Prevalence of sexually transmitted infections (STIs) among first time visitors at STIs clinic in Hangzhou, China: Assessing the influence of the COVID-19 pandemic.

BACKGROUND: This study assesses the prevalence of sexually transmitted infections (STIs) in first time visitors to the STIs clinic in Hangzhou, China, considering different genders, ages and symptoms. And also explores howthe COVID-19 pandemic has affected on STIs. METHODS: From 2019 to 2023, 27,283 first time visitors were tested for nine distinct STIs, including Human Papillomavirus (HPV), Human Immunodeficiency Virus (HIV), syphilis, Herpes Simplex Virus type 2 (HSV-2), Ureaplasma urealyticum (UU), Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Mycoplasma genitalium (MG), and vaginal Candida. RESULTS: Symptomatic male and female visitors showed overall STI-positive rates of 39.27% and 59.20%, respectively(p < .001). The top three pathogens in both genders were HPV (47.56% and 56.71%), UU (29.21% and 56.47%), and HSV-2 (22.41% and 52.94%). Among asymptomatic visitors, the total STI-positive rate was 36.63% in males and 52.03% in females. Age-stratified analysis revealed higher STI rates in visitors ≤ 20 or >50 years, regardless of gender and symptoms. During the COVID-19 pandemic, symptomatic visitors showed lower positive rates for HPV, HIV, syphilis, and HSV-2, while Candida, UU, CT, NG, and multiple infections increased. Among asymptomatic visitors, HPV had the lowest positive rate, while NG and multiple infections increased during the pandemic. CONCLUSION: STI prevalence is notably high, particularly in those aged ≤ 20 and >50 years. It emphasizes the need for enhanced health education, condom use, and vaccination. The COVID-19 pandemic impacting STIs through varied factors, such as reduced sexual activity and clinical service interruption.

Tryptophan 2,3-dioxygenase-positive matrix fibroblasts fuel breast cancer lung metastasis via kynurenine-mediated ferroptosis resistance of metastatic cells and T cell dysfunction.

BACKGROUND: Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer. METHODS: Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA-sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts (TDO2+ MFs) in lung metastasis. RESULTS: We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2+ MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MF-secreted chemokines C-C motif chemokine ligand 8 (CCL8) and C-C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2+ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation. CONCLUSIONS: Our study reveals crucial roles of TDO2+ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.

Pembrolizumab and cabozantinib in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC): long-term survival update with a biomarker analysis.

PURPOSE: Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent and/or metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) have immunomodulatory properties and improve clinical outcomes in combination with anti-PD-1 therapy. We report the long-term efficacy and safety of pembrolizumab and cabozantinib and include a correlative biomarker analysis. PATIENTS AND METHODS: This open-label, single-arm, multicenter, phase 2 study screened 50 patients with RMHNSCC, of whom 36 received pembrolizumab and cabozantinib. Primary endpoint was overall response rate (ORR), safety, and tolerability. Secondary endpoints included progression free survival (PFS), overall survival (OS), and correlative studies of tissue and blood. We report the long-term PFS, OS, safety, and describe correlative biomarkers. RESULTS: With median follow-up of 22.4 months, median PFS was 12.8 months 2-year PFS of 32.6% (95%CI 18.8-56.3%) and median OS of 27.7 months,2-year OS of 54.7% (95%CI 38.9-76.8%). Median duration of response was 12.6 months, with 2-year rate of 38.5% (95%CI 30.8-81.8%). Long-term TRAEs included manageable hypothyroidism (5.5%) and grade 1 elevated AST and ALT (2.8%). Baseline tumor p-MET expression correlated with ORR (p=0.0055). Higher density of CD8+, CD103+, and CSF1-R+ cells at baseline correlated with improved OS (hazard ratio [HR]=5.27, p=0.030; HR =8.79, p=0.017; HR =6.87, p=0.040, respectively). CONCLUSION: Pembrolizumab and cabozantinib provided prolonged encouraging long-term disease control and survival with a maintained favorable safety profile. The prognostic significance of increased CD8+, CD103+ and CSF1-R+ cell density in TIME deserve further evaluation in similar clinical settings.

