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Potassium vanadium fluorophosphate (KVPO4F) is regarded as a promising cathode candidate for potassium-ion batteries due to its high working voltage and satisfactory theoretical capacity. However, the usage of electrochemically inactive binders and redundant current collectors typically results in inferior electrochemical performance and low energy density, thus implying the important role of rational electrode structure design. Herein, we have reported a scalable and cost-effective synthesis of a cellulose-derived KVPO4F self-supporting electrode, which features a special surface hydroxyl chemistry, three-dimensional porous and conductive framework, as well as super flexible and stable architecture. The cellulose not only serves as a flexible substrate, a pore-forming agent, and a versatile binder for KVPO4F/conductive carbon but also enhances the K-ion migration ability. Benefiting from the special hydroxyl chemistry-induced storage mechanism and electrode structural stability, the flexible freestanding KVPO4F cathode exhibits high-rate performance (53.0% capacity retention with current densities increased 50-fold, from 0.2 C to 10 C) and impressive cycling stability (capacity retention up to 74.9% can be achieved over 1,000 cycles at a rate of 5 C). Such electrode design and surface engineering strategies, along with a deeper understanding of potassium storage mechanisms, provide invaluable guidance for better electrode design to boost the performance of potassium-ion energy storage systems.
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BACKGROUND: The objective of the study was to explore the potential biomarkers and risk factors in children with immunoglobulin A nephropathy (IgAN). METHODS: Untargeted metabolomics analysis was performed on children with IgAN before and after treatment. Subsequently, a retrospective study involving the past 15 years and a follow-up study were performed to verify the role of hyperuricemia in IgAN children. RESULTS: Serum metabolomics analyses showed that levels of serum xanthosine were closely related to the outcome of IgAN, and KEGG analyses showed that differential metabolites were significantly enriched in purine metabolism. Furthermore, retrospectively analyses of 252 children with IgAN showed that hyperuricemia was associated with poorer renal outcome. Logistic regression analysis showed that BMI, serum creatinine, eGFR, Lee's grade III, and crescents were risk factors of hyperuricemia in children with IgAN. Kaplan-Meier analysis revealed that kidney progression-free survival in IgAN children with hyperuricemia was lower than that without hyperuricemia, especially in females. CONCLUSIONS: We first performed a dynamic metabolomics study to reveal that hyperuricemia is closely related to the progression of IgAN in children. Then retrospective and follow-up studies confirmed that hyperuricemia is an important risk factor for poor renal outcomes. We need to pay more attention to the hyperuricemia in children with IgAN. IMPACT: We first performed a dynamic metabolomics study to reveal that hyperuricemia was closely related to the progression of IgAN in children. Retrospective analyses in past 15 years confirmed that IgAN children with hyperuricemia had poorer renal function and worse renal pathology. The BMI, Scr, eGFR, Lee's grade III, and crescents were risk factors of hyperuricemia in children with IgAN. The long-term follow-up study showed that hyperuricemia was an important risk factor for poor renal outcome in children with IgAN. We need to pay more attention to hyperuricemia in children with IgAN, especially in females.
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Glomerulonefritis por IGA , Hiperuricemia , Femenino , Humanos , Niño , Glomerulonefritis por IGA/complicaciones , Estudios Retrospectivos , Hiperuricemia/complicaciones , Estudios de Seguimiento , Riñón/patología , Progresión de la EnfermedadRESUMEN
BACKGROUND: To analyze the efficacy and safety of multi-target therapy in children with lupus nephritis (LN). METHODS: In our retrospective study from January 2009 to December 2021, the multi-target therapy of glucocorticoids, MMF and tacrolimus was adopted as induction therapy or re-induction therapy for 36 LN children who had combined proliferative and membranous LN or for who were ineffective to combination therapy of glucocorticoids with IV-CYC or MMF for at least 6 months. The clinical and pathological data were collected and analyzed. RESULTS: The levels of 24-h urinary protein, anti-dsDNA antibody and SLE disease activity index were decreased, while the levels of albumin and complement 3 were increased after multi-target therapy. More than 90% of LN children achieved partial or complete remission within 6 months. In terms of adverse effects, there was no significant difference between the level of eGFR before and after multi-target therapy. During the follow-up period, four children had infection, two children had hyperuricemia, and one child had liver dysfunction. All of them improved after symptomatic therapy. CONCLUSIONS: Multi-target therapy could be an effective treatment option with minimal adverse effects for LN children who are refractory to initial first-line induction therapies or had combined proliferative and membranous LN. IMPACT: The multi-target therapy of glucocorticoids, mycophenolate mofetil and tacrolimus was adopted in 36 children with lupus nephritis. Multi-target therapy could be an effective treatment option for lupus nephritis children who are refractory to initial first-line induction therapies or had combined proliferative and membranous lupus nephritis. Adverse effects of multi-target therapy were infrequent and minimal that can be improved by symptomatic therapy.
