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Clinically, chronic pain and depression often coexist in multiple diseases and reciprocally reinforce each other, which greatly escalates the difficulty of treatment. The neural circuit mechanism underlying the chronic pain/depression comorbidity remains unclear. The present study reports that two distinct subregions in the paraventricular thalamus (PVT) play different roles in this pathological process. In the first subregion PVT posterior (PVP), glutamatergic neurons (PVPGlu) send signals to GABAergic neurons (VLPAGGABA) in the ventrolateral periaqueductal gray (VLPAG), which mediates painful behavior in comorbidity. Meanwhile, in another subregion PVT anterior (PVA), glutamatergic neurons (PVAGlu) send signals to the nucleus accumbens D1-positive neurons and D2-positive neurons (NAcD1âD2), which is involved in depression-like behavior in comorbidity. This study demonstrates that the distinct thalamo-subcortical circuits PVPGluâVLPAGGABA and PVAGluâNAcD1âD2 mediated painful behavior and depression-like behavior following spared nerve injury (SNI), respectively, which provides the circuit-based potential targets for preventing and treating comorbidity.
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Cytomegalovirus (CMV) reactivation remains one of the major and life-threatening complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Yet, there is still a lack of safe and effective ways to prevent CMV reactivation in allo-HSCT patients. Here, we retrospectively analyzed a cohort of patients who underwent HSCT at our transplant center between 2018 and 2022 to evaluate the efficacy of prophylactic CMV-specific intravenous immunoglobulin (CMV-IVIg) against CMV reactivation. After Propensity Score Matching, the CMV reactivation rate was significantly decreased in the CMV-IVIg group (HR, 2.952; 95% CI,1.492-5.841; P = .002) compared with the control group. Additionally, the time duration of CMV reactivation (P = .001) and bacterial infection rate (P = .013) were significantly lower in the CMV-IVIg group. Moreover, prophylactic CMV-IVIg was more effective in CMV seropositive patients who received ATG as part of GVHD prevention (HR, 8.225; 95% CI,1.809-37.39; P = .006). In conclusion, CMV-IVIg is considered an effective and safe way to prevent CMV reactivation in HSCT recipients, which may be related to the acceleration of immune reconstitution in the early stage after transplantation.
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Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Humanos , Citomegalovirus , Imunoglobulinas Intravenosas/uso terapêutico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/tratamento farmacológico , Estudos Retrospectivos , Transplante Homólogo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Anticorpos AntiviraisRESUMO
Immunogenic cell death (ICD), one of cell-death types through release of damage-associated molecular patterns from dying tumor cells, activates tumor-specific immune response and elicits anti-tumor immunity by traditional radiotherapy and chemotherapy. However, whether natural products could induce ICD in leukemia is not elucidated. Here, we report dietary γ-mangostin eradicates murine primary leukemic cells and prolongs the survival of leukemic mice. As well, it restrains primary leukemic cells and CD34+ leukemic progenitor cells from leukemia patients. Strikingly, γ-mangostin attenuates leukemic cells by inducing ICD as characterized by expression of HSP90B1, ANXA1 and IL1B. Additionally, γ-mangostin accelerates cytoplasmic chromatin fragments generation, promoting DNA damage response, and enhances cGAS activation, leading to up-regulation of chemokines. Meanwhile, it induces HDAC4 degradation and acetylated histone H3 accumulation, which promotes chemokines transcription. Ultimately, CD8+ T cell is activated and recruited by γ-mangostin-induced chemokines in the microenvironment. Our study identifies γ-mangostin triggers ICD and activates cGAS signaling through DNA damage response and epigenetic modification. Therefore, dietary γ-mangostin would act as a potential agent to provoke anti-tumor immunity in the prevention and treatment of leukemia.
