Nucleolar-spindle-associated protein 1 (NUSAP1) participates in the assembly of microtubules and the mitotic spindle. Mitotic spindles are microtubule-based structures that segregate chromosomes during mitosis. Its overexpression and knockdown caused alterations in gene expression programs linked to tumor progression. It was also identified as one of the potential hub genes in various cancers, including the mediation of hepatocellular carcinoma. The present research addresses the NUSAP1 protein structure refinement and its targeting by the lead molecules identified using various computational approaches. The initial structure of NUSAP1 from the Alpha fold database is evaluated using the Ramachandran plot and subjected to multiple energy minimization steps through the YASARA program. The best-optimized structure of NUSAP1 is obtained and subjected to binding site analysis and virtual screening studies using I-TASSER and Mcule webservers, respectively. From the binding site analysis, His293 was considered the ligand binding site for docking ligands by AutoDock Vina. Selected ligands from the Mcule chemical library were chosen through various filters, and 50 hits were identified for further studies. Among the 50 hits, 27 were identified as non-toxic molecules using a toxicity checker. Further, based on the RO5 violation check, 18 hits exhibited no RO5 violations. Further, for all 18 hits, LigPlot analysis was performed, and 11 hits exhibited hydrogen and hydrophobic interactions with the NUSAP1 protein. Among 11, three hits showed promising hydrogen and hydrophobic interactions near the potential binding site His293. For the promising three hits with Mcule IDs 9300000909-0-6, 9753624331-0-3, and 1764527053-0-4, ADMET properties were predicted using the PreADMET server. The comparative studies of drug-likeness properties found that all three hits do not violate Lipinski's rule of 5. The comparative studies of ADME properties of three hits found that the 9753624331-0-3 compound exhibits non-inhibiting properties in liver enzymes and p-glycoprotein inhibition. Furthermore, 9753624331-0-3 is computed as the lowest solvation-free energy of -18.1300000 and found to be non-mutagenic, negative for all toxicity studies, including the Ames test, fishes, rats, mice, and daphnia. Based on the drug-likeness, ADME, and toxicity predictions, the 9753624331-0-3 presented favorable properties and hence may be considered the potential lead targeting the NUSAP1 protein.

Immunogenic cell death (ICD) is a regulated form of cell death that elicits an adaptive immune response, recognized as a promising strategy in cancer immunotherapy. Its therapeutic efficacy, however, can be influenced by tumor-intrinsic factors, particularly in heterogeneous diseases like breast cancer (BC). This study investigated the ICD-related gene expression signature in BC using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) cohorts. Analysis revealed significantly elevated expression of HSP90AA1, CXCR3, MYD88, FOXP3, PDIA3, XBP1, and IFNB1, and reduced expression of P2RX7 in BC tissues compared with normal tissues. Furthermore, the expression of these genes varied significantly across distinct BC subtypes, patient ages, and tumor stages. Concurrently, an investigation into the UPR pathway, known to intersect with ICD, highlighted Binding immunoglobulin Protein (BiP/GRP78/HSPA5) as a molecule of interest. To explore potential modulators of this pathway, in silico docking studies were performed, which predicted favorable binding interactions of quercetin and taxifolin with BiP. These findings suggest that characterizing the expression patterns of these ICD-related genes and UPR components could inform the development of personalized immunotherapeutic strategies for BC, tailored to specific tumor subtypes, stages, and patient demographics. Further exploration of BiP's role and its potential for therapeutic manipulation may offer novel avenues to enhance anti-tumor immunity.

Breast cancer is the most common cancer diagnosed in women. Increased exposure to oestrogens is one of the major risk factors for breast cancer. The synthesis of estrogens is mediated by the aromatase enzyme that encoded by CYP19A1 gene. Further, highest aromatase activities were documented in tumor-associated stroma tissues of breast. Genetic polymorphisms in CYP19A1 gene are known to modulate the estradiol and to the estradiol/testosterone ratio. The rs10046 T>C polymorphism in the 3' untranslated region of CYP19A1 gene has been linked to the risk of breast cancer. The studies conducted till date are not consistent in reporting the association of rs10046 polymorphism with breast cancer. In the present study, we have conducted a meta-analysis of data available for CYP19A1 rs10046 T>C and breast cancer from 23 studies. The outcome of the present meta-analysis showed that there is no association between rs10046 polymorphism and breast cancer risk in all genetic models [C vs. T: odds ratio (OR) = 0.99, confidence interval (CI) = 0.88-1.23; CC vs. TC + TT: OR = 1.02, CI = 0.88-1.18; TC + CC vs. GG: OR = 0.97, CI = 0.80-1.17]. Further, ethnicity based subgroups also failed to show the association between breast cancer and rs10046. Begg's funnel plots and Egger's tests did not reveal evidence for publication bias (Egger's P value = 0.832). In summary, the rs10046 T>C polymorphism on CYP19A1 is not a major risk factor for breast cancer.

