Search Results (115,259)

Background: With rectum-sparing protocols becoming more common for rectal cancer treatment, this study aimed to predict the pathological complete response (pCR) to preoperative chemoradiotherapy (pCRT) in rectal cancer patients using pre-treatment MRI and a radiomics-based machine learning approach. Methods: We divided MRI-data from 102 patients into a training cohort (n = 72) and a validation cohort (n = 30). In the training cohort, 52 patients were classified as non-responders and 20 as pCR based on histological results from total mesorectal excision. Results: We trained various machine learning models using radiomic features to capture disease heterogeneity between responders and non-responders. The best-performing model achieved a receiver operating characteristic area under the curve (ROC-AUC) of 73% and an accuracy of 70%, with a sensitivity of 78% and a positive predictive value (PPV) of 80%. In the validation cohort, the model showed a sensitivity of 81%, specificity of 75%, and accuracy of 80%. Conclusions: These results highlight the potential of radiomics and machine learning in predicting treatment response and support the integration of advanced imaging and computational methods for personalized rectal cancer management. Full article

Thyroid eye disease (TED) is a common extrathyroidal manifestation of hyperthyroidism, typically associated with Graves’ disease (GD). This condition can cause severe functional limitations as well as significant aesthetic concerns. Treatment for TED patients aims to restore functionality and address aesthetic concerns. Surgical TED treatment is usually performed by orbital wall resection, which effectively decompresses intraorbital tissues and corrects the orbital/ocular disorders. Several different scenarios of surgical TED treatment including one-, two-, and three-wall resections are known. More recently, a new minimally invasive technique, the so-called lateral valgization (LAVA) of the orbital wall, was reported to show promising results comparable to conventional wall resection techniques. Due to the relatively limited data on TED treatment, only a few quantitative investigations of alternative TED surgery scenarios exist. In this feasibility study, we estimate the soft tissue outcome of LAVA treatment using computational simulation. Our experimental results show that the amount of intraorbital tissue released into the extraorbital space by LAVA treatment is comparable with the outcome of two-wall resection. Our computational simulation confirms previously reported isolated clinical findings suggesting that the minimally invasive LAVA approach represents an attractive alternative to conventional wall resection approaches for surgical TED treatment. Full article

Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2) play a key role in DNA repair. As major sensors of DNA damage, they are activated to produce poly(ADP-ribose). PARP1/PARP2 inhibitors have emerged as effective drugs for the treatment of cancers with BRCA deficiencies. Here, we explored aminomethylmorpholino and aminomethylmorpholino glycine nucleosides as inhibitors of PARP1 and PARP2, using different enzymatic assays. The compounds bearing thymine or 5-Br(I)-uracil bases displayed the highest inhibition potency, with all of them being more selective toward PARP1. Interaction of the inhibitors with the NAD⁺ binding cavity of PARP1 (PARP2) suggested by the mixed-type inhibition was demonstrated by molecular docking and the RoseTTAFold All-Atom AI-model. The best PARP1 inhibitors characterized by the inhibition constants in the range of 12–15 µM potentiate the cytotoxicity of hydrogen peroxide by displaying strong synergism. The inhibitors revealed no impact on PARP1/PARP2 affinity for DNA, while they reduced the dissociation rate of the enzyme–DNA complex upon the autopoly(ADP-ribosyl)ation reaction, thus providing evidence that their mechanism of action for PARP trapping is due primarily to catalytic inhibition. The most active compounds were shown to retain selectivity toward PARP1, despite the reduced inhibition potency in the presence of histone PARylation factor 1 (HPF1) capable of regulating PARP1/PARP2 catalytic activity and ADP-ribosylation reaction specificity. The inhibitors obtained seem to be promising for further research as potential drugs. Full article

Background/Objectives: BRCA1 pathogenic variant (PV)-associated breast cancers are most commonly seen in hereditary genetic conditions such as the autosomal-dominant Hereditary Breast and Ovarian Cancer (HBOC) syndrome, and rarely in sporadic breast cancer. Such breast cancers tend to exhibit greater aggressiveness and poorer prognoses due to the influence of BRCA1 pathogenic variants (PVs) on the tumour microenvironment. Additionally, while the genetic basis of BRCA1 PV breast cancer is well-studied, the role of epigenetic mediators in the tumourigenesis of these hereditary breast cancers is also worth exploring. Results: PVs in the BRCA1 gene interact with stromal cells and immune cells, promoting epithelial–mesenchymal transition, angiogenesis, and affecting oestrogen levels. Additionally, BRCA1 PVs contribute to breast cancer development through epigenetic effects on cells, including DNA methylation and histone acetylation, leading to the suppression of proto-oncogenes and dysregulation of cytokines. In terms of epigenetics, lysine-specific demethylase 1 (LSD-1) is considered a master epigenetic regulator, governing both transcriptional repression and activation. It exerts epigenetic control over BRCA1 and, to a lesser extent, BRCA2 genes. The upregulation of LSD-1 is generally associated with a poorer prognosis in cancer patients. In the context of breast cancer in BRCA1/2 PV carriers, LSD-1 contributes to tumour development through various mechanisms. These include the maintenance of a hypoxic environment and direct suppression of BRCA1 gene expression. Conclusions: While LSD-1 itself does not directly cause mutations in BRCA1 or BRCA2 genes, its epigenetic influence sheds light on the potential role of LSD-1 inhibitors as a therapeutic approach in managing breast cancer, particularly in individuals with BRCA1/2 PVs. Targeting LSD-1 may help counteract its detrimental effects and provide a promising avenue for therapy in this specific subgroup of breast cancer. Full article

