Preliminary Study on Clinical Characteristics and Pathogenesis of IQSEC2 Mutations Patients.

Background: The IQ motif and Sec7 domain ArfGEF 2 (IQSEC2), an X-linked gene that encodes the BRAG1 protein, is a guanine nucleotide exchange factor for the ADP ribosylation factor (ARF) protein family in the small guanosine triphosphate (GTP) binding protein. Mutations in this gene result in disorders such as intellectual disability (ID) and epilepsy. In this study, we analyze the clinical features of two patients with IQSEC2-mutation-related disease and discuss their possible pathogenesis. Methods: The two patients were diagnosed with ID and epilepsy. Genetic testing was performed using whole-exome sequencing, and the three-dimensional protein structure was analyzed. UCSC Genome Browser was used to analyze the conservation of IQSEC2 in different species. We compared IQSEC2 expression in the proband families with that in a control group, as well as the expression of the postsynaptic identity protein 95 (PSD-95), synapse-associated protein 97 (SAP97), ADP ribosylation factor 6 (ARF-6), and insulin receptor substrate 53kDa (IRSP53) genes interacting with IQSEC2. Results: We identified two semi-zygote mutations located in conserved positions in different species: an unreported de novo mutation, C.3576C>A (p. Tyr1192*), and a known mutation, c.2983C>T (p. Arg995Trp). IQSEC2 mutations resulted in significant changes in the predicted three-dimensional protein structure, while its expression in the two probands was significantly lower than that in the age-matched control group, and IQSEC2 expression in proband 1 was lower than that in his family members. The expression levels of PSD-95, ARF-6, and SAP97, IRSP 53, which interact with IQSEC2, were also significantly different from those in the family members and age-matched healthy children. Conclusion: The clinical phenotype resulting from IQSEC2 mutations can be explained by the significant decrease in its expression, loss of function of the mutant protein, and change in the expression of related genes. Our results provide novel insights into the molecular phenotype conferred by the IQSEC2 variants.

Discovery of Orally Bioavailable and Potent CDK9 Inhibitors for Targeting Transcription Regulation in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) represents a highly aggressive and heterogeneous malignancy. Currently, effective therapies for TNBC are very limited and remain a significant unmet clinical need. Targeting the transcription-regulating cyclin-dependent kinase 9 (CDK9) has emerged as a promising avenue for therapeutic treatment of TNBC. Herein, we report the design, synthesis, optimization, and evaluation of a new series of aminopyrazolotriazine compounds as orally bioavailable, potent, and CDK9/2 selectivity-improved inhibitors, enabling efficacious inhibition of TNBC cell growth, as well as notable antitumor effect in TNBC models. The compound C35 demonstrated low-nanomolar potency with substantially improved CDK9/2 selectivity, downregulated the CDK9-downstream targets (e.g., MCL-1), and induced apoptosis in TNBC cell lines. Moreover, with the desired oral bioavailability, oral administration of C35 could significantly suppress the tumor progression in two TNBC mouse models. This study demonstrates that target transcriptional regulation is an effective strategy and holds promising potential as a targeted therapy for the treatment of TNBC.

Clinical characteristics and identification of novel CNOT1 variants in three unrelated Chinese families with Vissers-Bodmer Syndrome.

Vissers-Bodmer Syndrome, an autosomal dominant disease, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, hypotonia and autistic features with a highly variable phenotype. It is caused by variants in the CCR4-NOT transcription complex, subunit 1 gene (CNOT1). However, the pathophysiologic mechanism of the Vissers-Bodmer Syndrome remains unclear. Notably, this syndrome has not been previously reported in the Chinese. In this study, we utilized whole exome sequencing to identify three novel variants in the CNOT1 gene, encompassing one frameshift variant and two missense variants, in three Chinese patients mainly presenting with developmental delay, intellectual disability and/or autism. Interestingly, three patients exhibited novel manifestations including spina bifida occulta, horse-shoe kidney and café-au-lait spot. The frameshift variant, p.Gly172Alafs*5, occurring de novo, leading to a premature stop codon in the protein, was classified into pathogenic. Two missense variants c.3451A > G (p.Asn1151Asp) and c.557C > T (p.Ser186Phe) were predicted to be deleterious by multiple prediction algorithms with high conservation among a variety of species. Additionally, three-dimensional structure modeling and predicting indicated the substitution of the mutated amino acids would decrease the stability of CNOT1 protein. Given that CNOT1 is a relatively novel disease gene, we evaluated the gene-disease validity following ClinGen Standard Operating Procedure. The existing evidence substantiates a "Definitive" level of gene-disease relationship. The genetic findings provide a reliable basis for the genetic counseling of the family reproduction. Moreover, our results expand the genetic and phenotypic spectrum of CNOT1-related Vissers-Bodmer Syndrome.

