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Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare and relatively indolent B-cell lymphoma. Characteristically, the [lymphocyte-predominant (LP)] tumor cells are embedded in a microenvironment enriched in lymphocytes. More aggressive variants of mature B-cell and peripheral T-cell lymphomas exhibit nuclear expression of the polo-like kinase 1 (PLK1) protein, stabilizing MYC (alias c-myc) and associated with worse clinical outcomes. This study demonstrated expression of PLK1 in the LP cells in 100% of NLPHL cases (n = 76). In contrast, <5% of classic Hodgkin lymphoma cases (n = 70) showed PLK1 expression within the tumor cells. Loss-of-function approaches demonstrated that the expression of PLK1 promoted cell proliferation and increased MYC stability in NLPHL cell lines. Correlation with clinical parameters revealed that the increased expression of PLK1 was associated with advanced-stage disease in patients with NLPHL. A multiplex immunofluorescence panel coupled with artificial intelligence algorithms was used to correlate the composition of the tumor microenvironment with the proliferative stage of LP cells. The results showed that LP cells with PLK1 (high) expression were associated with increased numbers of cytotoxic and T-regulatory T cells. Overall, the findings demonstrate that PLK1 signaling increases NLPHL proliferation and constitutes a potential vulnerability that can be targeted with PLK1 inhibitors. An active immune surveillance program in NLPHL may be a critical mechanism limiting PLK1-dependent tumor growth.
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Doença de Hodgkin , Linfoma de Células B , Humanos , Inteligência Artificial , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Linfócitos/patologia , Linfoma de Células B/patologia , Quinase 1 Polo-Like , Microambiente TumoralRESUMO
ABSTRACT: Richter syndrome (RS) describes a phenomenon in which a patient with chronic lymphocytic leukemia (CLL) develops an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Reports of cutaneous RS remain exceedingly rare. We report a 61-year-old woman with relapsed/refractory CLL presenting with several subcutaneous nodules on her arms and legs and a single dermal plaque on her abdomen. Skin biopsy revealed a diagnosis of DLBCL, ABC-type, and her clinical status rapidly deteriorated following diagnosis. We review the variety of clinical presentations of cutaneous RS, its association with CLL, risk factors for RS development in CLL patients, and the distinctive histopathologic and immunophenotypic features of DLBCL. We hope to highlight the importance of prompt skin biopsy in patients with CLL presenting with progressive skin lesions and increase awareness of this aggressive clinical syndrome.
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Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Neoplasias Cutâneas , Humanos , Feminino , Pessoa de Meia-Idade , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/patologia , Neoplasias Cutâneas/patologia , Evolução Fatal , Síndrome , BiópsiaRESUMO
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells. Most patients with T-PLL present with lymphocytosis, anemia, thrombocytopenia, and hepatosplenomegaly. Correct identification of T-PLL is essential because treatment for this disease is distinct from that of other T-cell neoplasms. In 2019, the T-PLL International Study Group (TPLL-ISG) established criteria for the diagnosis, staging, and assessment of response to treatment of T-PLL with the goal of harmonizing research efforts and supporting clinical decision-making. T-PLL pathogenesis is commonly driven by T-cell leukemia 1 (TCL1) overexpression and ATM loss, genetic alterations that are incorporated into the TPLL-ISG diagnostic criteria. The cooperativity between TCL1 family members and ATM is seemingly unique to T-PLL across the spectrum of T-cell neoplasms. The role of the T-cell receptor, its downstream kinases, and JAK/STAT signaling are also emerging themes in disease pathogenesis and have obvious therapeutic implications. Despite improved understanding of disease pathogenesis, alemtuzumab remains the frontline therapy in the treatment of naïve patients with indications for treatment given its high response rate. Unfortunately, the responses achieved are rarely durable, and the majority of patients are not candidates for consolidation with hematopoietic stem cell transplantation. Improved understanding of T-PLL pathogenesis has unveiled novel therapeutic vulnerabilities that may change the natural history of this lymphoproliferative neoplasm and will be the focus of this concise review.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Prolinfocítica de Células T , Humanos , Leucemia Prolinfocítica de Células T/etiologia , Leucemia Prolinfocítica de Células T/genética , Alemtuzumab/uso terapêutico , MutaçãoRESUMO
