Cancer Research Articles

Assessing Postoperative Quality of Life and Psychological Impact of Free Flap Reconstruction in Advanced Head and Neck Cancer Patients

Assessing Postoperative Quality of Life and Psychological Impact of Free Flap Reconstruction in Advanced Head and Neck Cancer Patients

Prognostic Outcomes and Predictive Factors in Non-Metastatic Castration-Resistant Prostate Cancer Patients Not Treated with Second-Generation Antiandrogens

Background/Objectives: Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and high-risk features frequently have progression to life-threatening metastasis without second-generation antiandrogens. This study investigated nmCRPC patients for the survival and prognostic factors from a cohort before the approved use of second-generation antiandrogens. Methods: From March 2016 to January 2021, 326 patients treated with second-generation antiandrogens for metastatic castration-resistant prostate cancer (mCRPC) or metastatic castration-sensitive prostate cancer were retrieved. Forty-four patients experiencing nmCRPC with no use of second-generation antiandrogens were reviewed. The prognostic factors, at initial diagnosis or at nmCRPC, associated with metastasis-free survival (MFS) and overall survival (OS) were analyzed. Results: The median follow-up time after nmCRPC was 46 months. The median PSA level at nmCRPC was 2.7 ng/mL. Thirty-eight of forty-four patients with nmCRPC had a PSA doubling time (PSADT) of 10 months or shorter, and the median PSADT was 4 months. The median OS from nmCRPC was 53 months, and the median interval for nmCRPC patients progressing to mCRPC was 20 months. Upon univariate analysis, PSADT < 10 months (p = 0.049) and the very-high-risk group at the initial diagnosis (p = 0.043) were associated with significantly shorter post-nmCRPC MFS. The very-high-risk group (p = 0.031) was associated with significantly worse post-nmCRPC OS. In terms of survivals from the initial diagnosis of prostate cancer, Gleason grade ≥ 8 was the only independent factor with MFS and OS. Conclusions: Without second-generation antiandrogens, nmCRPC patients with PSADT <10 months and in the initial very-high-risk group developed subsequent mCRPC in a significantly faster fashion. Patients of the very-high-risk group had shorter survival rates after nmCRPC.

Mechanisms of tamoxifen resistance: insight from long non-coding RNAs

Breast cancer(BC) is the second most prevalent tumor in the world and one of the most lethal tumors in women. Patients with estrogen receptor-positive breast cancer can obtain significant advantages from endocrine therapies including tamoxifen, aromatase inhibitors, and others. However, the development of primary or acquired drug resistance ultimately leads to discontinuation of treatment with adverse consequences for breast cancer patients, and the underlying mechanisms have not been fully elucidated. Long non-coding RNAs (lncRNAs) play pivotal roles in orchestrating fundamental biochemical and cellular processes. They exert regulatory control over various processes including epigenetics, gene transcription, post-transcriptional modifications, and translation. Additionally, they influence key biological events like cell cycle progression, cell differentiation, and development. For the past few years, the relationship between lncRNAs and endocrine resistance has gained increasing attention, leading to a surge in related studies. LncRNAs mediate tamoxifen resistance in cancer by utilizing a variety of molecular mechanisms, including enhanced estrogen receptor (ER) signaling, inhibition of apoptosis, autophagy, exosome-mediated transfer, epigenetic alterations, epithelial-to-mesenchymal transition, and acting as competitive endogenous RNAs(ceRNAs). In this comprehensive review, we systematically summarize the critical role and intricate molecular mechanisms by which lncRNAs influence the development of tamoxifen resistance in breast cancer. Furthermore, we propose the potential clinical significance of lncRNAs as innovative therapeutic targets and prognostic biomarkers for breast cancer.

