndrome, syndrome-unified disease, and combined disease and syndrome, the research and development model of combined disease and syndrome is recommended. Clinical positioning is the key to new TCM drugs for syndromes. It is encouraged to conduct high-quality human use experience studies to determine the clinical positioning of new TCM drugs for syndromes, as well as the target population, dose, course of treatment, and initial therapeutic and safety, and apply for exemption from non-clinical effectiveness studies. Clinical trials of new TCM drugs for syndromes should take the target symptoms or signs as the main efficacy index and the efficacy of TCM syndromes as the secondary efficacy index. Clinical research program design should implement the "patient-centered" concept and introduce clinical outcome evaluation indicators. In the clinical safety evaluation, special conditions such as characteristic syndromes and changes should be considered. With the construction of the human use experience technology system and the promotion of the TCM registration and evaluation evidence system featuring the "combination of TCM theory, human use experience, and clinical trials", it is believed that many high-quality new TCM drugs for syndromes will be developed in the future.

KHDRBS1 as a novel prognostic signaling biomarker influencing hepatocellular carcinoma cell proliferation, migration, immune microenvironment, and drug sensitivity.

Background: Human tumors pose significant challenges, with targeted therapy against specific molecular targets or signaling pathways being a mainstay alongside surgical resection. Previous studies have implicated KHDRBS1 in the oncogenesis of certain human tumors such as colorectal and prostate cancers, underscoring its potential as a therapeutic target. However, the comprehensive expression pattern of KHDRBS1 in hepatocellular carcinoma (HCC) warrants further exploration. Methods: Integrating and analyzing multi-omics, multi-cohort data from public databases, coupled with clinical samples and molecular biology validation, we elucidate the oncogenic role of KHDRBS1 in HCC progression. Additionally, leveraging HCC single-cell sequencing data, we segregate malignant cells into KHDRBS1-positive and negative subsets, uncovering significant differences in their expression profiles and functional roles. Results: Our study identifies KHDRBS1 as a tumor-promoting factor in HCC, with its positivity correlating with tumor progression. Furthermore, we highlight the clinical significance of KHDRBS1-positive malignant cells, aiming to further propel its clinical utility. Conclusion: KHDRBS1 plays a key role in HCC development. This study provides crucial insights for further investigation into KHDRBS1 as a therapeutic target in HCC.

Ocu-miR-10a-5p promotes the chondrogenic differentiation of rabbit BMSCs by targeting BTRC-mediated Wnt/ß-catenin signaling pathway.

MicroRNAs (miRNAs) play an important role in articular cartilage damage in osteoarthritis (OA). However, the biological role of miRNAs in the chondrogenic differentiation of bone marrow mesenchymal stem cell (BMSC) remains largely unclear. Rabbit bone marrow mesenchymal stem cells (rBMSCs) were isolated, cultured, and identified. Afterwards, rBMSCs were induced to chondrogenic differentiation, examined by Alcian Blue staining. Differentially expressed miRNAs were identified in rBMSCs between induced and non-induced groups by miRNA sequencing analysis, part of which was validated via PCR assay. Cell viability and apoptosis were assessed by CCK-8 assay and Hoechst staining. Saffron O staining was utilized to assess chondrocyte hyperplasia. The expression of specific chondrogenic markers, including COL2A1, SOX9, Runx2, MMP-13, Aggrecan, and BMP-2, were measured at mRNA and protein levels. The association between beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) and miR-10a-5p in the miRNA family from rabbit (ocu-miR-10a-5p) was determined by luciferase reporter assay. A total of 76 differentially expressed miRNAs, including 52 downregulated and 24 upregulated miRNAs, were identified in rBMSCs from the induced group. Inhibition of ocu-miR-10a-5p suppressed rBMSC viability and chondrogenic differentiation, as well as downregulated the expression of ß-catenin, SOX9, COL2A1, MMP-13, and Runx2. BTRC was predicted and confirmed as a target of ocu-miR-10a-5p. Overexpression of BTRC rescued the promoting impacts of overexpressed ocu-miR-10a-5p on chondrogenic differentiation of rBMSCs and ß-catenin expression. Taken together, our data suggested that ocu-miR-10a-5p facilitated rabbit BMSC survival and chondrogenic differentiation by activating Wnt/ß-catenin signaling through BTRC.

