MicroRNA-630 inhibitor sensitizes chemoresistant ovarian cancer to chemotherapy by enhancing apoptosis.

MicroRNA-630 (miR-630) has been implicated in the development and progression of multiple cancers. The current study aimed to investigate the role of miR-630 in chemoresistant epithelial ovarian cancer. MiR-630 expression levels were detected in ovarian cancer cell line SKOV3 and paclitaxel-resistant SKOV3 (SKOV3-TR) via microarray and qRT-PCR. MiR-630 inhibitors and negative controls were transfected into SKOV3 and SKOV3-TR cells. Wound healing, invasion, chemosensitivity, and cell apoptosis assays were performed to determine proliferation and migration rates. Chemoresistant patient-derived xenograft (PDX) models were established and utilized to verify the effect of miR-630 on chemoresistant ovarian cancer. Inhibition of miR-630 decreased cell proliferation and enhanced the sensitivity of SKOV3-TR and SKOV3 cells to paclitaxel. In the chemosensitivity assay, we observed that the miR-630 inhibitor exhibited a synergistic effect with paclitaxel on SKOV3-TR cells. Inhibition was correlated with enhanced expression of apoptosis-related proteins. APAF-1 was predicted to be a potential target of miR-630. An in vivo PDX study showed that the miR-630 inhibitor sensitized chemoresistant ovarian cancer to paclitaxel. Thus, miR-630 inhibitor sensitizes chemoresistant epithelial ovarian cancer to chemotherapy by enhancing apoptosis. Our findings suggest that miR-630 might be a potential therapeutic target for chemotherapy-resistant ovarian cancer.

Evaluation and optimization of a conventional SPCE for FMD post-vaccination monitoring.

BACKGROUND: Foot-and-mouth disease (FMD) can be controlled by either stamping out or vaccination, a choice which depends on both the economic importance of the livestock sector as well as the disease status. In FMD-free countries with vaccination, such as Korea, vaccination programs should guarantee prevention against transmission of FMD. Monitoring of vaccination programs is also essential for ensuring sufficient coverage that will limit the transmission of FMDV. There are several methods to screen FMD virus (FMDV) structural protein (SP) antibodies including SPCE (Solid-phase competitive ELISA), LPBE (Liquid-phase blocking ELISA), and VNT (Virus neutralization test). Among these, SPCE is widely used for serological monitoring since VNT-the gold standard method-has certain practical limitations, such as high costs in terms of time and labor. However, whether SPCE can ensure the vaccination status of individual animals and whole farms is unclear. In this study, SPCE, LPBE and VNT were compared with respect to correlation with each other and sensitivity at commercial pig farms. RESULTS: The positive results obtained by PrioCHECK SPCE differed from those obtained by LPBE and VNT. The sensitivity of SPCE relative to those of the other tests was fairly low. The raw data of SPCE were most highly correlated with those of VNT with XJ strain, while their positivity and negativity were most highly correlated with LPBE. The results of ROC analysis proposed new cut-off for PrioCHECK SPCE higher than the previous 50% inhibition. CONCLUSIONS: The high false positive rate of PrioCHECK SPCE suggested that high seropositivity by SPCE may not guarantee a true vaccination coverage. Adjusting the cut-off percentage (%) inhibition value for SPCE is needed to address this problem, and it is highly recommended that routine FMDV serological monitoring programs using PrioCHECK SPCE should be combined with alternative methods such as LPBE or VNT.

Aggregation-prone GFAP mutation in Alexander disease validated using a zebrafish model.