Diffuse large B-cell lymphoma featuring overexpression of MYC and B-Cell Lymphoma 2 (double expressor lymphoma, DEL) is associated with poor outcomes. Existing evidence suggesting improved outcomes for DEL with the use of more intensive regimens than R-CHOP is restricted to younger patients and based on limited evidence from low patient numbers. We retrospectively evaluated the impact of intensive frontline regimens versus R-CHOP in a multicenter analysis across 7 academic medical centers in the United States. We collected 90 cases of DEL, 46 out of 90 patients (51%) received R-CHOP and 44/90 (49%) received an intensive regimen, which was predominantly DA-EPOCH-R. Treatment cohorts were evenly balanced for demographics and disease characteristics, though the intensive group had a higher lactate dehydrogenase (LDH, 326 vs. 230 U/L p = 0.06) and presence of B-symptoms (50% vs. 22%, p = 0.01) compared to the R-CHOP cohort. There was no difference in PFS (median 53 vs. 38 months, p = 0.49) or overall survival (67 vs. not reached months, p = 0.14) between the R-CHOP and intensive therapy cohorts, respectively. On multivariate analysis, intensive therapy was associated with a hazard ratio of 2.35 (95% CI 0.74-7.41), though this was not statistically significant. Additionally, a subgroup analysis of intermediate high-risk lymphoma defined by IPI ≥3 did not identify a difference in survival outcomes between regimens. We conclude that in our multi-center cohort there is no evidence supporting the use of intensive regimens over R-CHOP, suggesting that R-CHOP remains the standard of care for treating DEL.
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Linfoma Difuso de Grandes Células B/tratamento farmacológico , Idoso , Humanos , Linfoma Difuso de Grandes Células B/patologia , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
GATA-3 regulates the differentiation, proliferation, survival, and function of peripheral T cells and their thymic progenitors. Recent findings, reviewed here, not only implicate GATA-3 in the pathogenesis of molecularly, genetically, and clinically distinct T-cell lymphoproliferative disorders, but also have significant diagnostic, prognostic, and therapeutic implications.
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Fator de Transcrição GATA3/genética , Transtornos Linfoproliferativos/patologia , Mutação , Linfócitos T/patologia , Diferenciação Celular , Humanos , Transtornos Linfoproliferativos/genética , Linfócitos T/metabolismoAssuntos
Fibrina , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Fibrina/metabolismo , Criança , Masculino , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , PrognósticoRESUMO
Tributyltin (TBT), an organotin chemical used as a catalyst and biocide, can stimulate cholesterol efflux in non-steroidogenic cells. Since cholesterol is the first limiting step for sex hormone production, we hypothesized that TBT disrupts intracellular cholesterol transport and impairs steroidogenesis in ovarian theca cells. We investigated TBT's effect on cholesterol trafficking, luteinization, and steroidogenesis in theca cells of five species (human, sheep, cow, pig, and mice). Primary theca cells were exposed to an environmentally relevant dose of TBT (1 or 10 ng/ml) and/or retinoid X receptor (RXR) antagonist. The expression of RXRα in sheep theca cells was knocked down using shRNA. Steroidogenic enzymes, cholesterol transport factors, and nuclear receptors were measured by RT-qPCR and Western blotting, and intracellular cholesterol, progesterone, and testosterone secretion by ELISA. TBT upregulated StAR and ABCA1 in ovine cells, and SREBF1 mRNA in theca cells. TBT also reduced intracellular cholesterol and upregulated ABCA1 protein expression but did not alter testosterone or progesterone production. RXR antagonist and RXRα knockdown demonstrates that TBT's effect is partially through RXR. TBT's effect on ABCA1 and StAR expression was recapitulated in all five species. TBT, at an environmentally relevant dose, stimulates theca cell cholesterol extracellular efflux via the RXR pathway, triggers a compensatory upregulation of StAR that regulates cholesterol transfer into the mitochondria and SREBF1 for de novo cholesterol synthesis. Similar results were obtained in all five species evaluated (human, sheep, cow, pig, and mice) and are supportive of TBT's conserved mechanism of action across mammalian species.