Development of a Double-Stapled Peptide Stabilizing Both α-Helix and ß-Sheet Structures for Degrading Transcription Factor AR-V7.

Peptide drugs offer distinct advantages in therapeutics; however, their limited stability and membrane penetration abilities hinder their widespread application. One strategy to overcome these challenges is the hydrocarbon peptide stapling technique, which addresses issues such as poor conformational stability, weak proteolytic resistance, and limited membrane permeability. Nonetheless, while peptide stapling has successfully stabilized α-helical peptides, it has shown limited applicability for most ß-sheet peptide motifs. In this study, we present the design of a novel double-stapled peptide capable of simultaneously stabilizing both α-helix and ß-sheet structures. Our designed double-stapled peptide, named DSARTC, specifically targets the androgen receptor (AR) DNA binding domain and MDM2 as E3 ligase. Serving as a peptide-based PROTAC (proteolysis-targeting chimera), DSARTC exhibits the ability to degrade both the full-length AR and AR-V7. Molecular dynamics simulations and circular dichroism analysis validate the successful constraint of both secondary structures, demonstrating that DSARTC is a "first-in-class" heterogeneous-conformational double-stapled peptide drug candidate. Compared to its linear counterpart, DSARTC displays enhanced stability and an improved cell penetration ability. In an enzalutamide-resistant prostate cancer animal model, DSARTC effectively inhibits tumor growth and reduces the levels of both AR and AR-V7 proteins. These results highlight the potential of DSARTC as a more potent and specific peptide PROTAC for AR-V7. Furthermore, our findings provide a promising strategy for expanding the design of staple peptide-based PROTAC drugs, targeting a wide range of "undruggable" transcription factors.

Efficacy and safety evaluation of Ginkgo biloba dropping pill (GBDP) on stable angina pectoris complicated with depression: A placebo-controlled, randomized, double-blind, multicenter study.

BACKGROUND: Stable angina pectoris (SAP) is a clinical condition characterized by reversible and temporary myocardial ischemia and hypoxia. A majority of SAP patients also experience depressive disorders, which adversely affect their disease prognosis and overall quality of life. However, the clinical utility of existing antidepressants is constrained by their side effects. Ginkgo biloba dropping pill (GBDP), a Chinese patented medication, has demonstrated efficacy in the treatment of both coronary heart disease and mental disorders. This prospective, randomized, double-blind, multicenter clinical trial aimed to assess the effectiveness and safety of GBDP as an adjuvant therapy for SAP complicated by depression. METHODS: Participants were randomly assigned in a 1:1 ratio to receive either GBDP or a placebo (5 pills, three times a day) in addition to standard therapy for a duration of 12 weeks. The Seattle Angina Questionnaire (SAQ) was administered every 4 weeks during the treatment, and angina event frequency was assessed weekly. The 36-item Short-Form (SF-36) and Hamilton Depression Scale (HAMD) scores were measured both before and after the treatment. RESULTS: Out of the 72 patients, 68 (n = 34 per group) completed the entire study. At the first visit (4 weeks ± 3 days), the SAQ-Angina Stability score in the GBDP group was significantly higher than that in the placebo group (p < 0.05). While the average weekly frequency of angina episodes in the placebo group notably increased after 12 weeks of treatment (p < 0.05), it displayed an improving trend in the GBDP group (p > 0.05). By the endpoint, each subcategory score of SF-36 in the GBDP group exhibited significant improvement compared to baseline (p < 0.05). The comparison of score improvement between the two groups revealed that the SF-PCS score of the GBDP group was higher than that of the placebo group (p < 0.05). HAMD scores in both groups significantly increased after treatment (p < 0.05). No discernible difference in the incidence of adverse reactions was observed between the two groups (p > 0.05). CONCLUSION: In patients with SAP complicated by depression, GBDP, when combined with standard treatment, rapidly and safely alleviates angina pectoris symptoms. It demonstrates therapeutic potential in enhancing the quality of life and alleviating depressive symptoms.