BACKGROUND: Alexander disease (AxD) is an astrogliopathy that predominantly affects the white matter of the central nervous system (CNS), and is caused by a mutation in the gene encoding the glial fibrillary acidic protein (GFAP), an intermediate filament primarily expressed in astrocytes and ependymal cells. The main pathologic feature of AxD is the presence of Rosenthal fibers (RFs), homogeneous eosinophilic inclusions found in astrocytes. Because of difficulties in procuring patient' CNS tissues and the presence of RFs in other pathologic conditions, there is a need to develop an in vivo assay that can determine whether a mutation in the GFAP results in aggregation and is thus disease-causing. METHODS: We found a GFAP mutation (c.382G > A, p.Asp128Asn) in a 68-year-old man with slowly progressive gait disturbance with tendency to fall. The patient was tentatively diagnosed with AxD based on clinical and radiological findings. To develop a vertebrate model to assess the aggregation tendency of GFAP, we expressed several previously reported mutant GFAPs and p.Asp128Asn GFAP in zebrafish embryos. RESULTS: The most common GFAP mutations in AxD, p.Arg79Cys, p.Arg79His, p.Arg239Cys and p.Arg239His, and p.Asp128Asn induced a significantly higher number of GFAP aggregates in zebrafish embryos than wild-type GFAP. CONCLUSIONS: The p.Asp128Asn GFAP mutation is likely to be a disease-causing mutation. Although it needs to be tested more extensively in larger case series, the zebrafish assay system presented here would help clinicians determine whether GFAP mutations identified in putative AxD patients are disease-causing.

Morphometric analysis of high-intensity focused ultrasound-induced lipolysis on cadaveric abdominal and thigh skin.

Non-focused ultrasound and high-intensity focused ultrasound (HIFU) devices induce lipolysis by generating acoustic cavitation and coagulation necrosis in targeted tissues. We aimed to investigate the morphometric characteristics of immediate tissue reactions induced by 2 MHz, 13-mm focused HIFU via two-dimensional ultrasound images and histologic evaluation of cadaveric skin from the abdomen and thigh. Acoustic fields of a 2 MHz, 38-mm HIFU transducer were characterized by reconstruction of the fields using acoustic intensity measurement. Additionally, abdominal and thigh tissues from a fresh cadaver were treated with a HIFU device for a single, two, and three pulses at the pulse energy of 130 J/cm2 and a penetration depth of 13 mm. Acoustic intensity measurement revealed characteristic focal zones of significant thermal injury at the depth of 38 mm. In both the abdomen and thigh tissue, round to oval ablative thermal injury zones (TIZs) were visualized in subcutaneous fat layers upon treatment with a single pulse of HIFU treatment. Two to three HIFU pulses generated larger and more remarkable ablative zones throughout subcutaneous fat layers. Finally, experimental treatment in a tumescent infiltration-like setting induced larger HIFU-induced TIZs of an oval or columnar shape, compared to non-tumescent settings. Although neither acoustic intensity measurement nor cadaveric tissue exactly reflects in vivo HIFU-induced reactions in human tissue, we believe that our data will help guide further in vivo studies in investigating the therapeutic efficacy and safety of HIFU-induced lipolysis.

Multiplexed cancer biomarker detection using chip-integrated silicon photonic sensor arrays.

The analysis of disease-specific biomarker panels holds promise for the early detection of a range of diseases, including cancer. Blood-based biomarkers, in particular, are attractive targets for minimally-invasive disease diagnosis. Specifically, a panel of organ-specific biomarkers could find utility as a general disease surveillance tool enabling earlier detection or prognostic monitoring. Using arrays of chip-integrated silicon photonic sensors, we describe the simultaneous detection of eight cancer biomarkers in serum in a relatively rapid (1 hour) and fully automated antibody-based sandwich assay. Biomarkers were chosen for their applicability to a range of organ-specific cancers, including disease of the pancreas, liver, ovary, breast, lung, colorectum, and prostate. Importantly, we demonstrate that selected patient samples reveal biomarker "fingerprints" that may be useful for a personalized cancer diagnosis. More generally, we show that the silicon photonic technology is capable of measuring multiplexed panels of protein biomarkers that may have broad utility in clinical diagnostics.

A nonsynonymous SNP in BANK1 is associated with serum LDL cholesterol levels in three Korean populations.

