RESUMEN
BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type 1. The clinical course of ATLL is very heterogeneous, and many organs, including the gastrointestinal (GI) tract, can be involved. However, there are few detailed reports on ATLL infiltration in the GI tract. We investigated the clinical characteristics of ATLL infiltration in the GI tract. METHODS: This retrospective observational single-center study included 40 consecutive ATLL patients who underwent GI endoscopy. The patients' demographic and clinical characteristics and endoscopic findings were analyzed retrospectively. Patients with ATLL who were diagnosed by histological examination were divided into two groups based on GI tract infiltration. RESULTS: Multivariate analysis revealed that the absence of skin lesions was significantly associated with GI infiltration (P < 0.05). Furthermore, the infiltration group tended to have similar macroscopic lesions in the upper and lower GI tracts, such as diffuse type, tumor-forming type, and giant-fold type. CONCLUSIONS: GI endoscopy may be considered for ATLL patients without skin lesions.
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Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Linfoma , Adulto , Tracto Gastrointestinal , Humanos , Estudios RetrospectivosRESUMEN
Acquired mutations of JAK2 and TET2 are frequent in myeloproliferative neoplasms (MPNs). We examined the individual and cooperative effects of these mutations on MPN development. Recipients of JAK2V617F cells developed primary myelofibrosis-like features; the addition of loss of TET2 worsened this JAK2V617F-induced disease, causing prolonged leukocytosis, splenomegaly, extramedullary hematopoiesis, and modestly shorter survival. Double-mutant (JAK2V617F plus loss of TET2) myeloid cells were more likely to be in a proliferative state than JAK2V617F single-mutant myeloid cells. In a serial competitive transplantation assay, JAK2V617F cells resulted in decreased chimerism in the second recipients, which did not develop MPNs. In marked contrast, cooperation between JAK2V617F and loss of TET2 developed and maintained MPNs in the second recipients by compensating for impaired hematopoietic stem cell (HSC) functioning. In-vitro sequential colony formation assays also supported the observation that JAK2V617F did not maintain HSC functioning over the long-term, but concurrent loss of TET2 mutation restored it. Transcriptional profiling revealed that loss of TET2 affected the expression of many HSC signature genes. We conclude that loss of TET2 has two different roles in MPNs: disease accelerator and disease initiator and sustainer in combination with JAK2V617F.
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Proteínas de Unión al ADN/genética , Janus Quinasa 2/genética , Trastornos Mieloproliferativos/genética , Proteínas Proto-Oncogénicas/genética , Animales , Dioxigenasas , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
A 49-year-old woman visited a local hospital in October 2007 with complaint of fever and melena. Abdominal ultrasonography and abdominal computed tomography revealed an irregular mass in the lower abdomen, together with multiple masses in the liver. She was admitted because of anemia, and the high fever was determined to be an inflammatory response. Blood tests revealed elevated biliary enzyme levels. Percutaneous biopsy of the liver mass was performed, which revealed liver abscesses caused by Streptococcus constellatus. On abdominal angiography, the mass was suspected to be a tumor of the small intestine. In late November 2007, laparoscopy-assisted partial small bowel resection was performed, and pathological examination of the surgical specimen confirmed gastrointestinal stromal tumor (GIST) of the small bowel. Because reports of small intestinal GIST with liver abscesses caused by Streptococcus constellatus are rare, this case description could provide valuable information.
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Tumores del Estroma Gastrointestinal/complicaciones , Neoplasias del Íleon/complicaciones , Absceso Hepático/etiología , Infecciones Estreptocócicas/etiología , Streptococcus constellatus , Femenino , Humanos , Persona de Mediana EdadRESUMEN
X-linked anhidrotic ectodermal dysplasia with immunodeficiency (X-EDA-ID) is caused by hypomorphic mutations in the gene encoding nuclear factor-κB essential modulator protein (NEMO). Patients are susceptibile to diverse pathogens due to insufficient cytokine and frequently show severe chronic colitis. An 11-year-old boy with X-EDA-ID was hospitalized with autoimmune symptoms and severe chronic colitis which had been refractory to immunosuppressive drugs. Since tumor necrosis factor (TNF) α is responsible for the pathogenesis of NEMO colitis according to intestinal NEMO and additional TNFR1 knockout mice studies, and high levels of TNFα-producing mononuclear cells were detected in the patient due to the unexpected gene reversion mosaicism of NEMO, an anti-TNFα monoclonal antibody was administered to ameliorate his abdominal symptoms. Repeated administrations improved his colonoscopic findings as well as his dry skin along with a reduction of TNFα-expressing T cells. These findings suggest TNF blockade therapy is of value for refractory NEMO colitis with gene reversion.