Downregulation of dermatopontin in cholangiocarcinoma cells suppresses CCL19 secretion of macrophages and immune infiltration.

OBJECTIVE: The tumor microenvironment (TME) in cholangiocarcinoma (CHOL) is typically characterized by a low level of immune infiltration, which accounts for the dismal prognosis of this patient population. This study sought to investigate the mechanisms underlying the reduced infiltration of immune cells into the CHOL TME. METHODS: We constructed a Least Absolute Shrinkage and Selection Operator (LASSO) regression model to identify prognosis-related differentially expressed genes (DEGs). The 'Corrplot' package was employed to analyze the correlation between dermatopontin (DPT) and immune infiltration in CHOL. The Tumor and Immune System Interaction Database (TISIDB) was used to evaluate the association between DPT and immunology. Single-cell analysis was conducted to localize CCL19 secretions. Western blot and qPCR were utilized to detect DPT expression, while immunofluorescence was performed to investigate the cellular localization of DPT. Additionally, ELISA analysis was employed to assess the alteration in CCL19 secretion in cancer-associated fibroblasts (CAFs) and macrophages. RESULTS: Our findings revealed that CHOL patients with low DPT expression had a poorer prognosis. Enrichment analysis demonstrated a positive correlation between DPT levels and the infiltration of immunomodulators and immune cells. Moreover, high DPT levels were associated with enhanced anti-PD-1/PD-L1 immunotherapeutic responses. Furthermore, DPT expression impacted the landscape of gene mutations, showing a negative association with tumor grade, stage, and lymph node metastasis. Based on the results of protein peptides analysis and cell experiments, it was inferred that the downregulation of DPT in CHOL cells effectively suppressed the secretion of CCL19 in macrophages. CONCLUSIONS: DPT is a novel prognosis-related biomarker for CHOL patients, and this study provides preliminary insights into the mechanism by which DPT promotes the infiltration of immune cells into the CHOL TME.

[Pharmaceutical changes and countermeasures for transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on human use experience].

Traditional Chinese medicine(TCM) preparations in medical institutions, as a unique and important form of preparations in China, have a long history of human use and serve as a bridge between clinical experience prescriptions and new Chinese medicine preparations. The state encourages medical institutions to transform their preparations into new traditional Chinese medicines, emphasizing their role as "incubators". Since the proposal of the traditional Chinese medicine registration and evaluation evidence system with the integration of TCM theory, human use experience(HUE), and clinical experience, the idea of transforming preparations used in medical institutions into new drugs based on HUE has been increasingly valued by drug research and development organizations. In the transformation process, pharmaceutical changes should be concerned from multiple aspects. This paper discusses the pharmaceutical changes and countermeasures based on the transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on HUE from the aspects of excipients, dosage forms, production technology, production scale, packaging materials and containers, production sites, and registration standards. It is emphasized that scientific decisions should be made according to the characteristics and clinical needs of drugs to ensure the stability of drug quality. The impacts of pharmaceutical changes on drug quality should be objectively assessed based on appropriate evaluation indexes and detection methods. The layout should be carried out in advance, and the key pharmaceutical information of the preparations should be kept stable, so as to underpin the transformation of traditional Chinese medicine preparations in medical institutions into new drugs based on HUE.

Analyzing the composition of the editorial boards in high-impact medical ethics journals: a survey study.

