Early detection of hepatocellular carcinoma (HCC) remains challenging due to limitations including the lack of reliable biomarkers. While molecular diagnostics hold promise, their use is limited because tissue biopsies are not routinely performed in HCC. Long non-coding RNAs (lncRNA), such as HOXA transcript at the distal tip (HOTTIP), have been implicated in HCC, with single-nucleotide polymorphisms forming haplotypes that may influence disease progression. This study investigated the clinical relevance of HOTTIP SNPs rs17501292 and rs2067087 in 198 Egyptian HCC patients (129 non-metastatic, 69 metastatic). Moreover, molecular docking was used to design small interfering RNAs (siRNAs) targeting HOTTIP. Genotypes TT and TG (rs17501292) and GG and GC (rs2067087) were associated with reduced metastatic risk compared to GG and CC genotypes, respectively. Survival analysis revealed that TT (rs17501292) and GC (rs2067087) genotypes correlated with improved outcomes. ROC curve analysis confirmed the diagnostic and prognostic value of specific genetic models, affirming their value as biomarkers for metastasis and survival. Molecular docking identified two promising therapeutic candidates. Overall, we can conclude that HOTTIP SNPs may serve as promising potential non-invasive biomarkers for HCC metastasis and prognosis, while the identified siRNAs offer a novel targeted therapeutic approach.

Breast cancer remains a leading cause of mortality among women worldwide, presenting significant treatment challenges due to its aggressive nature and lack of targeted therapies. Traditional treatments, including surgery, radiation, and chemotherapy, have improved survival rates. However, limitations such as drug resistance and adverse side effects persist. Recent advancements in nanotechnology offer promising avenues for enhancing breast cancer treatment by improving drug delivery, increasing therapeutic efficacy, and minimizing systemic toxicity. This review explores breast cancer's pathophysiology and molecular mechanisms, evaluates current diagnostic and therapeutic strategies, and discusses emerging innovations in nanotechnology and integrative medicine. Recent studies have demonstrated the efficacy of green nanotechnology in transforming Ayurvedic medicine into scientifically credible treatments. These integrative approaches not only enhance the therapeutic potential of traditional medicine but also offer a pathway to overcome challenges associated with conventional cancer treatments. The convergence of nanotechnology and traditional medical systems holds transformative potential in breast cancer therapy. By leveraging the unique properties of nanoparticles and nanorobotics, it is possible to develop more effective, personalized, and less toxic treatment modalities. Future research should optimize these integrative approaches, conduct rigorous clinical trials, and elucidate the underlying mechanisms to fully realize their potential in combating breast cancer.

Background and Clinical Significance: Plasmablastic lymphoma (PBL) is a rare and highly aggressive B-cell neoplasm most often associated with immunodeficiency. Transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) into PBL is exceptionally uncommon, particularly in immunocompetent individuals. This paper describes a rare synchronous SLL-to-PBL transformation and summarizes current knowledge on synchronous and metachronous cases reported in the literature. Case Presentation A midle-aged immunocompetent patent presented with generalized lymphadenopathy and lumbar pain. Concurrent biopsies of an axillary lymph node and a retroperitoneal mass were obtained. Diagnostic evaluation included immunohistochemistry; fluorescent in situ hybridization (FISH); PCR-based assessment of IGH, IGK, and IGL loci; and next-generation sequencing (NGS) of IGHV to assess clonal relatedness. The patient was treated with six cycles of Dara-CHOP, followed by autologous stem cell transplantation and maintenance therapy with daratumumab and ibrutinib. The axillary node showed SLL (CD20+, CD5+, CD23+), while the retroperitoneal mass demonstrated classic features of PBL (CD138+, MUM1+, MYC+, Ki-67 ~100%, CD20-). FISH detected MYC rearrangement in the PBL component. PCR and NGS confirmed identical IGHV1-69 rearrangements, establishing clonal relatedness and Richter transformation. A review of published cases shows that both synchronous and metachronous CLL/SLL-to-PBL transformations are exceedingly rare. The patient achieved partial metabolic remission after treatment and remains in sustained metabolic response 24 months after diagnosis. Conclusions: This case highlights a rare example of synchronous CLL/SLL-to-PBL transformation in an immunocompetent patient. Integration of detailed molecular diagnostics enabled early recognition and guided a personalized treatment approach incorporating CD38-targeted therapy and BTK inhibition, resulting in an excellent long-term clinical outcome.

