Proliferation Pathways Research Articles

Molecular characterization of pregnancy-associated breast cancer and insights on timing from GEICAM-EMBARCAM study

Pregnancy-associated breast cancer (PABC), diagnosed during or shortly after pregnancy, is a challenging entity with an aggressive biology and poor prognosis. This study analyzed the clinicopathological characteristics and gene expression profile of 33 PABC and 26 non-PABC patients using the nCounter BC360 Panel (NanoString). Notably, PABC showed a higher prevalence of basal-like tumors than non-PABC (48.48% vs 15.38%, p = 0.012) and displayed 73 differentially expressed genes (e.g., DEPDC1, CCNA2, PSAT1, CDKN3, and FAM83D), enriched in DNA repair and cell proliferation pathways. Through the PPI network, we also identified a cluster of cell-cycle regulation genes like MYC, FOXM1, or PTEN. Interestingly, differences emerged when comparing patients diagnosed during gestation (PABC-GS) and the postpartum period (PABC-PP), with PABC-PP showing increased expression of immune-related genes, including PD-1, and greater immune cell infiltration (Tregs, macrophages, neutrophils, B-cells). These findings suggest an enhanced proliferative capacity and impaired DNA repair in PABC, and underscore the role of immune infiltration in postpartum cases; providing insights into its aggressive nature and potential targets.

Efficacy of Zenocutuzumab in NRG1 Fusion–Positive Cancer

BackgroundNeuregulin 1 (NRG1) fusions are recurrent oncogenic drivers found in multiple solid tumors. NRG1 binds to human epidermal growth factor receptor 3 (HER3), leading to heterodimerization with HER2 and activation of downstream growth and proliferation pathways. The efficacy and safety of zenocutuzumab, a bispecific antibody against HER2 and HER3, in patients with NRG1 fusion–positive solid tumors are unclear.MethodsIn this registrational, phase 2 clinical study, we assigned patients with advanced NRG1 fusion–positive cancer involving any tumor type to receive zenocutuzumab at a dose of 750 mg intravenously every 2 weeks. The primary end point was overall response (complete or partial response) according to investigator assessment. Secondary end points included duration of response, progression-free survival, and safety.ResultsA total of 204 patients with 12 tumor types were enrolled and treated. Among 158 patients who had measurable disease and were enrolled at least 24 weeks before the data-cutoff date, a response occurred in 30% (95% confidence interval [CI], 23 to 37). The median duration of response was 11.1 months (95% CI, 7.4 to 12.9); 19% of responses were ongoing at the data-cutoff date. Responses were observed in multiple tumor types — including in 27 of 93 patients (29%; 95% CI, 20 to 39) with non–small-cell lung cancer (NSCLC) and 15 of 36 patients (42%; 95% CI, 25 to 59) with pancreatic cancer — and across multiple NRG1 fusion partners. The median progression-free survival was 6.8 months (95% CI, 5.5 to 9.1). Adverse events were primarily grade 1 or 2. The most common adverse events that were considered by the investigator to be related to zenocutuzumab were diarrhea (in 18% of the patients), fatigue (in 12%), and nausea (in 11%). Infusion-related reactions (composite term) were observed in 14% of the patients. One patient discontinued zenocutuzumab owing to a treatment-related adverse event.ConclusionsZenocutuzumab showed efficacy in patients with advanced NRG1 fusion–positive cancer, notably NSCLC and pancreatic cancer, with mainly low-grade adverse events. (Funded by Merus; eNRGy ClinicalTrials.gov number, NCT02912949.)

Enhanced therapeutic effects of hypoxia-preconditioned mesenchymal stromal cell-derived extracellular vesicles in renal ischemic injury