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Nefritis Lúpica , Humanos , Niño , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/patología , Inmunosupresores/efectos adversos , Tacrolimus/efectos adversos , Ciclofosfamida/uso terapéutico , Estudios Retrospectivos , Ácido Micofenólico/efectos adversos , Glucocorticoides/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Branchio-oto-renal (BOR) syndrome is an inherited multi-systemic disorder. Auricular and branchial signs are highly suggestive of BOR syndrome but often develop insidiously, leading to a remarkable misdiagnosis rate. Unlike severe morphological abnormalities of kidneys, knowledge of glomerular involvement in BOR syndrome were limited. CASE PRESENTATION: Three cases, aged 8 ~ 9 years, visited pediatric nephrology department mainly for proteinuria and renal insufficiency, with 24-h proteinuria of 23.8 ~ 68.9 mg/kg and estimated glomerular filtration rate of 8.9 ~ 36.0 mL/min/1.73m2. Moderate-to-severe albuminuria was detected in case 1, while mixed proteinuria was detected in case 2 and 3. Insidious auricular and branchial fistulas were noticed, all developing since early childhood but being neglected previously. EYA1 variants were confirmed by genetic testing in all cases. Delay in diagnosis was 8 ~ 9 years since extra-renal appearances, and 0 ~ 6 years since renal abnormalities. In case 1, therapy of glucocorticoid and immunosuppressive agents to accompanying immune-complex mediated glomerulonephritis was unsatisfying. CONCLUSIONS: BOR syndrome is a rare cause of proteinuria and abnormal kidney function and easily missed, thus requiring more awareness. Careful medical history taking and physical examination are essential to early diagnosis. Massive proteinuria was occasionally seen in BOR syndrome, which might be related to immune complex deposits. A novel pathogenic variant (NM_000503.6 (EYA1): c.1171delT p.Ser391fs*9) was firstly reported.
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Síndrome Branquio Oto Renal , Glomerulonefritis , Insuficiencia Renal , Preescolar , Humanos , Niño , Síndrome Branquio Oto Renal/complicaciones , Síndrome Branquio Oto Renal/diagnóstico , Síndrome Branquio Oto Renal/genética , Insuficiencia Renal/diagnóstico , Riñón , Proteinuria/diagnóstico , Proteinuria/etiología , Albuminuria , Glomerulonefritis/complicaciones , Glomerulonefritis/diagnóstico , Glomerulonefritis/genéticaRESUMEN
BACKGROUND: Granulosa cell (GC) proliferation and apoptosis are critical events of the ovum energy supply, which lead to follicular growth retardation or atresia, and various ovulatory obstacles, eventually resulting in the development of ovarian disorders such as polycystic ovarian syndrome (PCOS). Apoptosis and dysregulated miRNA expression in GCs are manifestations of PCOS. miR-4433a-3p has been reported to be involved in apoptosis. However, there is no study reporting the roles of miR-4433a-3p in GC apoptosis and PCOS progression. METHODS: miR-4433a-3p and peroxisome proliferator-activated receptor alpha (PPAR-α) levels in GCs of PCOS patients or in tissues of a PCOS rat model were examined by quantitative polymerase chain reaction and immunohistochemistry. Bioinformatics analyses and luciferase assays were used to examine the association between miR-4433a-3p and PPAR-α, as well as PPAR-α and immune cell infiltration, in PCOS patients. RESULTS: miR-4433a-3p expression in GCs of PCOS patients was increased. miR-4433a-3p overexpression inhibited the growth of the human granulosa-like tumor cell line (KGN) and promoted apoptosis, while co-treatment with PPAR-α and miR-4433a-3p mimic rescued miR-4433a-3p-induced apoptosis. PPAR-α was a direct target of miR-4433a-3p and its expression was decreased in PCOS patients. PPAR-α expression was also positively correlated with the infiltration of activated CD4+ T cells, eosinophils, B cells, gamma delta T cells, macrophages, and mast cells, but negatively correlated with the infiltration of activated CD8+ T cells, CD56+ bright natural killer cells, immature dendritic cells, monocytes, plasmacytoid dendritic cells, neutrophils, and type 1 T helper cells in PCOS patients. CONCLUSION: The miR-4433a-3p/PPAR-α/immune cell infiltration axis may function as a novel cascade to alter GC apoptosis in PCOS.
