Search Results (10,907)

Chimeric Antigen Receptor (CAR) T cell therapy has achieved high response rates in patients with relapsed or refractory hematologic malignancies. However, comparable efficacy in solid tumors remains limited, partly due to poor CAR T cell persistence and immune-mediated rejection. A major contributor, which has hampered the clinical efficacy of CAR T cells in clinical practice, is the immunogenicity of the murine-derived single-chain variable fragments (scFvs) commonly used in CAR constructs. Cell and humoral immune responses to the murine parts of CARs have been implicated in CAR T cell rejection. Here, we describe the generation and in vitro characterization of humanized CAR T cells targeting prostate-specific membrane antigen (PSMA) on prostate cancer cells, based on two distinct murine scFvs (A5 and D7). Humanization improved the germinality index and successfully preserved CAR surface expression. Functional assays demonstrated that humanized PSMA-CAR T cells retained antigen-specific binding, activation and cytotoxicity, differentiation, exhaustion and cytokine secretion profiles comparable to their murine counterparts. These results support the feasibility of humanization as a strategy to reduce immunogenicity without compromising CAR T cell capabilities, providing a foundation for further in vivo validation in solid tumor settings. Full article

A current problem is the increase in skin damage, including cancer, caused mainly by prolonged exposure to ultraviolet rays from sunlight. Therefore, the aim of this work was to study the photoprotective effect to ultraviolet radiation of phenolics and acetogenic-rich extracts obtained from Annona muricata leaves applied to the skin of rats by means of gene expression in P53 and Rb, involved in tumor processes due to cell damage, in addition to the content of phenols, acetogenins and antioxidant activity present in the extract, which presented a total phenol content of 61.5 mg EAG/100 g of dry sample and flavonoids of 50 mg EQ/100 g. HPLC analysis revealed that the major compound was shikimic acid, followed by gallocatechin and 13 other phenols. DPPH analysis showed an inhibition of 64.37% and FRAP showed a value of 28,880 µmol Eq trolox/mL. The presence of acetogenins was verified by Kedde’s reagent in HPTLC. Histopathological findings in the treated groups (T4, T5) suggest thickening of the epidermis, which could be due to fibroblast proliferation. The results show a higher increase in P53 and Rb gene expression with the tested extracts compared to the positive control group, so it can be concluded that the extracts have positive effects. Full article

Colorectal cancer (CRC) remains a significant global health burden. While early-stage CRC has a high survival rate, most patients are diagnosed with advanced disease, necessitating more effective and less toxic therapeutic targets. This review examines recent advancements, challenges, and future directions in targeted therapies for CRC, focusing on HER inhibitors. We assess the efficacy of monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) and explore strategies to overcome resistance mechanisms. Targeted therapies like cetuximab and panitumumab have improved outcomes for CRC patients with wild-type KRAS. However, resistance mechanisms and intra- and inter-tumour heterogeneity limit their effectiveness. Recent advancements include the development of dual TKIs, antibody/drug conjugates (ADCs), bispecific antibodies, and CAR-T cells against HER family members and other targets that are showing promise in preclinical and clinical trials. Targeted therapies have transformed CRC treatment, but more research is needed to overcome some of the current challenges, such as late diagnosis and the heterogenous nature of CRC, as well as the discovery of more reliable biomarkers for response to the therapy and patient selection. Future research should focus on identifying novel biomarkers of diagnostic, prognostic, and predictive value, developing next-generation inhibitors, drug repurposing, and combining small-molecule targeted therapies with immunotherapy. Such advances could ultimately help increase both the treatment options and outcomes for patients with CRC. Full article