Serum levels of lipids, such as cholesterol and triglycerides, are heritable risk factors for cardiovascular disease and targets for therapeutic intervention. Because previous genome-wide association studies (GWASs) did not target functional genetic variants, we employed an alternate approach using nonsynonymous single-nucleotide polymorphisms (SNPs) to identify functional genetic variants associated with the regulation of serum lipid levels. We selected 3667 healthy individuals from a rural community-based cohort (CAVAS; Cardio Vascular disease Association Study) of the Korean Genome and Epidemiology Study project. We analyzed demographic and lifestyle information, lipid measurements and genotypes using the Illumina-1M SNP chip. For genotyping, we isolated 11 558 nonsynonymous SNPs and conducted a linear regression analysis with four lipid traits (total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterols and triglycerides). Significantly associated SNPs were validated in two independent Korean populations, Korean Association Resource (KARE) (n=4116) and Health Examinee (HEXA) (n=2178). Of the 11 558 SNPs, one SNP (rs3733197) from the CAVAS was significantly associated with serum LDL cholesterols (beta±s.e.=4.67±0.94, P-value=1.0 × 10(-6 and) Bonferroni corrected P-value=0.012). The replication results of HEXA and KARE were beta±s.e.=2.88±1.12, P-value=0.016 and beta±s.e.=1.26±0.97, P-value=0.196, respectively. An overall meta-analysis of the three data sets revealed beta=2.98±0.57, P-value=6.19 × 10(-7). The rs3733197 is located in the coding region of BANK1 (B-cell scaffold protein with ankyrin repeats 1), and the minor allele (A) resulted in the replacement of the Alanine at position 383 with Threonine.

Angiopoietin-like 3 regulates hepatocyte proliferation and lipid metabolism in zebrafish.

Loss-of-function mutations in angiopoietin-like 3 (ANGPTL3) cause familial hypobetalipoproteinemia type 2 (FHBL2) in humans. ANGPTL3 belongs to the angiopoietin-like family, the vascular endothelial growth factor family that is structurally similar to angiopoietins and is known for a regulator of lipid and glucose metabolism, although it is unclear how mutations in ANGPTL3 lead to defect in liver development in the vertebrates. We report here that angptl3 is primarily expressed in the zebrafish developing liver and that morpholino (MO) knockdown of Angptl3 reduces the size of the developing liver, which is caused by suppression of cell proliferation, but not by enhancement of apoptosis. However, MO knockdown of Angptl3 did not alter angiogenesis in the developing liver. Additionally, disruption of zebrafish Angptl3 elicits the hypocholesterolemia phenotype that is characteristic of FHBL2 in humans. Together, our findings propose a novel role for Angptl3 in liver cell proliferation and maintenance during zebrafish embryogenesis. Finally, angptl3 morphants will serve as a good model for understanding the pathophysiology of FHBL2.

Subpicogram per milliliter detection of interleukins using silicon photonic microring resonators and an enzymatic signal enhancement strategy.

The detection of biomolecules at ultralow (low to subpicogram per milliliter) concentrations and within complex, clinically relevant matrices is a formidable challenge that is complicated by limitations imposed by the Langmuir binding isotherm and mass transport, for surface-based affinity biosensors. Here we report the integration of an enzymatic signal enhancement scheme onto a multiplexable silicon photonic microring resonator detection platform. To demonstrate the analytical value of this combination, we simultaneously quantitated levels of the interleukins IL-2, IL-6, and IL-8 in undiluted cerebrospinal fluid in an assay format that is multiplexable, relatively rapid (90 min), and features a 3 order of magnitude dynamic range and a limit of detection ≤1 pg/mL. The modular nature of this assay and technology should lend itself broadly amenable to different analyte classes, making it a versatile tool for biomarker analysis in clinically relevant settings.

Biorenewable Polymer-Based Light-Absorbing Porous Hydrogel for Efficient Solar Steam Desalination.