Colitis-associated carcinoma (CAC) represents ~1% of colorectal carcinomas and has important differences from sporadic colorectal carcinoma (sCRC). The precursors and carcinomas that arise in the setting of IBD are uniquely challenging to visualize by endoscopy and diagnose via histology, and the rising prevalence of IBD amplifies the challenges of surveillance to informed management. Although in broad strokes, CAC and sCRC share molecular features (~85% chromosomal instability pathway 15% microsatellite instability high (MSI-H)), CAC has a distinct distribution of molecular abnormalities, including lower frequencies of APC and KRAS mutations, greater prevalence of IDH1R132H, and more frequent copy number alterations (e.g., MYC amplifications), and functional data indicate that most CACs show far less dependence on Wnt signaling than sCRC, suggesting a distinct pathogenesis from the earliest stages. Although there are significant gaps in our knowledge of the pathogenesis of CAC, our understanding is growing. This review summarizes how chronic colitis reshapes epithelial homeostasis and somatic evolution, resulting in the distinctive pathogenesis of CAC, and highlights knowledge gaps that could be addressed by applying multimodal technologies to well-annotated clinical material. The review is structured in two sections, the first introducing the IBDs and the homeostatic mechanisms that preserve integrity and prevent colorectal neoplasia. The second section compares failure modes in sporadic and colitic settings and describes the differences in the resulting neoplasms.

Transforming growth factor-β (TGF-β) signaling plays a central role in lung tissue homeostasis, coordinating epithelial repair, immune resolution, and stromal remodeling following injury. However, persistent or dysregulated TGF-β activation is a hallmark of both idiopathic pulmonary fibrosis (IPF) and lung cancer, two devastating pulmonary diseases that are traditionally studied as distinct entities. Emerging evidence suggests that this dichotomous view may obscure shared pathogenic mechanisms driven by aberrant TGF-β signaling dynamics. In this review, we synthesize experimental, translational, and clinical findings to propose a unifying framework in which IPF and lung cancer represent endpoints along a shared TGF-β-driven pathological continuum. We highlight how the duration and intensity of TGF-β signaling determine divergent cellular outcomes across epithelial cells, fibroblasts, and immune compartments-ranging from physiological wound repair to irreversible fibrotic remodeling and the establishment of a pro-tumorigenic niche. Particular emphasis is placed on the temporal transition from acute injury responses to chronic signaling states that promote epithelial plasticity, fibroblast fixation, immune suppression, and genomic instability. By integrating fibrosis and tumorigenesis into a single pathophysiological model, this review reframes TGF-β signaling as a time-dependent disease modifier rather than a disease-specific factor. This perspective provides a conceptual basis for therapeutic strategies targeting TGF-β signaling windows to intercept disease progression before irreversible fibrosis or malignant transformation occurs.

In our Special Issue titled "Molecular Mechanisms of Liver Metastases," we aimed to attract articles that connect metastasis mechanisms and biomarkers with clinical disease characteristics and patient outcomes [...].

Background. NOTCH receptors play a pivotal role in carcinogenesis. Upon ligand binding, a cascade of proteolytic cleavages mediated by ADAM proteases and the γ-secretase complex activates the receptor, ultimately releasing the NOTCH intracellular domain (NICD). NICD translocates to the nucleus, where it regulates gene expression. This review mainly aims to evaluate γ-secretase inhibitors (GSIs) as anticancer agents in preclinical and clinical settings, with a focus on their ability to block tumor progression, target cancer stem cells, and overcome resistance to standard therapies. Methods. A systematic search was conducted in the ISI Web of Science, PubMed, and Scopus databases, following PRISMA guidelines. The review included preclinical in vitro and in vivo studies, as well as clinical trials, investigating GSIs, either as monotherapy or in combination with other treatments, in TNBC, metastatic melanoma, PDAC, gastric cancer, and NSCLC. Exclusion criteria included duplicates, non-English articles, studies published before 2010, studies on non-cancer conditions, research unrelated to NOTCH signaling, and studies outside the selected cancer types. Overall, 69 articles were included and categorized into the five types of cancer analyzed (20 on NSCLC, 22 on TNBC, 11 on metastatic melanoma, 7 on GC, and 9 on PDAC). Of these, 60 studies corresponded to preclinical research in the types of cancer, and 9 studies corresponded to clinical trials in the types of cancer except for GC. Two independent authors screened and extracted relevant data, with disagreements resolved by the corresponding author. Findings were synthesized qualitatively across cancer types under study. Results. This review summarizes therapeutic advances involving GSIs in cancers driven by oncogenic NOTCH signaling, based on the 69 articles included. Preclinical studies show that GSIs synergize with chemotherapy and radiotherapy, particularly in NSCLC, melanoma, and TNBC, and block EMT, overcome therapeutic resistance, and improve prognosis. Commonly used GSIs include DAPT and RO4929097, which enhance the efficacy of agents, such as gemcitabine (PDAC), paclitaxel, osimertinib, erlotinib, and crizotinib (NSCLC), and 5-FU (gastric cancer, TNBC). Promising strategies include combining GSIs with SAHA, ATRA, CB-103, and other NOTCH signaling targeting molecules, either alone or with chemo- and radiotherapy. Clinical trials with GSIs, however, remain limited. RO4929097 is the most extensively tested GSI in clinical settings. PDAC trials combining GSIs with gemcitabine showed no benefit; melanoma trials yielded modest outcomes; and TNBC trials demonstrated partial responses to GSIs but overall low efficacy and significant adverse events. Discussion and Conclusions. Despite encouraging preclinical evidence, clinical trials with GSIs have underperformed, largely due to tumor heterogeneity, dosing limitations, and the non-selective nature of γ-secretase inhibition. Other NOTCH inhibitors, such as DLL4 antibodies, also resulted in partial responses and secondary effects. Future strategies should prioritize receptor-specific NOTCH inhibitors, patient stratification based on NOTCH pathway activation, and optimized combination regimens. Emerging approaches include integrating immunotherapy with advanced technologies such as CRISPR, CAR-T cells, and bispecific antibodies, as well as targeted delivery systems to enhance efficacy and reduce toxicity. Additional research directions include addressing the tumor microenvironment and EMT-driven resistance, elucidating the mechanisms of immune evasion, and inhibiting tumor angiogenesis. Finally, leveraging artificial intelligence and big-data-driven personalized medicine, including sex-specific considerations, will be essential for improving patient outcomes.