Key molecular pathways involved in colorectal cancer (CRC) progression include the activation of the heat shock protein 90 (HSP90) pathway, PI3K/AKT, TP53, and mismatch repair (MMR) pathways. In the current study, we identified that FKBP4 is overexpressed at the transcript and translational levels in CRC patient samples, suggesting it may be a predictive biomarker for diagnosis. Our STRING network data analysis identified a strong association (string score: 0.999) between FKBP4 and HSP90. HSP90 is involved in stability, transportation, and protein folding. TCGA CRC patient samples data revealed a strong positive correlation between FKBP4 and HSP90. Furthermore, molecular docking, dynamics simulations, and hydrogen bond analysis confirmed a strong interaction between FKBP4 and HSP90, suggesting its importance in CRC cell survival and progression. These findings highlight that disrupting the FKBP4-HSP90 complex could be a promising therapeutic approach for CRC.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (IFN) genes (STING) pathway emerges as a dual-functional role in urologic malignancies, exhibiting context-dependent tumor-suppressive and pro-tumorigenic activities. When this pathway is activated in urologic tumors, IFN transcription and CD8+ T cell infiltration are triggered, which has an anticancer effect. However, this pathway facilitates the development of prostate cancer through the up-regulation of regulatory B cells. STING palmitoylation triggers immune escape in renal cell carcinoma, and the STING/SLC14A1 axis also mediates chemoresistance in bladder cancer.

The immune microenvironment of the three most common gynaecological malignancies-tubo-ovarian cancer, endometrial cancer and cervical cancer-has not been systematically studied, limiting clinical application.

Tropomyosin 3 (TPM3), one of the four tropomyosin genes, is predominantly expressed in eukaryotic cells. As a crucial regulatory protein, TPM3 associates with actin within thin myofilaments, thereby playing an essential role in the regulation of muscle contraction. Beyond its fundamental function in muscle physiology, TPM3 is implicated in oncogenesis.

The causal relationship and mechanisms connecting Vitamin B12 (VB12) deficiency anemia, red cell distribution width (RDW), and prostate cancer (PCa) remain unclear due to small, methodologically limited studies.

Pediatric diffuse low-grade gliomas (LGGs) are heterogeneous group of central nervous system tumors that typically exhibit a relatively benign clinical course. These tumors represent a unique classification in pediatric neuro-oncology, distinct from adult counterparts in terms of biological behavior, molecular pathways, and clinical presentation. The evolving World Health Organization classification system has increasingly relied on combination of histopathologic, genetic, and radiologic criteria to define and distinguish among pediatric glioma subtypes. This article aims to synthesize current knowledge regarding the clinical, molecular, and radiologic features of these pediatric diffuse LGGs and highlights the nuances in diagnosis, treatment approaches, and prognostic outlook.

The 5th edition of the WHO CNS tumor classification (2021) emphasizes molecular alterations, especially in pediatric tumors, integrating histology with molecular profiling for precise diagnosis. Advances like DNA methylation profiling and Next Generation Sequencing have refined tumor subtypes, influencing targeted therapies. Radiogenomics correlates imaging features with genetic profiles, enabling non-invasive tumor characterization, crucial in pediatric cases where biopsies are risky. Artificial intelligence, including machine learning and deep learning, enhances image analysis, segmentation, and prediction of molecular markers, supporting personalized treatment. Despite challenges like data variability and ethical concerns, these technologies promise to revolutionize pediatric neuro-oncology.

Tumor predisposition syndromes (TPS) are inherited cancer syndromes linked to approximately 10% of all cancers and up to 20% pediatric central nervous system (CNS) tumors. TPS manifest with characteristic patterns of neoplasms throughout the body and require targeted, region-specific imaging for surveillance. Advances in cancer genomics have allowed options for therapies targeting specific molecular pathways. This article highlights CNS imaging features of TPS, with additional insights into the underlying genomic alterations that lead to their development.

