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The extracts from Psoralea corylifolia Linn. (P. corylifolia) seeds have been shown to display antitumor activity. To date, the prospects of this plant and its active compounds in the treatment of non-small-cell lung cancer (NSCLC) have not been thoroughly studied. In this study, we identified a novel psorachromene compound that displays selective cytotoxic effects on all NSCLC cells tested, including NSCLC cells harboring epidermal growth factor receptor (EGFR) activation mutants (H1975L858R/T790M and H1975-MS35L858R/T790M/C797S ). Psorachromene induces G1 arrest in NSCLC cells harboring wild-type EGFR but induces apoptosis in NSCLC cells harboring activating EGFR mutations. Psorachromene inhibits activated EGFR signaling and kinase activity and suppresses tumor growth of implanted H1975-MS35L858R/T790M/C797S cells in nude mice. Molecular docking analysis revealed that psorachromene could form stronger bonds with mutant EGFR than wild-type EGFR, which might account for the greater cytotoxic effects observed in NSCLC cells harboring activating EGFR mutations (H1975 and H1975-MS35) than wild-type EGFR (A549). In conclusion, it is suggested that psorachromene is an attractive agent to be further explored for its use in the treatment of NSCLC patients harboring EGFR L858R/T790M/C797S. [ABSTRACT FROM AUTHOR]

Graves disease (GD) is the most common cause of thyrotoxicosis in children and adolescents, accounting for 15% of all thyroid diseases during childhood. Anti-thyroid drugs (ATD) are recommended as the first-line treatment in children and adolescents. However, the remission rate is lower in children than in adults, and the optimal treatment duration and favorable factors associated with remission remain unknown. We aimed to investigate long-term outcomes of pediatric GD patients receiving ATD. We retrospectively reviewed medical charts of 396 GD subjects from 1985 to 2017 at MacKay Children's Hospital. Ninety–six patients were excluded from the analyses, including 71 patients followed for less than one year, 6 patients who received radioactive therapy and 19 patients who received surgery. The remaining 300 patients initially treated with ATD and followed up for more than 1 year constituted our study population. The 300 patients comprised 257 (85.7%) females and 43 (14.3%) males. Their median age at diagnosis was 11.6 (range 2.7–17.8) years with 11 patients (3.7%) younger than 5 years. Their median follow-up period was 4.7 (range 1.1–23.9) years. Overall, 122 patients achieved the criteria for discontinuing ATD treatment, and seventy-nine (39.9%) patients achieved remission, with a median follow-up period of 5.3 (range 1.5–20.1) years. Patients in the remission group were more likely to be aged <5 years (remission vs. relapse vs. ongoing ATD; 11.4 vs. 0 vs. 2.6%, P = 0.02), less likely to have a family history of thyroid disease (24.1 vs. 42.1 vs. 52.6%, P = 0.001), and had lower TSH receptor antibody (TRAb) levels (42.8 vs. 53.6 vs. 65.1%, P = 0.02) at the time of diagnosis. Long-term ATD remains an effective treatment option for GD in children. Pediatric GD patients aged <5 years, having no family history of thyroid disease and having initial lower TRAb levels were more likely to achieve remission. [ABSTRACT FROM AUTHOR]

Autoimmune thyroid disease (AITD), including Graves disease (GD) and Hashimoto disease (HD), is an organ-specific autoimmune disease with a strong genetic component. Although the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) polymorphism has been reported to be associated with AITD in adults, few studies have focused on children. The aim of our study was to investigate whether the CTLA4 polymorphisms, including -318C/T (rs5742909), +49A/G (rs231775), and CT60 (rs3087243), were associated with GD and HD in Han Chinese adults and children. We studied 289 adult GD, 265 pediatric GD, 229 pediatric HD patients, and 1058 healthy controls and then compared genotype, allele, carrier, and haplotype frequencies between patients and controls. We found that CTLA4 SNPs +49A/G and CT60 were associated with GD in adults and children. Allele G of +49A/G was significantly associated with GD in adults (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.21–1.84; corrected P value [Pc] < 0.001) and children (OR, 1.42; 95% CI, 1.15–1.77; Pc = 0.002). Allele G of CT60 also significantly increased risk of GD in adults (OR, 1.63; 95% CI, 1.27–2.09; Pc < 0.001) and GD in children (OR, 1.58; 95% CI, 1.22–2.04; Pc < 0.001). Significant linkage disequilibrium was found between +49A/G and CT60 in GD and control subjects (D’ = 0.92). Our results showed that CTLA4 was associated with both GD and HD and played an equivalent role in both adult and pediatric GD in Han Chinese population. [ABSTRACT FROM AUTHOR]