The etiology of pediatric cancers is unique, stemming from developmental dysregulation rather than acquired mutations from carcinogenic exposure. These diseases demonstrate vastly different underlying genetic and epigenetic alterations and unique tissue microenvironments which are only now beginning to be explored. While many pediatric cancers have seen improved overall and event-free survival rates thanks to innovations in diagnosis and treatment, many have seen little to no improvement in patient outcomes. This highlights a critical need for additional research into the underlying genetic and epigenetic alterations in these pathologies. Non-coding RNAs (ncRNAs) are functional RNA molecules known to regulate gene expression at epigenetic, transcriptional, and translational levels and can serve as biomarkers of disease. Here, we examine current knowledge of the roles of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in the onset, progression, and therapeutic response of pediatric solid tumors. We discuss the current and future potential and pitfalls of these molecules as therapeutics and biomarkers and highlight critical knowledge gaps where future research might provide insight to improve current therapeutic strategies and improve clinical outcomes.

Chemoresistance remains a major barrier to effective colorectal cancer (CRC) therapy, yet its metabolic underpinnings are poorly defined. Here, we integrate lipidomic profiling, enzymatic analysis, and functional perturbation approaches to elucidate the contribution of phosphatidylcholine (PC) metabolism and its biosynthetic regulator Choline Phosphotransferase 1 (CHPT1) to drug response. Comparative analysis of chemosensitive and chemoresistant CRC cell lines revealed that resistant HT29 cells exhibited significantly higher PC content and altered PC/lysophosphatidylcholine (LPC)ratios relative to sensitive counterparts. Importantly, functional perturbation confirmed causality: CHPT1 overexpression in SW620 cells was sufficient to promote PC accumulation and confer a chemoresistant phenotype. These findings identify CHPT1 as a metabolic gatekeeper of chemoresistance. Consistently, Human Protein Atlas survival analyses further support its clinical relevance, as elevated CHPT1 expression correlates with poor patient outcomes in CRC. Mechanistically, CHPT1-driven PC enrichment may sustain pro-survival signaling, while reducing lysophospholipid-mediated stress pathways. To therapeutically target this vulnerability, we investigated edelfosine (Edel), an alkyl-lysophospholipid that disrupts lipid rafts and inhibits PC biosynthesis upstream of CHPT1. Notably, edelfosine-mediated disruption of the Kennedy pathway enhances chemosensitivity in the resistant CRC model. Collectively, our study identifies CHPT1 and PC metabolism as central determinants of CRC drug response and proposes edelfosine-based metabolic reprogramming as a promising strategy to overcome resistance.

The heterogeneity of colorectal cancer (CRC) represents a great challenge in therapy. We integrated multiomics and machine learning, interpreted by SHAP models to provide a clinical rationale, to identify Calcineurin B Homologous Protein 2 (CHP2) as a core candidate, which was further validated via in vitro and zebrafish models. The expression of CHP2 are decreased in CRC, which is associated with a poor prognosis and an immune suppressed "cold" TIME. Functionally, CHP2 overexpression inhibits cell growth and invasion by inducing PANoptosis. Clinically, specific CHP2 expression profiles discriminate patients at high risk that are resistant to standard chemotherapy (e.g., 5-FU) but sensitive to targeted inhibitors. CHP2 is a powerful dual-function biomarker-prognostic for survival and predictive for the response to therapy-that could lead to a personalized approach in treating drug-resistant CRC.