BackgroundExtracellular vesicles (EVs) secreted by mesenchymal stromal cells (MSCs) have been shown to provide significant protection against renal ischemia–reperfusion injury (IRI). Hypoxia has emerged as a promising strategy to enhance the tissue repair capabilities of MSCs. However, the specific effects of hypoxia on MSCs and MSC-EVs, as well as their therapeutic potential in renal IRI, remain unclear. In this study, we investigated the alterations occurring in MSCs and the production of MSC-EVs following hypoxia pre-treatment, and further explored the key intrinsic mechanisms underlying the therapeutic effects of hypoxic MSC-EVs in the treatment of renal IRI.MethodsHuman umbilical cord MSCs were cultured under normoxic and hypoxic conditions. Proliferation and related pathways were measured, and RNA sequencing was used to detect changes in the transcriptional profile. MSC-EVs from both normoxic and hypoxic conditions were isolated and characterized. In vivo, the localization and therapeutic effects of MSC-EVs were assessed in a rat renal IRI model. Histological examinations were conducted to evaluate the structure, proliferation, and apoptosis of IRI kidney tissue respectively. Renal function was assessed by measuring serum creatinine and blood urea nitrogen levels. In vitro, the therapeutic potential of MSC-EVs were measured in renal tubular epithelial cells injured by antimycin A. Protein sequencing analysis of hypoxic MSC-EVs was performed, and the depletion of Glutathione S-Transferase Omega 1 (GSTO1) in hypoxic MSC-EVs was carried out to verify its key role in alleviating renal injury.ResultsHypoxia alters MSCs transcriptional profile, promotes their proliferation, and increases the production of EVs. Hypoxia-pretreated MSC-EVs demonstrated a superior ability to mitigate renal IRI, enhancing proliferation and reducing apoptosis of renal tubular epithelial cells both in vivo and in vitro. Protein profiling of the EVs revealed an accumulation of numerous anti-oxidative stress proteins, with GSTO1 being particularly prominent. Knockdown of GSTO1 significantly reduced the antioxidant and therapeutic effects on renal IRI of hypoxic MSC-EVs.ConclusionsHypoxia significantly promotes the generation of MSC-EVs and enhances their therapeutic effects on renal IRI. The antioxidant stress effect induced by GSTO1 is identified as one of the most critical underlying mechanisms. Our findings highlight that hypoxia-pretreated MSC-EVs represent a novel and promising therapeutic strategy for renal IRI.Graphical

Comprehensive genomic and transcriptomic profiling of pulmonary nodules in synchronous multiple primary lung cancer

BackgroundSynchronous multiple primary lung cancer (sMPLC) exhibits distinct histopathological characteristics among pulmonary nodules. However, a comprehensive understanding of the somatic mutation landscape and transcriptome heterogeneity is lacking. Therefore, our study aims to meticulously investigate genomic distinctions among multiple pulmonary nodules within individual patients.MethodsWe performed targeted DNA sequencing on tumor specimens and conducted bulk RNA transcriptome analysis on 53 multiple nodules originating from 26 lung cancer patients. The multiple nodules from the same patient was determined as major nodule and minor nodule. Additionally, the tumor tissues underwent histopathological evaluation through H&E staining, complemented by a comprehensive series of immunohistochemistry (IHC) analyses to detect protein expression. The detected protein markers encompassed PD-L1, Ki67, and others.ResultsFor the 53 nodule samples from 26 MPLCs patients, EGFR was the mostly mutated genes, and the TP53 mutation frequency was notably different between major and minor nodules. Furthermore, pathway enrichment analysis based on the differentially expressed genes (DEGs) between major and minor nodules revealed the significantly active cell cycle and p53 pathways in the major nodules. Additionally, both major and minor nodules demonstrated mostly similar immune microenvironment and PD-L1 protein expression, and a significantly higher expression of Ki67. A noteworthy suppression was observed in the immune microenvironment in nodules, revealed by the expression of macrophage, neutrophils, and NK cells. Furthermore, minor nodules exhibited a modestly elevated expression of macrophages compared to major nodules. Additionally, among the significantly up-regulated cell cycle-related genes in the major nodules when compared with minor nodules, CCNE1 mRNA expression demonstrated significant correlation with poor prognosis in the lung cancer. Furthermore, the MYC inhibitor demonstrated more sensitivity for the major nodules than minor nodules.ConclusionsThis study validated molecular distinctions between samples from major and minor nodules in patients with sMPLC at both genomic and transcriptomic levels. The major nodules exhibited heightened activity in tumor cell proliferation pathways and demonstrated malignancy-related biological characteristics, which correlated with pathological assessment results.

Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients

A substantial portion of patients infected with SARS-CoV-2 experience prolonged complications, known as Long COVID (LC). A subset of these patients exhibits the most debilitating symptoms, similar to those defined in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We performed bulk RNA sequencing (RNAseq) on the whole blood of LC with ME/CFS, at least 12 months post-onset of the acute disease, and compared them with controls. We found that LC patients had a distinct transcriptional profile compared to controls. Key findings include the upregulation of genes involved in immune dysregulation and neuronal development, such as Fezf2, BRINP2, HOXC12, MEIS2, ZFHX3, and RELN. These genes are linked to neuroinflammatory responses, cognitive impairments, and hematopoietic disturbances, suggesting ongoing neurological and immune disturbances in LC patients.RELN, encoding the Reelin protein, was notably elevated in LC patients, potentially serving as a biomarker for LC pathogenesis due to its role in inflammation and neuronal function. Immune cell analysis showed altered profiles in LC patients, with increased activated memory CD4 + T cells and neutrophils, and decreased regulatory T cells and NK cells, reflecting immune dysregulation. Changes in cytokine and chemokine expression further underscore the chronic inflammatory state in LC patients. Notably, a unique upregulation of olfactory receptors (ORs) suggest alternative roles for ORs in non-olfactory tissues.Pathway analysis revealed upregulation in ribosomal RNA processing, amino acid metabolism, protein synthesis, cell proliferation, DNA repair, and mitochondrial pathways, indicating heightened metabolic and immune demands. Conversely, downregulated pathways, such as VEGF signaling and TP53 activity, point to impaired tissue repair and cellular stress responses.Overall, our study underscores the complex interplay between immune and neuronal dysfunction in LC patients, providing insights into potential diagnostic biomarkers and therapeutic targets. Future research is needed to fully understand the roles and interactions of these genes in LC pathophysiology.

Covalent Bruton tyrosine kinase inhibitors across generations: A focus on zanubrutinib.

Bruton tyrosine kinase (BTK), the primary target of BTK inhibitors, is a key enzyme in the proliferation and survival pathway of neoplastic B-cells. BTK inhibitors are approved in many hematologic malignancies: chronic lymphocytic leukaemia, mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinaemia and follicular lymphoma. Second-generation BTK inhibitors display high target selectivity thus resulting in a reduction in off-target and off-tissue effects, better therapeutic index and improved tolerability. This paper summarizes the mechanisms of action of first and second generation BTK inhibitors and elucidates results in any disease setting, with a precise focus on zanubrutinib.

CTSL Promotes Autophagy in Laryngeal Cancer Through the IL6-JAK-STAT3 Signalling Pathway.

Cathepsin L (CTSL) is an important oncogene. However, its mechanism of action in laryngeal cancer is still unclear. This study aims to explore the role of CTSL in laryngeal cancer and its clinical significance. Conducting bioinformatics analysis utilising the Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. Performing CCK8 analysis, Western blotting, qRT-PCR, wound healing assay and transwell invasion assay. Additionally, conducting immunoprecipitation experiments and immunohistochemical staining to investigate the impact of CTSL on cell proliferation, autophagy and related signalling pathways. We observed a significant upregulation of CTSL in laryngeal cancer tissues, and its elevated levels are indicative of poor prognosis in laryngeal cancer patients. The proliferation of laryngeal cancer cells relies on the expression of CTSL, with overexpression of this gene enhancing the proliferative capacity of these cells. Concurrently, CTSL is closely associated with the autophagic levels in laryngeal cancer cells. During the autophagic process mediated by CTSL, the IL6-JAK-STAT3 signalling pathway is activated, suggesting that CTSL promotes autophagy through the IL6-JAK-STAT3 pathway. Considering the correlation between CTSL and autophagy, we developed and validated a multi-gene signature. The risk score derived from this signature demonstrates significant potential in predicting various aspects. We found that CTSL upregulates autophagy in laryngeal cancer cells by activating the IL6-JAK-STAT3 signalling pathway. By taking into account the autophagy-regulating role of CTSL, the clinical predictive ability of CTSL in HNSC can be enhanced.

Triterpenoid phthalimides as selective anti-cancer agents targeting mitochondrial apoptosis.

