While acute myeloid leukemia (AML) treatment has significantly advanced in recent years, many promising novel agents remain unapproved in Japan. This review focuses on menin inhibitors and covers IDH inhibitors, oral azacitidine, antibody-drug conjugates, bispecific antibodies, radioisotope therapies, and CAR-T cell therapies for AML. Menin inhibitors, which are particularly effective against AML with KMT2A rearrangements or NPM1 mutations, have shown promising results in clinical trials. These novel agents may expand treatment options and improve outcomes for AML patients.

Acute myeloid leukemia (AML) is common in elderly adults and is a genetically heterogeneous disease. Many factors such as adverse chromosomal and/or genetic abnormalities contribute to disease risk, along with defining features related to antecedent hematologic disorders and a history of exposure to radiation or cytotoxic agents in the case of secondary AML. The "7+3" regimen combining cytarabine and anthracycline, along with its reduced-dose variant, was once the only first-line treatment option for AML in Japan. However, treatment options have expanded in recent years to include azacitidine with or without venetoclax, as well as CPX-351 and quizartinib combination chemotherapy. Nevertheless, there are still many high-risk conditions with a low chance of cure even with these new drugs or allogeneic transplantation, and many other issues remain to be addressed. This article outlines the current best treatment options and future prospects for high-risk disease types.

Acute myeloid leukemia (AML) is associated with various genetic abnormalities in its development and progression, which also affect treatment response and prognosis. The advent of gene panel testing is expected to clarify the involvement of these genetic mutations, which will provide useful information for treatment decision-making and prediction of prognosis in clinical practice. Some therapies have already been developed for actionable mutations: quizartinib for FLT3-ITD mutations is available for newly diagnosed AML, and ivosidenib for IDH1 mutations is awaiting approval. Knowledge of baseline genetic characteristics also allows for diagnosis according to the ICC 2022 and 5th edition of the WHO Classification, as well as risk stratification by the ELN2022 risk classification for patients receiving intensive chemotherapy and ELN2024 risk classification for patients receiving reduced-intensity chemotherapy. CPX-351, a liposomal formulation of cytarabine and daunorubicin, has also shown efficacy in patients with MDS-related gene mutations. Decisions on allogeneic transplantation and accessibility of investigational drugs are also expected. Detailed diagnosis and prognosis prediction based on the profile of genetic abnormalities should enable precision medicine.

Polycystic Ovary Syndrome (PCOS) is a common endocrine condition that affects women of reproductive age. The study used high-throughput sequencing to profile gene expression in PCOS and control samples. The sequenced reads were quality assessed and aligned to the human reference genome hg38 using FastQC and the Hisat2 aligner. The R software "DESeq2" identified 1193 differentially expressed genes (DEGs) in SRP224633 and 82 DEGs in SRP353681. Notably, 8 DEGs were shared by the two datasets, and a total of 1267 DEGs were found. GO analysis revealed that DEGs in SRP224633 were enriched in biological processes related to immune response and cell activation, whereas DEGs in SRP353681 were associated with response to external stimuli and immune processes. Pathway analysis highlighted the involvement of chemokine signaling receptor, and cytokine-cytokine receptor interaction pathways in both datasets. The STRING database was used to evaluate protein-protein interaction (PPI) networks. Hub genes like IL1B, PTPRC, ITGAM, TYROBP, ITGB2, FCGR3A, CCR7, SYK, TLR2, FCGR3B were identified as crucial nodes using Cytohubba plugins in Cytoscape, highlighting their potential role in PCOS pathogenesis. Regulatory networks discovered miRNAs such as has-mir-34a-5p, hsa-miR-26a-5p, has-let-7b-5p and transcription factors such as SP1, RUNX1, ER as possible regulators of target genes implicated in PCOS pathogenesis. LASSO regression and ROC analysis indicated certain hub genes, such as IL1B, PTPRC, ITGB2, FCGR3A, CCR7, FCGR3B as relevant biomarkers due to their high coefficients, emphasizing their significance in PCOS. CCR7, FCGR3A, FCGR3B, and ITGB2 have been discovered as novel genes with significant potential as PCOS biomarkers. Our research adds to a deeper knowledge of PCOS at the molecular level by offering an extensive understanding of the etiological reasons and molecular mechanisms. The discovered DEGs, pathways, and regulatory networks and novel biomarker are promising targets for future studies and treatments in PCOS management.