The ketogenic diet (KD), a high-fat, low-carbohydrate diet, causes profound metabolic adaptations that go beyond energy production and affect endocrine function and thyroid hormone regulation. By shifting the body’s primary fuel source from glucose to fatty acids and ketones, the KD alters insulin signaling, inflammation levels and deiodinase activity, which together affect thyroid hormone metabolism. While this metabolic shift offers potential benefits such as improved insulin sensitivity and reduced systemic inflammation, it also raises concerns about reduced triiodothyronine (T3) levels and altered hypothalamic–pituitary–thyroid (HPT) axis dynamics. This review explores the mechanisms by which the KD affects thyroid function, highlighting both the potential therapeutic benefits and associated risks. Special attention is given to how genetic predispositions, gut microbiota composition and sex-based hormonal differences influence thyroid adaptation to a KD. In addition, there are indications that the influence of the KD on cell metabolism could have therapeutic potential in conditions such as autoimmune thyroid diseases and thyroid cancer. Understanding the delicate balance between the benefits and risks of KD for thyroid health is essential for optimizing its clinical applications and defining individual nutritional strategies. Full article

Background: Breast cancer remains a critical public health problem worldwide and is a leading cause of cancer-related mortality. Optimizing clinical outcomes is contingent upon the early and precise detection of malignancies. Advances in medical imaging and artificial intelligence (AI), particularly in the fields of radiomics and deep learning (DL), have contributed to improvements in early detection methodologies. Nonetheless, persistent challenges, including limited data availability, model overfitting, and restricted generalization, continue to hinder performance. Methods: This study aims to overcome existing challenges by improving model accuracy and robustness through enhanced data augmentation and the integration of radiomics and deep learning features from the CBIS-DDSM dataset. To mitigate overfitting and improve model generalization, data augmentation techniques were applied. The PyRadiomics library was used to extract radiomics features, while transfer learning models were employed to derive deep learning features from the augmented training dataset. For radiomics feature selection, we compared multiple supervised feature selection methods, including RFE with random forest and logistic regression, ANOVA F-test, LASSO, and mutual information. Embedded methods with XGBoost, LightGBM, and CatBoost for GPUs were also explored. Finally, we integrated radiomics and deep features to build a unified multimodal feature space for improved classification performance. Based on this integrated set of radiomics and deep learning features, 13 pre-trained transfer learning models were trained and evaluated, including various versions of ResNet (50, 50V2, 101, 101V2, 152, 152V2), DenseNet (121, 169, 201), InceptionV3, MobileNet, and VGG (16, 19). Results: Among the evaluated models, ResNet152 achieved the highest classification accuracy of 97%, demonstrating the potential of this approach to enhance diagnostic precision. Other models, including VGG19, ResNet101V2, and ResNet101, achieved 96% accuracy, emphasizing the importance of the selected feature set in achieving robust detection. Conclusions: Future research could build on this work by incorporating Vision Transformer (ViT) architectures and leveraging multimodal data (e.g., clinical data, genomic information, and patient history). This could improve predictive performance and make the model more robust and adaptable to diverse data types. Ultimately, this approach has the potential to transform breast cancer detection, making it more accurate and interpretable. Full article