Starting from benzyl 30-oxobetulinate and 30-oxobetulin diacetate, substituted dienes were synthesized and subjected to Diels-Alder reaction, yielding a variety of triterpenoid phthalates, phthalimides, and related derivatives. A total of 55 new compounds were prepared and tested for in vitro cytotoxic activity against eight cancer cell lines and two non-cancerous cell lines. Four compounds with IC50 values of 5μM or lower were selected for further investigation. These compounds induced apoptosis in CCRF-CEM cells in a concentration-dependent manner, accompanied by mitochondrial depolarization and altered expression of key proteins involved in mitochondrial apoptosis. The compounds also disrupted DNA replication and transcriptional activity. Modulation of key proliferation pathways, including PI3K/Akt and STAT3, further supported the antiproliferative potential of these derivatives. Considering their high cytotoxicity and antiproliferative activity in CCRF-CEM cells, compounds 19, 26, 28, and 30 have been identified as promising candidates for further development.

DETERMINATION OF THE ANTIPROLIFERATIVE EFFECT OF STERNBERGIA LUTEA (L.) KER GAWL. EX SPRENG. EXTRACTS ON A375 MALIGNANT MELONOMA CELL LINE

Epidemiological evidence confirms that plants are primary sources of drugs used to reduce the incidence of cancer and prevent cancer-related deaths. Sternbergia species are used for therapeutic purposes due to the amaryllidaceae alkaloids, lectins, phenolic acids, pigments, and volatile components they contain. In this study, the anticancer properties of S. lutea extracts were tested on the A375 malignant melonoma cell line. In addition, in the study, the transcriptional expression of BCL-XL and Cas9 genes, which function in cell proliferation and apoptotic pathways, in cells treated with plant extracts were determined by qRT-PCR. According to the cytotoxicity results made by the MTT test, the highest inhibition percentage was determined at the plant's concentration of 500 μg/𝑚L. At this concentration, A375 cells were inhibited by 83.63%, and the IC50 value of the extract was calculated as 194.64 μg/𝑚L. In addition, in qRT-PCR analyses, a statistically significant increase was observed in the mRNA expression levels of Cas9 genes, which are positively correlated with the apoptotic pathway, in the extract and cisplatin-applied groups compared to the control group.

Integrated Computational Analysis Reveals Early Genetic and Epigenetic AML Susceptibility Biomarkers in Benzene-Exposed Workers

Benzene, a well-known carcinogenic airborne pollutant, poses significant health risks, particularly in industries such as petroleum, shoemaking, and painting. Despite strict regulations, chronic occupational exposure persists, contributing to the onset of acute myeloid leukemia (AML) and other malignancies. Benzene’s carcinogenicity stems from its metabolic activation, leading to increased oxidative stress, DNA damage, and cancer transformation. While its toxicity is well-documented, the link between genetic and epigenetic alterations and cancer susceptibility in exposed workers remains underexplored. This study aims to identify early biomarkers of benzene exposure and AML risk by analyzing gene expression and DNA methylation datasets from GEO DataSets, integrated with molecular pathway analyses, as well as miRNA-target and protein-protein network evaluations. This multi-approach led to the identification of nine deregulated genes (CRK, CXCR6, GSPT1, KPNA1, MECP2, MELTF, NFKB1, TBC1D7, ZNF331) in workers exposed to benzene, with NFKB1 showing strong discriminatory potential. Also, dose-dependent DNA methylation changes were observed in CXCR6 and MELTF, while selected miRNAs such as let-7d-5p, miR-126-3p, and miR-361-5p emerged as key post-transcriptional regulators. Furthermore, functional enrichment linked these genes to immune response, inflammation, cell proliferation, and apoptosis pathways. While network analyses highlighted NFKB1, CRK, and CXCR6 as central to benzene-associated leukemogenesis. Altogether, these findings provide novel insights into an early biomarker fingerprint for benzene exposure and AML susceptibility, supporting the future development of biomolecular-based targeted occupational health monitoring and personalized preventive strategies for at-risk workers.