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Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Colitis/complicaciones , Colitis/tratamiento farmacológico , Displasia Ectodermal Anhidrótica Tipo 1/complicaciones , Síndromes de Inmunodeficiencia/complicaciones , Secuencia de Bases , Niño , Colitis/genética , Colon/patología , Displasia Ectodermal Anhidrótica Tipo 1/genética , Humanos , Quinasa I-kappa B/genética , Síndromes de Inmunodeficiencia/genética , Infliximab , Masculino , Mutación , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
As opportunistic infections among human T-lymphotrophic virus type 1 (HTLV-1) carriers and patients with adult T-cell leukemia/lymphoma (ATL) pose a serious problem, it is necessary to clarify their clinical characteristics and outcomes in these patients. We retrospectively analyzed the clinical features and outcomes of opportunistic infections in 127 HTLV-1 carriers and 153 ATL patients between 2006 and 2016. The cumulative incidence rates of opportunistic infections among HTLV-1 carriers and ATL patients were 1.5% (2/127) and 6.5% (10/153), respectively. The etiology of opportunistic infections was as follows: fungal infections (3 cases), pneumocystis pneumonia, and cytomegalovirus (CMV) infections. Even after aggressive treatment, the prognosis of opportunistic infections was poor (50% of overall survival at 28 days). Regarding prognostic factors affecting the OS of opportunistic infections, higher SOFA scores (especially the respiratory subscore) and higher LDH values were identified by univariate analysis. Moreover, 3 out of 6 patients achieved spontaneous remission of ATL as the short-term outcome after the development of opportunistic infection. However, 5 out of 6 surviving patients exhibited ATL progression or relapse after a median of 194 days (133-226) after contracting an opportunistic infection as the long-term outcome of ATL. In conclusion, opportunistic infections should be carefully followed among HTLV-1 carriers and ATL patients because of their aggressive clinical course and poor outcomes. Furthermore, early diagnosis and subsequent prompt treatment are necessary in clinical practice.
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Infecciones por Citomegalovirus , Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Infecciones Oportunistas , Neumonía por Pneumocystis , Adulto , Anciano , Infecciones por Citomegalovirus/mortalidad , Infecciones por Citomegalovirus/terapia , Supervivencia sin Enfermedad , Femenino , Humanos , Incidencia , Leucemia-Linfoma de Células T del Adulto/mortalidad , Leucemia-Linfoma de Células T del Adulto/terapia , Masculino , Persona de Mediana Edad , Infecciones Oportunistas/mortalidad , Infecciones Oportunistas/terapia , Neumonía por Pneumocystis/mortalidad , Neumonía por Pneumocystis/terapia , Tasa de SupervivenciaRESUMEN
Calreticulin (CALR) exon 9 frameshift mutations, commonly detected in essential thrombocythemia (ET) and primary myelofibrosis patients, activate signal transducer and activator of transcription (STAT) proteins in the presence of Myeloproliferative Leukemia Virus (MPL) and induce ET in vivo. Loss of the KDEL motif, an endoplasmic reticulum retention signal, and generation of many positively charged amino acids (AAs) in the mutated C-terminus are thought to be important for disease induction. To test this hypothesis, we generated mice harboring a Calr frameshift mutation using the CRISPR/Cas9 system. Deletion of 19-base pairs in exon 9 (c.1099-1117del), designated the del19 mutation, induced loss of the KDEL motif and generated many positively charged AAs, similar to human mutants. Calr del19 mice exhibited mild thrombocytosis, slightly increased megakaryocytes, and mild splenomegaly. In vitro experiments revealed that the murine CALR del19 mutant had a weaker ability to combine with murine MPL than the human CALR del52 mutant. Consequently, STAT5 activation was also very weak downstream of the murine mutant and murine MPL, and may be the reason for the mild disease severity. In summary, loss of the KDEL motif and positively charged AAs in the C-terminus of CALR is insufficient for MPL binding and ET development.