To assess the role of endothelial nitric oxide synthase (eNOS) in cervical cancer, we investigated the association between eNOS -786T/C and intron 4 VNTR 4b/a eNOS gene variations, plasma nitric oxide (NO) levels, cervical lesion occurrence, and disease progression. This study included 78 cervical lesions and 126 healthy controls. Genotyping was performed using polymerase chain reaction (PCR), and plasma NO levels were determined using the Griess reaction. We found that the -786C allele was significantly associated with cervical lesion risk (OR = 2.25; CI 95 % [1.15-4.41]; p = 0.025) and low-grade squamous intraepithelial lesion (L-SIL) risk (OR = 3.22; CI 95 % [1.09-9.686]; p = 0.042) but not with high-grade squamous intraepithelial lesion (H-SIL) and squamous cell carcinoma (SCC). Haplotype analysis showed that the C-4a haplotype was associated with a high risk of cervical lesion development (OR = 2.19, CI 95 % [1.149-4.2]; p = 0.025). Plasma NO levels differed depending on the eNOS variant genotype in cervical lesions and healthy controls. The presence of risk alleles (-786C and/or 4a) correlated with increased plasma NO levels in cervical lesions compared to healthy controls (p = 0.033 and p = 0.039, respectively). As well, the plasma NO levels were higher among cervical lesions than in healthy controls (p = 0.027), mainly among L-SIL (p = 0.004). Moreover, higher plasma NO levels were significantly associated with the presence of human papillomavirus (HPV) DNA among cervical lesions, as well as with a higher HPV circulating viral load. In conclusion, our findings highlight a significant association between eNOS genetic variants, plasma NO levels, and the occurrence and progression of cervical lesions.

Approximately 20% of individuals diagnosed with ovarian cancer (OC) have an inherited pathogenic or likely pathogenic variant (P/LP) in a cancer risk gene. Though genetic testing for hereditary cancer risk is currently recommended at OC diagnosis, individuals who have not received risk information and their at-risk relatives (ARR) can benefit from genetic testing at any point. In a single-arm implementation study, the Genetic Risk Assessment in Ovarian CancEr (GRACE) study offered traceback genetic testing using a panel of cancer risk genes to (1) living survivors with a prior OC diagnosis who had not received genetic testing at diagnosis and (2) first-degree relatives of deceased eligible probands with a prior OC diagnosis who had not received genetic testing. For survivors and first-degree relatives with a positive result (i.e., P/LP detected), we offered cascade testing to ARR, including providing support resources to facilitate communication with their relatives and offering to directly contact relatives. Traceback testing occurred on average 10-12 years from the incident OC diagnosis, resulting in 20 positive findings with 93 ARR eligible for cascade testing. Overall, cascade testing uptake was 38%, with similar rates among relatives of living (40%) and deceased (33%) probands. Cascade testing identified 11 individuals with OC-risk variants and 3 incidental findings in genes not associated with OC risk. Women were more likely to complete cascade testing than men (45% vs. 30%, respectively). Initially, only two probands consented to direct contact with ARR by the study genetic counselor; 6 additional probands requested direct contact with relatives over subsequent interactions. These findings represent some of the first U.S. data available on cascade testing outcomes of traceback programs and suggest feasibility and effectiveness in U.S. health system settings.

Studying intercellular and interorgan interactions in animal models is key to understanding development, physiology, and disease. We introduce EyaHOST, a system for clonal combinatorial loss- and gain-of-function genetics in fluorescently labeled cells under QF2-QUAS eya promoter control. Distinct from mosaic analysis with a repressible cell marker (MARCM), it reserves the use of genome-wide GAL4-UAS tools to manipulate any host tissue. EyaHOST-driven RasV12 overexpression with scribble knockdown recapitulates key cancer features, including systemic catabolic switching and organ wasting. We demonstrate effective tissue-specific manipulation of host compartments, including homotypic epithelial neighbors, immune cells, fat body, and muscle. Organ-specific inhibition of autophagy or stimulation of growth signaling via PTEN knockdown in fat body or muscle prevents cachexia-like wasting. Additionally, tumors trigger caspase-driven apoptosis in the neighboring epithelium, and blocking apoptosis with p35 enhances tumor growth. EyaHOST provides a modular platform to dissect mechanisms of intercellular and interorgan communication under physiological or disease conditions.

