ABSTRACT
Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.
Subject(s)
Brain Neoplasms , Glioma , Humans , Glioma/genetics , Glioma/pathology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Genomics , Genetic Predisposition to Disease , Whole Genome Sequencing , Calcium-Binding Proteins/genetics , DNA-Binding Proteins/genetics , Tumor Suppressor Proteins/geneticsSubject(s)
Psychometrics , Resilience, Psychological , Child , Humans , China , Reproducibility of Results , Surveys and Questionnaires , LanguageABSTRACT
BACKGROUND: Polypharmacy, frailty and malnutrition are known predictors of adverse outcomes in dialysis patients. Little has reported about their interaction and composite prognostic values. We aimed to describe the interaction between polypharmacy, frailty, nutrition, hospitalization, and survival in peritoneal dialysis patients. METHODS: In this prospective cohort study, we recruited 573 peritoneal dialysis patients. Drug burden was measured by medication number and daily pill load. Frailty and nutrition were assessed by the validated Frailty Score (FQ) and Subjective Global Assessment (SGA) respectively. All patients were followed for two years. Primary outcome was all-cause mortality. Secondary outcomes were fall and fracture episodes, hospitalization, change in FQ and SGA. RESULTS: At baseline, each patient took 7.5 ± 2.6 medications with 15.5 ± 8.5 tablets per day. Medication number, but not daily pill load predicted baseline FQ (p = 0.004) and SGA (p = 0.03). Over 2 years, there were 69 fall and 1,606 hospitalization episodes. In addition, 148 (25.8%) patients died, while FQ and SGA changed by 0.73 ± 4.23 and -0.07 ± 1.06 respectively in survivors. Medication number (hospitalization: p = 0.02, survival: p = 0.005), FQ (hospitalization: p < 0.001; survival: p = 0.01) predicted hospitalization and survival. Medication number also predicted fall episodes (p = 0.02) and frailty progression (p = 0.002). Daily pill load did not predict any of these outcomes. CONCLUSIONS: Drug burden is high in peritoneal dialysis patients, and it carries important prognostic implication. Medication number but not pill load significantly predicted onset and progression of frailty, malnutrition, fall, hospitalization, and mortality.
Subject(s)
Frailty , Malnutrition , Peritoneal Dialysis , Humans , Frailty/complications , Polypharmacy , Prospective Studies , Peritoneal Dialysis/adverse effects , Malnutrition/etiology , Malnutrition/complicationsSubject(s)
Anemia , Neutropenia , Child , Humans , Copper , Neutropenia/etiology , Anemia/etiology , JejunumSubject(s)
Lung Neoplasms , Pulmonary Blastoma , Child , Hong Kong , Humans , Lung Neoplasms/genetics , Pulmonary Blastoma/geneticsABSTRACT
BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis. METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK. RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing. CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.
Subject(s)
Bronchiectasis , Ciliary Motility Disorders , Ciliopathies , Kartagener Syndrome , Humans , Mutation , Bronchiectasis/diagnosis , Bronchiectasis/genetics , Cilia , Ciliary Motility Disorders/diagnosis , Ciliary Motility Disorders/genetics , Ciliopathies/complications , Kartagener Syndrome/diagnosis , Kartagener Syndrome/geneticsSubject(s)
COVID-19 , SARS-CoV-2 , COVID-19/complications , Child , Humans , Systemic Inflammatory Response Syndrome/diagnosisABSTRACT
BACKGROUND: Mycophenolate has been shown to be effective in glomerular disease. However, the role of mycophenolate in the first-line treatment of adult-onset idiopathic minimal change disease (MCD) has not been systematically studied in a randomized fashion. AIM: To evaluate the therapeutic efficacy of enteric-coated mycophenolate sodium combined with low-dose corticosteroid as first-line treatment for MCNS. DESIGN: A prospective, open-label, randomized clinical trial. METHODS: Twenty adult patients with biopsy proven MCD were recruited and randomly assigned to receive either enteric-coated Mycophenolate Sodium (EC-MPS) plus low-dose prednisolone (Group 1: Prednisolone 0.25 mg/kg/day, n = 10) or standard-dose prednisolone (Group 2: Prednisolone 1 mg/kg/day, n = 10). RESULTS: After 24 weeks of therapy, eight patients in Group 1 vs. seven of patients in Group 2 achieved complete remission (P = 0.606). Both groups showed a significant reduction of urine protein excretion (P < 0.05) and increased serum albumin (P < 0.001) vs. baseline levels. However, no significant between-group differences were demonstrated. The relapse rate was also similar in both groups. Both treatment regimens were well tolerated but there were more patient reported adverse effects in the standard-dose prednisolone group. CONCLUSION: EC-MPS plus low-dose prednisolone is non-inferior to standard-dose prednisolone therapy in inducing clinical remission and preventing relapse in adult-onset idiopathic MCD and is associated with better tolerability and less adverse effects. This trial is registered with the ClinicalTrials.gov number NCT01185197.