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Calreticulina/genética , Trombocitosis/etiología , Animales , Humanos , Ratones , MutaciónRESUMEN
A 66-year-old man patient with chronic hepatitis (CH) C and complications from ulcerative colitis (UC) was treated with interferon-beta (IFN-beta). Endoscopically, the UC disease activity was moderate before IFN-beta treatment but was in remission eight week after treatment. However, a few months after stopping IFN treatment, endoscopy revealed that the UC disease activity had returned to moderate levels. This result shows that UC improved with IFN treatment.
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Colitis Ulcerosa/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Interferón beta/uso terapéutico , Anciano , Humanos , Masculino , Inducción de RemisiónRESUMEN
Because there are limited clinical reports on the impact of human T-lymphotropic virus type 1 (HTLV-1) on organ transplantation, its effects on the development of adult T-cell leukemia-lymphoma (ATL), post-transplantation lymphoproliferative disorder (PTLD) and HTLV-1-associated myelopathy (HAM) or atypical HAM after organ transplantation remain unclear.We retrospectively analyzed the impact of HTLV-1 in 54 allogeneic hematopoietic stem cell transplantation (allo-HSCT) cases and 31 renal transplantation cases between January 2006 and December 2016.Among the 54 allo-HSCT cases, nine recipients with ATL tested positive for HTLV-1, and one was found to be an HTLV-1 carrier. All donors tested negative for HTLV-1. Only one HTLV-1 carrier did not present with ATL or HAM development after allo-HSCT. Among nine ATL cases after allo-HSCT, four eventually relapsed due to proliferation of recipient-derived ATL cells. However, in one ATL case, atypical HAM developed rapidly at 5 months after allo-HSCT.Among the 31 renal transplantation cases, all donors tested negative for HTLV-1, and only recipients tested positive. Only one HTLV-1 carrier recipient did not present with ATL or HAM development after renal transplantation. However, one HTLV-1-negative recipient developed PTLD in the brain 10 years after renal transplantation.In clinical practice, careful follow-up of HTLV-1 infected recipients after organ transplantation is important because atypical HAM can develop in ATL patients after allo-HSCT. Furthermore, to clarify the risk of ATL or HAM development in HTLV-1 infected recipients, we prospectively followed up our cohort.
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Trasplante de Células Madre Hematopoyéticas , Virus Linfotrópico T Tipo 1 Humano , Trasplante de Riñón , Leucemia-Linfoma de Células T del Adulto , Enfermedades de la Médula Espinal , Adulto , Aloinjertos , Femenino , Humanos , Leucemia-Linfoma de Células T del Adulto/sangre , Leucemia-Linfoma de Células T del Adulto/epidemiología , Leucemia-Linfoma de Células T del Adulto/patología , Leucemia-Linfoma de Células T del Adulto/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Enfermedades de la Médula Espinal/sangre , Enfermedades de la Médula Espinal/epidemiología , Enfermedades de la Médula Espinal/patología , Enfermedades de la Médula Espinal/terapiaRESUMEN
BACKGROUND/AIM: In myeloproliferative neoplasms (MPN), Janus kinase 2 (JAK2) is activated by mutations including JAK2V617F (JAK2VF). It is unclear whether JAK kinases [i.e. JAK1, JAK2, JAK3, or tyrosine kinase 2 (TYK2)] other than JAK2 have cooperative actions such as enhancement or suppression of JAK2. If other kinases enhance activation, therapies that co-target them could have a therapeutic efficacy. We examined the role of TYK2 in Jak2VF-induced murine MPN. MATERIALS AND METHODS: We crossed Jak2VF transgenic mice and Tyk2-knockout (Tyk2KO) mice to generate Jak2VF/Tyk2KO mice. The disease severity and treatment effect with a JAK2 inhibitor was compared between Jak2VF and Jak2VF/Tyk2KO mice. RESULTS: Both types of mice developed MPN, and there were no differences in peripheral blood counts, spleen weight, or survival period. Upon JAK2 inhibitor therapy, both types of mice had equally improved leukocytosis and splenomegaly. CONCLUSION: TYK2 does not have cooperative effects with JAK2VF upon MPN onset nor in the presence of a JAK2 inhibitor.
