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Heparan sulfate proteoglycans (HSPGs) are composed of a core protein and glycosaminoglycan (GAG) chains and serve as coreceptors for many growth factors and morphogens. To understand the molecular mechanisms by which HSPGs regulate morphogen gradient formation and signaling, it is important to determine the relative contributions of the carbohydrate and protein moieties to the proteoglycan function. To address this question, we generated ΔGAG alleles for dally and dally-like protein (dlp), two Drosophila HSPGs of the glypican family, in which all GAG-attachment serine residues are substituted to alanine residues using CRISPR/Cas9 mutagenesis. In these alleles, the glypican core proteins are expressed from the endogenous loci with no GAG modification. Analyses of the dallyΔGAG allele defined Dally functions that do not require heparan sulfate (HS) chains and that need both core protein and HS chains. We found a new, dallyΔGAG-specific phenotype, the formation of a posterior ectopic vein, which we have never seen in the null mutants. Unlike dallyΔGAG, dlpΔGAG mutants do not show most of the dlp null mutant phenotypes, suggesting that HS chains are dispensable for these dlp functions. As an exception, HS is essentially required for Dlp's activity at the neuromuscular junction. Thus, Drosophila glypicans show strikingly different levels of HS dependency. The ΔGAG mutant alleles of the glypicans serve as new molecular genetic toolsets highly useful to address important biological questions, such as molecular mechanisms of morphogen gradient formation.
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Proteínas de Drosophila , Drosophila melanogaster , Glipicanos , Heparitina Sulfato , Animales , Proteínas de Drosophila/metabolismo , Glipicanos/genética , Glipicanos/química , Glipicanos/metabolismo , Proteoglicanos de Heparán Sulfato/genética , Proteoglicanos de Heparán Sulfato/metabolismo , Heparitina Sulfato/genética , Heparitina Sulfato/metabolismo , Glicoproteínas de Membrana/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismoRESUMEN
Type 1 Bartter syndrome causes hypokalaemia and metabolic alkalosis owing to mutation in the SLC12A1 gene. Meanwhile, hypocalcaemia is rare in Bartter syndrome, except in type 5 Bartter syndrome. Herein, we describe two siblings with type 1 Bartter syndrome with recurrent transient severe hypocalcaemia. They each visited our hospital several times with chief complaints of numbness in the limbs, shortness of breath and tetany after stresses such as exercise or fever. Severe hypocalcaemia was also observed with a serum calcium level of approximately 6.0 mg/dL at each visit. The clinical symptoms and abnormalities in laboratory findings quickly improved with rest and intravenous treatment. In a steady state, no severe hypocalcaemia was evident, but serum intact parathyroid hormone (PTH) levels were high. In recent years, a large-scale study has revealed that type 1 and type 2 Bartter syndrome have high PTH values. In addition, there are reports that these patients develop hypocalcaemia due to PTH resistance. Therefore, our patient was also in a PTH-resistant state, and hypocalcaemia was thought to be exacerbated by physical stress. It is not well known that Bartter syndrome patients other than those with type 5 suffer from hypocalcaemia. And hypocalcaemia was not detected in normal examinations under steady-state conditions. Therefore, in patients with type 1 and type 2 Bartter syndrome, severe hypocalcaemia may occur, but may go unnoticed. When following up these patients, the attending physician must keep in mind that such patients are in a PTH-resistant state and that physical stress can cause severe hypocalcaemia.