Tumour reoxygenation after intratumoural hydrogen peroxide (KORTUC) injection: a novel approach to enhance radiosensitivity

BackgroundKORTUC (0.5% hydrogen peroxide (H2O2) in 1% sodium-hyaluronate) releases cytotoxic levels of H2O2 in tissues after intratumoural injection. High levels of tumour control after radiotherapy plus KORTUC are reported in breast cancer patients. Here, we use human xenograft models to test the hypothesis that oxygen microbubbles released post-KORTUC are effective in modifying the hypoxic tumour microenvironment.Methods and materialsPimonidazole and Image-iT™ Red (live hypoxia marker) were utilised to assess dose-dependent changes in hypoxia post-H2O2 in HCT116 and LICR-LON-HN5 spheroids. Using a dual 2-nitroimidazole-marker technique and phospho-ATM we evaluated changes in hypoxia and reactive oxygen species (ROS) respectively, in HCT116 and LICR-LON-HN5 xenografts following intratumoural KORTUC.ResultsA significant reduction in Image-iT™ Red fluorescence was observed in spheroids 1 h post-H2O2 at ≥1.2 mM, maintained at 24 h. Ultrasound demonstrated sustained release of oxygen microbubbles within tumours, 1 h post-KORTUC. Hypoxia markers demonstrated significant tissue reoxygenation in both models post-KORTUC and significantly increased phospho-ATM foci reflecting increased ROS production.ConclusionIntratumoural KORTUC represents a novel oxygen delivery method, which can be exploited to enhance radiation response. If efficacy is confirmed in the ongoing phase 2 breast trial it could improve treatment of several tumour types where hypoxia is known to affect radiotherapy outcomes.

5-Fluorouracil induces apoptosis in nutritional deprived hepatocellular carcinoma through mitochondrial damage.

5-Fluorouracil (5-FU) is the leading chemotherapeutic drug used to treat hepatocellular carcinoma, one of the major cancer diseases after atherosclerosis. Because of chemo-resistance, the success rate of treatment declines with time due to continuous drug exposure. Though autophagy induction is majorly responsible for acquired resistance, the exact role of this evolutionary conserved mechanism is unknown in cancer cell survival and suppression. The usual practice involves the combinatorial use of chemotherapeutic drugs with autophagy inhibitors like Chloroquine and Bafilomycin A, while neglecting the side effects caused by autophagy impairment in healthy cells. Starvation is a well-known physiological inducer of autophagy. In this study, by caloric modulation, we tried to circumvent the resistance imposed by prolonged drug exposure and investigated the effect of 5-FU in nutrient-sufficient and deficient conditions. Our findings show a substantial correlation between autophagy and increased cancer cell death in the presence of 5-FU, with negligible effects on normal cells. Experimental data revealed that nutritional deprivation augmented cell death in the presence of 5-FU through mitochondrial membrane damage and excessive reactive oxygen species (ROS) production, initiating apoptosis. Lipidation study also unveiled that under such combinatorial treatment cellular metabolism shifts from glucose to lipid biosynthesis. Overall, our experimental findings suggest that nutritional deprivation in combination with chemotherapeutic medication can be a new effective strategy to control hepatocellular carcinoma.

Impact of the COVID-19 Prioritization Recommendations on Pathological Stages of Urologic Malignancies: A Real-World Analysis at a High-Volume Referral Institution

Background: In response to the COVID-19 pandemic, the European Association of Urology (EAU) Guidelines defined priority groups to guide the prioritization of surgery for urological malignancies. The objective of this study was to evaluate the impact of the COVID-19 prioritization recommendations on tumor pathological characteristics in a real-world setting at our academic referral institution. Methods: We compared baseline and pathological tumor features of all patients with urological malignancies treated during the pandemic period (2020–2021) versus in the post-pandemic period (2022–2023). Our institution adhered to the international recommendations and prioritized those cases defined as “high-risk”. Results: Data from 9196 patients treated for urological malignancies were reviewed and grouped according to period of surgery (4401 in the pandemic period vs. 4785 in the post-pandemic period). The overall number of surgical procedures was comparable for all diseases except for the number of radical prostatectomies (1117 vs. 1405; p = 0.03) and partial nephrectomies (609 vs. 759; p = 0.02), which were significantly lower in the pandemic period. Regarding tumor pathological features, none of the recorded variables were found to differ according to period of surgery, including disease stage, tumor grading, presence of necrosis, lymphovascular invasion, and histological variants. Conclusions: A correct policy of prioritization of oncological pathologies during emergency periods and a centralization of oncological cases in reference centers reduce the possible risk of worsening cancer disease features related to the reorganization of healthcare resources.

The effect of knowledge and person-related factors on breast cancer susceptibility genes (BRCA1/2) testing perception in Turkish women.

