mRNA-HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV-mediated cancers via subcutaneous immunization.

The E6 and E7 proteins of specific subtypes of human papillomavirus (HPV), including HPV 16 and 18, are highly associated with cervical cancer as they modulate cell cycle regulation. The aim of this study was to investigate the potential antitumor effects of a messenger RNA-HPV therapeutic vaccine (mHTV) containing nononcogenic E6 and E7 proteins. To achieve this, C57BL/6j mice were injected with the vaccine via both intramuscular and subcutaneous routes, and the resulting effects were evaluated. mHTV immunization markedly induced robust T cell-mediated immune responses and significantly suppressed tumor growth in both subcutaneous and orthotopic tumor-implanted mouse model, with a significant infiltration of immune cells into tumor tissues. Tumor retransplantation at day 62 postprimary vaccination completely halted progression in all mHTV-treated mice. Furthermore, tumor expansion was significantly reduced upon TC-1 transplantation 160 days after the last immunization. Immunization of rhesus monkeys with mHTV elicited promising immune responses. The immunogenicity of mHTV in nonhuman primates provides strong evidence for clinical application against HPV-related cancers in humans. All data suggest that mHTV can be used as both a therapeutic and prophylactic vaccine.

Toll-Like Receptor 5 Promotes the Neurogenesis From Embryonic Stem Cells and Adult Hippocampal Neural Stem Cells in Mice.

Toll-like receptors (TLRs) make a crucial contribution to the innate immune response. TLR5 was expressed in embryoid body derived from mouse embryonic stem cells (mESCs) and ßIII-tubulin-positive cells under all-trans retinoic acid-treated condition. TLR5 was upregulated during neural differentiation from mESCs and augmented the neural differentiation of mESCs via nuclear factor-κB and interleukin 6/CREB pathways. Besides, TLR5 was expressed in SOX2- or doublecortin-positive cells in the subgranular zone of the hippocampal dentate gyrus where adult neurogenesis occurs. TLR5 inhibited the proliferation of adult hippocampal neural stem cells (NSCs) by regulating the cell cycle and facilitated the neural differentiation from the adult hippocampal NSCs via JNK pathway. Also, TLR5 deficiency impaired fear memory performance in mice. Our data suggest that TLR5 is a crucial modulator of neurogenesis from mESCs and adult hippocampal NSCs in mice and represents a new therapeutic target in neurological disorders related to cognitive function.

Mechanism of action of genicular artery embolization in a rabbit model of knee osteoarthritis.

OBJECTIVES: To establish a rabbit osteoarthritis model for genicular artery embolization (GAE) experiments and to investigate the cellular mechanism of action of this novel procedure for interventional radiologists. METHODS: Rabbit knee osteoarthritis was surgically modeled by anterior cruciate ligament transection and medial partial meniscectomy of the bilateral hindlimbs followed by 10 weeks of incubation. Rabbits exhibiting synovitis on magnetic resonance imaging were randomly divided into two groups: the bilateral GAE group and the control (sham procedure) group. Four weeks later, the rabbits' mobility (moving time, sec/10 min) and the histopathological features of each knee were assessed, and inter-group differences were evaluated using Student's t-test and ordinal/linear logistic models with generalized estimating equations. RESULTS: Osteoarthritis modeling and endovascular procedures were successful in 15 of 20 rabbits (8 and 7 in the GAE and control groups, respectively). There was no significant difference in moving times between the two groups (p = .958). The degree of structural cartilage damage was similar in both groups (p = .780). However, the synovial proliferation (p = .016), synovial hypertrophy (p < .001), and villous hyperplasia of the synovial stroma (p = .002) scores were significantly lower in the GAE group than in the control group. The CD3+ cell density (p = .018) and CD3 + cell-infiltrated area (p = .019) were also significantly lower in the GAE group than in the control group. CONCLUSION: GAE can limit inflammatory processes in the synovium of osteoarthritis-affected knees. KEY POINTS: Surgical transection of the anterior cruciate ligament and medial partial meniscectomy of rabbit knees provides a useful animal model for research of genicular artery embolization. Osteoarthritic knees treated by genicular artery embolization showed milder synovial proliferation (p = .016), synovial hypertrophy (p < .001), and villous hyperplasia of the synovial stroma (p = .002) than the untreated knees. Osteoarthritic knees treated by genicular artery embolization presented lower CD3+ cell density (p = .018) and CD3+ cell-infiltrated area (p = .019) in the synovium than the untreated knees.