Subject(s)
Immunosuppressive Agents/administration & dosage , Mycophenolic Acid/administration & dosage , Nephrosis, Lipoid/drug therapy , Prednisolone/administration & dosage , Adolescent , Adult , Aged , Dose-Response Relationship, Drug , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/methods , Female , Hong Kong , Humans , Immunosuppressive Agents/adverse effects , Male , Middle Aged , Mycophenolic Acid/adverse effects , Nephrosis, Lipoid/immunology , Prednisolone/adverse effects , Prospective Studies , Recurrence , Remission Induction/methods , Treatment Outcome , Young AdultSubject(s)
Cancer Survivors , Exercise/physiology , Health Education/methods , Health Promotion , Adolescent , Child , Female , Humans , Male , Quality of Life , Single-Blind MethodABSTRACT
Proinflammatory cytokines such as TNF-α and type I interferons (IFN) are pathogenic signatures of systemic lupus erythematosus, and plasmacytoid dendritic cells (pDCs) play a major role by predominantly producing IFN-α. Given the rise of importance in identifying tumor necrosis stimulated gene 6 (TSG-6) as a key anti-inflammatory regulator, we investigate its function and its ability to counteract proinflammatory cytokine secretion by pDCs in vitro. CpG-A and R837 induced significant endogenous TSG-6 expression in the pDC cell-line GEN2.2. Following recombinant human TSG-6 treatment and CpG-A or R837 stimulation, significant reduction in IFN-α and TNF-α was observed in healthy donors' pDCs, and the same phenomenon was confirmed in GEN2.2. By CD44 blocking assay, we deduced that the suppressive effect of TSG-6 is mediated by CD44, by reducing IRF-7 phosphorylation. Our findings suggest that TSG-6 and its downstream signalling pathway could potentially be targeted to modulate proinflammatory cytokine expression in pDCs.
Subject(s)
Cell Adhesion Molecules/pharmacology , Dendritic Cells/metabolism , Interferon-alpha/metabolism , Tumor Necrosis Factor-alpha/metabolism , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Interferon Regulatory Factor-7 , Phosphorylation/drug effects , Real-Time Polymerase Chain Reaction , Signal Transduction/drug effectsABSTRACT
Congenital factor VII (FVII) deficiency is the commonest type of the rare bleeding disorders. Very few cases of congenital FVII deficiency developed inhibitor and liver transplant is considered as definitive treatment. In the literature, twelve patients with congenital FVII deficiency developed inhibitors. Two had spontaneous resolution of inhibitors and one did not respond to high dose recombinant factor VIIa (rFVIIa) and died. Regarding liver transplant in congenital FVII patients, seven patients underwent liver transplant with good prognosis. We report a 5-year-old girl with confirmed severe congenital FVII deficiency since neonatal period. She suffered from recurrent intracranial bleeding despite rFVIIa replacement. After auxiliary liver transplant at the age of 4, she continued to show persistent deranged clotting profile and was found to have inhibitor towards FVII. Interestingly, she was still responsive to rFVIIa replacement.
Subject(s)
Factor VII Deficiency/therapy , Factor VII/therapeutic use , Intracranial Hemorrhages/prevention & control , Liver Transplantation , Recombinant Proteins/therapeutic use , Child, Preschool , Factor VII Deficiency/complications , Female , Humans , Infant , Infant, Newborn , Intracranial Hemorrhages/etiologyABSTRACT
A 7-year-old male with Stage 4 neuroblastoma was treated with chemotherapy and autologous hematopoietic stem cell transplantation (HSCT), resulting in partial response with residual bone and marrow disease. He proceeded to haploidentical-HSCT with his mother as donor and achieved remission. The patient developed marrow relapse 2 years after haploidentical-HSCT with cytopenia and dropping donor chimerism. Donor lymphocyte infusion (DLI) using mother's whole blood was given resulting in clearance of marrow disease, resolution of cytopenia, and full donor chimerism. This is the first report of successful treatment for neuroblastoma relapse after haploidentical-HSCT using DLI alone, supporting the role of adoptive cell therapy post-HSCT in neuroblastoma.
Subject(s)
Antineoplastic Agents/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Immunotherapy, Adoptive/methods , Neoplasm Recurrence, Local/therapy , Neuroblastoma/therapy , Child , Humans , Male , Transplantation, HomologousABSTRACT
Renal transplant recipients (RTRs) are subject to a variety of opportunistic infections. We present a rare case of varicella zoster virus-derived progressive outer retinal necrosis in an RTR, who presented with painless visual blurring. This clinical entity heralds an extremely poor visual prognosis and is an important condition to consider in any immunocompromised host. Early diagnosis by aqueous fluid sampling and immediate institution of combined systemic and intravitreal antiviral therapy was successful in this individual.
