Design, synthesis, and biological evaluation of novel benzimidazole derivatives as anti-cervical cancer agents through PI3K/Akt/mTOR pathway and tubulin inhibition.

Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cervical cancer treatment. In this study, we designed and synthesized a series of benzimidazole derivatives and evaluated their anti-cervical cancer activity. Compound 4r exhibited strong antiproliferative activity in different cervical cancer cell lines HeLa, SiHa and Ca Ski, and relative lower cytotoxicity to normal hepatic and renal cell lines LO2 and HEK-293t (IC50 values were at 21.08 µM and 23.96 µM respectively). Its IC50 value was at 3.38 µM to the SiHa cells. Further mechanistic studies revealed that 4r induced apoptosis, arrested cell cycle in G2/M phase, suppressed PI3K/Akt/mTOR pathway and inhibit the polymerization of tubulin. Molecular docking study suggested that 4r formed key H-bonds action with PI3Kα (PDB ID:8EXU) and tubulin (PDB ID:1SA0). Zebrafish acute toxicity experiments showed that high concentrations of 4r did not cause death or malformation of zebrafish embryos. All these results demonstrated that 4r would be a promising lead candidate for further development of novel PI3K and tubulin dual inhibitors in cervical cancer treatment.

The Dmc1 recombinase physically interacts with and promotes the meiotic crossover functions of the Mlh1-Mlh3 endonuclease.

The accurate segregation of homologous chromosomes during the Meiosis I reductional division in most sexually reproducing eukaryotes requires crossing over between homologs. In baker's yeast approximately 80 percent of meiotic crossovers result from Mlh1-Mlh3 and Exo1 acting to resolve double-Holliday junction (dHJ) intermediates in a biased manner. Little is known about how Mlh1-Mlh3 is recruited to recombination intermediates to perform its role in crossover resolution. We performed a gene dosage screen in baker's yeast to identify novel genetic interactors with Mlh1-Mlh3. Specifically, we looked for genes whose lowered dosage reduced meiotic crossing over using sensitized mlh3 alleles that disrupt the stability of the Mlh1-Mlh3 complex and confer defects in mismatch repair but do not disrupt meiotic crossing over. To our surprise we identified genetic interactions between MLH3 and DMC1, the recombinase responsible for recombination between homologous chromosomes during meiosis. We then showed that Mlh3 physically interacts with Dmc1 in vitro and in vivo. Partial complementation of Mlh3 crossover functions was observed when MLH3 was expressed under the control of the CLB1 promoter (NDT80 regulon), suggesting that Mlh3 function can be provided late in meiotic prophase at some functional cost. A model for how Dmc1 could facilitate Mlh1-Mlh3's role in crossover resolution is presented.

APF-S2T: Steering to Target Redirection Walking Based on Artificial Potential Fields.

Redirected walking (RDW) enables users to walk naturally within a virtual environment that is larger than the physical environment. Recently, several artificial potential field (APF) and alignment-based redirected controllers have been developed and have been demonstrated to significantly outperform conventional controllers. APF Steer-to-Gradient (APF-S2G) and APF Redirected Walking (APF-RDW) utilize the negative gradient and the total force vector, respectively, which are localized to the user's position. These vectors usually point towards the opposite wall when the user is in corridors, resulting in frequent resets within those regions. This paper introduces the APF Steer-to-Target (APF-S2T), a redirected controller that first finds the target sample point with the lowest score in the user's walkable area in both physical and virtual environments. The score of a sample point is determined by the APF value at the point and the distance from the user's position. The direction from the user's position to the target point is then used as the steering direction for setting RDW gains. We conducted a simulation-based evaluation to compare APF-S2T, APF-S2G, APF-RDW, Visibility Polygon-based alignment (Vis.-Poly.) and Alignment-Optimized controllers in terms of the number of resets and the average distance between resets. The results indicated that APF-S2T significantly outperformed the state-of-the-art controllers.

Metabolism, fibrosis, and apoptosis: The effect of lipids and their derivatives on keloid formation.