This study provides a comprehensive overview of the role of immunotherapy in the treatment of mismatch repair-deficient (MMRd) endometrial carcinomas. Immunotherapy has emerged as a transformative approach in the treatment of MMRd due to the high mutation rate and subsequent PD-1/PD-L1 overexpression seen in these tumors. This review analyzes the current landscape of existing randomized clinical trials, highlighting the efficacy of immune checkpoint inhibitors (ICIs) like pembrolizumab, avelumab, and dostarlimab. Additionally, the focus extends to the potential of combined therapeutic strategies, such as the integration of ICIs with targeted agents, while also exploring the application of immunotherapy in non-traditional settings beyond advanced or recurrent disease. This includes emerging roles in the adjuvant and neoadjuvant contexts to prevent recurrence and target early-stage disease. These findings underscore the importance of tailoring treatments based on the molecular characteristics of each tumor and paving the way for future advancements in the field of gynecologic oncology. Despite promising results, this article acknowledges the necessity of further research to refine patient selection criteria and explore combination strategies that can overcome resistance mechanisms. Full article

Background: This study aimed to investigate the expression and prognostic significance of the MRPL23 protein and mRNA in clear-cell renal cell carcinoma (ccRCC) and adjacent non-tumorous tissues. The goal was to assess the impact of MRPL23 expression on tumor behavior, progression, and patient outcomes. Methods: Using immunohistochemistry (IHC), MRPL23 protein expression was analyzed in 99 cases of ccRCC and 30 adjacent non-tumorous tissues. mRNA levels were assessed using data from The Cancer Genome Atlas (TCGA). Correlations between MRPL23 expression and clinicopathological features were examined, and survival outcomes were evaluated using Kaplan–Meier survival curves and Cox regression analyses. Results: MRPL23 protein expression was significantly lower in ccRCC tissues compared to normal tissues. In contrast, mRNA levels of MRPL23 were significantly elevated in ccRCC tissues. Expression levels were correlated with clinicopathological features, including gender, tumor grade, pT status, and disease stage, underlining their impact on tumor progression. Elevated MRPL23 protein expression was associated with poorer overall survival (OS) in ccRCC patients and remained an independent prognostic marker for adverse outcomes after adjustment for confounding variables. While high MRPL23 mRNA expression was also linked to worse OS, it did not retain its status as an independent prognostic factor after adjustments. Conclusion: MRPL23 protein expression is a potential independent prognostic biomarker in ccRCC, emphasizing its utility in predicting patient outcomes and potentially guiding therapeutic decisions. These findings highlight the importance of further research into the role of MRPL23 in ccRCC pathogenesis and its potential as a therapeutic target. Full article

Hepatobiliary cancers, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are among the deadliest malignancies worldwide, leading to a significant number of cancer-related deaths. While bone metastases from these cancers are rare, they are highly aggressive and linked to poor prognosis. This review focuses on RNA-based molecular mechanisms that contribute to bone metastasis from hepatobiliary cancers. Specifically, the role of two key factors, microRNAs (miRNAs) and RNA-binding proteins (RBPs), which have not been extensively studied in the context of HCC and CCA, is discussed. These molecules often exhibit abnormal expression in hepatobiliary tumors, influencing cancer cell spread and metastasis by disrupting bone homeostasis, thereby aiding tumor cell migration and survival in the bone microenvironment. This review also discusses potential therapeutic strategies targeting these RNA-based pathways to reduce bone metastasis and improve patient outcomes. Further research is crucial for developing effective miRNA- and RBP-based diagnostic and prognostic biomarkers and treatments to prevent bone metastases in hepatobiliary cancers. Full article

