Large-scale analysis of Drosophila core promoter function using synthetic promoters.

The core promoter plays a central role in setting metazoan gene expression levels, but how exactly it "computes" expression remains poorly understood. To dissect its function, we carried out a comprehensive structure-function analysis in Drosophila. First, we performed a genome-wide bioinformatic analysis, providing an improved picture of the sequence motifs architecture. We then measured synthetic promoters' activities of ~3,000 mutational variants with and without an external stimulus (hormonal activation), at large scale and with high accuracy using robotics and a dual luciferase reporter assay. We observed a strong impact on activity of the different types of mutations, including knockout of individual sequence motifs and motif combinations, variations of motif strength, nucleosome positioning, and flanking sequences. A linear combination of the individual motif features largely accounts for the combinatorial effects on core promoter activity. These findings shed new light on the quantitative assessment of gene expression in metazoans.

Different Clinical Features of Pediatric Generalized Pustular Psoriasis in Patients with or without IL36RN Variants.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare and life-threatening autoinflammatory dermatological disease. IL36RN was reported to be the main pathogenetic basis for GPP. Only a few studies have reported on the correlation analysis of IL36RN variants and the phenotype of pediatric-onset GPP. METHODS: IL36RN was screened in 60 children diagnosed with GPP from January 2013 to January 2020, and their detailed clinical profiles were obtained. RESULTS: Forty-six out of 60 (76.67%) patients harbored IL36RN variants, and six IL36RN variants were found, of which two were novel variants that were reported for the first time. The frequency of IL36RN variants was significantly different among the subtypes of GPP (GPP with acrodermatitis continua of Hallopeau group (ACH), 100%; GPP without plaque psoriasis (PV) and ACH, 78.05%; GPP with PV group, 44.44%) (p = 0.018), while the percentage of IL36RN variants in the GPP with ACH group was higher than that in the GPP with PV group (p < 0.05). IL36RN variants were associated with a lower percentage of PV, longer length of hospitalization, and longer time to reach normal body temperature after treatment (p < 0.05). After treatment, marked responses, moderate responses, and no responses were recorded in 75.00%, 8.33%, and 16.67% of patients, respectively. No significant difference was observed during efficacy assessment in patients with or without IL36RN variants (χ2 = 1.122, p > 0.05). CONCLUSIONS: IL36RN variants are associated with GPP with ACH subtypes, an absence of concurrent PV, and a greater extent of severe inflammation. Acitretin was an effective treatment for patients in our study and mostly resulted in a marked response in our cohort.

Identification of discriminative neuroimaging markers for patients on hemodialysis with insomnia: a fractional amplitude of low frequency fluctuation-based machine learning analysis.

BACKGROUND AND OBJECTIVE: Insomnia is one of the common problems encountered in the hemodialysis (HD) population, but the mechanisms remain unclear. we aimed to (1) detect the spontaneous brain activity pattern in HD patients with insomnia (HDWI) by using fractional fractional amplitude of low frequency fluctuation (fALFF) method and (2) further identify brain regions showing altered fALFF as neural markers to discriminate HDWI patients from those on hemodialysis but without insomnia (HDWoI) and healthy controls (HCs). METHOD: We compared fALFF differences among HDWI subjects (28), HDWoI subjects (28) and HCs (28), and extracted altered fALFF features for the subsequent discriminative analysis. Then, we constructed a support vector machine (SVM) classifier to identify distinct neuroimaging markers for HDWI. RESULTS: Compared with HCs, both HDWI and HDWoI patients exhibited significantly decreased fALFF in the bilateral calcarine (CAL), right middle occipital gyrus (MOG), left precentral gyrus (PreCG), bilateral postcentral gyrus (PoCG) and bilateral temporal middle gyrus (TMG), whereas increased fALFF in the bilateral cerebellum and right insula. Conversely, increased fALFF in the bilateral CAL/right MOG and decreased fALFF in the right cerebellum was observed in HDWI patients when compared with HDWoI patients. Moreover, the SVM classification achieved a good performance [accuracy = 82.14%, area under the curve (AUC) = 0.8202], and the consensus brain regions with the highest contributions to classification were located in the right MOG and right cerebellum. CONCLUSION: Our result highlights that HDWI patients had abnormal neural activities in the right MOG and right cerebellum, which might be potential neural markers for distinguishing HDWI patients from non-insomniacs, providing further support for the pathological mechanism of HDWI.