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MicroARNs , Síndrome del Ovario Poliquístico , Femenino , Humanos , Ratas , Animales , PPAR alfa/genética , PPAR alfa/metabolismo , Síndrome del Ovario Poliquístico/patología , Células de la Granulosa/metabolismo , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , MicroARNs/genética , MicroARNs/metabolismo , Apoptosis/genética , Proliferación Celular/genéticaRESUMEN
BACKGROUND: The recurrence rate of focal segmental glomerulosclerosis (FSGS) post-renal transplantation is as high as 30%-50%. However, the pathogenesis is unclear. At present, there is no unified standard for the treatment of recurrent FSGS post-transplantation. Its treatment is full of risks and challenges. METHODS: We report a child with recurrent FSGS with massive proteinuria 6~9 g/m2 /day and resistance to plasma exchange (PE) and rituximab (RTX). On the basis of receiving anti-rejection therapy of prednisone, tacrolimus, and mycophenolate mofetil (MMF), we treated the child with adrenocorticotropic hormone (ACTH), and reviewed the literature on the application of ACTH in the recurrence of FSGS post-transplantation. RESULTS: After 1 year of treatment with ACTH, the patient's urinary protein decreased and fluctuated between 0.6 and 1.1 g/m2 /day. The albumin (ALB) and cholesterol (CHOL) returned to the normal range. The patient achieved complete remission after 19 months of ACTH treatment and maintained until now. There was no obvious adverse reaction. Literature review showed that up to February 2021, a total of 8 studies showed the use of ACTH in kidney transplant patients, and all the patients in the study achieved remission. CONCLUSIONS: ACTH is a potential option for treating recurrent FSGS post-transplantation with fewer side effects and relatively safe for patients. However, further evaluation is needed to better adapt to different populations.
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Hormona Adrenocorticotrópica/uso terapéutico , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Trasplante de Riñón , Preescolar , Progresión de la Enfermedad , Humanos , Terapia de Inmunosupresión/métodos , Masculino , RecurrenciaRESUMEN
S-RNase plays vital roles in the process of self-incompatibility (SI) in Rutaceae plants. Data have shown that the rejection phenomenon during self-pollination is due to the degradation of pollen tube RNA by S-RNase. The cytoskeleton microfilaments of pollen tubes are destroyed, and other components cannot extend downwards from the stigma and, ultimately, cannot reach the ovary to complete fertilisation. In this study, four S-RNase gene sequences were identified from the 'XiangShui' lemon genome and ubiquitome. Sequence analysis revealed that the conserved RNase T2 domains within S-RNases in 'XiangShui' lemon are the same as those within other species. Expression pattern analysis revealed that S3-RNase and S4-RNase are specifically expressed in the pistils, and spatiotemporal expression analysis showed that the S3-RNase expression levels in the stigmas, styles and ovaries were significantly higher after self-pollination than after cross-pollination. Subcellular localisation analysis showed that the S1-RNase, S2-RNase, S3-RNase and S4-RNase were found to be expressed in the nucleus according to laser confocal microscopy. In addition, yeast two-hybrid (Y2H) assays showed that S3-RNase interacted with F-box, Bifunctional fucokinase/fucose pyrophosphorylase (FKGP), aspartic proteinase A1, RRP46, pectinesterase/pectinesterase inhibitor 51 (PME51), phospholipid:diacylglycerol acyltransferase 1 (PDAT1), gibberellin receptor GID1B, GDT1-like protein 4, putative invertase inhibitor, tRNA ligase, PAP15, PAE8, TIM14-2, PGIP1 and p24beta2. Moreover, S3-RNase interacted with TOPP4. Therefore, S3-RNase may play an important role in the SI of 'XiangShui' lemon.