Background: The emergence and prevalence of antibiotic-resistant bacteria (ARBs) have become a serious global threat, as the morbidity and mortality associated with ARB infections are continuously rising. The activation of quorum sensing (QS) genes can promote biofilm formation, which contributes to the acquisition of drug resistance and increases virulence. Therefore, there is an urgent need to develop new antimicrobial agents to control ARB and prevent further development. Antimicrobial peptides (AMPs) are naturally occurring defense molecules in organisms known to suppress pathogens through a broad range of antimicrobial mechanisms. Methods: In this study, we utilized a previously developed deep-learning model to identify AMP candidates from the venom gland transcriptome of the spider Pardosa astrigera, followed by experimental validation. Results: PA-Win2 was among the top-scoring predicted peptides and was selected based on physiochemical features. Subsequent experimental validation demonstrated that PA-Win2 inhibits the growth of Bacillus subtilis, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and multidrug-resistant P. aeruginosa (MRPA) strain CCARM 2095. The peptide exhibited strong bactericidal activity against P. aeruginosa, and MRPA CCARM 2095 through the depolarization of bacterial cytoplasmic membranes and alteration of gene expression associated with bacterial survival. In addition, PA-Win2 effectively inhibited biofilm formation and degraded pre-formed biofilms of P. aeruginosa. The gene expression study showed that the peptide treatment led to the downregulation of QS genes in the Las, Pqs, and Rhl systems. Conclustions: These findings suggest PA-Win2 as a promising drug candidate against ARB and demonstrate the potential of in silico methods in discovering functional peptides from biological data. Full article

Background/Objectives: Uterine carcinosarcomas (UCSs) are rare and aggressive malignancies with limited epidemiological data. This study aims to evaluate the clinical and pathological features and prognostic factors of UCS in a retrospective cohort of 80 patients, contributing to improved management strategies. Methods: We conducted a retrospective analysis of UCS cases treated from 1995 to 2024 at three institutions. Data on demographics, clinical features, histopathology, treatment, and outcomes were collected. Overall survival (OS) and prognostic factors were assessed using Kaplan–Meier and Cox proportional hazards regression analyses. Results: The median age of patients was 66 years, with a median overall survival of 34.5 months. Disease recurrence occurred in 32.5% of cases, with a median disease-free interval of 17.92 months. Age, tumour stage, and size emerged as significant predictors of survival. Stage I–II patients had a significantly better prognosis than those with Stage III–IV (HR = 0.438, p = 0.008). Tumour size >4 cm was associated with increased mortality (HR = 2.154, p = 0.019). Lymphadenectomy was not independently associated with improved survival. Adjuvant chemotherapy, mainly carboplatin and paclitaxel, was administered to 67.5% of patients, achieving a complete response in 66.67%. Conclusions: Tumour stage and age are significant independent predictors of survival in UCS, underscoring the need for early diagnosis and intervention. Tumour size is also crucial in determining prognosis. The role of lymphadenectomy remains uncertain, emphasizing the importance of individualized treatment approaches. Future research should explore molecular profiling to further refine prognostication and therapeutic strategies for this challenging malignancy. Full article

Melanoma is one of the most malignant forms of skin cancer, characterised by the highest mortality rate among affected patients. This study aims to analyse and compare the effects of lipid extracts from the microalgae Nannochloropsis oceanica (N.o.) and Chlorococcum amblystomatis (C.a.) on the intra and extracellular proteome of UVA-irradiated melanoma cells using a three-dimensional model. Proteomic analysis revealed that UVA radiation significantly increases the levels of pro-inflammatory proteins in melanoma cells. Treatment with algae extracts reduced these protein levels in both non-irradiated and irradiated cells. Furthermore, untreated cells released proteins responsible for cell growth and proliferation into the medium, a process hindered by UVA radiation through the promotion of pro-inflammatory molecules secretion. The treatment with algae extracts effectively mitigated UVA-induced alterations. Notably, UVA radiation significantly induced the formation of 4-HNE and 15-PGJ2 protein adducts in both cells and the medium, while treatment with algae extracts stimulated the formation of 4-HNE-protein adducts and reduced the level of 15-PGJ2-protein adducts. However, both algae extracts successfully prevented these UVA-induced modifications. In conclusion, lipid extracts from N.o. and C.a. appear to be promising agents in supporting anti-melanoma therapy. However, their potent protective capacity may limit their applicability, particularly following cells exposure to UVA. Full article

Background: Modulated electro-hyperthermia (mEHT) is unique due to its combination of thermal and non-thermal effects. Method: This report summarizes the literature on the effects of mEHT observed in vitro and in vivo. Results: The thermal and electrical heterogeneity of tissues allows the radiofrequency signal to selectively target malignant tissue. The applied modulation appears to activate various apoptotic pathways, predominantly leading to immunogenic cell death (ICD). ICD promotes the release of damage-associated molecular patterns, potentially producing tumour-specific antigen-presenting cells. This abscopal-type effect may target distant metastases while treating the primary tumour locally. This immune memory effect is like vaccination mechanisms. Conclusions: The application of mEHT has the potential to expand from local to systemic disease, enabling the simultaneous treatment of micro- and macro-metastases. Full article