The in vitro mouse lymphoma assay cell (MLA) is one of the most widely practiced assays in genetic toxicology. MLA detects forward mutations at the thymidine kinase (Tk) locus of the L5178Y (Tk+/- 3.7.2C) cell line derived from a mouse thymic lymphoma. This assay is capable of detecting a wide range of genetic events including point mutations, deletions (intragenic) and multilocus, chromosomal rearrangements, mitotic recombination and non-disjunction. There are two equally accepted versions of the assay, one using soft agar cloning and the second method using liquid media cloning in 96-microwell plates. There are two morphologically distinct types of mutant colonies recovered in the MLA: small and large colony mutants. The induction of small colony mutants is associated with chemicals inducing gross chromosomal aberrations whereas the induction of large mutant colonies is generally associated with chemicals inducing point mutations. The source and karyotype of the cell line as well as the culture conditions are important variables that could influence the assay performance. The assay when performed according to the standards recommended by the International Workshops on Genotoxicity Testing (IWGT) and the Organization of Economic Cooperation and Development Test Guideline 490 is capable of providing valuable genotoxicity hazard information as part of the overall safety assessment process of various classes of test substances.

Breast cancer (BC) is the second leading cause of cancer-related deaths among women, primarily due to late-stage detection and therapy resistance. Therefore, identifying novel therapeutic targets is critical for improving BC outcomes. Long non-coding RNAs (lncRNAs) have recently emerged as promising candidates for cancer prognosis and treatment, owing to their ability to modulate oncogenic signaling pathways. Among them, the tumor-suppressive lncRNA Nkx2-2as has shown inhibitory effects in certain cancers; however, its role in BC remains poorly understood. To the best of our current knowledge, the relationship between Nkx2-2as and the Wnt/β-catenin signaling pathway in BC has not been previously characterized. To address this, we used computational tools including lncHUB2, RPISeq, GeneMANIA, TCGA and ENCORI to predict functional interactions of Nkx2-2as, which guided our focus toward its involvement in the Wnt/β-catenin signaling pathway, a key driver in BC progression. We hypothesized that Nkx2-2as may act as a pharmacologically actionable molecule in this context. To test this, MCF-7 breast cancer cells were transfected with either Nkx2-2as siRNA or an Nkx2-2as-pcDNA3.1 overexpression vector, individually and in combination. Overexpression of Nkx2-2as led to a significant reduction in proliferation (~ 85%), suppression of migration, and increased apoptosis. Conversely, silencing Nkx2-2as enhanced tumorigenic properties. Mechanistic analyses revealed that Nkx2-2as downregulates oncogenic targets such as β-catenin, TCF7 and MYC, while upregulating tumor suppressors AXIN2 and BTG2, the latter being a known inhibitor of β-catenin. Western blot analysis confirmed the transcriptional trends, showing decreased β-catenin and MYC and elevated BTG2 protein levels upon Nkx2-2as overexpression. These findings indicate that Nkx2-2as acts as a negative regulator of Wnt/β-catenin signaling through BTG2 activation, suggesting its potential role as a tumor suppressor and a candidate for RNA-based therapeutic strategies in BC. Targeting the Nkx2-2as/BTG2 axis may provide a conceptual framework for future studies aimed at developing RNA-based interventions to enhance chemosensitivity and overcome therapy resistance in BC.

Infantile hemangiomas (IHs) are the most prevalent noncancerous childhood tumors, affecting up to 10% of infants. IHs develop de novo and following excessive proliferation in the first 4-9 months; they typically degenerate spontaneously in 4-7 years. While treatment is not usually required, 10-15% of cases necessitate clinical or surgical intervention due to functional impairments. Here, we present a complicated capillary IH case, from a clinical and genetic perspective.

Gorlin syndrome (GS) or basal cell nevus syndrome type 1 (BCNS1) is a rare genetic disease belonging to the spectrum of genodermatoses. Here, we present a case with BCNS1 that was caused by haploinsufficiency of PTCH1 gene, which is associated with BCNS1.

Neuroblastoma (NB) is a common pediatric malignant tumor, accounting for approximately 13% of childhood cancer-related deaths. It has a poor prognosis, and its pathogenesis and genetic characteristics remain complex. Although recent studies have suggested a potential association between immune cells and NB, the causal relationship remains unclear. In this study, we utilized genome-wide association studies (GWAS) summary statistics of 731 immune traits (n = 3757) and three NB subtypes: MYCN-amplified NB (n = 5369), 11q-deletion NB (n = 5222), and 1p-deletion NB (n = 5178). We conducted Mendelian randomization (MR) analyses to assess the causal relationship between immune cells (exposure) and these NB subtypes (outcome). After false discovery rate (FDR) correction, neither 11q-deletion NB nor 1p-deletion NB showed significant associations with immunophenotypes. However, and only one immunophenotype was positively correlated with the risk of MYCN-amplified NB: HLA DR on monocyte (OR: 1.754 [95% CI = 1.288 to 2.390], p = 3.6 × 10-4, q value = 0.194). Reverse MR analysis did not support a causal effect of MYCN-amplified NB on HLA DR expression in monocytes. Sensitivity analyses further confirmed the stability and reliability of these findings. Our MR study provides strong evidence for a causal relationship between HLA DR on monocyte and MYCN-amplified NB, suggesting that elevated HLA DR expression may be a risk factor for this aggressive subtype. These findings could inform clinical decision-making regarding prognosis and treatment strategies for MYCN-amplified NB and may also identify potential therapeutic targets.

