Pediatric NTRK-rearranged gliomas: A clinicopathological and molecular analysis of six cases.

The potential and innovative applications of CRISPR gene editing technology in enzyme gene development.

Multi-enzyme cascade colouring for meat without nitrite at low-temperature: Catalysis by NOS-YkuN-YumC and glucose dehydrogenase.

Oral delivery of engineered Lactococcus lactis microcapsules expressing antioxidant enzymes for inflammatory bowel disease: Mechanisms of intestinal barrier repair and microbiota modulation.

ABL2 rearrangements represent a subtype of acute lymphoblastic leukaemia (ALL) associated with poor prognosis and survival. This study reports a high-risk T-cell ALL (T-ALL) case with a novel TPR::ABL2 gene fusion resulting from a chromosomal deletion. Overexpression of TPR::ABL2 in Ba/F3 cells promoted cytokine-independent growth, demonstrating its oncogenic nature. Both primary patient and Ba/F3 cells carrying TPR::ABL2 exhibited kinase activation and sensitivity to tyrosine kinase inhibitors (TKIs). This study expands the repertoire of ABL2 fusions identified in ALL and supports the incorporation of TKIs into T-ALL treatment regimens to improve outcomes for this subtype.

Dysregulation of the ALDH1A3/PML-RARα axis promotes the progression of acute promyelocytic leukemia.

From prostate specific antigen to genomic signatures: Advances in biomarkers for prostate cancer diagnosis and prognosis.

Design, synthesis and biological evaluation of macrocyclic NTRK heterobifunctional degraders.

SEAP-GETNE consensus on prognostic and predictive molecular biomarkers in thyroid cancer.

Chronic myeloid leukemia (CML) was the first leukemia to be described in medical literature and remains one of the most well-studied hematologic malignancies. This review traces the historical evolution of CML research, from its first clinical recognition in the mid-19th century to modern molecular diagnostics and targeted therapy. Key milestones include the discovery of the Philadelphia chromosome in 1960, identification of the BCR::ABL1 fusion gene in the 1980s, and the subsequent development of tyrosine kinase inhibitors (TKIs). The introduction of imatinib in the early 2000s revolutionized CML treatment, transforming a fatal disease into a chronic condition with near-normal life expectancy for most patients. Second- and third-generation TKIs have since been introduced to overcome drug resistance and target specific BCR::ABL1 mutations, such as T315I. Recently, research has focused on mechanisms of TKI resistance, novel signaling pathways, and strategies to achieve treatment-free remission (TFR). Emerging therapies such as vamotinib, KF1601, and combination regimens are being explored. Furthermore, new insights into non-kinase functions of BCR::ABL1 and the role of microRNAs in resistance open additional therapeutic avenues. This review provides a concise overview of CML from a historical and molecular perspective, highlighting diagnostic advances, evolving response criteria, and future directions in treatment.

Astroblastoma, MN1-altered, is a newly recognized entity in the 5th edition of the WHO Classification of CNS Tumors. Its genetic definition is the presence of an alteration, most commonly gene fusions, in the MN1 gene, with BEND2 being the most frequent fusion partner. However, some astroblastomas and astroblastoma-like tumors with fusion of non-MN1 to BEND2 have been reported recently. These tumors exhibit epigenetic profiles similar to those of astroblastomas with MN1::BEND2, suggesting that BEND2 may play a more important role than MN1 in tumorigenesis. Therefore, investigation of BEND2 fusion will be essential to make an accurate diagnosis of astroblastomas in the near future. In this study, we aimed to explore the diagnostic utility of BEND2 immunohistochemistry using a commercially available rabbit polyclonal antibody. As a result, nuclear expression of BEND2 was observed in all 15 cases of astroblastomas with BEND2 fusion (9 with MN1::BEND2, 4 with EWSR1::BEND2, 1 with MAMLD1::BEND2, and 1 with TCF3::BEND2), whereas it was not found in 147 cases of other CNS tumors from 48 different entities. In contrast, negative nuclear staining for BEND2 was observed in a previously reported case of spindle cell sarcoma with MN1::BEND2, whose fusion junction differed from those of the astroblastomas analyzed in this study. In conclusion, we demonstrated that BEND2 immunohistochemistry has extremely high sensitivity and specificity, suggesting its utility as a reliable marker for the diagnosis of astroblastoma with BEND2 fusion.