The TNFα content in the blood serum of 109 patients with uterine fibroids was studied. Cytokine concentrations ranged from 4.65 to 25.88 pg/ml regardless of the clinical parameters of the disease, but were associated with complex genotypes of different structural and functional organization (TNFA, IL1B, IL4, IL6, IL8, IL10, IL17A, VEGFA, MMP2, MMP3, MMP9). The interaction of multiple genes that affect the level of serum TNFα production has been revealed. In particular, on the one hand, the complex genotype TNF-308GG/VEGF-2578CA is positively associated with high levels of TNFα (OR = 10.00, pcor = 0.0274), and on the other hand, the combined genotype of 4 polymorphisms TNF-308GG/TNF-238GG/VEGF-2578AA/MMP2-1306CC is closely associated with its low level (OR = 25.00, pcor = 0.0469). The obtained results allow better understand the mechanisms of the manifestation of the genetic predisposition to uterine fibroids associated with the presence in the genome of highly specific gene compositions that underlie tumorogenesis in this disease.

Glioblastoma (GBM) is characterized by the highly infiltrative growth of cancer cells into the surrounding brain parenchyma. DnaJ Heat Shock Protein Family (Hsp40) Member C10 (DNAJC10, also known as ERDJ5 and PDIA19), involved in endoplasmic reticulum-associated degradation (ERAD), has been identified as a tumor suppressor in several cancers. However, its precise role and underlying mechanism in GBM remain unclear. We found that DNAJC10 expression is downregulated in GBM patients and correlated with poor survival outcomes. Overexpression of DNAJC10 reduced GBM cell migration and invasion in vitro, while its knockdown promotes these processes. Moreover, DNAJC10 overexpression inhibits infiltrative growth of GBM cells, suppresses tumor propagation and prolongs survival in xenografted mice. Mechanistically, DNAJC10 regulates multiple molecules and pathways involved in cell motility, including the epidermal growth factor receptor (EGFR) pathway. Importantly, DNAJC10 overexpression decreases EGFR transcription by inhibiting spliced X-box binding protein 1 (XBP-1s). DNAJC10 regulates XBP-1s splicing through the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response (UPR). XBP-1s binds the EGFR promoter and enhances recruitment of SET7/9 methyltransferase, H3K4me3, and H3K4me1. Pharmacological inhibition of histone methylation attenuates XBP-1s-induced EGFR transcription, indicating XBP-1s promotes EGFR expression via recruiting SET7/9 for H3K4 methylation. XBP-1s overexpression reverses DNAJC10-mediated EGFR downregulation. Collectively, DNAJC10 suppresses EGFR transcription by inhibiting the UPR IRE1α-XBP-1s axis, reducing SET7/9 recruitment and H3K4 methylation at the EGFR promoter. Targeting DNAJC10 or XBP-1s could be a potential approach for inhibiting GBM infiltration and may represent a novel avenue for GBM treatment.

Pilocytic astrocytoma (PA) is a circumscribed low-grade glioma, typically defined by biphasic architecture, Rosenthal fibres, eosinophilic granular bodies, and MAPK pathway activation. However, PAs may sometimes display atypical morphologies, creating diagnostic dilemmas. DNA methylation profiling has emerged as a robust adjunct for resolving such ambiguity.

Molecular glioblastoma (molGBM) is a variant lacking the full histopathological profile of glioblastoma. We report a trial aimed at addressing the optimal management of this newly recognized rarer form of glioma.

Chronic lymphocytic leukemia (CLL), a common B-cell malignancy, exhibits diverse clinical outcomes influenced by microRNA (miRNA) dysregulation. This study investigates the expression and regulatory roles of miRNA-133a and miRNA-452 in CLL.