Galectins are a family of proteins that are involved in various aspects of cancer, including tumor growth, cell migration, invasion, and metastasis. Galectins are subdivided into three families: prototype (such as Gal-1), chimera type (such as Gal-3), and tandem repeat type (such as Gal-9). Despite the evidence linking galectins to the risk of neuroblastoma (NB), the causal association between galectins and NB remains unclear. The primary objective of this study is to clarify the causal effect of galectins (including Gal-1, Gal-3, and Gal-9) on NB risk through a two-sample Mendelian randomization (MR) study. The MR study was performed using summary statistics from extensive genome-wide association studies. Single-nucleotide polymorphisms (SNPs) related to the exposure variables were used as instrumental variables. The primary outcome was NB risk, and the exposure variables included Gal-1, Gal-3, and Gal-9. We chose inverse-variance weighted (IVW), constrained maximum likelihood and model averaging (cML-MA), MR-robust adjusted profile score (MR-RAPS), simple mode, weighted median, and weighted mode as the statistical methods to assess the causal effect; and the IVW method was the primary statistical method. Odds ratio (OR) and 95% confidence interval (CI) were used as the evaluation indices for causality. According to the IVW with fixed-effect results, genetically predicted Gal-9 was associated with an increased risk of NB (OR = 1.639, 95% CI 1.171-2.293, P = 0.004). Similar risk estimates were obtained using cML-MA, MR-RAPS, simple mode, weighted median, and weighted mode. Additionally, the IVW with fixed-effect revealed there was no statistically significant association between Gal-1 and NB (P = 0.605), or between Gal-3 and NB (P = 0.258). No evidence of reverse causality was observed in the MR Steiger test. The results of the leave-one-out sensitivity test confirmed the stability and reliability of the causal effect estimates. This study identified a possible causal association between Gal-9 levels and the risk of NB through a two-sample MR analysis, which might provide preliminary yet insightful findings into the role of Gal-9 in the development of NB. We hope that our findings would promote the exploration of therapeutic strategies for NB.

Recent developments in genetic testing have demonstrated that cancer predisposition syndrome (CPS) is present in approximately 15% of pediatric central nervous system (CNS) tumors; however, the optimal eligibility and timing of germline genetic testing in these patients have not been determined yet.

Afatinib, an irreversible ErbB family inhibitor, is approved for the treatment of non-small cell lung cancer (NSCLC) with both common and selected uncommon EGFR mutations. Evidence in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD) is scarce, especially with pharmacokinetic (PK) data. Here, we report the case of a patient with metastatic NSCLC harboring an EGFR G719C mutation who was successfully treated with afatinib during regular hemodialysis. Afatinib was initiated at 20 mg once daily under fasting conditions and later escalated to 30 mg once daily. PK sampling was conducted on two consecutive HD days at each dose level. At 20 mg, the trough concentration (Ctrough) was 4.02 ng/mL, with peak concentrations (Cmax) of 6.09 and 8.75 ng/mL, both lower than reported values in patients with normal renal function. At 30 mg, Ctrough increased to 26.3 ng/mL, while Cmax values of 48.2 and 55.5 ng/mL were comparable to steady-state exposures in patients with preserved renal function. Notably, no adverse events were observed, and the patient has maintained a partial response for over eight months. This case suggests that afatinib can be administered without major dose modification in HD patients, with PK data indicating minimal impact of dialysis and underscoring the importance of accumulating real-world evidence in this underrepresented population.

This phase 1 study aimed to determine the maximum tolerated dose (MTD) and evaluate the safety and preliminary efficacy of rucaparib (RUB), a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor, combined with liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU) in metastatic gastrointestinal (GI) cancers. RUB targets DNA repair pathways, showing efficacy in tumors with homologous recombination deficiency, such as BRCA mutations. Preclinical data suggest synergy with irinotecan, but overlapping toxicities pose challenges.