BACKGROUND: The underrepresentation of scholarly works from low- and middle-income countries (LMICs) in academic literature is a documented concern, attributed partly to editorial biases. This trend, prevalent across various disciplines, has been less explored in the context of medical ethics journals. This study aimed to examine the composition of editorial board members (EBM) in high-impact medical ethics journals and to evaluate the extent of international diversity within these editorial teams. METHODS: This study incorporated an analysis of 16 high-impact medical ethics journals. Information regarding the EBM of these journals was systematically gathered and categorized based on the World Bank's country income classifications. An in-depth examination of the editorial board compositions was then conducted. RESULTS: The study identified 669 EBM across the selected journals. A predominant 89.84% (601) of these members were from high-income countries (HICs), with upper-middle-income countries contributing 7.47% (50) and lower-middle-income countries 2.69% (18). No EBM were associated with low-income countries. A regional breakdown indicated that North America was the most represented area, accounting for 48.88% (327), followed by Europe & Central Asia (27.50%, 184), East Asia & Pacific (13.45%, 90), Latin America & Caribbean (4.63%, 31), Sub-Saharan Africa (4.19%, 28), Middle East & North Africa (0.75%, 5), and South Asia (0.60%, 4). In total, these EBMs hailed from 46 different countries, with the United States representing the largest proportion (43.80%, 293), followed by the United Kingdom (13.15%, 88), Australia (7.92%, 53), Germany (6.73%, 45), and Canada (5.08%, 34). CONCLUSIONS: There is a significant lack of international representation within the EBM of high-impact medical ethics journals. The majority of editors in this field are affiliated with HICs, leading to a severe underrepresentation of LMICs within the editorial boards.

Th1 cells contribute to retinal ganglion cell loss in glaucoma in a VCAM-1-dependent manner.

Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease.

Negative linear compressibility and strong enhancement of emission in Eu[Ag(CN)2]3·3H2O under pressure.

The framework material Eu[Ag(CN)2]3·3H2O exhibits a negative linear compressibility (NLC) of -4.2(1) TPa-1 over the largest pressure range yet observed (0-8.2 GPa). High-pressure single-crystal X-ray diffraction data show that the rapid contraction of the Kagome silver layers under compression causes the wine-rack lattice to expand along the c-axis. The hydrogen bonds between the water molecules and the main frameworks constrain the structural deformation under pressure and eventually a weak NLC effect generated. Furthermore, we found that the pressure-induced emission intensity increases almost 800-fold at 4.0 GPa, followed by a gradual decrease and disappearance at 8.1 GPa. Under compression, high pressure significantly tunes the triplet level positions near the Eu3+ ions, and horizontal displacement between a quenching excited state and the excited levels of Eu3+ facilitates the energy transfer process to the 5D0 excited state and limits the nonradiative corssover at elevated pressures, thus increasing the emission intensity. In addition, we observe a gradual band gap reduction with increasing pressure, and the sample could not be returned to the initial state after the pressure was completely released. By controlling the structural flexibility, we observe a coupled NLC and pressure-induced strong enhancement of the emission properties of Eu[Ag(CN)2]3·3H2O, which provides a new route for the design of new optical devices with intriguing luminescence properties under extreme environments.

Cartilage Endplate-Derived Stem Cells for Regeneration of Intervertebral Disc Degeneration: An Analytic Study.

Purpose: Intervertebral disc degeneration (IDD) is considered the predominant cause of low back pain (LBP) and accounts for global disability and a substantial socioeconomic burden. Given the unsatisfactory outcomes of current treatment strategies, cartilage endplate-derived stem cells (CESCs) are increasingly used in intervertebral disc regeneration. However, comprehensive analyses on CESCs remain rare. Herein, we examined the biological functions and applications of CESCs in IDD. Methods: PubMed, Embase, and Cochrane Library databases were searched to identify studies focused on CESCs. Relevant information from included studies was extracted. Descriptive statistics were performed. Correlation analysis was conducted to determine the relationship among Web of Science (WoS) citations, Dimensions, and Altmetric Attention Score (AAS). Results: Twenty-six studies were included in this study. Most studies (n=20) isolated CESCs from humans, followed by rats (n=5) and rabbits (n=1). Twenty studies were performed in vitro, and the remaining six were implemented both in vivo and in vitro. The findings of this study provide insight into the biological properties of CESCs and clarify their potential application for intervertebral disc regeneration. There was a very high correlation between WoS and Dimensions citation count (p<0.001, r=0.988). Conclusion: This study, for the first time, elaborates biological features of CESCs and analyzes their potential applications in regenerating intervertebral discs. CESCs may be promising candidates for protecting the intervertebral disc from degeneration and contributing to intervertebral disc regeneration.