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Janus Quinasa 2/genética , Mutación , Trastornos Mieloproliferativos/patología , TYK2 Quinasa/metabolismo , Animales , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Hígado/metabolismo , Pulmón/metabolismo , Ratones , Ratones Transgénicos , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/veterinaria , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Bazo/metabolismoRESUMEN
Ten-eleven translocation-2 (TET2) mutation is frequently observed in myeloid malignancies, and loss-of-function of TET2 is essential for the initiation of malignant hematopoiesis. TET2 mutation presents across disease entities and was reported in lymphoid malignancies. We investigated TET2 mutations in 27 diffuse large B-cell lymphoma (DLBCL) patients and found a frameshift mutation in 1 case (3.7%). TET2 mutation occurred in some populations of DLBCL patients and was likely involved in the pathogenesis of their malignancies.
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Proteínas de Unión al ADN/genética , Mutación del Sistema de Lectura , Linfoma de Células B Grandes Difuso/genética , Proteínas Proto-Oncogénicas/genética , Anciano , Dioxigenasas , Femenino , Neoplasias Hematológicas/etiología , Hematopoyesis , Humanos , Leucemia Mieloide/etiología , Linfoma de Células B Grandes Difuso/epidemiología , Masculino , Persona de Mediana EdadRESUMEN
AIM: To evaluate the efficacy and safety of a regimen containing sofosbuvir (SOF) and ledipasvir (LDV) in Japanese patients aged ≥ 75 years with hepatitis C genotype 1. METHODS: This multicenter, retrospective study consisted of 246 Japanese patients with HCV genotype 1 at nine centers in Miyazaki prefecture in Japan. Demographic, clinical, virological, and adverse effects (AE)-related data obtained during and after SOF/LDV therapy were collected from medical records. These patients were divided into two groups, younger (aged < 75 years) and elderly (aged ≥ 75 years). Virological data and AEs were analyzed by age group. RESULTS: The sustained virological response (SVR) rates at 12 wk after treatment were 99.2%, 99.4%, and 98.7% in the overall population and in patients aged < 75 and ≥ 75 years, respectively. Common AEs during therapy were headache, pruritus, constipation, and insomnia. These occurred in fewer than 10% of patients, and their incidence was not significantly different between the younger and elderly groups. Two patients discontinued treatment, one due to a skin eruption and the other due to cerebral bleeding. CONCLUSION: Compared with younger patients, elderly patients had a similar virological response and tolerance to SOF/LDV therapy.
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Background and Aim. It is difficult to master the skill of discriminating gastric adenoma from early gastric cancer by conventional endoscopy or magnifying endoscopy combined with narrow-band imaging, because the colors and morphologies of these neoplasms are occasionally similar. We focused on the surrounding gastric mucosa findings in order to determine how to discriminate between early gastric cancer and gastric adenoma by analyzing the characteristics of the gastric background mucosa. Methods. We retrospectively examined 146 patients who underwent endoscopic submucosal dissection for gastric neoplasm between October 2009 and January 2015. The boundary of atrophic gastritis was classified endoscopically according to the Kimura-Takemoto classification system. Of 146 lesions, 63 early gastric cancers and 21 gastric adenomas were ultimately evaluated and assessed. Results. Almost all gastric adenomas were accompanied by open-type gastritis, whereas 47 and 16 early gastric cancers were accompanied by open-type and closed-type gastritis, respectively (p = 0.037). Conclusions. The evaluation of the boundary of atrophic gastritis associated with gastric neoplasms appears to be useful for discrimination between early gastric cancer and gastric adenoma. When gastric neoplasm is present in the context of surrounding localized gastric atrophy, gastric cancer is probable but not certain.