Keloids, pathological scars resulting from skin trauma, have traditionally posed significant clinical management challenges due to their persistence and high recurrence rates. Our research elucidates the pivotal roles of lipids and their derivatives in keloid development, driven by underlying mechanisms of abnormal cell proliferation, apoptosis, and extracellular matrix deposition. Key findings suggest that abnormalities in arachidonic acid (AA) synthesis and non-essential fatty acid synthesis are integral to keloid formation. Further, a complex interplay exists between lipid derivatives, notably butyric acid (BA), prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), and the regulation of hyperfibrosis. Additionally, combinations of docosahexaenoic acid (DHA) with BA and 15-deoxy-Δ12,14-Prostaglandin J2 have exhibited pronounced cytotoxic effects. Among sphingolipids, ceramide (Cer) displayed limited pro-apoptotic effects in keloid fibroblasts (KFBs), whereas sphingosine 1-phosphate (S1P) was found to promote keloid hyperfibrosis, with its analogue, FTY720, demonstrating contrasting benefits. Both Vitamin D and hexadecylphosphorylcholine (HePC) showed potential antifibrotic and antiproliferative properties, suggesting their utility in keloid management. While keloids remain a prevalent concern in clinical practice, this study underscores the promising potential of targeting specific lipid molecules for the advancement of keloid therapeutic strategies.

Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling.

Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.

The Cby3/ciBAR1 complex positions the annulus along the sperm flagellum during spermiogenesis.

Proper compartmentalization of the sperm flagellum is essential for fertility. The annulus is a septin-based ring that demarcates the midpiece (MP) and the principal piece (PP). It is assembled at the flagellar base, migrates caudally, and halts upon arriving at the PP. However, the mechanisms governing annulus positioning remain unknown. We report that a Chibby3 (Cby3)/Cby1-interacting BAR domain-containing 1 (ciBAR1) complex is required for this process. Ablation of either gene in mice results in male fertility defects, caused by kinked sperm flagella with the annulus mispositioned in the PP. Cby3 and ciBAR1 interact and colocalize to the annulus near the curved membrane invagination at the flagellar pocket. In the absence of Cby3, periannular membranes appear to be deformed, allowing the annulus to migrate over the fibrous sheath into the PP. Collectively, our results suggest that the Cby3/ciBAR1 complex regulates local membrane properties to position the annulus at the MP/PP junction.

A Grading System of Microvascular Invasion for Patients with Hepatocellular Carcinoma Undergoing Liver Resection with Curative Intent: A Multicenter Study.

Background: Microvascular invasion (MVI) is closely correlated with poor clinical outcomes in patients with hepatocellular carcinoma (HCC). A grading system of MVI is needed to assist in the management of HCC patient. Methods: Multicenter data of HCC patients who underwent liver resection with curative intent was analyzed. This grading system was established by detected number and distance from tumor boundary of MVI. Survival outcomes were compared among patients in each group. This system was verified by time-receiver operating characteristic curve, time-area under the curve, calibration curve, and decision curve analyses. Cox regression analysis was performed to study the associated factors of prognosis. Logistic analysis was used to study the predictive factors of MVI. Results: All patients were classified into 4 groups: M0: no MVI; M1: 1~5 proximal MVIs (≤1 cm from tumor boundary); M2a: >5 proximal MVIs (≤1 cm from tumor boundary); M2b: ≥1 distal MVIs (>1 cm from tumor boundary). The recurrence-free survival (RFS), overall survival (OS), and early RFS rates among all the individual groups were significantly different. Based on the number of proximal MVI (0~5 vs >5), patients in the M2b group were further divided into two subgroups which also showed different prognosis. Multiple methods showed this grading system to be significantly better than the MVI two-tiered system in prognostic evaluation. Four multivariate models for RFS, OS, early RFS, late RFS, and a predictive model of MVI were then established and were shown to satisfactorily evaluate prognosis and have a great discriminatory power, respectively. Conclusion: This MVI grading system could precisely evaluate prognosis of HCC patients after liver resection with curative intent and it could be employed in routine pathological reports. The severity of MVI from both adjacent and distant from tumor boundary should be stated. A hypothesis about two occurrence modes of distal MVI was proposed.

Regulation of forkhead box O transcription factor by insulin signaling pathway controls the reproductive diapause of the lady beetle, Coccinella septempunctata.

In biological control programs, knowledge about diapause regulation in natural enemy insects provides important insight for improving long-term storage, transportation, and field adoption of these biological control agents. As a natural predator of agricultural pests, the lady beetle Coccinella septempunctata has been commercially mass-cultured and widely employed in pest management. In some insects, insulin signaling, in conjunction with the downstream transcription factor Forkhead box O (FoxO), are master regulators of multiple physiological processes involved in diapause, but it is unclear whether insulin signaling and FoxO affect the diapause of C. septempunctata. In this study, we use a combination of approaches to demonstrate that insulin signaling and FoxO mediate the diapause response in C. septempunctata. In diapausing beetles, application of exogenous insulin and knocking down expression of CsFoxo with RNA interference (RNAi) both rescued beetles from developmental arrest. In non-diapausing beetles, knocking down expression of the insulin receptor (CsInR) with RNA interference (RNAi) arrested ovarian development and decreased juvenile hormone (JH) content to levels comparable to the diapause state. Taken together, these results suggest that a shutdown of insulin signaling prompts the activation of the downstream FoxO gene, leading to the diapause phenotype.