RARγ promotes the invasion and metastasis of thyroid carcinoma by activating the JAK1-STAT3-CD24/MMPs axis.

The nuclear receptor superfamily RAR is generally considered to play a crucial role in the development of tumors by regulating the transcription of target genes. Nevertheless, whether RARγ performs tumor-promoting or tumor-suppressing functions and its specific mechanism in thyroid carcinoma (TC) remain unknown. Here, our study demonstrated that RARγ was abnormally overexpressed in TC tissues compared with normal thyroid tissues. Moreover, RARγ expression was remarkably correlated with cell phenotypes such as cell proliferation, migration and invasion. Mechanistically, RARγ knockdown effectively decreased the phosphorylation levels of JAK1 and STAT3, leading to decreased expression of the membrane protein CD24. In a coculture system, TC cells with high levels of CD24 in the membrane were more likely to escape phagocytosis by macrophages via the combination of CD24 with the inhibitory receptor Siglec-10 in the membrane of macrophages. In contrast, the ability of macrophages to engulf TC cells was notably elevated through exogenous addition of CD24 antibody. Collectively, our study revealed a previously undiscovered molecular mechanism of RARγ in promoting the development of TC, shedding light on RARγ as a promising therapeutic target for TC.

Fecal calprotectin as an intestinal inflammation marker is elevated in glaucoma.

Objective: The aim of this study was to investigate the potential association between glaucoma and fecal calprotectin. Methods: A total of 144 glaucomatous patients and 66 healthy controls were enlisted for this study. The fecal calprotectin was assessed using enzyme-linked immunosorbent assay. Results: The median fecal calprotectin levels were significantly elevated in glaucoma (73.67 vs 41.97 µg/g; p < 0.001), primary angle-closure glaucoma (76.85 µg/g; p < 0.001) and primary open-angle glaucoma (69.29 µg/g; p = 0.016) groups compared with controls. A notable proportion of the glaucoma (24%; p < 0.001), primary angle-closure glaucoma (21%; p < 0.001) and primary open-angle glaucoma (24%; p < 0.001) subgroups exhibited highly abnormal fecal calprotectin levels (≥250 µg/g). Conclusion: Elevated fecal calprotectin might indicate potential intestinal inflammation in glaucoma.

Impact of inflammation and anti-inflammatory modalities on diabetic cardiomyopathy healing: From fundamental research to therapy.

Diabetic cardiomyopathy (DCM) is a prevalent cardiovascular complication of diabetes mellitus, characterized by high morbidity and mortality rates worldwide. However, treatment options for DCM remain limited. For decades, a substantial body of evidence has suggested that the inflammatory response plays a pivotal role in the development and progression of DCM. Notably, DCM is closely associated with alterations in inflammatory cells, exerting direct effects on major resident cells such as cardiomyocytes, vascular endothelial cells, and fibroblasts. These cellular changes subsequently contribute to the development of DCM. This article comprehensively analyzes cellular, animal, and human studies to summarize the latest insights into the impact of inflammation on DCM. Furthermore, the potential therapeutic effects of current anti-inflammatory drugs in the management of DCM are also taken into consideration. The ultimate goal of this work is to consolidate the existing literature on the inflammatory processes underlying DCM, providing clinicians with the necessary knowledge and tools to adopt a more efficient and evidence-based approach to managing this condition.