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Síndrome de Bartter , Hipocalcemia , Humanos , Hipocalcemia/etiología , Hipocalcemia/genética , Síndrome de Bartter/complicaciones , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/genética , Hermanos , Hormona Paratiroidea , Miembro 1 de la Familia de Transportadores de Soluto 12RESUMEN
MgtE is a Mg 2+-selective channel regulated by the intracellular Mg 2+ concentration. MgtE family proteins are highly conserved in all domains of life and contribute to cellular Mg 2+ homeostasis. In humans, mutations in the SLC41 proteins, the eukaryotic counterparts of the bacterial MgtE, are known to be associated with various diseases. The first MgtE structure from a thermophilic bacterium, Thermus thermophilus, revealed that MgtE forms a homodimer consisting of transmembrane and cytoplasmic domains with a plug helix connecting the two and that the cytoplasmic domain possesses multiple Mg 2+ binding sites. Structural and electrophysiological analyses revealed that the dissociation of Mg 2+ ions from the cytoplasmic domain induces structural changes in the cytoplasmic domain, leading to channel opening. Thus, previous works showed the importance of MgtE cytoplasmic Mg 2+ binding sites. Nevertheless, due to the limited structural information on MgtE from different species, the conservation and diversity of the cytoplasmic Mg 2+ binding site in MgtE family proteins remain unclear. Here, we report crystal structures of the Mg 2+-bound MgtE cytoplasmic domains from two different bacterial species, Chryseobacterium hispalense and Clostridiales bacterium, and identify multiple Mg 2+ binding sites, including ones that were not observed in the previous MgtE structure. These structures reveal the conservation and diversity of the cytoplasmic Mg 2+ binding site in the MgtE family proteins.
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Antiportadores , Proteínas Bacterianas , Humanos , Antiportadores/química , Antiportadores/genética , Antiportadores/metabolismo , Proteínas Bacterianas/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Modelos Moleculares , Rayos X , Thermus thermophilusRESUMEN
Background: Although the addition of immune checkpoint inhibitors (ICIs) to platinum-doublet chemotherapy has improved the efficacy of first-line therapy in extensive-disease small cell lung cancer (SCLC) patients, the best treatment option for patients with recurrent SCLC has not yet been determined. We conducted a retrospective study to evaluate the efficacy and safety of amrubicin (AMR) therapy after treatment with ICIs. Methods: We retrospectively assessed patients with recurrent SCLC who received AMR after chemoimmunotherapy at the Niigata Lung Cancer Treatment Group from August 2019 to February 2021. Results: This analysis included 30 patients. The median progression-free survival (PFS) and overall survival (OS) were 3.8 (95% CI: 2.7-4.2) and 10 (95% CI: 7.4-14.8) months, respectively. The median PFS and OS did not significantly differ between the sensitive and refractory groups [PFS; 3.1 (95% CI: 1.1-4.0) vs. 4.2 (95% CI: 2.3-4.8) months, P=0.1142, OS; 10.0 (95% CI: 5.2-14.8) vs. 10.4 (95% CI: 3.8-NE) months, P=0.5525]. The most common adverse event was grade ≥3 neutropenia, which occurred in 22 of 30 patients (73%), and 2 patients (7%) discontinued AMR due to adverse events. Conclusions: AMR after chemoimmunotherapy shows good clinical efficacy and safety in patients with recurrent SCLC.
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The evolution of the biphasic life cycle in marine invertebrates has attracted considerable interest in zoology. We recently provided evidence that retinoic acid (RA) is involved in the regulation of metamorphosis in starfish. It also functions in life cycle transitions of jellyfish (cnidaria). Thus, documenting the evolutionarily conserved role of RA in such transitions will help to trace the life cycle evolution of bilaterians and cnidarians. In this study, we examined the molecular mechanisms by which RA signaling is involved in the commencement of metamorphosis in starfish. First, we measured RA levels during the larval and metamorphosis stages by liquid chromatography-tandem mass spectrometry. We found that all-trans RA levels in the larval body are high before larvae acquire competence for metamorphosis, suggesting that the commencement of metamorphosis is not controlled by increased RA synthesis. Furthermore, the suppression of rar gene expression by TALEN-mediated gene knockout revealed that RA receptor (RAR) is essential for metamorphosis. These observations suggest that the initiation of metamorphosis is regulated at the level of synthesized RA to activate RAR. We discuss the divergence of ligand molecules and receptors during the evolution of life cycle regulation.