Desmoplastic small round cell tumor (DSRCT), an aggressive malignancy classically seen in adolescents and young adults with a strong male predominance, is exceptionally rare in the ovary. We report a 33-year-old woman with ovarian DSRCT presenting as a pelvic mass and peritoneal metastases. Histopathology revealed small round cell nests within desmoplastic stroma, exhibiting atypical architectural patterns (single-file, follicular-like cystic, microcystic, and solid). Immunohistochemistry demonstrated coexpression of epithelial (pan-keratin) and mesenchymal markers (vimentin, desmin), while molecular analysis confirmed the EWSR1::WT1 gene fusion. Despite multimodal therapy, the patient died 24 months after surgery. A review of 23 ovarian DSRCTs proposed a classification: ovarian-dominant and extraovarian-dominant subtypes. Ovarian-dominant patients showed significantly prolonged median survival (24 vs 10 months, P = .026), underscoring the prognostic relevance of anatomical classification. Ovarian DSRCT poses diagnostic challenges due to histomorphological mimicry of common malignancies. Although this subclassification may aid prognostication, multicenter validation is warranted.

Detection of known gene fusions in cancer cell lines using whole-genome bisulfite sequencing data.

Unraveling the miRNA-EMT-stemness interplay in fusion-positive supratentorial ependymomas: Identifying therapeutic vulnerabilities.

There is a growing international need to support somatic genomic testing, standardised variant curation and improved patient access to molecular profiling for somatic conditions, including cancer. We conducted a survey of scope, curation, reporting and sharing practices of diagnostic laboratories performing somatic testing in Australia and New Zealand. Laboratories with accreditation (n = 41) were invited in 2023 to complete a semi-structured, 25-question interview. Responses were received for 27 laboratories (66% response rate) offering solid tumour, haematological malignancy and non-cancer services. Only 36% of laboratories offered tests capturing the full breadth of variants, from single-nucleotide variants to gene fusions. Knowledge sharing was rare, with only one laboratory submitting variant classifications to a public knowledge base. Most laboratories (96%) conducted somatic testing in oncology. Of cancer laboratories, 35% offered testing considered capable of comprehensive genomic profiling (CGP). Almost half of cancer laboratories had already adopted the 2022 ClinGen/CGC/VICC oncogenicity guidelines, and 84% were using AMP/ASCO/CAP 2017 clinical significance guidelines. Only 47% of mixed disciplinecancer laboratories reported biomarkers such as tumour mutational burden, with wide variation in reporting of matched therapy options. Our study has generated a unique overview of somatic laboratory practices in the region, and areas for global standardisation in somatic molecular testing and reporting. We also provide a model for practice and guideline uptake assessment, for application by other country-wide networks. This is particularly relevant in anticipation of CGP mainstreaming, with the increasing complexity of sequencing interpretation for laboratories and clinicians.

Tropomyosin receptor kinase (TRK) is an important therapeutic target for tumors driven by NTRK gene fusions. However, the clinically approved TRK inhibitors, including Larotrectinib and Entrectinib, are limited by insufficient efficacy and resistance due to kinase mutations. Here, we report DZX19 (C02), a novel phenyl thiophene-3-carboxamide TRK inhibitor developed via a pharmacophore-guided scaffold-hopping approach combined with structure-based design, based on the key binding features of Entrectinib. DZX19 demonstrated stronger in vitro activity and an improved resistance profile against Entrectinib-resistant TRKA mutants, including G595R, F589L, and G667C. In the TPM3-NTRK1 fusion-positive Km-12 cell line, DZX19 induced G1 arrest, promoted apoptosis, and suppressed TRK downstream signaling. DZX19 displayed excellent plasma stability and moderate microsomal stability. In the Km-12 xenograft model, DZX19 significantly suppressed tumor growth. These results indicate that DZX19 serves as a novel TRK-targeting lead compound for further investigation.