Polychlorinated biphenyls induced toxicities upon cell lines and stem cells: a review.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants emitted during e-waste activities. Upon release into the environment, PCBs can pose harmful effects to the humans and environment. The present review focused on the effects of PCBs on cell proliferation, apoptosis, functional and developmental toxicity and potential possible molecular mechanisms upon cells and stem cells. The review also highlights the effects of low- and high-chlorinated, and dioxin and non-dioxin PCBs. The review suggested that high chlorinated and dioxin like PCBs at higher concentrations posed more toxic effects to cells and stem cells. PCBs at higher levels induced hepatotoxicity, carcinogenicity, reproductive toxicity, neurotoxicity and lung cell toxicity. PCBs triggered reactive oxygen species which actives mitogen activated pathways, nuclear factor and cytochrome pathway for cell proliferation and apoptosis. Further, review highlights PCBs induced toxicity in stem cells with the focus on developmental and functional toxicity. The review could be useful to understand the PCBs toxicities and mechanisms and will guide to policy makers to design policies for e-waste pollutant.

Exhaustion of CD8pos central memory regulatory T cell differentiation is involved in renal allograft rejection

BackgroundThe role of regulatory CD8pos T cells (CD8pos Tregs) and cytotoxic CD8pos responder T cells (CD8pos Tresps) in maintaining stable graft function in kidney transplant recipients (KTR) remains largely unclear. The pathogenesis of graft deterioration in case of rejection involves the exhaustive differentiation of both CD8pos T cell subsets, but the causal mechanisms have not yet been identified.MethodsIn this study, we separately investigated the differentiation of CD8posTregs/Tresps in 134 stable KTR with no evidence of renal graft rejection, in 41 KTR diagnosed with biopsy-confirmed rejection at enrolment and in 5 patients who were unremarkable at enrolment, but developed rejection within three years of enrolment. We were investigating whether changed differentiation of CCR7posCD45RAposCD31pos recent thymic emigrant (RTE) cells via CD45RAnegCD31pos memory (CD31pos memory) cells (pathway 1), via direct proliferation (pathway 2), or via CCR7posCD45RA+CD31neg resting mature naïve (MN) cells (pathway 3) into CD45RAnegCD31neg memory (CD31neg memory) cells affects the CD8pos Treg/Tresp ratio or identifies a CD8pos Treg/Tresp subset that predicts or confirms renal allograft rejection.ResultsWe found that RTE Treg differentiation via pathway 1 was age-independently increased in KTR, who developed graft rejection during the follow-up period, leading to abundant MN Treg and central memory Treg (CM Treg) production and favoring a strongly increased CD8pos Treg/Tresp ratio. In KTR with biopsy-confirmed rejection at the time of enrolment, an increased differentiation of RTE Tregs into CCR7negCD45RAposCD31neg terminally differentiated effector memory (CD31neg TEMRA Tregs) and CD31pos memory Tregs was observed. CD31neg memory Treg production was maintained by alternative differentiation of resting MN Tregs, resulting in increased effector memory Treg (EM Treg) production, while the CD8pos Treg/Treg ratio was unaffected. An altered differentiation of CD8pos Tresps was not observed, shifting the Treg/Tresp ratio in favor of Tregs.ConclusionsOur results show that exhaustive CD8pos Treg differentiation into CM Tregs may lead to future rejection, with a shift towards EM Treg production and an accumulation of CD31neg TEMRA Tregs in KTR with current rejection.

Menopausal Hormone Therapy: Its Role in the Prevention of Cardiovascular Diseases and the Risk of Breast Cancer in Women