Background/Objectives: DAPK-1 plays a crucial role among molecules that may be affected by DNA hypermethylation. The aim of this study is to investigate the DNA methylation of DAPK-1 gene in oral potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC) compared to normal oral epithelium and to evaluate the possible role of methylated DAPK-1 as an indicator of the early onset of malignant transformation of oral potentially malignant disorders. Methods: The paraffin embedded tissue samples were retrieved from the archives of the Department of Oral Medicine/Pathology, School of Dentistry, Aristotle University of Thessaloniki, Greece and St Lukas Hospital of Thessaloniki, Greece during the period of 2014–2019. The tissue samples included 83 OPMDs samples, 39 OSCC samples and 12 samples of normal oral epithelium. The PCR process followed, targeting four different DAPK-1 gene primers. Results: Regarding OSCC, it was found that all 39 OSCCs samples were methylated in DAPK-1 promoter region, whereas only 2 out of 12 normal tissues samples showed DAPK-1 promoter hypermethylation (p < 0.001 Fisher’s exact test). A total of 17 out of 83 OPMDs were DAPK-1 methylated (five erosive oral lichen planus samples, three non-dysplastic oral leukoplakias, eight mildly dysplastic oral leukoplakias and one sample belonging to the group of moderately and severely dysplastic oral leukoplakia). Conclusions: Since epigenetic changes occur early in carcinogenesis and are potentially reversible, they could be used as disease biomarkers for diagnosis, prognosis and prediction, as well as therapeutic targets. DAPK-1 methylation is mostly present in the early stages of dysplasia as well as in all cases of oral cancer. Full article

Locally recurrent rectal cancer (LRRC), which occurs in 6–12% of patients previously treated with surgery, with or without pre-operative chemoradiation therapy, represents a complex and heterogeneous disease profoundly affecting the patient’s quality of life (QoL) and long-term survival. Its management usually requires a multidisciplinary approach, to evaluate the several aspects of a LRRC, such as resectability or the best approach to reduce symptoms. Surgical treatment is more complex and usually needs high-volume centers to obtain a higher rate of radical (R0) resections and to reduce the rate of postoperative complications. Multiple factors related to the patient, to the primary tumor, and to the surgery for the primary tumor contribute to the development of local recurrence. Accurate pre-treatment staging of the recurrence is essential, and several classification systems are currently used for this purpose. Achieving an R0 resection through radical surgery remains the most critical factor for a favorable oncologic outcome, although both chemotherapy and radiotherapy play a significant role in facilitating this goal. If a R0 resection of a LRRC is not feasible, palliative treatment is mandatory to reduce the LRRC-related symptoms, especially pain, minimizing the effect of the recurrence on the QoL of the patients. The aim of this manuscript is to provide a comprehensive narrative review of the literature regarding the management of LRRC. Full article

Background: Colon capsule endoscopy (CCE) is becoming more widely available across Europe, but its uptake is slow due to the need for follow-up colonoscopy for therapeutic procedures and biopsies, which impacts its cost-effectiveness. One of the major factors driving the conversion to colonoscopy is the detection of excess polyps in CCE that cannot be matched during subsequent colonoscopy. The capsule’s rocking motion, which can lead to duplicate reporting of the same polyp when viewed from different angles, is likely a key contributor. Objectives: This review aims to explore the types of polyp matching reported in the literature, assess matching techniques and matching accuracy, and evaluate the development of machine learning models to improve polyp matching in CCE and subsequent colonoscopy. Methods: A systematic literature search was conducted in EMBASE, MEDLINE, and PubMed. Due to the scarcity of research in this area, the search encompassed clinical trials, observational studies, reviews, case series, and editorial letters. Three directly related studies were included, and ten indirectly related studies were included for review. Results: Polyp matching in colon capsule endoscopy still needs to be developed, with only one study focused on creating criteria to match polyps within the same CCE video. Another study established that experienced CCE readers have greater accuracy, reducing interobserver variability. A machine learning algorithm was developed in one study to match polyps between initial CCE and subsequent colonoscopy. Only around 50% of polyps were successfully matched, requiring further optimisation. As Artificial Intelligence (AI) algorithms advance in CCE polyp detection, the risk of duplicate reporting may increase when clinicians are presented with polyp images or timestamps, potentially complicating the transition to AI-assisted CCE reading in the future. Conclusions: Polyp matching in CCE is a developing field with considerable challenges, especially in matching polyps within the same video. Although AI shows potential for decent accuracy, more research is needed to refine these techniques and make CCE a more reliable, non-invasive alternative to complement conventional colonoscopy for lower GI investigations. Full article