An efficient interfacial heating system composed of a light-absorbing material and a hydrophilic porous support is developed through eco-friendly and energy-effective fabrication processes. Lignin nanoparticles (NPs) and cellulose nanofibers (CNFs) are harnessed as biorenewable light absorbers and hydrophilic supports, respectively. Lignin NPs are prepared using a solvent exchange process of the fractionated lignin with organic solvents to improve its π-π stacking and light-absorbing property for efficient photothermal conversion. Then, the lignin NPs are mixed with CNFs and lyophilized to obtain a light-absorbing porous hydrogel (LAPH), and the resulting LAPHs are covalently cross-linked and hybridized with Au NPs through a seed-mediated growth to further enhance their mechanical stability, hydrophilicity, and photothermal conversion properties. The resulting LAPHs exhibit an outstanding and prolonged performance as a solar steam generator such as high salt and pH tolerance, evaporation rate (3.17 kg m-2 h-1), and solar steam generation efficiency (83.4%) under 1 sun irradiation.

Reduced Electron Temperature in Silicon Multi-Quantum-Dot Single-Electron Tunneling Devices.

The high-performance room-temperature-operating Si single-electron transistors (SETs) were devised in the form of the multiple quantum-dot (MQD) multiple tunnel junction (MTJ) system. The key device architecture of the Si MQD MTJ system was self-formed along the volumetrically undulated [110] Si nanowire that was fabricated by isotropic wet etching and subsequent oxidation of the e-beam-lithographically patterned [110] Si nanowire. The strong subband modulation in the volumetrically undulated [110] Si nanowire could create both the large quantum level spacings and the high tunnel barriers in the Si MQD MTJ system. Such a device scheme can not only decrease the cotunneling effect, but also reduce the effective electron temperature. These eventually led to the energetic stability for both the Coulomb blockade and the negative differential conductance characteristics at room temperature. The results suggest that the present device scheme (i.e., [110] Si MQD MTJ) holds great promise for the room-temperature demonstration of the high-performance Si SETs.

A case of pulmonary thromboembolism possibly associated with the use of creatine supplements.

Drug administration should be considered a risk factor for venous thromboembolism (VTE) in younger healthy patients. We present a case of new-onset pulmonary embolism (PE), possibly associated with excessive creatine supplement intake. A 24-year-old non-smoker male presented to the emergency department with sudden-onset dyspnoea and chest discomfort. Computed tomography pulmonary angiography and venography confirmed PE in the left and right pulmonary artery branches and a thrombus in the left popliteal vein. The patient had no family history of VTE, and other causes of thrombophilia were unlikely. He reported a recent increase in the intensity of his workouts and the dose of his creatine supplements in preparation for a bodybuilding competition. The creatine supplements likely promoted dehydration during intense workouts and profuse sweating. He received anticoagulation therapy, and the creatine supplements were discontinued. Creatine supplements should be used cautiously when there is a higher risk of becoming dehydrated.

Enhanced photocatalytic crystal-violet degradation performances of sonochemically-synthesized AC-CeO2 nanocomposites.

Semiconductor-based photocatalysis is one of the favorable techniques for the wastewater treatment. Herein, we synthesized the activated carbon-decorated cerium dioxide (AC-CeO2) nanocomposites via the facile ultrasonication method by using the biomass-derived AC nanoflakes and the sonochemically-synthesized CeO2 nanoparticles. The AC-CeO2 nanocomposites exhibited the aggregated morphology with the AC nanoflakes-anchored CeO2 nanoparticles. Since the hybridization of conductive AC and semiconductive CeO2 would lead to the increased photocarrier transport and the reduced photocarrier recombination, during the photocatalytic reaction, the AC-CeO2 nanocomposites showed the enhanced crystal violet dye-degradation efficiency up to 97.9 % within 135 min. The results suggest that the AC-CeO2 nanocomposites hold promise as a prominent photocatalyst for future green environmental technology.

