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29 records · Page 2Linked to original sources
PubMed2006

A self-consistent field theory study on the morphologies of linear ABCBA and H-shaped (AB)(2)C(BA)(2) block copolymers.

By using a combinatorial screening method based on the self-consistent field theory, we investigate the equilibrium morphologies of linear ABCBA and H-shaped (AB)(2)C(BA)(2) block copolymers in two dimensions. The triangle phase diagrams of both block copolymers are constructed by systematically varying the volume fractions of blocks A, B, and C. In this study, the interaction energies between species A, B, and C are set to be equal. Four different equilibrium morphologies are identified, i.e., the lamellar phase (LAM), the hexagonal lattice phase (HEX), the core-shell hexagonal lattice phase (CSH), and the two interpenetrating tetragonal lattice phase (TET2). For the linear ABCBA block copolymer, the reflection symmetry is observed in the phase diagram except for some special grid points, and most of grid points are occupied by LAM morphology. However, for the H-shaped (AB)(2)C(BA)(2) block copolymer, most of the grid points in the triangle phase diagram are occupied by CSH morphology, which is ascribed to the different chain architectures of the two block copolymers. These results may help in the design of block copolymers with different microstructures.

Journal Article↗
PubMed2026

Intramuscular patient-derived xenografts achieve high engraftment rates in gastric cancer: implications for pharmacodynamic testing and genomic biomarker discovery.

BACKGROUND: Gastric cancer (GC) exhibits marked inter-patient heterogeneity, limiting empirical chemotherapy efficacy. Patient-derived xenograft (PDX) models preserve the molecular features of parental tumors and can serve as pharmacodynamic surrogates, but conventional subcutaneous PDX suffers from low engraftment rates. This study evaluated an optimized intramuscular PDX platform for individualized drug testing in GC and applied whole exome sequencing (WES) for biomarker identification (Clinical trial registry: ChiCTR-OOC-17012731). MATERIALS AND METHODS: Ninety-eight treatment-naive GC patients were enrolled between April 2018 and December 2020. Fresh tumor tissues were engrafted into NCG mice by intramuscular transplantation. Drug efficacy was evaluated using tumor cell necrosis rate and Ki-67 expression. WES was performed on 32 engrafted tumorgrafts to characterize driver mutations in fast- and slow-growing subgroups. RESULTS: An engraftment rate of 71.7% (43/60) was achieved, substantially exceeding rates reported in prior studies. Clinical characteristics were independent of engraftment success and outgrowth time (all p > 0.05). Fast- and slow-growing tumorgrafts diverged in frequently altered genes: KMT2C, APOB, CDK12 and MSH2 predominated in fast-growing grafts, whereas TP53, CHD3 and TET2 were enriched in slow-growing grafts. Slow-growing tumorgrafts correlated with longer progression-free survival (p = 0.02). PDX-guided treatment was associated with improved prognosis. CONCLUSIONS: Intramuscular transplantation into NCG mice yields high engraftment rates for GC PDX. PDX-guided chemotherapy selection is associated with favorable outcomes. Driver mutation divergence between fast- and slow-growing tumorgrafts provides candidate prognostic biomarkers.

Animals↗
PubMed2001

Identification of human candidate genes for male infertility by digital differential display.

Evidence for the importance of genetic factors in male fertility is accumulating. In the literature and the Mendelian Cytogenetics Network database, 265 cases of infertile males with balanced reciprocal translocations have been described. The candidacy for infertility of 14 testis-expressed transcripts (TETs) were examined by comparing their chromosomal mapping position to the position of balanced reciprocal translocation breakpoints found in the 265 infertile males. The 14 TETs were selected by using digital differential display (electronic subtraction) to search for apparently testis-specific transcripts in the TIGR database. The testis specificity of the 14 TETs was further examined by reverse transcription-polymerase chain reaction (RT-PCR) on adult and fetal tissues showing that four TETs (TET1 to TET4) were testis-expressed only, six TETs (TET5 to TET10) appeared to be differentially expressed and the remaining four TETs (TET11 to TET14) were ubiquitously expressed. Interestingly, the two tesis expressed-only transcripts, TET1 and TET2, mapped to chromosomal regions where seven and six translocation breakpoints have been reported in infertile males respectively. Furthermore, one ubiquitously, but predominantly testis-expressed, transcript, TET11, mapped to 1p32-33, where 13 translocation breakpoints have been found in infertile males. Interestingly, the mouse mutation, skeletal fusions with sterility, sks, maps to the syntenic region in the mouse genome. Another transcript, TET7, was the human homologue of rat Tpx-1, which functions in the specific interaction of spermatogenic cells with Sertoli cells. TPX-1 maps to 6p21 where three cases of chromosomal breakpoints in infertile males have been reported. Finally, TET8 was a novel transcript which in the fetal stage is testis-specific, but in the adult is expressed in multiple tissues, including testis. We named this novel transcript fetal and adult testis-expressed transcript (FATE).

