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Archives of Pathology & Laboratory... Apr 2024Rare thalassemia subtypes are often undiagnosed because conventional testing methods can only identify 23 common types of α- and β-thalassemia.
CONTEXT.—
Rare thalassemia subtypes are often undiagnosed because conventional testing methods can only identify 23 common types of α- and β-thalassemia.
OBJECTIVE.—
To assess a comprehensive approach for the screening and diagnosis of rare thalassemia.
DESIGN.—
The study cohort included 72 individuals with suspected rare thalassemia variants. Screening was conducted by next-generation sequencing (NGS) combined with third-generation sequencing (TGS) and chromosomal microarray analysis (CMA)/copy number variation sequencing.
RESULTS.—
Of the 72 individuals with suspected rare thalassemia, 49 had rare α- or β-gene variants. NGS combined with gap polymerase chain reaction detected a total of 42 cases, resulting in a positive detection rate of 58.3%. Additionally, 4 α-globin genetic deletions were identified by TGS, which increased the variant detection rate by 5.6%. Two samples with a microdeletion of chromosome 16 or 11 were detected by CMA, which increased the detection rate by 2.8%. For one sample, reanalysis of the NGS and TGS data confirmed the presence of the β41-42/βN and βN/βN mosaic. The HBB:c.315 + 2delT mutation was initially reported in Guangdong Province, China. Two HBB gene mutations (HBB:c.315 + 5G>C and HBB:c.295G>A) and 4 rare HBA gene deletions (-11.1, -α27.6, -α2.4, and -α21.9) were initially identified in the Zhonshan region. The hematologic phenotypes of all rare cases in this study were clarified.
CONCLUSIONS.—
Rare thalassemia variants are more common than previously thought. Despite advancements in TGS, there is still no foolproof method for detection of all types of thalassemia. Thus, a comprehensive approach is necessary for accurate screening and diagnosis of rare thalassemia variants.
PubMed: 38649152
DOI: 10.5858/arpa.2023-0382-OA -
Cureus Mar 2024Glioblastoma and astrocytoma, grade 4, are the most common and aggressive brain tumors. Several biomarkers, such as the isocitrate dehydrogenase mutation (IDH-1),...
INTRODUCTION
Glioblastoma and astrocytoma, grade 4, are the most common and aggressive brain tumors. Several biomarkers, such as the isocitrate dehydrogenase mutation (IDH-1), alpha-thalassemia/mental retardation, and the X-linked mutation (ATRX), enable more accurate glioma classification and facilitate patient management. This study aimed to determine the prognostic value of clinical and molecular factors (IDH, TP53, and ATRX mutations). We also studied the relationship between these molecular markers and the overall survival (OS) of 126 patients with grade 4 glioblastoma/astrocytoma.
METHODS
The immunohistochemical study was conducted using antibodies namely, IDH1, R132H, p53, and ATRX. Statistical tests were used to investigate factors that might influence overall survival using IBM SPSS Statistics, version 25.0 (IBM Corp., Armonk, NY).
RESULTS
The median age at diagnosis was 51.5 years. Patients with a Karnofsky performance score (KPS) <70 presented less favorable survival outcomes compared to those with a KPS ≥70. The median OS for patients was found to be 11.17 months. Expression of IDH1 R132H was found in 13.5% of patients, p53 overexpression was identified in 55.6% of cases, and loss of ATRX expression was detected in 11.9%. The group of patients with IDH mutant/ATRX mutant/p53 wild-type had the best prognosis (OS = 27.393 months; p = 0.015). Our results were in line with previous studies.
CONCLUSION
The clinical value of IDH and ATRX mutations in prognostic assessment was confirmed (p ≤0.05). The overexpression of p53 had no significant impact on OS (p = 0.726). Therefore, p53 alone cannot predict survival in glioblastoma patients. Based on the results, these biomarkers may be a potential therapeutic target to prolong patient survival, hence the need for further investigations.
PubMed: 38633919
DOI: 10.7759/cureus.56361 -
Scientific Reports Apr 2024To assess the diagnostic performance of three cardiothoracic (CT) ratio techniques, including diameter, circumference, and area, for predicting hemoglobin (Hb) Bart's...