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Proteasas de Ácido Aspártico , Citrus , Autoincompatibilidad en las Plantas con Flores , Citrus/metabolismo , Diacilglicerol O-Acetiltransferasa , Endorribonucleasas , Fucosa , Giberelinas , Fosfolípidos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Polen/genética , ARN , ARN Ligasa (ATP) , Ribonucleasas/genética , Ribonucleasas/metabolismo , Autoincompatibilidad en las Plantas con Flores/genética , beta-FructofuranosidasaRESUMEN
OBJECTIVE: To study the clinicopathological features of children with lupus nephritis (LN) with positive anti-neutrophil cytoplasmic antibody (ANCA). METHODS: A retrospective analysis was performed for the children who were diagnosed with LN in the First Affiliated Hospital of Sun Yat-sen University from January 2003 to December 2019. According to the results of serum ANCA, they were divided into two groups: ANCA-positive group (n=59) and ANCAnegative group (n=454). The two groups were compared in terms of clinical manifestations, histopathological features, remission rate, and prognosis. RESULTS: Compared with the ANCA-negative group, the ANCA-positive group had a significant reduction in leukocytes and a significant increase in erythrocyte sedimentation rate (P < 0.05). There were no significant differences between the two groups in serum creatinine, urine protein, and urine red blood cell count (P > 0.05). A total of 308 children underwent kidney biopsy. The results on light microscopy showed that compared with the ANCAnegative group, the ANCA-positive group had a significantly higher proportion of children with cellular fibrous crescents (P < 0.05) and a significantly lower proportion of children with immune complex deposition (P < 0.05). There were no significant differences between the two groups in the remission rate and survival rate (P > 0.05). CONCLUSIONS: Children with ANCA-positive LN tend to have more severe renal pathological injury, which is not exactly parallel with clinical manifestations, suggesting that timely renal biopsy is of great importance.
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Anticuerpos Anticitoplasma de Neutrófilos , Nefritis Lúpica , Niño , Creatinina , Humanos , Riñón , Estudios RetrospectivosRESUMEN
Cytomegalovirus (CMV) is a major pathogen in immunocompromised population and CMV infections in immunocompromised patients cause substantial morbidity and mortality. The common clinical manifestations of CMV infection are pneumonia, hepatitis, colitis and so on, while CMV peritonitis without gut perforation is rare. Reviewing the literature, CMV peritonitis in patients with nephrotic syndrome (NS) had not been reported. Only four cases of CMV peritonitis without gut perforation were reported in adults with other diseases. Two cases were diagnosed by reverse-transcription polymerase chain reaction (RT-PCR) of ascites while the other two cases by histopathological examination of peritoneal tissue. We report four cases of primary nephrotic syndrome complicated with CMV peritonitis. Four cases all diagnosed by RT-PCR of ascites (659-455 000 copies/mL). We mainly discusses the diagnosis and treatment of CMV peritonitis without gut perforation.
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Infecciones por Citomegalovirus/diagnóstico , Citomegalovirus/genética , ADN Viral/aislamiento & purificación , Síndrome Nefrótico/patología , Peritonitis/diagnóstico , Adolescente , Niño , Preescolar , Citomegalovirus/aislamiento & purificación , Diagnóstico Precoz , Femenino , Humanos , Huésped Inmunocomprometido , Masculino , Síndrome Nefrótico/complicaciones , Peritonitis/virología , Radiografía Torácica , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The aim of this study was to report aseptic, erosive polyarthritis in a patient with common variable immunodeficiency (CVID), which is quite different from the vastly more common nonerosive form. Peripheral blood mononuclear cells of the patient were isolated. Flow cytometry was used to analyze the proportion and function of lymphocytes. A Parker-Pearson needle biopsy was performed on the right knee. Four of her unaffected family members were enrolled as controls. A 21-year-old woman was admitted for recurrent polyarthritis of 3-year duration. The right knee, hip, wrist, proximal interphalangeal joints, and left elbow were involved, with progressive joint destruction. She was diagnosed as having CVID based on her recurrent infections, poor response to vaccines, and marked hypogammaglobulinemia. No bacterium or mycobacterium was detected in synovium or synovial fluid. The synovium was infiltrated by lymphocytes rather than neutrophils. Polyarthritis did not resolve by adequate intravenous immunoglobulin substitution and empirical antibiotic treatment, but resolved gradually after treatment with methylprednisolone and tacrolimus, supporting the diagnosis of aseptic polyarthritis. Further analyses showed that although only 0.5% of residual B lymphocytes were existent in peripheral blood of the patient, expressions of activation marker CD69 and production of IL-1ß, IL-6, and TNF-α were high. Marked infiltration with CD19+B lymphocytes (as well as CD4+ or CD8+ T lymphocytes) was detected in the synovium. The proportion of IL21+CD4+Th cells from peripheral blood of the patient was high. CD4+ Th cells from the patient secreted nearly 3 times more IL-21 than the same cell type analyzed from unaffected family members, perhaps due to excessive compensation to assist the function of residual B lymphocytes. A novel hypothesis in CVID concurrent with aseptic, erosive polyarthritis is that excessive activation of residual B lymphocytes infiltrate into the synovium of the involved joints and lead to polyarthritis and joint destruction.