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Colesterol/metabolismo , Receptores X de Retinoides/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Tecais/efeitos dos fármacos , Células Tecais/metabolismo , Compostos de Trialquitina/toxicidade , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Bovinos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Fosfoproteínas/efeitos dos fármacos , Fosfoproteínas/metabolismo , Cultura Primária de Células , Progesterona/metabolismo , Ovinos , Especificidade da Espécie , Suínos , Testosterona/metabolismoRESUMO
Septic systems are typically designed to treat domestic wastewater from households without access to centralized facilities. The installation of a food waste disposer (FWD) may increase the discharge of food waste (FW) into the wastewater; therefore, the installation of a FWD is discouraged in households that have a septic system. This study was conducted to determine how a typical dose of FW from a FWD can affect the performance of a septic system in terms of sewage treatment and solids accumulation. A 20-L control tank was compared with an experiment tank to which FW was added, increasing the amount of total suspended solids (TSS) by 31.3% and total chemical oxygen demands by 46.3% for a period of 110 days. Although the influent water quality changed dramatically, the effluent from the experiment tank had a substantially lower percentage increase in water quality parameters compared with the effluent from the control. It was found that in the experiment tank, 75.8% of FW TSS was degraded, whereas only 36.7% of sewage TSS was degraded, and that 18.8% of FW TSS and 44.9% of sewage TSS accumulated in the experiment tank. The addition of FW increased the scum accumulation, even though the dry matter of the scum layer was much less in quantity than the sludge layer. It also increased the lipid content in the sludge. The increase in the scum layer was mainly due to the increase in protein from the addition of the FW. Overall, compared with sewage TSS, FW TSS tends to be more biodegradable, which indicates that the impact on pumping frequency from adding FW will be insignificant.
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Alimentos , Eliminação de Resíduos , Análise da Demanda Biológica de Oxigênio , Reatores Biológicos , Esgotos , Eliminação de Resíduos Líquidos , Águas ResiduáriasRESUMO
PKM2 (pyruvate kinase M2), a critical regulator of glycolysis, is phosphorylated by numerous growth factor receptors and oncogenic tyrosine kinases including NPM-ALK which is expressed in a subset of aggressive T-cell non-Hodgkin lymphomas known as anaplastic large cell lymphoma, ALK-positive. Our previous work demonstrated that phosphorylation of Y105-PKM2 by NPM-ALK regulates a major metabolic shift to promote lymphomagenesis. In addition to its role in metabolism, recent studies have shown that PKM2 promotes oncogenesis by phosphorylating nuclear STAT3 (signal transducer and activator of transcription 3) and regulating transcription of genes involved in cell survival and proliferation. We hypothesized that identification of novel PKM2 interactors could provide additional insights into its expanding functional role in cancer. To this end, immunocomplexes of FLAG-tagged PKM2 were isolated from NPM-ALK-positive ALCL (anaplastic large cell lymphoma) cells and subjected to liquid chromatography tandem mass spectrometry (LC-MS/MS) which led to the identification of polypyrimidine tract-binding protein (PTBP1) as a novel interactor of PKM2. The interaction between PTBP1 and PKM2 was restricted to the nucleus and was dependent on NPM-ALK mediated Y105 phosphorylation of PKM2. Stable shRNA-mediated silencing of PTBP1 resulted in a marked decrease in pY105-PKM2 and pY705-STAT3 which led to decreased ALCL cell proliferation and colony formation. Overall, our data demonstrate that PTBP1 interacts with PKM2 and promotes ALCL oncogenesis by facilitating PKM2-dependent activation of STAT3 within the nucleus.