Objective: This review was conducted to explain how menopausal hormone therapy (MHT) benefits cardiovascular diseases (CVDs) and how to control the risk of breast cancer. Mechanism: Estrogen deficiency, altered energy homeostasis, adipocyte changes, inflammation, and insulin resistance are responsible for the development of metabolic syndrome and CVDs. Estrogen influences hypothalamic function and maintains the energy balance, protecting menopausal women from these cardiovascular risk factors. However, estrogen metabolism plays a crucial role in the genotoxic pathway that leads to breast cancer. Moreover, MHT is associated with cell proliferation and mutation signaling pathways in breast cancer, as well as the process of growing the breast cancer stem cell. Findings in Brief: While MHT may have favorable effects when started early, introducing it later in the course of atherosclerosis may pose major dangers, underlining the importance of timing in hormone therapy. Estrogen-only therapy has a greater favorable effect on CVDs than the estrogen-progesterone combination. Although the connection between MHT and breast cancer is well-documented, significant knowledge gaps remain, especially regarding the long-term effects of newer MHT formulations. Current studies support using the lowest effective dose for the shortest possible duration, with a focus on tailoring therapy to individual risk factors, such as obesity, smoking, and alcohol consumption. Thus, MHT should be customized due to the intricacy of individual risk factors and differences in responses to therapy. Conclusions: Although MHT is effective for controlling CVDs in women entering menopause, it must be used with caution, especially in women at high risk of breast cancer.

Sotatercept in pulmonary hypertension and beyond.

Sotatercept binds free activins by mimicking the extracellular domain of the activin receptor type IIA (ACTRIIA). Additional ligands are BMP/TGF-beta, GDF8, GDF11 and BMP10. The binding with activins leads to the inhibition of the signalling pathway and the deactivation of the bone morphogenic protein (BMP) receptor type 2. In this way, sotatercept activates an antiproliferative signalling to the cells of the pulmonary arteries and arterioles with the aim of rebalancing the proliferative and antiproliferative pathway that characterizes the pulmonary arterial hypertension (PAH). Sotatercept is indicated for the treatment of group 1 PAH in combination with drugs that act through the endothelin receptor, nitric oxide or prostacyclin. Its effects, demonstrated in the STELLAR study, are the improvement of exercise capacity and the FC-WHO functional class, together with the reduction of the risk of clinical worsening events. In addition to its antiremodeling effects on the pulmonary circulation, sotatercept has several haematological effects that could suggest its use in the treatment of some blood disorders other than PAH. In this review, we will discuss the effects of the drug on PAH and in parallel provide an in-depth overview of its application in haematological disorders, focusing on clinical and preclinical studies.

Benzo[a]pyrene exposure and incident risks of digestive system cancers: Insights from nested case-control studies and adverse outcome pathway network analysis.

Benzo[a]pyrene (B[a]P) is a recognized carcinogen for lung cancer, but its associations with digestive system cancers (DSCs) remain unclear and the common carcinogenic mechanisms are not fully understood. We conducted five nested case-control studies within the Dongfeng-Tongji cohort, including esophageal (EC, n = 58), gastric (GC, n = 103), colorectal (CRC, n = 220), hepatic (HC, n = 117), and pancreatic cancers (PC, n = 45). For each case, two sex and age ( ± 5 years) matched healthy controls were selected. We observed significant J-shaped associations between plasma concentrations of benzo[a]pyrene diol epoxide-albumin (BPDE-Alb) adducts and five DSCs (all P for non-linear <0.05). The subjects with high BPDE-Alb exposure exhibited a separate 2.19, 2.14, 1.67, 2.40, and 1.78-fold incident risks of EC, GC, CRC, HC, and PC (95%CI: 1.00-4.83, 1.24-3.67, 1.15-2.43, 1.48-3.90, and 0.71-4.47, respectively) than those with low exposure. Furthermore, the adverse outcome pathway (AOP) network indicated five molecular initiation events and 18 subsequent key events, particularly, the alterations in receptors of AhR, EGFR accompanied by regulations of cell proliferation and apoptosis pathways (e.g., PI3K-Akt, TNF signaling) may facilitate common carcinogenic processes. Our findings revealed the positive associations of B[a]P exposure with five DSCs, and the dysregulation of proliferation and apoptosis may initiate B[a]P-induced cancer development.

The Efficacy and Safety of Anlotinib in the Treatment of Thyroid Cancer: A Systematic Review.

