The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway is a central regulator of B cell biology, influencing survival, proliferation, metabolism, and immune responses. This Review explores how in both normal and malignant B cells, signaling operates within a finely tuned "comfort zone", where appropriate levels support cell growth and survival. This comfort zone is dynamically modulated by the developmental stage, costimulatory signals, and the duration, magnitude, and subcellular localization of signaling events. In chronic lymphocytic leukemia, aberrant PI3K/AKT activation drives disease progression and resistance to therapy. Notably, deviations from the comfort zone-whether through excessive hyperactivation or insufficient signaling-can trigger cell death, presenting therapeutic opportunities. Signaling thresholds influence normal B cell development and chronic lymphocytic leukemia pathogenesis, including mechanisms of immune escape and Richter's transformation, an aggressive progression from chronic lymphocytic leukemia. Therapeutic strategies targeting PI3K/AKT are evaluated, with a focus on challenges such as toxicity. By understanding the nuanced modulation of the signaling comfort zone, we can refine therapies to selectively eliminate leukemic cells while preserving normal B cell function, offering new hope for improved treatment outcomes.

Cancer remains a leading cause of mortality worldwide, with genetic alterations such as single nucleotide polymorphisms (SNPs) playing a critical role in tumor progression and therapy resistance. Non-synonymous SNPs (nsSNPs) in AKT2, a key kinase in the PI3K/AKT signaling pathway, can impact protein structure and function, leading to reduced efficacy of targeted cancer therapies. This study employs computational approaches to investigate the structural and functional consequences of nsSNPs in the AKT2 and their impact on inhibitor interactions. Three structurally and functionally significant nsSNPs (Y265N, R274H, and R467W) were identified where only R274H and R467W were associated with reduced inhibitor binding. R274H, and R467Wwere found to disrupt key molecular mechanisms, including metal binding, loss of allosteric sites, and alterations in post-translational modifications. Molecular docking revealed that R274H, in kinase domain, disrupts key hydrogen bonds with THR292 and GLU279, leading to more flexible binding pocket and significantly reduced binding affinity for Capivasertib and Ipatasertib. Similarly, R467W, in AGC-kinase C-terminal domain, causes the loss of hydrogen bonds with THR292, ASN280, and GLU279, leading to decreased binding affinity for Akt1/Akt2-IN-1, Capivasertib, and Ipatasertib inhibitors. MD simulations further demonstrated that R274H and R467W caused substantial structural deviations and increased residue flexibility, with R467W exhibiting the most pronounced destabilizing effect. These findings suggest that these mutations may contribute to inhibitor resistance by weakening inhibitor interactions and destabilizing the protein-inhibitor complex. This study underscores the importance of genetic screening in optimizing cancer treatment and highlights the need for mutation-specific therapeutic strategies targeting AKT2.

T-cell receptor (TCR) repertoire diversity has been implicated in the progression and prognosis of multiple myeloma (MM). This study aimed to evaluate the association between T-cell clonality, immune response, and clinical outcomes in patients with plasma cell dyscrasias using next-generation sequencing of the TCR β chain (TCRB). TCRB sequencing was performed on peripheral blood samples from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma (MM). Healthy individuals served as controls. No significant differences in TCR repertoire diversity were observed between healthy individuals and those with MGUS, SMM or MM after adjusting for age. Furthermore, TCR diversity did not correlate with treatment response in newly diagnosed MM or SMM patients. However, machine learning analysis revealed distinct TCR clusters differentially abundant between healthy individuals and those with plasma cell dyscrasias, exhibiting different amino acid properties. These findings suggest that shared T-cell receptor specificities among patients with plasma cell dyscrasias reflect underlying differences in antigen recognition and underscore the need for further studies to unravel the functional and clinical significance of these distinct immune signatures.