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Artritis/metabolismo , Artritis/fisiopatología , Linfocitos B/inmunología , Adulto , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , China , Inmunodeficiencia Variable Común/complicaciones , Citocinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Interleucina-2/metabolismo , Leucocitos Mononucleares/metabolismo , Activación de Linfocitos/inmunología , Masculino , Adulto JovenRESUMEN
Hepatitis B virus (HBV) reactivation is a well-recognized complication in patients who undergo immunosuppressive drug therapy. Although the recommendation of antiviral prophylaxis made by the American Gastroenterological Association in 2015 focuses on the risk stratification of different immunosuppressive drugs, risk factors for HBV reactivation are also worth identifying in clinical practice. Recent studies have shown that the uncommon serological pattern of coexistent circulating HBV surface antigen (HBsAg) and its antibody (anti-HBs) was associated with double mutations (A1762T/G1764A) in the basal core promoter (BCP) region of the HBV genome, which is critical for HBV replication. Here, we depicted rheumatoid arthritis (RA) patients with coexistent HBsAg and anti-HBs in our medical center, who developed HBV reactivation during immunosuppressive drug therapy. DNA sequencing analysis of the HBV genome revealed triple mutations (A1762T, G1764A, and T1753V) in the BCP region, which could further enhance the ability of HBV replication. Hence, a novel hypothesis is advanced for the first time that patients with coexistent HBsAg and anti-HBs may have a strong predisposition to HBV reactivation due to specific BCP mutations. This hypothesis would, if correct, justify the concurrent detection of HBsAg and anti-HBs in HBV screening in patients with rheumatic diseases and quickly recognize patients with high risk of HBV reactivation. Further controlled studies are needed to confirm this hypothesis.
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Anticuerpos contra la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/análisis , Antígenos de Superficie de la Hepatitis B/inmunología , Antivirales/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Secuencia de Bases/genética , Femenino , Predisposición Genética a la Enfermedad , Hepatitis B/virología , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Hepatitis B Crónica/virología , Humanos , Terapia de Inmunosupresión , Inmunosupresores/uso terapéutico , Inmunoterapia/métodos , Masculino , Mutación , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genéticaRESUMEN
BACKGROUND: Self-care is critical for postdischarge heart failure (HF) patients. Short message service (SMS) is a promising way to promote HF self-care. OBJECTIVE: The aim of this study is to investigate knowledge status in Chinese HF patients, as well as the acceptance of SMS as a way to improve self-care. METHODS: A survey using a self-developed questionnaire was conducted in patients with decompensated HF 2 days before discharge. RESULTS: A total of 540 patients completed the survey. Among them, only 69.8% and 63.3% of patients were aware of their HF status and medication regimen, respectively. A total of 95.6% patients were willing to receive SMS. Patient himself/herself, caregiver, or both patient and caregiver were almost equally selected as the preferred receiver of SMS. Educational and/or reminder SMS was considered "very helpful" by 50.2% of the patients as a way of promoting self-care, similar to that of telephone education and brochure education. "Take your medicine", "avoid getting flu," and "keep follow-up" were regarded as the most important self-care contents, whereas "weigh yourself every day" and "restrict fluid intake" were considered the least important. CONCLUSION: As a way of promoting HF self-care, SMS intervention combining educational and reminder function might be well accepted by HF patients in China. The status of HF, medication, weight control, and fluid restriction should be emphasized during the practice. Caution should be drawn as the survey was not tested elsewhere. Further clinical trials would be conducted to examine the effect of SMS intervention on self-care behaviors and outcomes of HF patients.