Gut-licensed ß7+ CD4+ T cells contribute to progressive retinal ganglion cell damage in glaucoma.

Glaucoma is the leading cause of irreversible blindness. Currently, most therapeutic strategies aim to reduce elevated intraocular pressure (EIOP), but this does not always halt disease progression. Evidence suggests a role for T cells in glaucoma pathogenesis, but the underlying mechanisms remain largely unknown. Here, we found that the percentage of circulating CD4+ T cells expressing a gut-homing integrin ß7 was increased in patients with glaucoma and was associated with disease stage. In an EIOP-triggered glaucoma mouse model, ß7+ CD4+ T cells infiltrated the retina in the progressive phase of glaucoma via eliciting retinal endothelial cell expression of mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1). MAdCAM-1 was minimally detected in retinas of healthy mice, and neutralization with an MAdCAM-1 antibody ameliorated retinal ganglion cell (RGC) loss and glial activity in mice with glaucoma. We furthermore found that EIOP-induced ß7+ CD4+ T cells homed to the gut during the acute phase of glaucoma, which was essential for progressive RGC damage in diseased mice. Gut-homing ß7+ CD4+ T cells underwent transcriptional reprogramming, showing up-regulated pathways enriched in autoimmune diseases, bacteria responses, mucosal immunity, and glial activity. Gut-homing ß7+ CD4+ T cells gained the competence to induce retinal MAdCAM-1 expression and to cross the blood-retina barrier. Together, our study reveals a role of gut-licensed ß7+ CD4+ T cells and MAdCAM-1 in RGC degeneration and emphasizes the importance of the "gut-retina" axis in glaucoma.

How international are the editorial boards in the field of hand research? A cross-sectional study of leading subspecialty hand journals.

BACKGROUND: Although low- and middle-income countries (LMIC) have great disease burden, but the lack of studies from LMIC have been shown in several fields. Multiple researchers from LMIC perceive editorial bias against their studies. Editorial board members (EBMs) from LMIC are under-represented across many medical journals. It is still unclear whether this phenomenon exists in the field of hand research. The purpose of this study was to investigate the composition of EBMs in leading subspecialty hand journals, and to reveal the international representation of EBMs in the field of hand research. METHODS: This cross-sectional study included seven leading subspecialty hand journals. The EBMs were obtained from the journals' websites. The country affiliations of EBMs were categorized based on their locations and economy status. The composition of EBMs was investigated. RESULTS: There were 211 EBMs in the seven journals. A total of 185 EBMs (87.7%) were affiliated with high-income countries (HIC), 18 (8.5%) with upper middle-income countries, and 8 (3.8%) with lower middle-income countries. None EBMs were affiliated with low income countries. The EBMs were affiliated with 30 countries. The biggest number of EBMs were affiliated with the USA 74 (35.07%), followed by the United Kingdom (45, 21.33%), and France (13, 6.16%). Most of EBMs were based in Europe and Central Asia (86, 40.8%) and North America (81, 38.4%). CONCLUSIONS: The EBMs of leading subspecialty hand journals are dominated by HIC with a very low representation of LMIC. There is a need to make the editorial boards more international in the field of hand research.