Genetic testing for breast cancer susceptibility genes (BRCA1/2) plays a pivotal role in risk assessment and preventive interventions. However, individuals' awareness, knowledge, and attitudes toward genetic testing can vary across different societies. This study focuses on understanding Turkish women's knowledge, perceptions, and attitudes toward BRCA1/2 testing, considering demographic factors and awareness. In this cross-sectional study, 301 Turkish participants, including breast/ovarian cancer patients and their first-degree relatives, were surveyed. Information on sociodemographics, cancer history, awareness, knowledge, and perceptions was collected. The study aimed to assess knowledge levels about breast cancer inheritance and BRCA1/2 testing, describe perspectives about testing in women with a family history of breast or ovarian cancer, and determine associations between knowledge, personal factors, anxiety, and genetic testing perspectives. Results showed a wide range in correct responses (31.6%-96.7%) for knowledge items. No significant relationship between knowledge levels and positive perception was observed. However, participants answering a specific question incorrectly showed higher negative perceptions. While most participants recognized the benefits of genetic testing, concerns centered around passing the genes to future generations. Participants who were younger, more educated, had higher income, were employed, at an earlier disease stage, and were social media users demonstrated more positive attitudes. Negative perceptions were higher among younger patients, physicians, and healthcare professionals. Interestingly, anxiety in cancer patients did not correlate with either positive or negative perceptions. In conclusion, this study identifies participant-related factors influencing perceptions of hereditary genetic tests. Understanding these factors and addressing associated issues can enhance the utilization of genetic testing and promote preventive oncology applications.

Tissue-based Profiling Techniques to Achieve Precision Medicine in Cancer: Opportunities and Challenges in Melanoma.

Immunotherapies targeting the programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) checkpoint receptors have revolutionised the treatment of metastatic melanoma. However, half of treated patients do not respond to or eventually progress on standard therapies and many experience adverse events as a result of drug toxicity. The identification of accurate biomarkers of clinical outcomes are required in order to move away from the one-size-fits-all treatment approach of standard clinical practice, and towards a more personalised approach to enable the administration of the optimal therapy for any given patient and further improve patient outcomes. Recent clinical trials have proven the potential of multi-omics analyses, including genomic, gene expression, and tumour immune profiling, of patients' tumour biopsies, to predict a patient's response to subsequently administered immunotherapies. However, reproducibility of such multi-omics analyses, tissue requirements, and clinical validation have limited the practical application of these approaches in routine clinical workflows. In this review, we discuss several pivotal tissue-based profiling techniques that can be utilised to identify potential genomic, transcriptomic and immune biomarkers predictive of clinical outcomes following treatment with immune checkpoint inhibitors in melanoma. Furthermore, we highlight the key opportunities and challenges associated with the use of each of these techniques. The development and implementation of multimodal predictive models which combine data derived from these various methods is the future for achieving precision medicine for patients with melanoma.

Effect of extending the period from oral administration of 5-aminolevulinic acid hydrochloride to photodynamic diagnosis during transurethral resection for non-muscle invasive bladder cancer on diagnostic accuracy and safety: a single-arm multicenter phase III trial.

In Japan, the authorized period (2-4 h) between oral administration of 5-aminolevulinic acid hydrochloride (5-ALA) and transurethral resection for non-muscle invasive bladder cancer (NMIBC) may restrict photodynamic diagnosis (PDD) usage. Therefore, this prospective, single-arm, phase III study aimed to evaluate the diagnostic accuracy and safety of PDD at an extended administration period (4-8h). From January 2022 to May 2023, 161 patients with NMIBC were enrolled from eight hospitals. The primary endpoint was the blue light (BL) sensitivity of pathologically positive biopsies. The secondary endpoints were a comparison of the specificity and positive and negative prediction rates under BL and white light (WL) conditions. A total of 1242 specimens comprising 337 histological NMIBC specimens were analyzed. BL-sensitivity was 95.3%. Its lower limit of 95% confidence interval (92.4-97.3%) exceeded the threshold (70%) of non-inferiority to authorized usage. Sensitivity and specificity were significantly higher and lower for BL than those for WL (95.3% vs. 61.1%, P < 0.001; 52.7% vs. 95.2%, P < 0.001), respectively. The positive and negative predictive rates were significantly lower and higher for BL than those for WL (42.9% vs. 82.7%, P < 0.001; 96.8% vs. 86.8%, P < 0.001), respectively. Of the 145 patients receiving 5-ALA, 136 (93.8%) and 75 (51.7%) experienced 377 adverse events and 95 adverse reactions, respectively, most of which were grade 1 or 2. For extended period, the efficacy of PDD for NMIBC was similar to that of authorized period, in terms of higher sensitivity and lower specificity compared with WL, and the safety was acceptable.