Effects of home medication review on drug-related problems and health-related quality of life among community-dwelling older adults in China.

BACKGROUND: There is a lack of research on the nature of drug-related problems (DRPs) in older adult communities in China and the impact of home medication review on DRP reduction and health-related quality-of-life (HRQoL) improvement. OBJECTIVES: To identify and categorize DRPs in older adults in China and to assess the impact of home medication review. METHODS: The prospective study was conducted in 2 community health service centers in Shanghai, China from December 2018 to December 2019. Eligible patients received a home medication review by a clinical pharmacist to assess for DRPs and adherence, propose pharmaceutical interventions, and measure outcomes of HRQoL. All enrolled patients were followed up for 3 months. RESULTS: Medication use in 412 patients was analyzed. A total of 362 DRPs were identified, an average of 0.88 per patient. Treatment effectiveness was the primary DRP type (249; 68.8%). The most common causes of DRPs were patient-related (35.1%) and drug selection (31.0%). Pharmacists made 733 interventions, an average of 2 per DRP. A total of 82.1% of these interventions were accepted. At a 3-month follow-up, home medication review led to a statistically significant reduction in the mean number of DRPs (0.4 vs. 0.88, P < 0.001) and an increase in medication adherence (1.42 vs. 0.85, P < 0.001). Both HRQoL indicators also improved, EuroQol 5 Dimension scale (0.75 vs. 0.78, P < 0.001) and EuroQol-visual analog scale (70 vs. 77.65, P < 0.001). CONCLUSION: Home medication review is a practical means to optimize drug therapy and improve patients' HRQoL in community settings.

Exome sequencing as the first-tier test for pediatric respiratory diseases: A single-center study.

The high clinical and genetic heterogeneity makes it difficult to reach a confirmative diagnosis of suspected pediatric respiratory inherited diseases. Many patients with monogenic respiratory disorders could be missed without genetic testing. We performed a single-center study in Beijing Children's Hospital to demonstrate the clinical utility of exome sequencing (ES) as a first-tier test by evaluating the diagnostic yields of ES for inherited diseases with respiratory symptoms. A total of 107 patients were recruited in this study. We identified 51 pathogenic or likely pathogenic variants in 37 patients by ES (with or without copy number variants sequencing). The overall diagnostic yield was 34.6% (37/107). The most frequent disorders in our cohort were primary immunodeficiency disease (PIDs) (18/37, 48.6%) and primary ciliary dyskinesia (PCD) (9/37, 24.3%). We further reviewed the directive outcomes of genetic testing on the 37 positive cases. Our study demonstrated the effectiveness of ES as a first-tier test in China for diagnosing monogenic diseases of the respiratory system. In the era of precision medicine, ES as a first-tier test can rapidly make a molecular diagnosis and direct the intervention of the positive cases in pediatric respiratory medicine.

