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Objective: Diagnosing attention-deficit/hyperactivity disorder (ADHD) in adults is often hard. This study aimed to determine differences in absolute EEG power and frontal asymmetry between individuals with ADHD and non-ADHD in young adults aged 18-30 years. Methods: Young adult (age: 18-30 years) outpatients (n = 103) including ADHD patients (n = 51) and non-ADHD patients (n = 52) were enrolled. QEEG was performed for both groups for each region of the brain. The absolute power of each frequency measured in three frontal regions (Lt., Mid., Rt.) of the scalp area was compared between the two groups. Differences between the two groups including theta/beta ratio were compared. Frontal asymmetries were also evaluated for prefrontal (Fp2-Fp1), middle frontal (F4-F3), lateral frontal (F8-F7) pairs at all frequencies. Correlation analysis was performed for absolute powers, frontal asymmetry, and Stroop tests. Results: Demographic data, neuropsychological tests, and psychiatric symptoms were not significantly different between the two groups. Delta band was significantly increased while beta band was decreased in the middle frontal area of the ADHD group as compared with those of the non-ADHD group. For frontal asymmetries, all frequencies in the middle frontal area were more rightward in ADHD patients than in non-ADHD patients. Absolute powers in delta, beta band, and frontal asymmetry in all frequencies had correlations with Stroop tests. Conclusion: This study revealed that ADHD patients had significant differences in absolute powers in delta, beta bands, and frontal asymmetries in all frequencies. Our findings suggest that QEEG can be a helpful tool for diagnosing ADHD in psychiatric patients. [ABSTRACT FROM AUTHOR]

Introduction: Cissus quadrangularis is a vining plant widely used as a traditional herbal remedy for various ailments. In this study, the therapeutic effects of C. quadrangularis extract (CQR-300) on type 2 diabetes mellitus (T2DM) were investigated in a leptin receptor-mutated db/db mouse model. Methods: CQR-300was orally administered to db/db mice (n = 6/group) at different doses (50, 100, and 200mg/kg) for 8 weeks. Blood glucose levels and oral glucose tolerance were assessed using the AccuCheck glucometer. Enzyme-linked immunosorbent assay was performed to evaluate insulin and hemoglobin A1c (HbA1c) levels in the blood of db/db mice. Liver and pancreatic tissues from db/db mice were examined by hematoxylin and eosin (H&E) and immunohistochemical staining. The protein levels of gluconeogenesis-, lipogenesis-, and oxidative stressrelated factors were evaluated using western blotting. Results and discussion: CQR-300 treatment effectively reduced body weight, blood glucose, and insulin levels. HbA1c levels were increased by leptin receptor mutation. Additionally, in the oral glucose tolerance tests, the CQR-300 treated group had a faster blood glucose recovery rate than the db/db group. H&E and Oil red-O staining of the liver showed decreased lipid accumulation in the CQR-300 treated group than the db/db group. Western blot analysis confirmed that CQR-300 effectively inhibited gluconeogenesis, lipogenesis, and oxidative stressrelated factors. Our findings suggest that CQR-300 has the potential to be used as a T2DM supplement. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to report the results from an early-phase study of rivoceranib, an oral tyrosine kinase inhibitor highly selective for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors. Materials and Methods: In this open-label, single-arm, dose-escalating, multicenter three-part phase 1/2a trial, patients had advanced solid tumors refractory to conventional therapy. Part 1 evaluated the safety and pharmacokinetics of five ascending oncedaily doses of rivoceranib from 81 mg to 685 mg. Part 2 evaluated the safety and antitumor activity of once-daily rivoceranib 685 mg. Part 3 was conducted later, due to lack of maximum tolerated dose determination in part 1, to evaluate the safety and preliminary efficacy of once-daily rivoceranib 805 mg in patients with unresectable or advanced gastric cancer. Results: A total of 61 patients were enrolled in parts 1 (n=25), 2 (n=30), and 3 (n=6). In parts 1 and 2, patients were white (45.5%) or Asian (54.5%), and 65.6% were male. The most common grade ≥ 3 adverse events were hypertension (32.7%), hyponatremia (10.9%), and hypophosphatemia (10.9%). The objective response rate (ORR) was 15.2%. In part 3, dose-limiting toxicities occurred in two out of six patients: grade 3 febrile neutropenia decreased appetite, and fatigue. The ORR was 33%. Conclusion The recommended phase 2 dose of rivoceranib was determined to be 685 mg once daily, which showed adequate efficacy with a manageable safety profile (NCT01497704 and NCT02711969). [ABSTRACT FROM AUTHOR]