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Morte Celular Imunogênica , Leucemia Mieloide Aguda , Humanos , Animais , Camundongos , Leucemia Mieloide Aguda/tratamento farmacológico , Dieta , Quimiocinas , Microambiente TumoralRESUMO
Breast cancer (BC) is a life-threatening malignant tumor that affects females more commonly than males. The mechanisms underlying BC proliferation, metastasis and glycolysis require further investigation. Homeobox C13 (HOXC13) is highly expressed in BC; however, the specific mechanisms in BC are yet to be fully elucidated. Therefore, the aim of the present study was to investigate the role of HOXC13 in BC proliferation, migration, invasion and glycolysis. In the present study, the UALCAN database was used to predict the expression levels of HOXC13 in patients with BC. Western blot analysis and reverse transcription-quantitative PCR were used to determine the expression levels of HOXC13 in BC cell lines. Moreover, HOXC13 knockdown was induced using cell transfection, and the viability, proliferation and apoptosis of cells were detected using Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining and flow cytometry. Migration, invasion and epithelial-mesenchymal transition (EMT) were measured using wound healing assay, Transwell assay and western blotting. In addition, XF96 extracellular flux analyzer and corresponding kits were used to detect glycolysis. The JASPAR database was used to predict promoter binding sites for the transcription factors HOXC13 and DNA methyltransferase 3α (DNMT3A). HOXC13 expression was silenced and DNMT3A was simultaneously overexpressed using cell transfection. The results of the present study revealed that HOXC13 expression was significantly elevated in BC tissues and cells. Following HOXC13 knockdown in BC cells, the viability, proliferation, glycolysis, migration, invasion and EMT were significantly decreased, and apoptosis was significantly increased. In addition, HOXC13 positively regulated the transcription of DNMT3A in BC cells, thus playing a regulatory role in the malignant progression of cells. In conclusion, HOXC13 promoted cell viability, proliferation, migration, invasion, EMT and glycolysis in BC by regulating DNMT3A.
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BACKGROUND: We retrospectively analyzed the application and clinical efficacy of second allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute leukemia patients who relapsed or had primary graft failure (PGF) after first transplantation. METHODS: From 2007 to 2021, eight patients with acute leukemia who received second allo-HSCT in our hospital were collected, including 6 relapsed patients and 2 patients with PGF after the first HSCT. RESULTS: All the patients received complete donor implantation after second transplantation. The median time of neutrophils and platelet implantation were 12 days (10 days - 13 days) and 23 days (12 days - 123 days). Two cases (25.0%) developed grade II aGVHD, and 4 cases (50.0%) developed cGVHD. Leukemia-free survival (LFS) and overall survival (OS) at 1 year both were 71.4% and at 3 years both were 28.6%. After a median follow-up of 1,556 days (range, 257 - 5,252 days), 3 of the patients (37.5%) survived and 5 (62.5%) died. One patient with NR before second transplantation, treated with a conditioning regime of CLAG-M bridging BuCy, has survived for more than 5 years (61 months). Relapse was the main death reason. CONCLUSIONS: Second allo-HSCT is an effective means to treat acute leukemia patients with relapsed and PGF after first transplantation.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Doença Enxerto-Hospedeiro/etiologia , Leucemia Mieloide Aguda/terapia , Doença AgudaRESUMO
Cytomegalovirus (CMV) infection remains a frequent complication after hematopoietic stem cell transplantation (HSCT) and causes significant morbidity and mortality in transplantation recipients. In this review, we highlight the role of major risk factors that are associated with the incidence of CMV infection. Advances in immunosurveillance may predict CMV infection, allowing early interventions to prevent severe infection. Furthermore, numerous therapeutic strategies against CMV infection after HSCT are summarized. A comprehensive understanding of the current situation of CMV treatment may provide a hint for clinical practice and even promote the development of novel strategies for precision medicine.