Case Report : Li-Fraumeni Syndrome with Central Nervous System Tumors in Two Siblings.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome caused by germline TP53 gene mutations. It is characterized by high risk of early-onset cancer, and has been confirmed as associated with multiple tumors clinically. So pediatricians should be more alert to LFS in children with tumors. Choroid plexus carcinoma (CPC) is a rare, malignant tumor which account for less than 1% of all central nervous system (CNS) tumors. However, when such tumorigenesis occurs, it is important to be vigilant for the presence of LFS. CASE PRESENTATION: The first patient is a 32-month-old boy admitted for convulsions and then was found intracranial space-occupying lesion. Underwent operation, he was diagnosis as choroid plexus carcinoma (WHO Grade III). After 5 months, his elder sister, a 13-year-old girl, was brought to emergency department for confusion and intermittent convulsions. Surgery was performed immediately after head CT examination found the lesion. The pathology result indicated glioblastoma. Because the siblings of the same family have successively suffered from malignant tumors, we performed genetic testing on this family. TP53 gene mutation occurred in both children of these two cases from their father, and their other brother was not spared either. So the two siblings both met the diagnostic criteria of LFS. Then they all received systematic anti-tumor therapy, and follow-up hitherto. CONCLUSION: Here we reported a rare LFS case that two siblings were inherited the same TP53 germline mutations from their father. They suffered from choroid plexus carcinoma and glioblastoma and were finally diagnosed with LFS. In this LFS family, the primary tumors of the two children were both central nervous system tumors, which were not reported in the previous literature. It is suggested that clinicians should be alert to LFS related tumors, which is helpful for early diagnosis. Timely detection of TP53 gene is an important way for early diagnosis of LFS, especially in children with tumor. The incidence of secondary tumor in LFS patients is significantly higher, and other family members of the LFS patient also have an increased risk of suffering from the tumors. Therefore, early diagnosis and timely tumor surveillance can obtain better therapeutic effect and prognosis for both proband and their family.

Duplications involving the long range HMX1 enhancer are associated with human isolated bilateral concha-type microtia.

BACKGROUND: Microtia is a congenital anomaly of ear that ranges in severity from mild structural abnormalities to complete absence of the outer ears. Concha-type microtia is considered to be a mild form. The H6 family homeobox 1 transcription factor gene (HMX1) plays an important role in craniofacial structures development. Copy number variations (CNVs) of a downstream evolutionarily conserved enhancer region (ECR) of Hmx1 associated with ear and eye abnormalities have been reported in different animals, but not yet in human. To date, no genetic defects responsible for isolated human microtia has been reported except for mutations in HOXA2. Here we recruited five Chinese families with isolated bilateral concha-type microtia, and attempt to identify the underlying genetic causes. METHODS: Single Nucleotide polymorphism (SNP) array was performed to map the disease locus and detect CNVs on a genome scale primarily in the largest family (F1). Whole genome sequencing was performed to screen all SNVs and CNVs in the candidate disease locus. Array comparative genomic hybridization (aCGH) was then performed to detect CNVs in the other four families, F2-F5. Quantitative real-time polymerase chain reaction (qPCR) was used to validate and determine the extent of identified CNVs containing HMX1-ECR region. Precise breakpoints in F1 and F2 were identified by gap-PCR and sanger sequencing. Dual-luciferase assays were used to detect the enhancer function. qPCR assays were also used to detect HMX1-ECR CNVs in 61 patients with other types mictrotia. RESULTS: Linkage and haplotype analysis in F1 mapped the disease locus to a 1.9 Mb interval on 4p16.1 containing HMX1 and its downstream ECR region. Whole genome sequencing detected no potential pathogenic SNVs in coding regions of HMX1 or other genes within the candidate disease locus, but it detected a 94.6 Kb duplication in an intergenic region between HMX1 and CPZ. aCGH and qPCRs also revealed co-segregated duplications in intergenic region downstream of HMX1 in the other four families. The 21.8 Kb minimal overlapping region encompassing the core sequences consensus with mouse ECR of Hmx1. Luciferase assays confirmed the enhancer function in human sequences, and proved that HOXA2 could increase its enhancer activity. No CNVs were detected in HMX1-ECR regions in 61 patients with other type of microtia. CONCLUSION: Duplications involving long range HMX1 enhancers are associated with human isolated bilateral concha-type microtia. We add to evidences in human that copy number variations in HMX1-ECR associates with ear malformations, as in other species. This study also provides an additional example of functional conserved non-coding elements (CNEs) in humans.