Expression of the melatonergic system during meiotic maturation of cynomolgus monkey cumulus-oocyte complexes.

BACKGROUND: Melatonin is a multifunctional hormone synthesized in the pineal gland and peripheral reproductive tissues that regulates many biological processes. There is increasing evidence for a role of melatonin in oocyte maturation and embryonic development in various mammals. However, no study has reported evidence for the existence of melatonergic system, such as melatonin synthesis enzymes, melatonin membrane receptors, or melatonin binding sites in non-human primate cumulus-oocyte complexes (COCs). METHODS: Reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry were performed to detect transcripts and proteins of the rate-limiting enzyme in melatonin synthesis (arylalkylamine N-acetyltransferase, AANAT), melatonin membrane receptors (MT1 and MT2), and a melatonin binding site (NRH: quinone oxidoreductase 2, NQO2) in cynomolgus monkey COCs. RESULTS: RT-PCR analyses revealed the presence of AANAT, MT1, MT2, and NQO2 transcripts in granulosa cells, germinal vesicle (GV)- and metaphase II (MII)-stage cumulus cells, and oocytes. Immunocytochemistry revealed the presence of AANAT, MT1, MT2, and NQO2 proteins in GV- and MII-stage COCs. CONCLUSIONS: Our results provide the first evidence for the existence of the rate-limiting enzyme required for melatonin synthesis, melatonin membrane receptors, and a melatonin binding site in non-human primate COCs.

Antiinflammatory effect of the ethanolic extract of Korean native herb Potentilla rugulosa Nakai in Bisphenol-a-stimulated A549 cells.

Potentilla rugulosa Nakai (P. rugulosa) is a perennial herb in the Rosaceae family and found in the Korean mountains. Previously, our findings demonstrated that P. rugulosa contains numerous polyphenols and flavonoids exhibiting important antioxidant and anti-obesity bioactivities. Bisphenol A (BPA) is a xenoestrogen that was shown to produce pulmonary inflammation in humans. However, the mechanisms underlying BPA-induced inflammation remain to be determined. The aim of this study was to examine whether ethanolic extract of P. rugulosa exerted an inhibitory effect on BPA-induced inflammation utilizing an adenocarcinoma human alveolar basal epithelial cell line A549. The P. rugulosa extract inhibited BPA-mediated cytotoxicity by reducing levels of reactive oxygen species (ROS). Further, P. rugulosa extract suppressed the upregulation of various pro-inflammatory mediators induced by activation of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. In addition, inhibition of the NF-κB and MAPK signaling pathways by P. rugulosa extract was found to occur via decrease in the transcriptional activity of NF-κB. Further, blockade of phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK) was noted. Thus, our findings suggest that the ethanolic extract of P. rugulosa may act as a natural anti-inflammatory therapeutic agent.

Association Between Internet Searches Related to Suicide/Self-harm and Adolescent Suicide Death in South Korea in 2016-2020: Secondary Data Analysis.