Background and Objectives: Laryngeal cancer is a common head and neck tumor burden, with no significant improvements in long term patient survival. Despite the progress of molecular genetics and oncology strategies, there is still a lack of biomarker use in routine clinical practice for early laryngeal cancer screening or diagnosis. miRNAs are explored as promising molecules, that could serve as liquid biopsy. Our goal is to explore the screening potential of miR-31-3p and miR-196a-5p in early- and advanced-stage laryngeal HPV-negative plasma samples. Methods: In this study, 50 plasma samples obtained from early and advanced HPV-negative laryngeal cancer patients were included. The expression levels of mir-31-3p and miR-196a-5p were analyzed via TaqMan RT-qPCR. SPSS v27.0 was used for statistical analysis. Results: For the first time, miR-31-3p and miR-196a-5p were analyzed in plasma samples from early HPV-negative primary LSCC patients. Both circulating miRNAs showed significantly elevated expression levels in early and advanced laryngeal cancer samples. miR-31-3p was significantly associated with T stages (p < 0.001) and N stages (p = 0.009). The ROC analysis revealed that miR-31-3p could significantly discriminate early-stage from advanced-stage LSCC with an AUC of 0.850 (95% CI: 0.743–0.956, p < 0.001) at an RQ cutoff of 2.03, achieving a sensitivity of 95.5% and a specificity of 64%. Nevertheless, miR-196a-5p was found to be significantly overexpressed in early-stage LSCC, which could contribute to the development of its screening potential. For the first time, both miRNAs revealed a significant positive correlation, which indicates that miR-31-3p and miR-196a-5p could coregulate cancerogenesis. Conclusions: In conclusion, the data revealed that miR-31-3p has greater potential as an LSCC screening marker in comparison to miR-196a-5p. Still, miR-196a-5p also showed promising results in early-stage laryngeal cancer monitoring. The utilization of circulating miR-31-3p or miR-196a-5p analysis could enable liquid biopsy approaches, with results potentially informing treatment monitoring strategies, personalized oncological protocols, and early diagnosis. These advancements could ultimately benefit patient outcomes by improving laryngeal organ preservation and survival rates. Full article

Background: A number of viruses are oncogenic. These include the human papilloma virus (HPV), Epstein–Barr virus (EBV), Kaposi sarcoma human herpes virus 2/human herpes virus 8 (KSHHV/HHV8), hepatitis B virus, (HBV), hepatitis C virus (HCV), Merkel cell polyoma virus (McPyV), and the human T-cell leukemia virus type 1 (HTLV- 1). These viruses cause malignancies ranging from carcinomas, sarcomas, lymphomas, to leukemias. This review aims to study the effects and efficacy of vaccines against these viruses and the cancers they cause in their prevention and treatment. Methods: The literature in the past 30 years was searched employing Scopus and Google Scholar using the keywords “oncogenic viruses, HPV, EBV, KSHHV, HHV8, Polyoma virus, HTLV-1, COVID-19, carcinoma, sarcoma, lymphoma, leukemia, anti-virus vaccines”. Results: Prophylactic vaccines against the HPV and HBV are highly effective in preventing and reducing the incidence of uterine cervical and hepatocellular carcinomas. Prophylactic vaccines against other oncogenic viruses have been less successful, though efficacious in some experimental animals. Therapeutic vaccines are still mostly under evaluation and development. Conclusions: Identification of oncogenic viruses has rendered anti-viral vaccines conspicuous tools for preventing and treating cancers they cause. Many endeavors for the development of such vaccines have been met with limited success, apart from the very effective anti-HPV and anti-HBV vaccines in universal vaccination programs. With the development of new vaccine technologies, it is hoped that effective vaccines against other oncogenic viruses will be developed in the future. Full article

Background: Ovarian cancer ranks as the fifth leading cause of cancer-related mortality among women worldwide. Owing to its insidious onset and lack of early symptoms, over 70% of patients are diagnosed at advanced stages. Methods: This study provides a comprehensive transcriptomic analysis of tumor-infiltrating CD4⁺ T cells in ovarian cancer, highlighting regulatory T cells (Tregs) as the dominant subset. By integrating seven multicenter ovarian cancer single-cell RNA-seq datasets, a robust metadata resource was created for detailed Treg investigation. Using the BayesPrism algorithm, Treg scores from TCGA bulk RNA-seq data enabled patient stratification into high and low Treg groups. These findings were further validated through survival analyses across five independent bulk RNA-seq cohorts. We experimentally validated the inhibitory role of Tregs in modulating CD8⁺ T-cell activity in ovarian cancer. Results: We conducted an in-depth investigation into the clustering patterns, differentiation trajectories, intercellular interactions, and enrichment profiles of tumor-infiltrating T cells in ovarian cancer. Among the seven functionally defined subclusters (C1–C7), we delineated two distinct “terminal states” of CD4⁺ T-cell differentiation: FOXP3⁺ regulatory T cells and STMN1⁺ proliferative T cells. The OCSCDs dataset comprises seven datasets totaling 137,648 single cells. Using the TCGA dataset, we quantified the proportion of tumor-infiltrating regulatory T cells (Tregs) in OCSCDs through the BayesPrism algorithm and performed survival analyses across five independent bulk RNA-seq datasets from different platforms. Conclusions: Our results establish a framework for studying Treg biology in ovarian cancer and these cells may be become an important point in the field of immunotherapy. Full article

