Central Nervous System Manifestations of Cutaneous LymphomasChakravarty
Curr Neurol Neurosci Rep (2025) 25 (1), 27
Abstract: Primary cutaneous lymphomas (PCL) are an uncommon malignancy of the lymphocytes, primarily presenting with dermatologic lesions. Central nervous system(CNS) metastatic manifestations, are even rarer. This review focus mainly on three aspects namely early suspicion of CNS involvement, selection of cases for CNS chemo-prophylaxis and lastly, the rare occurrence from skin straight to brain without other organ involvement.Primary extranodal large B-cell lymphomas are very heterogeneous. Recent molecular data have thrown some light on such divergent clinical behaviour. The peculiar, stage-independent risk of CNS spread in testicular, breast, uterine, and possibly Primary Cutaneous Diffuse Large B Cell Lymphoma Leg type (PCDBLCL-LT), may be related to prevalent MCD (MYD88/CD79B-mutated) genomic subtype in these lymphomas. It remains to be seen how this genotype might facilitate invasion of the CNS parenchyma, and whether therapies targeting the B-cell receptor or NF-κB signalling pathways could lower the risk. Some sites of extranodal involvement, almost always indicate disseminated disease with a high propensity to invade the bone marrow and leptomeningeal compartments, particularly in double-hit lymphoma. Conversely, unifocal bone, craniofacial, thyroid, or gastric DLBCL show a relatively favourable prognosis with standard immunochemotherapy. Their risk of CNS recurrence might be largely driven by potential local invasion due to anatomic proximity when epidural, orbital, or skull involvement is present, thus requiring a case-by-case approach to prophylaxis. Future studies can help clarify the relationship between extranodal DLBCLs and their indolent MALT counterparts, and whether the favorable behavior of some ABC-like lymphomas (Activated B-cell-like (ABC) diffuse large B-cell lymphomas (e.g. in the stomach or craniofacial sites) might be explained by less aggressive genotypes (e.g. BCL6/NOTCH2 subtype). MALT lymphoma is a type of non-Hodgkin lymphoma (NHL) that starts in the mucosa lining some body organs and cavities. It is a type of NHL called marginal zone lymphoma. PCL can be defined as non-Hodgkin lymphomas that initially present in the skin without any extra cutaneous manifestations at the time of diagnosis. The skin is the second most common site of occurrence of non-Hodgkin lymphomas, second only to the lymphatic system. PCL can be broadly divided into two types-T cell lymphomas and B cell lymphomas.Major subtypes of T cell lymphomas include mycosis fungoides (MF) and its variants, Sezary syndrome, CD30 + lymphoproliferative disorders, and other more rare entities like subcutaneous panniculitis- like T-cell lymphoma, extranodal NK/T cell lymphoma nasal type, primary cutaneous peripheral T-cell lymphoma not otherwise specified, and adult T-cell leukemia/lymphoma. Cutaneous B-cell lymphomas comprise approximately 25% of all cutaneous lymphomas. There are three main morphologic groups: primary cutaneous marginal zone lymphoma, cutaneous follicle-centre lymphoma, and diffuse large B-cell lymphoma, leg type(DLBCL). Other subtypes include - DLBCL other type (non-leg), and intravascular large B-cell lymphoma. Immunohistochemically cutaneous marginal zone lymphoma is classically bcl-2 positive and bcl-6 negative. This condition has an excellent prognosis, with five-year disease related survival noted to be > 95%. Primary cutaneous follicle-centre lymphoma is a lymphoma of cells of the follicle centre, usually including a combination of centrocytes and centroblasts. Immunohistochemically, the neoplastic follicle cells express bcl-6, and expression of bcl-2 is typically absent or faint. Prognosis is again excellent, with five-year disease related survival noted to be over 95%. Primary cutaneous diffuse large B-cell lymphoma, leg type is a neoplastic disorder of centroblasts and immunoblasts, which typically presents as a red to violaceous nodules or tumours on the lower extremities. Phenotypically, bcl-2 and bcl-6 are often expressed, as is MUM-1. Extracutaneous disease is common, with these tumours having a relatively high propensity to disseminate. Prognosis is variable with disease related 5-year survival being 40-50% in patients with multiple lesions at time of diagnosis, to 100% in those patients that present with a single lesion. Other, rare large B-cell lymphomas can also present in the skin. Intravascular large B-cell lymphoma is a subtype in which neoplastic B-cells have accumulated within blood vessels and often affect many organ systems (including brain), however rarely skin lesions only can occur. CNS involvement is uncommon in both types of cutaneous lymphomas and overall prognosis is not good. Brain masses and meningeal infiltration are the usual patterns though imaging may be negative with demonstration of lymphoma cells only in the CSF by flow cytometry. At times, no other organ involvement may be noted, albeit very rarely. Selection of patients who might benefit with CNS prophylactic agents is of utmost importance. On the whole, most cases of high grade cutaneous DLBCLs need to have CNS chemo-prophylaxis.© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Notch 2 from bone marrow mesenchymal stem cells alleviates smoke inhalation-induced lung injury by mediating alveolar cell differentiationYin, Wang, Tao
