The CD6 cell surface glycoprotein is expressed by almost all T cells, a small subset of B cells and a substantial proportion of human natural killer (NK) cells. CD6 has multiple ligands and multiple functional epitopes. It is a component of the immunological synapse, and can positively or negatively influence signal transduction in T cells through complex interactions with multiple kinases and adapter molecules. Antibodies to CD6 are effective in the treatment of autoimmune diseases in experimental systems and in humans. The recent discovery that CD318 (CDCP1), a driver molecule in many cancers, is a ligand for CD6 has prompted investigation of CD6 as a possible new target for immunotherapy of cancer. A monoclonal antibody to CD6 rapidly internalizes CD6 and alters gene expression in CD8+ T cells and NK cells to augment the cytotoxicity of human lymphocytes to human cancer cells from a range of neoplasms. This review, using a question and answer format, describes recent work on anti-CD6 as a candidate immunotherapy for cancer as well as relevant advances in our understanding of other aspects of the biology of CD6, and explores the possibility that this approach could avoid the autoimmune complications that are encountered with checkpoint inhibitor treatment of cancer.

Repair of damaged DNA is a complex process, particularly when it is compacted into nucleosomes. There are a number of genetic disorders with deficiencies in DNA repair. Knowledge of the genes and proteins involved in these repair deficiencies is critical in developing an understanding of the molecular mechanisms utilized by proteins in the DNA repair pathways. One of these genetic disorders is xeroderma pigmentosum (XP), which is defective in nucleotide excision repair (NER). Patients in XP complementation group A (XP-A) are among the most severely affected with the lowest levels of DNA repair. The XPA protein, which is defective in these patients, plays a number of roles in the DNA repair process. One particularly important role proposed is acting as a processivity factor enabling endonucleases (XPF and XPG) and the XPB/TFIIH translocase to localize to damage sites using a processive mechanism of action. Another proposed role is in interacting with chromatin-remodeling proteins so as to enhance accessibility of lesions in nucleosomal DNA to endonucleolytic incision and other DNA repair activities. In XP-A cells, the XPA protein is proposed to be defective in ability to act as a processivity factor; endonucleases localize damage sites by a distributive mechanism and are also defective in incision of damaged nucleosomal DNA. This defect is corrected by recombinant normal human XPA. Mutations in exons 3 and 5 in the DNA binding domain of the XPA gene lead to loss of ability of XPA to act as a processivity factor. The mutation in exon 5 was found in two XP-A patients with severe XP. These studies emphasize the importance of correlating specific mutations in an XP gene and the resulting defect in a particular repair protein with the clinical severity of XP and could lead to development of novel therapeutic approaches for this disorder.

To compare perioperative management and clinical outcomes of patients undergoing head and neck free flap reconstruction before and during the COVID-19 pandemic.

Retrospective cohort study of 220 patients who underwent microvascular free flap reconstruction by a single surgeon at a tertiary academic medical center. Perioperative practices and postoperative outcomes, including length of stay, wound infection, complications, two-year survival, and recurrence, were compared between cohorts. Poisson regression with robust error variance was used to calculate adjusted relative risks (RRs).

Demographic and baseline oncologic characteristics were largely similar between cohorts. During the pandemic, patients were less likely to undergo intraoperative tracheostomy and PEG placement. Regression analysis showed the pandemic period was independently associated with increased wound infection risk and reduced recurrence.

Head and neck free flap reconstruction remained safe during the COVID-19 pandemic, with stable cancer outcomes despite shifts in perioperative practice. However, the higher risk of wound infection highlights the need for targeted preventive strategies during times of healthcare disruption.

Lipids serve as both metabolic substrates and signaling mediators that critically regulate immune cell fate, function, tolerance, and intercellular communication. In hepatocellular carcinoma (HCC), it remains unclear how intratumoral linoleic acid (LA) allocation between desaturation and oxidative catabolism influences immunometabolic remodeling and post-transplant recurrence.