Exploring the Impact of Molecular Hydrogen Therapy on Oxidative Stress in Bleomycin-Induced Idiopathic Pulmonary Fibrosis: A Research Protocol

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is an intensifying respiratory disorder triggered by bleomycin in cancer patients, characterized by its lack of a definitive remedy. Bleomycin induces mitochondrial leakage and elevates Reactive Oxygen Species (ROS) in the pulmonary cavity, causing a reduction in glutathione (GSH), a vital lung antioxidant. This reduction in GSH levels, coupled with ROS's inactivation of the tumor suppressor gene p53, increases the chance of developing fibrosis. Although no antioxidant treatments that currently target these effects, Molecular Hydrogen Therapy (MHT) has proven effective in mitigating ROS in diseases like Chronic Obstructive Pulmonary Disease (COPD). This study aims to explore the impact of bleomycin-induced IPF on ROS and p53, investigating MHT as a potential treatment to alleviate oxidative stress in fibrosis. Methods: The experimental design includes four groups of mice, two receiving bleomycin injections and two receiving a control buffer solution. Within each subgroup, one group will undergo MHT, while the other will receive sterile air. Bronchoalveolar lavage will be used to measure GSH levels before and after MHT, and RNA sequencing will monitor p53 activity in all treatment and control groups. Results: Anticipated outcomes include elevated GSH levels in the MHT-treated bleomycin group, indicating an antioxidative effect. Consequently, improved p53 activity is expected compared to controls. Discussion: Anticipated results, based on existing literature, suggest that MHT enhances antioxidant defenses and modulates p53 activity, thereby reducing oxidative damage and fibrotic remodeling. These findings highlight the potential of MHT as a therapeutic intervention for IPF, with broader implications for managing other oxidative stress-mediated lung diseases. However, further research, including preclinical studies and clinical trials, is needed to validate these anticipated findings and ensure the long-term safety and efficacy of MHT in clinical practice. Conclusion: The study aims to replicate findings in human populations and proposes a paradigm shift in treating such diseases by addressing the root cause, ROS.

Therapeutic advantage of combinatorial CAR T cell and chemo-therapies.

Chimeric antigen receptor (CAR) T cell therapies have transformed outcomes for many patients with hematological malignancies. However, some patients do not respond to CAR T cell treatment, and adapting CAR T cells for solid and brain tumors has been met with many challenges including a hostile tumor microenvironment and poor CAR T cell persistence. Thus, it is unlikely that CAR T cell therapy alone will be sufficient for consistent, complete tumor clearance across cancer patients. Combinatorial therapies of CAR T cells and chemotherapeutics are a promising approach for overcoming this as chemotherapeutics could augment CAR T cells for improved anti-tumor activity or work in tandem with CAR T cells to clear tumors. Herein, we review efforts towards achieving successful CAR T cell and chemical drug combination therapies. We focus on combination therapies with approved chemotherapeutics as these will be more easily translated to the clinic, but also review non-approved chemotherapeutics and drug screens designed to reveal promising new CAR T cell and chemical drug combinations. Together, this review highlights the promise of CAR T cell and chemotherapy combinations with specific focus on how combinatorial therapy overcomes challenges faced by either monotherapy and supports the potential of this therapeutic strategy to improve outcomes for cancer patients. Significance Statement Improving currently available CAR T cell products via combinatorial therapy with chemotherapeutics has the potential to drastically expand the types of cancers and number of patients that could benefit from these therapies when neither alone has been sufficient to achieve tumor clearance. Herein, we provide a thorough review of the current efforts towards studying CAR T and chemotherapy combinatorial therapies and provide perspectives on optimal ways to identify new and effective combinations moving forward.