Background and Objectives: Anlotinib, a novel multi-kinase inhibitor targeting angiogenesis and tumor proliferation pathways, has shown promising efficacy in various cancers. Its role in treating thyroid cancer, particularly radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), is of significant clinical interest. This systematic review aims to evaluate the efficacy and safety of Anlotinib in patients with thyroid cancer, analyzing outcomes such as progression-free survival (PFS), overall survival (OS), response rates, and adverse events. Methods: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases up to October 2023. The review included randomized controlled trials and prospective studies assessing Anlotinib in thyroid cancer patients. Data extraction and quality assessment were performed independently by two reviewers following PRISMA guidelines. Results: Six studies involving a total of 277 patients were included. In patients with RAIR-DTC, Anlotinib demonstrated significant improvement in median PFS and objective response rates. In advanced or metastatic MTC, Anlotinib significantly prolonged median PFS compared to placebo, with high objective response rates. Subgroup analyses showed that older patients and those with bone metastases benefited significantly from Anlotinib treatment. In patients with ATC, Anlotinib-based chemotherapy yielded a 60% objective response rate. Anlotinib was also effective as neoadjuvant therapy in locally advanced thyroid cancer, achieving an objective response rate of 76.9%. Common adverse events included hypertension, proteinuria, and palmar-plantar erythrodysesthesia syndrome, which were generally manageable. Conclusions: Anlotinib appears to be an effective and well-tolerated treatment option for patients with various types of thyroid cancer, providing significant improvements in PFS and objective response rates. Further large-scale randomized studies are warranted to confirm these findings and to explore long-term outcomes.

Association between dietary fructose and human colon DNA methylation: implication for racial disparities in colorectal cancer risk using a cross-sectional study.

An increasing body of evidence has linked fructose intake to colorectal cancer (CRC). African American (AA) adults consume greater quantities of fructose and are more likely to develop right-side colon cancer than European American (EA) adults. We examined the hypothesis that fructose consumption leads to epigenomic and transcriptomic differences associated with CRC tumor biology. Deoxyribonucleic acid (DNA) methylation data from this cross-sectional study was obtained using the Illumina Infinium MethylationEPIC kit (GSE151732). Right and left colon differentially methylated regions (DMRs) were identified using DMRcate through analysis of food frequency questionnaire data on fructose consumption in normal colon biopsies (n=79) of AA adults undergoing screening colonoscopy. Secondary analysis of CRC tumors was carried out using data derived from TCGA-COAD, GSE101764 and GSE193535. Right colon organoids derived from AA (n=5) and EA (n=5) adults were exposed to 4.4mM of fructose for 72 hours. Differentially expressed genes (DEGs) were identified using DESeq2. We identified 4,263 right colon fructose-associated DMRs (FDR<0.05). In contrast, only 24 DMRs survived multiple testing corrections (FDR<0.05) in matched, left colon. Almost 50% of right colon fructose-associated DMRs overlapped regions implicated in CRC in at least one of three datasets. A highly significant enrichment was also observed between genes corresponding to right colon fructose-associated DMRs and DEGs associated with fructose exposure in right colon organoids of AA individuals (P=3.28E-30). Overlapping and significant enrichments for fatty acid metabolism, glycolysis and cell proliferation pathways were also found. Cross-referencing genes within these pathways to DEGs in CRC tumors reveals potential roles for ankyrin repeat domain-containing protein 23 (ANKRD23) and phosphofructokinase, platelet (PFKP) in fructose-mediated CRC risk for AA individuals. Our data support that dietary fructose exerts a greater CRC risk-related effect in right than left colon among AA adults, alluding to its potential role in contributing to racial disparities in CRC.

Chaperonin containing TCP1 subunit 6A may activate Notch and Wnt pathways to facilitate the malignant behaviors and cancer stemness in oral squamous cell carcinoma