Therapeutic Targeting of the GLS1-c-Myc Positive Feedback Loop Suppresses Glutaminolysis and Inhibits Progression of Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is addicted to glutaminolysis. Targeting this metabolic dependency has emerged as a potential therapeutic approach for HNSCC. Here, we conducted a bioinformatic analysis of the TCGA HNSCC cohort that revealed a robust correlation between expression of c-Myc and GLS1, which catalyzes the first step in glutaminolysis. Intriguingly, disruption of GLS1 signaling in HNSCC cells by genetic depletion or CB-839 treatment resulted in a reduction in c-Myc protein stability via a USP1-dependent ubiquitin-proteasome pathway. On the other hand, c-Myc directly binds to the promoter region of GLS1 and upregulates its transcription. Notably, the GLS1-c-Myc pathway enhanced ACC-dependent SLUG acetylation, prompting cancer cell invasion and metastasis. Thus, the GLS1-c-Myc axis emerged as a positive feedback loop critical for driving the aggressiveness of HNSCC. Therapeutically, combining CB-839 with the c-Myc inhibitor MYCi975 strongly suppressed GLS1-c-Myc signaling, resulting in a superior antitumor effect compared to either single agent in an orthotopic mouse model of HNSCC. These findings hold promise for the development of effective therapies for HNSCC patients, addressing an urgent need arising from the significant incidence and high metastatic rate of the disease.

Knowledge of Alzheimer's disease and associated factors among adults in Zhuhai, China: a cross-sectional analysis.

BACKGROUND: This study aimed to assess the public knowledge regarding Alzheimer's Disease (AD) in Zhuhai, China, focusing on identifying knowledge gaps and the influence of demographic and health factors. METHODS: A cross-sectional study was conducted in Zhuhai, China, from October to November 2022. A total of 1986 residents from 18 communities were selected employing stratified multi-stage equi-proportional sampling. Questionnaires covering general information and the Alzheimer's Disease Knowledge Scale (ADKS) were investigated face-to-face. Ordinal multiclass logistic regression was applied to assess the relationship between AD awareness and demographic and health characteristics. RESULTS: The average ADKS score was 18.5 (SD = 3.36) in Zhuhai. The lowest awareness rates were observed in the "Symptoms" and "Caregiving" subdomains of ADKS, with rates of 51.01% and 43.78%, respectively. The correct rates for the 30 ADKS questions ranged from 16.62 to 92.6%, showing a bimodal pattern with clusters around 80% and 20%. Women (OR = 1.203, 95% CI: 1.009-1.435), individuals aged 60 years or older (OR = 2.073, 95% CI: 1.467-2.932), those living in urban areas (OR = 1.361, 95% CI: 1.117-1.662), higher average monthly household income per capita (OR = 1.641, 95% CI: 1.297-2.082), and without any neurological or mental disorders (OR = 1.810, 95% CI: 1.323-2.478) were more likely to have higher levels of awareness about Alzheimer's disease. CONCLUSIONS: Adults in Zhuhai show a limited knowledge of AD, particularly in the 'Symptoms' and 'Caregiving' subdomains. Upcoming health campaigns must focus on bridging the knowledge gaps in different subdomains of AD, especially among subgroups with lower awareness, as identified in our study.

Helicobacter pylori-Induced Angiopoietin-Like 4 Promotes Gastric Bacterial Colonization and Gastritis.