A novel in-frame GFAP p.E138_L148del mutation in Type II Alexander disease with atypical phenotypes.

Alexander disease (AxD) is a neurodegenerative astrogliopathy caused by mutation in the glial fibrillary acidic protein (GFAP) gene. A 42-year-old Korean man presented with temporary gait disturbance and psychiatric regression after a minor head trauma in the absence of bulbar symptoms and signs. Magnetic resonance images of the brain and spinal cord showed significant atrophy of the medulla oblongata and the entire spinal cord as well as contrast-enhanced T2 hypointensity in the basal ganglia. DNA sequencing revealed a novel 33-bp in-frame deletion mutation (p.Glu138_Leu148del) within the 1B rod domain of GFAP, which was predicted to be deleterious by PROVEAN analysis. To test whether the deletion mutant is disease-causing, we performed in vitro GFAP assembly and sedimentation assays, and GFAP aggregation assays in human adrenal carcinoma SW13 (Vim-) cells and rat primary astrocytes. All the assays revealed that GFAP p.Glu138_Leu148del is aggregation prone. Based on these findings, we diagnosed the patient with Type II AxD. This is a report that demonstrates the pathogenicity of InDel mutation of GFAP through functional studies. This patient's atypical presentation as well as the discrepancy between clinical symptoms and radiologic findings may extend the scope of AxD.

Multidimensional Early Prediction Score for Drug-Resistant Epilepsy.

BACKGROUND AND PURPOSE: Achieving favorable postoperative outcomes in patients with drug-resistant epilepsy (DRE) requires early referrals for preoperative examinations. The purpose of this study was to investigate the possibility of a user-friendly early DRE prediction model that is easy for nonexperts to utilize. METHODS: A two-step genotype analysis was performed, by applying 1) whole-exome sequencing (WES) to the initial test set (n=243) and 2) target sequencing to the validation set (n=311). Based on a multicenter case-control study design using the WES data set, 11 genetic and 2 clinical predictors were selected to develop the DRE risk prediction model. The early prediction scores for DRE (EPS-DRE) was calculated for each group of the selected genetic predictors (EPS-DREgen), clinical predictors (EPS-DREcln), and two types of predictor mix (EPS-DREmix) in both the initial test set and the validation set. RESULTS: The multidimensional EPS-DREmix of the predictor mix group provided a better match to the outcome data than did the unidimensional EPS-DREgen or EPS-DREcln. Unlike previous studies, the EPS-DREmix model was developed using only 11 genetic and 2 clinical predictors, but it exhibited good discrimination ability in distinguishing DRE from drug-responsive epilepsy. These results were verified using an unrelated validation set. CONCLUSIONS: Our results suggest that EPS-DREmix has good performance in early DRE prediction and is a user-friendly tool that is easy to apply in real clinical trials, especially by nonexperts who do not have detailed knowledge or equipment for assessing DRE. Further studies are needed to improve the performance of the EPS-DREmix model.

Inhibition of ganglioside GD1a synthesis suppresses the differentiation of human mesenchymal stem cells into osteoblasts.

In this study, we investigated the regulatory role of ganglioside GD1a in the differentiation of osteoblasts from human mesenchymal stem cells (hMSCs) by using lentivirus-containing short hairpin (sh)RNA to knockdown ST3 ß-galactoside α-2, 3-sialyltransferase 2 (ST3Gal II) mRNA expression. After hMSCs were infected for 72 h with the lentivirus constructed with ST3Gal II shRNAs, the puromycin-resistant cells were selected and subcultured to produce hMSCs with ST3Gal II mRNA knockdown. The hMSCs established from human dental papilla abundantly expressed CD44 and CD105, but not CD45 and CD117. Osteoblasts that differentiated from normal hMSCs showed a significant increase in alkaline phosphatase (ALP) activity and ganglioside GD1a expression level compared with those in hMSCs. Lentiviral infection of hMSCs successfully induced a marked inhibition of ST3Gal II mRNA expression and caused a significant decrease in ALP activity and ganglioside GD1a expression. During osteoblastic differentiation, the increased ALP activity remarkably reduced by suppression of ganglioside GD1a expression by ST3Gal II shRNA. Ganglioside GD1a and ALP were mainly expressed in the cell body of hMSCs and osteoblasts with colocalization. The phosphorylation of extracellular signal-regulated kinases (ERK) 1/2 mitogen-activated protein (MAP) kinase and epidermal growth factor receptor (EGFR) was significantly reduced in the osteoblasts that had differentiated from the hMSCs with ST3Gal II mRNA knockdown. These results suggest that ganglioside GD1a plays an important role in the regulation of osteoblastic differentiation of hMSCs through the activation of ERK 1/2 MAP kinase and EGFR.