ABSTRACT Chaperonin containing TCP1 subunit 6A (CCT6A) was recently discovered to be involved in cancer pathogenesis and stemness; however, its role in oral squamous cell carcinoma (OSCC) has not been reported. The current study aimed to investigate the impact of CCT6A on OSCC cell malignant behaviors and stemness and to explore its potentially interreacted pathways. SCC-15 and HSC-3 cells were transfected with the plasmid loading control overexpression, CCT6A overexpression, control knockout, or CCT6A knockout. Wnt4 overexpression or Notch1 overexpression plasmids were transfected into CCT6A-knockout SCC-15 cells. Cell proliferation, apoptosis, invasion, stemness, Notch, and Wnt pathways were detected in both cell lines, whereas RNA sequencing was only performed in SCC-15 cells. CCT6A was upregulated in five OSCC cell lines, including SCC-15, HSC-3, SAT, SCC-9, and KON, compared to that in the control cell line. In SCC-15 and HSC-3 cells, CCT6A overexpression increased cell proliferation, invasion, sphere formation, CD133, and Sox2 expression, but decreased cell apoptosis; on the contrary, CCT6A knockout exhibited an opposite effect on the above indexes. RNA-sequencing data revealed that the Wnt and Notch pathways were involved in the CCT6A’effect on SCC-15 cell functions. CCT6A positively regulates the Wnt and Notch pathways in SCC-15 and HSC-3 cells. Importantly, it was shown that activation of the Wnt or Notch pathways attenuated the effect of CCT6A knockout on SCC-15 cell survival, invasion, and stemness. CCT6A may promote OSCC malignant behavior and stemness by activating the Wnt and Notch pathways.

Increased Anti-Proliferation Performance of NanoChitosan-Moringa Seeds Extract and Co-Treatment with Doxorubicin in Liver Cancer Cells

Hepatocellular carcinoma (HCC) with high epidemiological report data. Pathogenesis in HCC also involves several signaling pathways. This study aims to evaluate the in vitro activity of Moringa seed NanoChitosan against Hep G2 liver cancer cells and Co-Treatment with Doxorubicin. Initially, nanoparticles were prepared by extracting Moringa seeds, formulating them into nano chitosan, and then characterizing the compounds and particle sizes. The IC50 dose was investigated using the MTT assay. Then, the IC50 dose was confirmed in more detail through immunofluorescence, betatrophin gene, several genes in the Wnt-βcatenin-CyclinD1 proliferation pathway, and the addition of the apoptotic effector Caspase-3 using RT-qPCR analysis. Each treatment used a single dose of NCH-Mosee and co-treatment or combination with 4 μg/ml doxorubicin. The IC50 dose was 994 μg/ml in single treatment and 649 μg/ml in combined treatment with Dox. Hep G2 showed a decrease in the expression level of each parameter measured with increasing single dose and combination treatment (p &lt; 0.050). Histologically, cells shrank, betatrophin expression was inhibited, and luminescence was seen, which decreased with increasing dose. In conclusion, NCH-Mosee with dose-tracking toxicity combined with Dox can suppress the viability of Hep G2 cells.

Enhanced Immunogenicity of Foot-and-Mouth Disease Virus-like Particles Using a Water-in-Oil-in-Water Adjuvant.

Foot-and-mouth disease (FMD) causes significant economic losses, prompting vaccination as a primary control strategy. Virus-like particles (VLPs) have emerged as promising candidates for FMD vaccines but require adjuvants to enhance their immunogenicity. In this study, we evaluated the immunogenicity of a VLP-based vaccine with a water-in-oil-in-water (W/O/W) emulsion adjuvant, named WT. The WT adjuvant was mixed with FMD VLPs to form the VLPs+WT vaccine. The size and stability of the vaccine were analyzed. BALB/c mice were immunized with the VLPs+WT vaccine, and immunological responses were assessed through antibody measurements, cytokine profiling, and gene expression analysis. In addition, splenic lymphocyte proliferation and signaling pathways were examined. The VLPs+WT vaccine exhibited a homogeneous size of 324.60 ± 2.30 nm and a viscosity of 8.76 mPa·s, indicating good stability. Immunized mice showed steady weight gain and no organ abnormalities. Compared to the VLPs group, the VLPs+WT group induced significantly higher levels of specific antibodies that persisted for 12 weeks, similar to the commercial VLPs+ISA201 vaccine. The VLPs+WT vaccine also enhanced the secretion of Th1-related (IgG2a, IFN-γ) and Th2-related (IgG1, IL-4) molecules. WT stimulated splenic lymphocyte proliferation and differentiation, primarily activating B-cell receptor signaling and phagosome pathways. It also upregulated genes associated with MHC and interferon stimulation while promoting the expression of MyD88, PI3K, AKT, p65, and p-p65 proteins. These findings suggest that WT is an effective adjuvant for FMD VLP-based vaccines, with potential for improving vaccine efficacy.