et alJ Mol Histol (2025) 56 (2), 113
Abstract: Smoke inhalation-induced lung injury (SILI) is the major fatality in fire- and blast-related accidents. Bone marrow mesenchymal stem cells (BMSCs) have a potential therapeutic role in SILI through directional differentiation into AT1, AT2, and pulmonary vascular endothelial cells. The present study proposes to evaluate the effect of Notch 2 on the directional differentiation of BMSCs and to characterize its reparative role in a SILI model.pGMLV-SC5 RNAi and pcDNA 3.1 lentivirus exogenously regulate Notch 2 expression in rat-derived BMSCs and BMSCs were injected into the tail vein of the SILI rat model. H&E, Masson and TUNEL stains characterized pathological changes in rat lung tissue. ELISA, western blot, and RT-qPCR identified inflammatory factors (IL-1β, IL-6 and TNF-α), Notch 2 pathway- (Notch 2 and Hes1), lung fibrosis- (α-SMA and E-cadherin), AT1- (AQP5), and AT2- (SPC and SPD) associated markers.pGMLV-SC5 RNAi or pcDNA 3.1 lentivirus could decrease or increase Notch 2 expression in BMSCs. In vivo imaging showed that BMSCs could be localized in the lungs of the SILI model at 24 h after model development. Treatment with BMSCs alleviated diffuse congestion, lung fibrosis, and alveolar cell apoptosis in lung tissues of the SILI model. Treatment of BMSCs decreased the levels of IL-1β, IL-6, TNF-α, and α-SMA and increased the expression of Notch 2, Hes1, E-cadherin, AQP5, SPC, and SPD in the SILI model. Overexpression of Notch 2 enhances the therapeutic effect of BMSCs on lung injury in the SILI model. Notably, overexpression of Notch 2 attenuated the BMSCs-induced upregulation of AQP5 expression and enhanced the BMSCs-induced upregulation of SPC and SPD expression.Notch 2 contributes to lung injury repair in the SILI rat model by facilitating the differentiation of BMSCs to AT2. This study provides a new idea and target for the treatment of BMSCs for SILI.© 2025. The Author(s), under exclusive licence to Springer Nature B.V.
Notch2 Signaling Drives Cardiac Hypertrophy by Suppressing Purine Nucleotide MetabolismWang, Li, Chen
et alResearch (Wash D C) (2025) 8, 0635
Abstract: Gain-of-function mutations of Notch2 cause the rare autosomal dominant disorder known as Hajdu-Cheney syndrome (HCS). Most patients with HCS develop congenital heart disease; however, the precise mechanisms remain elusive. Here, a murine model expressing the human Notch2 intracellular domain (hN2ICD) in cardiomyocytes (hN2ICD-TgCM) was generated and the mice spontaneously developed ventricular diastolic dysfunction with preserved ejection fraction and cardiac hypertrophy. Ectopic hN2ICD expression promoted cardiomyocyte hypertrophy by suppressing adenylosuccinate lyase (ADSL)-mediated adenosine 5'-monophosphate (AMP) generation, which further enhanced the activation of the mammalian target of rapamycin complex 1 pathway by reducing AMP-activated kinase activity. Hairy and enhancer of split 1 silencing abrogated hN2ICD-induced cardiomyocyte hypertrophy by increasing Adsl transcription. Importantly, pharmacological activation of AMP-activated kinase ameliorated cardiac hypertrophy and dysfunction in hN2ICD-TgCM mice. The frameshift mutation in Notch2 exon 34 (c.6426dupT), which causes early-onset HCS, induces AC16 human cardiomyocyte hypertrophy through suppressing ADSL-mediated AMP generation. Thus, targeting Notch2-mediated purine nucleotide metabolism may be an attractive therapeutic approach to heart failure treatment.Copyright © 2025 Yuhong Wang et al.
The Notch ligand Jagged1 plays a dual role in cochlear hair cell regenerationLi, Morgan, Li
et albioRxiv (2025)
Abstract: Hair cells (HCs) within the inner ear cochlea are specialized mechanoreceptors required for hearing. Cochlear HCs are not regenerated in mammals, and their loss is a leading cause of deafness in humans. Cochlear supporting cells (SCs) in newborn mice have the capacity to regenerate HCs, but persistent Notch signaling, presumably activated by SC-specific Notch ligand Jagged1 (JAG1), prevents SCs from converting into HCs. Here, employing an organoid platform, we show that while JAG1 participates in HC-fate repression, JAG1's primary function is to preserve the "progenitor-like characteristics" of cochlear SCs. Transcriptomic and mechanistic studies reveal that JAG1/Notch signaling maintains the expression of progenitor and metabolic genes in cochlear SCs and sustains pro-growth pathways, including PI3K-Akt-mTOR signaling, a function that is mediated by Notch1 and Notch2. Finally, we show that JAG1/Notch signaling stimulation with JAG1-Fc peptide enhances the HC-forming capacity of cochlear SCs undergoing maturation in cochlear explants and in vivo .
膜杰作
Star Staining