BACKGROUND: Previous studies have investigated the association between suicide and internet search volumes of terms related to suicide or self-harm. However, the results varied by people's age, period, and country, and no study has exclusively investigated suicide or self-harm rates among adolescents. OBJECTIVE: This study aims to determine the association between the internet search volumes of terms related to suicide/self-harm and the number of suicides among South Korean adolescents. We investigated gender differences in this association and the time lag between the internet search volumes of the terms and the connected suicide deaths. METHODS: We selected 26 search terms related to suicide and self-harm among South Korean adolescents, and the search volumes of these terms for adolescents aged 13-18 years were obtained from the leading internet search engine in South Korea (Naver Datalab). A data set was constructed by combining data from Naver Datalab and the number of suicide deaths of adolescents on a daily basis from January 1, 2016, to December 31, 2020. Spearman rank correlation and multivariate Poisson regression analyses were performed to identify the association between the search volumes of the terms and the suicide deaths during that period. The time lag between suicide death and the increasing trend in the search volumes of the related terms was estimated from the cross-correlation coefficients. RESULTS: Significant correlations were observed within the search volumes of the 26 terms related to suicide/self-harm. The internet search volumes of several terms were associated with the number of suicide deaths among South Korean adolescents, and this association differed by gender. The search volume for "dropout" showed a statistically significant correlation with the number of suicides in all adolescent population groups. The correlation between the internet search volume for "dropout" and the connected suicide deaths was the strongest for a time lag of 0 days. In females, self-harm and academic score showed significant associations with suicide deaths, but academic score showed a negative correlation, and the time lags with the strongest correlations were 0 and -11 days, respectively. In the total population, self-harm and suicide method were associated with the number of suicides, and the time lags with the strongest correlations were +7 and 0 days, respectively. CONCLUSIONS: This study identifies a correlation between suicides and internet search volumes related to suicide/self-harm among South Korean adolescents, but the relatively weak correlation (incidence rate ratio 0.990-1.068) should be interpreted with caution.

Comparison of n-butyl-2-cyanoacrylate and polyvinyl alcohol particles for bronchial artery embolisation in primary lung cancer: a retrospective cohort study.

BACKGROUND: Bronchial artery embolisation (BAE) is an effective treatment option to control haemoptysis in primary lung cancer. However, no studies have investigated optimal embolisation material for BAE in lung cancer patients. Thus, this study aimed to compare the safety and efficacy of BAE performed using n-butyl-2-cyanoacrylate (NBCA) and polyvinyl alcohol (PVA) particles in primary lung cancer patients to determine which embolic material is better for patients with haemoptysis. METHODS: This retrospective study was approved by the institutional review board, and consent was waived. The rates of hemostasis, complications, procedure time, dose-area product, and haemoptysis-free survival were retrospectively compared between primary lung cancer (non-small cell [n = 111] and small cell [n = 11]) patients who underwent BAE using NBCA (n = 58) or PVA particles (n = 64) between January 2004 and December 2019. Predictors of recurrent haemoptysis were analysed using the Cox proportional hazard regression model. RESULTS: Among 122 patients (mean age, 66 ± 10 years; range 32-86 years; 103 men), more patients in the NBCA group (81.0%; 47 of 58) achieved complete hemostasis than did patients in the PVA group (53.1%; 34 of 64) (P = 0.002). No major complications were observed in either group. The procedure time (36.4 ± 21.6 vs. 56.3 ± 27.4 min, P < 0.001) was shorter, and the dose-area product (58.6 ± 64.0 vs. 233.5 ± 225.0 Gy*cm2, P < 0.001) was smaller in the NBCA group than in the PVA group. The median haemoptysis-free survival was 173.0 in the NBCA group compared with 20.0 days in the PVA group (P < 0.001). The PVA use (P < 0.001) and coagulopathy (P = 0.014) were independent predictors of shortened haemoptysis-free survival. CONCLUSION: BAE using NBCA showed significantly superior initial hemostasis with longer haemoptysis-free survival, shorter procedure time, and reduced radiation dose than BAE using PVA particles. The PVA use and coagulopathy were independent predictors of recurrent haemoptysis. TRIAL REGISTRATION: Retrospectively registered.

Comparison between Antegrade versus Retrograde Ureteral Stent Placement for Malignant Ureteral Obstruction.