Plasmacytoid dendritic cell-expansion in acute myeloid leukemia (pDC-AML) is an uncommon AML subset that differs from conventional AML and from blastic plasmacytoid dendritic cell neoplasm (BPDCN). This review synthesizes the clinicopathologic, immunophenotypic, cytogenetic, and molecular features of pDC-AML, highlights its outcomes, and discusses emerging therapeutic approaches, while underscoring the need for further studies to refine classification and guide therapy.

BackgroundCD137L plays a substantial role in immune regulation and has been associated with tumor progression. However, its expression pattern and clinical significance in colorectal cancer remain unclear. The current study was planned to evaluate the expression levels of CD137L in colorectal cancer tissues and investigate its association with clinicopathological characteristics and patient survival.Methodology36 tissue samples were collected from colorectal cancer patients followed by RNA extracted. Following the cDNA synthesis, qRT-PCR was conducted to evaluate the CD137L expression, normalized against GAPDH and the comparative expression was determined using the ΔΔCt method. Chi-square test was applied to evaluate the relation of CD137L expression with clinical parameters. Meanwhile, the TCGA database was explored to find the relationship between the prognosis of colorectal cancer patients and different levels of CD137L expression and to analyze the distribution characteristics of differentially expressed genes.ResultsCD137L expression was significantly correlated with patient survival (P < 0.05), with higher expression observed in patients who were alive at the time of analysis. Clinical parameters such as age and gender were insignificantly associated (P > 0.05) with CD137L expression. However, a significant correlation (P = 0.03) was noted between CD137L expression and tumor staging, suggesting its potential involvement in CRC progression. Furthermore, Analysis of TCGA data showed that patients with elevated CD137L expression exhibited improved overall survival compared to those with lower expression levels. Enrichment analysis revealed that CD137 was primarily enriched with immune cell proliferation, T cell activation and Th1/Th2 balance-related signaling pathways.ConclusionCD137L may serve as a reliable indicator for forecasting the outcome of colorectal cancer patients, providing guidance for colorectal cancer prognosis.

Despite advances in diagnosis and treatment, the prognosis of non-small cell lung cancer (NSCLC) remains poor. Therefore, it is urgent to identify potential molecular targets. In this study, we investigated the function and internal mechanism of CPNE3 in the malignant biological behaviour via RACK1/c-MET signalling in NSCLC, and explored the feasibility of the MET inhibitor in NSCLC treatment. The expression of CPNE3 in normal tissues and lung cancer tissues was compared using a public database. The function of CPNE3 was investigated using CCK-8 assays, clonogenic assays, EdU assays, Transwell assays and cell cycle analysis. Western blotting was used to detect the protein expression. The interaction between CPNE3 and RACK1 was examined by immunofluorescence staining and co-immunoprecipitation (co-IP). The in vitro and in vivo functions of the MET inhibitor JNJ-38877605 were investigated. CPNE3 is overexpressed in NSCLC and facilitates tumorigenesis and metastasis by interacting with RACK1 through the VWFA domain, which further induces the activation of MET signalling. Accordingly, this process could be suppressed by the MET inhibitor and RACK1 knockdown in vitro and in vivo. CPNE3 is highly expressed in NSCLC and can promote the proliferation and migration of tumour cells. CPNE3 could interact with RACK1 through the VWFA domain and activate MET signalling. These findings may provide new insights into the development of novel therapeutic strategies for NSCLC.

Prenatally androgenised (PA) sheep are a clinically realistic model of polycystic ovary syndrome (PCOS). They have dysfunctional subcutaneous adipose tissue (SAT) with reduced adipogenesis in adolescence and enlarged adipocytes with increased inflammation in adulthood. We hypothesised that analysis of SAT in young adults, after adipogenesis is complete but before inflammation is apparent, would give insights into the evolution of adipose tissue dysfunction. Pregnant sheep were treated intramuscularly with 100 mg testosterone propionate or vehicle control (C) twice weekly from day 62-102 of gestation. Weight-matched female offspring (PA = 10; C = 10) were studied up to 22 months of age. Glucose tolerance testing was performed, and at sacrifice SAT was fixed for histological analysis and frozen for RNA sequencing (RNAseq) and gene expression analysis. There was no difference in the average size of SAT adipocytes between PA and C young adults. There were no differences in the expression of the adipogenesis markers PPARG, CEBPA and CEBPB, or the inflammatory markers TNF and IL6, although PA sheep were already hyperinsulinaemic. RNAseq identified 792 potentially differentially expressed (P < 0.05) genes in PA sheep SAT (406 upregulated; 386 downregulated). Ingenuity Pathway Analysis highlighted upregulation of fibrotic pathways in the SAT of PA sheep. POSTN, associated with tissue fibrosis, and COL1A1, COL1A2 and COL3A1 were significantly elevated, and histochemistry showed significantly increased SAT fibrosis in PA sheep. Early fibrotic changes in SAT occur before inflammatory gene expression in PA sheep. A fibrotic barrier to healthy adipocyte expansion may have a mechanistic role in the development of inflammation in PCOS.