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Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Citomegalovirus , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Transplantados , Transplante Homólogo/efeitos adversosRESUMO
Breast cancer is characterized by high morbidity and mortality. GDC-0941 is a PI3K inhibitor with oncogenic effects in breast cancer. However, certain breast cancer cells are insensitive to GDC-0941. Hence, the mechanism of GDC-0941 in breast cancer resistance was investigated in this study. Breast cancer cell lines BT-474, MCF7, Hs-578-T, MDA-MB-231, MDA-MB-453, and MDA-MB-468 were cultured in different medium and then treated with 100 or 500 nM GDC-0941, 100 nM OSU-T315, or TNF-α antibody. Moreover, ILK and shILK were transfected into cells. The half maximal inhibitory concentrations (IC50) for GDC-0941 were detected using CCK-8 assay. The levels of ILK, AKT, PDK1, S6, and p70S6K expression were detected using western blotting and qPCR. In addition, the mouse model of breast cancer was constructed to measure the tumor size, volume, and weight. The results showed that GDC-0941 decreased cell survival rate, downregulated the phosphorylation of AKT, S6, and p70S6K, and promoted the expression of ILK, while it had little effect on PDK1 expression. GDC-0941 inhibited the increases in p-AKT, p-S6, and p-p70S6K caused by ILK overexpression and promoted ILK knockdown-induced reduction of p-AKT, p-S6, and p-p70S6K. In addition, the combination of OSU-T315 and GDC-0941 decreased p-AKT, p-S6, and p-p70S6K level, tumor volume, and tumor weight. GDC-0941 promoted ILK expression by upregulating TNF-α level. Taken together, GDC-0941 increased ILK level by upregulating TNF-α, thus affecting AKT expression and the sensitivity of breast cancer cells to GDC-0941.
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Neoplasias da Mama , Proteínas Quinases S6 Ribossômicas 70-kDa , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Indazóis , Integrinas , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Sulfonamidas , Fator de Necrose Tumoral alfa/genéticaRESUMO
The epigenetic treatment by 3-Deazaneplanocin A (DZNep), a histone methyltransferase inhibitor, shows great potential against acute myeloid leukemia (AML). However, the variant sensitivity and incomplete response to DZNep are commonly observed. Here, we reveal that vitamin C (Vc) dramatically promotes DZNep response against leukemic cells in different cell lines and primary AML samples. Vc enhances apoptosis and differentiation induced by DZNep in different AML cell lines in vitro and reduces leukemia progression in vivo. At the molecular level, Vc downregulates an enzyme of serine synthesis named D-3-phosphoglycerate dehydrogenase (PHGDH), as well as BCL2, an anti-apoptotic gene. Over-expression of PHGDH reverses the Vc-enhanced anti-leukemic effect of DZNep in AML cells. Therefore, our findings provide an effective approach to reduce the resistance against epigenetic treatment by Vc, which shows a potential improvement of their combination in AML patients.
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Proteína Potenciadora do Homólogo 2 de Zeste , Leucemia Mieloide Aguda , Adenosina/análogos & derivados , Ácido Ascórbico/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Histona Metiltransferases , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismoRESUMO
We conducted a prospective study to evaluate the efficacy and safety of cladribine, cytarabine, mitoxantrone, and granulocyte colony-stimulating factor (CLAG-M) regimen combined with busulfan and cyclophosphamide (BuCy) as new intensive conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of relapsed/refractory acute myeloid leukemia (AML). 24 patients were enrolled. The median follow-up was 15.2 months (range 1.9-67.0 months). Except for one patient who died before graft infusion, the evaluable 23 patients (96%) achieved complete remission (CR). The two-year overall survival (OS) rate and leukemia-free survival (LFS) rate were 61.4% and 59.4%, respectively. The non-relapse mortality (NRM) was 9.1%. Univariate analysis revealed that the myeloid blast phase of chronic myelomonocytic leukemia (CMML), an EVI1 mutated, blood blasts ≥20% at transplant, and extramedullary disease were risk factors for LFS.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/terapia , Estudos Prospectivos , Condicionamento Pré-TransplanteRESUMO
The FMS-like tyrosine kinase 3 (FLT3)- internal tandem duplication (ITD) mutation can be found in approximately 25% of all acute myeloid leukemia (AML) cases and is associated with a poor prognosis. The main treatment for FLT3-ITD-positive AML patients includes genotoxic therapy and FLT3 inhibitors, which are rarely curative. Inhibiting STAT3 activity can improve the sensitivity of solid tumor cells to radiotherapy and chemotherapy. This study aimed to explore whether Stattic (a STAT3 inhibitor) affects FLT3-ITD AML cells and the underlying mechanism. Stattic can inhibit the proliferation, promote apoptosis, arrest cell cycle at G0/G1, and suppress DNA damage repair in MV4-11cells. During the process, through mRNA sequencing, we found that DNA damage repair-related mRNA are also altered during the process. In summary, the mechanism by which Stattic induces apoptosis in MV4-11cells may involve blocking DNA damage repair machineries.
