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PubMed2025

Combination of cycling hyperthermia and echinacoside creates a synergistic curing effect on pancreatic cancer PANC-1 cells.

Therapy targeting the suppression of human MutT homolog 1 (MTH1) has been gaining ground in recent years, thanks to its resulting significant increase of 8-hydroxy-2'-deoxyguanosine triphosphate (8-oxo-dGTP) accumulation in genomic DNA, causing DNA damage and apoptotic cell death. Echinacoside (Ech), a natural phenylethanoid glycoside first extracted from Echinacea angustifolia or desert plant Cistanches, is one of a few natural products that are capable of inhibiting the MTH1 function. It, however, is difficult to apply it in clinical trials, due to high cost for effective dosage in need. In this study, we show that the integration of Ech with thermal cycling-hyperthermia (TC-HT), a novel physical treatment, significantly augments its anticancer efficacy while simultaneously decreasing the necessary dosage. Specifically, 20 μM Ech with TC-HT reduced human pancreatic carcinoma cell line PANC-1 viability to 29.6% of the control, comparable to 28.7% of the control by 100 μM Ech alone. The combined treatment reduced MTH1 expression to 0.42-fold, initiating oxidative damage and apoptosis. Notably, 8-oxo-dGTP increased to 3.67-fold of the control, indicating enhanced oxidative DNA damage and 31.8% apoptosis. This oxidative stress further influenced critical signaling pathways, as p-ERK and p-JNK shifted to 0.59- and 5.55-fold, respectively, indicating a switch from survival to apoptotic signaling. Concurrently, mitochondrial apoptotic markers Bax/Bcl-2 and cleaved poly (ADP-ribose) polymerase increased to 4.22- and 7.12-fold, respectively. These results indicate that its effect is expected to be comparable to the treatment strategy containing MTH1, Bcl-2, and extracellular signal-regulated kinase inhibitors, posing as new promising approach in cancer treatment.

DNA damage↗

PubMed2026

The Novel Hypomethylating Agent NTX-301 Reprograms Epigenetic and Hippo Signaling Pathways and Exhibits Preclinical Activity in Venetoclax-Resistant and TP53-Mutant AML.

PURPOSE: Hypomethylating agent (HMA) and the BCL-2 inhibitor venetoclax (VEN) combinations have evolved into first-line therapies for patients with acute myeloid leukemia (AML), yielding high response rates. However, most patients ultimately relapse, particularly those with TP53 mutations. We investigated mechanisms of action and therapeutic efficacy of NTX-301, a next-generation HMA. EXPERIMENTAL DESIGN: Methods used include flow cytometry-based cell viability assays, Western blotting, reverse-phase protein arrays, RNA sequencing, Cytometry by Time-Of-Flight single-cell mass cytometry, and methylation profiling in various therapy-resistant AML models. RESULTS: We demonstrate that NTX-301 exhibits superior efficacy compared with 5-azacytidine (5-AZA) in 5-AZA- or VEN-resistant AML. It synergizes with VEN in VEN- or VEN/HMA-resistant and TP53-mutant AML blasts and stem/progenitor cells (combination index <1). NTX-301 inhibits DNA methyltransferase 1 (DNMT1) and increases p73 and caspase 8 (CASP8)/activated CASP8 levels in TP53 wild-type and TP53-mutant AML and activates p53 signaling. It extends survival (≥45%) in both xenograft and patient-derived xenograft models. Methylation profiling revealed that NTX-301 is a more targeted HMA compared with 5-AZA, enabling suppression of functionally enriched genes/pathways. Pathway analysis of 954 commonly hypomethylated genes showed profoundly greater enrichment of Hippo signaling in NTX-301-treated compared with 5-AZA-treated cells and enrichment of insulin signaling, VEGF pathway, and cell cycle selectively in NTX-301- but not in 5-AZA-treated cells. NTX-301-mediated Hippo signaling was validated at protein levels. CONCLUSIONS: Data suggest that NTX-301 exerts potent antileukemic activities superior to 5-AZA and synergizes with VEN in VEN-resistant and TP53-mutant AML, in part by suppressing DNMT1, inducing DNA damage responses and apoptosis through p53 signaling, and demethylating LATS1/2, thereby activating Hippo signaling.

Humans↗

PubMed1992

A human lymphoma cell line with multiple immunoglobulin rearrangements.

