Effects of Intronic and Exonic Polymorphisms of Paraoxonase 1 (PON1) Gene on Serum PON1 Activity in a Korean Population

Paraoxonase 1 (PON1) hydrolyzes a number of toxic organophosphorous compounds and reduces lipid peroxide accumulation, and PON1 genetic polymorphisms in the coding region modulate serum PON1 activity. In this study, we investigated the association between 3 polymorphisms of PON1 located in intron 5 (17899insdelTT and 17974CT) and exon 6 (192QR) and serum PON1 activity. The genetic polymorphisms and serum activity of PON1 were analyzed in 153 healthy Koreans by using a direct sequencing assay and spectrophotometric method, respectively. A significant linkage disequilibrium (LD) was observed between all tested single nucleotide polymorphisms, with the strongest LD observed between 17899insdelTT and 192QR (D' = 0.984). The 17899insdelTT, 17974CT and 192QR genetic polymorphisms were associated with significant differences in serum paraoxonase activity. In multiple regression analyses, smoking, triglyceride level, high-density lipoprotein (HDL) level, and the 17899insdelTT and 192QR genetic polymorphisms were significant determinants of serum paraoxonase activity, while age, smoking, triglyceride level, HDL level, and the 192QR genetic polymorphism were significant determinants of serum arylesterase activity. These results suggest that although the 192QR genetic polymorphism in the coding region of PON1 is primarily associated with serum PON1 activity, the intronic polymorphisms are also involved in serum PON1 activity, and this association may be mediated by LD

Long-term efficacy and safety of tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: final analysis of phase IIb results

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Oral HDAC inhibitor tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: phase IIb results

Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval : 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652)

Comparison of first-line treatment with CHOP versus ICED in patients with peripheral T-cell lymphoma eligible for upfront autologous stem cell transplantation

IntroductionUpfront autologous stem cell transplantation (ASCT) has been recommended for patients who are newly diagnosed with peripheral T-cell lymphoma (PTCL), and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), an anthracycline-based chemotherapy has been the frontline chemotherapy for PTCL. However, it is not clear whether anthracycline-based chemotherapies such as CHOP could be standard induction therapy for PTCL.MethodsWe conducted a randomized phase II study to compare CHOP with fractionated ifosfamide, carboplatin, etoposide, and dexamethasone (ICED) for patients eligible for ASCT. The primary endpoint was progression-free survival (PFS) and secondary endpoints included objective response rate, overall survival (OS), and safety profiles.ResultsPatients were randomized into either CHOP (n = 69) or ICED (n = 66), and the characteristics of both arms were not different. PTCL-not otherwise specified (NOS, n = 60) and angioimmunoblastic T-cell lymphoma (AITL, n = 53) were dominant. The objective response rate was not different between CHOP (59.4%) and ICED (56.1%), and the 3-year PFS was not different between CHOP (36.7%) and ICED (33.1%). In AITL patients, CHOP was favored over ICED whereas ICED was associated with more cytopenia and reduced dose intensity. Patients who received upfront ASCT after achieving complete response to CHOP or ICED showed 80% of 3-year OS.DiscussionIn summary, our study showed no therapeutic difference between CHOP and ICED in terms of response and PFS. Thus, CHOP might remain the reference regimen especially for AITL based on its better outcome in AITL, and upfront ASCT could be recommended as a consolidation of complete response in patients with PTCL

Highly Transparent Conducting Electrodes Based on a Grid Structure of Silver Nanowires