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BACKGROUND: Hepatocyte growth factor (HGF) modulates intestinal epithelial cell proliferation and migration, serving as a critical regulator of intestinal wound healing. The aim of this study was to clarify the effects of administration of recombinant human HGF on colonic mucosal damage in vivo. METHODS: Rats were given 7.5 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS) per rectum on day 0. On day 5, the degree of TNBS-induced colitis was evaluated endoscopically, and rats suffering from large ulcers (occupying more than two thirds of the luminal circumference) were treated with intravenous bolus injections of recombinant human HGF (1.0 mg/kg per day) or phosphate-buffered saline (PBS) for 5 days. RESULTS: Rats with TNBS-induced colitis given human HGF showed a significant reduction in colonic ulcer coverage and large intestinal shortening compared with those treated with PBS. Administration of recombinant human HGF also stimulated the proliferation of epithelial cells and reduced the inflammatory cell infiltrate. Finally, HGF treatment decreased the myeloperoxidase activity and tumor necrosis factor alpha levels in the TNBS-inflamed colon tissues. CONCLUSIONS: These results indicate that intravenous injection of HGF accelerates colonic mucosal repair and reduces infiltration of inflammatory cells in rats with TNBS-induced colitis and suggest that HGF has the potential to be a new therapeutic modality to promote intestinal mucosal repair in patients with inflammatory bowel disease.
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Enfermedades del Colon/tratamiento farmacológico , Enfermedades del Colon/fisiopatología , Factor de Crecimiento de Hepatocito/farmacología , Factor de Crecimiento de Hepatocito/fisiología , Úlcera/tratamiento farmacológico , Úlcera/fisiopatología , Cicatrización de Heridas , Animales , Proliferación Celular , Enfermedades del Colon/veterinaria , Masculino , Ratas , Ratas Wistar , Proteínas Recombinantes , Ácido Trinitrobencenosulfónico/administración & dosificación , Ácido Trinitrobencenosulfónico/toxicidad , Úlcera/veterinariaRESUMEN
OBJECTIVE: Despite the remarkable advances in chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), adult T-cell leukemia-lymphoma (ATL) is still associated with a high mortality rate. It is therefore essential to elucidate the current features of ATL. METHODS: We retrospectively analyzed 81 patients with aggressive type ATL at our institution over a 7-year period based on Shimoyama's diagnostic criteria. RESULTS: Eighty-one patients with a median age of 67.5 years were classified as having acute (n=47), lymphoma (n=32), or chronic type (n=2) ATL. They were initially treated by either palliative therapy (n=25) or systemic chemotherapy [n=56; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy (n=25)/vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP)-doxorubicin, ranimustine, and prednisone (AMP)-vindesine, etoposide, carboplatin, and prednisone (VECP) therapy (VCAP-AMP-VECP) or CHOP-VMMV therapy (n=31)], and showed median survival durations of 16 and 277 days, respectively. Subsequent to the initial treatment, HSCT (n=6) was performed for certain patients, thus revealing that two-thirds (n=4) relapsed, and one-third (n=2) survived for 131 days and 203 days, respectively. The relapsed ATL patients were treated with conventional salvage therapy (n=29) or anti-CC chemokine receptor 4 antibody (mogamulizumab) (n=3). The patients treated with mogamulizumab demonstrated complete response (2) and partical response (1) with short duration periods of 82 days, 83 days, and 192 days, respectively. Among the five long-term survivors (>5 years) who received chemotherapy, most showed a low and intermediate risk according to the ATL prognostic index. CONCLUSION: In our study, the overall survival of ATL remains poor due to the advanced age of the patients at diagnosis, a high proportion of patients receiving palliative therapy, and a small proportion of long-term survivors receiving chemotherapy and undergoing HSCT. This study illustrates the current clinical features, treatment strategies, and outcomes in clinical practice.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma de Células T del Adulto/mortalidad , Leucemia-Linfoma de Células T del Adulto/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Doxorrubicina/administración & dosificación , Esquema de Medicación , Femenino , Humanos , Leucemia-Linfoma de Células T del Adulto/patología , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