The development of a cell culture system efficient in the establishment of lymphoma cell lines has made it possible to dissect basic biological and molecular aspects of lymphoma cells. We have established a lymphoma cell line from a patient with B cell lymphoma. The cell line has a complex karyotype with translocations involving bands 8q24, 14q32, and 18q21. Molecular analysis revealed that the Myc gene was rearranged; we were unable to demonstrate rearrangement of the Bcl-2 gene. Evaluation of the structure of the heavy chain Ig genes revealed that the cell line carried the same rearrangements as the cells from which the cell line was derived. The pattern of rearrangement, however, was unusual in that there were at least four rearranged bands when DNA cut with HindIII was probed with a fragment of the heavy chain joining region. To further characterize the cell line, subclones were derived. Individual subclones had the same pattern of rearrangement as the parent cell line. The results of these studies provide evidence that multiple rearranged Ig genes may be present in a single clone of cells.

Gene Rearrangement↗

PubMed2026

A tumor suppressor role of the miR-15b/16-2 cluster in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy arising from the neoplastic transformation of immature T cells during their development in the thymus. Deciphering the developmental programs whose dysregulation drives T-ALL pathogenesis is critical for the development of novel targeted therapies, which remain an urgent unmet need for the treatment of this disease. MicroRNAs (miRNAs) have emerged as key posttranscriptional regulators of numerous physiological processes, including cancer. However, the specific role of miRNAs in human T-cell development and T-ALL pathogenesis remains largely unexplored. In this study, we comprehensively evaluated miRNA expression profiles across human T-cell development using microarray analysis and identified a dynamic expression pattern of miR-16-2, which is upregulated during early pre-T-cell proliferative stages up to the resting stage of immature thymocytes immediately preceding T-cell receptor αβ expression and is subsequently downregulated. We also confirmed the coordinated regulation of miR-15b expression, consistent with the reported clustered genomic location of both miRNAs. Notably, functional studies identified the miR-15b/16-2 cluster as a negative regulator of early thymocyte proliferation and demonstrated that overexpression of miR-15b/16-2 in T-ALL cells impaired leukemic growth in vitro and tumor progression in patient-derived xenotransplantation assays. Mechanistically, miR-15b/16-2 represses the expression of the genes encoding BCL-2 and cyclin D3, thereby promoting apoptosis and cell cycle dysregulation in T-ALL cells, characterized by an accumulation of G0-phase cells and a defective transition to the G2/M phase. Overall, these findings support a novel tumor-suppressive function for miR-15b/16-2 in T-ALL and highlight its potential as a promising therapeutic target.

MicroRNAs↗

PubMed1992

Selective anti-gene therapy for cancer: principles and prospects.

Oligodeoxynucleotides can act as antisense complements to target sense sequences of natural mRNAs to selectively regulate gene expression by translation arrest. This is a form of interventional gene therapy. Chemically modified analogs that are nuclease-resistant enable this strategy to be utilized in practice. Of the chemically modified backbone analogs of oligodeoxynucleotides we have used the phosphorothioate (PS) analog, in which a non-bridging phosphate oxygen atom is substituted with a sulfur atom. We have shown that these oligodeoxynucleotide analogs inhibit beta-globin expression in cell free systems, and that they are taken up by cells. Specific sequences have been shown to selectively regulate viral and cellular gene expression, for example the bcl-2 oncogene that is found in ca. 90% of lymphomas. However, the PS analog has certain disadvantages, notably reduced hybridization and non-selective inhibition of translation. We have therefore synthesized a series of (PS-PO) co-polymers and characterized their properties. Other related approaches include catalytic ribozymes, and formation of triplexes by direct interaction of oligomers in the major groove of DNA. In general, a chemically modified oligodeoxynucleotide analog can be regarded as a novel form of informational drug.

Animals↗

PubMed2025

Network pharmacology approach to unveiling the mechanism of berberine in the amelioration of morphine tolerance.