Clinical features and underlying mechanisms of KAT6B disease in a Chinese boy.

BACKGROUND: Lysine acetyltransferase 6B (KAT6B) encodes a highly conserved histone acetyltransferase that regulates the expression of multiple genes and is essential for human growth and development. METHODS: We identified a novel frameshift variant c.3185del (p.leu1062Argfs*52) in a 5-year-old Chinese boy and further analyzed KAT6B expression and its interacting complexes and downstream products using real-time quantitative polymerase chain reaction (qPCR). Furthermore, we assessed its three-dimensional protein structure and compared the variant with other reported KAT6B variants. RESULTS: The deletion changed the leucine at position 1062 into an arginine, resulting in translation termination after base 3340, which may have affected protein stability and protein-protein interactions. KAT6B mRNA expression levels in this case were substantially different from those of the parents and controls in the same age range. There were also significant differences in mRNA expression levels among affected children's parents. RUNX2 and NR5A1, downstream products of the gene, affect the corresponding clinical symptoms. The mRNA expression levels of the two in children were lower than those of their parents and controls in the same age range. CONCLUSION: This deletion in KAT6B may affect protein function and cause corresponding clinical symptoms through interactions with key complexes and downstream products.

Clinical characteristics and genetics of ten Chinese children with PRRT2-associated neurological diseases.

Background: Proline-rich transmembrane protein 2 (PRRT2) plays an important role in the central nervous system and mutations in the gene are implicated in a variety of neurological disorders. This study aimed to summarize the clinical characteristics and gene expression analysis of neurological diseases related to the PRRT2 gene and explore the clinical characteristics, therapeutic effects, and possible pathogenic mechanisms of related diseases. Methods: We enrolled 10 children with PRRT2 mutation-related neurological diseases who visited the Children's Hospital affiliated with the Shanghai Jiaotong University School of Medicine/Shanghai Children's Hospital between May 2017 and February 2022. Video electroencephalography (VEEG), cranial imaging, treatment regimens, gene results, and gene expression were analyzed. Genetic testing involved targeted sequencing or whole-exome genome sequencing (WES). We further analyzed the expression and mutation conservation of PRRT2 and synaptosome-associated protein 25 (SNAP25) in blood samples using quantitative polymerase chain reaction (qPCR) and predicted the protein structure. Summary analysis of the reported gene maps and domains was also performed. Results: Ten children with PRRT2 gene mutations were analyzed, and 4 mutations were identified, consisting of 2 new (c.518A > C, p.Glu173 Ala; c.879 + 112G > A, p.?) and two known (c. 649 dup, p. Arg217Profs * 8; c. 649 del, p. Arg217Glufs * 12) mutations. Among these mutations, one was de novo(P6), and three could not be determined because one parent refused genetic testing. The clinical phenotypes were paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), epilepsy, infantile spasms, and intellectual disability. The qPCR results showed that PRRT2 gene expression levels were significantly lower in children and parent carriers than the control group. The SNAP25 gene expression level of affected children was significantly lower (P ≤ 0.001) than that of the control group. The mutation sites reported in this study are highly conserved in different species. Among the various drugs used, oxcarbazepine and sodium valproate were the most effective. All 10 children had a good disease prognosis, and 8 were completely controlled with no recurrence, whereas 2 had less severe and fewer seizures. Conclusion: Mutation of PRRT2 led to a significant decrease in its protein expression level and that of SNAP25, suggesting that the mutant protein may lead to the loss of its function and that of related proteins. This mutation site is highly conserved in most species, and there was no significant correlation between specific PRRT2 genotypes and clinical phenotypes. Asymptomatic carriers also have decreased gene expression levels, suggesting that more factors are involved.

