Polycystic ovary syndrome (PCOS) is a female endocrine disorder with metabolic issues. Hyperandrogenism combined with hyperinsulinemia exacerbates the reproductive, metabolic, and inflammatory ...problems in PCOS patients. The etiology of PCOS is unclear. Patient-specific induced pluripotent stem cells (iPSCs) offer a promising model for studying disease mechanisms and conducting drug screening. Here, we aim to use mesenchymal progenitor cells (MPCs) derived from PCOS iPSCs to explore the mechanism of PCOS. We compared the transcriptome profiles of PCOS and healthy control (HC) iPSC-derived MPCs (iPSCMs). Moreover, we assess the impact of androgens on iPSCMs. In the comparison between PCOS and HC, the expression levels of 1026 genes were significantly different. A gene set enrichment analysis (GSEA) revealed that adipogenesis- and metabolism-related genes were downregulated, whereas inflammation-related genes were upregulated in the PCOS iPSCMs. Dysregulation of the TGF-β1 and Wnt signaling pathways was observed in the PCOS iPSCMs. Furthermore, there was impaired adipogenesis and decreased lipolysis in the PCOS iPSCMs-derived adipocytes. With testosterone treatment, genes related to metabolism were upregulated in the HC iPSCMs but downregulated in the PCOS iPSCMs. The impact of testosterone varied among HCs and PCOS iPSCMs, possibly because of a genetic predisposition toward PCOS. This study found specific signaling pathways that could serve as therapeutic targets for PCOS.
BACKGROUND
ABO subtypes are characterized by the alteration of antigens present and their expression levels on red blood cells and many are linked to genetic changes in the ABO gene. Weakened ...expression of antigens should be identified to prevent transfusion reactions or ABO‐incompatible transplantations. Genotyping can be applied to identify subtypes to complement serologic testing. Next‐generation sequencing (NGS) has shown to provide sensitive and accurate genotyping results as well as valuable cis/trans information. Here we took advantage of NGS and applied it to resolve serology discrepancies in ABO typing.
STUDY DESIGN AND METHODS
In this study, we customized capture probes targeting the entire ABO gene and sequenced on MiSeq Illumina. The subtype‐causing variants were identified, and cis/trans association to ABO alleles was determined. The results from NGS, serology, and Sanger sequencing were compared.
RESULTS
Four control samples typed A, B, O, and AB were correctly genotyped. Of 24 serologically discrepant samples, subtype‐causing variations were found in 20 cases, with two unresolved and two identified as weakening of ABO antibody in reverse. The types of variations include 17 known subtype alleles, one novel variant, one novel large deletion, and one microchimerism. Haplotypes encompassing Exons 6 and 7 of ABO were reconstructed in 17 of the 20 samples.
CONCLUSION
This study demonstrated a full coverage of ABO by capture‐based panel, phasing analysis with NGS in ABO genotyping resolved heterogeneity with novel allele and microchimerism findings. This approach provided a more precise method for subtyping and thereby leading to safer transfusion.
Background and purpose
The NOTCH3 mutation is a common cause of hereditary cerebral small vessel disease (CSVD) and may be a cause of spontaneous intracerebral haemorrhage (ICH). The aim was to ...investigate the clinical/imaging features for identifying the NOTCH3‐mutation‐related ICH.
Methods
The study was based on a cohort of 749 CSVD patients in Taiwan who received next‐generation sequencing of CSVD genes including NOTCH3. Patients with a history of ICH (n = 206) were included for analysis. The CSVD neuroimaging markers were compared between the patients with NOTCH3 and those without known genetic mutations.
Results
After excluding patients with other causes of ICH (structural lesions, systemic/medication related or amyloid angiopathy) and those without neuroimaging, 45 NOTCH3 mutation patients and 109 nongenetic ICH patients were included. The NOTCH3 mutation patients were more likely to have thalamic haemorrhage, a family history of stroke and more severe CSVD neuroimaging markers. A five‐point NOTCH3‐ICH score was constructed and consisted of a history of stroke in siblings, thalamic haemorrhage, any deep nuclei lacunae, any hippocampal cerebral microbleed (CMB) and a thalamic CMB >5 (one point for each). A score ≥2 had a sensitivity of 88.9% and a specificity of 64.2% in identifying the NOTCH3 mutation. The NOTCH3 mutation patients had a higher risk of recurrent stroke (9.1 vs. 4.5 per 100 person‐years, log‐rank p = 0.03) during follow‐up.