To assess the diagnostic performance of three cardiothoracic (CT) ratio techniques, including diameter, circumference, and area, for predicting hemoglobin (Hb) Bart's disease between 17 and 22 weeks' gestation, and to create a multivariable scoring system using multiple ultrasound markers. Before invasive testing, three CT ratio techniques and other ultrasound markers were obtained in 151 singleton pregnancies at risk of Hb Bart's disease. CT diameter ratio demonstrated the highest sensitivity among the other techniques. Significant predictors included CT diameter ratio > 0.5, middle cerebral artery-peak systolic velocity (MCA-PSV) > 1.5 multiples of the median, and placental thickness > 3 cm. MCA-PSV exhibited the highest sensitivity (97.8%) in predicting affected fetuses. A multivariable scoring achieved excellent sensitivity (100%) and specificity (84.9%) for disease prediction. CT diameter ratio exhibited slightly outperforming the other techniques. Increased MCA-PSV was the most valuable ultrasound marker. Multivariable scoring surpassed single-parameter analysis in predictive capabilities.
Topics: Pregnancy; Female; Humans; Hydrops Fetalis; Placenta; Ultrasonography, Prenatal; Hemoglobins, Abnormal; alpha-Thalassemia; Biomarkers
PubMed: 38632453
DOI: 10.1038/s41598-024-59719-8 -
PloS One 2024Oxidative damage to erythroid cells plays a key role in the pathogenesis of thalassemia. The oxidative stress in thalassemia is potentiated by heme, nonheme iron, and...
Oxidative damage to erythroid cells plays a key role in the pathogenesis of thalassemia. The oxidative stress in thalassemia is potentiated by heme, nonheme iron, and free iron produced by the Fenton reaction, due to degradation of the unstable hemoglobin and iron overload. In addition, the levels of antioxidant enzymes and molecules are significantly decreased in erythrocytes in α- and β-thalassemia. The control of oxidative stress in red blood cells (RBCs) is known to be mediated by microRNAs (miRNAs). In erythroid cells, microR-214 (miR-214) has been reported to respond to external oxidative stress. However, the molecular mechanisms underlying this phenomenon remain unclear, especially during thalassemic erythropoiesis. In the present study, to further understand how miR-214 aggravates oxidative stress in thalassemia erythroid cells, we investigated the molecular mechanism of miR-214 and its regulation of the oxidative status in thalassemia erythrocytes. We have reported a biphasic expression of miR-214 in β- and α-thalassemia. In the present study the effect of miR-214 expression was investigated by using miR -inhibitor and -mimic transfection in erythroid cell lines induced by hemin. Our study showed a biphasic expression of miR-214 in β- and α-thalassemia. Subsequently, we examined the effect of miR-214 on erythroid differentiation in thalassemia. Our study reveals the loss-of-function of miR-214 during translational activation of activating transcription factor 4 mRNA, leading to decreased reactive oxygen species levels and increased glutathione levels in thalassemia erythroid cell. Our results suggest that the expression of activating transcription factor 4 regulated by miR-214 is important for oxidative stress modulation in thalassemic erythroid cells. Our findings can help to better understand the molecular mechanism of miRNA and transcription factors in regulation of oxidative status in erythroid cells, particularly in thalassemia, and could be useful for managing and relieving severe anemia symptoms in patients in the future.
Topics: Humans; alpha-Thalassemia; Activating Transcription Factor 4; Oxidative Stress; Erythroid Cells; beta-Thalassemia; MicroRNAs; Iron
PubMed: 38625890
DOI: 10.1371/journal.pone.0300958 -
IScience May 2024ATR-X (alpha thalassemia, mental retardation, X-linked) syndrome features genital and testicular abnormalities including atypical genitalia and small testes with few...
ATR-X (alpha thalassemia, mental retardation, X-linked) syndrome features genital and testicular abnormalities including atypical genitalia and small testes with few seminiferous tubules. Our mouse model recapitulated the testicular defects when was deleted in Sertoli cells (ScKO) which displayed G2/M arrest and apoptosis. Here, we investigated the mechanisms underlying these defects. In control mice, Sertoli cells contain a single novel "GATA4 PML nuclear body (NB)" that contained the transcription factor GATA4, ATRX, DAXX, HP1α, and PH3 and co-localized with the Y chromosome short arm (Yp). ScKO mice contain single giant GATA4 PML-NBs with frequent DNA double-strand breaks (DSBs) in G2/M-arrested apoptotic Sertoli cells. HP1α and PH3 were absent from giant GATA4 PML-NBs indicating a failure in heterochromatin formation and chromosome condensation. Our data suggest that ATRX protects a Yp region from DNA damage, thereby preventing Sertoli cell death. We discuss Y chromosome damage/decondensation as a mechanism for testicular failure.