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Estrellas de Mar , Tretinoina , Animales , Tretinoina/farmacología , Tretinoina/metabolismo , Metamorfosis Biológica/fisiología , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Estadios del Ciclo de Vida , Larva/metabolismoRESUMEN
Peripherally inserted central venous catheters (PICCs) have a potential advantage in preventing central line-associated bloodstream infection (CLABSI) compared with the centrally inserted ones (CICCs). However, due to a limited number of studies with insufficient statistical evaluation, the superiority of PICCs is difficult to be generalized in adult hematology unit. We conducted a single-center retrospective study and compared the risk of CLABSI between 472 CICCs and 557 PICCs inserted in adult patients with hematological disorders through conventional multivariate models and a propensity score-adjusted analysis. The overall CLABSI incidence in CICCs and PICCs was 5.11 and 3.29 per 1000 catheter days (P = 0.024). The multivariate Cox regression analysis (hazard ratio [HR]: 0.48; 95% confidence interval [CI]: 0.31-0.75; P = 0.001) and Fine-Gray subdistribution analysis (HR: 0.59; 95% CI: 0.37-0.93; P = 0.023) demonstrated that PICC was independently associated with a reduced risk of CLABSI. Moreover, the stabilized inverse probability of treatment weighting analysis, which further reduced the selection bias between CICCs and PICCs, showed that PICCs significantly prevented CLABSI (HR: 0.58; 95% CI: 0.35-0.94; P = 0.029). Microbiologically, PICCs showed a significant decrease in gram-positive cocci (P = 0.001) and an increase in gram-positive bacilli (P = 0.002) because of a remarkable reduction in Staphylococci and increase in Corynebacterium species responsible for CLABSI. Our study confirmed that PICC was a superior alternative to CICC in preventing CLABSI in the adult hematology unit, while it posed a microbiological shift in local epidemiology.
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Infecciones Relacionadas con Catéteres , Cateterismo Venoso Central , Cateterismo Periférico , Catéteres Venosos Centrales , Hematología , Sepsis , Adulto , Infecciones Relacionadas con Catéteres/epidemiología , Infecciones Relacionadas con Catéteres/prevención & control , Cateterismo Venoso Central/efectos adversos , Cateterismo Periférico/efectos adversos , Catéteres Venosos Centrales/efectos adversos , Humanos , Puntaje de Propensión , Estudios Retrospectivos , Factores de Riesgo , Sepsis/epidemiologíaRESUMEN
Magnesium is an important nutrient for plants, but much is still unknown about plant Mg2+ transporters. Combining with the structural prediction of AlphaFold2, we used mutagenesis and 28Mg uptake assay to study the highly conserved "GMN" motif of Arabidopsis thaliana MRS2-1 (AtMRS2-1) transporter. We demonstrated that the glycine and methionine in GMN motif are essential for AtMRS2-1 to transport Mg2+.
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Proteínas de Arabidopsis , Arabidopsis , Proteínas de Transporte de Catión , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Transporte de Catión/genética , Magnesio/metabolismo , MutagénesisRESUMEN
Tissue aging is a major cause of aging-related disabilities and a shortened life span. Understanding how tissue aging progresses and identifying the factors underlying tissue aging are crucial; however, the mechanism of tissue aging is not fully understood. Here we show that the biosynthesis of S-adenosyl-methionine (SAM), the major cellular donor of methyl group for methylation modifications, potently accelerates the aging-related defects during Drosophila oogenesis. An aging-related increase in the SAM-synthetase (Sam-S) levels in the germline leads to an increase in ovarian SAM levels. Sam-S-dependent biosynthesis of SAM controls aging-related defects in oogenesis through two mechanisms, decreasing the ability to maintain germline stem cells and accelerating the improper formation of egg chambers. Aging-related increases in SAM commonly occur in mouse reproductive tissue and the brain. Therefore, our results raise the possibility suggesting that SAM is the factor related to tissue aging beyond the species and tissues.
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Drosophila , S-Adenosilmetionina , Envejecimiento , Animales , Metionina Adenosiltransferasa , Ratones , OogénesisRESUMEN
The identification of acquired resistance mutations has been essential in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) active mutations. Rebiopsy plays a pivotal role in selecting the optimal treatment for patients who develop resistance to initial EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This multicenter, observational study was conducted to investigate the details of rebiopsy in Japanese clinical practice. The primary endpoints were the implementation rate of rebiopsy and the concordance rate for T790M mutation detection between histological and cytological specimens using the cobas EGFR Mutation Test, version 2. One hundred ninety-four patients with EGFR-mutant NSCLC were enrolled, and 120 patients developed acquired resistance to EGFR-TKIs. The median age was 68 years (range 20-87), and 52.5% of the patients were women. Rebiopsy was performed in 109 patients, and the implementation rate of rebiopsy was 90.8%. The success rates of rebiopsy in the total, histology, cytology and liquid biopsy populations were 67.9%, 81.3%, 66.7% and 43.8%, respectively. The positive percent agreement and the negative percent agreement in the detection of the T790M mutation between the histological and cytological specimens were both 90.9%. Obtaining histological or cytological tissue samples at rebiopsy may contribute to improving the detection rate of the T790M mutation (trial registration number: UMIN000026019).