Harnessing the power of AI in precision medicine: NGS-based therapeutic insights for colorectal cancer cohort

PurposeDeveloping innovative precision and personalized cancer therapeutics is essential to enhance cancer survivability, particularly for prevalent cancer types such as colorectal cancer. This study aims to demonstrate various approaches for discovering new targets for precision therapies using artificial intelligence (AI) on a Polish cohort of colorectal cancer patients. MethodsWe analyzed 71 patients with histopathologically confirmed advanced resectional colorectal adenocarcinoma. Whole exome sequencing was performed on tumor and peripheral blood samples, while RNA sequencing (RNAseq) was conducted on tumor samples. We employed three approaches to identify potential targets for personalized and precision therapies. First, using our in-house neoantigen calling pipeline, ARDentify, combined with an AI-based model trained on immunopeptidomics mass spectrometry data (ARDisplay), we identified neoepitopes in the cohort. Second, based on recurrent mutations found in our patient cohort, we selected corresponding cancer cell lines and utilized knock-out gene dependency scores to identify synthetic lethality genes. Third, an AI-based model trained on cancer cell line data was employed to identify cell lines with genomic profiles similar to selected patients. Copy number variants and recurrent single nucleotide variants in these cell lines, along with gene dependency data, were used to find personalized synthetic lethality pairs. ResultsWe identified approximately 8,700 unique neoepitopes, but none were shared by more than two patients, indicating limited potential for shared neoantigenic targets across our cohort. Additionally, we identified three synthetic lethality pairs: the well-known APC-CTNNB1 and BRAF-DUSP4 pairs, along with the recently described APC-TCF7L2 pair, which could be significant for patients with APC and BRAF variants. Furthermore, by leveraging the identification of similar cancer cell lines, we uncovered a potential gene pair, VPS4A and VPS4B, with therapeutic implications. ConclusionOur study highlights three distinct approaches for identifying potential therapeutic targets in cancer patients. Each approach yielded valuable insights into our cohort, underscoring the relevance and utility of these methodologies in the development of precision and personalized cancer therapies. Importantly, we developed a novel AI model that aligns tumors with representative cell lines using RNAseq and methylation data. This model enables us to identify cell lines closely resembling patient tumors, facilitating accurate selection of models needed for in vitro validation.

Mutations of the Cx43 Gene in Non-Small Cell Lung Cancer: Association with Aberrant Localization of Cx43 Protein Expression and Tumor Progression

Background and Objectives: The Connexin43 (Cx43) gene is a suspected tumor suppressor gene, as re-expressed wild-type Cx43 genes reduce the malignancy potential of tumor cells. However, the role of Cx43 gene expression in human lung tumorigenesis remains unclear. Materials and Methods: Tumor tissues from 165 primary lung cancer patients were collected to study Cx43 protein expression and gene mutations using immunohistochemistry and direct DNA sequencing. In addition, Cx43 genes with or without mutations were transfected to CL-3 human lung cancer cells to confirm the function of these mutant forms of the Cx43 gene. Results: Aberrant localization of Cx43 protein in the nucleus and cytoplasm of tumor cells was detected in 14 out of 165 non-small cell lung cancer (NSCLC) patients. Mutations in the Cx43 gene were also found in patients with aberrant Cx43 localization, and transfection of these mutant genes into lung cancer cells enhanced their proliferation. Conclusions: To our knowledge, this is the first study to demonstrate Cx43 gene mutations in human lung neoplasm, supporting the hypothesis that Cx43 may function as a tumor suppressor in some lung cancer patients. Additionally, the findings suggest an association between aberrant localization of Cx43 protein expression and tumor progression.

Infertility treatment and offspring blood pressure-a systematic review and meta-analysis.