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BACKGROUND: The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified. METHODS: Paw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, and microarray analysis were performed to explore the molecular mechanism. RESULTS: We found that paclitaxel treatment increased the nuclear expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TTS of target genes in dorsal horn after paclitaxel treatment. We further found that NFATc2 occupancy may directly upregulate the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel. CONCLUSION: These results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain.
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Quimiocinas CXC/biossíntese , Epigênese Genética/efeitos dos fármacos , Fatores de Transcrição NFATC/biossíntese , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Paclitaxel/toxicidade , Animais , Antineoplásicos Fitogênicos/toxicidade , Sequência de Bases , Quimiocinas CXC/genética , Epigênese Genética/fisiologia , Masculino , Fatores de Transcrição NFATC/genética , Neuralgia/genética , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
RAD52 (Radiation sensitive 52) is a key factor in DNA damage repair (DDR) bypass, which participates in singlestrand annealing (SSA) after DNA damage end excision, while breast cancer type 1 susceptibility protein (BRCA1)/breast cancer type 2 susceptibility protein (BRCA2) play critical roles in homologous recombination (HR) repair. The present study aimed to determine whether RAD52induced regulation of repair bypass occurs in acute myeloid leukemia (AML) cells and to explore the underlying mechanism. Herein, we applied an RAD52 aptamer to AML cells with downregulated BRCA1/2. RAD52 aptamer inhibited AML cell proliferation detected by cell counting, promoted cell apoptosis obtained by flow cytometry, and suppressed DNA damage repair behavior measured by comet assay and flow cytometry, after drug intervention during low expression of BRCA1/2. During this process, DDRrelated cell cycle checkpoint proteins were activated, and the cells were continuously arrested in the S/G2 phase, which affected the cell damage repair process. Concurrently, the expression levels of apoptosisrelated proteins were also altered. Furthermore, the expression of STAT3 and pSTAT3 was downregulated by the RAD52 aptamer, suggesting that RAD52 affects the STAT3 signaling pathway. In summary, we present a possible role for RAD52 in DDR of BRCA1/2deficient AML cells that involves the STAT3 signaling pathway.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Leucemia Mieloide Aguda/genética , Proteína Rad52 de Recombinação e Reparo de DNA/genética , Fator de Transcrição STAT3/genética , Apoptose/genética , Aptâmeros de Nucleotídeos/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Dano ao DNA/genética , Reparo do DNA/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Leucemia Mieloide Aguda/patologiaRESUMO