Despite improved diagnostic and treatment protocols, cancer remains a leading cause of morbidity and mortality globally. There are increasing rates of certain cancer types, including the highly drug-resistant colorectal cancer, in younger population cohorts. Therapeutic advances in oncology have led to the application of immunotherapy-based agents, including checkpoint inhibitors, antibodies, and adoptive cell therapies. Such immunotherapy approaches are greatly hindered by the tumour microenvironment and lack of specificity. Therapeutic vaccines are an innovative and rapidly advancing area of oncology, having potential for application as mono- and combined therapy in clinical settings, offering long term efficacy against disease recurrence. Advances in vaccine production using gene editing and bioprocessing techniques allows for novel vaccine types, including protein-based subunit vaccines, virus-like particle vaccines, and viral vector- and nucleic acid-based (RNA and DNA) vaccines. Cancer vaccines are designed to deliver specific tumour antigens, which activate anti-cancer cytotoxic T cells and helper T cells to produce immune memory, providing long term anti-cancer action. When coupled with advances in machine learning and artificial intelligence, anti-cancer vaccines may revolutionise oncology protocols and improve patient prognosis. This review aims to discuss current immunotherapy options in cancer treatment and recent advances in anti-cancer vaccine modalities. Full article

The breast microbiome remains stable throughout a woman’s life. The breast is not a sterile organ, and its microbiota exhibits a distinct composition compared to other body sites. The breast microbiome is a community characterized by an abundance of Proteobacteria and Firmicutes, which represent the result of host microbial adaptation to the fatty acid environment in the tissue. The breast microbiome demonstrates dynamic adaptability during lactation, responding to maternal physiological changes and infant interactions. This microbial plasticity modulates local immune responses, maintains epithelial integrity, and supports tissue homeostasis, thereby influencing both breast health and milk composition. Disruptions in this balance, the dysbiosis, are closely linked to inflammatory breast conditions such as mastitis. Risk factors for breast cancer (BC) include genetic mutations, late menopause, obesity, estrogen metabolism, and alterations in gut microbial diversity. Gut microbiota can increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties. Perturbations of this set of bacterial genes and metabolites, called the estrobolome, increases circulating estrogens and the risk of BC. Fusobacterium nucleatum has recently been associated with BC. It moves from the oral cavity to other body sites hematogenously. This review deals with the characteristics of the breast microbiome, with a focus on F. nucleatum, highlighting its dual role in promoting tumor growth and modulating immune responses. F. nucleatum acts both on the Wnt/β-catenin pathway by positively regulating MYC expression and on apoptosis by inhibiting caspase 8. Furthermore, F. nucleatum binds to TIGIT and CEACAM1, inhibiting T-cell cytotoxic activity and protecting tumor cells from immune cell attack. F. nucleatum also inhibits T-cell function through the recruitment of myeloid suppressor cells (MDSCs). These cells express PD-L1, which further reduces T-cell activation. A deeper understanding of F. nucleatum biology and its interactions with host cells and co-existing symbiotic microbiota could aid in the development of personalized anticancer therapy. Full article