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Carcinogênese/metabolismo , Proteínas de Transporte/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Linfoma Anaplásico de Células Grandes/metabolismo , Proteínas de Membrana/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Fator de Transcrição STAT3/metabolismo , Hormônios Tireóideos/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/química , Núcleo Celular/metabolismo , Proliferação de Células , Citoplasma/química , Citoplasma/metabolismo , Humanos , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Proteínas de Ligação a Hormônio da TireoideRESUMO
The mechanisms underlying the pathogenesis of the constitutively active tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressing anaplastic large cell lymphoma are not completely understood. Here we show using an integrated phosphoproteomic and metabolomic strategy that NPM-ALK induces a metabolic shift toward aerobic glycolysis, increased lactate production, and biomass production. The metabolic shift is mediated through the anaplastic lymphoma kinase (ALK) phosphorylation of the tumor-specific isoform of pyruvate kinase (PKM2) at Y105, resulting in decreased enzymatic activity. Small molecule activation of PKM2 or expression of Y105F PKM2 mutant leads to reversal of the metabolic switch with increased oxidative phosphorylation and reduced lactate production coincident with increased cell death, decreased colony formation, and reduced tumor growth in an in vivo xenograft model. This study provides comprehensive profiling of the phosphoproteomic and metabolomic consequences of NPM-ALK expression and reveals a novel role of ALK in the regulation of multiple components of cellular metabolism. Our studies show that PKM2 is a novel substrate of ALK and plays a critical role in mediating the metabolic shift toward biomass production and tumorigenesis.
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Proteínas de Transporte/metabolismo , Regulação Neoplásica da Expressão Gênica , Linfoma Anaplásico de Células Grandes/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Tirosina Quinases/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Metabolômica , Camundongos , Camundongos SCID , Transplante de Neoplasias , Fosforilação , Proteômica , Especificidade por Substrato , Proteínas de Ligação a Hormônio da TireoideRESUMO
The introduction of food wastes into anaerobic digestion (AD) brings a promising scenario of increasing feedstock availability and overall energy production from AD. This study evaluated the biodegradability and methane potential from co-digestion of two typical food wastes, kitchen waste and chicken fat, with dairy manure. For single substrate, the bio-methane potential assays showed that kitchen waste had the highest methane yield of 352 L-CH4 kg(-1)-VS added, 92% more than dairy manure alone. Chicken fat at the same Volatile Solid (VS) level (2 g L(-1)) inhibited bio-methane production. Addition of kitchen waste and chicken fat to a VS percentage of up to 40% improved overall methane yield by 44% and 34%, respectively. Synergistic effect was observed when either combining two or three substrates as AD feedstock, possibly as a result of increased biodegradability of organic materials in chicken fat and kitchen waste compared with dairy manure. Addition of chicken fat improved methane yield more than kitchen waste. However, addition of chicken fat VS over 0.8 g L(-1) should be cautiously done because it may cause reactor failure due to decrease in pH. The maximum methane yield was 425 L-CH4 kg(-1)-VS, achieved at a VS ratio of 2:2:1 for kitchen waste, chicken fat, and dairy manure. Results from batch AD experiment demonstrated that supplementing dairy manure to chicken fat and/or kitchen waste improved alkalinity of substrate due to the inclusion of more titratable bases in dairy manure, and therefore stabilized the methanogenesis and substantially improved biogas yield. A mixture of substrates of kitchen waste, chicken fat, and dairy manure at a ratio of 1:1:3 was fed to a continuously stirred tank reactor operated at organic loading rates of 3.28, 6.55, and 2.18 g-COD L(-1)-day (hydraulic retention time of 20, 10, and 30 days, respectively) under mesophilic condition, and methane production rate reached 0.65, 0.95, and 0.34 L-CH4 L(-1)-reactor-day.