Helicobacter pylori infection is characterized as progressive processes of bacterial persistence and chronic gastritis with features of infiltration of mononuclear cells more than granulocytes in gastric mucosa. Angiopoietin-like 4 (ANGPTL4) is considered a double-edged sword in inflammation-associated diseases, but its function and clinical relevance in H. pylori-associated pathology are unknown. Here, we demonstrate both pro-colonization and pro-inflammation roles of ANGPTL4 in H. pylori infection. Increased ANGPTL4 in the infected gastric mucosa was produced from gastric epithelial cells (GECs) synergistically induced by H. pylori and IL-17A in a cagA-dependent manner. Human gastric ANGPTL4 correlated with H. pylori colonization and the severity of gastritis, and mouse ANGPTL4 from non-bone marrow-derived cells promoted bacteria colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Il17a -/-, Angptl4 -/-, and Il17a -/- Angptl4 -/- mice. Mechanistically, ANGPTL4 bound to integrin αV (ITGAV) on GECs to suppress CXCL1 production by inhibiting ERK, leading to decreased gastric influx of neutrophils, thereby promoting H. pylori colonization; ANGPTL4 also bound to ITGAV on monocytes to promote CCL5 production by activating PI3K-AKT-NF-κB, resulting in increased gastric influx of regulatory CD4+ T cells (Tregs) via CCL5-CCR4-dependent migration. In turn, ANGPTL4 induced Treg proliferation by binding to ITGAV to activate PI3K-AKT-NF-κB, promoting H. pylori-associated gastritis. Overall, we propose a model in which ANGPTL4 collectively ensures H. pylori persistence and promotes gastritis. Efforts to inhibit ANGPTL4-associated pathway may prove valuable strategies in treating H. pylori infection.

Exploring the impact of GSTM1 as a novel molecular determinant of survival in head and neck cancer patients of African descent.

BACKGROUND: Blacks/African American (BAA) patients diagnosed with head and neck squamous cell carcinoma (HNSCC) have worse survival outcomes than White patients. However, the mechanisms underlying racial disparities in HNSCC have not been thoroughly characterized. METHODS: Data on gene expression, copy number variants (CNVs), gene mutations, and methylation were obtained from 6 head and neck cancer datasets. Comparative bioinformatics analysis of the above genomic features was performed between BAAs and Whites. The expression pattern of GSTM1 was validated by immunohistochemistry using tumor tissue microarray (TMA). Effect of GSTM1 knockdown were assessed by cell proliferation, colony formation, and tumor development in an orthotopic mouse model. The changes in protein kinases were determined using the Proteome Profiler Human Phospho-Kinase Array Kit in HNSCC cells with or without GSTM1 knockdown. RESULTS: We identified ancestry-related differential genomic profiles in HNSCC. Specifically, in BAA HNSCC, FAT1 mutations were associated with its gene expression, SALL3 gene expression correlated with its gene CNVs, and RTP4 gene expression showed an inverse correlation with its methylation. Notably, GSTM1 emerged as a prognostic risk factor for BAA HNSCC, with high gene CNVs and expression levels correlating with poor overall survival in BAA patients. Immunohistochemistry results from newly developed in-house TMA validated the expression pattern of GSTM1 between BAA HNSCC and White HNSCC. In an orthotopic mouse model, GSTM1 knockdown significantly inhibited malignant progression in tumors derived from BAAs. In contrast, loss of GSTM1 did not affect the development of HNSCC originating in Whites. Mechanistically, GSTM1 knockdown suppressed HSP27 phosphorylation and ß-catenin in BAA HNSCC cells, but not in White HNSCC cells. This differential effect at least partially contributes to tumor development in BAA patients. CONCLUSION: This study identifies GSTM1 as a novel molecular determinant of survival in HNSCC patients of African descent. It also provides a molecular basis for future research focused on identifying molecular determinants and developing therapeutic interventions to improve outcomes for BAA patients with HNSCC.

Lung-Specific mRNA Delivery Enabled by Sulfonium Lipid Nanoparticles.