Transfer RNAs (tRNAs) are essential regulators of protein synthesis, and dysregulation of their abundance and modification status is involved in many human diseases including cancer. Despite the rapid development of novel tRNA sequencing approaches, due to tRNAs' stable secondary structure and abundant modification sites, the human tRNA landscape has remained mostly unexplored. Here, we evaluated the new RNA004 chemistry of Oxford Nanopore Technologies, that is integrated with updated Dorado base-caller models, for tRNA quantification and modification annotation in human cancer models. We demonstrated that this technology identifies variations in tRNA expression across cancer cell lines and in response to external stress conditions, with highly reproducible results. We also show that analysis of base-calling error rate can indicate the presence of known modifications, including the cancer-associated tRNAPhe-Wybutosine modification. Furthermore, implementing the updated Dorado modification-calling feature, we showed the potential of RNA004 tRNA-seq in predicting common tRNA modifications. We also pinpointed possible limitations and challenges associated with both modification calling methods. Overall, RNA004 tRNA-seq can potentially enhance our understanding of the human tRNAome by simultaneously analyzing both tRNA abundance and modifications.

Genomic instability and the accumulation of DNA damage are hallmarks of cancer, often resulting from defects in DNA repair pathways. While normal cells rely on highly coordinated DNA damage response (DDR) mechanisms to maintain genomic integrity, cancer cells exploit aberrant DDR regulation to sustain uncontrolled proliferation and survival. Despite significant advancements in chemotherapy, targeted therapy, and immunotherapy, the emergence of resistance remains a major challenge in cancer treatment. Small molecule inhibitors targeting key DDR proteins have emerged as promising therapeutic agents, not only as direct anticancer drugs but also as indispensable tools for dissecting the molecular intricacies of DNA repair. Recent therapeutic approaches leverage synthetic lethality and DDR pathway vulnerabilities to selectively eradicate tumor cells while minimizing damage to normal tissues. These inhibitors provide insights into mechanisms of tumor resistance, facilitating the rational design of combination therapies to enhance treatment efficacy. This review examines the latest advancements in DNA repair-targeted therapeutics, with a focus on small molecule inhibitors currently under clinical investigation. Additionally, we discuss emerging strategies for optimizing DDR-targeted interventions, including biomarker-driven patient selection and rational drug combinations. Understanding these molecular interactions will contribute to the development of novel, more effective treatment paradigms for cancer therapy.

The dysfunction of membraneless organelles (MLOs) has been implicated in tumorigenesis and progression by aberrant liquid-liquid phase separation (LLPS). However, the role of MLOs in the prognosis and tumor immune microenvironment (TIME) of colorectal cancer (CRC) remains unclear.

Clear cell renal cell carcinoma (ccRCC) is a prevalent pathological subtype of renal cell carcinoma that arises from renal tubular epithelial cells. ccRCC has long been characterized by high mortality, and at present, surgical resection is the only curative treatment, but its effectiveness is low and survival rates are low. N-acetyltransferase 10 (NAT10) is a protein that acts as an acetyltransferase, has distinct catalytic and regulatory functions, and is involved in the progression of various cancers such as bladder cancer, hepatocellular carcinoma, and multiple myeloma. Ferroptosis is a novel form of programmed cell death that is iron-dependent and distinct from apoptosis, necrosis, and autophagy. Therefore, this study aimed to investigate the potential functions of NAT10 in this context, with a particular focus on its interactions and mechanisms involving ferroptosis.