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Bactérias/metabolismo , Esterco/análise , Metano/análise , Eliminação de Resíduos/métodos , Resíduos/análise , Anaerobiose , Animais , Biodegradação Ambiental , Biocombustíveis/análise , Reatores Biológicos , Galinhas , Digestão , Esterco/microbiologia , Metano/metabolismo , Eliminação de Resíduos/instrumentaçãoRESUMO
Oculocerebral renal syndrome of Lowe (OCRL or Lowe syndrome), a severe X-linked congenital disorder characterized by congenital cataracts and glaucoma, mental retardation and kidney dysfunction, is caused by mutations in the OCRL gene. OCRL is a phosphoinositide 5-phosphatase that interacts with small GTPases and is involved in intracellular trafficking. Despite extensive studies, it is unclear how OCRL mutations result in a myriad of phenotypes found in Lowe syndrome. Our results show that OCRL localizes to the primary cilium of retinal pigment epithelial cells, fibroblasts and kidney tubular cells. Lowe syndrome-associated mutations in OCRL result in shortened cilia and this phenotype can be rescued by the introduction of wild-type OCRL; in vivo, knockdown of ocrl in zebrafish embryos results in defective cilia formation in Kupffer vesicles and cilia-dependent phenotypes. Cumulatively, our data provide evidence for a role of OCRL in cilia maintenance and suggest the involvement of ciliary dysfunction in the manifestation of Lowe syndrome.
Assuntos
Cílios/metabolismo , Síndrome Oculocerebrorrenal/metabolismo , Monoéster Fosfórico Hidrolases/análise , Monoéster Fosfórico Hidrolases/genética , Animais , Cílios/química , Embrião não Mamífero/metabolismo , Fibroblastos/metabolismo , Genótipo , Humanos , Imuno-Histoquímica , Túbulos Renais/metabolismo , Mutação , Síndrome Oculocerebrorrenal/genética , Monoéster Fosfórico Hidrolases/metabolismo , Transfecção , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismoRESUMO
[This corrects the article DOI: 10.1371/journal.pgph.0001330.].
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PURPOSE: Many peripheral and cutaneous T-cell lymphoma (CTCL) subtypes are poorly responsive to conventional chemotherapeutic agents and associated with dismal outcomes. The zinc finger transcription factor GATA-3 and the transcriptional program it instigates are oncogenic and highly expressed in various T-cell neoplasms. Posttranslational acetylation regulates GATA-3 DNA binding and target gene expression. Given the widespread use of histone deacetylase inhibitors (HDACi) in relapsed/refractory CTCL, we sought to examine the extent to which these agents attenuate the transcriptional landscape in these lymphomas. EXPERIMENTAL DESIGN: Integrated GATA-3 chromatin immunoprecipitation sequencing and RNA sequencing analyses were performed in complementary cell line models and primary CTCL specimens treated with clinically available HDACi. RESULTS: We observed that exposure to clinically available HDACi led to significant transcriptional reprogramming and increased GATA-3 acetylation. HDACi-dependent GATA-3 acetylation significantly impaired both its ability to bind DNA and transcriptionally regulate its target genes, thus leading to significant transcriptional reprogramming in HDACi-treated CTCL. CONCLUSIONS: Beyond shedding new light on the mechanism of action associated with HDACi in CTCL, these findings have significant implications for their use, both as single agents and in combination with other novel agents, in GATA-3-driven lymphoproliferative neoplasms.
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Linfoma Cutâneo de Células T , Neoplasias Cutâneas , Humanos , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/genética , Acetilação , Inibidores de Histona Desacetilases/farmacologia , DNA , Transcrição GênicaRESUMO
OBJECTIVES: Because of its low frequency in adult populations and clinical and laboratory overlap with hemophagocytic lymphohistiocytosis and other T-cell lymphomas, T-cell/natural killer (NK) cell systemic, chronic, active Epstein-Barr virus (EBV) (T/NK sCAEBV) infection remains underdiagnosed, preventing critical, prompt therapeutic interventions. METHODS: We report a 5-case series that included 2 adult patients with T/NK sCAEBV and 3 additional adult patients with T/NK lymphomas with concomitant systemic EBV infection to review these entities' overlapping diagnostic and clinical features. RESULTS: Approximately 95% of the world population has been infected with EBV during their lifetime, and infection is usually asymptomatic, with symptomatic cases eventually resolving spontaneously. A small subset of immunocompetent patients develops CAEBV, a life-threatening complication resulting from EBV-infected T-cell or NK cell neoplastic lymphocytes. The sites of end-organ damage in T/NK sCAEBV demonstrate pathologic findings such as reactive lymphoid proliferations, making the diagnosis difficult to establish, with the only curative option being an allogeneic hematopoietic stem cell transplant. CONCLUSIONS: This diagnosis is most prevalent in Asia, with few cases reported in Western countries. Adult age is an independent risk factor for poor outcomes, and most cases are diagnosed in pediatric populations.