Segawa syndrome caused by TH gene mutation and its mechanism.

Dopa-responsive dystonia (DRD), also known as Segawa syndrome, is a rare neurotransmitter disease. The decrease in dopamine caused by tyrosine hydroxylase (TH) gene mutation may lead to dystonia, tremor and severe encephalopathy in children. Although the disease caused by recessive genetic mutation of the tyrosine hydroxylase (TH) gene is rare, we found that the clinical manifestations of seven children with tyrosine hydroxylase gene mutations are similar to dopa-responsive dystonia. To explore the clinical manifestations and possible pathogenesis of the disease, we analyzed the clinical data of seven patients. Next-generation sequencing showed that the TH gene mutation in three children was a reported homozygous mutation (c.698G>A). At the same time, two new mutations of the TH gene were found in other children: c.316_317insCGT, and c.832G>A (p.Ala278Thr). We collected venous blood from four patients with Segawa syndrome and their parents for real-time quantitative polymerase chain reaction analysis of TH gene expression. We predicted the structure and function of proteins on the missense mutation iterative thread assembly refinement (I-TASSER) server and studied the conservation of protein mutation sites. Combined with molecular biology experiments and related literature analysis, the qPCR results of two patients showed that the expression of the TH gene was lower than that in 10 normal controls, and the expression of the TH gene of one mother was lower than the average expression level. We speculated that mutation in the TH gene may clinically manifest by affecting the production of dopamine and catecholamine downstream, which enriches the gene pool of Segawa syndrome. At the same time, the application of levodopa is helpful to the study, diagnosis and treatment of Segawa syndrome.

Clinical characteristics and prognosis of pediatric myelin oligodendrocyte glycoprotein antibody-associated diseases in China.

BACKGROUND: Research on myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disease (MOGAD) among Chinese children is relatively rare. Therefore, this study aimed to explore and analyze the clinical characteristics and prognoses of Chinese children with acquired demyelinating syndromes (ADSs) who tested positive or negative for MOG-Ab. METHODS: The clinical data of children with MOGAD who were treated in the Department of Neurology at Shanghai Children's Hospital from January 2017 to October 2021 were retrospectively collected. RESULTS: Among 90 children with ADSs, 30 were MOG-Ab-positive, and 60 were MOG-Ab-negative. MOG-Ab-positive children experienced more prodromal infections than did MOG-Ab-negative children (P < 0.05). Acute disseminated encephalomyelitis was the most common ADSs in both groups. There were ten cases of a rebound increase in MOG-Ab titers. There were significant differences in the MOG titer-related prognosis and disease time course between the disease relapse group and the non-relapse group (P < 0.01). Among the MOG-Ab-positive patients, the most affected brain areas detected via magnetic resonance imaging (MRI) were the temporal lobe, cerebellar hemispheres, brainstem, and periventricular lesions. The most common shapes of the lesions were commas, triangles, or patches. The average improvement time based on brain MRI was much longer in MOG-Ab-positive than in MOG-Ab-negative children (P < 0.05). The initial treatment time correlated with the disease time course, and the prognosis may be affected by the disease time course and serum MOG-Ab titer (P < 0.05). CONCLUSION: The clinical characteristics and imaging features of ADSs differed between MOG-Ab-positive and MOG-Ab-negative children. In addition to existing treatment plans, additional diagnoses and treatment plans should be developed to reduce recurrence and improve the prognoses of children with MOGAD.

Identification of ST3GAL5 as a prognostic biomarker correlating with CD8+ T cell exhaustion in clear cell renal cell carcinoma.