Introduction: The anti-inflammatory effect of green tea extract (GTE) has been confirmed in asthmatic mice, however, the pharmacological mechanism is not fully elucidated. Methods: To investigate the therapeutic efficacy of GTE in asthma and identify specific pathways, murinemodel of allergic asthma was established by ovalbumin (OVA) sensitization and the challenge for 4 weeks, with oral treatment using GTE and dexamethasone (DEX). Inflammatory cell counts, cytokines, OVA-specific IgE, airway hyperreactivity, and antioxidant markers in the lung were evaluated. Also, pulmonary histopathological analysis and western blotting were performed. In vitro, we established themodel by stimulating the human airway epithelial cell line NCI-H292 using lipopolysaccharide, and treating with GTE and mitogenactivated protein kinases (MAPKs) inhibitors. Results: The GTE100 and GTE400 groups showed a decrease in airway hyperresponsiveness and the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) compared to theOVA group. GTE treatment also reduced interleukin (IL)-13, IL-5, and IL-4 levels in the BALF, andOVA-specific immunoglobulin E levels in the serum compared to those in the OVA group. GTE treatment decreased OVA-induced mucus secretion and airway inflammation. In addition, GTE suppressed the oxidative stress, and phosphorylation of MAPKs, which generally occurs after exposure to OVA. GTE administration also reduced matrix metalloproteinase-9 activity and protein levels. Conclusion: GTE effectively inhibited asthmatic respiratory inflammation and mucus hyperproduction induced by OVA inhalation. These results suggest that GTE has the potential to be used for the treatment of asthma. [ABSTRACT FROM AUTHOR]

Background: Hepatic steatosis, which involves the excessive accumulation of lipid droplets in hepatocytes, presents a significant global health concern due to its association with obesity and metabolic disorders. Inflammation plays a crucial role in the progression of hepatic steatosis; however, the precise molecular mechanisms responsible for this process remain unknown. Methods: This study investigated the involvement of the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome and the forkhead box O6 (FoxO6) transcription factor in the pathogenesis of hepatic steatosis. We monitored the NLRP3 inflammasome and lipogenesis in mice overexpressing the constitutively active (CA)-FoxO6 allele and FoxO6- null mice. In an in vitro study, we administered palmitate to liver cells overexpressing CA-FoxO6 and measured changes in lipid metabolism. Results: We administered palmitate treatment to clarify the mechanisms through which FoxO6 activates cytokine interleukin (IL)-1β through the NLRP3 inflammasome. The initial experiments revealed that dephosphorylation led to palmitate-induced FoxO6 transcriptional activity. Further palmitate experiments showed increased expression of IL-1β and the hepatic NLRP3 inflammasome complex, including adaptor protein apoptotic speck protein containing a caspase recruitment domain (ASC) and pro-caspase-1. Furthermore, thioredoxin-interacting protein (TXNIP), a key regulator of cellular redox conditions upstream of the NLRP3 inflammasome, was induced by FoxO6 in the liver and HepG2 cells. Conclusion: The findings of this study shed light on the molecular mechanisms underpinning the FoxO6-NLRP3 inflammasome axis in promoting inflammation and lipid accumulation in the liver. [ABSTRACT FROM AUTHOR]

Asian sand dust (ASD), also called China dust or yellow dust, mainly occurs in East Asia during spring and autumn. Because ASD enters the body mainly through the respiratory system, it can cause respiratory disorders or worsen underlying diseases. Because of this, it has become an important health concern that threatens the well-being of humans and animals. In this study, we investigated the effects of 15 and 30 mg/kg of Pycnogenol (PYC15 and 30 groups), a pine bark extract, on ASD-induced pulmonary inflammation in mice. We evaluated the inflammatory cell counts, inflammatory cytokines, and matrix-metalloproteinase (MMP)-9 expression in animal models. PYC administration significantly decreased inflammatory cell infiltration into lung tissue; this was accompanied by a reduction in the levels of proinflammatory mediators including interleukin (IL)-1ß (P < 0.01), IL-6 (P < 0.01) and tumour necrosis factor-a (P < 0.01) in bronchoalveolar lavage fluids of ASD-exposed mice (ASD group). Histological analysis revealed that PYC suppressed ASD-induced pulmonary inflammation. Moreover, PYC suppressed the levels of matrix-metalloproteinase (MMP)-9 in the lung tissue of ASD-exposed mice, indicating that PYC reduced ASD-induced pulmonary inflammation by suppressing MMP-9. Together, these results indicate that PYC as the potential to treat ASD-driven pulmonary inflammation. [ABSTRACT FROM AUTHOR]