Multi-omics profiling was conducted in a liver transplant-associated HCC cohort using paired tumor/non-tumor tissues and serum samples. The intratumoral lipid milieu (C4-C24 fatty acids) was quantified by targeted gas chromatography, whereas lipid-immune programs were resolved by single-nucleus RNA sequencing (snRNA-seq) integrated with targeted transcriptomic profiling. Key immune phenotypes and candidate genes were validated by serum inflammatory mediator profiling, flow cytometric lymphocyte immunophenotyping, spatially resolved tissue assays, and qRT-PCR. LA perturbation experiments provided functional support in vitro.

Fatty acid profiling revealed that non-recurrent tumors were characterized by a higher intratumoral LA/AA ratio and a lower estimated Δ6-desaturation index than recurrent tumors, whereas recurrent tumors exhibited a higher estimated Δ6-desaturation index than their matched distant non-tumor liver tissues. snRNA-seq identified fatty acid catabolism as the most prominently downregulated metabolic pathway in recurrent tumors; malignant-cell analysis further highlighted EHHADH and ACSL3 as key genes involved in recurrence-associated lipid metabolic remodeling. In vitro, exogenous LA-BSA increased ROS accumulation and reduced SPP1 and NECTIN2 expression in HCC cells. Cell-cell communication analysis showed enhanced tumor-Treg signaling in recurrence, with VISTA- and CD80-related networks shifting from Kupffer cells toward SPP1⁺ macrophages and Tregs. Peripheral and tissue immunophenotyping showed reduced CD8⁺ T cells and higher IL-10 in recurrent tumors.

Multi-omics analyses indicate that, in primary pre-transplant HCC, post-transplant recurrence is associated with an imbalance between a higher estimated Δ6-desaturation index and attenuated oxidative catabolism-related features of linoleic acid, accompanied by Treg-associated immunosuppressive remodeling. These findings provide a biologically informed framework for post-transplant recurrence risk stratification and further translational investigation.

Gliomas show intertumoral and intratumoral heterogeneity, and isocitrate dehydrogenase (IDH) status is linked to biological behavior and clinical aggressiveness. Evidence suggests glioma progression depends on reciprocal crosstalk between glioma stem-like tumor cells (GSTCs) and the tumor microenvironment, where immune and vascular remodeling promote plasticity, invasion, and immune evasion. However, GSTC state architecture across IDH backgrounds and its links to vascular-immune cues remain unclear. We aimed to define IDH-associated GSTC states and their functional and regulatory features.

Single-cell RNA-sequencing data from 33 glioma patients (GSE278456) were analyzed using Seurat integration, clustering, differential expression analysis, and inferCNV-assisted malignant cell identification. Reclustered GSTCs were assessed by Gene Ontology (GO)/Hallmark enrichment, Area Under the Curve-based Cell-wise Gene Set Enrichment Analysis (AUCell), CytoTRACE, Monocle, Slingshot, CellChat, and pySCENIC to characterize states, developmental trajectories, cell-cell communication, and regulatory networks. After CEBPD silencing in U251 and LN229 cells, quantitative real-time PCR (qRT-PCR), Cell Counting Kit-8 (CCK-8), colony formation, Transwell migration, and apoptosis assays were performed.

Six cell populations and five GSTC subgroups were identified. A VIM+ GSTC state (C0), enriched in IDH-wild-type tumors, highly expressed CHI3L1, VIM, LGALS3, VEGFA, and SEC61G. Compared with other states, C0 showed stronger angiogenesis, hypoxia, IL6/JAK/STAT3 signaling, and epithelial-mesenchymal transition-related activities, with enrichment of oxidative phosphorylation, focal adhesion, cell-substrate junction, and actin/cadherin-binding programs. Trajectory analyses placed C0 at an early-to-intermediate node linked to divergent later states, indicating plasticity distinct from a purely proliferative state. CellChat suggested prominent myeloid-to-C0 communication, with OSM as a candidate input and LIFR/IL6ST as the receptor basis. pySCENIC identified a C0-preferential regulon landscape centered on CEBPD, RUNX2, POU2F3, TEAD3, and TEAD4, plus an M2 regulon module associated with stress adaptation and intracellular homeostasis. CEBPD knockdown reduced proliferation, colony formation, and migration while increasing apoptosis.