[Clinical practice guidelines for albinism].

Albinism is an autosomal or X-linked recessive Mendelian trait in man, which mainly manifests as hypopigmentation and related lesions of eye, skin and hair. At least 18 genes have so far been identified as causative genes for albinism. The mutational spectrum is population-specific. Molecular genotyping of albinism is important for genetic and prenatal diagnosis, and is a prerequisite for the practice of precision medicine. Based on long-term study of albinism in Chinese population, a guideline for the clinical management of albinism is provided.

Simpson-Golabi-Behmel syndrome with 46,XY disorders of sex development: A case report.

We present a case of a Chinese child with X-linked Simpson-Golabi-Behmel syndrome (SGBS). To the best of our knowledge, this is the first report of 46,XY disorders of sex development (ambiguous genitalia, cryptorchidism, and uterus in the pelvis) in surviving SGBS patients. Other external anomalies included characteristic facial anomalies, overgrowth, macrocephaly, organomegaly, pectus excavatum, and cryptorchidism. It could be that the GPC3 gene mutation caused Leydig cell dysfunction in our patient. Disorders of sex development can be included as part of the clinical spectrum of SGBS.

Congenital hyperinsulinism in Chinese patients: 5-yr treatment outcome of 95 clinical cases with genetic analysis of 55 cases.

AIM: The aim of this study is to investigate the clinical features, therapeutic outcomes, and genetic mutations of congenital hyperinsulinism (CHI) in Chinese patients. METHODS: The clinical features and therapeutic outcomes of 95 CHI cases were recorded, and genetic analyses were conducted to identify mutations in ABCC8 and KCNJ11 in 55 cases. Direct sequencing was carried out in 25 of the cases with ABCC8 and KCNJ11 mutations. Additionally, 16 samples with no mutations and the remaining 30 samples were sequenced using Ion Torrent platform. RESULTS: Clinical misdiagnosis occurred in 36/95 (38%) of the cases. Most (82/95; 84%) of the patients were given diazoxide therapy combined with age-dependent frequent feeding, which was effective in 54/95 (66%) cases. The side effects of diazoxide included sodium and water retention, gastrointestinal reactions, polytrichia, and thrombocytopenia. Five patients were treated with octreotide for 1-4 months, of which 80% (4/5) showed a positive response. Non-surgical therapy was effective in 71/95 (75%) cases. Of the four children who received subtotal pancreatectomy, only one had a good outcome. The remission rate of hypoglycemia was 59% for children over 2-yr-old. The CHI-related gene mutation rate was 38% for potassium channel-related genes. Early onset of CHI and a lower diazoxide response rate were associated with potassium-ATP channel gene mutations. CONCLUSION: Age-dependent frequent feeding is an acceptable therapy for CHI. Non-surgical therapy may be highly effective, in part, due to the low rate of potassium channel gene mutations. Surgical outcomes are unreliable without 18F-fluoro-L-DOPA positron emission tomography. Therefore, we do not recommend operation without definitive identification of the pathologic type.

[Patterns of recurrence in patients with stage pT3N0M0 thoracic esophageal squamous cell carcinoma after two-field esophagectomy].