OBJECTIVE: To investigate the mechanism underlying the effect of the Huanglian decoction (, HLD) on morphine tolerance (MT), using network pharmacology, and to verify these mechanisms in vitro and in vivo. METHODS: Available biological data on each drug in the HLD were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. The target proteins of MT were retrieved from the GeneCards, PharmGkb, Therapeutic Target Database, DrugBank, and Online Mendelian Inheritance in Man databases. Information regarding MT and the drug targets was compared to obtain overlapping elements. This information was imported into the Search Tool for the Retrieval of Interacting Genes/Proteins platform to obtain a protein-protein interaction network diagram. Then, a "component-target" network diagram was constructed using screened drug components and target information, viaCytoscape (Institute for Systems Biology, Seattle, WA, USA). The database for annotation, visualization, and integrated discovery was used for Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathways analyses. Pathway information predicted by network pharmacology was verified using animal studies and cell experiments. RESULTS: Network pharmacology analysis identified 22 active compounds of HLD and revealed that HLD partially ameliorated MT by modulating inflammatory, apoptosis, and nuclear factor kappa B (NF-κB) signaling pathways. Berberine (BBR), one of the main components of HLD, inhibited the development of MT in mice. BBR reduced cell viability while increasing B-cell lymphoma 2 (Bcl-2) protein expression and decreasing CD86, NF-κB, Bax, and Caspase-3 protein expression in brain vascular 2 (BV2) mcroglia cells treated with morphine. Additionally, BBR contributed to a reduction in pro-inflammatory cytokine release and apoptotic cell number. CONCLUSIONS: BBR, a key component of HLD, effectively suppressed microglial activation and neuro-inflammation by regulating the NF-κB and apoptosis signaling pathways, thereby delaying MT. This study offers a novel approach to enhance the clinical analgesic efficacy of morphine.

Berberine↗

PubMed1992

Survival of the myeloid progenitor cell line FDC-P1 is prolonged by interferon-gamma or interleukin-4.

Continuous proliferation of the immortalized myeloid progenitor cell line FDC-P1 depends on stimulation with either interleukin-3 (IL-3) or granulocyte-macrophage colony stimulating factor (GM-CSF). Two other cytokines, interferon-gamma (IFN-gamma) and IL-4, were found to prolong FDC-P1 survival for several days. Surviving cells incorporated [3H]thymidine and a minority completed up to 3 cell divisions before dying. This transient proliferative response was a direct effect of IFN-gamma and IL-4 since these cytokines did not induce production of detectable IL-3 or GM-CSF and the response was unaffected by cell concentration. IL-6, a constitutive product of FDC-P1 cells whose secretion was increased by IL-3, GM-CSF and IL-4 but not by IFN-gamma, was not responsible for the proliferative response. FDC-P1 lines that constitutively expressed the cell cycle-associated oncogene myc or the survival-associated oncogene bcl-2 also responded only transiently to IFN-gamma or IL-4, indicating that expression of these genes did not complement the signals delivered by IFN-gamma or IL-4. By contrast, the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) prolonged survival of FDC-P1 cells on its own and potentiated the response to IFN-gamma or IL-4, although the combination of stimuli did not support long-term growth. It is concluded that IFN-gamma and IL-4 trigger only some of the signalling events that lead to mitogenesis; these events are complemented by stimulation with PMA but additional signals are required for sustained proliferation.

Animals↗

PubMed1992

Recent results on the biology of Hodgkin and Reed-Sternberg cells. I. Biopsy material.

The most recent sophisticated investigations have provided new and revealing, but also contradictory and controversial information on the biological nature and the cellular origin of Hodgkin and Reed-Sternberg cells (H-RS). Immunophenotypic analyses have shown variable phenotypic antigen expression; but, on balance the data suggest a lymphoid cell expressing T- and/or B-cell-associated markers and certain activation antigens while lacking immunological features of monocytes-macrophages or other lineages. Molecular genetic studies have demonstrated heterogenous findings with respect to rearrangements of T-cell receptor and immunoglobulin genes. Only a small percentage of the cases has rearrangements; this might be due to the threshold of sensitivity of the method combined with the scarcity of the malignant cells. Epstein-Barr virus (EBV) genomes are clonally integrated in the H-RS cells of about half the cases. The significance of these findings--whether EBV is a causative agent or an epiphenomenon--remains to be elucidated. H-RS cells express mRNA and proteins of various cytokines and cytokine receptors implying a predominant role for cytokines in the pathophysiology of HD. The mononuclear and polynuclear H-RS cells are capable of DNA synthesis and nuclear division; the lack of cellular division leads to multinuclearity through the process of endomitosis. Mutations and expression of only a limited number of oncogenes have been tested thus far. Whether the bcl-2 oncogene is involved in HD remains a matter of debate. Aneuploidy and non-random chromosomal abnormalities are the results of cytogenetic analyses of H-RS cells. However, no chromosomal marker specific for HD has yet been found. Thus, while studies of EBV involvement, growth factor production, oncogene expression and chromosomal abnormalities contributed a fair amount of new data on the nature of H-RS cells, only immunophenotyping and genotyping provided some indication of the cellular derivation: an activated lymphoid cell that possibly expresses oncogenes, that probably is infected with EBV, that most likely produces cytokines, that certainly has multiple karyotypic abnormalities.