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos , Receptores ErbB , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto JovenRESUMEN
Although diffuse large B-cell lymphoma (DLBCL) occasionally lacks surface immunoglobulin light chain restriction (iLCR) on flow cytometry (FCM), little evidence is available for iLCR-negative DLBCL. We retrospectively compared clinicopathological features of iLCR-positive and iLCR-negative DLBCL diagnosed at our institute between April 2007 and March 2018. iLCR-positive was defined as a κ/λ ratio less than 0.5 or greater than 3 in the gated population on dual-color FCM, and iLCR-negative as other values. Of 81 DLBCL cases with available immunophenotyping by FCM, 63 iLCR-positive DLBCL (78%) and 18 iLCR-negative DLBCL (22%) cases were identified. Survival outcomes of patients with iLCR-negative DLBCL were comparable with those of patients with iLCR-positive DLBCL. Pathological analysis revealed no significant difference except for the lower expression of BCL6 in iLCR-negative DLBCL (12.5% vs 65.5%, p < 0.001), although there was a slightly higher frequency of necrosis (47.1% vs 20.7%, p = 0.058) and lower expression of CD10 (11.8% vs 35.0%, p = 0.078) in iLCR-negative DLBCL than in iLCR-positive DLBCL. The underlying mechanism remains unclear; however, low expression of germinal center markers and tumor necrosis may be associated with the loss of iLCR in DLBCL.
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Cadenas Ligeras de Inmunoglobulina , Linfoma de Células B Grandes Difuso , Citometría de Flujo , Humanos , Inmunofenotipificación , Linfoma de Células B Grandes Difuso/patología , Estudios RetrospectivosRESUMEN
Although effective combination of antiretroviral medications is being developed, the incidence of non-Hodgkin lymphoma (NHL) with human immunodeficiency/acquired immunodeficiency syndrome (HIV/AIDS) still remains significantly higher than that in individuals without infection. Primary cardiac lymphoma (PCL) is an NHL that involves the heart and/or the pericardium. PCL is very rare and often causes serious complications, which can be a diagnostic challenge. To our knowledge, no study has reported the measurement of rituximab concentration under venoarterial extracorporeal membrane oxygenation (VA-ECMO). Herein, we report the case of a 54-year-old male patient with AIDS-associated primary cardiac NHL who developed right ventricular outflow tract obstruction. The patient experienced fatigue and dyspnea on exertion. Contrast-enhanced computed tomography showed a bulky tumor mass in his right atrium and ventricle, and an echocardiogram revealed severe hypokinesis of his heart and poor cardiac output. A biopsy was performed, and immunohistochemistry revealed diffuse large B-cell lymphoma. Therefore, he was treated with rituximab-combined chemotherapy under VA-ECMO. Blood levels of rituximab were measured during chemotherapy with VA-ECMO. Thereafter, he was temporarily discharged from the hospital. This clinical case suggests that VA-ECMO and rituximab-combined chemotherapy are useful in rescuing patients with severe cardiopulmonary failure due to AIDS-associated PCL.
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A 70-year-old man, treated for asthma for 2 years and chronic sinusitis for several months, presented with fever, numbness in the lower limbs, heaviness in the head, gross hematuria, and black stools. He also had eosinophilia, elevated serum IgG4 levels, high levels of myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA), and pulmonary infiltrative shadows. Bronchoscopy revealed multiple white flattened lesions (white moss) on the airway mucosa, suggesting mycobacterial infection or malignancy. A biopsy from tracheal mucosa revealed airway inflammation with marked eosinophil infiltration. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) and treated with steroids, and all findings improved. However, a year and a half after the initiation of treatment, eosinophils and IgE gradually increased; subjective symptoms, such as asthma symptoms and numbness in the lower limbs, worsened; and ANCA, which had been negative, turned positive. Therefore, we suspected disease relapse and anti-IL-5 antibody (mepolizumab) treatment was initiated. Thereafter, ANCA turned negative again, eosinophils and IgE normalized, and subjective symptoms decreased. The presence of airway mucosal lesions in EGPA is relatively rare, and we report this case as a valuable case owing to the interesting bronchoscopic findings that are worth comprehending as a respiratory physician.