Case report: 177Lu DOTA-TATE: a new scheme for the treatment of prostate neuroendocrine cancer.

Background: Most instances of small cell carcinoma originate from the lungs, while the gastrointestinal tract serves as a secondary site. Only a minuscule proportion of cases manifest within the urogenital system. Prostate small cell carcinoma (SCCP) represents an exceedingly uncommon pathological subtype within the realm of prostate cancer, displaying significant rarity in clinical settings. This scarcity has resulted in a paucity of adequate foundational and clinical research for SCCP treatment. While investigations have unveiled a certain therapeutic efficacy of radiotherapy and chemotherapy for SCCP, clinical practice has revealed suboptimal treatment outcomes. We hereby present a case report detailing the utilization of 177Lu-DOTA-TATE in the treatment of SCCP, aiming to investigate the therapeutic efficacy of 177Lu-DOTA-TATE for SCCP. Case presentation: A male patient in his 80s presented with elevated prostate-specific antigen (PSA) levels and underwent a biopsy that revealed prostate adenocarcinoma. The patient received CAB (bicalutamide + goserelin) therapy. One year later, disease progression was detected, and a second biopsy confirmed the presence of prostate small cell carcinoma. Following the diagnosis of prostate small cell carcinoma, the patient underwent two cycles of 177Lu-DOTA-TATE treatment. Subsequent to the treatment, the original lesions showed shrinkage, metastatic lesions disappeared, and there was significant improvement, approaching complete remission. Conclusion: SCCP exhibits a high degree of malignancy and aggressive invasiveness, currently lacking effective therapeutic modalities. The treatment course of this patient serves as compelling evidence for the efficacy of 177Lu-DOTA-TATE in managing SCCP, thereby opening new avenues for future SCCP treatments.

Reference values of gait parameters in healthy Chinese university students: A cross-sectional observational study.

BACKGROUND: Gait is influenced by race, age, and diseases type. Reference values for gait are closely related to numerous health outcomes. To gain a comprehensive understanding of gait patterns, particularly in relation to race-related pathologies and disorders, it is crucial to establish reference values for gait in daily life considering sex and age. Therefore, our objective was to present sex and age-based reference values for gait in daily life, providing a valuable foundation for further research and clinical applications. AIM: To establish reference values for lower extremity joint kinematics and kinetics during gait in asymptomatic adult women and men. METHODS: Spatiotemporal, kinematics and kinetics parameters were measured in 171 healthy adults (70 males and 101 females) using the computer-aided soft tissue foot model. Full curve statistical parametric mapping was performed using independent and paired-samples t-tests. RESULTS: Compared with females, males required more time (cycle time, double-limb support time, stance time, swing time, and stride time), and the differences were statistically significant. In addition, the step and stride lengths of males were longer. Compared to males, female cadence was faster, and statures-per-second and stride-per-minute were higher. There were no statistical differences in speed and stride width between the two groups. After adjusting for height, it was observed that women walked significantly faster than men, and they also had a higher cadence. However, in terms of step length, stride length, and stride width, both genders exhibited similarities. CONCLUSION: We established reference values for gait speed and spatiotemporal gait parameters in Chinese university students. This contributes to a valuable database for gait assessment and evaluation of preventive or rehabilitative programs.

The Dmc1 recombinase physically interacts with and promotes the meiotic crossover functions of the Mlh1-Mlh3 endonuclease.

The accurate segregation of homologous chromosomes during the Meiosis I reductional division in most sexually reproducing eukaryotes requires crossing over between homologs. In baker's yeast approximately 80 percent of meiotic crossovers result from Mlh1-Mlh3 and Exo1 acting to resolve double-Holliday junction (dHJ) intermediates in a biased manner. Little is known about how Mlh1-Mlh3 is recruited to recombination intermediates and whether it interacts with other meiotic factors prior to its role in crossover resolution. We performed a haploinsufficiency screen in baker's yeast to identify novel genetic interactors with Mlh1-Mlh3 using sensitized mlh3 alleles that disrupt the stability of the Mlh1-Mlh3 complex and confer defects in mismatch repair but do not disrupt meiotic crossing over. We identified several genetic interactions between MLH3 and DMC1, the recombinase responsible for recombination between homologous chromosomes during meiosis. We then showed that Mlh3 physically interacts with Dmc1 in vitro and at times in meiotic prophase when Dmc1 acts as a recombinase. Interestingly, restricting MLH3 expression to roughly the time of crossover resolution resulted in a mlh3 null-like phenotype for crossing over. Our data are consistent with a model in which Dmc1 nucleates a polymer of Mlh1-Mlh3 to promote crossing over.