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Infecções por Vírus Epstein-Barr , Humanos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Células Matadoras Naturais/patologia , Células Matadoras Naturais/imunologia , Transtornos Linfoproliferativos/virologia , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/patologia , Herpesvirus Humano 4/isolamento & purificação , Idoso , Doença Crônica , Linfoma Extranodal de Células T-NK/patologia , Linfoma Extranodal de Células T-NK/virologia , Linfoma Extranodal de Células T-NK/diagnósticoRESUMO
T-cell lymphomas are aggressive neoplasms characterized by poor responses to current chemotherapeutic agents. Expression of the l-type amino acid transporter 1 (LAT 1, SLC7A5) allows for the expansion of healthy T-cell counterparts, and upregulation of LAT1 has been reported in precursor T-cell acute leukemia. Therefore, the expression of LAT1 was evaluated in a cohort of cutaneous and peripheral T-cell lymphomas. The findings demonstrated that LAT1 is upregulated in aggressive variants and absent in low-grade or indolent disease such as mycosis fungoides. In addition, upregulated LAT1 expression was seen in a large proportion of aggressive peripheral T-cell lymphomas, including peripheral T-cell lymphoma not otherwise specific (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL). The anti-tumor effects of two novel non-cleavable and bifunctional compounds, QBS10072S and QBS10096S, that combine a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate (aromatic ß-amino acid) were tested in vitro and in vivo in T-cell lymphoma cell lines. The findings demonstrated decreased survival of T-cell lymphoma lines with both compounds. Overall, the results demonstrate that LAT1 is a valuable biomarker for aggressive T-cell lymphoma counterparts and QBS10072S and QBS10096S are successful therapeutic options for these aggressive diseases.
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We recently reported that mutations in the widely expressed nuclear protein TOPORS (topoisomerase I-binding arginine/serine rich) are associated with autosomal dominant retinal degeneration. However, the precise localization and a functional role of TOPORS in the retina remain unknown. Here, we demonstrate that TOPORS is a novel component of the photoreceptor sensory cilium, which is a modified primary cilium involved with polarized trafficking of proteins. In photoreceptors, TOPORS localizes primarily to the basal bodies of connecting cilium and in the centrosomes of cultured cells. Morpholino-mediated silencing of topors in zebrafish embryos demonstrates in another species a comparable retinal problem as seen in humans, resulting in defective retinal development and failure to form outer segments. These defects can be rescued by mRNA encoding human TOPORS. Taken together, our data suggest that TOPORS may play a key role in regulating primary cilia-dependent photoreceptor development and function. Additionally, it is well known that mutations in other ciliary proteins cause retinal degeneration, which may explain why mutations in TOPORS result in the same phenotype.