The t(12;21)(p13;q22) is the most common chromosomal translocation in pediatric Bcell precursor acute lymphoblastic leukemia (BCP-ALL), occurring in 2-5% of healthy newborns. This alteration generates the ETV6::RUNX1 (E::R) fusion gene, encoding an aberrant transcription factor that is insufficient to directly cause leukemia, but establishes a clinically silent pre-leukemic progenitor not yet fully characterized. We previously showed that E::R expression in the murine pro-B BaF3 cells caused the slowdown of cell cycle progression and increased phospho-histone H2AX levels, both features of Oncogene-Induced Senescence (OIS). This study investigates E::R's ability to induce senescence in pro-B and immature hematopoietic cells, revealing new therapeutic targets for pre-leukemic cells. We observed that E::R caused a senescence-like phenotype in BaF3 cells, characterized by altered morphology, increased β-galactosidase activity, elevated reactive oxygen species (ROS) and Senescence-Associated Secretory Phenotype (SASP) factor secretion. It dysregulated genes within the p53 pathway, including senescence-related genes, causing the accumulation of p53 protein and alteration in its post-translational modifications. In E::R positive cells, while p53-mediated cell cycle arrest occurred, apoptosis was impaired, providing a survival advantage under genotoxic stress. Multiple therapeutic approaches targeting these vulnerabilities were tested. Senolytics SSK1 and piperlongumine selectively eliminated E::R+ cells by exploiting elevated β-gal activity and ROS levels, respectively. TM5441 leveraged caspase-3 inhibitor PAI-1 upregulation to induce apoptosis. Furthermore, using Sca1-E::R transgenic mice, we validated E::R-induced OIS in the pre-leukemic Lin-Sca1+ immature population and observed reduced pre-B colony formation after SSK1 treatment. These findings demonstrate E::R's dual role in inducing OIS and conferring apoptosis resistance, highlighting the potential of senescence-targeted therapies to prevent leukemia progression and relapse in E::R carriers.

ALK-positive large B-cell lymphoma (ALK + LBCL) is a rare subtype of large B-cell lymphoma characterized by plasmablastic morphology, intra-sinusoidal or sheet-like proliferation, loss of pan-B-cell markers, and expression of plasmacytic markers. According to WHO classification, CD30 expression is generally absent and Epstein-Barr virus (EBV) infection is not detected [1,2,5] . We aim to report the first case of ALK-positive, EBV-positive large B-cell lymphoma (ALK + EBV + LBCL) in an HIV-infected patient. A 60-year-old Thai male with HIV infection and severe immunosuppression (CD4 count: 93 cells/mm3) presented with generalized lymphadenopathy and an epiglottic mass. Biopsy showed a plasmablastic neoplasm proliferating in loose sheets, negative for pan-B-cell markers except OCT2, and positive for plasmacytic markers and CD30. The tumor also expressed EBER, ALK1 (paranuclear dot pattern), and ALK D5F3; HHV8 was negative. FISH confirmed ALK gene rearrangement, and targeted sequencing revealed a GORASP2::ALK fusion gene. The diagnosis of ALK + EBV + LBCL in the setting of HIV-related immunodeficiency was established. The patient developed pneumonia with septic shock and died during admission. EBV-positive plasmablastic B-cell neoplasms in HIV-infected patients are not always plasmablastic lymphoma. Immunohistochemistry for ALK and HHV8 should be included in the diagnostic panel. Importantly, CD30 and EBER positivity do not exclude ALK + LBCL.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive malignant primary brain tumor, marked by rapid growth, extensive invasiveness, and a median survival of only ∼15 months despite current multimodal therapy. To identify new therapeutic vulnerabilities, we investigated the actin-regulatory protein AVIL, previously implicated through a MARS-AVIL gene fusion in rhabdomyosarcoma. Comprehensive genomic and transcriptomic analyses across REMBRANDT, TCGA, and CGGA datasets revealed recurrent AVIL amplification and consistently elevated AVIL expression in GBM compared with normal brain tissue. AVIL was overexpressed across all GBM molecular subtypes and glioma stem cell (GSC) states but was nearly undetectable in normal astrocytes, neural stem cells, and brain tissues. Functional studies demonstrated that AVIL is both necessary and sufficient for glioma genesis: AVIL silencing eradicated GBM cells in vitro and suppressed xenograft growth invivo, while AVIL overexpression enhanced proliferation, migration, and transformation. Mechanistically, AVIL drives tumor progression through actin cytoskeleton remodeling and activation of the FOXM1-LIN28B oncogenic pathway. Using a small molecule microarray screen, we identified a selective AVIL-binding compound (compound A) that potently inhibited GBM cell growth with minimal toxicity to normal astrocytes. Gene expression changes induced by compound A mirrored those following AVIL knockdown, indicating on-target activity. Compound A demonstrated robust antitumor efficacy in multiple preclinical GBM models, including orthotopic xenografts, GSC-derived tumors, patient-derived xenografts, and temozolomide-resistant GBM with favorable pharmacokinetics and blood-brain barrier penetration. The minimal AVIL expression in normal tissues and lack of phenotype in AVIL-deficient mice underscore its potential as a low-toxicity therapeutic target. Together, these findings establish AVIL as a critical oncogenic driver in GBM and introduce a first-in-class AVIL inhibitor with strong translational promise for precision neuro-oncology.

Increased detection of NRG1 fusions in non-squamous non-small cell lung cancer using combined DNA and RNA sequencing in a real-world cohort.