Antigens, Surface↗

PubMed2022

Human Macrophages Exhibit GM-CSF Dependent Restriction of Mycobacterium tuberculosis Infection via Regulating Their Self-Survival, Differentiation and Metabolism.

GM-CSF is an important cytokine that regulates the proliferation of monocytes/macrophages and its various functions during health and disease. Although growing evidences support the notion that GM-CSF could play a major role in immunity against tuberculosis (TB) infection, the mechanism of GM-CSF mediated protective effect against TB remains largely unknown. Here in this study we examined the secreted levels of GM-CSF by human macrophages from different donors along with the GM-CSF dependent cellular processes that are critical for control of M. tuberculosis infection. While macrophage of different donors varied in their ability to produce GM-CSF, a significant correlation was observed between secreted levels of GM-CSF, survial of macrophages and intra-macrophage control of Mycobacterium tuberculosis bacilli. GM-CSF levels secreted by macrophages negatively correlated with the intra-macrophage M. tuberculosis burden, survival of infected host macrophages positively correlated with their GM-CSF levels. GM-CSF-dependent prolonged survival of human macrophages also correlated with significantly decreased bacterial burden and increased expression of self-renewal/cell-survival associated genes such as BCL-2 and HSP27. Antibody-mediated depletion of GM-CSF in macrophages resulted in induction of significantly elevated levels of apoptotic/necrotic cell death and a simultaneous decrease in autophagic flux. Additionally, protective macrophages against M. tuberculosis that produced more GM-CSF, induced a stronger granulomatous response and produced significantly increased levels of IL-1β, IL-12 and IL-10 and decreased levels of TNF-α and IL-6. In parallel, macrophages isolated from the peripheral blood of active TB patients exhibited reduced capacity to control the intracellular growth of M. tuberculosis and produced significantly lower levels of GM-CSF. Remarkably, as compared to healthy controls, macrophages of active TB patients exhibited significantly altered metabolic state correlating with their GM-CSF secretion levels. Altogether, these results suggest that relative levels of GM-CSF produced by human macrophages plays a critical role in preventing cell death and maintaining a protective differentiation and metabolic state of the host cell against M. tuberculosis infection.

Cell Differentiation↗

PubMed2026

[Aggressive B-cell lymphomas with MYC gene cluster amplification: a clinicopathological analysis of eight cases].

Objective: To investigate the clinicopathological characteristics, molecular genetics, treatments and prognosis of aggressive B-cell lymphomas (ABCL) with MYC gene cluster amplification. Methods: Eight cases of ABCL with MYC gene cluster amplification were collected, including 6 cases from the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China and 2 consultation cases from outside hospitals. The histomorphology, immunohistochemical profiles, and molecular genetic characteristics were analyzed. Clinical follow-up and literature review were also conducted. Results: Among the eight patients, six were male and two were female, with an age 71.5 (61.7, 74.2) years. All six in-house patients presented with abdominal pain at onset, without B symptoms. Most cases were classified as Ann Arbor stage Ⅲ-Ⅳ. Extranodal involvement occurred in 5 of the 6 in-house cases, primarily affecting the gastrointestinal tract (4/5). All initial bone marrow biopsies showed no evidence of lymphoma. One patient had a history of immunosuppression following renal transplantation. Two cases exhibited diffuse large B-cell lymphoma (DLBCL) morphology. The other six showed high-grade features, while three of them showed Burkitt lymphoma-like morphology. Except for one case of blastoid variant mantle cell lymphoma, the remaining six cases (6/7) displayed a germinal center B-cell phenotype. None of the in-house cases harbored bcl-2 or bcl-6 rearrangements as shown by fluorescence in situ hybridization. 11q alterations were identified in all but one consultation case, including gain/loss type in five cases and 11q gain in two. 11q telomere loss of heterozygosity by chromosomal microarray analysis was not detected in one of the two cases with 11q gain that was subject to the test. The duration of follow-up ranged from 5.9 to 55.5 months, with 5 patients alive at the end of the study. Conclusions: ABCL with MYC gene cluster amplification often presents high-grade morphology and gastrointestinal involvement, which strongly suggests the alteration of 11q. It seems to have a favorable prognosis.