OBJECTIVE: To evaluate the patterns of recurrence and the related factors in patients with pT3N0M0 thoracic esophageal squamous cell carcinoma (ESCC) after two-field esophagectomy. METHODS: From Jan 2008 to Dec 2009, 208 patients with stage pT3N0M0(2002, UICC) thoracic ESCC were treated with two-field esophagectomy in our hospital. There were 138 males and 70 females, and the median age was 60 years old (range 33-78). There were 33 patients in the upper-, 134 in the middle-, and 41 in the lower-thoracic esophagus, with a median length of lesion of 5 cm. There were 32 patients with no-, 78 with mild- and 98 patients with severe adhesions at surgery. The median number of dissected lymph nodes was 9 (range 1-27). 98 patients were treated with surgery alone and 110 with postoperative adjuvant chemotherapy. The statistical analysis was conducted using SPSS 13.0 software. RESULTS: The follow-up was ended on July 2013. In the total group of 208 patients, the total recurrence rate was 41.8% (87/208). Among them, 52 patients had locoregional recurrence (LR), 15 had distant metastasis (DM) and 20 patients had both local recurrence and distant metastasis. 40.2% (35/87) of all recurrences were found within one year after operation, 67.8% (59/87) within 2 years, 86.2% (75/87) within 3 years, and 100% (87/87) within 4 years. The 1-, 3-, and 5-year progression-free survival (PFS) rate was 83.0%, 62.8% and 56.3%, respectively. The overall locoregional recurrence rate was 34.6% (72/208), among them, 9 cases had recurrence in the cervix (all were supraclavicular lymph node metastasis), 66 cases in the mediastinum and 4 cases had para-aortic lymph node metastasis. 83.3% (60/72) of the locoregional recurrence was located in the carinal region or upper area. The 1-, 3-, 5-year locoregional recurrence rate was 15.6%, 32.2%, and 36.8%, respectively, and the median time of recurrence was 15.5 months. The overall distant metastasis (DM) rate was 16.8% (35/208). The 1-, 3-, and 5-year DM rate was 4.4%, 15.3%, and 20.1%, respectively, and the median time of DM was 24 months. The most common site of DM was the lung and bone. The univariate analysis showed that age and tumor site were associated with PFS, tumor site and small lymph node in the mediastinum (diamter <1 cm) before surgery were related with LR (P<0.05 for all), and tumor site, histological differentiation and LR were related with distant metastasis after surgery (P<0.05). Multivariate analysis showed that the tumor site was an independent prognostic factor affecting the progression-free survival and locoregional recurrence (P<0.05), and histological differentiation and LR were independent factors associated with distant metastasis (P<0.05 for all). CONCLUSIONS: The recurrence rate is very high in patients with pT3N0M0 thoracic ESCC after surgery, and most of them occur within 3 years after operation. Locoregional recurrence occurs more frequently and shortly than distant metastasis, and most of LR is located in the carinal region or upper-mediastinum. LR rate in upper-thoracic ESCC is very high, therefore, postoperative radiotherapy (PORT) is strongly suggested. LR rate in middle thoracic ESCC is also rather high and PORT is suggested. LR occur much less in the lower-thoracic ESCC, thus, PORT is not suggested routinely. Patients with poorly differentiated ESCC and LR have a high rate of distant metastasis.

[Therapeutic effects and mechanisms of Opuntia dillenii Haw on atherosclerosis of rats].

The research aimed to investigate the therapeutic effects and mechanisms of Opuntia dillenii Haw polysaccharide (OPS) on atherosclerosis of rats. First atherosclerotic rat models were established by high-fat and high-calcium diet. Thirty days later, the rats were treated with low dosage of OPS (0.2 g x kg(-1) x d(-1)) or high dosage of OPS (0.4 g x kg(-1) x d(-1)) by intraperitoneal injection for 60 days continuously. At the end of treatment, thoracic aorta rings were prepared and vasorelaxation of rat thoracic aorta in different experiment groups were determined by using 620M multi wire myograph system in vitro. Blood and livers of rats were collected. Then plasma levels of total cholesterol (TC), triglyceride (TG) and low density lipoprotein (LDL) of rats were separately determined using whole automatic biochemical analyzer; protein level of hepatic apolipoprotein B (ApoB) and that of hepatic diglyceride acyltransferase (Dgat1) were measured by Western Blot technique. Results showed that the ability of rat thoracic aorta to relax decreased markedly in the model group compared with that in the normal group, and significant differences existed in vasorelaxation ratios induced by different concentrations of carbamylcholine chloride (Carb) between these two groups (P < 0.01). After OPS treatment, the ability of rat thoracic aorta to relax improved markedly, the vasorelaxation ratios induced by Carb at 5 and 10 µmol x L(-1) were respectively 0.34 ± 0.08 and 0.62 ± 0.15 in the group treated with low dosage of OPS, while the ratios induced by Carb at 1 and 5 µmol x L(-1) were respectively 0.54 ± 0.08 and 0.98 ± 0.02 in the group treated with high dosage of OPS, which were all significantly different with those in the model group (P < 0.01). Plasma contents of TC, TG and LDL reduced significantly by the treatments both with low and high dosages of OPS compared with those in the model group (P < 0.01). Protein level of hepatic ApoB and that of hepatic Dgat1 decreased significantly after the treatment with high dosage of OPS compared with those in the model group (P < 0.01). These results indicate that OPS can markedly improve the vasorelaxation of thoracic aorta of atherosclerotic rats and has significant anti-atherosclerotic effect; inhibiting the expression of ApoB and Dgat1 and thus decreasing the amounts of TC, LDL and TG serving as one of the molecular mechanisms of its antiatherosclerosis effect.