PURPOSE: To compare the technical success of antegrade uteral stent (AUS) and retrograde ureteral stent (RUS) placements in patients with malignant ureteral obstruction (MUO) and to determine the predictors of technical failure of RUS. MATERIALS AND METHODS: This study retrospectively included 61 AUS placements (44 patients) performed under fluoroscopic guidance and 76 RUS placements (55 patients) performed under cystoscopic guidance in patients with MUO from January 2019 to December 2020. Technical success rates of the 2 techniques were compared using inverse probability of treatment weighting (IPTW) analysis. Logistic regression was used to identify predictive factors for technical failures. RESULTS: Technical success was achieved in 98.4% of the AUS group and 47.4% of the RUS group. After stabilized IPTW, the technical success rate was higher in the AUS group than in the RUS group (adjusted risk difference, 49.4%; 95% confidence interval [CI], 35.4%-63.1%). The independent predictors for technical failure of the RUS procedure were age of ≥65 years (odds ratio [OR], 5.56; 95% CI, 1.73-21.27), ureteral orifice invasion (OR, 4.21; 95% CI, 1.46-13.46), and extrinsic cancer (OR, 15.58; 95% CI, 2.92-111.81). CONCLUSIONS: The technical success rate of AUS placement was higher than that of RUS placement in patients with MUO. RUS failure was associated with age of ≥65 years, cancer with ureteral orifice invasion, and extrinsic ureteral obstruction.

Effects of vinpocetine on atopic dermatitis after administration via three different routes in HR-1 hairless mice.

This study aimed to examine the effects of vinpocetine on atopic dermatitis (AD) by administering it via oral, intraperitoneal, and topical routes to HR-1 hairless mice. AD was induced in the mice for five weeks with ovalbumin, and vinpocetine was administered twice daily through each route of administration for two weeks after the induction of AD. Vinpocetine (20, 10, and 2 mg/kg) was administered by oral, intraperitoneal, and topical routes, respectively. The administration of vinpocetine suppressed the increase in serum immunoglobulin (Ig) E and IgG1 levels and the production of interleukin (IL)-4 and IL-13-cytokines linked to T helper 2 cells in skin tissue. In addition, the invasion of inflammatory cells, including eosinophils, into the skin tissue was reduced, and changes in skin structure were also suppressed. These results show the potential for the use of vinpocetine in patients with AD and even for targeted treatment against PDE. In most of the experiments, symptom relief in the groups receiving oral and topical vinpocetine was slightly superior to that in the group receiving vinpocetine intraperitoneally. In particular, topical application of vinpocetine was found to be the most effective route when considering the dose of vinpocetine used in each route.

Extract of Pinus densiflora needles suppresses acute inflammation by regulating inflammatory mediators in RAW264.7 macrophages and mice.

CONTEXT: Pinus densiflora Siebold & Zucc. (Pinaceae) needle extracts ameliorate oxidative stress, but research into their anti-inflammatory effects is limited. OBJECTIVE: To investigate antioxidant and anti-inflammatory effects of a Pinus densiflora needles (PINE) ethanol extract in vitro and in vivo. MATERIALS AND METHODS: We measured levels of reactive oxygen species (ROS), superoxide dismutase (SOD) and inflammatory mediators in lipopolysaccharide (LPS)-stimulated RAW264.7 cells at various PINE concentrations (25, 50 and 100 µg/mL; but 6.25, 12.5 and 25 µg/mL for interleukin-1ß and prostaglandin E2 (PGE2)). Thirty ICR mice were randomized to six groups: vehicle, control, PINE pre-treatment (0.1, 0.3 and 1 mg/left ear for 10 min followed by arachidonic acid treatment for 30 min) and dexamethasone. The posttreatment ear thickness and myeloperoxidase (MPO) activity were measured. RESULTS: PINE 100 µg/mL significantly decreased ROS (IC50, 70.93 µg/mL, p < 0.01), SOD (IC50, 30.99 µg/mL, p < 0.05), malondialdehyde (p < 0.01), nitric oxide (NO) (IC50, 27.44 µg/mL, p < 0.01) and tumour necrosis factor-alpha (p < 0.05) levels. Interleukin-1ß (p < 0.05) and PGE2 (p < 0.01) release decreased significantly with 25 µg/mL PINE. PINE 1 mg/ear inhibited LPS-stimulated expression of cyclooxygenase-2 and inducible NO synthase in RAW264.7 macrophages and significantly inhibited ear oedema (36.73-15.04% compared to the control, p < 0.01) and MPO activity (167.94-105.59%, p < 0.05). DISCUSSION AND CONCLUSIONS: PINE exerts antioxidant and anti-inflammatory effects by inhibiting the production of inflammatory mediators. Identified flavonoids such as taxifolin and quercetin glucoside can be attributed to effect of PINE.

