Faecal incontinence (FI) is a common and debilitating late effect of chemoradiotherapy in patients with anal cancer. While its clinical relevance is well recognized, the underlying histopathological mechanisms remain poorly understood. This exploratory study aimed to describe structural tissue changes in the anal canal following radiotherapy and assess their potential contribution to FI.

Histological specimens from patients who underwent salvage abdominoperineal excision after chemoradiotherapy for anal cancer (AC group) were compared with those from low rectal cancer patients treated surgically without neoadjuvant therapy (RC group). Degenerative changes were assessed in peritumoral regions, including evaluation of collagen fibre composition via polarized light microscopy and ImageJ software.

Indicative trends were observed, with the AC group showing higher rates of muscle fibre atrophy (73% vs 27%, p = 0.049) and intramuscular edema (78% vs 22%, p = 0.015), and a non-significant increase in lamina propria fibrosis (p = 0.069). No statistically significant differences were found in collagen fibre type distribution. Due to the limited sample size, these findings should be interpreted as descriptive rather than confirmatory.

Radiotherapy appears to induce notable structural alterations within the anal sphincter complex, including muscle atrophy and oedema, which may contribute to post-treatment faecal incontinence. These changes seem independent of collagen fibre composition. Despite the small sample size and lack of clinical data, this study provides preliminary histological insights that warrant further investigation in larger, clinically integrated cohorts.

During cancer immunoediting, cancer cells deregulate cell death executioner mechanisms to escape immunotherapy-induced antitumor immunity. Ferroptosis, a type of regulated necrosis triggered by lipid peroxidation, plays a pivotal role in the anti-tumor activity of T cell-based immunotherapies; however, mechanisms for the modulation of ferroptosis in immune-refractory tumor cells are unclear. In this study, using preclinical models of immune refractory tumors obtained following the course of immunoediting by PD-1 blockade and adoptive T cell therapy (ACT), we find that T cell-based immunotherapy drives the development of ferroptosis resistance of tumor cells. In this process, E2F1 is upregulated by immunotherapy and it in turn binds to the promoter of the HMGCR gene to upregulate HMGCR, thereby contributing to the resistance to ferroptosis. Notably, HMGCR inhibition renders immune-refractory tumor cells susceptible to ACT and PD-1 blockade. Thus, our results reveal a mechanism by which cancer cells modulate ferroptosis to acquire resistance to immunotherapy and implicate the E2F1-HMGCR axis as a central molecular target for controlling ferroptosis resistance of immune-refractory cancer.

This research introduces an improved method for identifying colorectal tumors through a combination of deep convolutional neural networks (CNNs), transfer learning, and sophisticated image processing techniques used on histopathological images. The suggested ensemble-based on ResNet50 and enhanced with a dual attention mechanism-surpasses individual model architectures by enhancing both accuracy and interpretability, allowing the model to emphasize crucial tissue areas pertinent to diagnosis. Segmentation techniques, such as watershed and distance transform, are utilized to define tumor margins and possible lesion regions. The dataset, obtained from Kather et al. (2019), includes 5,000 histopathological images spanning eight unique categories (tumor, stroma, complex, lymph, debris, mucosa, adipose, empty). The experimental findings demonstrate impressive results, achieving a training accuracy of 98.74%, a validation accuracy of 94.35%, an F1-score of 0.94, a recall of 0.94, a precision of 0.95, a specificity of 0.96, and a Cohen's kappa score of 0.9354, signifying outstanding inter-class consensus. These results showcase the model's strength across different class distributions and emphasize its possible clinical value in aiding the early identification and management of colorectal cancer.

The widespread clinical application of paclitaxel (PTX) in cancer treatment has been significantly limited by the emergence of drug resistance and the presence of drug-tolerant persister cells. To systematically identify key regulators of this resistance, we conducted a genome-wide CRISPR/Cas9 knockout screen, which revealed that cell division cycle 6 (CDC6) is a critical determinant of cell adhesion-mediated PTX resistance. Furthermore, our results illustrate that CDC6, an essential DNA replication licensing factor, functions through a pathway distinct from previously well-characterized resistance mechanisms. Genetic depletion of CDC6 considerably sensitizes cells, markedly increasing PTX-induced cell death. In addition to its established role in chromosome stability, CDC6 physically interacts with tropomodulin-3 (Tmod3) in the cytoplasmic compartment. This interaction enhances CDC6 protein stability and drives drug resistance phenotypes through the regulation of actin cytoskeleton remodeling and facilitating focal adhesion assembly. In addition, combination treatment with PTX and actin filament inhibitors synergistically enhanced the antitumor efficacy both in vitro and in vivo. Overall, our studies elucidate the mechanisms through which CDC6 functions as a key regulator of PTX resistance and provide a potential therapeutic strategy to increase PTX efficacy through the modulation of the cytoskeletal-adhesion axis.