Conclusion
The patients with NOTCH3‐mutation‐related ICH had a higher burden of CMBs in the hippocampus/thalamus and a higher recurrent stroke risk. The NOTCH3‐ICH score may assist in identifying genetic causes of ICH.
The NOTCH3‐ICH score consisting of a history of stroke in siblings, thalamic haemorrhage, any deep nuclei lacunae, any hippocampal cerebral microbleed and a thalamic cerebral microbleed >5 (one point for each) can assist in identifying genetic causes of ICH.
Recent genetic progress allows the molecular diagnosis of young‐onset dementia, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). We aimed to identify the mutational and clinical ...spectra of causal genes in a Taiwanese cohort of young‐onset dementia. Ninety‐one patients with young‐onset dementia and 22 age/gender‐matched controls were recruited. Genetic causes were identified by a targeted panel containing 90 causative genes for AD, FTD, and related neurodegenerative disorders. Plasma biomarkers, including total tau, Aβ42, and Aβ40, were assayed. Molecular amyloid and tau PET scans were performed in some patients carrying mutations. Nine of 52 patients (17.3%) with young‐onset AD had mutations: 2 (22.2%), 4 (44.5%), 2 (22.2%), and 1 (11.1%) in APP, PSEN1, PSEN2, and TREM2, respectively. Two of 33 patients (6.1%) with young‐onset FTD had mutations in MAPT and LRRK2. Three of the 6 patients (50.0%) with possible FTD combined with other neurodegenerative disorders had individual mutations in APP, PSEN2, or MAPT. Patients with PSEN1 mutations had earlier onset of disease than those without mutations (p = .02). Plasma level of total tau was increased and Aβ42 and Aβ40 levels decreased in all groups of dementia patients compared to controls. Our findings provide a genetic spectrum of young‐onset dementia in our population.
To investigate speech and language outcomes in children with cochlear implants (CIs) who had mutations in common deafness genes and to compare their performances with those without mutations.
...Prospective study.
Patients who received CIs before 18 years of age and had used CIs for more than 3 years were enrolled in this study. All patients underwent mutation screening of three common deafness genes: GJB2, SLC26A4 and the mitochondrial 12S rRNA gene. The outcomes with CIs were assessed at post-implant years 3 and 5 using the Categories of Auditory Performance (CAP) scale, Speech Intelligibility Rating (SIR) scale, speech perception tests and language skill tests.
Forty-eight patients were found to have confirmative mutations in GJB2 or SLC26A4, and 123 without detected mutations were ascertained for comparison. Among children who received CIs before 3.5 years of age, patients with GJB2 or SLC26A4 mutations showed significantly higher CAP/SIR scores than those without mutations at post-implant year 3 (p = 0.001 for CAP; p = 0.004 for SIR) and year 5 (p = 0.035 for CAP; p = 0.038 for SIR). By contrast, among children who received CIs after age 3.5, no significant differences were noted in post-implant outcomes between patients with and without mutations (all p > 0.05).
GJB2 and SLC26A4 mutations are associated with good post-implant outcomes. However, their effects on CI outcomes may be modulated by the age at implantation: the association between mutations and CI outcomes is observed in young recipients who received CIs before age 3.5 years but not in older recipients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Phospholipase A2 group VI (PLA2G6) mutations associated with neurodegeneration (PLAN) manifest as heterogeneous neurodegenerative disorders with variable ages of onset. The genotype-phenotype ...correlation is not well-established. We aim to describe three adult patients with PLAN and combined these data with results from previous studies to elucidate adult-onset PLA2G6 phenotype-genotype correlations.