Red cell manufacturing using parallel stirred-tank bioreactors at the final stages of differentiation enhances reticulocyte maturation.

The aim of this study was to develop a robust, quality controlled, and reproducible erythroid culture system to obtain high numbers of mature erythroblasts and red blood cells (RBCs). This was achieved using a fully controlled stirred-tank bioreactor by the design of experiments (DOE) methods in the serum-free medium by defining the appropriate culture parameters. Human cord blood CD34+ cells were first cultured in static flasks and then inoculated to stirred-tank bioreactors. Cell diameter was gradually decreased and final RBC yields were significantly higher when cells were inoculated at sizes smaller than 12 µm. The larger immature cells in the basophilic stage did not survive, while smaller mature erythroid cells were successfully expanded at high agitation speeds, demonstrating that appropriate seeding timing is critical. A high inoculation cell density of 5 × 106 cells/ml was achieved reaching 1.5 × 107 cells/ml. By using DOE analysis fitted to precise stages of erythropoiesis, we were able to acquire the optimal culture parameters for pH (7.5), temperature (37°C), dissolved oxygen, agitation speed (500 rpm), inoculation timing (cell diameter 12-13 µm), media feeding regimen, and cell seeding density (5 × 106 cells/ml). The final pure RBCs showed appropriate functions compared with fresh donor RBCs, confirming that manufacturing mature RBCs with reproducibility is possible.

Transhepatic stent placement for portal vein obstruction after hepatobiliary and pancreatic surgery: long-term efficacy and risk factor for stent failure.

OBJECTIVES: To evaluate the long-term efficacy of transhepatic portal vein (PV) stent placement in patients with postoperative PV obstruction and to identify risk factors for stent failure. METHODS: Between January 2007 and October 2019, percutaneous transhepatic PV stent placement was attempted in 60 patients with postoperative PV obstruction. Technical and clinical success, complications, and stent patency were retrospectively evaluated. Thirteen clinical variables were analyzed to determine risk factors for stent failure. RESULTS: Stent placement was technically successful in all patients. Thromboaspiration (n = 19) and jejunal variceal embolization (n = 7) were performed in the same session. Clinical symptoms related to portal hypertension were resolved in 54 patients (90.0%). There was no procedure-related complication. During the follow-up period (mean 630 days), stent failure occurred in 13 patients. One- and 5-year stent patency rate was 74.8% and 64.9%, respectively. The presence of a pancreatic fistula was the only independent risk factor associated with stent failure (HR 7.54; 95% CI 2.02-28.10, p = 0.003). CONCLUSIONS: Percutaneous transhepatic PV stent placement is a technically feasible and effective treatment for postoperative PV obstruction. The pancreatic fistula is a risk factor for stent failure. KEY POINTS: • Percutaneous transhepatic stent placement is an effective treatment to improve portal hypertension-related symptoms in patients with portal vein obstruction after hepatobiliary and pancreatic surgery. • The pancreatic fistula is an independent risk factor for portal vein stent failure.

Hepatic Artery Embolization for Postoperative Hemorrhage: Importance of Arterial Collateral Vessels and Portal Venous Impairment.

