Pei‐Lung Chen

BACKGROUND: Tuberous sclerosis complex is a genetic disorder affecting every organ system, but disease manifestations vary significantly among affected individuals. The diverse and varied presentations and progression can be life-threatening with significant impact on cost and quality of life. Current surveillance and management practices are highly variable among region and country, reflective of the fact that last consensus recommendations occurred in 1998 and an updated, comprehensive standard is lacking that incorporates the latest scientific evidence and current best clinical practices. METHODS: The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 separate subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important clinical management implications and was charged with formulating key clinical questions to address within its focus area, reviewing relevant literature, evaluating the strength of data, and providing a recommendation accordingly. RESULTS: The updated consensus recommendations for clinical surveillance and management in tuberous sclerosis complex are summarized here. The recommendations are relevant to the entire lifespan of the patient, from infancy to adulthood, including both individuals where the diagnosis is newly made as well as individuals where the diagnosis already is established. CONCLUSIONS: The 2012 International Tuberous Sclerosis Complex Consensus Recommendations provide an evidence-based, standardized approach for optimal clinical care provided for individuals with tuberous sclerosis complex.

Graves' disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined=6.75 × 10(-32)) and HLA-DRB1*08:03 (Pcombined=1.83 × 10(-9)) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13-41.48) and 6.13 (95% confidence interval=3.28-11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined=3.32 × 10(-21), 95% confidence interval=21.66-108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.

PURPOSE: Here, we aim to investigate the molecular mechanism of regorafenib and verify the potential druggable target for the treatment of hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.

BACKGROUND: Recent genetic progress has allowed for the molecular diagnosis of Parkinson's disease. However, genetic causes of PD vary widely in different ethnicities. Mutational frequencies and clinical phenotypes of genes associated with PD in Asian populations are largely unknown. The objective of this study was to identify the mutational frequencies and clinical spectrums of multiple PD-causative genes in a Taiwanese PD cohort. METHODS: A total of 571 participants including 324 patients with early-onset parkinsonism (onset age, <50 years) and 247 parkinsonism pedigrees were recruited at a tertiary referral center in Taiwan from 2002 to 2017. Genetic causes were identified by an integrated approach including gene dosage analysis, a targeted next-generation sequencing panel containing 40 known PD-causative genes, repeat-primed polymerase chain reaction, and whole-exome sequencing analysis. RESULTS: Thirty of the 324 patients with early-onset parkinsonism (9.3%) were found to carry mutations in Parkin, PINK1, or PLA2G6 or had increased trinucleotide repeats in SCA8. Twenty-nine of 109 probands with autosomal-recessive inheritance of parkinsonism (26.6%) were found to carry mutations in Parkin, PINK1, GBA, or HTRA2. The genetic causes for the 138 probands with an autosomal-dominant inheritance pattern of parkinsonism were more heterogeneous. Seventeen probands (12.3%) carried pathogenic mutations in LRRK2, VPS35, MAPT, GBA, DNAJC13, C9orf72, SCA3, or SCA17. A novel missense mutation in the UQCRC1 gene was found in a family with autosomal-dominant inheritance parkinsonism via whole-exome sequencing analysis. CONCLUSIONS: Our findings provide a better understanding of the genetic architecture of PD in eastern Asia and broaden the clinical spectrum of PD-causing mutations. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.