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The Drosophila female germline stem cell (GSC) niche provides an excellent model for understanding the stem cell niche in vivo. The GSC niche is composed of stromal cells that provide growth factors for the maintenance of GSCs and the associated extracellular matrix (ECM). Although the function of stromal cells/growth factors has been well studied, the function of the ECM in the GSC niche is largely unknown. In this study, we investigated the function of syndecan and perlecan, molecules of the heparan sulfate proteoglycan (HSPG) family, as the main constituents of the ECM. We found that both of these genes were expressed in niche stromal cells, and knockdown of them in stromal cells decreased GSC number, indicating that these genes are important niche components. Interestingly, our genetic analysis revealed that the effects of syndecan and perlecan on the maintenance of GSC were distinct. While the knockdown of perlecan in the GSC niche increased the number of cystoblasts, a phenotype suggestive of delayed differentiation of GSCs, the same was not true in the context of syndecan. Notably, the overexpression of syndecan and perlecan did not cause an expansion of the GSC niche, opposing the results reported in the context of glypican, another HSPG gene. Altogether, our data suggest that HSPG genes contribute to the maintenance of GSCs through multiple mechanisms, such as the control of signal transduction, and ligand distribution/stabilization. Therefore, our study paves the way for a deeper understanding of the ECM functions in the stem cell niche.
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Drosophila , Proteoglicanos de Heparán Sulfato , Animales , Células Germinativas , Proteoglicanos de Heparán Sulfato/genética , Células Madre , Sindecanos/genéticaRESUMEN
Treatment of patients with malignancy sometimes be delayed due to various reasons. Several studies revealed that an influence of diagnosis-to-treatment interval (DTI) on outcomes differs depending on the type of malignancy. In this study, we evaluated the influence of DTI on clinical outcomes in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). A total of 199 patients were identified with a median DTI of 22 days. At 2 years, patients with short DTI (0-22 days) showed significantly poorer OS (62.7% vs 86.4%) and PFS (55.1% vs 75.9%) compared to those with long DTI (over 22 days). Although short DTI was strongly correlated with several known adverse factors, it remained to be an independent prognostic factor by multivariate analysis. In conclusion, our study confirmed the importance of DTI in patients with DLBCL. Researchers should consider DTI as one of the important prognostic factors and plan clinical trials to be able to enroll patients with aggressive disease requiring urgent treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Tiempo de Tratamiento/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/uso terapéutico , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Factores de Tiempo , Vincristina/uso terapéuticoRESUMEN
Allogeneic peripheral blood stem cell transplantation (PBSCT) is associated with an increased risk of severe acute and chronic graft-versus-host disease (GVHD) compared to bone marrow transplantation. Anti-thymocyte globulin (ATG) can reduce severe acute and chronic GVHD in PBSCT; however, an optimal dose of ATG remains undefined. We conducted a multicenter phase II study to investigate safety and efficacy of low-dose ATG (a total of 2 mg/kg Thymoglobulin) in patients undergoing HLA-matched PBSCT after myeloablative conditioning. The primary endpoint was grades III-IV GVHD at 100 days. Seventy-seven patients were enrolled and 72 patients with a median age of 46.5 years were eligible for analysis. The primary endpoint, cumulative incidence of grades III-IV acute GVHD at 100 days was 1.4% (95% CI, 0.1-6.7%), which was greatly less than our pre-defined statistical threshold value (18.0%). The incidence of chronic GVHD at 1 year was also low (all-grade; 15.3%, moderate to severe; 5.6%). Non-relapse mortality, relapse, overall survival, disease-free survival, and GVHD-free, relapse-free survival at 1 year were 4.2%, 20.8%, 84.7%, 75.0%, and 69.4%, respectively. Low dose thymoglobulin is promising to reduce severe acute and chronic GVHD in HLA-matched PBSCT following myeloablative conditioning.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Trasplante de Células Madre de Sangre Periférica , Suero Antilinfocítico , Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Persona de Mediana Edad , Acondicionamiento PretrasplanteAsunto(s)