Transparent conducting electrodes (TCEs) formed with silver nanowires (AgNWs) have attracted attention as substitutes for indium tin oxide (ITO). However, the randomly deposited AgNW film performs poorly in terms of the transmittance and sheet resistance to serve as a substitute of ITO. To improve the performance of the AgNW film, we fabricated a grid-patterned AgNW by modifying the surface energy of the substrate. The hydrophobized surface was selectively etched by UV light through a quartz chrome mask, and a suspension of AgNWs in isopropyl alcohol/ethylene glycol mixture was coated on the substrate by a meniscus dragging deposition process. The grid-patterned AgNW film has a lower percolation threshold and a 13% higher figure-of-merit value compared to the randomly deposited AgNW film. The transparent thin films with a grid structure of AgNWs exhibit the high electrical conductivity with a sheet resistance of 33 Ohm/sq at a transmittance of 92.7% (λ = 550 nm)

Identification and characterization of D410E, a novel mutation in the loop 3 domain of CaSR, in autosomal dominant hypocalcemia and therapeutic approaches with novel calcilytics, AXT914

Background: Autosomal dominant hypocalcemia (ADH) is a rare disorder characterized by benign hypocalcemia, inappropriately low parathyroid hormone (PTH) levels and mostly hypercalciuria. ADH can be caused by activating mutations of the calcium-sensing receptor (CaSR) gene located on chromosome 3q13.3-21. Calcium-sensing receptor plays a pivotal role in the regulation of calcium homeostasis and is abundantly expressed in parathyroid gland, thyroid C cell, and renal tubular system. Activation of CaSR by increased Ca2+ inhibits PTH secretion, stimulates calcitonin secretion, and promotes urinary Ca2+ excretion, and thereby maintains the Ca2+ at the normal level. Herein, we report a novel activating mutation in the CaSR gene in a Korean family with ADH. Meanwhile, antagonist of the CaSR, calcilytics could be a therapeutic option in the treatment of ADH. Method: We identified a 55-yr-old woman with mild hypocalcemia (7.7 mg/dL) and hypercalciuria (24-hr urine Ca: 868 mg/d) caused by missense mutations of the CaSR gene. She showed low normal serum PTH level (10.14 pg/mL). We performed mutational analysis of the genes encoding GCMB, pre-pro-PTH and CaSR using PCR-amplified genomic DNA in her family members. The ability of wild-type and mutant CaSR to activate the MAPK signaling cascade was assessed by examining phosphorylation of ERK1/2. Intacellular Ca2+ concentration was measured by Fura-2 dye. Blocking of CaSR with calcilytics, AXT914 was also tested by Fura-2 with a variety of concentrations. Result: Direct sequencing analysis of the CaSR gene showed that the proband and her daughter possess a T to A transition at nucleotide 1230 resulting in a D410E missense mutation in exon 4 of the CaSR. No mutation was detected in GCMB and Prepro-PTH genes. HEK293 cells were stably transfected with plasmids encoding wild-type or mutant CaSR genes. Escalation of the extracellular Ca2+ concentration from 0.5 to 5.0 mM resulted in increased phosphorylation of ERK1/2 and escalation of the extracellular Ca2+ concentration from 1.0 to 10 mM resulted in increased intracellular Ca2+ detected by Fura-2 in mutant CaSR-expressing cell than wild-type-expressing one. These results indicate that D410E mutation of CaSR is associated with ADH in this family. Finally, AXT914 successively blunted the increased intracellular signaling via CaSR. Conclusion: Over 60 activating mutations in the CaSR gene have been identified to cause ADH so far. Here we add one more activating mutation that causes ADH. This could be of interest because this novel mutation occurred in the loop 3 region of the VFT domain in CaSR where little was known to be important in its function. Further clinical study is needed to validate the effectiveness of calcilytics in the treatment of ADH in vivo

A Case of Cecal Endometriosis Presenting as Subepithelial Tumor

Endometriosis is a benign gynecologic disease, characterized by the presence and growth of functional endometrial-like tissue outside uterus. This ectopic endometrial tissue is most commonly found in the peritoneum, ovaries and uterosacral ligaments, but extremely rarely there is involvement of the appendix or cecum. Here we report a case of cecal endometriosis presenting as a subepithelial tumor diagnosed by surgical excision. (Korean J Gastroenterol 2016;68:214-217