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Insuficiencia Cardíaca/rehabilitación , Aceptación de la Atención de Salud/estadística & datos numéricos , Cooperación del Paciente/estadística & datos numéricos , Envío de Mensajes de Texto/estadística & datos numéricos , Anciano , China , Femenino , Insuficiencia Cardíaca/psicología , Humanos , Masculino , Persona de Mediana Edad , Aceptación de la Atención de Salud/psicología , Cooperación del Paciente/psicología , Sistemas Recordatorios/estadística & datos numéricos , Autocuidado/métodosRESUMEN
Two new biflavonone compounds, sikokianin D (1) and sikokianin E (2), were isolated from the capitulum of Coreopsis tinctoria. The structures of these compounds were elucidated by spectroscopic techniques including NMR, HRESIMS and circular dichroism (CD).
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Biflavonoides/aislamiento & purificación , Coreopsis/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Biflavonoides/química , Cromatografía Líquida de Alta Presión , Medicamentos Herbarios Chinos/química , Estructura Molecular , Resonancia Magnética Nuclear BiomolecularRESUMEN
OBJECTIVE: To explore the clinical and pathological features and the diagnosis of childhood Alport syndrome (AS). METHODS: A retrospective analysis was performed on clinical data of 91 children with AS. RESULTS: Hematuria was observed in all 91 patients, of whom 86 were accompanied with proteinuria. Sixty-one children with X-Linked AS (XL-AS) had positive family history. Renal biopsy was performed on 82 children. Mild to moderate mesangial proliferation was observed in 74 cases. Small amounts of immune complexes deposits in the glomerular mesangial area were observed in 48 cases. Glomerular basement membrane (GBM) attenuation, thickening and layering were observed in 53 cases by electron microscopy (EM). In 63 cases receiving renal tissue type IV collagen α3 and α5 chain immunofluorescence detection, 58 were diagnosed with AS, including 53 cases of XL-AS and 5 cases of autosomal recessive AS. In 91 cases of AS, 58 were diagnosed as AS by renal tissue type IV collagen α3 and α5 chain immunofluorescence, 21 were diagnosed by EM, one was diagnosed by skin biopsy, and 12 were diagnosed by gene detection. Six novel mutations of COL4A5 gene were found. Forty-five cases were misdiagnosed before the diagnosis of AS. Forty-one of the 45 cases received steroids and/or immunosuppressant therapy. CONCLUSIONS: The clinical manifestations and pathological changes are not specific in children with AS, resulting in a higher rate of misdiagnosis. Typical lesions of GBM under EM are only observed in a part of patients. There is a high novel mutation rate of COL4A5 in the detected AS children.
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Errores Diagnósticos , Nefritis Hereditaria/diagnóstico , Niño , Preescolar , Colágeno Tipo IV/genética , Femenino , Membrana Basal Glomerular/patología , Humanos , Masculino , Nefritis Hereditaria/genética , Nefritis Hereditaria/patología , Estudios RetrospectivosRESUMEN
The product of the Ph chromosome, the BCR-ABL1 tyrosine kinase activates diverse signaling pathways in leukemic cells from patients with chronic myeloid leukemia (CML) and Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Previous studies showed that nuclear factor κB (NF-κB) is activated in BCR-ABL1-expressing cells, but the mechanism of activation and importance of NF-κB to the pathogenesis of BCR-ABL1-positive myeloid and lymphoid leukemias are unknown. Coexpression of BCR-ABL1 and a superrepressor mutant of inhibitory NF-κB α (IκBαSR) blocked nuclear p65/RelA expression and inhibited the proliferation of Ba/F3 cells and primary BCR-ABL1-transformed B lymphoblasts without affecting cell survival. In retroviral mouse models of CML and B-ALL, coexpression of IκBαSR attenuated leukemogenesis, prolonged survival, and reduced myeloid leukemic stem cells. Coexpression of dominant-negative mutants of IκB kinase α (IKKα)/IKK1 or IKKß/IKK2 also inhibited lymphoid and myeloid leukemogenesis by BCR-ABL1. Blockade of NF-κB decreased expression of the NF-κB targets c-MYC and BCL-X and increased the sensitivity of BCR-ABL1-transformed lymphoblasts to ABL1 kinase inhibitors. These results demonstrate that NF-κB is activated through the canonical IKK pathway and plays distinct roles in the pathogenesis of myeloid and lymphoid leukemias induced by BCR-ABL1, validating NF-κB and IKKs as targets for therapy of Ph(+) leukemias.