Studies have inconsistently observed that children conceived by IVF or ICSI have higher blood pressure compared to children not conceived by these ARTs. The aim was to perform a systematic review and meta-analysis of blood pressure measures of offspring conceived by ART and those conceived naturally. Resolving the suspicion of ART as a risk factor of higher blood pressure, and therefore of heart disease, has public health and clinical implications. A biomedical librarian searched the Embase, PubMed, and Web of Science databases. Searches were limited to records published in English since 1978. Grey literature was searched. Inclusion criteria were humans born via infertility treatment (vs no treatment) who underwent a blood pressure assessment. Exclusion criteria were non-human participants, non-quantitative studies, absence of a control group, and specialty populations (e.g. cancer patients only). Two reviewers independently screened each record's title and abstract and full text using Covidence, extracted data using Excel, and assessed bias using the National Heart, Lung, and Blood Institute's Quality Assessment Tool for cohort studies. Of 5082 records identified, 79 were included in the systematic review and 36 were included in the meta-analysis of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in ART and non-ART groups. Overall, 34 reports including 40 effect sizes from 25 unique cohorts, compared blood pressure between ART (N = 5229) and non-ART (N = 8509, reference) groups with no covariate adjustment. No standardized mean differences (SMD) in SBP (0.06 per SD of mmHg, 95% CI = -0.05, 0.18) or DBP (0.11, 95% CI = -0.04, 0.25) by treatment were found, but the heterogeneity was considerable (I2=76% for SBP and 87% for DBP). Adjusted analyses were presented in 12 reports, representing 28 effect sizes from 21 unique cohorts (N = 2242 treatment vs N = 37590 non-treatment). Studies adjusted for varied covariates including maternal (e.g. age, education, body mass index, smoking, pregnancy complications), child (e.g. sex, age, physical activity, BMI, height), and birth characteristics (e.g. birth weight and gestational age). Adjusted results similarly showed no SMD for SBP (-0.03, 95% CI = -0.13, 0.08) or DBP (0.02, 95% CI = -0.12, 0.16), though heterogeneity remained high (I2 = 64% and 86%). Funnel plots indicated a slight publication bias, but the trim and fill approach suggested no missing studies. Removal of five studies which adjusted for birth outcomes (potentially over-adjusting for mediators) made no material difference. Type of treatment (e.g. IVF vs ICSI), period effects by birth year (≤2000 vs >2000), offspring age group (<8, 8-14, 15+), or study location (e.g. Europe) did not modify the results. In conclusion, conception by ART was not associated with offspring blood pressure in a meta-analysis, although considerable heterogeneity was observed. Given the increasing number of children born using ART, perpetuating a difference in blood pressure would mean unnecessary risk screening for many children/adults on a population level. At a clinical level, couples considering these reproductive technologies have some reassurance that there is no evidence of strong vascular 'programming' due to the techniques used. PROSPERO No. CRD42022374232.

Applicability of epigenetic age models to next-generation methylation arrays

BackgroundEpigenetic clocks are mathematical models used to estimate epigenetic age based on DNA methylation at specific CpG sites. As new methylation microarrays are developed and older models discontinued, existing epigenetic clocks might become obsolete. Here, we explored the effects of the changes introduced in the new EPICv2 DNA methylation array on existing epigenetic clocks.MethodsWe tested the performance of four epigenetic clocks on the probeset of the EPICv2 array using a dataset of 10,835 samples. We developed a new epigenetic age prediction model compatible across the 450 k, EPICv1, and EPICv2 microarrays and validated it on 2095 samples. We estimated technical noise and intra-subject variation using two datasets with repeated sampling. We used data from (i) cancer survivors who had undergone different therapies, (ii) breast cancer patients and controls, and (iii) an exercise-based interventional study, to test the ability of our model to detect alterations in epigenetic age acceleration in response to theoretically antiaging interventions.ResultsThe results of the four epiclocks tested are significantly distorted by the EPICv2 probeset, causing an average difference of up to 25 years. Our new model produced highly accurate chronological age predictions, comparable to a state-of-the-art epiclock. The model reported the lowest epigenetic age acceleration in normal populations, as well as the lowest variation across technical replicates and repeated samples from the same subjects. Finally, our model reproduced previous results of increased epigenetic age acceleration in cancer patients and in survivors treated with radiation therapy, and no changes from exercise-based interventions.ConclusionExisting epigenetic clocks require updates for full EPICv2 compatibility. Our new model translates the capabilities of state-of-the-art epigenetic clocks to the EPICv2 platform and is cross-compatible with older microarrays. The characterization of epigenetic age prediction variation provides useful metrics to contextualize the relevance of epigenetic age alterations. The analysis of data from subjects influenced by radiation, cancer, and exercise-based interventions shows that despite being good predictors of chronological age, neither a pathological state like breast cancer, a hazardous environmental factor (radiation), nor exercise (a beneficial intervention) caused significant changes in the values of the “epigenetic age” determined by these first-generation models.