Purpose of Review: In approximately 10–15% of patients with prostate cancer (PCa), pathological lymph node metastases (pN1) are detected at radical prostatectomy (RP). The aim of this review is to describe the various treatment options for pN1 patients, with a focus on the most recent evidence reported in the literature. Evidence Synthesis: Due to the lack of prospective studies, several retrospective analyses were conducted according to different types of treatment. Most common strategies are represented by observation plus early salvage radiotherapy (RT) in case of PSA rising, adjuvant androgen deprivation therapy (ADT) alone, or adjuvant RT with or without ADT. Patients with pN1 disease and favorable disease characteristics (lower T stage and ISUP ≤ 2 at RP, <3 metastatic nodes at pathology) have a similar overall mortality risk if observed with PSA testing and eventual use of early salvage RT compared to patients directly treated with adjuvant RT with or without ADT. While conflicting results in terms of survival benefit were reported for the use of adjuvant ADT only, several studies showed an overall survival benefit in patients with pN1 disease treated with adjuvant RT when high-risk features (such as an increasing number of positive nodes, ISUP > 3) were detected at RP. Lastly, few studies analyzed the rate of adverse events following adjuvant ADT or RT, leaving the issue of treatment-related side effects still open. Summary: There is no clearly established standard of care for men with pN1 PCa, and disease characteristics should guide the choice of optimal post-operative management for these patients. Prospective data and clinical trials are clearly needed to define the most effective therapeutic strategy. Full article

Papillary thyroid cancer (PTC) is linked to obesity, but the biological mechanisms that may explain this connection have been only partially described. Potential factors that combine overweight/obesity with this cancer should be searched for in the immune pathways and chronic inflammation onset. In this study, we evaluated the role of the immune system in patients affected by PTC and stratified them according to Body Mass Index (BMI). An analysis of the expression profiles of >700 immune-related genes was performed in 36 PTCs, subdivided into four categories: underweight (A), normal weight (B), overweight (C), and subjects living with obesity (D). B was considered a reference category. In our study, the immune microenvironment of PTCs did not seem strongly influenced by BMI. However, based on the interaction from in silico protein–protein analysis, we found that the dysregulation profiles of groups A or D were similar as concerns pathways involved in T-cell differentiation, macrophage activation, regulation of the cell cycle, and senescence processes. Furthermore, we found significant downregulation of HMGB1 in the A and D categories, with upregulation of ARG2 in the D category. Although further studies are necessary, these genes may provide an opportunity to better understand immunometabolism in thyroid cancer. Full article

Background: Cervical cancer is considered to be a global health challenge, particularly in low- and middle-income countries. Romania reports one of the highest burdens in Europe due to limited access to screening and HPV vaccination. Chemoradiotherapy is standard for locally advanced disease, but the impact on quality of life (QoL) for a low- and middle-income population has not yet been explored. This study aims to evaluate the effect of chemoradiotherapy on the QoL of cervical cancer survivors in the Romanian population. Methods: This prospective observational study included 111 patients with stage I–IV cervical cancer undergoing chemoradiotherapy. QoL was assessed using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire before, during, and after treatment. Demographic and clinical data were collected. The statistical analyses included t-tests, ANOVA, and linear mixed-effects models to evaluate changes over time and the influence of sociodemographic and treatment-related factors. Results: FACT-G scores significantly increased after treatment, with improvements in physical and functional well-being. Better before-treatment QoL was associated with urban residence, early-stage disease, marital status, and higher education. Among treatment toxicities, only nausea had a statistically significant negative effect on QoL during treatment, while other toxicities showed no significant impact. Conclusions: Chemoradiotherapy in cervical cancer patients was not associated with a substantial deterioration in quality of life during treatment and was followed by significant improvement after therapy completion. These findings highlight a favorable short-term QoL trajectory and emphasize the need for longitudinal studies to assess whether such benefits are maintained over the long term. Full article