Humans↗

PubMed2026

Role of Sanqi Baiji San in Mitigating Ethanol-Induced Gastric Epithelial Cell Injury via PI3K/AKT-related Signaling.

This work aimed to clarify the protective mechanism of Sanqi Baiji San (SQBJ) against ethanol-induced gastric epithelial cell injury and to explore its potential relevance to gastric ulcer (GU). Network pharmacology was used to screen SQBJ's active components (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform [TCMSP], Oral Bioavailability [OB] ≥ 20%, Drug-Likeness [DL] ≥ 0.1), map their targets (Universal Protein Resource [UniProt]), collect GU-related targets (GeneCards/OMIM/DrugBank), and analyze overlapping targets via Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and molecular docking. Ethanol-injured Gastric Epithelial Cell Line-1 (GES-1) cells were treated with SQBJ or the PI3K inhibitor LY294002. CCK-8 was used to determine the optimal SQBJ concentration. Network pharmacology analyses identified 126 common targets enriched within PI3K/AKT/MAPK-related cascades and suggested potential interactions between principal SQBJ constituents and PI3K/AKT-related proteins. In ethanol-challenged cells, SQBJ alleviated cell injury by reducing inflammatory mediator release and oxidative stress, as evidenced by decreased intracellular reactive oxygen species and malondialdehyde levels. SQBJ restored mitochondrial membrane potential and ATP content and reduced apoptosis-associated changes in B-cell lymphoma-2, cleaved caspase-3, and Bcl-2-associated X protein levels. SQBJ also modulated PI3K/AKT- and MAPK-associated signaling markers. These protective effects were largely weakened by LY294002, suggesting that PI3K/AKT-related signaling is involved in SQBJ-mediated cytoprotection. These findings provide an in vitro mechanistic basis for the potential application of SQBJ in GU, although further validation in animal models of ethanol-induced gastric ulcer is required.

Ethanol↗

PubMed2026

Distributed Clonal Deletion Prevents Autoimmune Disease Progression.

Self-reactive B cells are generated during normal development and can acquire increased pathogenicity through activation-induced cytidine deaminase (AID)-mediated diversification following activation. Clonal deletion is thought to eliminate these cells, yet how deletion is distributed across developmental and activation stages to prevent autoimmune disease remains unclear. Here, we show that clonal deletion is enforced through temporally distinct mitochondrial apoptosis (MOMP) checkpoints that differentially regulate autoreactive B cell fate and disease progression. Using conditional Bcl-2 expression to inhibit MOMP either before or after B cell activation, we find that early inhibition permits the survival and maturation of autoreactive B cells after peripheral egress, expanding the pool of cells available for activation. These cells subsequently undergo AID-dependent diversification, producing class-switched IgG autoantibodies with expanded antigen breadth that target a wider range of self-antigens and drive lethal, female-biased autoimmune disease characterized by complement activation and kidney pathology. In contrast, inhibition of MOMP only after activation allows the accumulation of germinal center, switched memory, and plasma cells and promotes autoantibody production, but results in more restricted IgG autoreactivity, limited complement activation and limited tissue damage, and normal survival. Notably, early MOMP inhibition does not expand immature bone marrow B cells, indicating that a major clonal deletion checkpoint operates in the periphery rather than during initial B cell generation. Together, these findings support a Distributed Clonal Deletion Model in which early checkpoints restrict the entry of autoreactive B cells into diversification pathways, while later checkpoints limit the persistence of diversified autoreactive clones, thereby constraining autoimmune disease progression.

Journal Article↗

PubMed1992

Induction of apoptosis--new targets for cancer chemotherapy.

Many anticancer agents induce an active cell death process, apoptosis, in sensitive tumour cells. Elucidation of molecular mechanisms underlying apoptosis may shed light on why some tumour cells survive chemotherapy, and may identify new targets for anticancer agents whose effects are not tightly linked to proliferative status. The signal transduction events which initiate apoptosis are unclear. A change in cytosolic calcium is generally assumed to be a key signal for apoptosis although the evidence for this is not conclusive. Other putative signal transducers which may modulate apoptosis are protein kinase C and cAMP. Genes which induce apoptosis in response to such signals are largely unidentified, but certain oncogenes, notably bcl-2, act to delay or suppress apoptosis in several cell types.