LLT1 is a novel immune checkpoint molecule and potential therapeutic target. Immunotherapy has improved outcomes in advanced gastric cancer; however, many patients do not respond or develop resistance, and predictive biomarkers are lacking. The role of LLT1 in gastric cancer immune evasion and its effect on immunotherapy response remain unclear. To assess this, LLT1 expression was analyzed in the Cancer Genome Atlas (TCGA) gastric adenocarcinoma dataset using multiple algorithms (TIMER, CIBERSORT, and ESTIMATE) to quantify immune cell infiltration. Protein expression was validated by immunohistochemistry (IHC) in 268 gastric adenocarcinoma samples and by multiplex immunofluorescence (MIF) in 115 post-immunotherapy tissues. Integrated transcriptomic and proteomic data were analyzed for associations with tumor microenvironment features and clinical immunotherapy outcomes. The results showed that high LLT1 protein expression was significantly associated with less advanced tumor characteristics (lower invasion depth and nodal metastasis; P < 0.05) and longer overall survival (P = 0.012). LLT1 mRNA and protein levels correlated with greater CD8+ T-cell and M1 macrophage infiltration and elevated PD-L1 expression in the tumor microenvironment. Among the first cohort of 198 patients with available prognostic data, patients with high LLT1 expression (n=117) demonstrated significantly longer overall survival compared to those with low expression (n=81). In the second cohort of patients treated with combined immunotherapy and chemotherapy, tumors with high LLT1 expression (n=48) had longer progression-free survival (P = 0.014) than those with low LLT1 expression (n=67). A significant increase (P < 0.05) in PD-1+CD161+ immune cell populations was observed in Immunotherapy-effective patients (n=62) relative to treatment-resistant patients (n=53). Conclusively, LLT1 expression is a promising biomarker of a favorable prognosis in gastric cancer. To our knowledge, this is the first study to demonstrate that LLT1 expression predicts improved response to combined chemotherapy and immunotherapy in gastric cancer, supporting its potential in guiding immunotherapeutic strategies.

Colorectal cancer (CRC) is a leading cause of global cancer-related mortality, necessitating the identification of novel therapeutic targets. Integrating genetic and transcriptomic data may reveal key molecular drivers of CRC progression and treatment opportunities.

The success of targeted therapy in non-small cell lung cancer (NSCLC) hinges on the precise identification of driver alterations, including mutations, gene fusions, and amplifications. Next-generation sequencing (NGS) has emerged as a comprehensive molecular diagnostic tool, capable of detecting both known and novel genomic aberrations, providing critical support for personalized NSCLC treatment. However, NGS remains a complex and technically challenging method. Despite its widespread adoption, NGS still faces some challenges, including technical complexity and prolonged turnaround times. Here, the ISO15189-certified NGS workflow implemented in the clinical laboratory is introduced. The standardized protocol encompassed tumor cellularity assessment (≥20 %), DNA extraction from formalin-fixed paraffin-embedded (FFPE) tissues (DNA input ≥ 50 ng), automated library preparation, and bioinformatics analysis. By integrating stringent quality control (QC) measures at each step, the workflow ensures high data reliability. Besides, the key innovation in workflow was the automation of NGS library construction. The automated system of NGS library construction included end repair, A-tailing, adapter ligation, hybridization capture, and purification, effectively minimizing human error, enhancing experimental reproducibility, reducing hands-on time, and thus improving efficiency. Together, experience demonstrates that rigorous QC and automated library preparation are essential for maintaining accuracy and scalability in clinical NGS testing. This optimized approach not only ensures compliance with ISO15189 standards but also supports the growing demand for precision oncology in NSCLC management.

Radiation exposure is a well-established risk factor for leukemia. Clonal hematopoiesis (CH), the expansion of mutated hematopoietic cells, is also associated with increased leukemia risk and its frequency is higher in cancer patients following radiotherapy and chemotherapy. We investigated whether low to moderate environmental ionizing radiation determined by state-of-the-art dosimetric analysis was associated with CH in the Chornobyl Family Study (CFS). Our study conducted targeted high-depth sequencing and array genotyping to identify and characterize clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) in 882 participants from 292 CFS families. Fathers had mean bone marrow radiation doses of 0.24 Gy (range: 0-3.86) and mothers had mean doses of 0.009 Gy (range: 2 × 10-5-0.63). The expected relationship between increasing age and CHIP was observed. No detectable effect of red bone marrow radiation dose was observed for CHIP risk (Fathers: Excess OR (EOR)/Gy = 0.41; 95% confidence interval (CI) = -0.57,1.39; P-value = .42; Mothers (categorical model due to limited dose range): odds ratio (OR)0.01-0.09 versus <0.001 Gy = 0.73; 95% CI = 0.39,1.38; P-value = .33) and the distribution and types of CHIP and mCAs detected in CFS participants did not differ from that seen in previously published studies of unexposed populations. No transgenerational effect of parental gonadal radiation exposure was detected in the children (Fathers: P-value = .08; Mothers: P-value = .67). Our findings suggest the type and levels of radiation exposure investigated in CFS families are unlikely to be strong contributors to CH risk, which could have important implications for public health concerns following environmental exposure to low to moderate ionizing radiation.