Aberrant sialylation is frequently observed in tumor development, but which sialyltransferases are involved in this event are not well known. Herein, we performed comprehensive analyses on six ST3GAL family members, the α-2,3 sialyltransferases, in clear cell renal cell carcinoma (ccRCC) from public datasets. Only ST3GAL5 was consistently and significantly overexpressed in ccRCC (n = 791 in total), compared with normal kidney tissues. Its overexpression was positively correlated with tumor stage, grade, and the poor prognosis in ccRCC patients. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated the involvement of ST3GAL5 in tumor immunoregulation. Then we revealed that ST3GAL5 expression showed a positive correlation with CD8+ T cell infiltration, using multiple tools on TIMER2.0 web server. Notably, ST3GAL5 overexpression was further identified to be associated with expression signature of CD8+ T cell exhaustion in ccRCC samples from three datasets (n = 867 in total; r > 0.3, p < 0.001). In our own ccRCC cohort (n = 45), immunohistochemistry and immunofluorescence staining confirmed that ST3GAL5 overexpression was accompanied by high CD8+ T cell infiltration with the increased exhaustion markers. Altogether, ST3GAL5 as a promising prognostic biomarker with CD8+ T cell exhaustion in ccRCC is indicated.

Comprehensive landscape of the ST3GAL family reveals the significance of ST3GAL6-AS1/ST3GAL6 axis on EGFR signaling in lung adenocarcinoma cell invasion.

Sialylation aberration has been implicated in lung cancer development by altering signaling pathways. Hence, it is urgent to identify key sialyltransferases in the development of lung adenocarcinoma (LUAD), which is a common malignant subtype of non-small cell lung cancer. Herein, by systematically investigating the expression levels of ST3GAL family members in several public databases, we consistently found the frequent downregulation of ST3GAL6 in LUAD samples. Its downregulation is significantly negatively associated with stage, and significantly reduced in proximal-proliferative molecular subtype and predicts poor clinical outcomes. By protein-protein interaction network analysis and validation, we found that ST3GAL6 deficiency promotes LUAD cell invasiveness with the activated EGFR/MAPK signaling, accompanied by the elevated expression levels of matrix metalloproteinases 2 and 9, which can be partially reversed by EGFR inhibitor, gefitinib. Additionally, the ST3GAL6 level was positively regulated by ST3GAL6-AS1, an antisense long non-coding RNA to its host gene. The downregulation of ST3GAL6-AS1 also heralds a worse prognosis in LUAD patients and promotes LUAD cell invasiveness, recapitulating the function of its host gene, ST3GAL6. Altogether, ST3GAL6-AS1-regulated ST3GAL6 is a frequently downregulated sialyltransferase in LUAD patients and negatively regulates EGFR signaling, which can serve as a promising independent prognostic marker in LUAD patients.

The Study on the Clinical Phenotype and Function of HPRT1 Gene.

Background: Lesch-Nyhan disease (LND) is a rare x-linked purine metabolic neurogenetic disease caused by enzyme hypoxanthine-guanine phosphoriribosyltransferase(HGprt) deficiency, also known as self-destructive appearance syndrome. A series of manifestations are caused by abnormal purine metabolism. The typical clinical manifestations are hyperuricemia, growth retardation, mental retardation, short stature, dance-like athetosis, aggressive behavior, and compulsive self-harm. Methods: We identified a point mutation c.151C > T (p. Arg51*) in a pedigree. We analyzed the clinical characteristics of children in a family, and obtained the blood of their parents and siblings for second-generation sequencing. At the same time, we also analyzed and compared the expression of HPRT1 gene and predicted the three-dimensional structure of the protein. And we analyzed the clinical manifestations caused by the defect of the HPRT1 gene. Results: The mutation led to the termination of transcription at the 51st arginine, resulting in the production of truncated protein, and the relative expression of HPRT1 gene in patients was significantly lower than other family members and 10 normal individuals. Conclusion: This mutation leads to the early termination of protein translation and the formation of a truncated HPRT protein, which affects the function of the protein and generates corresponding clinical manifestations.

Induced pluripotent stem cells (SHCDNi006-A cells) isolated from the peripheral blood mononuclear cells of a five-month-old Chinese girl with the heterozygous missense mutation (c.2800 G>A) in the KCNT1 gene.

Epilepsy of infancy with migrating focal seizures (EIMFS) is a kind of epileptic encephalopathy with high genetic heterogeneity. The most common pathogenic gene for EIMFS is potassium sodium-activated channel subfamily T member 1 (KCNT1). Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of a five-month-old Chinese girl with heterozygous missense mutation (c.2800 G>A) in the KCNT1 gene. The iPSCs were stable during amplification, expressed pluripotent genes, maintained a normal karyotype, and showed characteristics of the three germs layers in an in vitro differentiation assay.