Myeloproliferative neoplasms (MPNs) are clinically characterized by the chronic overproduction of differentiated peripheral blood cells and the gradual expansion of malignant intramedullary/extramedullary hematopoiesis. In MPNs mutations in JAK2 MPL or CALR are detected mutually exclusive in more than 90% of cases [1,2]. Mutations in them lead to the abnormal activation of JAK/STAT signaling and the autonomous growth of differentiated cells therefore they are considered as "driver" gene mutations. In addition to the above driver gene mutations mutations in epigenetic regulators such as TET2 DNMT3A ASXL1 EZH2 or IDH1/2 are detected in about 5%-30% of cases respectively [3]. Mutations in TET2 DNMT3A EZH2 or IDH1/2 commonly confer the increased self-renewal capacity on normal hematopoietic stem cells (HSCs) but they do not lead to the autonomous growth of differentiated cells and only exhibit subtle clinical phenotypes [4,6-8,5]. It was unclear how mutations in such epigenetic regulators influenced abnormal HSCs with driver gene mutations how they influenced the disease phenotype or whether a single driver gene mutation was sufficient for the initiation of human MPNs. Therefore we focused on JAK2V617F and loss of TET2-the former as a representative of driver gene mutations and the latter as a representative of mutations in epigenetic regulators-and examined the influence of single or double mutations on HSCs (Lineage(-)Sca-1(+)c-Kit(+) cells (LSKs)) by functional analyses and microarray whole-genome expression analyses [9]. Gene expression profiling showed that the HSC fingerprint genes [10] was statistically equally enriched in TET2-knockdown-LSKs but negatively enriched in JAK2V617F-LSKs compared to that in wild-type-LSKs. Double-mutant-LSKs showed the same tendency as JAK2V617F-LSKs in terms of their HSC fingerprint genes but the expression of individual genes differed between the two groups. Among 245 HSC fingerprint genes 100 were more highly expressed in double-mutant-LSKs than in JAK2V617F-LSKs. These altered gene expressions might partly explain the mechanisms of initiation and progression of MPNs which was observed in the functional analyses [9]. Here we describe gene expression profiles deposited at the Gene Expression Omnibus (GEO) under the accession number GSE62302 including experimental methods and quality control analyses.
RESUMEN
Loss-of-function of ten-eleven translocation-2 (TET2) is a common event in myeloid malignancies, and plays pleiotropic roles, including augmenting stem cell self-renewal and skewing hematopoietic cells to the myeloid lineage. TET2 mutation has also been reported in lymphoid malignancies; 5.7ï½12% of diffuse large B-cell lymphomas and 18ï½83% of angioimmunoblastic T-cell lymphomas had TET2 mutations. We investigated TET2 mutations in 22 adult T-cell leukemia/lymphoma (ATLL) patients and identified a missense mutation in 3 cases (14%). TET2 mutation occurred in a number of ATLL patients and was likely involved in their leukemogenesis.
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Proteínas de Unión al ADN/genética , Leucemia-Linfoma de Células T del Adulto/genética , Mutación , Proteínas Proto-Oncogénicas/genética , Anciano , Anciano de 80 o más Años , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Proteínas de Unión al ADN/metabolismo , Dioxigenasas , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Inmunohistoquímica , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/mortalidad , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
OBJECTIVE: Disseminated intravascular coagulation (DIC) is a clinical condition with high mortality that is characterized by the systemic activation of coagulation pathways resulting in multiple organ failure. Although no standard treatment for DIC has been established, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC. METHODS: To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 92 DIC patients who were treated with rTM at Miyazaki Prefectural Hospital over a 4-year period (62 patients had infectious diseases and 30 patients had hematological diseases). A diagnosis of DIC was made based on the diagnostic criteria of the Japanese Association for Acute Medicine (JAAM) and Japanese Ministry of Health and Welfare (JMHW) for infectious diseases and hematological diseases, respectively. In addition to treating the underlying disease, rTM was administered for six consecutive days. RESULTS: In this study, 49 of the 92 DIC patients (53.3%) experienced resolution of DIC seven days after administration (46.8% patients with infectious disease and 66.7% with hematological disease). A higher survival rate was observed after a 28-day observation period in 69 of the 92 patients (75.0%) (72.6% of the patients with infectious disease and 80.0% of the patients with hematological disease). A lower DIC score at the initiation of rTM treatment was closely related to a higher rate of resolution of DIC. CONCLUSION: Our findings indicate that rTM therapy is an effective, safe and feasible treatment for DIC patients. Furthermore, making an accurate and early diagnosis of DIC and providing subsequent immediate treatment with rTM may improve the resolution of DIC.