[Identification of three novel frameshift mutations in the RUNX2 gene in three sporadic Chinese cases with cleidocranial dysplasia].

OBJECTIVE: To investigate the molecular etiology of three patients with sporadic cleidocranial dysplasia (CCD) and to provide genetic counseling and prenatal diagnosis for the family members based on the identified mutations. METHODS: Genomic DNA was extracted from peripheral blood samples using a standard method. All 7 coding exons of the RUNX2 gene and their flanking intronic sequences were amplified by PCR and sequenced directly. The PCR products of the exons with mutations from the three patients were cloned into a T-vector. Positive clones were sequenced. RESULTS: The three patients who have the typical CCD phenotypes involving clavicles, calvarium, stature, and teeth have carried various frameshift mutations in the RUNX2 gene. Patient 1 has a gross deletion of 80 nucleotides in exon 1 (c.227_306del), which caused a frameshift beginning at the Q/A repeat of the polypeptide and a premature termination (p.Ala76GlyfsX58). Patient 2 has a 2-bp duplication in exon 2 (c.471_472dupGG), which also caused a frameshift and a premature termination (p.Ala158GlyfsX19). Patient 3 has a T duplication in exon 7 (c.1321dupT), which caused a frameshift and a premature termination (p.Ser370PhefsX13) as well. CONCLUSION: The three novel mutations in RUNX2 are the underlying molecular mechanism for the CCD phenotypes of three sporadic Chinese patients, respectively. These have broadened the mutation spectrum of RUNX2 gene and provided a molecular basis for the genetic counseling and prenatal diagnosis for the affected families.

Research on plasma modified fly ash denitration.

The effects of reactor parameters and process parameters on the denitration rate of modified fly ash in different gas atmospheres were studied by using a dielectric barrier plasma reactor and using orthogonal experiments. The characteristics of modified fly ash were analyzed using scanning electron microscope, specific surface area analyzer, X-ray diffraction, Boehm titration and Fourier transform infrared spectroscopy. The experimental data were processed by variance analysis and linear regression to induce the denitration mechanism. R2 of the linear regression analysis model is 0.789, which means that the adsorption pore size, acid groups and basic group can explain 78.9% of the change in denitration rate. The basic group will have a significant positive impact on the denitration rate, and the adsorption pore size and acidic group will have a significant negative impact on the denitration rate. Through variance analysis of the experimental data, it was found that the input power and discharge gap have a significant effect on the denitration rate, but the ionization time and discharge length have no significant effect. The input power affects the denitration rate by impacting the basic group, and the discharge gap affects the denitration rate by influencing the adsorption pore size. There are three denitration mechanisms on the surface of fly ash: physical adsorption, chemical adsorption and absorption process. Among them, chemical adsorption is the main mechanism of action, accounting for approximately 60.86%.

Genetic screening reveals hotspot variants and prevalence rates of Hermansky-Pudlak syndrome in the Chinese population.