Atomic bomb survivors have been found to have an excess risk of late adverse effects, including leukemia, various solid cancers, and non-cancer diseases, depending on the dose of radiation exposure. Radiation-induced DNA damage can lead to errors in DNA repair, resulting in the induction of somatic mutations in cells. Since these mutations are thought to contribute to an increased risk of radiation-induced carcinogenesis, various approaches, such as mutation analysis at specific genetic loci and chromosomal analysis, have been used to investigate their characteristics. However, previous methods were only capable of detecting a subset of radiation-induced mutations, making it difficult to quantitatively and comprehensively capture their specificity, including the mutation spectrum. Recently, whole-genome sequencing combined with of ex vivo single-cell culture has enabled a comprehensive analysis of radiation-induced mutations in individual cells. Such studies, including our own, have demonstrated that short, non-repeat deletions occurring outside of tandem repeats represent the most distinctive signature of radiation-induced mutagenesis, showing clear dose dependence and consistency across multiple tissues. Structural variants (excluding retroelement insertions) and multisite mutations also showed radiation specificity, albeit to a lesser extent and at a lower frequency than non-repeat deletions. These findings may offer insights into the molecular mechanisms underlying radiation-induced oncogenesis and non-cancer disease development.

We present a case of a 41-year-old non-smoker male patient presenting with ameloblastoma which metastasized to the lung 14 years post excision of the primary mandibular tumor. A biopsy of the pulmonary mass was initially diagnosed as squamous cell carcinoma by a non-specialist pathologist who was not provided a history of the patient's prior ameloblastoma diagnosis. The patient subsequently underwent neoadjuvant chemo-immunotherapy followed by surgical resection of the lung mass. The definitive diagnosis of metastasizing ameloblastoma (MA) was made on the surgical resection and compared to the original mandible lesion. Confounding morphological features were attributed to the impact of neoadjuvant treatment. Molecular analysis of the metastasis and original jaw lesion revealed a mutation of AKT1 (c.49G > A p.(Glu17Lys) COSMIC ID: COSM33765) but no mutations in the BRAF gene were identified. This case illustrates the critical necessity of a thorough clinical history of previous neoplasia, even many years following treatment, as well as the role of molecular profiling for identifying novel targeted treatment options.

The 2021 WHO classification describes a specific subgroup of diffuse midline glioma, H3 K27-altered (DMG-H3 K27-altered), which arises in the thalamus or other midline structures. To date, the prognosis of thalamic DMG-H3 K27-altered remains controversial, and no studies have compared its overall survival (OS) with that of glioblastoma (GBM). The present study aimed to compare the clinical features and survival outcomes of patients with thalamic DMG-H3 K27-altered and those with thalamic GBM.

RAD21, a key cohesin subunit, participates in chromatin regulation and may influence tumor metabolism and immunity. Its role in liver HCC remains unclear. We investigated whether RAD21 regulates PON1 and how this axis integrates metabolic and immune signals in HCC. Multi-omics integration (transcriptomic, ChIP-seq, and scRNA-seq) datasets to identify the RAD21-PON1 regulatory axis, with immune infiltration, metabolic remodeling, and prognostic impact assessed via GSVA, TIDE, and LASSO modeling. RAD21 upregulation inversely correlated with PON1 expression. RAD21 binds the promoter of PON1, impacting metabolic pathway activity and shaping the immune microenvironment. Low PON1 expression was linked to immunosuppressive patterns and poor prognosis. A RAD21-PON1 risk signature robustly stratified survival. Our findings highlight the RAD21-PON1 axis as a central regulator connecting metabolism and immunity in HCC, providing prognostic and therapeutic insights.

Adenocarcinoma and adenosquamous carcinoma of the cervix together account for up to 20% of all cervical cancers. These histologic subtypes are characterized by a worse prognosis compared with squamous cell cancer of the same grade and have specific epidemiologic, morphologic and molecular features. Despite fundamental differences, therapeutic approaches for cervical cancer are similar regardless of tumor histology. This article discusses promising companion diagnostic markers for cervical cancer treatment, including MSI, PD-L1 and TIL's, that may find application in the therapy of prognostically unfavorable subtypes of cervical cancer. The literature review revealed that despite the low frequency of immunotherapy markers among adenocarcinomas and adenosquamous carcinomas of the cervix, analyzing them will allow us to identify a group of patients who will benefit most from immunotherapy, a key step towards improving treatment outcomes.

Germ cell tumors are rare testicular neoplasms that occur in young men, and their proportion is 2%. Pathological changes in the immune landscape of seminoma - the interaction of mast cells, T-, B-lymphocytes and macrophages with atypical spermatogenic cells, possibly impart a certain uniqueness to seminoma, and their number determines the stage of tumor growth. At the same time, the question of the participation of mast cells in the progression of seminoma remains debatable.

Lung adenocarcinoma (LAC) is one of the leading causes of cancer mortality, which is most likely due to the presence of cancer stem cells (CSC) in the tumor, which form a heterogeneous hierarchy and are responsible for the occurrence and progression of carcinoma, as well as its unfavorable prognosis. The ability of CSC to form heterogeneous tumor populations in lung cancer has not been sufficiently studied.