Among various mRNA carrier systems, lipid nanoparticles (LNPs) stand out as the most clinically advanced. While current clinical trials of mRNA/LNP therapeutics mainly address liver diseases, the potential of mRNA therapy extends far beyond─yet to be unraveled. To fully unlock the promises of mRNA therapy, there is an urgent need to develop safe and effective LNP systems that can target extrahepatic organs. Here, we report on the development of sulfonium lipid nanoparticles (sLNPs) for systemic mRNA delivery to the lungs. sLNP effectively and specifically delivered mRNA to the lungs following intravenous administration in mice. No evidence of lung and systemic inflammation or toxicity in major organs was induced by sLNP. Our findings demonstrated that the newly developed lung-specific sLNP platform is both safe and efficacious. It holds great promise for advancing the development of new mRNA-based therapies for the treatment of lung-associated diseases and conditions.

Cell death shapes cancer immunity: spotlighting PANoptosis.

PANoptosis represents a novel type of programmed cell death (PCD) with distinctive features that incorporate elements of pyroptosis, apoptosis, and necroptosis. PANoptosis is governed by a newly discovered cytoplasmic multimeric protein complex known as the PANoptosome. Unlike each of these PCD types individually, PANoptosis is still in the early stages of research and warrants further exploration of its specific regulatory mechanisms and primary targets. In this review, we provide a brief overview of the conceptual framework and molecular components of PANoptosis. In addition, we highlight recent advances in the understanding of the molecular mechanisms and therapeutic applications of PANoptosis. By elucidating the complex crosstalk between pyroptosis, apoptosis and necroptosis and summarizing the functional consequences of PANoptosis with a special focus on the tumor immune microenvironment, this review aims to provide a theoretical basis for the potential application of PANoptosis in cancer therapy.

Improving resistant starch content of cassava starch by pulsed electric field-assisted esterification.

This study aims to investigate the effect of pulsed electric field (PEF) assisted OSA esterification treatment on the multi-scale structure and digestive properties of cassava starch and structure-digestion relationships. The degree of substitution (DS) of starch dually modified at 1.5-4.5 kV/cm was 37.6-55.3 % higher than that of starch modified by the conventional method. Compared with native starch, the resistant starch (RS) content of esterified starch treated with 3 kV/cm significantly increased by 17.13 %, whereas that of starch produced by the conventional method increased by only 5.91 %. Furthermore, assisted esterification at low electric fields (1.5-3 kV/cm) promotes ester carbonyl grafting on the surface of starch granules, increases steric hindrance and promotes the rearrangement of the amorphous regions of starch, which increases the density of the double-helical structure. These structural changes slow down starch digestion and increase the RS content. Therefore, this study presents a potential method for increasing the RS content of starch products using PEF to achieve the desired digestibility.

Innovative Approach to Chiral Polyurethanes: Asymmetric Copolymerization with Isocyanates.

The introduction of nitrogen-containing functional groups to chiral polymer backbones enables the tailoring of physical properties and offers opportunities for further post-polymerization modification. However, the substrate scope of such polymers is extremely limited because monomers having nitrogen-containing groups can change coordination state with respect to the metal centers, thus decreasing the activity and enantioselectivity and even poisoning the catalyst completely. In this paper, we report our attempts to carry out the asymmetric copolymerization of meso-epoxide with highly reactive isocyanates. In particular, we found that biphenol-linked bimetallic Co(III) complexes with multiple chiral centers are very efficient in catalyzing this asymmetric copolymerization reaction, affording optically active polyurethanes with a completely alternating nature and a high enantioselectivity of up to 94 % ee. Crucially, we identified that the steric hindrance at the phenolate ortho position of the ligand strongly influences the catalytic activity and product enantioselectivity. In addition, density functional theory calculations revealed that the highly sterically bulky substituents change the mechanism from bimetallic to monometallic, and result in the unexpected inversion of the chiral induction direction. Moreover, the high stereoregularity of the produced polyurethanes enhances their thermal stability, and they can be selectively decomposed into oxazolidinones. This study offers a versatile methodology for the synthesis of chiral polymers containing nitrogen functionalities.

Intensity-Modulated Reirradiation Therapy With Nivolumab in Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma: A Nonrandomized Controlled Trial.