A chimeric porcine reproductive and respiratory syndrome virus (PRRSV)-2 vaccine is safe under international guidelines and effective both in experimental and field conditions.

Vaccination is currently the most effective strategy to control porcine reproductive and respiratory syndrome (PRRS). New-generation PRRS vaccines are required to be safe and broadly cross-protective. We have recently created the chimeric PRRS virus K418DM which proved to be a good vaccine candidate under field conditions. In the present study, we designed safety and efficacy tests under experimental and field conditions for further evaluation of K418DM1.1, a plaque-purified K418DM. In the homologous challenge study, K418DM1.1 induced high serum virus neutralization (SVN) antibody titers (i.e., 4.2 log2 ± 1.7) at 21 days post-challenge (dpc) and provided protection as demonstrated by the significantly lower levels of viremia at 3 and 7 dpc and significantly lower microscopic lung lesion scores compared to the unvaccinated group. K418DM1.1 was also protective in the heterologous challenge study, with vaccinated pigs showing significantly lower levels of viremia at 14 dpc compared to the unvaccinated pigs. A field study was performed to evaluate the efficacy of K418DM1.1 against heterologous exposure and vaccinated pigs presented significantly lower viremia than unvaccinated pigs. According to the safety test for the examination of virulence reversion, no infectivity was observed in tissue homogenate filtrate both in the vaccinated and comingled groups. Thus, the risk of virulence, as well as transmission, appeared negligible. These overall results indicate that K418DM1.1 is a good vaccine candidate based on its safety and protective efficacy.

A zebrafish model of nondystrophic myotonia with sodium channelopathy.

Nondystrophic myotonias are disorders of Na+ (Nav1.4 or SCN4A) and Cl- (CLCN1) channels in skeletal muscles, and frequently show phenotype heterogeneity. The molecular mechanism underlying their pathophysiology and phenotype heterogeneity remains unclear. As zebrafish models have been recently exploited for studies of the pathophysiology and phenotype heterogeneity of various human genetic diseases, a zebrafish model may be useful for delineating nondystrophic myotonias. Here, we generated transgenic zebrafish expressing a human mutant allele of SCN4A, referred to as Tg(mylpfa:N440K), and needle electromyography revealed increased number of myotonic discharges and positive sharp waves in the muscles of Tg(mylpfa:N440K) than in controls. In addition, forced exercise test at a water temperature of 24 °C showed a decrease in the distance moved, time spent in and number of visits to the zone with stronger swimming resistance. Finally, a forced exercise test at a water temperature of 18 °C exhibited a higher number of dive-bombing periods and drifting-down behavior than in controls. These findings indicate that Tg(mylpfa:N440K) is a good vertebrate model of exercise- and cold-induced human nondystrophic myotonias. This zebrafish model may contribute to provide insight into the pathophysiology of myotonia in sodium channelopathy and could be used to explore a new therapeutic avenue.

Wnt-PLC-IP3-Connexin-Ca2+ axis maintains ependymal motile cilia in zebrafish spinal cord.