Correlation Between Tic Disorders and Serum 25-Hydroxyvitamin D Levels in Chinese Children.

Objective: To explore the correlation between serum 25-hydroxyvitamin D levels and tic disorders (TDs) in Chinese children. Methods: We selected 2960 children with TD and 2665 healthy controls, aged 5-14 years, from the Department of Neurology of the Shanghai Children's Hospital. Serum 25-hydroxyvitamin D levels and degrees of vitamin D deficiency were compared between patients with TD and healthy children. Results: The mean serum 25-hydroxyvitamin D level in the TD group was significantly lower than that in the control group (P < 0.001). The proportion of patients with 25-hydroxyvitamin D deficiency in the TD group was significantly higher than that in the control group. However, there was no correlation between 25-hydroxyvitamin D deficiency and the severity of TD. In addition, for age-wise comparison, mean levels of 25-hydroxyvitamin D and its deficiency in the TD group were the most significant in children over 9 years of age. Conclusion: There is a correlation between 25-hydroxyvitamin D deficiency and TD in Chinese children, but not between 25-hydroxyvitamin D deficiency and the severity of TD. There was a correlation between age and deficiency of 25-hydroxyvitamin D; this deficiency was most pronounced among those over the age of 9 years.

Clinical Study of 8 Cases of CHD2 Gene Mutation-Related Neurological Diseases and Their Mechanisms.

Background: The chromodomain helicase DNA-binding protein 2 (CHD2) gene, is an ATPase and part of the CHD family of chromatin remodelers. Mutations in the CHD2 gene are inherited in an autosomal-dominant manner and can lead to intellectual disability, epilepsy, and autism. We investigated the clinical characteristics of CHD2-related conditions and their possible pathogenesis. Methods: We collected and analysed the clinical data of patients that were identified as having CHD2 mutations. Genetic testing was performed using targeted sequencing or whole-exome sequencing. We analysed the expression of CHD2 and repressor element 1-silencing transcription factor (REST) in blood samples using quantitative PCR and the conservation of the mutations. The CHD2 mutations we identified were compared with the known mutations reported in the CHD2-related literature. Results: Eight patients with CHD2 gene mutations were analysed. Six mutations were identified; four were unreported previously (c.670C>T; c.4012A>C; c.2416dup; c.1727-1728insAT), and two were known mutations: c.5035C>T (two cases) and c.4173dup (two cases). Among these mutations, seven were de novo mutations, and one could not be determined because the parents refused genetic testing. The clinical manifestations included mild or severe intellectual disability, epilepsy, and behavioural abnormalities. Quantitative PCR showed that the CHD2 gene expression levels among the patients, parents, and the controls were not significantly different. The levels of REST gene expression in the patients were significantly higher than those of the controls; thus, mutation of the CHD2 gene led to an increase in the expression level of the REST gene. The mutations reported were all located in conserved positions in different species. Among the various medications administered for treatment, valproate showed the best results for the treatment of epilepsy caused by CHD2 gene mutation. Conclusion: Mutation in CHD2 did not lead to a significant decrease in its expression level, indicating that the clinical phenotype was unrelated to its expression level, and the mutant protein may retain some function. Most of the mutations relatively stable. In addition, the clinical manifestations from the same mutation in the CHD2 gene were different among the known cases; this may be related to the regulation of REST or other regulatory factors.

Generation of an induced pluripotent stem cell line from an Ohtahara syndrome patient with the hemizygous mutation p.Q503Afs*28 (c.1507_1508del) in the ARX gene.

Aristaless-related homeobox (ARX)-related disorders are recessive X-linked intellectual disability disorders. We encountered a patient with a hemizygous mutation (c.1507_1508del) showing intellectual disability, early-onset epileptic encephalopathy and Ohtahara syndrome. The patient had female genitals, but an XY karyotype. We established an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of a six-month Chinese child with a hemizygous mutation (c.1507_1508del) in ARX. The PBMCs were reprogrammed with Sendai viral vectors. The iPSCs showed stable amplification, pluripotency-related gene expression, and trilineage differentiation potential. Karyotype analysis of the iPSCs showed 23 pairs of chromosomes with normal structure and sex chromosome is XY.

Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene.

The gene encoding collagen like tail subunit of asymmetric acetylcholinesterase (COLQ) is responsible for the transcription of three strands of collagen of acetylcholinesterase, which is attached to the endplate of neuromuscular junctions. Mutations in the COLQ gene are inherited in an autosomal-recessive manner and can lead to type V congenital myasthenia syndrome (CMS), which manifests as decreased muscle strength at birth or shortly after birth, respiratory failure, restricted eye movements, drooping of eyelids, and difficulty swallowing. Here we reported three variants within COLQ in two unrelated children with CMS. An intronic variant (c.393+1G>A) and a novel missense variant (p.Q381P) were identified as compound heterozygous in a 13-month-old boy, with the parents being carriers of each. An intragenic deletion including exons 14 and 15 was found in a homozygous state in a 12-year-old boy. We studied the relative expression of the COLQ and AChE gene in the probands' families, performed three-dimensional protein structural analysis, and analyzed the conservation of the missense mutation c.1142A>C (p.Q381P). The splicing mutation c.393+1G>A was found to affect the normal splicing of COLQ exon 5, resulting in a 27-bp deletion. The missense mutation c.1142A>C (p.Q381P) was located in a conserved position in different species. We found that homozygous deletion of COLQ exons 14-15 resulted in a 241-bp deletion, which decreased the number of amino acids and caused a frameshift translation. COLQ expression was significantly lower in the probands than in the probands' parents and siblings, while AChE expression was significantly higher. Moreover, the mutations were found to cause significant differences in the predicted three-dimensional structure of the protein. The splicing mutation c.393+1G>A, missense mutation c.1A>C (p.Q381P), and COLQ exon 14-15 deletion could cause CMS.

Very long chain acylcarnitines and lysophosphatidylcholines in screening of peroxisomal disease in children by tandem mass spectrometry.

To investigate the value of very long chain acylcarnitine (VLCAC) and lysophosphatidylcholine (LPC) in screening of peroxisomal disease in children. Eighteen children with peroxisomal disease, including 14 cases of X-linked adrenoleukodystrophy (X-ALD group) and 4 cases of Zellweger syndrome (ZS group) diagnosed based on clinical symptoms, MRI and genetic tests were enrolled in the study; and 200 healthy children were selected as control group. Samples of dried blood spots were collected from all subjects, VLCAC and LPC in dried blood spots were extracted by solvent containing internal isotopic standards hexacosanoylcarnitine (H-C26) and C26:0 lysophosphatidylcholine (H-C26:0-LPC). The eicosanoylcarnitine (C20), docosanoylcarnitine (C22), tetracosanoylcarnitine (C24), hexacosanoylcarnitine (C26), C20:0 lysophosphatidylcholine (C20:0-LPC), C22:0 lysophosphatidylcholine (C22:0-LPC), C24:0 lysophosphatidylcholine (C24:0-LPC) and C26:0 lysophosphatidylcholine (C26:0-LPC) were detected by tandem mass spectrometry (MS/MS). The above 8 indicators and the ratios were compared among the groups using Kruskal-Wallis test and Mann-Whitney test; the contribution of each index to the disease were analyzed by partial least square method. Except C24:0-LPC/C20:0-LPC, there were significant differences in all indicators and ratios among all groups (<0.05 or <0.01). There were differences in most indicators and ratios between X-ALD group and the control group, as well as between ZS group and the control group, but there was no difference between the X-ALD group and the ZS group. PLS-DA analysis showed that the peroxisome disease group (including X-ALD group and ZS group) and the control group were able to be completely separated, and C26 had the highest variable importance for the projection (VIP) value. MS/MS detection of VLCAC and LPC can be used as a screening method for peroxisomal disease, and C26 may be a sensitive indicator for diagnosis.

Efficacy of Oxidized Regenerated Cellulose/Collagen Dressing for Management of Skin Wounds: A Systematic Review and Meta-Analysis.