Subject(s)
Antiviral Agents/therapeutic use , Ganciclovir/therapeutic use , Herpesvirus 3, Human/isolation & purification , Kidney Transplantation/adverse effects , Retinitis/diagnosis , Female , Humans , Immunocompromised Host , Intravitreal Injections , Middle Aged , Necrosis , Retinitis/drug therapy , Retinitis/virologyABSTRACT
BACKGROUND: The incidence of diabetes mellitus is ever increasing. Individuals with diabetes mellitus may have concurrent mental health disorders and are shown to have poorer disease outcomes. The objectives of this study were to determine the prevalence of depression, anxiety and stress (DAS) in diabetes patients aged 20 years or more in the primary care setting. METHODS: This was a cross-sectional study involving the use of self-administered questionnaire conducted in eight primary care private and government clinics in Pulau Pinang and Melaka, Malaysia. The validated DASS-21 questionnaire was used as a screening tool for the symptoms of DAS. Prior permission was obtained from the patients and, clearance from ethical committee was obtained before the start of the study. Data analysis was done using SPSS statistical software. RESULTS: A total of 320 patients with diabetes from eight centres were enrolled via convenience sampling. Sample size was calculated using the Kish's formula. The prevalence of DAS among patients with diabetes from our study was 26.6%, 40% and 19.4%, respectively. Depression was found to be significantly associated with marital status and family history of DAS; anxiety was significantly associated with monthly household income, presence of co-morbidities and family history of DAS; and stress was significantly associated with occupation and family history of DAS. CONCLUSION: The prevalence of DAS was higher in patients with diabetes compared with the general community. We recommend to routinely screen all patients with diabetes using the DASS-21 questionnaire because it is easy to perform and inexpensive.
ABSTRACT
High cellular heterogeneity within neuroblastomas (NBs) may account for the non-uniform response to treatment. c-KIT(+) cells are frequently detected in NB, but how they influence NB behavior still remains elusive. Here, we used NB tumor-initiating cells to reconstitute NB development and demonstrated that c-KIT(+) cells are de novo generated and dynamically maintained within the tumors to sustain tumor progression. c-KIT(+) NB cells express higher levels of neural crest and stem cell markers (SLUG, SOX2 and NANOG) and are endowed with high clonogenic capacity, differentiation plasticity and are refractory to drugs. With serial transplantation assays, we found that c-KIT expression is not required for tumor formation, but c-KIT(+) cells are more aggressive and can induce tumors ninefold more efficiently than c-KIT(-/low) cells. Intriguingly, c-KIT(+) cells exhibited a long-term in vivo self-renewal capacity to sustain the formation of secondary and tertiary tumors in mice. In addition, we showed that Prokineticin signaling and mitogen-activated protein kinase pathways are crucial for the maintenance of c-KIT(+) cells in tumor to promote NB progression. Our results highlight the importance of this de novo population of NB cells in sustainable growth of NB and reveal specific signaling pathways that may provide targets leading to more effective NB therapies.
Subject(s)
Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Neuroblastoma/pathology , Proto-Oncogene Proteins c-kit/metabolism , Vascular Endothelial Growth Factor, Endocrine-Gland-Derived/physiology , Animals , Cell Proliferation , Disease Progression , Gene Knockdown Techniques , Humans , Male , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Invasiveness , Neuroblastoma/genetics , Neuroblastoma/metabolism , Proto-Oncogene Proteins c-kit/genetics , Signal Transduction , Tumor Cells, CulturedABSTRACT
BACKGROUND AND PURPOSE: Patients with ß-thalassemia require blood transfusion to prolong their survival, which could cause iron overload in multiple organs, including the heart, liver, and brain. In this study, we aimed to quantify iron loading in the brains of patients with ß-thalassemia major through the use of MR quantitative susceptibility imaging. MATERIALS AND METHODS: Thirty-one patients with thalassemia with a mean (± standard deviation) age of 25.3 (±5.9) years and 33 age-matched healthy volunteers were recruited and underwent MR imaging at 3T. Quantitative susceptibility images were reconstructed from a 3D gradient-echo sequence. Susceptibility values were measured in the caudate nucleus, putamen, globus pallidus, red nucleus, substantia nigra, dentate nucleus, and choroid plexus. General linear model analyses were performed to compare susceptibility values of different ROIs between the patients with thalassemia and healthy volunteers. RESULTS: Of the 31 patients, 27 (87.1%) had abnormal iron deposition in one of the ROIs examined. Significant positive age effect on susceptibility value was found in the putamen, dentate nucleus, substantia nigra, and red nucleus (P = .002, P = .017, P = .044, and P = .014, respectively) in the control subjects. Compared with healthy control subjects, patients with thalassemia showed significantly lower susceptibility value in the globus pallidus (P < .001) and substantia nigra (P = .003) and significantly higher susceptibility value in the red nucleus (P = .021) and choroid plexus (P < .001). CONCLUSIONS: A wide range of abnormal susceptibility values, indicating iron overloading or low iron content, was found in patients with thalassemia. MR susceptibility imaging is a sensitive method for quantifying iron concentration in the brain and can be used as a potentially valuable tool for brain iron assessment.