BACKGROUND: Hermansky-Pudlak Syndrome (HPS) is a rare autosomal recessive genetic disorder associated with varied clinical manifestations, including oculocutaneous albinism, bleeding tendency, and systemic complications. Early and accurate diagnosis is crucial for medical interventions and genetic counseling. We aimed to characterize the prevalence and spectrum of pathogenic variants of HPS in the Chinese population through genetic screening of newborns. METHODS: Genetic screening for HPS mutations was conducted in 29,622 Chinese newborns from 13 provinces using next-generation sequencing. Pathogenic variants were identified and classified according to ACMG guidelines. Prevalence rates were estimated, and potential hotspot variants were identified. RESULTS: Among screened newborns, 215 carriers with 103 distinct pathogenic variants were identified, including two carriers with additional missense variants. Potential hotspot variants in seven genes were identified, collectively representing over 20 % of carriers in each respective gene. Particularly, the HPS3 c.1838C>G variant was exclusively reported in the Chinese population, suggesting a potential founder effect. The estimated prevalence rate of HPS in China was 2.84/1,000,000. CONCLUSION: Our study provides valuable insights into the genetic landscape of HPS in the Chinese population, aiding in genetic counseling, early diagnosis, and management strategies. These findings contribute to enhancing the understanding and management of HPS in China.

Data mining and analysis of adverse event signals associated with teprotumumab using the Food and Drug Administration adverse event reporting system database.

BACKGROUND: Teprotumumab was approved by the US Food and Drug Administration (FDA) for the treatment of thyroid eye disease in 2020. However, its adverse events (AEs) have not been investigated in real-world settings. AIM: This study aimed to detect and evaluate AEs associated with teprotumumab in the real-world setting by conducting a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database. METHOD: Reporting odds ratio (ROR) was used to detect risk signals from the data from January 2020 to March 2023 in the FAERS database. RESULTS: A total of 3,707,269 cases were retrieved, of which 1542 were related to teprotumumab. The FAERS analysis identified 99 teprotumumab-related AE signals in 14 System Organ Classes (SOCs). The most frequent AEs were muscle spasms (n = 287), fatigue (n = 174), blood glucose increase (n = 121), alopecia (n = 120), nausea (n = 118), hyperacusis (n = 117), and headache (n = 117). The AEs with strongest signal strengths were autophony (ROR = 14,475.49), deafness permanent (ROR = 1853.35), gingival recession (ROR = 190.74), deafness neurosensory (ROR = 129.89), nail growth abnormal (ROR = 103.67), onychoclasis (ROR = 73.58), ear discomfort (ROR = 72.88), and deafness bilateral (ROR = 62.46). Eleven positive AE signals were found at the standardized MedDRA queries (SMQs) level, of which the top five SMQs were hyperglycemia/new-onset diabetes mellitus, hearing impairment, gastrointestinal nonspecific symptoms and therapeutic procedures, noninfectious diarrhea, and hypertension. Age significantly increased the risk of hearing impairment. CONCLUSION: This study identified potential new and unexpected AE signals of teprotumumab. Our findings emphasize the importance of pharmacovigilance analysis in the real world to identify and manage AEs effectively, ultimately improving patient safety during teprotumumab treatment.

The first Chinese intellectual developmental disorder, autosomal recessive 57 patient with two novel MBOAT7 variants.

BACKGROUND: Intellectual disability (ID) is a con neurodevelopmental disorder in children. The genetic etiology of ID is complex, but more subtypes are defined due to the broad application of next-generation sequencing. METHODS: Whole-exome sequencing (WES) and Sanger sequencing was applied in a family with ID. RESULTS: We report a Chinese 7.5-year-old boy, born to non-consanguineous parents. He showed severe intellectual disability, seizures and autistic features. Two previously unreported variants in MBOAT7, c.669C>G (p.(Tyr223*)) and c.1095C>G (p.(Ser365Arg)) were identified by trio-WES. His mother is a heterozygous carrier of the c.1095C>G variant. The c.669C>G variant is a de novo variant which was undetected in his parents. By construction of the full-length cDNA of the patient's MBOAT7, we verified that these two variants were trans-compound heterozygous variants, which support the genetic etiology of this patient. CONCLUSION: This patient is the first Chinese case of intellectual developmental disorder (IDD), autosomal recessive 57 (OMIM:617188) with two unreported MBOAT7 variants.