Ependymal cells (ECs) are multiciliated neuroepithelial cells that line the ventricles of the brain and the central canal of the spinal cord (SC). How ependymal motile cilia are maintained remains largely unexplored. Here we show that zebrafish embryos deficient in Wnt signaling have defective motile cilia, yet harbor intact basal bodies. With respect to maintenance of ependymal motile cilia, plcδ3a is a target gene of Wnt signaling. Lack of Connexin43 (Cx43), especially its channel function, decreases motile cilia and intercellular Ca2+ wave (ICW) propagation. Genetic ablation of cx43 in zebrafish and mice diminished motile cilia. Finally, Cx43 is also expressed in ECs of the human SC. Taken together, our findings indicate that gap junction mediated ICWs play an important role in the maintenance of ependymal motile cilia, and suggest that the enhancement of functional gap junctions by pharmacological or genetic manipulations may be adopted to ameliorate motile ciliopathy.

Perceptual and Acoustic Outcomes of Early-Stage Glottic Cancer After Laser Surgery or Radiotherapy: A Meta-Analysis.

Laser surgery (LS) or radiotherapy (RT) is normally recommended in early glottic cancer. The objective of this study was to perform a comprehensive meta-analysis of acoustic and perceptual outcomes to compare voice quality of LS or RT in early-stage glottic cancer. Data sources were obtained after searching PubMed, Google Scholar, EBSCO, and RISS using the following search terms: glottic cancer, glottic carcinoma, endoscopic surgery, laser surgery, radiotherapy, radiation, voice, voice quality, and grade, roughness, breathiness, asthenia, and strain (GRBAS) scale. Articles that compared voice outcomes between LS and RT were identified. This meta-analysis included 15 articles with 744 patients, including 400 in the LS group and 344 in the RT group. Random effects models were selected. Forest plots included standardized mean differences, standard errors, variance, 95% confidence intervals (lower limit to upper limit), z-values, and P-values. In perceptual analysis, grade (G) and asthenia (A) of RT were significantly better than LS. There was no statistically significant difference in roughness (R), breath (B), or strain (S) between LS and RT groups. Jitter, shimmer, and noise to harmonic ratio measurements showed significant differences, resulting in enhanced posttreatment effect of RT compared to LS. Results of our meta-analysis suggested that RT might lead to superior voice quality than LS in early glottic cancer.

Genetic Profiles Associated with Chemoresistance in Patient-Derived Xenograft Models of Ovarian Cancer.

PURPOSE: Recurrence and chemoresistance (CR) are the leading causes of death in patients with high-grade serous carcinoma (HGSC) of the ovary. The aim of this study was to identify genetic changes associated with CR mechanisms using a patient-derived xenograft (PDX) mouse model and genetic sequencing. MATERIALS AND METHODS: To generate a CR HGSC PDX tumor, mice bearing subcutaneously implanted HGSC PDX tumors were treated with paclitaxel and carboplatin. We compared gene expression and mutations between chemosensitive (CS) and CR PDX tumors with whole exome and RNA sequencing and selected candidate genes. Correlations between candidate gene expression and clinicopathological variables were explored using the Cancer Genome Atlas (TCGA) database and the Human Protein Atlas (THPA). RESULTS: Three CR and four CS HGSC PDX tumor models were successfully established. RNA sequencing analysis of the PDX tumors revealed that 146 genes were significantly up-regulated and 54 genes down-regulated in the CR group compared with the CS group. Whole exome sequencing analysis showed 39 mutation sites were identified which only occurred in CR group. Differential expression of SAP25, HLA-DPA1, AKT3, and PIK3R5 genes and mutation of TMEM205 and POLR2A may have important functions in the progression of ovarian cancer chemoresistance. According to TCGA data analysis, patients with high HLA-DPA1 expression were more resistant to initial chemotherapy (p=0.030; odds ratio, 1.845). CONCLUSION: We successfully established CR ovarian cancer PDX mouse models. PDX-based genetic profiling study could be used to select some candidate genes that could be targeted to overcome chemoresistance of ovarian cancer.