Apoptosis↗

PubMed1992

The apoptosis endonuclease and its regulation.

Activation of an endogenous endonuclease has been observed in conjunction with the structural changes of apoptosis in a wide variety of cell types and circumstances. The endonuclease is present constitutively in some cells (e.g. rodent cortical thymocytes) in which apoptosis is readily triggered by many unrelated stimuli, but is inducible in others. Purification of this enzyme is an objective of some importance in apoptosis research, as it might act as a marker of susceptibility to apoptosis and lead to better understanding of the regulation of the process as a whole. Early data suggest that the thymocyte endonuclease is an anionic protein of molecular weight greater than 110 kDa, with a pH optimum of 7.5 and a double-strand cleavage preference. Its activity, and the induction of apoptosis as a whole, is regulated by several familiar cellular proto-oncogenes and oncosuppressor genes, including c-myc, Ha-ras, bcl-2 and p53.

Animals↗

PubMed1992

Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci.

The first association study of cleft lip with or without cleft palate (CL/P), with candidate genes, found an association with the transforming growth-factor alpha (TGFA) locus. This finding has since been replicated, in whole or in part, in three independent studies. Here we extend our original analysis of the TGFA TaqI RFLP to two other TGFA RFLPs and seven other RFLPs at five candidate genes in 117 nonsyndromic cases of CL/P and 113 controls. The other candidate genes were the retinoic acid receptor (RARA), the bcl-2 oncogene, and the homeobox genes 2F, 2G, and EN2. Significant associations with the TGFA TaqI and BamHI RFLPs were confirmed, although associations of clefting with previously reported haplotypes did not reach significance. Of particular interest, in view of the known teratogenic role of retinoic acid, was a significant association with the RARA PstI RFLP (P = .016; not corrected for multiple testing). The effect on risk of the A2 allele appears to be additive, and although the A2A2 homozygote only has an odds ratio of about 2 and recurrence risk to first-degree relatives (lambda 1) of 1.06, because it is so common it may account for as much as a third of the attributable risk of clefting. There is no evidence of interaction between the TGFA and RARA polymorphisms on risk, and jointly they appear to account for almost half the attributable risk of clefting.

Blotting, Southern↗

PubMed1992

T-cell-rich B-cell lymphomas. A clinicopathologic study of 19 cases.

T-cell-rich B-cell lymphomas (TCRBCLs) are recently described, unusual non-Hodgkin's lymphomas that have a diffuse morphology, a predominance of reactive T-cells, and a minority of neoplastic B-cells. The clinical and pathological features of 19 TCRBCLs, all of which demonstrated B-cell clonality, are presented. These lymphomas generally affected older patients by widespread disease and usually were nodal in origin. Treatment varied, but continuous complete remissions (eight patients) were achieved only in those receiving chemotherapy directed at intermediate-grade lymphomas. Although morphologically heterogeneous, all cases resembled peripheral T-cell lymphomas (PTCLs); several TCRBCLs also contained Reed-Sternberg-like cells. Flow cytometry or frozen-section immunoperoxidase failed to detect monotypic immunoglobulin (Ig) in eight of eight cases tested. In contrast, paraffin immunoperoxidase was very useful diagnostically, showing large L26 (CD20-associated) positive cells scattered singly or in small clusters among numerous small T-cells (UCHL1[CD45RO] positive) in all cases. Monotypic cytoplasmic Ig was present in 16 of 19 cases, one of which exhibited plasmacytic differentiation. Southern blot analysis demonstrated relatively faint Ig JH and/or JK bands, indicating a small monoclonal B-cell population in nine of 11 cases, one of which also showed a bcl-2 rearrangement. No T-cell receptor gene rearrangements were observed. These results showed that TCRBCLs may be easily confused with PTCLs or occasionally confused with Hodgkin's disease. TCRBCLs are probably heterogeneous biologically; some cases are of follicular center cell origin. These lymphomas respond to chemotherapy directed at intermediate-grade lymphomas, apparently have a better prognosis than PTCLs, and seem to represent morphological variants of different types of large B-cell lymphomas.

Adolescent↗

PubMed2026

Suppression of HIV-1 replication in CEM-A cell cultures by trans-splicing group I introns targeting PAS/PBS sequences and conditionally expressing ΔN-Bax.