BACKGROUND: Although the action mechanism of antineoplastic agents is different, oxaliplatin, paclitaxel, or bortezomib as first-line antineoplastic drugs can induce painful neuropathy. In rodents, mechanical allodynia is a common phenotype of painful neuropathy for 3 chemotherapeutics. However, whether there is a common molecular involved in the different chemotherapeutics-induced painful peripheral neuropathy remains unclear. METHODS: Mechanical allodynia was tested by von Frey hairs following i.p. injection of vehicle, oxaliplatin, paclitaxel, or bortezomib in Sprague-Dawley rats. Reduced representation bisulfite sequencing and methylated DNA immunoprecipitation were used to detect the change of DNA methylation. Western blot, quantitative polymerase chain reaction, chromatin immunoprecipitation, and immunohistochemistry were employed to explore the molecular mechanisms. RESULTS: In 3 chemotherapeutic models, oxaliplatin, paclitaxel, or bortezomib accordantly upregulated the expression of transient receptor potential cation channel, subfamily C6 (TRPC6) mRNA and protein without affecting the DNA methylation level of TRPC6 gene in DRG. Inhibition of TRPC6 by using TRPC6 siRNA (i.t., 10 consecutive days) relieved mechanical allodynia significantly following application of chemotherapeutics. Furthermore, the downregulated recruitment of DNA methyltransferase 3 beta (DNMT3b) at paired box protein 6 (PAX6) gene led to the hypomethylation of PAX6 gene and increased PAX6 expression. Finally, the increased PAX6 via binding to the TPRC6 promoter contributes to the TRPC6 increase and mechanical allodynia following chemotherapeutics treatment. CONCLUSIONS: The TRPC6 upregulation through DNMT3b-mediated PAX6 gene hypomethylation participated in mechanical allodynia following application of different chemotherapeutic drugs.
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Antineoplásicos/farmacologia , DNA (Citosina-5-)-Metiltransferases/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Gânglios Espinais/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Hiperalgesia/induzido quimicamente , Neuralgia/induzido quimicamente , Fator de Transcrição PAX6/efeitos dos fármacos , Canais de Cátion TRPC/efeitos dos fármacos , Animais , Bortezomib/farmacologia , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Neuralgia/complicações , Oxaliplatina/farmacologia , Paclitaxel/farmacologia , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPC/antagonistas & inibidores , Regulação para Cima/efeitos dos fármacos , DNA Metiltransferase 3BRESUMO
Achievement of immunocompetent and therapeutic T lymphopoiesis from pluripotent stem cells (PSCs) is a central aim in T cell regenerative medicine. To date, preferentially reconstituting T lymphopoiesis in vivo from PSCs remains a practical challenge. Here we documented that synergistic and transient expression of Runx1 and Hoxa9 restricted in the time window of endothelial-to-hematopoietic transition and hematopoietic maturation stages in a PSC differentiation scheme (iR9-PSC) in vitro induced preferential generation of engraftable hematopoietic progenitors capable of homing to thymus and developing into mature T cells in primary and secondary immunodeficient recipients. Single-cell transcriptome and functional analyses illustrated the cellular trajectory of T lineage induction from PSCs, unveiling the T-lineage specification determined at as early as hemogenic endothelial cell stage and identifying the bona fide pre-thymic progenitors. The induced T cells distributed normally in central and peripheral lymphoid organs and exhibited abundant TCRαß repertoire. The regenerative T lymphopoiesis restored immune surveillance in immunodeficient mice. Furthermore, gene-edited iR9-PSCs produced tumor-specific T cells in vivo that effectively eradicated tumor cells. This study provides insight into universal generation of functional and therapeutic T cells from the unlimited and editable PSC source.