Mesilato de Imatinib/uso terapéutico , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Transactivadores/genética , Adulto , Médula Ósea/metabolismo , Médula Ósea/patología , Terapia Combinada , Trasplante de Células Madre de Sangre del Cordón Umbilical , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Resultado del Tratamiento , Adulto JovenRESUMEN
Hermaphroditic invertebrates and plants have a self-recognition system on the cell surface of sperm and eggs, which prevents their self-fusion and enhances non-self-fusion, thereby contributing to genetic variation. However, the system of sperm-egg recognition in mammals is under debate. To address this issue, we explored the role of major histocompatibility complex class I (MHC class I, also known as histocompatibility 2-Kb or H2-Kb and H2-Db in mice) antigens by analyzing H2-Kb-/-H2-Db-/-ß2-microglobulin (ß2M)-/- triple-knockout (T-KO) male mice with full fertility. T-KO sperm exhibited an increased sperm number in the perivitelline space of wild-type (WT) eggs in vitro. Moreover, T-KO sperm showed multiple fusion with zona pellucida (ZP)-free WT eggs, implying that the ability of polyspermy block for sperm from T-KO males was weakened in WT eggs. When T-KO male mice were intercrossed with WT female mice, the percentage of females in progeny increased. We speculate that WT eggs prefer fusion with T-KO sperm, more specifically X-chromosome-bearing sperm (X sperm), suggesting the presence of preferential (non-random) fertilization in mammals, including humans.
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Fertilidad/genética , Antígenos de Histocompatibilidad Clase I/genética , Óvulo/metabolismo , Razón de Masculinidad , Interacciones Espermatozoide-Óvulo/genética , Espermatozoides/metabolismo , Animales , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Femenino , Fertilización In Vitro , Regulación de la Expresión Génica , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Masculino , Ratones , Ratones Noqueados , Óvulo/citología , Recuento de Espermatozoides , Espermatozoides/citología , Microglobulina beta-2/deficiencia , Microglobulina beta-2/genética , Microglobulina beta-2/inmunologíaRESUMEN
Donor cell-derived hematological disorder (DCHD) is a rare complication of allogeneic hematopoietic stem cell transplantation (HSCT). The number of reports of DCHD has been increasing in the last decade, which likely reflects the growing number of HSCTs and the improved ability to identify the donor cell origin. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematological disorder arising in the context of clonal expansion of hematopoietic stem cells harboring a somatic mutation in phosphatidylinositol glycan anchor biosynthesis, class A. We report here a patient with adult T-cell leukemia/lymphoma, who developed PNH 7 years after umbilical cord blood transplantation. The patient has maintained complete remission with full-donor chimerism after HSCT. Thus, PNH was derived from stem cells of donor origin. The immature immune environment in the recipient after cord blood transplantation might have contributed to the rapid clonal expansion for neonatal stem cells in cord blood to develop typical symptomatic PNH in a short period. To the best of our knowledge, this is the first report in the literature of a case of PNH that developed in donor stem cells after HSCT.
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Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Células Madre Hematopoyéticas/metabolismo , Hemoglobinuria Paroxística/diagnóstico , Hemoglobinuria Paroxística/etiología , Donantes de Tejidos , Biomarcadores , Evolución Clonal , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Humanos , Proteínas de la Membrana/genética , Mutación , Trasplante HomólogoRESUMEN
Hyperviscosity syndrome (HVS) can cause multiple organ damage if not treated immediately. IgM multiple myeloma (IgM MM) is a very rare form of myeloma with clinical features such as elevated serum IgM, and anemia, that resemble Waldenström macroglobulinemia (WM). Distinguishing between these two diseases is important, but can be a challenging problem. It is well known that MyD88 mutations and t(11;14) translocations are useful for differential diagnosis. We diagnosed HVS in a 29-year-old male with IgM MM. He was treated with triplet therapy, autologous hematopoietic stem cell transplantation, and carfilzomib consolidation therapy. His clinical course was monitored by serum IgM levels, and bone marrow myeloma cell counts by multiparameter flow cytometry analysis. After this series of treatments, his HSV disappeared and he reached stringent complete response. In cases of early onset of HVS, IgM MM should be considered in addition to WM.