PubMed: 38616920
DOI: 10.1016/j.isci.2024.109629 -
Annals of Medicine Dec 2024Thalassemia is the most prevalent hereditary anaemia worldwide. Severe forms of thalassemia can lead to reduced life expectancy due to disease-related complications.
BACKGROUND
Thalassemia is the most prevalent hereditary anaemia worldwide. Severe forms of thalassemia can lead to reduced life expectancy due to disease-related complications.
OBJECTIVES
To investigate the survival of thalassemia patients across varying disease severity, causes of death and related clinical factors.
PATIENTS AND METHODS
We conducted a retrospective review of thalassemia patients who received medical care at Chiang Mai University Hospital. The analysis focused on survival outcomes, and potential associations between clinical factors and patient survival.
RESULTS
A total of 789 patients were included in our study cohort. Among them, 38.1% had Hb H disease, 35.4% had Hb E/beta-thalassemia and 26.5% had beta-thalassemia major. Half of the patients (50.1%) required regular transfusions. Sixty-five patients (8.2%) had deceased. The predominant causes of mortality were infection-related (36.9%) and cardiac complications (27.7%). Transfusion-dependent thalassemia (TDT) (adjusted HR 3.68, 95% CI 1.39-9.72, 0.008) and a mean serum ferritin level ≥3000 ng/mL (adjusted HR 4.18, 95% CI 2.20-7.92, < 0.001) were independently associated with poorer survival.
CONCLUSIONS
Our study highlights the primary contributors to mortality in patients with thalassemia as infection-related issues and cardiac complications. It also underscores the significant impact of TDT and elevated serum ferritin levels on the survival of thalassemia patients.
Topics: Humans; beta-Thalassemia; Thailand; Cause of Death; Thalassemia; Risk Factors; Heart Diseases; Iron Overload
PubMed: 38604224
DOI: 10.1080/07853890.2024.2338246 -
Advanced Science (Weinheim,... Jun 2024FOXG1 syndrome is a developmental encephalopathy caused by FOXG1 (Forkhead box G1) mutations, resulting in high phenotypic variability. However, the upstream...
FOXG1 syndrome is a developmental encephalopathy caused by FOXG1 (Forkhead box G1) mutations, resulting in high phenotypic variability. However, the upstream transcriptional regulation of Foxg1 expression remains unclear. This report demonstrates that both deficiency and overexpression of Men1 (protein: menin, a pathogenic gene of MEN1 syndrome known as multiple endocrine neoplasia type 1) lead to autism-like behaviors, such as social defects, increased repetitive behaviors, and cognitive impairments. Multifaceted transcriptome analyses revealed that Foxg1 signaling is predominantly altered in Men1 deficiency mice, through its regulation of the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (Atrx) factor. Atrx recruits menin to bind to the transcriptional start region of Foxg1 and mediates the regulation of Foxg1 expression by H3K4me3 (Trimethylation of histone H3 lysine 4) modification. The deficits observed in menin deficient mice are rescued by the over-expression of Foxg1, leading to normalized spine growth and restoration of hippocampal synaptic plasticity. These findings suggest that menin may have a putative role in the maintenance of Foxg1 expression, highlighting menin signaling as a potential therapeutic target for Foxg1-related encephalopathy.
Topics: Animals; Mice; Nerve Tissue Proteins; Forkhead Transcription Factors; Proto-Oncogene Proteins; Disease Models, Animal; Autistic Disorder; Brain Diseases; Behavior, Animal; Male
PubMed: 38582517
DOI: 10.1002/advs.202307953 -
Acta Medica Indonesiana Jan 2024Osteoporosis is a major problem in transfusion-dependent thalassemia patients (TDT) patients. Osteoprotegerin (OPG) is one of several bone markers that are closely...
BACKGROUND
Osteoporosis is a major problem in transfusion-dependent thalassemia patients (TDT) patients. Osteoprotegerin (OPG) is one of several bone markers that are closely associated with osteoporosis in TDT patients. OPG is a glycoprotein that functions as a feedback receptor for the Receptor Activator of Nuclear Factor kappa B Ligand (RANKL), which is an alpha tumor necrosis factor receptor. One of the causes of decreased bone mass density is iron toxicity, which can be identified by showing elevated transferrin saturation. Bone mass dual X-ray absorptiometry (DEXA) is a gold standard for the diagnosis of osteoporosis, these procedures are not commonly available in Indonesia. This study was conducted to analyze the correlation between serum levels of OPG and transferrin saturation in TDT patients.