We identify an IDH-wild-type-enriched VIM+ glioma stem-like state with angiogenic, hypoxic, mesenchymal-like, and inflammatory features, and nominate myeloid-derived OSM signaling and CEBPD as candidate mediators of this vascular-immune-linked malignant phenotype. These findings provide a hypothesis-generating, state-based perspective on glioma progression across IDH backgrounds and highlight candidate biomarkers and mechanistic entry points for validation and therapeutic stratification.

Gastric cancer remains a highly lethal malignancy characterized by late diagnosis, limited therapeutic responsiveness, and a profoundly immunosuppressive tumor microenvironment. Among the diverse cellular components shaping this ecosystem, tumor-associated macrophages (TAMs) have emerged as central orchestrators of gastric carcinogenesis, metastatic dissemination, and therapeutic resistance. TAMs promote tumor initiation through inflammatory recruitment and polarization, facilitate invasion and angiogenesis via cytokines, matrix-remodeling enzymes, and exosomal cargo, and impair antitumor immunity by suppressing T-cell and natural killer cell function. In addition, TAMs contribute to resistance to immune checkpoint blockade by sustaining an immunosuppressive tumor immune microenvironment enriched in Tregs, myeloid-derived suppressor cells, and inhibitory mediators such as TGF-β, IL-10, and PD-L1. Recent advances further highlight the translational promise of macrophage-targeted strategies, including polarization reprogramming, recruitment blockade, and chimeric antigen receptor macrophage therapy. Previous reviews primarily focus on the general biological roles of TAMs, this review synthesizes newly emerging mechanisms of TAM-mediated immunotherapy resistance, including spatial heterogeneity, stromal-vascular remodeling, and exosomal crosstalk, with the latest clinical advances in macrophage-directed immunotherapies. We specifically highlight the translational potential and current clinical trial landscape of chimeric antigen receptor macrophage (CAR-M) therapy and targeted reprogramming strategies, providing a forward-looking perspective on overcoming immune checkpoint blockade resistance in gastric cancer.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma with poor clinical outcomes and limited therapeutic options. The contribution of metabolic reprogramming and immune microenvironmental alterations to AITL progression remains insufficiently defined.

We conducted integrative transcriptomic and proteomic analyses of AITL samples compared with reactive lymphoid hyperplasia to identify molecules associated with treatment response and prognosis. Immune infiltration and pathway enrichment analyses were performed, and findings were validated in independent GEO cohorts (GSE19069 and GSE58445). Key protein expression was confirmed by immunohistochemistry and multiplex immunofluorescence.

Differential expression analyses revealed that lysosomal alpha-glucosidase (GAA), a key enzyme involved in glycogen metabolism, was significantly upregulated at both the RNA and protein levels in patients who failed to respond to standard chemotherapy. Elevated GAA expression was associated with inferior overall survival in multivariate analysis. Immunohistochemistry staining and multiplex immunofluorescence further confirmed the spatial expression pattern of GAA in AITL tissues. Immune deconvolution and pathway enrichment analyses suggested that GAA-high tumors exhibited increased CD8⁺ T-cell infiltration accompanied by transcriptional features of T-cell exhaustion, as well as transcriptionally inferred metabolic alterations characterized by enhanced glycolysis-related signatures and reduced oxidative phosphorylation-related signatures. These findings were further validated in an independent AITL cohort from the GEO database.

Our study identifies GAA as a candidate biomarker associated with adverse clinical outcomes, immune microenvironmental features, and metabolic pathway alterations in AITL, highlighting glycogen metabolism as a previously underexplored biological axis and a potential therapeutic vulnerability warranting further functional investigation.