Bibliometric analysis of artificial intelligence and optical coherence tomography images: research hotspots and frontiers.

AIM: To explore the latest application of artificial intelligence (AI) in optical coherence tomography (OCT) images, and to analyze the current research status of AI in OCT, and discuss the future research trend. METHODS: On June 1, 2023, a bibliometric analysis of the Web of Science Core Collection was performed in order to explore the utilization of AI in OCT imagery. Key parameters such as papers, countries/regions, citations, databases, organizations, keywords, journal names, and research hotspots were extracted and then visualized employing the VOSviewer and CiteSpace V bibliometric platforms. RESULTS: Fifty-five nations reported studies on AI biotechnology and its application in analyzing OCT images. The United States was the country with the largest number of published papers. Furthermore, 197 institutions worldwide provided published articles, where University of London had more publications than the rest. The reference clusters from the study could be divided into four categories: thickness and eyes, diabetic retinopathy (DR), images and segmentation, and OCT classification. CONCLUSION: The latest hot topics and future directions in this field are identified, and the dynamic evolution of AI-based OCT imaging are outlined. AI-based OCT imaging holds great potential for revolutionizing clinical care.

Research progress in intelligent control of intrapartum oxytocin (unrevised version).

With the development of precision medicine and artificial intelligence, the infusion of many drugs has been intelligently controlled according to patients' conditions. However, the infusion of oxytocin (OT) still relies on medical staff responsible for implementing artificial regulation based on observation of fetal electronic monitoring and other maternal and fetal conditions. In this review, we discussed recent trends in intelligent infusion systems, the development status and dilemma of intelligent control of OT infusion, the drug intelligent feedback control system principle, and current risks and challenges to further promote obstetric informatization.

TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2.

Metastatic colorectal cancer (mCRC) is characterized by poorer prognosis of patients and limited therapeutic approach, partly due to the lack of effective target. Using mouse models and tumor organoids, this study reported a tripartite motif 21 (TRIM21) protein, exerting potential inhibitory effects on the invasion and metastasis of CRC. Mechanistically, TRIM21 directly interacted with and ubiquitinated MST2 at lysine 473 (K473) via K63-linkage. This ubiquitination enabled the formation of MST2 homodimer and enhanced its kinase activity, ultimately resulting in the functional inactivation of yes-associated protein (YAP) and inhibition of an epithelial-mesenchymal transition (EMT) feature. We identified that vilazodone, an antidepressant, directly bound to TRIM21 to exert effective anti-metastatic action both in vitro and in vivo. Collectively, these findings revealed a previously unrecognized interplay between TRIM21 and the Hippo-YAP signaling. These results suggested that vilazodone could be repositioned as an anti-tumor drug to inhibit CRC metastasis by targeting TRIM21.

Traditional Chinese Medicine Treatment, Gua Sha, can Induce Subtle Molecular Changes in Gene Expression.

Objective: Here, we explored molecular changes that could potentially mediate healing effects of Gua Sha - a method employed by the Chinese traditional medicine with proven track records of safe and efficient applications dating back to ancient times as well as support from randomized controlled trials performed by modern medical studies - yet remaining almost entirely unexplored by the modern-day high-throughput methods of the -omics sciences. Methods: We investigated transcriptome changes occurring shortly after Gua Sha treatment in the whole blood of healthy volunteers using bulk RNA-seq analysis. We applied various analytical tools to identify genes with consistent expression changes in multiple individuals in response to Gua Sha and their networks. Results: We found that while the changes were very subtle and individual-specific, we could identify consistent upregulation of three histone genes. Further analysis of the potential regulatory networks of these histone genes revealed the enrichment of functions involved in the immune response and inflammation. Conclusion: The significance of these results in the context of potential effects of Gua Sha and the next steps in exploring the molecular mechanisms of action of this technique are discussed.

Mitochondria in cancer stem cells: Achilles heel or hard armor.