Dynamic instability is an essential phenomenon in eukaryotic nuclear division and prokaryotic plasmid R1 segregation. Although the molecular machines used in both systems differ greatly in composition, strong similarities and requisite nuances in dynamics and segregation mechanisms are observed. This brief examination of the current literature provides a functional comparison between prokaryotic and eukaryotic dynamically unstable filaments, specifically ParM and microtubules. Additionally, this mini-review should support the notion that any dynamically unstable filament could serve as the molecular machine driving DNA segregation, but these machines possess auxiliary features to adapt to temporal and spatial disparities in either system. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved treatments for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations. The EGFR C797S mutation is one of the known acquired-resistance mutations to the latest third-generation TKIs. At present, there are no clear options for treating patients who acquire resistance to third-generation TKIs. The acquisition of the EGFR C797S mutation was shown to upregulate the expression of AXL, a receptor tyrosine kinase of the TAM (TYRO3-AXL-MER) family, and the suppression of AXL is effective in reducing the growth of NSCLC cells harboring EGFR C797S. As quercetin was recently shown to inhibit AXL, quercetin may be effective in treating NSCLC cells harboring the EGFR C797S mutation. In this work, the cytotoxic effects of quercetin and its ability to inhibit tumor growth were examined in TKI-resistant NSCLC cells harboring the EGFR C797S mutation. We demonstrated that quercetin exhibited potent cytotoxic effects on NSCLC cells harboring the EGFR C797S mutation by inhibiting AXL and inducing apoptosis. Quercetin inhibited the tumor growth of xenografted NSCLC cells harboring the EGFR C797S mutation and appeared to act synergistically with brigatinib to inhibit of tumor growth in vivo. In summary, herein, we revealed that quercetin is an effective inhibitor for the treatment of non-small-cell lung cancer harboring the EGFR C797S mutation. [ABSTRACT FROM AUTHOR]

Abstract: We have reported previously that LIM homeobox transcription factor 1α (LMX1A) is hypermethylated and functions as a metastasis suppressor in cervical cancer cells. However, the regulation of LMX1A in carcinogenesis has not been reported. We aim to clarify whether specificity protein 1 (Sp1) and enhancer of zeste homolog 2 (EZH2) are involved in the regulation of LMX1A in cervical cancer. First we characterized the LMX1A promoter and used overexpression, knockdown, and reporter assays to show that Sp1 increased LMX1A promoter activity. Next, we used site-directed mutagenesis and electrophoresis mobility shift assays (EMSAs) to demonstrate that Sp1-binding sites were important for Sp1-mediated activation of the LMX1A promoter. Chromatin immunoprecipitation data demonstrated that Sp1 could bind directly to the LMX1A promoter and activate endogenous LMX1A expression in cells pretreated with 5-aza-2′-deoxycytidine (5-aza-dC). Knockdown of EZH2 decreased H3K27me3 histone modification but was insufficient to restore LMX1A expression. To explore the effect of EZH2 on the endogenous LMX1A promoter, we treated EZH2-knockdown cells with 5-aza-dC and trichostatin A (TSA) and then depleted the cells of drugs for 3days. H3K14ac was enriched at the LMX1A promoter in EZH2-knockdown cells and LMX1A mRNA was still expressed. Taken together, these data imply that Sp1 may activate LMX1A expression upon oncogenic stress during cervical cancer development. Moreover, suppression of EZH2 may delay resilencing of LMX1A after the removal of 5-aza-dC and TSA. [Copyright &y& Elsevier]