Advancements in cellular immunotherapy demanded efficient immune cell delivery. To meet this need, we introduced hydrogel-based immune millirobots designed for high immune cell loading and precise tumor targeting. These ultrasoft robots, embedded with magnetic nanoparticles, exhibited adaptable locomotion: walking, rolling, climbing, and undulating, enabling navigation through complex biological environments and alignment with varied tumor morphologies. They responded to magnetic fields and ionic or pH changes, facilitating propulsion, grasping, and localized delivery. In vitro, the millirobots eradicated three-dimensional tumor models in four days; in vivo, they notably reduced tumor growth in HepG2-luc tumor-bearing nude mice within 15 days. Bioluminescence imaging confirmed enhanced natural killer cell activity at tumor sites. The robots demonstrated excellent biocompatibility and biodegradability and caused no adverse effects postimplantation. This work showcased a responsive, soft robotic system with potential for advancing immune cell delivery and exploring tumor-immune dynamics in cancer therapy.

Ovarian cancer is the deadliest gynecological malignancy. The fluorescence-guided surgery technique provides a real-time visualization of the desired regions to guide the tumor resection. However, the fluorescent probes used in clinics suffer from the limited selectivity of ovarian tumors and short blood circulation half-lives. Here, we design an activatable trident-like fluorescent peptide probe (RMN) to bind with the ovarian tumor-overexpressed N-cadherin and respond to the matrix metalloproteinases (MMPs). Upon intravenous administration, the RMN initially hitchhikes on the red blood cell (RBC) surface with prolonged circulation half-lives. When arriving at the tumor regions, the peptide sequence is cleaved by the tumor-secreted MMPs to recover the fluorescent signals. The released "spears" containing N-cadherin-targeting moiety and fluorophore can specifically recognize the ovarian tumor cells, thereby facilitating the visualization of primary or metastatic tumor regions. Overall, this study highlights the potential of RBC-hitchhiking fluorescent probes in advancing the intraoperative diagnosis of human ovarian tumor tissues during the fluorescence-guided surgery process in clinics.

B cell involvement in neoantigen-driven antitumor immunity remains largely unexplored because of challenges in predicting B cell responses. Here, we developed a method to identify B cell epitopes by characterizing >437,000 peptides tested for IgG binding and >370 million B cell receptor (BCR) clones. Our single-cell BCR sequencing of pre- and post-severe acute respiratory syndrome coronavirus 2 vaccination validates the performance of this method. Mouse vaccination experiments demonstrate that B cell neoepitopes enhance immune responses, driving BCR expansion and tumor regression. Genomic analysis of >8000 The Cancer Genome Atlas (TCGA) samples reveals an inverse correlation between predicted B cell reactivity and mutation allele frequencies, indicating B cell-mediated neoantigen elimination. Applying our multiomics model to checkpoint blockade responses in 2074 patients highlights the clinical relevance of B cell neoepitope prediction. A meta-analysis of 11 personalized vaccine trials involving 1739 neoantigens suggests that incorporating B cell neoepitopes may improve vaccination efficacy. These results underscore the significance of B cell-reactive neoantigens in antitumor immunity.