The first index patient presented with dystonia-parkinsonism starting at age 31 years, accompanied by major depression and cognitive decline. Genetic analysis using targeted next generation sequencing (NGS) panel, Sanger sequencing, and segregation analyses revealed a compound heterozygous mutation, c.991G > T (p.D331Y)/c.1077G > A (M358IfsX), in PLA2G6. The other two patients had levodopa-responsive, early-onset parkinsonism, starting in their late twenties. Both patients had homozygous c.991G > T (p.D331Y) mutations in PLA2G6. Patient characteristics of our reported 3 cases were compared to those of 32 previously described (2008 to 2019) patients with adult-onset PLAN. Among the combined cohort of 35 patients with adult-onset PLAN, 14 had dystonia-parkinsonism, 17 had early-onset Parkinson's disease, 3 had hereditary spastic paraparesis, and one had ataxia. The c.991G > T (p. D331Y) mutation was almost exclusively found in Chinese patients, suggesting a common founder effect. All patients with homozygous p.D331Y mutations had levodopa-responsive, early-onset PD (100%); while other mutations mostly led to dystonia-parkinsonism, ataxia, spasticity, and combine psychiatric comorbidities.
We showed that adult-onset PLAN could present as purely parkinsonism features, without brain iron accumulation, particularly patients with homozygous p.D331Y mutations. Compound heterozygous mutations, including heterozygous p.D331Y, produced heterogeneous phenotypes, without obvious levodopa responsiveness.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Here, we aim to investigate the molecular mechanism of regorafenib and verify the potential druggable target for the treatment of hepatocellular carcinoma (HCC).
HCC cell lines (PLC5, HepG2, Hep3B, ...SK-Hep1, and HA59T) were used to investigate the in vitro effect of regorafenib. Phosphatase activity was analyzed in HCC cells and purified SHP-1 proteins. PLC5-bearing mice were used to test the therapeutic efficiency of 20 and 40 mg/kg/d treatment with regorafenib (Formula: see text mice). The clinical relevance of STAT3 signaling was investigated with 142 tumor samples from different patients with HCC. Descriptive statistical analysis was used to compare the baseline characteristics of patients and the expression of p-STAT3.
Regorafenib inhibited STAT3-related signaling in a dose-dependent manner and was a more potent inhibitor of STAT3 than sorafenib. Regorafenib increased SHP-1 phosphatase activity in purified SHP-1 protein directly. N-SH2 domain deletion and D61A mutants mimicking open-form SHP-1 partially abolished regorafenib-induced STAT3 inhibition and apoptosis. Importantly, a higher level of expression of STAT3 was found in patients with advanced clinical stages (P = 0.009) and poorly differentiated tumors (P = 0.035).
Regorafenib induced significant tumor inhibition by relieving the autoinhibited N-SH2 domain of SHP-1 directly and inhibiting p-STAT3 signals. STAT3 may be suitable as a prognostic marker of HCC development, and may be a druggable target for HCC-targeted therapy using regorafenib.
Rotor syndrome is a rare, benign, inherited disorder that is commonly associated with mild hyperbilirubinemia. It is caused by bi-allelic pathological variants in both SLCO1B1 and SLCO1B3 genes, ...causing defective OATP1B1 and OATP1B3 in the sinusoidal membrane and interrupted bilirubin uptake of the hepatocytes. We report five Taiwanese pediatric and adult patients aged 5–32 years presenting with conjugated hyperbilirubinemia, and were found to have genetic variants of SLCO1B1 and SLCO1B3. Two also had history of prolonged neonatal jaundice. Genetic analysis using panel-based next generation sequencing revealed three patients with homozygous mutations c.1738C>T (p.R580∗) in SLCO1B1 and a transposon LINE-1 insertion in SLCO1B3, one patient with homozygous mutations for another haplotype, c.757C>T (p.R253∗) in SLCO1B1 and c.1747+1G>A in SLCO1B3. Another patient had heterozygous c.1738C>T (p.R580∗) in SLCO1B1 linked with a LINE-1 insertion in SLCO1B3, and heterozygous c.757C>T (p.R253∗) in SLCO1B1 linked with c.1747+1G>A in SLCO1B3. In conclusion, we present the first time of genetic diagnosis of Rotor syndrome in Taiwan. Advanced genetic testing has enhanced the diagnosis of rare diseases with mild symptoms.
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