METHODS
A correlational study with a cross-sectional approach analyzed data from TDT patients at Hemato-Oncology Medic Outpatient Clinic, Hasan Sadikin General Hospital, Bandung, Indonesia. Primary data were obtained through blood sampling and anthropometry measurement while secondary data were obtained from the patient's medical records. OPG and transferrin saturation levels were assessed using the ELISA method. Research data were analyzed using the rank Spearman correlation test.
RESULTS
Data were collected from 51 research subjects (30 women dan 21 men). The median OPG level was 380 (170-1230) pg/mL and the median transferrin saturation level was 89.4 (66.7 - 96.2)%. Analysis of correlation showed a significant correlation between and transferrin saturation level with a coefficient value of r -0.539 and p-value <0.001.
CONCLUSION
There was a significant inverse correlation between OPG with transferrin saturation in TDT patients.
Topics: Male; Humans; Female; Osteoprotegerin; Bone Density; Osteoporosis; Thalassemia; Transferrins; RANK Ligand
PubMed: 38561882
DOI: No ID Found -
International Journal of Molecular... Mar 2024In this short review, we presented and discussed studies on the expression of globin genes in β-thalassemia, focusing on the impact of α-globin gene expression and... (Review)
Review
In this short review, we presented and discussed studies on the expression of globin genes in β-thalassemia, focusing on the impact of α-globin gene expression and α-globin modifiers on the phenotype and clinical severity of β-thalassemia. We first discussed the impact of the excess of free α-globin on the phenotype of β-thalassemia. We then reviewed studies focusing on the expression of α-globin-stabilizing protein (AHSP), as a potential strategy of counteracting the effects of the excess of free α-globin on erythroid cells. Alternative processes controlling α-globin excess were also considered, including the activation of autophagy by β-thalassemia erythroid cells. Altogether, the studies reviewed herein are expected to have a potential impact on the management of patients with β-thalassemia and other hemoglobinopathies for which reduction in α-globin excess is clinically beneficial.
Topics: Humans; beta-Thalassemia; alpha-Globins; Hemoglobinopathies; Phenotype; Gene Expression; Blood Proteins; Molecular Chaperones
PubMed: 38542374
DOI: 10.3390/ijms25063400 -
Arquivos Brasileiros de Cardiologia 2024This was a 30-year retrospective cohort study that approximates closely to the natural history of cardiac tumors diagnosed in the fetus, since there was no case of...
BACKGROUND
This was a 30-year retrospective cohort study that approximates closely to the natural history of cardiac tumors diagnosed in the fetus, since there was no case of pregnancy interruption.
OBJECTIVE
To assess morbidity and mortality in the perinatal period and at long term in fetuses diagnosed with cardiac tumor. Our secondary objective was to assess the evaluating factors of perinatal and postnatal results.
METHODS
This was a retrospective cohort study with 74 pregnant women with an echocardiographic diagnosis of fetal cardiac tumor at two referral centers between May 1991 and November 2021. A descriptive analysis was performed, and data were expressed as absolute (n) and relative (%) frequencies, median and interquartile range. Fisher's exact test was used to evaluate the association of echocardiographic characteristics and clinical manifestations with perinatal and postnatal results. Global survival was calculated using the Kaplan-Meier method and the curves were compared by the log-rank test. The time of follow-up, calculated in months, corresponded to the time elapsed from hospital discharge to current status (survived/ censoring or death). The level of significance was set at 5% (p<0.05).
RESULTS
Rhabdomyoma is the most common type of cardiac tumor (85%), with a high morbidity (79.3%) and overall mortality of 17.4%. The presence of fetal hydrops was a predictor of death.
CONCLUSION
The presence of fetal hydrops had an impact on mortality, and hence is an important factor in counselling and determining the prognosis. Most deaths occurred before hospital discharge.
Topics: Pregnancy; Humans; Female; Cohort Studies; Follow-Up Studies; Hydrops Fetalis; Retrospective Studies; Fetus; Heart Neoplasms; Ultrasonography, Prenatal
PubMed: 38536996
DOI: 10.36660/abc.20220469