Detection and isolation of brain tumors in cancer patients using neural network techniques in MRI images

MRI imaging primarily focuses on the soft tissues of the human body, typically performed prior to a patient's transfer to the surgical suite for a medical procedure. However, utilizing MRI images for tumor diagnosis is a time-consuming process. To address these challenges, a new method for automatic brain tumor diagnosis was developed, employing a combination of image segmentation, feature extraction, and classification techniques to isolate the specific region of interest in an MRI image corresponding to a brain tumor. The proposed method in this study comprises five distinct steps. Firstly, image pre-processing is conducted, utilizing various filters to enhance image quality. Subsequently, image thresholding is applied to facilitate segmentation. Following segmentation, feature extraction is performed, analyzing morphological and structural properties of the images. Then, feature selection is carried out using principal component analysis (PCA). Finally, classification is performed using an artificial neural network (ANN). In total, 74 unique features were extracted from each image, resulting in a dataset of 144 observations. Principal component analysis was employed to select the top 8 most effective features. Artificial Neural Networks (ANNs) leverage comprehensive data and selective knowledge. Consequently, the proposed approach was evaluated and compared with alternative methods, resulting in significant improvements in precision, accuracy, and F1 score. The proposed method demonstrated notable increases in accuracy, with improvements of 99.3%, 97.3%, and 98.5% in accuracy, Sensitivity and F1 score. These findings highlight the efficiency of this approach in accurately segmenting and classifying MRI images.

Low Serum Alanine Aminotransferase Blood Activity Is Associated with Shortened Survival of Renal Cell Cancer Patients and Survivors: Retrospective Analysis of 1830 Patients

Background: Sarcopenia is characterized by a loss of muscle mass and function and is often associated with frailty, a syndrome linked to physical disability and shortened survival in various patient populations, including cancer patients. Low serum alanine aminotransferase (ALT) values, serving as a biomarker for sarcopenia, were previously associated with frailty and shortened survival in several cancers. In the current study, we aimed to test the association between low ALT and shorter survival in renal cell carcinoma (RCC) patients and survivors. Methods: This was a retrospective analysis of RCC patients and survivors, both in- and outpatients. We defined patients with sarcopenia as those presenting with ALT &lt; 17 IU/L. Results: We identified records of 3012 RCC patients. The cohort included 1830 patients (mean age 65.6 ± 13.3 years, 68% were men) of whom only 179 underwent surgical treatment. Out of the eligible cohort, 811 patients (44.3%) had ALT &lt; 17 IU/L, with a mean ALT value of patients within the low-ALT group of 11.79 IU/L, while the mean value in the higher ALT level group was 24.44 IU/L (p &lt; 0.001). Patients in the low-ALT group were older (67.9 vs. 63.7 years; p &lt; 0.001) and had lower BMIs (26.6 vs. 28; p &lt; 0.001). In addition, patients with low ALT had lower hemoglobin values (12.14 vs. 12.91 g/dL; p &lt; 0.001), higher serum creatinine (1.49 vs. 1.14; p &lt; 0.001) and higher platelet to lymphocyte ratios (178 vs. 156; p &lt; 0.001). In a univariate analysis, low ALT levels were associated with a 72% increase in mortality (95% CI 1.46–2.02, p &lt; 0.001). In a multivariate model controlled for age, gender, hemoglobin, platelets, LDH, neutrophil to lymphocyte ratios and platelet to lymphocyte ratios, low ALT levels were still associated with a 27% increase in mortality (HR = 1.27, 95% CI 1.08–1.51; p = 0.005). Conclusion. Low ALT values, associated with sarcopenia and frailty, are also associated with shortened survival in RCC patients, and survivors and could potentially be applied for optimizing individual treatment decisions.