Objective: Segmentectomy has recently been accepted as a valid anatomical resection in the early stages non-small cell lung cancer, even if different segment numbers and combinations are included. The aim of this study is to analyze prognostic factors in patients who underwent segmentectomy, with particular attention to segment numbers and characteristics. Methods: Characteristics of patients who underwent uniportal VATS segmentectomy from 1/01/2017 to 31/12/2022 were reviewed and retrospectively analyzed. Patients with nodal involvement and/or distant metastases, tumors > 4 cm, who received neoadjuvant treatment and those who underwent completion lobectomy were excluded. Operatory and pathological reports were reviewed to collect data on surgical characteristics and pathology. Segmentectomies were categorized according to numbers of resected segments as single/multiple. Clinico-pathological characteristics, number of segments and nodal parameters were associated to overall survival (OS) using Kaplan–Meier curves. The log-rank test was used to assess differences between subgroups. A multivariable model was built using Cox-regression analysis including variables with p-values < 0.10 at univariable analysis. Results: The final analysis was conducted on 95 patients who met the inclusion criteria. Multiple segmentectomies were performed in 47 (49.4%) cases, of which 37 (39%) were complex cases. At univariable analysis, tumor size ≤ 2 cm (p = 0.006, HR:0.260; 95%CI 0.099–0.686) significantly correlated with OS: patients with pT ≤ 2 cm presented a 5YOS of 85.3% vs. 48.3% of patients with pT >2 cm, with multivariable-confirmed tumor size ≤ 2 cm as an independent prognostic factor (p = 0.004, HR:0.204; 95%CI 0.069–0.607). Considering the tumor size according to number of resected segments, patients who underwent single segmentectomy presented a significantly better survival for pT ≤ 2 cm: 5YOS 91.7% vs. 41.3% for pT > 2 cm (p = 0.001). Conversely, no significant differences in OS were present in multiple segmentectomy: 5YOS 78.9% vs. 77.1% (p = 0.700). Similarly, pT ≤ 2 cm correlated with OS in complex segmentectomy (p = 0.010) but not in simple segmentectomy (p = 0.098). Conclusions: Our study confirms the distinct prognosis associated with tumor dimensions in patients who underwent uniportal VATS segmentectomy. We confirmed the tumor dimension cut-off of 2 cm as a robust prognosticator in single and complex segmentectomies. However, no significant differences in survival were observed in multiple and simple segmentectomies, implying that tumors larger than 2 cm may necessitate extended resections. Full article

Background: The incidence of early-onset gastric cancer (EOGC) has been steadily increasing in recent years. However, the efficacy of adjuvant chemotherapy (AC) in this population remains unclear. This study aimed to investigate the clinicopathological characteristics, survival outcomes, and efficacy of AC between EOGC and average-onset gastric cancer (AOGC) patients. Methods: Patients with stage II–III gastric adenocarcinomas who underwent curative D2 gastrectomy at the Sixth Affiliated Hospital of Sun Yat-sen University from January 2014 to December 2021 were enrolled and classified into two groups: EOGC (≤45 years) and AOGC (>45 years) groups. Clinicopathological characteristics, overall survival (OS), and efficacy of AC were compared between the two groups. Western and East Asian cohorts were included as external validation sets to compare the efficacy of AC between different age groups. Results: Compared to AOGC, EOGC patients exhibited a higher proportion of females, poor differentiation, diffuse Lauren type, middle-third GC, perineural invasion (PNI), and receipt of AC. Univariate and multivariate analyses identified that T stage, N stage, PNI, and AC were independent prognostic factors for OS. After balancing the baseline characteristics between patients who received AC and those who did not, the Kaplan–Meier survival curves indicated that AC significantly improved OS across all patients. Further subgroup analysis revealed a survival benefit of AC in AOGC patients, whereas no significant survival difference was observed in the EOGC subgroup. Consistently, external validation in both Western and East Asian cohorts confirmed that AC did not confer a survival advantage in EOGC patients. Conclusions: EOGC exhibits aggressive pathological characteristics, and chemotherapy does not consistently improve survival in EOGC patients. Full article