Previous studies have shown that mitochondria play core roles in not only cancer stem cell (CSC) metabolism but also the regulation of CSC stemness maintenance and differentiation, which are key regulators of cancer progression and therapeutic resistance. Therefore, an in-depth study of the regulatory mechanism of mitochondria in CSCs is expected to provide a new target for cancer therapy. This article mainly introduces the roles played by mitochondria and related mechanisms in CSC stemness maintenance, metabolic transformation, and chemoresistance. The discussion mainly focuses on the following aspects: mitochondrial morphological structure, subcellular localization, mitochondrial DNA, mitochondrial metabolism, and mitophagy. The manuscript also describes the recent clinical research progress on mitochondria-targeted drugs and discusses the basic principles of their targeted strategies. Indeed, an understanding of the application of mitochondria in the regulation of CSCs will promote the development of novel CSC-targeted strategies, thereby significantly improving the long-term survival rate of patients with cancer.

Exo1 protects DNA nicks from ligation to promote crossover formation during meiosis.

In most sexually reproducing organisms crossing over between chromosome homologs during meiosis is essential to produce haploid gametes. Most crossovers that form in meiosis in budding yeast result from the biased resolution of double Holliday junction (dHJ) intermediates. This dHJ resolution step involves the actions of Rad2/XPG family nuclease Exo1 and the Mlh1-Mlh3 mismatch repair endonuclease. Here, we provide genetic evidence in baker's yeast that Exo1 promotes meiotic crossing over by protecting DNA nicks from ligation. We found that structural elements in Exo1 that interact with DNA, such as those required for the bending of DNA during nick/flap recognition, are critical for its role in crossing over. Consistent with these observations, meiotic expression of the Rad2/XPG family member Rad27 partially rescued the crossover defect in exo1 null mutants, and meiotic overexpression of Cdc9 ligase reduced the crossover levels of exo1 DNA-binding mutants to levels that approached the exo1 null. In addition, our work identified a role for Exo1 in crossover interference. Together, these studies provide experimental evidence for Exo1-protected nicks being critical for the formation of meiotic crossovers and their distribution.

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OBJECTIVES: To study the expression of V-domain Ig suppressor of T cell activation (VISTA) in peripheral blood of children with juvenile idiopathic arthritis (JIA) and its role in the pathogenesis of JIA. METHODS: In this prospective study, peripheral blood was collected from 47 children with different subtypes of JIA and 10 healthy children. Flow cytometry was used to measure the expression levels of VISTA, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) on CD14+ mononuclear cells, CD4+ T lymphocytes, and CD8+ T lymphocytes. RESULTS: The children with JIA had a significantly lower expression level of VISTA than the healthy children (P<0.05). There was a significant difference in the expression of VISTA between the children with different subtypes of JIA, with the lowest expression level in those with systemic JIA (P<0.05). There was also a significant difference in the expression of VISTA between different immune cells, with a significantly higher expression level on the surface of monocytes (P<0.05). Correlation analysis showed that VISTA was negatively correlated with the expression of IFN-γ and TNF-α on CD4+ T cells (r=-0.436 and -0.382 respectively, P<0.05), CD8+ T cells (r=-0.348 and -0.487 respectively, P<0.05), and CD14+ mononuclear cells (r=-0.582 and -0.603 respectively, P<0.05). CONCLUSIONS: The insufficient expression of VISTA may be associated with the pathogenesis of JIA, and enhancing the immunomodulatory effect of VISTA might be one option for the treatment of JIA in the future.

Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity.

Autoimmune diseases such as ankylosing spondylitis (AS) can be driven by emerging neoantigens that disrupt immune tolerance. Here, we developed a workflow to profile posttranslational modifications involved in neoantigen formation. Using mass spectrometry, we identified a panel of cysteine residues differentially modified by carboxyethylation that required 3-hydroxypropionic acid to generate neoantigens in patients with AS. The lysosomal degradation of integrin αIIb [ITGA2B (CD41)] carboxyethylated at Cys96 (ITGA2B-ceC96) generated carboxyethylated peptides that were presented by HLA-DRB1*04 to stimulate CD4+ T cell responses and induce autoantibody production. Immunization of HLA-DR4 transgenic mice with the ITGA2B-ceC96 peptide promoted colitis and vertebral bone erosion. Thus, metabolite-induced cysteine carboxyethylation can give rise to pathogenic neoantigens that lead to autoreactive CD4+ T cell responses and autoantibody production in autoimmune diseases.