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Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Homeodomínio/genética , Linfopoese , Células-Tronco Pluripotentes/fisiologia , Linfócitos T/imunologia , Animais , Células Cultivadas , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células-Tronco Embrionárias/fisiologia , Rejeição de Enxerto/imunologia , Proteínas de Homeodomínio/metabolismo , Linfopoese/genética , Camundongos , Neoplasias Experimentais/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/química , Transplante de PeleAssuntos
Bortezomib/efeitos adversos , Quimiocina CCL21/genética , Epigênese Genética/genética , Fator de Transcrição GATA3/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/metabolismo , Animais , Quimiocina CCL21/metabolismo , Epigênese Genética/efeitos dos fármacos , Fator de Transcrição GATA3/genética , Imuno-Histoquímica , Imunoprecipitação , Masculino , Análise em Microsséries , Neuralgia/induzido quimicamente , Ratos Sprague-DawleyRESUMO
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH), as known as Hemophagocytic syndrome (HPS), is deemed to a severe clinical syndrome caused by excessive human being immune system activation. Bacteria of Ralstonia genus is a non-fermentative, gram-negative bacillus and also in the category of human opportunistic pathogenic bacteria. In this article, authors report a rare case of Hemophagocytic lymophohistiocytosis which probably was triggered by Ralstonia solanacearum (R. solanacearum) infection. METHODS: Hematologic investigation, biochemical examination, high throughput genetic test for infectious agents and bone marrow puncture. RESULTS: The patient achieved complete remission and no signs of relapse have as yet been found. CONCLUSIONS: The bacteria of Ralstonia genus merely infect humans, and there were no reports about the infection of R. solanacearum in humans and secondary HLH. The prognosis of the patient in this case was very good. This result, we think shows that the relationship between HLH and R. solanacearum infection should be taken into the diagnosis process. Recognition of this will promote the correct diagnosis in clinical work.
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Infecções por Bactérias Gram-Negativas/complicações , Linfo-Histiocitose Hemofagocítica/etiologia , Adulto , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Prognóstico , Ralstonia solanacearum/imunologia , Ralstonia solanacearum/fisiologiaRESUMO
BACKGROUND: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct neurodevelopmental disorders caused by absence of paternally or maternally expressed imprinted genes on chromosome 15q11.2-q13.3 region. METHODS: 3331 individuals was recruited from June 2013 to December 2016 under an institutional review board-approved protocol of informed consent. The methylation-specific PCR was employed as a first-tier screening test. The multiplex-fluorescent-labeled STR linkage analysis was carried out to define the underlying genetic mechanisms. The chromosomal microarray analysis was employed to identify chromosomal breakpoints in confirmed cases, and to detect other chromosomal abnormalities in undiagnosed cases. Genetic counseling and recurrence risk assessment were provided to families with affected individuals. RESULTS: The methylation-specific PCR identified 36 PWS suspected patients and 13 AS suspected patients. UBE3A sequence analysis identified another 1 patient with AS. The STR linkage analysis define the underlying genetic mechanisms. Thirty PWS patients were with paternal deletions on chromosome region 15q11-q13, 5 with isodisomic uniparental disomy and 1 with mixed segmental isodisomic/ heterodisomic uniparental disomy of maternal chromosome 15. Twelve AS patients were with maternal deletions, 1 with isodisomic uniparental disomy and 1 with UBE3A gene mutation. The chromosomal microarray analysis identified chromosomal breakpoints in confirmed cases, and detected chromosomal abnormalities in another 4 patients with clinically overlapped features but tested negative for PWS/AS. Genetic counseling was offered to all families with affected individuals. CONCLUSIONS: Identifying the disorders at early age, establishing the molecular mechanisms, carrying out treatment intervention and close monitoring can significantly improve the prognosis of PWS/AS patients.
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BACKGROUND: After allogeneic haematopoietic stem cell transplantation (allo-HSCT), Hepatitis B virus reactivation (HBVr) can be observed in patients with previous resolved Hepatitis B virus (HBV) infections. Nephrotic syndrome (NS) is the main clinical manifestation of HBsAg-positive glomerulonephritis. However, the development of HBVr combined with NS after allo-HSCT is uncommon. CASE PRESENTATION: We presented a case of a 47-year-old female with acute myelogenous leukemia who underwent HLA-identical sibling allo-HSCT and achieved leukemia free survival. She had pretransplant serological markers of a resolved HBV infection (HBsAg-negative, anti-HBc and anti-HBs positive). However, she developed HBVr combined with nephrotic syndrome (NS) 16 months after HSCT. Her histological renal lesion was mesangial proliferative glomerulonephritis. IgA+, IgM+, and C1q deposits but not HBV antigens (HBsAg and HBcAg) were identified in her renal biopsy material. Long-term entecavir and immunosuppression resulted in decrease of HBV virus replication, amelioration of proteinuria and stabilisation of renal function. CONCLUSIONS: Entecavir combined with immunosuppression has efficacy in the treatment of HBVr combined with NS after allo-HSCT, but long course of treatment is needed. Closely monitoring and antiviral prophylaxis might be necessary for allo-HSCT recipients to prevent reactivation of resolved HBV infection and its related complications.