PURPOSE: To investigate the association between hepatic ischemic complications and hepatic artery (HA) collateral vessels and portal venous (PV) impairment after HA embolization for postoperative hemorrhage. MATERIALS AND METHODS: From October 2003 to November 2019, 42 patients underwent HA embolization for postoperative hemorrhage. HA collateral vessels were classified according to visualization after embolization (grade 1, none; grade 2, 1-4 segmental HA; and grade 3, ≥4 segmental HA). Transhepatic portal vein stent placements were performed in the same session for 5 patients (11.9%) with poor HA collateral vessels (grade 1 or 2) and compromised PV flow (>70% stenosis). Hepatic ischemic complications were analyzed for relevance to HA collateral vessels and PV compromise. RESULTS: After HA embolization, HA flow was found to be preserved (grade 3) through intra- and/or extrahepatic collateral vessels in 23 patients (54.8%), and hepatic complications did not occur regardless of PV flow status (0%). Of the 19 patients (45.2%) with poor HA collateral vessels (grade 1 or 2), segmental hepatic infarction occurred in 2 of 15 patients (13.3%) with preserved PV flow (10 naïve and 5 stented). The remaining 4 patients with poor HA collateral vessels and untreated compromised PV flow experienced multisegmental hepatic infarction (n = 3) or hepatic failure (n = 1) (100%) (P < .005). CONCLUSIONS: After HA embolization, preserved HA flow (≥4 segmental HA) lowered the risk of hepatic complications regardless of the PV flow. Based on these findings, transhepatic PV stent placement seems to be an effective intervention for the prevention of hepatic complications in cases of poor HA collateral vessels and compromised PV flow.

Spectral CT-Based Iodized Oil Quantification to Predict Tumor Response Following Chemoembolization of Hepatocellular Carcinoma.

PURPOSE: To quantify iodized oil retention in tumors after transarterial chemoembolization using spectral computed tomography (CT) imaging in patients with hepatocellular carcinoma (HCC) and evaluate its performance in predicting 12-month tumor responses. MATERIALS AND METHODS: From September 2017 to December 2018, 111 patients with HCC underwent initial conventional transarterial chemoembolization. Immediately after the procedure, unenhanced CT was performed using a spectral CT scanner, and the iodized oil densities in index tumors were measured. In tumor-level analyses, a threshold level of iodized oil density in the tumors was calculated using clustered receiver operating characteristic curve analyses to predict the 12-month tumor responses. In patient-level analyses, significant factors associated with a 12-month complete response, including the presence of tumors below the threshold value (ie, suspected residual tumors), were evaluated by logistic regression. RESULTS: Forty-eight HCCs in 39 patients were included in the analyses. The lower 10th percentile of the iodine density was identified as the threshold for determining the 12-month nonviable responses. The area under the curve of the iodine density measurements in predicting the 12-month nonviable responses was 0.893 (95% confidence interval, 0.797-0.989). The threshold value of the iodine density of 10.68 mg/mL yielded a sensitivity of 82.76% and specificity of 94.74% (P < .001). In the patient-level analysis, the 12-month complete response was significantly associated with the presence of a suspected residual tumor, with an odds ratio of 72.0 (95% confidence interval, 7.273-712.770). CONCLUSIONS: Spectral CT imaging using quantitative analysis of the iodized oil retention in target HCCs can predict tumor responses after a conventional transarterial chemoembolization procedure.

Improved motility in the gastrointestinal tract of a postoperative ileus rat model with ilaprazole.