Importance: Intensity-modulated radiation therapy (IMRT) reirradiation of nonmetastatic recurrent or second primary head and neck squamous cell carcinoma (HNSCC) results in poor progression-free survival (PFS) and overall survival (OS). Objective: To investigate the tolerability, PFS, OS, and patient-reported outcomes with nivolumab (approved standard of care for patients with HNSCC) during and after IMRT reirradiation. Design, Setting, and Participants: In this multicenter nonrandomized phase 2 single-arm trial, the treatment outcomes of patients with recurrent or second primary HNSCC who satisfied recursive partitioning analysis class 1 and 2 definitions were evaluated. Between July 11, 2018, and August 12, 2021, 62 patients were consented and screened. Data were evaluated between June and December 2023. Intervention: Sixty- to 66-Gy IMRT in 30 to 33 daily fractions over 6 to 6.5 weeks with nivolumab, 240 mg, intravenously 2 weeks prior and every 2 weeks for 5 cycles during IMRT, then nivolumab, 480 mg, intravenously every 4 weeks for a total nivolumab duration of 52 weeks. Main Outcomes and Measures: The primary end point was PFS. Secondary end points included OS, incidence, and types of toxic effects, including long-term treatment-related toxic effects, patient-reported outcomes, and correlatives of tissue and blood biomarkers. Results: A total of 62 patients were screened, and 51 were evaluable (median [range] age was 62 [56-67] years; 42 [82%] were male; 6 [12%] had p16+ disease; 38 [75%] had salvage surgery; and 36 [71%.] had neck dissection). With a median follow-up of 24.5 months (95% CI, 19.0-25.0), the estimated 1-year PFS was 61.7% (95% CI, 49.2%-77.4%), rejecting the null hypothesis of 1-year PFS rate of less than 43.8% with 1-arm log-rank test P = .002 within a 1-year timeframe. The most common treatment-related grade 3 or higher adverse event (6 [12%]) was lymphopenia with 2 patients (4%) and 1 patient each (2%) exhibiting colitis, diarrhea, myositis, nausea, mucositis, and myasthenia gravis. Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Head and Neck Questionnaire quality of life scores remained stable and consistent across all time points. A hypothesis-generating trend favoring worsening PFS and OS in patients with an increase in blood PD1+, KI67+, and CD4+ T cells was observed. Conclusions and Relevance: This multicenter nonrandomized phase 2 trial of IMRT reirradiation therapy and nivolumab suggested a promising improvement in PFS over historical controls. The treatment was well tolerated and deserves further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT03521570.

Assessing survival outcomes of patients with oral tongue squamous cell carcinoma: Focus on age, sex, and stage.

BACKGROUND: The purpose of this study was to provide further insights into whether age and/or sex are associated with prognosis in oral tongue squamous cell carcinoma. METHODS: This was a retrospective cohort study utilizing hospital registry data from 2006 to 2016 obtained from the National Cancer Database. Identified patients were divided into various cohorts based on age, sex, and staging. A descriptive analysis was performed using chi-square tests and overall survival rates were estimated using Kaplan-Meier method. RESULTS: A total of 17 642 patients were included in the study. The 5-year overall survival rates were 82.0% (95% CI: 79.8%-84.0%) in younger patients versus 67.5% (95% CI: 66.7%-68.3%, p-value <0.0001) older patients. The median overall survival for females was 143.4 months (95% CI: 133.2-NA) versus 129.8 (95% CI: 125.4-138.7, p-value <0.0001) in males. CONCLUSIONS: Our analysis suggests that younger age and female sex are both predictors of improved survival in oral tongue squamous cell carcinoma.

Molecularly defined sinonasal malignancies: an overview with focus on the current WHO classification and recently described provisional entities.