ENO1 (α-enolase) expression is significantly correlated with reduced survival and poor prognosis in many cancer types, including lung cancer. However, the function of ENO1 in carcinogenesis remains elusive. In this study, we found that high expression of ENO1 is present in metastatic lung cancer cell lines and malignant tumors and is associated with poor overall survival of patients with lung cancer. Knockdown of ENO1 decreased cancer cell proliferation and invasiveness, whereas overexpression of ENO1 enhanced these processes. Moreover, ENO1 expression promoted tumor growth in orthotopic models and enhanced lung tumor metastasis in tail-vein injection models. These effects were mediated by upregulation of mesenchymal markers N-cadherin and vimentin and the epithelial-to-mesenchymal transition regulator SLUG, along with concurrent downregulation of E-cadherin. Mechanistically, ENO1 interacted with hepatocyte growth factor receptor (HGFR) and activated HGFR and Wnt signaling via increased phosphorylation of HGFR and the Wnt coreceptor LRP5/6. Activation of these signaling axes decreased GSK3β activity via Src-PI3K-AKT signaling and inactivation of the β-catenin destruction complex to ultimately upregulate SLUG and β-catenin. In addition, we generated a chimeric anti-ENO1 mAb (chENO1-22) that can decrease cancer cell proliferation and invasion. chENO1-22 attenuated cancer cell invasion by inhibiting ENO1-mediated GSK3β inactivation to promote SLUG protein ubiquitination and degradation. Moreover, chENO1-22 prevented lung tumor metastasis and prolonged survival in animal models. Taken together, these findings illuminate the molecular mechanisms underlying the function of ENO1 in lung cancer metastasis and support the therapeutic potential of a novel antibody targeting ENO1 for treating lung cancer. SIGNIFICANCE: This study shows that ENO1 promotes lung cancer metastasis via HGFR and WNT signaling and introduces a novel anti-ENO1 antibody for potential therapeutic use in lung cancer., (©2021 American Association for Cancer Research.)

Solid tumors characteristically display higher levels of lactate production due to anaerobic metabolism of glucose. Meanwhile, the U.S. Food and Drug Administration (FDA) has approved virotherapy for use in cancer treatment; however systemic administration remains as a particular challenge. Here we report exploitation of tumor lactate production in designing a hypoxia-responsive carrier, self-assembled from hyaluronic acid (HA) conjugated with 6-(2-nitroimidazole)hexylamine, for localized release of recombinant adeno-associated virus serotype 2 (AAV2). The carrier is loaded with lactate oxidase (LOX) and is permeable to small molecules such as the lactate that accumulates in the tumor. Subsequently, LOX oxidizes the lactate to pyruvate inside the carrier, accompanied by internal lowering of oxygen partial pressure. Bioreduction of the 2-nitroimidazole of the HA conjugated with 6-(2-nitroimidazole)hexylamine converts it into a hydrophilic moiety and electrostatically dissociates the carrier and virus. Efficacious and specific delivery was proven by transduction of a photosensitive protein (KillerRed), enabling significant limitation in tumor growth in vivo with photodynamic therapy. An approximate 2.44-fold reduction in tumor weight was achieved after a 2-week course, compared with control groups. Furthermore, conjugation of the AAV2 with iron oxide nanoparticles ("magnetized" AAV2) facilitated magnetic resonance imaging tracking of the virus in vivo. Taken together, the solid tumor microenvironment promotes bioreduction of the lactate-responsive carrier, providing rapid and specific delivery of AAV2 for light-triggered virotherapy via systemic administration.

CTP Synthetase (CtpS) is a universally conserved and essential metabolic enzyme. While many enzymes form small oligomers, CtpS forms large-scale filamentous structures of unknown function in prokaryotes and eukaryotes. By simultaneously monitoring CtpS polymerization and enzymatic activity, we show that polymerization inhibits activity, and CtpS's product, CTP, induces assembly. To understand how assembly inhibits activity, we used electron microscopy to define the structure of CtpS polymers. This structure suggests that polymerization sterically hinders a conformational change necessary for CtpS activity. Structure-guided mutagenesis and mathematical modeling further indicate that coupling activity to polymerization promotes cooperative catalytic regulation. This previously uncharacterized regulatory mechanism is important for cellular function since a mutant that disrupts CtpS polymerization disrupts E. coli growth and metabolic regulation without reducing CTP levels. We propose that regulation by large-scale polymerization enables ultrasensitive control of enzymatic activity while storing an enzyme subpopulation in a conformationally restricted form that is readily activatable., (Copyright © 2014, Barry et al.)