TIGIT immune checkpoint blockade enhances immunity of human peripheral blood NK cells against castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) patients have a 14-month median survival, emphasizing the need for alternative treatments. Previously, we demonstrated that expanded high-dose natural killer (NK) cells derived from human peripheral blood exhibit therapeutic efficacy against CRPC. However, which immune checkpoint blockade promotes NK cell antitumor immunity against CRPC remains unknown. Here, we explored immune checkpoint molecule expression in NK and CRPC cells during their interactions, and identified that the T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) monoclonal antibody (mAb), vibostolimab, significantly enhanced NK cell cytotoxicity against CRPC cells and cytokine production in vitro, demonstrated by upregulation of degranulation marker CD107a and Fas-ligand (Fas-L) and increased interferon-gamma (IFN-γ) and tumor necrosis factor-alpha secretion. TIGIT blockade increased Fas-L expression and IFN-γ production via the NF-κB signaling pathway and restored degranulation via the mitogen-activated protein kinase ERK (extracellular signal-regulated kinase) kinase/ERK pathway in activated NK cells. Vibostolimab significantly enhanced NK cell antitumor effects against CRPC in two xenograft mouse models. Vibostolimab also increased T cell chemotaxis induced by activated NK cells in vitro and in vivo. Overall, blocking TIGIT/CD155 signaling enhances the antitumor effect of expanded NK cells against CRPC; this finding supports the translational application of TIGIT mAb and NK cell combination strategies from bench to bedside for CRPC treatment.

Establishment of HIV-negative neurosyphilis risk score model based on logistic regression.

OBJECTIVE: To establish the risk scoring model for HIV-negative neurosyphilis (NS) patients and to optimize the lumbar puncture strategy. METHODS: From 2016 to 2021, clinical information on 319 syphilis patients was gathered. Multivariate logistic regression was used to examine the independent risk factors in NS patients who tested negative for human immunodeficiency virus (HIV). Receiver operating characteristic curves (ROC) were used to assess the risk scoring model's capacity for identification. According to scoring model, the timing of lumbar puncture was suggested. RESULTS: There were statistically significant differences between HIV-negative NS and non-neurosyphilis (NNS) patients in the following factors. These included age, gender, neuropsychiatric symptoms (including visual abnormalities, hearing abnormalities, memory abnormalities, mental abnormalities, paresthesia, seizures, headache, dizziness), serum toluidine red unheated serum test (TRUST), cerebrospinal fluid Treponema pallidum particle agglutination test (CSF-TPPA), cerebrospinal fluid white blood cell count (CSF-WBC), and cerebrospinal fluid protein quantification (CSF-Pro) (P < 0.05). Logistic regression analysis of HIV-negative NS patients risk factors showed that age, gender, and serum TRUST were independent risk factors for HIV-negative NS (P = 0.000). The total risk score (- 1 ~ 11 points) was obtained by adding the weight scores of each risk factor. And the predicted probability of NS in HIV-negative syphilis patients (1.6 ~ 86.6%) was calculated under the corresponding rating. ROC calculation results showed that the score had good discrimination value for HIV-negative NS and NNS: area under the curve (AUC) was 0.80, the standard error was 0.026 and 95% CI was 74.9-85.1% (P = 0.000). CONCLUSION: The risk scoring model in this study can classify the risk of neurosyphilis in syphilis patients, optimize the lumbar puncture strategy to a certain extent, and provide ideas for the clinical diagnosis and treatment of HIV-negative neurosyphilis.

The long noncoding RNA CIRBIL is a regulator of steroidogenesis in mice.

Infertility affects roughly 8-12 % of couples worldwide, and in above 50 % of couples, male factors are the primary or contributing cause. Many long noncoding RNAs (lncRNAs) are detected in the testis, but their functions are not well understood. CIRBIL was 862 nucleotides in length and was found to be localized mostly in the cytosol of Leydig cell, a small portion was positioned inside the seminiferous tubules. Loss of CIRBIL in mice resulted in male subfertility, characterized by smaller testis and increased germ cell apoptosis. Deletion of CIRBIL significant decreased the number of sperm and impaired the integrity of sperm head and tail. In CIRBIL KO mice, testosterone levels in serum and expression of testosterone biosynthesis genes (STAR and 3ß-HSD) were both reduced. Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were primarily enriched in steroid synthesis process in CIRBIL-binding proteins. Protein-protein (PPI) interaction networks revealed that both cis- and trans-regulated target genes of CIRBIL were associated with testosterone synthesis. Collectively, our results strongly suggest that CIRBIL is a regulator of steroid hormone synthesis.