Classification of tumors of the head and neck has evolved in recent decades including a widespread application of molecular testing in tumors of the sinonasal tract, salivary glands, and soft tissues with a predilection for the head and neck. The availability of new molecular techniques has allowed for the definition of multiple novel tumor types unique to head and neck sites. Moreover, an expanding spectrum of immunohistochemical markers specific to genetic alterations facilitates rapid identification of diagnostic molecular abnormalities. As such, it is currently possible for head and neck pathologists to benefit from a molecularly defined tumor classification while making diagnoses that are still based largely on histopathology and immunohistochemistry. This review covers the principal molecular alterations in sinonasal malignancies, such as alterations in DEK, AFF2, NUTM1, IDH1-2, and SWI/SNF genes in particular, that are important from a practical standpoint for diagnosis, prognosis, and prediction of response to treatment.

Combined IL6 and CCR2 blockade potentiates antitumor activity of NK cells in HPV-negative head and neck cancer.

BACKGROUND: While T cell-activating immunotherapies against recurrent head and neck squamous cell carcinoma (HNSCC) have shown impressive results in clinical trials, they are often ineffective in the majority of patients. NK cells are potential targets for immunotherapeutic intervention; however, the setback in monalizumab-based therapy in HNSCC highlights the need for an alternative treatment to enhance their antitumor activity. METHODS: Single-cell RNA sequencing (scRNA-seq) and TCGA HNSCC datasets were used to identify key molecular alterations in NK cells. Representative HPV-positive ( +) and HPV-negative ( -) HNSCC cell lines and orthotopic mouse models were used to validate the bioinformatic findings. Changes in immune cells were examined by flow cytometry and immunofluorescence. RESULTS: Through integration of scRNA-seq data with TCGA data, we found that the impact of IL6/IL6R and CCL2/CCR2 signaling pathways on evasion of immune attack by NK cells is more pronounced in the HPV - HNSCC cohort compared to the HPV + HNSCC cohort. In orthotopic mouse models, blocking IL6 with a neutralizing antibody suppressed HPV - but not HPV + tumors, which was accompanied by increased tumor infiltration and proliferation of CD161+ NK cells. Notably, combining the CCR2 chemokine receptor antagonist RS504393 with IL6 blockade resulted in a more pronounced antitumor effect that was associated with more activated intratumoral NK cells in HPV - HNSCC compared to either agent alone. CONCLUSIONS: These findings demonstrate that dual blockade of IL6 and CCR2 pathways effectively enhances the antitumor activity of NK cells in HPV-negative HNSCC, providing a novel strategy for treating this type of cancer.

Identification and analysis of the molecular targets of statins in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer in the world. According to several types of research, statins may impact the development and treatment of CRC. This work aimed to use bioinformatics to discover the relationship between statin targets and differentially expressed genes (DEGs) in CRC patients and determine the possible molecular effect of statins on CRC suppression. We used CRC datasets from the GEO database to select CRC-related DEGs. DGIdb and STITCH databases were used to identify gene targets of subtypes of statin. Further, we identified the statin target of CRC DEGs hub genes by using a Venn diagram of CRC DEGs and statin targets. Funrich and enrichr databases were carried out for the KEGG pathway and gene ontology (GO) enrichment analysis, respectively. GSE74604 and GSE10950 were used to identify CRC DEGs. After analyzing datasets,1370 genes were identified as CRC DEGs, and 345 targets were found for statins. We found that 35 genes are CRC DEGs statin targets. We found that statin targets in CRC were enriched in the receptor and metallopeptidase activity for molecular function, cytoplasm and plasma membrane for cellular component, signal transduction, and cell communication for biological process genes were substantially enriched based on FunRich enrichment. Analysis of the KEGG pathways revealed that the overexpressed DEGs were enriched in the IL-17, PPAR, and Toll-like receptor signaling pathways. Finally, CCNB1, DNMT1, AURKB, RAC1, PPARGC1A, CDKN1A, CAV1, IL1B, and HSPD1 were identified as hub CRC DEGs statin targets. The genetic and molecular aspects of our findings reveal that statins might have a therapeutic effect on CRC.

Combination of Molecule-Targeted Therapy and Photodynamic Therapy Using Nanoformulated Verteporfin for Effective Uveal Melanoma Treatment.