Background: The CTLA4 gene is involved in the activity of T cells., Aim: To determine the association between Graves' disease (GD) susceptibility and CT60 polymorphism of the CTLA4 gene., Patients: 189 children with GD and 620 healthy controls., Methods: We determined the genotype with restriction fragment length polymorphism and compared results., Results: Genotype G/G was significantly associated with GD (odds ratio [OR] = 1.71, 95% confidence interval [CI] 1.20-2.44, Pc = 0.006); however, allele A could reverse its effect. Allele G was significantly more frequent (OR = 1.61, 95% CI 1.18-2.19, Pc = 0.0049) but allele A (OR = 0.62, 95% CI 0.46-0.85, Pc = 0.0049) and phenotype A (OR = 0.58, 95% CI 0.41-0.83, Pc = 0.006) were less frequent in patients with GD than in controls., Conclusion: The CT60 SNP was associated with susceptibility to GD. The G allele increased the risk of GD.

Background: The incidence of type 1 diabetes (T1D) is increasing rapidly worldwide, predominantly in younger individuals. We developed a checklist of all symptoms of T1D reported in the literature and compared the completeness of the recording of symptoms at initial presentation before and after the checklist was adopted., Methods: We retrospectively reviewed the records of patients newly diagnosed with T1D from January 1, 1979 through September 30, 2006 to assess the presenting features and test the usefulness of a symptom checklist in evaluating the history on presentation. The checklist was incorporated into the records as of October 1, 1994., Results: Of the 304 patients identified, 130 (43%) had checklists in the charts. There were 146 (48%) boys, 98 (32%) who were diagnosed under the age of 6 years, and 198 (65%) presented with diabetic ketoacidosis (DKA). Records with a checklist noted diabetic symptoms that were subtle and easily ignored more often than records without the checklist. As compared with those diagnosed at an older age, patients diagnosed at < or = 6 years were more likely to be male, have DKA and a shorter symptom duration, and report more episodes of preceding viral infection and dyspnea. Patients with DKA also had a shorter symptom duration., Conclusions: A diabetic symptom checklist was helpful in identifying clinical diabetic symptoms and signs which were otherwise easily ignored. Younger children were more likely to have a shorter symptom duration and a higher incidence of DKA.

Background: Type 2 diabetes mellitus (T2DM) in children and adolescents is increasing in incidence worldwide. It is the leading type of newly diagnosed diabetes in Taiwan among school children. T2DM is associated with metabolic syndrome in adults, so we tried to find out if these metabolic disorders are present in children., Methods: From 1989 to 2003, 22 children and adolescents were diagnosed with T2DM in our hospital. Their ages ranged from 8.8 to 17.0 (11.7+/-2.3) years; 6 of them were boys. We compared their clinical characteristics with those of 42 healthy and 237 obese children and adolescents. Physical examination was performed and plasma glucose and serum cholesterol, triglycerides, uric acid, creatinine, HDL-cholesterol, and insulin levels were measured and LDL-cholesterol was calculated. Demographic and laboratory data were compared among the T2DM, obese and control groups., Results: The female: male ratio among the patients was 2.7: 1; 18% were overweight and 68% obese, and 64% had acanthosis nigricans. There were no significant differences between the T2DM and obese groups in terms of biochemistry profiles except for the higher plasma glucose in the T2DM group. Children with T2DM had higher levels of cholesterol and triglycerides but lower levels of HDL-cholesterol compared with healthy children. Among obese children without T2DM, the levels of glucose, triglycerides, uric acid, insulin, HOMA-IR were higher than in the healthy group, and HDL-cholesterol levels were lower., Conclusions: Children with T2DM or obesity should be evaluated for metabolic disorders.

The CBLB gene functions as a negative regulator of autoimmunity. Impairment of the Cbl-b signaling pathway may contribute to human autoimmune disease. dbSNP rs2305035 is a C/T polymorphism located in exon 10 of the CBLB gene. We report an association study of this polymorphism in children with Graves' disease. The patients were 158 unrelated children (125 girls) with Graves' disease, aged 9.8 +/- 3.3 years. The controls consisted of 237 adults without a history of autoimmune disease. The C allele and phenotype frequencies of patients and controls were 247 (78.2%) vs 356 (75.1%) (OR = 1.19, p >0.05) and 151 (95.6%) vs 221 (93.2%) (OR = 1.56, p >0.05), respectively. The allelic polymorphism in patients and controls with and without DRB1*09012 were also not significantly different. This study demonstrates that the C/T polymorphism in exon 10 of the CBLB gene is not associated with Graves' disease in children.