Modulation of Tumor Suppressor Genes by Histone Deacetylase Inhibitors in Cancer Therapy

Histone deacetylase (HDAC) inhibitors have emerged as promising therapeutics for various cancers due to their ability to modulate gene expression profiles and restore normal cellular functions. Among the key targets of HDAC inhibitors are tumor suppressor genes, which play crucial roles in regulating cell cycle progression, apoptosis, and DNA repair. However, despite their therapeutic potential, HDAC inhibitors come with significant drawbacks. These include off-target effects that can lead to unintended alterations in gene expression, toxicity to normal cells, and the development of drug resistance in some cancer patients. Additionally, the non-specific nature of some HDAC inhibitors can result in side effects such as fatigue, gastrointestinal disturbances, and hematological toxicity, limiting their clinical utility. This review provides a comprehensive overview of the impact of HDAC inhibitors on tumor suppressor genes in cancer therapy. We discussed the mechanisms by which HDAC inhibitors regulate the expression of tumor suppressor genes, including p53, p21, BRCA1, PTEN, and others, through histone hyperacetylation and chromatin remodeling. Furthermore, we described the therapeutic implications of HDAC inhibitor-induced modulation of tumor suppressor genes in various cancer types, highlighting the potential for combination therapies and personalized treatment approaches. Understanding the interplay between HDAC inhibitors and tumor suppressor genes is critical for optimizing the efficacy of HDAC inhibitor-based therapies and advancing precision medicine in oncology.

Pre-treatment [18F]FDG PET/CT biomarkers for the prediction of antibody-drug conjugates efficacy in metastatic breast cancer.

This study aimed to evaluate the association between pretreatment [18F]FDG PET/CT-derived biomarkers and outcomes in metastatic breast cancer (mBC) patients treated with antibody-drug conjugates (ADCs) Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd). A retrospective bicentric analysis was conducted on triple-negative mBC (mTNBC) patients treated with SG and HER2-low mBC patients treated with T-DXd, who underwent [18F]FDG PET/CT scans before therapy. Key biomarkers, including maximum standardized uptake value (SUVmax), total metabolic tumor volume (TMTV) and maximum tumor dissemination (Dmax), were measured. Their prognostic value for progression-free survival (PFS) and overall survival (OS) was assessed using Cox models and Kaplan-Meier curves. 128 patients were included: 71 mTNBC treated with SG and 57 HR-positive and -negative HER2-low mBC treated with T-DXd. Median follow-up was 12.9months. In the SG cohort, median PFS and OS were 4.8 and 8.9months, respectively. High Dmax (HR 2.1, 95% CI 1.1-4.3) and high TMTV (HR 2.9, 95% CI 1.2-6.6) were independently associated with shorter OS. In the T-DXd cohort, median PFS and OS were 5.8 and 9.0months, respectively. High Dmax (HR 2.1, 95% CI 1.2-3.9) and high TMTV (HR 2.4, 95% CI 1.0-6.5) independently correlated with shorter PFS and shorter OS, respectively. Pretreatment [18F]FDG PET/CT-derived biomarkers, namely TMTV and Dmax, have significant prognostic value in patients with mTNBC and HER2-low mBC treated with SG and T-DXd. These biomarkers improve prognostic prediction and may optimize treatment strategies, warranting their clinical use, but larger studies are needed to validate these findings.

HNRNPC mediates lymphatic metastasis of cervical cancer through m6A-dependent alternative splicing of FOXM1

Cervical cancer (CCa) patients with lymph node (LN) metastasis face poor prognoses and have limited treatment options. Aberrant N6-methyladenosine (m6A) modification of RNAs are known to promote tumor metastasis, but their role in CCa remains unclear. Our study reveals that HNRNPC, an alternative splicing (AS) factor and m6A reader, increases tumor-related variants through m6A-dependent manner, thereby promoting lymphatic metastasis in CCa. We found that HNRNPC overexpression correlates with lymphatic metastasis and poorer prognoses in CCa patients. Functionally, knocking down HNRNPC markedly inhibited the migration and invasion of several CCa cell lines, while supplementing HNRNPC restored the malignant phenotypes of these cells. Mechanistically, HNRNPC regulates exon skipping of FOXM1 by binding to its m6A-modified motif. Mutating the m6A site on FOXM1 weakened the interaction between HNRNPC and FOXM1 pre-RNA, leading to a reduction in the metastasis-related FOXM1-S variant. In conclusion, our findings demonstrate that m6A-dependent alternative splicing mediated by HNRNPC is essential for lymphatic metastasis in CCa, potentially providing novel clinical markers and therapeutic strategies for patients with advanced CCa.