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Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatite B/tratamento farmacológico , Hepatite B/etiologia , Síndrome Nefrótica/virologia , Antivirais/uso terapêutico , Biomarcadores/sangue , Feminino , Glomerulonefrite/virologia , Guanina/análogos & derivados , Guanina/uso terapêutico , Anticorpos Anti-Hepatite B/sangue , Antígenos do Núcleo do Vírus da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Vírus da Hepatite B/fisiologia , Humanos , Terapia de Imunossupressão/métodos , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/etiologia , Transplante Homólogo/efeitos adversos , Ativação Viral/efeitos dos fármacosRESUMO
BACKGROUND: X-linked thrombocytopenia (XLT) is a milder form of Wiskott-Aldrich syndrome (WAS), characterized predominantly by thrombocytopenia with small-sized platelets. Mutations in the WAS gene are responsible for the disease. We herein detected a new mutation in the WAS gene responsible for XLT in a 3-generation Chinese pedigree. METHODS: Peripheral blood samples were collected from 7 members in the family. WAS gene was amplified from genomic DNA isolated from leucocytes, and then direct sequencing was performed. RESULTS: Three male members of this family (the proband, his younger brother and maternal uncle) had thrombocytopenia and decreased mean platelet volume. A homozygous mutation (T>C) was found at nucleotide position 319 in exon 3, causing the amino acid Tyr (T) to be abnormally changed to His (H) at position 107. Two female members (the proband's mother and grandmother) were carriers of the mutation. CONCLUSIONS: XLT is easy to misdiagnose as immune thrombocytopenic purpura (ITP). The diagnosis of XLT should be considered in any male with congenital microthrombocytopenia or early onset of microthrombocytope-nia (< 7 fL). This article adds to the growing number of known mutations associated with XLT.
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Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação de Sentido Incorreto , Trombocitopenia/genética , Proteína da Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/genética , Adolescente , Povo Asiático/genética , Sequência de Bases , China , Análise Mutacional de DNA , Éxons/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/etnologia , Humanos , Masculino , Volume Plaquetário Médio , Linhagem , Trombocitopenia/sangue , Trombocitopenia/etnologia , Síndrome de Wiskott-Aldrich/sangue , Síndrome de Wiskott-Aldrich/etnologiaRESUMO
Nd1-S is the nuclear-localizing short variant form of Nd1 (Ivns1abp) encoding a Kelch family transcription factor. While the function of Nd1 has been investigated in the context of metastasis and doxorubicin-induced cardiotoxicity, little is known about its role in hematopoiesis. In this study, we investigated the function of Nd1-S in hematopoiesis by transplanting the Nd1-S-overexpressing murine hematopoietic stem and progenitor cells (HSPCs) into recipient mice (Nd1-S mice). Enforced expression of Nd1-S led to erythroid and megakaryocyte dysplasia, demonstrated by dramatically decreased red blood cells and platelets, and megakaryocytes in the peripheral blood and bone marrow of the Nd1-S mice. Moreover, phenotypic megakaryocyte-erythroid progenitors (MEPs) accumulated in these Nd1-S mice with aberrant morphology and defective colony-forming capability. Furthermore, these phenotypic MEPs showed impaired pathways regulating erythroid differentiation and megakaryocyte development. Therefore, our study provides de novo evidence that overexpression of Nd1-S in HSPCs leads to erythroid and megakaryocyte dysplasia in vivo by targeting MEPs.