The proposed renaming of polycystic ovary syndrome (PCOS) as polyendocrine metabolic ovarian syndrome (PMOS) is an important step toward recognizing the systemic endocrine-metabolic nature of a condition historically misrepresented by ovarian cystic morphology. However, the persistence of the word ovarian remains conceptually limiting and reinforces the perception of a female-exclusive disorder. Published reports have provocatively proposed a male PCOS equivalent, particularly in male relatives of women with PCOS. We posit that those observations may be better conceptualized as male Endocrine-Metabolic Syndrome (male EMS), rather than male PCOS, hoping to offer a more coherent depiction of this clinical condition. In this perspective, male EMS is thus proposed as a sex-specific expression of shared endocrine-metabolic alteration characterized by insulin resistance, compensatory hyperinsulinemia, altered sex hormone-binding globulin dynamics, adrenal androgen dysregulation, early-onset androgenetic alopecia, acne or seborrhea, hypertrichosis, cardiometabolic vulnerability, and possible testicular or reproductive abnormalities. Unlike classical metabolic syndrome, male EMS would include endocrine-androgenic and dermatological features and may emerge earlier in life, particularly in individuals with a family history of female PCOS/PMOS/EMS. The present hypothesis remains to be validated prospectively, and male EMS should be considered a conceptual, research-oriented construct, not yet a defined clinical diagnosis. Nevertheless, such framework may help generate testable hypotheses and stimulate early identification of endocrine and cardiometabolic risk in men.

Colorectal cancer (CRC) remains one of the most diagnosed malignancies worldwide and continues to rank among the leading causes of cancer-related death. Cancer progression involves dynamic transcriptional and immunological changes, and although many key molecular alterations driving CRC progression have been described, stage-specific differences remain poorly understood. This study aimed to characterize transcriptomic changes in Hispanics living in Puerto Rico (PRH) to identify relevant pathways, target genes, and stage-specific immune and molecular signatures.

We conducted RNA sequencing (RNA-seq) from colorectal tissues, including early-stage CRC (stages I & II), advanced-stage CRC (stage III only), and adjacent mucosal tissue, to elucidate key mechanisms that modulate CRC progression.

Transcriptomic analysis revealed distinct gene expression patterns across stages, with a total of 1666 and 1955 differentially expressed genes at early and advanced stages, respectively. Early-stage CRC was significantly enriched for biological pathways associated with immune regulation, including cytokine signaling, epithelial barrier function, and tissue repair mechanisms, reflected in part by activation of components of the Wnt signaling pathway. In contrast, advanced-stage (stage III) CRC displayed immunosuppressive transcriptional profiles and activation of tumor-promoting pathways, including TNF signaling, enhancement of IL-17 and Wnt signaling pathways, NF-κB signaling, angiogenesis, epithelial-mesenchymal transition (EMT), and stromal remodeling.

Pathway enrichment analyses supported a shift from immune engagement and matrix remodeling in early CRC to immune evasion and pro-metastatic programs in advanced-stage disease (comprised of stage III; metastatic stage IV was not sampled). While Wnt signaling components were differentially expressed across stages, they appeared as part of a broader network of developmental and inflammatory signals driving progression. This study provides preliminary transcriptomic evidence to inform stage-specific biomarker discovery in PRH CRC that warrants further validation in larger cohorts.

Inflammatory myofibroblastic tumor (IMT) is an uncommon mesenchymal neoplasm. Urachal involvement is exceedingly rare, and evidence regarding its clinical presentation, diagnosis, and management remains limited.

We report the case of a 62-year-old female patient who presented with urinary frequency and dysuria for 8 days. Computed tomography (CT) revealed a mass at the junction of the urachus and the anterosuperior wall of the bladder, which was further confirmed by cystoscopy. The patient underwent laparoscopic resection of the urachal mass combined with partial cystectomy. Histopathological examination of the surgical specimen confirmed IMT, and immunohistochemical staining was positive for anaplastic lymphoma kinase (ALK) and vimentin. At the 3-month postoperative follow-up, CT and cystoscopy showed no evidence of local recurrence.

UIMT should be considered in the differential diagnosis of urachal or anterosuperior bladder-wall masses. Definitive diagnosis requires integrated histopathological and immunohistochemical assessment, and complete resection with negative margins is the preferred treatment for localized, resectable disease.