Triple-negative breast cancer (TNBC) characterizes one of the most antagonistic subtypes of breast hostilities, due to lacking targeted and potential therapies. In this study, it is investigated and performed an integrative in silico investigation into the pharmacological potential of a series of dihydropyranocoumarins (Visnadine (L01), Pteryxin (L02), Isosamidin (L03), and Suksdorfin (L04)) as forthcoming TNBC therapeutics. A many-sided computational workflow was employed encompassing quantum chemical calculations, drug-likeness profiling, in silico, molecular docking, and molecular dynamics (MD) simulations. First of all, all ligands were sourced from the PubChem database and performed the geometry optimization with calculating the quantum descriptors using Density Functional Theory (DFT) via the DMol³ module in BIOVIA Materials Studio, applying the B3LYP functional and DNP basis set. Frontier molecular orbital (FMO) analyses in terms of HOMO-LUMO energy gaps and associated global reactivity descriptors, were evaluated to ascertain electronic stability and reactivity trends. Subsequent, PASS prediction, drug-likeness and ADMET assessments, performed using way2drug, SwissADME and pkCSM platforms, revealed favorable pharmacokinetic profiles, with all candidates exhibiting high gastrointestinal absorption, acceptable aqueous solubility, and minimal cytochrome P450 inhibition. Next, Target-based molecular docking against key TNBC-related proteins (PDB IDs: 5HA9 and 7L1X) was conducted using AutoDock Vina within PyRx. These complexes were further validated through 100-ns all-atom MD simulations using Desmond software under the AMBER14 force field, demonstrating stable RMSD values and compact, persistent protein-ligand interactions throughout the simulation period. For resulting, to begin with, PASS prediction suggested high probabilities for antineoplastic activity, substantiating their biological relevance, and initially, it was revealed that the ligands showed the anti-cancer properties. Next, despite predicted hepatotoxicity, the compounds showed no AMES mutagenicity or genotoxicity, indicating an acceptable safety profile. Overall, dihydropyranocoumarins, especially L03, emerge as promising TNBC leads. Docking analysis revealed strong binding affinities across the ligand set, with Isosamidin (L03) showing the most pronounced interaction (-9.1 kcal/mol), primarily mediated through hydrogen bonding and π-stacking interactions within the active sites. On based on quantum calculation, among the derivatives, L01 exhibited the highest chemical stability, while L04 showed greater electrophilic reactivity, as reflected in the MEP surface and charge distribution profiles. Lastly, the MD indicates indicative of strong conformational stability under physiological conditions of docked complex by RMSD, RMSF, SASA, H bonding and interactions. However, these in silico studies and computational approaches warrant to the future scope for experimental validation through in-vitro assays such as MTT cytotoxicity, apoptosis induction, and cell migration studies to confirm the anti-TNBC potential of these compounds.

Ramucirumab plus paclitaxel after progression on fluoropyrimidine/platinum in metastatic gastric (GA) and gastroesophageal junction adenocarcinoma (GEJC) has shown improvement in overall survival over paclitaxel alone. However, the incidence of neuropathy was 46%. Therefore, there is an unmet need for novel treatment to minimize the long-term toxicity of neuropathy. We conducted a single arm phase II study of ramucirumab and trifluridine/tipiracil (FTD/TPI) in metastatic GA/GEJC.

Patients received ramucirumab at 8 mg/kg intravenously on day 1 and 15, and FTD/TPI at 35 mg/m2 orally twice daily on days 1-5 and days 8-12 on every 28-days cycle. The primary endpoint was 6-months overall survival (OS) rate and secondary endpoints were progression free survival (PFS), objective response rate and safety.

At data cut-off of August 15, 2021, 23 pts were enrolled. The median age was 62 years. Most common treatment-related toxicities were diarrhea (39%), fatigue (39%), hypertension (39%), and nausea (35%). Most common treatment related Grade 3 or 4 adverse events were neutropenia (17%) and anemia (13%). The median PFS and OS was 4.8 and 6.1 months, respectively. The 6-month OS rate was 57% (95% CI: 36.4%-79.8%). Of the 18 evaluable patients with at least one post-baseline imaging, 2 (11%) patients demonstrated objective partial response, and 15 (83%) had stable disease.

The combination of ramucirumab and FTD/TPI demonstrated well-manageable safety profile. Our study did not meet primary endpoint. Ongoing clinical trials will help us understand if ramucirumab plus FTD/TPI is noninferior to ramucirumab/paclitaxel. The trial was registered at www.clinicaltrials.gov (NCT03686488).

Mesothelin (MSLN) is among the most studied cancer-related antigens, and it is extensively studied as a therapeutic target for the treatment of various malignancies, including pleural mesothelioma, pancreatic ductal adenocarcinoma, and ovarian cancer. However, despite the development of many MSLN-targeting strategies, such as antibody-drug conjugates (ADC), bispecific antibodies, and CAR-T cells, clinical responses have remained limited, underscoring the need for a deeper understanding of MSLN biology. Over the past decades, many studies have highlighted a link between MSLN and cancer progression and its association with specific features within the tumor microenvironment (TME). More recently, mechanistic evidence has emerged showing the involvement of MSLN in the establishment of key malignant features, such as the epithelial-to-mesenchymal transition (EMT) and matrix metalloproteinase 7-mediated remodeling of the extracellular matrix (ECM). Furthermore, these studies also show a direct role for MSLN in the immunosuppressive polarization of the TME through the interaction with CD206 macrophage receptors (leading to an M2-like polarization) and by promoting the transition of mesothelial cells into specific cancer-associated fibroblasts (CAFs). This review synthesizes current evidence on MSLN transcriptional regulation and its functional implications in invasion, metastasis, and immune evasion. We also summarize ongoing therapeutic strategies targeting MSLN and discuss how TME-driven resistance mechanisms are shaping the next generation of MSLN-directed therapies. By integrating molecular insights with translational perspectives, this work provides a comprehensive overview of MSLN biology and its emerging therapeutic relevance in cancer.