OBJECTIVE: The purpose of this study was to evaluate the wound healing efficacy of oxidized regenerated cellulose (ORC)/collagen dressing and ORC/collagen/silver-ORC dressings compared to standard of care or control in treatment of chronic skin wounds such as diabetic foot ulcers (DFUs), venous leg ulcers (VLUs), and pressure injuries sore ulcers (PISUs). METHODS: An electronic search was carried out in four popular databases PubMed, Scopus, Embase, and CENTRAL to identify thirteen included studies, comparing the clinical efficacy of ORC/collagen dressings when compared to control in management of chronic skin wounds, especially DFUs, VLUs, and PISUs, and skin graft donor site wounds. RESULTS: Consolidated data from thirteen comparative clinical studies undertaken for management of DFUs, VLUs, and PISUs showed favorable outcomes towards use of ORC/collagen compared to other traditional and hydrocolloid foam dressings in terms of wound healing rate (P=0.02) and percentage wound relative reduction (P=0.003). The time taken to achieve complete wound healing in the included studies did not show any statistical significant difference (P=0.24). There was no significant difference in adverse events between ORC/collagen-treated group and comparative group (P=0.19). CONCLUSION: ORC/collagen wound dressings are beneficial in terms of improved wound healing rate and percentage wound relative reduction compared to already existing traditional standard of care with non-MMP, inhibiting biomaterials such as moistened gauze, autologous growth factors, hydrocolloid foam dressings, or ovine extracellular matrix.

Novel Mutations of the ALMS1 Gene in Patients with Alström Syndrome.

Objective Alström syndrome is an autosomal recessive genetic disease caused by a mutation in the ALMS1 gene. Alström syndrome is clinically characterized by multisystem involvement, including sensorineural deafness, cone-rod dystrophy, nystagmus, obesity, insulin resistance, type 2 diabetes and hypogonadism. The diagnosis is thus challenging for patients without this characteristic set of clinical symptoms. We explored the effectiveness of whole-exome sequencing in the diagnosis of Alström syndrome. Methods A girl with symptoms of Alström syndrome was tested and diagnosed with the disease by whole-exome sequencing. Results Whole-exome sequencing revealed two novel variants, c.6160_6161insAT: p.Lys2054Asnfs*21 (exon 8) and c.10823_10824 delAG:p.Glu 3608Alafs*9 (exon16) in the ALMS1 gene, leading to premature termination codons and the domain of ALMS1 protein. Blood sample testing of her asymptomatic parents revealed them to be heterozygous carriers of the same mutations. Assembly showed that the mutations on both alleles were located in conserved sequences. A review of the ALMS1 gene nonsense mutation status was performed. Conclusion We herein report two novel variants of the ALMS1 gene discovered in a Chinese Alström syndrome patient that expand the mutational spectrum of ALMS1 and provided new insight into the molecular mechanism underlying Alström syndrome. Our findings add to the current knowledge concerning the diagnosis and treatment of Alström syndrome.

Generation and characterization of the induced pluripotent stem cell line SHCDNi004-A from a ten-year-old Chinese boy with X-linked mental retardation in IL1RAPL1 deficiency.

Mental retardation, X-linked 21/34 (MRX21/34), is a rare intellectual disability disease caused by mutations in the IL1RAPL1 (Interleukin-1 Receptor Accessory Protein-Like 1) gene. Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from PBMCs collected from a ten-year-old boy with MRX21/34. The iPSCs showed stable amplification, expressed pluripotent genes, displayed a normal karyotype, and had characteristics of trilineage differentiation potential in an in vitro differentiation assay.

Generation of an induced pluripotent stem cell line (SHCDNi003-A) from a one-year-old Chinese Han infant with Allan-Herndon-Dudley syndrome.

Allan-Herndon-Dudley syndrome (AHDS) is a rare, X-chromosome-linked inherited disorder that affects brain development and is caused by a mutation in SLC16A2. Herein, we generated an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells of a one-year-old male infant with AHDS using Sendai-virus-mediated reprogramming. These iPSCs exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three germ layers in vitro. Additionally, this iPSC line was found to maintain a normal karyotype and retain the pathogenic mutation in SLC16A2, facilitating the study of disease mechanisms and development of new therapies of AHDS.