HIF1α/ATF3 partake PGK1 K191/K192 succinylation by modulating P4HA1/succinate signaling in glioblastoma.

BACKGROUND: Hypoxia is a pathological hallmark in most cancers, including glioblastoma (GBM). Hypoxic signaling activation and posttranslational modification (PTM) of oncogenic proteins are well-studied in cancers. Accumulating studies indicate glycolytic enzyme PGK1 plays a crucial role in tumorigenesis, yet the underlying mechanisms remain unknown. METHODS: We first used ChIP assays to uncover the crosstalk between HIF1α and ATF3 and their roles in P4HA1 regulation. Protein degradation analysis, LC-MS/MS, and in vitro succinate production assays were performed to examine the effect of protein succinylation on GBM pathology. Seahorse assay measured the effects of PGK1 succinylation at K191/192 or its mutants on glucose metabolism. We utilized an in vivo intracranial mouse model for biochemical studies to elucidate the impact of ATF3 and P4HA1 on aerobic glycolysis and the tumor immune microenvironment. RESULTS: We demonstrated that HIF1α and ATF3 positively and negatively regulate the transcription of P4HA1, respectively, leading to an increased succinate production and increased activation of HIF1α signaling. P4HA1 expression elevated the succinate concentration, resulting in the enhanced succinylation of PGK1 at the K191 and K192 sites. Inhibition of proteasomal degradation of PGK1 by succinylation significantly increased aerobic glycolysis to generate lactate. Furthermore, ATF3 overexpression and P4HA1 knockdown reduced succinate and lactate levels in GBM cells, inhibiting immune responses and tumor growth. CONCLUSION: Together, our study demonstrates that HIF1α/ATF3 participated in P4HA1/succinate signaling, which is the major regulator of succinate biosynthesis and PGK1 succinylation at K191 and K192 sites in GBM. The P4HA1/succinate pathway might be a novel and promising target for aerobic glycolysis in GBM.

Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression.

BACKGROUND: Paroxysmal dyskinesias (PDs), a clinically and genetically heterogeneous group of episodic movement disorders, include kinesigenic PD (PKD), exercise-induced PD (PED) and non-kinesigenic PD (PNKD). These disorders are all transmitted as autosomal dominant traits with incomplete penetrance. Several PD-related genetic disorders, including PKD and familial infantile convulsions with paroxysmal choreoathetosis (ICCA), mapped to the same region on chromosome 16. Independent genetic studies have recently revealed that PKD can be caused by loss-of-function mutations in the proline-rich transmembrane protein 2 gene (PRRT2). We tested the hypothesis that other forms of PDs are also due to PRRT2 mutations. METHODS/RESULTS: The whole genomic region of PRRT2 was sequenced in six Han Chinese families and 15 sporadic cases of PD-related phenotypes. The previously reported mutation, c.649dupC (p.R217Pfs*7), was found in two families with PKD, one family with ICCA, one family with PNKD-like phenotype, and two sporadic cases with PED. In an additional ICCA family, a novel frameshift mutation, c.904dupG (p.D302Gfs*38), was identified. A missense mutation, c.913G→A (p.G305R), and a synonymous substitution, c.1011C→T (p.G337G), were also detected in two sporadic PKD cases. CONCLUSION: This study shows that PKD, ICCA and some other PD-related phenotypes are part of the same phenotypic spectrum, caused by mutations in PRRT2. This underscores the complexity of the phenotypic consequences of PRRT2 mutations.