Chromosome Mapping↗
PubMed2026

Mast cell leukemia with complex genomic alterations in an elderly patient with prior hematologic and solid malignancies: a case report.

INTRODUCTION: Mast cell leukemia (MCL) is the rarest and most aggressive variant of systemic mastocytosis (approximately 1% of cases), with a median survival of under 2 years. Diagnosis requires ≥20% atypical mast cells in the marrow aspirate, and the disease frequently overlaps with myeloid neoplasms. CASE PRESENTATION: An 86-year-old man with paranasal sinus diffuse large B-cell lymphoma in remission since 2017 after R-CHOP and methotrexate, and prostate adenocarcinoma treated in 2019, presented with acute pancytopenia, presumed to represent lymphoma relapse. Serum tryptase exceeded 11 999 ng/mL; the aspirate showed 20% pleomorphic mast cells (CD117+, weak CD25, CD2-), confirming aleukemic MCL. Formal CMML criteria could not be confirmed due to the unavailability of monocyte differential data; however, the findings raised suspicion for an associated myeloid neoplasm, with SM with an associated hematological neoplasm remaining an alternative classification. Karyotyping was normal; next-generation sequencing revealed pathogenic variants in TP53, RB1, DAXX, ASXL1, TET2, and SRSF2, and a rare extracellular-domain KIT p.D419del. He declined inpatient midostaurin, deteriorated rapidly, and died 2 weeks later. CLINICAL DISCUSSION: This case illustrates a therapy-related MCL (plausible but unconfirmed given the non-leukemogenic profile of methotrexate and the focal nature of prostate stereotactic body radiation therapy) with a suspected associated myeloid neoplasm and complex pathogenic mutations. The KIT p.D419del extracellular domain variant is a rare non-D816V mutation; the canonical D816V was not detected on NGS, though the presence of a low-variant allele fraction D816V cannot be fully excluded due to assay sensitivity. Despite midostaurin, the disease remained aggressive. CONCLUSION: Persistent unexplained cytopenias warrant heightened suspicion of MCL, and comprehensive genomic profiling clarifies diagnosis, distinguishes overlapping myeloid disease, and informs prognosis in this aggressive, refractory neoplasm.

case report↗
PubMed2026

Age as a core disease modifier: Distinct clinical, molecular and prognostic landscapes of essential thrombocythaemia in adolescents and young adults.

Essential thrombocythaemia (ET) in adolescents and young adults (AYA, 15-39 years) is a distinct entity with an incompletely defined prognosis. In this multicentre retrospective study, 1728 ET patients from 29 centres across China were stratified into AYA (n = 328) and non-AYA (≥40 years, n = 1400) cohorts. We compared their clinical profiles, genomic landscapes, long-term outcomes and risk factors for progression to post-ET myelofibrosis (MF). AYA patients had fewer cardiovascular risks and lower thrombosis rates, but higher rates of extreme thrombocytosis. Molecularly, AYA patients were enriched for calreticulin (CALR) mutations, whereas Janus kinase 2 (JAK2) predominated in older patients. The burden of non-driver mutations (tet methylcytosine dioxygenase 2 [TET2], DNA methyltransferase 3A [DNMT3A], ASXL transcriptional regulator 1 [ASXL1], SH2‑B adaptor protein 3 [SH2B3]) was lower in AYA patients. Consequently, AYA patients achieved superior long-term outcomes across all key survival endpoints, including overall, myelofibrosis-free and leukaemia-free survival. Analysis of post-ET MF progression risks identified age-specific patterns: CALR mutations are enriched in younger patients and show an age-specific association with MF progression. AYA-ET constitutes a unique clinicomolecular subtype with a favourable prognosis, supporting age-stratified management. The enrichment of CALR mutations and their specific link to MF progression in young patients underscore the urgent need for targeted therapies against CALR-mutant clones.

adolescents and young adults (AYA)↗
PubMed2026

Epigenetics and In Silico Transcriptome Analysis of Pediatric Acute Myeloid Leukemia.