One of the main prognostic factors for meningioma recurrence is histological diagnosis with an assessment of tumor grade. Despite this, there are no clear microscopic criteria for recurrence prognosis in benign forms, and there is no common understanding of meningioma recurrence and continued growth clinical management.

To study the microenvironment features of MMR-proficient (pMMR) and MMR-deficient (dMMR) endometrial cancer.

Thyroid transcription factor 1 (TTF1) is the most common and reliable marker for immunohistochemical diagnostics of various thyroid tumors and lung adenocarcinoma. At the same time, some of scientific studies have been published that describe aberrant expression of TTF1 by cells of various tumors, including lymphomas. Researchers reported the possibility of TTF1 expression in diffuse large B-cell lymphoma, angioimmunoblastic T-cell lymphoma, and T-cell leukemia. However, there were no reports of this marker expression in anaplastic large cell lymphoma, which, due to its morphological characteristics, may resemble a metastatic process.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with high-risk cases showing increased aggressiveness and poor prognosis. Recent studies suggest that long noncoding RNAs (lncRNAs) such as C6orf223 may play crucial roles in CRC progression. This study investigated the expression and regulatory role of C6orf223 in high-risk versus low-risk CRC patients, focusing on its potential as a biomarker for diagnosis and prognosis. We conducted differential expression analysis using RNA-seq data to identify key genes in high-risk CRC, followed by correlation and pathway enrichment analyses to understand C6orf223. Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves assessed the prognostic and diagnostic potential of C6orf223. RNA methylation and mutation patterns were analyzed to explore post-transcriptional regulation and genetic alterations in high-risk CRC. C6orf223 was significantly upregulated in high-risk CRC. High C6orf223 expression was associated with poor overall survival, and a biomarker panel that includes C6orf223 and microRNAs showed strong potential for accurate diagnosis. Methylation and mutation analyses revealed potential mechanisms enhancing C6orf223's stability and oncogenic activity. Our findings indicate that C6orf223 acts as a binder to and inhibits tumor-suppressive microRNAs, reducing their availability to regulate cancer-promoting genes and may serve as a valuable biomarker for CRC diagnosis and prognosis. Further research on lncRNA-microRNA interactions could provide insights for novel CRC therapies.

Cisplatin resistance presents a significant challenge in cancer therapy, emphasizing the necessity for identifying new regulatory elements that influence drug response. Recent research has revealed the importance of long noncoding RNAs (lncRNAs) in chemotherapy resistance, with LINC02381 identified as a potential regulatory factor. Through an in-depth bioinformatics analysis, we investigated the impact of LINC02381 on cisplatin resistance in ovarian cancer across various datasets. By conducting differential expression analysis, survival analysis, gene set enrichment analysis (GSEA), and constructing protein-protein interaction (PPI) networks, we identified key pathways associated with LINC02381 expression. The results indicated that the altered expression of LINC02381 in patients treated with cisplatin was associated with reduced survival. Functional studies and correlation analyses further demonstrated that this LncRNA influences critical pathways and genes related to apoptosis, efflux, DNA repair, and EMT. Lastly, through an examination of its interactions with microRNA and protein networks, we identified LINC02381 as a ceRNA implicated in cisplatin resistance. Our findings suggest that LINC02381 may influence cisplatin sensitivity in ovarian cancer and establish a basis for further experimental validation, including molecular assays or in vivo analyses, and suggest the potential therapeutic targeting of LINC02381 to combat chemoresistance.

Cervical cancer is a significant public health concern, particularly in women infected with the human papillomavirus (HPV). Recent evidence suggests that host genetic factors, specifically those related to the human leukocyte antigen (HLA) system, may also play a crucial role in determining susceptibility to cervical cancer in HPV-infected individuals. In this study, 86 patients with HPV and 27 healthy donors were selected from May 2023 to February 2024. HLA-DRB1 genotypes were determined using polymerase chain reaction followed by high-resolution melting curve analysis (HRM). Genotype frequencies in patients were compared with those in the control group from donors. Based on the HRM analysis, 10 genotypes were found in both patients and controls (profiles A-J). In the analysis of HLA-DRB1 genotypes, C, F, and I showed significant associations with HPV infection, indicating a possible protective effect against infection. Notably, genotype B was strongly linked to high-risk HPV, while genotype A was associated with low-risk HPV and is relevant to infection history. However, the remaining genotypes examined in the study did not exhibit significant associations with the analyzed parameters. This study contributes valuable evidence regarding the role of HLA-DRB1 genotypes in cervical cancer susceptibility and highlights the potential clinical implications for risk assessment and targeted immunotherapies. The use of HRM for HLA typing offers advantages that are efficient, accurate, and scalable, making it suitable for large-scale studies and clinical applications.