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Transformación Celular Neoplásica/metabolismo , Quinasa I-kappa B/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , FN-kappa B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Animales , Southern Blotting , Western Blotting , Transformación Celular Neoplásica/genética , Activación Enzimática/fisiología , Técnica del Anticuerpo Fluorescente , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Ratones , Microscopía Confocal , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transducción GenéticaRESUMEN
BACKGROUND: Oxidative stress has been reported to play an important role in children with primary nephrotic syndrome (PNS). However, the results of previous studies are controversial. METHODS: Forty children with steroid-sensitive nephrotic syndrome (SSNS) and 20 age- and sex-matched healthy controls were enrolled. Patients were followed-up for 12-18 months and divided into three subgroups: frequent relapse (n = 10), non-frequent relapse (n = 12), and non-relapse (n = 18). The plasma levels of advanced oxidation protein products (AOPP), malondialdehyde (MDA), and superoxide dismutase (SOD) were tested in controls and patient group at first presentation and after 4 weeks of steroid treatment. RESULTS: Patients had higher AOPP and MDA levels but lower SOD compared with controls. AOPP levels were significantly higher in the frequent relapse subgroup compared with the non-frequent relapse and non-relapse subgroups, respectively. No significant differences were found in the plasma levels of MDA and SOD among the three subgroups. AOPP >87.55 µmol/l before steroid treatment and AOPP >78.5 µmol/l after 4-week steroid treatment were positively correlated with the relapse frequency in patients with SSNS. CONCLUSIONS: Children with SSNS have oxidative stress. The plasma levels of AOPP before and after 4-week steroid treatment may predict whether patients with SSNS will relapse frequently.
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Productos Avanzados de Oxidación de Proteínas/sangre , Síndrome Nefrótico/sangre , Síndrome Nefrótico/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Esteroides/uso terapéutico , Adolescente , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Malondialdehído/sangre , Síndrome Nefrótico/diagnóstico , Valor Predictivo de las Pruebas , Estudios Prospectivos , Recurrencia , Factores de Riesgo , Superóxido Dismutasa/sangre , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIM: The aim of the present study was to investigate the clinicopathologic characteristics of biopsy-proven childhood renal diseases and to compare the trends and changes during two different time intervals between 1984 and 2011 at the First Affiliated Hospital of Sun Yat-sen University in China. METHODS: We retrospectively analyzed kidney biopsy data from children with renal diseases and compared the data during two time intervals, namely 1984-1997 and 1998-2011. RESULTS: A total of 1313 children were enrolled in the present study. There were 921 children with primary glomerular disease (PGD) and 312 children with secondary glomerular disease (SGD), accounting for 70.1% and 23.8% of participants, respectively. The major clinical manifestation of PGD was nephrotic syndrome (NS), which accounted for 31.2% of cases, while the main aetiology of SGD was lupus nephritis (40.7%). The main biopsy patterns of PGD were IgA nephritis (27.6%), minimal change disease (24.0%), and mesangial proliferative glomerulonephritis (16.9%). PGD was the major class of disease in both time intervals, but the ratio of PGD decreased over time, while the ratio of SGD and other glomerular diseases increased. PGD was also the major class of disease in each age group; however, the incidence of PGD decreased with increasing age. CONCLUSION: The incidence patterns of paediatric renal diseases changed over the 28-year period of this study. Our results show that different renal diseases characterize different age intervals. Furthermore, there are several associations between clinical presentation and biopsy features in childhood renal disease.
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Glomerulonefritis por IGA/patología , Glomerulonefritis/patología , Glomérulos Renales/patología , Nefritis Lúpica/patología , Nefrosis Lipoidea/patología , Síndrome Nefrótico/patología , Adolescente , Distribución por Edad , Biopsia , Niño , Preescolar , China/epidemiología , Femenino , Glomerulonefritis/epidemiología , Glomerulonefritis por IGA/epidemiología , Humanos , Incidencia , Lactante , Recién Nacido , Nefritis Lúpica/epidemiología , Masculino , Nefrosis Lipoidea/epidemiología , Síndrome Nefrótico/epidemiología , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Factores de TiempoRESUMEN
The chemokine receptor CXCR4, which normally regulates stromal stem cell interactions in the bone marrow, is highly expressed on a variety of malignant hematologic cells, including lymphoma and lymphocytic leukemias. A new treatment concept has arisen wherein CXCR4 may be an effective therapeutic target as an adjunct to treatment of hematologic neoplasms with chemo- and immunotherapy. In the present study, we developed pepducins, cell-penetrating lipopeptide antagonists of CXCR4, to interdict CXCL12-CXCR4 transmembrane signaling to intracellular G-proteins. We demonstrate that pepducins targeting the first (i1) or third (i3) intracellular loops of CXCR4 completely abrogate CXCL12-mediated cell migration of lymphocytic leukemias and lymphomas. Stromal-cell coculture protects lymphoma cells from apoptosis in response to treatment with the CD20-targeted Ab rituximab. However, combination treatment with CXCR4 pepducins and rituximab significantly increases the apoptotic effect of rituximab. Furthermore, treatment of mice bearing disseminated lymphoma xenografts with pepducins alone or in combination with rituximab significantly increased their survival. These data demonstrate that CXCL12-CXCR4 signaling can be effectively inhibited by cell-penetrating pepducins, which represents a potential new treatment strategy for lymphoid malignancies.