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Centrossomo/metabolismo , Cílios/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Degeneração Retiniana/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Cílios/genética , Humanos , Camundongos , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Células Fotorreceptoras/metabolismo , Transporte Proteico , Retina/metabolismo , Degeneração Retiniana/genética , Ubiquitina-Proteína Ligases/genética , Peixe-ZebraRESUMO
Bisphenol S (BPS) is an endocrine disrupting chemical and the second most abundant bisphenol detected in humans. We have recently demonstrated that in utero exposure to BPS reduces human placenta cell fusion by interfering with epidermal growth factor (EGF)-dependent EGF receptor (EGFR) activation. Our previous work suggests that this occurs via binding of BPS to the extracellular domain of EGFR. However, whether BPS directly binds to EGFR has not been confirmed. We evaluated the binding ability of BPA, BPF and BPS to EGFR to determine whether EGFR binding is a unique attribute of BPS. To test these hypotheses, we first exposed HTR-8/SVneo cells to BPS, BPA, or BPF, with or without EGF. When co-exposed to EGF, BPS, but not BPA nor BPF, reduced EGFR phosphorylation by â¼60%, demonstrating that only BPS can interfere with EGF-dependent EGFR activation. As this indicates that BPS binding to the extracellular domain is responsible for its effect, we performed a computational search for putative binding sites on the EGFR extracellular domain, and performed ligand docking of BPS, BPA, and BPF at these sites. We identified three sites where polar interactions between positively charged residues and the sulfonyl group of BPS could lead binding selectivity over BPA and BPF. To test whether EGFR mutations at the predicted BPS binding sites (Arg255, Lys454, and Arg297) could prevent BPS's interference on EGFR activation, mutations for each EGFR target amino acids (R255A, R297A, and K454A) were introduced. For variants with R297A or K454A mutations, BPS did not affect EGF-mediated EGFR phosphorylation or EGFR-mediated cell invasion, suggesting that these residues are needed for the BPS antagonism effect on EGFR. In conclusion, BPS, but not BPA or BPF, interferes with EGFR-mediated trophoblast cell functions through binding at Arg297 and Lys454 amino acid residues in the extracellular domain of EGFR.
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Fator de Crescimento Epidérmico , Trofoblastos , Feminino , Gravidez , Humanos , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/metabolismo , Sítios de Ligação , Compostos Benzidrílicos/metabolismoRESUMO
While the peripheral T-cell lymphomas (PTCL) remain a therapeutic challenge, and increasingly account for a disproportionate number of lymphoma-related deaths, improved understanding of disease pathogenesis and classification, and the development of novel therapeutic agents over the past decade, all provide reasons for a more optimistic outlook in the next. Despite their genetic and molecular heterogeneity, many PTCL are dependent upon signaling input provided by antigen, costimulatory, and cytokine receptors. While gain-of-function alterations effecting these pathways are recurrently observed in many PTCL, more often than not, signaling remains ligand-and tumor microenvironment (TME)-dependent. Consequently, the TME and its constituents are increasingly recognized as "on target". Utilizing a "3 signal" model, we will review new-and old-therapeutic targets that are relevant for the more common nodal PTCL subtypes.
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Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/patologia , Microambiente TumoralRESUMO
The dynamins are a family of ubiquitously expressed GTPase proteins, best known for their role in membrane remodeling. Their contribution to hematopoiesis is incompletely recognized. Individuals with Charcot-Marie-Tooth disease with dynamin-2 (DNM2) mutations often develop neutropenia. We previously reported that dynamin (DNM) inhibition impairs SDF1a-mediated migration in megakaryocytes. Here, we report on conditionally Dnm2 deleted mice in hematopoietic tissues using the Vav-Cre murine strain. Homozygous Dnm2 deletion in blood tissues is embryonic lethal. Dnm2het male mice only developed a slightly decreased hemoglobin level. Dnm2het female mice developed leukopenia by 40 weeks of age and neutropenia by 65 weeks of age. Flow cytometry revealed decreased lineage-negative cells and granulocyte-monocyte progenitors in Dnm2het female mice. Immunohistochemical staining of bone marrow (BM) for mature neutrophils with Ly6G was decreased and myelodysplastic features were present in the BM of Dnm2het female mice. A linear distribution of Ly6G+ BM cells along blood vessels was observed in fewer Dnm2het mice than in controls, suggesting that the migration pattern in the marrow is altered. Marrow neutrophils treated with dynamin inhibitor, dynasore, showed increased cell surface CXCR4, suggesting that abnormal migration results in marrow neutrophil retention. Dnm2het female mice also developed splenomegaly secondary to germinal center hyperplasia at younger ages, suggesting perturbed immunity. In summary, female mice with BM Dnm2 haploinsufficiency developed neutropenia as they aged with decreased granulocyte progenitor production and migration defects. Our studies indicate a potential mechanism for the development of chronic idiopathic neutropenia, a disease that predominantly presents in middle-aged women.