Postoperative ileus (POI), a symptom that occurs after abdominal surgery, reduces gastrointestinal motility. Although its mechanism is unclear, POI symptoms are known to be caused by inflammation 6 to 72 h after surgery. As proton pump inhibitors exhibit protective effect against acute inflammation, the purpose of this study was to determine the effect of ilaprazole on a POI rat model. POI was induced in rats by abdominal surgery. Rats were divided into six groups: control: normal rat + 0.5% CMC-Na, vehicle: POI rat + 0.5% CMC-Na, mosapride: POI rat + mosapride 2 mg/kg, ilaprazole 1 mg/kg: POI rat + ilaprazole 1 mg/kg, ilaprazole 3 mg/kg: POI rat + ilaprazole 3 mg/kg, and ilaprazole 10 mg/kg: POI rat + ilaprazole 10 mg/kg. Gastrointestinal motility was confirmed by measuring gastric emptying (GE) and gastrointestinal transit (GIT). In the small intestine, inflammation was confirmed by measuring TNF-α and IL-1ß; oxidative stress was confirmed by SOD, GSH, and MDA levels; and histological changes were observed by H&E staining. Based on the findings, GE and GIT were decreased in the vehicle group and improved in the ilaprazole 10 mg/kg group. In the ilaprazole 10 mg/kg group, TNF-α and IL-1ß levels were decreased, SOD and GSH levels were increased, and MDA levels were decreased. Histological damage was also reduced in the ilaprazole-treated groups. These findings suggest that ilaprazole prevents the decrease in gastrointestinal motility, a major symptom of postoperative ileus, and reduces inflammation and oxidative stress.

Protein arginine methyltransferase-1 stimulates dopaminergic neuronal cell death in a Parkinson's disease model.

Recent studies have revealed that protein arginine methyltransferases (PRMTs) are responsible for diverse neurodegenerative diseases. However, their pathophysiological role in dopaminergic neuronal death in Parkinson's disease (PD) has not been evaluated. In this study, we demonstrated that 1-Methyl-4-phenylpyridinium iodide (MPP+), rotenone and paraquat, which cause dopaminergic neuronal cell death, increased PRMT1 expression in dopaminergic cell line. Dopaminergic neuronal cell death was increased by PRMT1 overexpression. MPP+-induced cell death was attenuated by PRMT1 knockdown. Poly (ADP-ribose) polymerase-1 (PARP1) expression and activity, poly-ADP-ribosylation (PARylation), were elevated by MPP+. Moreover, we found that PRMT1 positively regulates nuclear translocation of apoptosis-inducing factor (AIF). Elevated PRMT1 expression was observed in the substantia nigra pars compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected mice. Furthermore, MPTP-induced dopaminergic neuronal death was reduced in PRMT1 haploinsufficient (prmt1+/-) mice. These data suggest that PRMT1 is implicated in PARP1/AIF-mediated dopaminergic neuronal cell death, which might be involved in the pathology of PD. Therefore, our results propose PRMT1 as a new target to develop a potential treatment of PD.

Spectral CT Imaging-Based Quantification of Iodized Oil Retention following Chemoembolization: Phantom and Animal Studies.

PURPOSE: To evaluate accuracy of iodine quantification using spectral CT and the potential of quantitative iodized oil analysis as an imaging biomarker of chemoembolization. MATERIALS AND METHODS: A phantom of an artificial liver with 6 artificial tumors containing different amounts of iodized oil (0-8 vol%) was scanned by spectral CT, and iodized oil density (mg/mL) and Hounsfield unit (HU) values were measured. In addition, VX2 hepatoma was induced in 23 rabbits. After chemoembolization using iodized oil chemoemulsion, the rabbits were scanned by spectral CT. The accumulation of iodized oil in the tumor was quantified in terms of iodized oil density and HUs, and the performances in predicting a pathologic complete response (CR) were evaluated by receiver operating characteristic curve analyses. RESULTS: The mean difference between true iodine densities and spectral image-based measurements was 0.5 mg/mL. Mean HU values were highly correlated with mean iodine density (r2 = 1.000, P < .001). In the animal study, a pathologic CR was observed in 17 of 23 rabbits (73.9%). The range of area under the curve values of iodine and HU measurements was 0.863-0.882. A tumoral iodine density of 3.57 mg/mL, which corresponds to 0.7 vol% iodized oil in the tumor, predicted a pathologic CR with a sensitivity of 70.6% and a specificity of 100.0%. CONCLUSIONS: Spectral CT imaging has a potential to predict tumor responses after chemoembolization by quantitatively assessing iodized oil in targets.

Stent Placement for Palliative Treatment of Malignant Colorectal Obstruction: Extracolonic Malignancy Versus Primary Colorectal Cancer.