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Enfermedades Transmisibles/tratamiento farmacológico , Coagulación Intravascular Diseminada/tratamiento farmacológico , Enfermedades Hematológicas/tratamiento farmacológico , Trombomodulina/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Enfermedades Transmisibles/diagnóstico , Enfermedades Transmisibles/mortalidad , Coagulación Intravascular Diseminada/diagnóstico , Coagulación Intravascular Diseminada/mortalidad , Femenino , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Mortalidad/tendencias , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenAsunto(s)
Calreticulina/genética , Janus Quinasa 2/genética , Trombocitemia Esencial/diagnóstico , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Niño , ADN/química , ADN/genética , ADN/metabolismo , Exones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Receptores de Trombopoyetina/genética , Análisis de Secuencia de ADN , Factores Sexuales , Trombocitemia Esencial/genética , Adulto JovenRESUMEN
BACKGROUND: Hepatocyte growth factor (HGF) is the primary agent promoting the proliferation of mature hepatocytes. The purpose of the present paper was to clarify the effects of HGF on the proliferation and differentiation of hepatic oval cells using a 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH) model in rats. METHODS: Recombinant human HGF (0.2 mg/day) was administered to 2-AAF/PH rats for 7 days using osmotic pumps intraperitoneally implanted in conjunction with hepatectomy (day zero). RESULTS: Periportal basophilic areas consisting of oval cells were significantly enlarged by treatment with HGF on day 8. In control animals, expression of alpha-fetoprotein (AFP) in the liver was gradually upregulated, leading a marked increase on day 12. In HGF-treated rats, AFP expression was stimulated at an earlier date and decreased to an undetectable level on day 12. Conversely, expression of albumin transcripts, which was stimulated by HGF-treatment at a later date, continued to increase even after HGF administration ceased, leading to an extremely high level on day 12. Moreover, treatment with HGF also stimulated the expression of hepatocyte nuclear factor-1alpha and -4alpha at an early date. CONCLUSIONS: These results indicate that, besides the proliferation of hepatic oval cells, HGF possibly promotes the differentiation to hepatocytes in vivo, suggesting that recombinant human HGF accelerates the regeneration of severely damaged livers, a situation in which the proliferation of mature hepatocytes is impaired.
Asunto(s)
2-Acetilaminofluoreno/farmacología , Hepatectomía , Factor de Crecimiento de Hepatocito/farmacología , Regeneración Hepática/efectos de los fármacos , Hígado/fisiopatología , Albúminas/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hepatectomía/métodos , Factor de Crecimiento de Hepatocito/administración & dosificación , Factor de Crecimiento de Hepatocito/farmacocinética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 4 del Hepatocito/metabolismo , Humanos , Inyecciones Intraperitoneales , Hígado/metabolismo , Hígado/patología , Masculino , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-met/metabolismo , Ratas , Ratas Endogámicas F344 , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacología , Factores de Tiempo , Tirosina/metabolismo , alfa-Fetoproteínas/metabolismoRESUMEN
Hepatocyte growth factor (HGF) modulates intestinal epithelial cell proliferation and migration, serving as a critical regulator of intestinal wound healing. In this study, we examined the effect of administration of recombinant human HGF on colonic mucosal damage in vivo. Acute colitis was induced in rats by feeding with 5% dextran sulfate sodium (DSS) for 7 days, and colitis was subsequently maintained by feeding with 1% DSS. On the 5th day of DSS administration, osmotic pumps releasing recombinant human HGF (200 microg/day) were implanted into the peritoneum of the rats. Continuous intraperitoneal delivery of HGF led to both increased serum human HGF levels and c-Met tyrosine phosphorylation within the colonic mucosa. Compared with mock-treated rats, those administered human HGF showed a reduction in colitis-associated weight loss, large intestinal shortening, and improved colonic erosions. Enhanced epithelial regeneration and cellular proliferation were observed in rats treated with recombinant human HGF. The weights of the liver, kidneys, and spleen were not affected by HGF administration. These results indicate that HGF administration accelerates colonic mucosal repair in rats with DSS-induced colitis and suggest that recombinant human HGF may be a useful therapeutic tool to facilitate intestinal wound healing in patients with ulcerative colitis.