Pediatric acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that accounts for about 15%-20% of childhood leukemias. Despite therapeutic advances, relapses remain common, and survival for high-risk patients is below 60%. Unlike adult AML, pediatric AML displays distinct genetic mutations, including FLT3-ITD, NPM1, KMT2A rearrangements, and core-binding factors (CBF) fusions, as well as extensive epigenetic dysregulation. Aberrant DNA methylation, histone modifications, and altered non-coding RNA expressions disrupt hematopoietic differentiation and activate oncogenic transcriptional networks. Recent advances in silico transcriptomic analysis have transformed the study of pediatric AML by integrating gene expression and epigenetic data to identify molecular drivers and regulatory networks. Computational RNA-seq pipelines and pathway analyses have highlighted key epigenetic regulators, including DNMT3A, TET2, and HDACs, as potential therapeutic targets. Multi-omics approaches combining transcriptomic, methylomic, and chromatin accessibility data are increasingly used to define biomarkers for diagnosis, prognosis, and therapeutic response. This review provides a comprehensive overview of the molecular and epigenetic landscape of pediatric AML, emphasizing the power of in silico transcriptome analysis to uncover disease mechanisms, refine patient stratification, and guide the development of precision-based epigenetic therapies aimed at improving long-term outcomes in children with AML.

Humans↗
PubMed2026

Germline noncoding risk variants influence clonal hematopoiesis through altered hematopoietic enhancer activity.

Clonal hematopoiesis of indeterminate potential (CHIP) is a precursor condition characterized by the expansion of mutant hematopoietic stem and progenitor cell (HSPC) clones that increases the risk of hematologic malignancies. Although genome-wide association studies have identified multiple non-coding loci associated with CHIP susceptibility, their mechanisms remain unclear. We hypothesized that CHIP risk variants alter enhancer activity in HSPCs. To test this, we screened 1,374 non-coding variants from 51 CHIP-associated loci using a Massively Parallel Reporter Assay (MPRA) in the CD34+ fraction of MUTZ-3 cells. We identified 87 regulatory variants across 32 loci. Targeted genome editing in hematopoietic cells and complementary reporter assays in primary human HSPCs validated enhancer activity for variants regulating NKD2, FLT3, and MSI2. Functional studies demonstrated that increased MSI2 expression, modeling the effect of the CHIP risk allele, promotes clonal expansion of TET2-deficient HSPCs, providing a mechanistic link between inherited non-coding variation and CHIP clonal expansion.

Journal Article↗
PubMed2016

A probabilistic generative model for quantification of DNA modifications enables analysis of demethylation pathways.

We present a generative model, Lux, to quantify DNA methylation modifications from any combination of bisulfite sequencing approaches, including reduced, oxidative, TET-assisted, chemical-modification assisted, and methylase-assisted bisulfite sequencing data. Lux models all cytosine modifications (C, 5mC, 5hmC, 5fC, and 5caC) simultaneously together with experimental parameters, including bisulfite conversion and oxidation efficiencies, as well as various chemical labeling and protection steps. We show that Lux improves the quantification and comparison of cytosine modification levels and that Lux can process any oxidized methylcytosine sequencing data sets to quantify all cytosine modifications. Analysis of targeted data from Tet2-knockdown embryonic stem cells and T cells during development demonstrates DNA modification quantification at unprecedented detail, quantifies active demethylation pathways and reveals 5hmC localization in putative regulatory regions.

5-Methylcytosine↗
PubMed2026

LymphGen-Sig: Integrating Genetic and Transcriptional States to Predict Therapeutic Response in Diffuse Large B-Cell Lymphoma.