OBJECTIVE. The purpose of this study is to compare the clinical outcomes of stent placement for the palliative treatment of colorectal obstruction in patients with extracolonic malignancy (ECM) versus those with primary colorectal cancer (CRC) and to identify the risk factors for stent failure. MATERIALS AND METHODS. Between January 2005 and December 2017, a total of 85 patients underwent stent placement for the palliative treatment of inoperable malignant colorectal obstructions caused by ECM (n = 56) or CRC (n = 29). Technical and clinical success, reintervention rates, and stent patency were compared between the two groups. Predictive factors associated with stent failure were identified. RESULTS. Stent placement was technically successful in 54 patients with ECM (96.4%) and 27 patients with CRC (93.1%) (p = 0.60). The proportion of patients with ECM who required reintervention was greater than that of patients with CRC (20.4% vs 3.7%, respectively; p = 0.04); however, they had a marginally lower clinical success rate (88.9% vs 100.0%, respectively; p = 0.07). The 6- and 12-month stent patency rates were 64.2% and 22.0%, respectively, in patients with ECM and 68.4% and 31.3%, respectively, in patients with CRC (p = 0.89). Long obstructions (hazard ratio, 1.40) and multiple obstructions (hazard ratio, 4.03) were independent factors associated with stent failure. CONCLUSION. Stent placement for the palliative treatment of colorectal obstruction is less effective and more frequently requires reintervention in patients with ECM than in patients with CRC. Long obstructions and multiple obstructions were associated with stent failure.

Fluoroscopic Rescue of Failed Endoscopic Stent Placement for Obstructing Colorectal Malignancy.

OBJECTIVE. This study evaluated the technical feasibility and clinical effectiveness of fluoroscopic stent placement in malignant colorectal obstructions after failed endoscopic stent placement. MATERIALS AND METHODS. Between January 2004 and December 2017, 41 patients with malignant colorectal obstructions were referred for fluoroscopic stent placement after failed endoscopy. The procedures were performed for palliation (n = 35) or as a bridge to surgery (n = 6). The technical and clinical success, complications, stent patency duration, and patient survival were retrospectively analyzed. RESULTS. Fluoroscopic stent placement was technically successful in 38 patients (92.7%). The causes of technical failure were complete obstruction (n = 1), redundant sigmoid colon (n = 1), and colon perforation (n = 1). Clinical success was achieved in 37 patients with technical success (97.4%). Major complications occurred in three patients (7.9%) and included colon perforation (n = 2) and anal pain (n = 1). The six patients with stenting as a bridge to surgery underwent elective colectomy uneventfully (100%). In 32 patients with technically successful palliative stenting, the median primary stent patency duration and patient survival were 353 days (95% CI, 162-353 days) and 335 days (95% CI, 116-335 days), respectively. CONCLUSION. Fluoroscopic colorectal stent placement is technically feasible and clinically effective in most patients with failed endoscopic procedures.

Establishment and Characterization of Immortalized Miniature Pig Pancreatic Cell Lines Expressing Oncogenic K-RasG12D.

In recent decades, many studies on the treatment and prevention of pancreatic cancer have been conducted. However, pancreatic cancer remains incurable, with a high mortality rate. Although mouse models have been widely used for preclinical pancreatic cancer research, these models have many differences from humans. Therefore, large animals may be more useful for the investigation of pancreatic cancer. Pigs have recently emerged as a new model of pancreatic cancer due to their similarities to humans, but no pig pancreatic cancer cell lines have been established for use in drug screening or analysis of tumor biology. Here, we established and characterized an immortalized miniature pig pancreatic cell line derived from primary pancreatic cells and pancreatic cancer-like cells expressing K-rasG12D regulated by the human PTF1A promoter. Using this immortalized cell line, we analyzed the gene expression and phenotypes associated with cancer cell characteristics. Notably, we found that acinar-to-ductal transition was caused by K-rasG12D in the cell line constructed from acinar cells. This may constitute a good research model for the analysis of acinar-to-ductal metaplasia in human pancreatic cancer.