Asunto(s)
Leucemia Linfoide/tratamiento farmacológico , Lipopéptidos/uso terapéutico , Linfoma/tratamiento farmacológico , Receptores CXCR4/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Subunidad gamma Común de Receptores de Interleucina/genética , Leucemia Linfoide/metabolismo , Leucemia Linfoide/patología , Lipopéptidos/administración & dosificación , Lipopéptidos/síntesis química , Lipopéptidos/química , Linfoma/metabolismo , Linfoma/patología , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Modelos Moleculares , Terapia Molecular Dirigida , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVES: To explore the correlation of serum IgG4 (sIgG4) with clinical manifestations or therapeutic response in rheumatoid arthritis (RA). METHODS: Consecutive 136 RA patients were recruited and followed up at regular interval. SIgG4 was detected by immunonephelometry. Serial synovial tissue sections from 46 RA patients were stained immunohistochemically for IgG4. RESULTS: Forty-six percent of 136 RA patients had elevated sIgG4. Patients with elevated sIgG4 had higher sIgG4/sIgG ratio, C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and anticyclic citrullinated peptide antibodies than those with normal sIgG4 (all P < 0.05). Among 45 patients who received methotrexate and leflunomide therapy, 50% (9/18) of patients with elevated sIgG4 and 85% (23/27) of patients with normal sIgG4 reached therapeutic target (disease activity score of 28 joints < 3.2) at 6-month visit (χ(2) = 6.508, P = 0.011). IgG4-positive plasma cell count correlated positively with sIgG4, total synovitis score, and CD3-, CD20-, and CD38-positive cell counts (all P < 0.05). CONCLUSIONS: Our results showed that elevated sIgG4 in RA is common and disproportional to total IgG and RA with elevated sIgG4 may be a specific clinical phenotype with higher disease activity, higher level of autoantibodies, and poor response to methotrexate and leflunomide therapy.
Asunto(s)
Artritis Reumatoide/sangre , Inmunoglobulina G/sangre , ADP-Ribosil Ciclasa 1/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD20/metabolismo , Autoanticuerpos/sangre , Biopsia , Sedimentación Sanguínea , Proteína C-Reactiva/metabolismo , Complejo CD3/metabolismo , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Péptidos Cíclicos/sangre , Fenotipo , Factor Reumatoide/sangre , Líquido Sinovial/metabolismo , Sinovitis/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: To explore the correlation between matrix metalloproteinase- (MMP-) 3 and histological synovitis in rheumatoid arthritis (RA). METHODS: Serum MMP-3 of 62 patients with active RA was detected by ELISA. Serial synovial tissue sections from all RA patients, 13 osteoarthritis, and 10 orthopedic arthropathies patients were stained with hematoxylin and eosin and immunohistochemically for MMP-3, CD3, CD20, CD38, CD68, and CD15. RESULTS: The percentage of lining MMP3+ cells was significantly higher in RA patients especially with high grade synovitis and it was significantly correlated with Krenn's synovitis score (r = 0.574, P < 0.001) and sublining inflammatory cells. Multivariate stepwise linear regression analysis revealed that the association of the percentage of lining MMP3+ cells with activation of synovial stroma, sublining CD68+ macrophages, and CD15+ neutrophils was stronger than other histological indicators. The percentage of lining MMP3+ cells was significantly correlated with serum MMP-3 in RA (r = 0.656, P < 0.001). Serum MMP-3 was higher in RA patients with high grade synovitis than that of low grade synovitis and significantly correlated with synovitis score and activation of synovial stroma subscore (all P < 0.05). CONCLUSION: Serum MMP-3 may be an alternative noninvasive biomarker of histological synovitis and RA diagnosis.