Anti-HIV group I introns containing antisense guide sequences directed against the HIV-1 primer activation signal and primer-binding site (PAS/PBS) were designed and evaluated. Because PAS/PBS sequences are present in the viral RNA species examined, these RNAs can serve as trans-splicing substrates. The introns were active against both artificial target RNAs and viral RNA generated during infection. Cleavage and degradation of targeted viral RNA may have contributed to suppression, whereas inclusion of a 3' exon encoding the proapoptotic protein ΔN-Bax was associated with increased programmed cell death and may have augmented suppression of viral replication. In cultured CEM-A cells, transgene expression of these introns markedly suppressed HIV-1 replication, with p24 levels falling below the assay detection limit in selected clones. RESULTS: RT-PCR and sequence analysis detected splice products containing the expected PAS/PBS junctions. In the dual-luciferase assay, intron expression reduced normalized Gaussia luciferase signal by approximately 70% relative to the negative control. Qualitative Annexin V imaging and caspase-3 assays were consistent with infection-dependent apoptosis after ΔN-Bax splice-product formation. Transient expression of each intron in HEK293T cells followed by infection with VSV-G-pseudotyped HIV-1NL4-3 at an MOI of 2 reduced p24 levels by approximately 50% at 4 days post-infection. Construct 128L produced the strongest RT-PCR band under the tested conditions and was selected for subsequent experiments. A canonical splice product and a low-abundance noncanonical splice product were detected; both involved the intended HIV-derived target RNA, although transcriptome-wide off-target splicing was not assessed. Heterogeneous transformed HEK293T populations showed an approximately 2-log10 reduction in p24. In selected clonal HEK293T and CEM-A lines, p24 was below the assay detection limit at the measured endpoints, including up to 90 days after infection in some CEM-A clones. CONCLUSIONS: PAS/PBS-targeting group I introns suppressed HIV-1-associated p24 production in the tested cell-culture models. Linking the introns to a ΔN-Bax 3' exon was associated with infection-dependent apoptosis and may further limit viral replication and spread. The use of highly conserved, functionally constrained target sequences may reduce the likelihood of escape, but viral evolution and transcriptome-wide off-target effects were not assessed. This conditional death-upon-infection strategy warrants further evaluation in primary-cell and in vivo models.

Humans↗

PubMed2026

Overlapping genetic etiology of pediatric and adult germ cell tumors.

BACKGROUND: Germ cell tumors are heterogeneous neoplasms arising from primordial germ cells. Although genome-wide association studies have identified numerous susceptibility loci for adult testicular germ cell tumors, the heritable basis of pediatric testicular germ cell tumors and germ cell tumors that arise outside the testes remain poorly understood. METHODS: We conducted a multi-ancestry genome-wide association study of pediatric germ cell tumors, including 1927 cases from the Germ Cell Tumor Epidemiology Study and 10 601 controls. Cases were diagnosed with testicular (n = 678), ovarian (n = 441), intracranial (n = 435), and extragonadal (n = 373) germ cell tumor between the ages of 0 and 19 years. RESULTS: We identified 4 loci reaching genome-wide significance, including variants near BAK1 (chr 6: rs3831846), SPRY4 (chr 5: rs12515244), DMRT1 (chromosome [chr] 9: rs10815910), and DEPTOR (chr 8: rs13277786). Additional genome-wide statistically significant associations were identified in subgroup analyses, including 6 loci for intracranial germ cell tumors (rs2758612 [PMF1/BGLAP], rs9854760 [PLCL2], rs6851498 [KIT], rs11816992 on chromosome 10, rs3830273 [TFAM], and rs13054014 [LZTR1]), 1 locus for testicular germ cell tumor (rs1907702 [KITLG]), and 1 locus for males (rs4610628 [MAD1L1]). After Bonferroni correction, 18 of 78 previously reported testicular germ cell tumor loci were significantly associated with germ cell tumor overall or in at least 1 subgroup with a particularly strong correlation between testicular germ cell tumor and intracranial germ cell tumor effect estimates (rho = 0.63, P = 5.5 × 10-10). Expression quantitative trait locus (QTL) analyses identified candidate genes in the regions identified on chromosome 6 (BAK1, LINC003366, and ITPR3) and chromosome 8 (DEPTOR and RP11-760H22.2). CONCLUSIONS: Our data support a role for germline genetic variation in the development of germ cell tumors in locations outside the testes and highlight shared genetic architecture across age group and tumor location.

Humans↗