Uveal melanoma (UM) is the most common primary ocular malignancy in adults and has high mortality. Recurrence, metastasis, and therapeutic resistance are frequently observed in UM, but no beneficial systemic therapy is available, presenting an urgent need for developing effective therapeutic drugs. Verteporfin (VP) is a photosensitizer and a Yes-Associated Protein (YAP) inhibitor that has been used in clinical practice. However, VP's lack of tumor targetability, poor biocompatibility, and relatively low treatment efficacy hamper its application in UM management. Herein, we developed a biocompatible CD44-targeting hyaluronic acid nanoparticle (HANP) carrying VP (HANP/VP) to improve UM treatment efficacy. We found that HANP/VP showed a stronger inhibitory effect on cell proliferation than that of free VP in UM cells. Systemic delivery of HANP/VP led to targeted accumulation in the UM-tumor-bearing mouse model. Notably, HANP/VP mediated photodynamic therapy (PDT) significantly inhibited UM tumor growth after laser irradiation compared with no treatment or free VP treatment. Consistently, in HANP/VP treated tumors after laser irradiation, the tumor proliferation and YAP expression level were decreased, while the apoptotic tumor cell and CD8+ immune cell levels were elevated, contributing to effective tumor growth inhibition. Overall, the results of this preclinical study showed that HANP/VP is an effective nanomedicine for tumor treatment through PDT and inhibition of YAP in the UM tumor mouse model. Combining phototherapy and molecular-targeted therapy offers a promising approach for aggressive UM management.

Modulation of Dendritic Cell Function via Nanoparticle-Induced Cytosolic Calcium Changes.

Calcium nanoparticles have been investigated for applications, such as drug and gene delivery. Additionally, Ca2+ serves as a crucial second messenger in the activation of immune cells. However, few studies have systematically studied the effects of calcium nanoparticles on the calcium levels and functions within immune cells. In this study, we explore the potential of calcium nanoparticles as a vehicle to deliver calcium into the cytosol of dendritic cells (DCs) and influence their functions. We synthesized calcium hydroxide nanoparticles, coated them with a layer of silica to prevent rapid degradation, and further conjugated them with anti-CD205 antibodies to achieve targeted delivery to DCs. Our results indicate that these nanoparticles can efficiently enter DCs and release calcium ions in a controlled manner. This elevation in cytosolic calcium activates both the NFAT and NF-κB pathways, in turn promoting the expression of costimulatory molecules, antigen-presenting molecules, and pro-inflammatory cytokines. In mouse tumor models, the calcium nanoparticles enhanced the antitumor immune response and augmented the efficacy of both radiotherapy and chemotherapy without introducing additional toxicity. Our study introduces a safe nanoparticle immunomodulator with potential widespread applications in cancer therapy.

HSP90 inhibition suppresses tumor glycolytic flux to potentiate the therapeutic efficacy of radiotherapy for head and neck cancer.

Glycolytic metabolism may account for antitumor immunity failure. Pyruvate kinase M2 (PKM2) and platelet phosphofructokinase (PFKP), two key enzymes involved in the glycolytic pathway, are hyperactivated in head and neck squamous cell carcinoma (HNSCC). Using ganetespib as a drug model for heat shock protein 90 (HSP90) inhibition and combining results from clinical trials and animal treatment, we demonstrated that HSP90 inhibition leads to a blockade of glycolytic flux in HNSCC cells by simultaneously suppressing PKM2 and PFKP at both the transcriptional and posttranslational levels. Down-regulation of tumor glycolysis facilitates tumor infiltration of cytotoxic T cells via suppression of glycolysis-dependent interleukin-8 signaling. The addition of ganetespib to radiation attenuates radiation-induced up-regulation of PKM2 and PFKP and potentiates T cell-mediated antitumor immunity, resulting in a more potent antitumor effect than either treatment alone, providing a molecular basis for exploring the combination of HSP90 inhibitors with radiotherapy to improve outcomes for patients with HNSCC.