PURPOSE: Genetic classification may advance precision medicine in diffuse large B-cell lymphoma (DLBCL), but existing tools like LymphGen (LG) are limited by complexity and incomplete classification and do not incorporate nongenetic features that affect disease biology and therapeutic outcomes. To address these limitations, we developed LG-sig (LGsig), a gene expression-based platform that classifies all DLBCLs and harmonizes both genetic and nongenetic dimensions of the disease. METHODS: LGsig was built on the distinct subtype-specific gene expression signature of each LG class using paired genomic and transcriptomic data (National Cancer Institute/British Columbia Cancer Agency; N = 764). Model development was restricted to DLBCLs classified into MYD88L265P and CD79B mutations (MCD), BCL6 translocation and NOTCH2 mutations (BN2), EZH2 mutations and BCL2 translocation (EZB), or SGK1 and TET2 mutations (ST2). Gene features were selected by differential gene expression, with 294 genes being optimal for classification using a nearest shrunken centroid classifier. LGsig classifications were designated as MCDsig, BN2sig, ST2sig, and EZBsig. The final model was applied to RNAseq from archival samples from the POLARIX trial (N = 678) to assess outcomes after polatuzumab vedotin-R-CHP (pola-R-CHP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for each LGsig subtype. RESULTS: LGsig accurately identified LG subtypes using transcriptional data alone and extended assignments to all previously LG-unclassified cases. Importantly, LG-unclassified DLBCLs reassigned by LGsig mirrored the transcriptional and clinical features of their corresponding LG counterparts, supporting their reclassification. In addition, LGsig reassigned LG A53 DLBCLs, characterized by aneuploidy and TP53 alterations, into more biologically and therapeutically relevant LGsig clusters. Finally, LGsig improved the performance of LG as a biomarker in the POLARIX study, by identifying distinct DLBCL subtypes exhibiting a survival benefit with pola-R-CHP over R-CHOP in both LG-classified and LG-unclassified cases. CONCLUSION: LGsig expands molecular classification beyond current genetic classifiers in DLBCL by integrating both genetic and transcriptional dimensions of the disease to better inform subtype-specific therapeutic strategies.

Journal Article↗
PubMed2026

Baseline Plasma Cell-Free and Circulating Tumor DNA Across Lymphoma Subtypes and Its Prognostic Impact in Diffuse Large B-Cell Lymphoma.

BACKGROUND: Circulating tumor DNA (ctDNA) analysis enables real‑time assessment of the tumor burden and genomic complexity in lymphomas. However, real‑world evidence across lymphoma subtypes is limited. METHODS: We analyzed cell‑free DNA (cfDNA) and ctDNA data from 336 consecutive patients with newly diagnosed Hodgkin or non-Hodgkin lymphoma in 2022 and evaluated their prognostic impact in diffuse large B‑cell lymphoma (DLBCL). RESULTS: We detected somatic alterations in 248 of 336 patients (73.8%). DLBCL and follicular lymphoma showed the highest variant prevalences and ctDNA burdens. Epigenetic regulators, including KMT2D, CREBBP, TET2, and HIST1H1E, constituted the dominant class of genes with recurrent alterations. Plasma variant profiles closely mirrored publicly available, tissue‑based next-generation sequencing datasets. The baseline ctDNA burden correlated with adverse clinical features, and ctDNA positivity was associated with failure to achieve complete remission. In DLBCL, elevated cfDNA (top quartile) and a high International Prognostic Index (IPI) were independently associated with shorter overall and progression‑free survival. However, the total variant count per patient was not significantly associated with survival after adjustment. CONCLUSIONS: Baseline plasma cfDNA and ctDNA assessments are feasible in routine practice and recapitulate tissue-variant landscapes. Elevated cfDNA concentrations-but not the total variant count-were independently associated with survival in DLBCL, providing prognostic information beyond the IPI and supporting integration of plasma-based biomarkers into multiparameter risk models. Gene‑level ctDNA associations should be regarded as exploratory and hypothesis‑generating.

Cell-free DNA↗
PubMed2026

Identification of elements determining KIR gene demethylation at the CD56-bright stage of NK cell development.

The variegated expression of the KIR family of class I MHC receptors generates specialized natural killer (NK) cells capable of allele-specific HLA recognition. Understanding the mechanism of KIR gene activation will lead to improved methods for the generation of fully functional NK cells. A central RUNX-binding site in the KIR proximal promoter is required for gene activation. RUNX proteins recruit ten-eleven translocation (TET) proteins that generate 5-hydroxymethylcytosine (5hmC) and drive DNA demethylation. Assessment of 5-methylcytosine (5mC) and 5hmC residues at four stages of NK cell development reveals deposition of 5hmC primarily in a CREB site next to the RUNX site at the CD56Bright stage but not the subsequent CD56Dim stage representing fully mature NK cells. KIR promoter demethylation is delayed relative to other lineage-associated genes, indicating a high threshold for KIR gene demethylation in developing NK cells, and a window of opportunity for RUNX/TET-dependent KIR gene activation in CD56Bright NK cells.

6-base sequencing↗