Objective: Antipsychotic drugs are known as the major cause of non-neoplastic hyperprolactinemia. This study aimed to investigate the levels of serum prolactin depending on the use of antipsychotic drugs in patients through the Clinical Data Warehouse (CDW). Methods: We conducted a cohort search in the CDW application and got 260 patients' medical records diagnosed with schizophrenia, schizotypal and delusional disorders, manic episodes, and bipolar affective disorders who were taking one of risperidone, blonanserin, amisulpride, and olanzapine. After that, we reviewed the medical data and used the ANCOVA analysis and the post hoc test to compare serum prolactin levels among four antipsychotic drug groups. Results: Among the 117 subjects included in the analysis, the mean serum prolactin level was 64.6 ± 54.6 ng/ml. Serum prolactin levels were significantly higher in subjects taking risperidone or amisulpride compared to blonanserin and olanzapine. The female subjects who took blonanserin, olanzapine, and risperidone had significantly higher prolactin levels, but there was no difference in serum prolactin levels between sex in the subjects who took amisulpride. Conclusion: This study suggests the need for regular monitoring of serum prolactin levels in patients who are taking antipsychotics, especially in female patients. And we showed that there is a possibility to conduct more effective and simpler big data research using the CDW. Further studies on the subjects with controlled confounding variables and larger sample groups are needed. [ABSTRACT FROM AUTHOR]

It aims to explore ChatGPT's (GPT-3.5 version) functionalities, including reinforcement learning, diverse applications, and limitations. ChatGPT is an AI chatbot powered by OpenAI's Generative Pre-trained Transformer (GPT) model. The chatbot's applications span education, programming, content generation, and more, demonstrating its versatility. ChatGPT can enhance education by creating assignments and offering personalized feedback, as shown by its notable performance in medical exams and the USMLE. However, concerns include plagiarism, reliability, and educational disparities. It aids in various research tasks, from design to writing, and has shown proficiency in summarizing and suggesting titles. Its use in scientific writing and language translation is promising, but professional oversight is needed for accuracy and originality. It assists in programming tasks like writing code, debugging, and guiding installation and updates. It offers diverse applications, from cheering up individuals to generating creative content like essays, news articles, and business plans. ChatGPT, unlike search engines, provides interactive, generative responses and understands context, making it more akin to human conversation. These characteristics are contrasted with conventional search engines' keyword-based, non-interactive nature. ChatGPT has limitations, such as potential bias, dependence on outdated data, and revenue generation challenges. Despite these issues, ChatGPT is seen as a transformative AI tool poised to redefine the future of generative technology. In conclusion, advancements in AI, like ChatGPT, are altering how knowledge is acquired and applied, marking a shift from search engines to creativity engines. This transformation highlights the increasing importance of AI literacy and the ability to utilize AI in various life aspects effectively. [ABSTRACT FROM AUTHOR]

Purpose Recent clinical trials have reported response rates < 50% among patients treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for microsatellite instability-high (MSI-H) colorectal cancer (CRC), and factors predicting treatment response have not been fully identified. This study aimed to identify potential biomarkers of PD-1/PD-L1 inhibitor treatment response among patients with MSI-H CRC. Materials and Methods MSI-H CRC patients enrolled in three clinical trials of PD-1/PD-L1 blockade at Asan Medical Center (Seoul, Republic of Korea) were screened and classified into two groups according to treatment response. Their histopathologic features and expression of 730 immune-related genes from the NanoString platform were evaluated, and a machine learning-based classification model was built to predict treatment response among MSI-H CRCs patients. Results A total of 27 patients (15 responders, 12 non-responders) were included. A high degree of lymphocytic/neutrophilic infiltration and an expansile tumor border were associated with treatment response and prolonged progression-free survival (PFS), while mucinous/signet-ring cell carcinoma was associated with a lack of treatment response and short PFS. Gene expression profiles revealed that the interferon-γ response pathway was enriched in the responder group. Of the top eight differentially expressed immune-related genes, PRAME had the highest fold change in the responder group. Higher expression of PRAME was independently associated with better PFS along with histologic subtypes in the multivariate analysis. The classification model using these genes showed good performance for predicting treatment response. Conclusion We identified histologic and immune-related gene expression characteristics associated with treatment response in MSI-H CRC, which may contribute to optimal patient stratification. [ABSTRACT FROM AUTHOR]

Six-year-old red ginseng, which is processed from the whole ginseng root via steaming and drying, has been shown to have preventive effects such as antioxidative, anti-inflammatory, and immunomodulatory. In this study, we evaluated the therapeutic effects of Korean red ginseng (KRG) against ovalbumin (OVA)-induced allergic asthma and the underlying mechanisms involved. We injected 20 µg of OVA on days 0 and 14, and mice were challenged with aerosolized OVA via a nebulizer for 1 h on days 21, 22, and 23. KRG was administered at 100 and 300 mg/kg from days 18 to 23. The KRG-treated mice showed significant reductions in their airway hyperresponsiveness, production of reactive oxygen species (ROS), and the number of inflammatory cells compared with the OVA-treated mice. The levels of type 2 cytokines in the bronchoalveolar lavage fluid and expression of OVA-specific immunoglobulin E in the serum, which were elevated in the OVA group, were reduced in the KRG-treated groups. The pro-inflammatory factors, inducible nitric oxide synthase and nuclear factor kappa-light-chain-enhancer of activated B cells, were downregulated by the KRG administration in a dose-dependent manner. KRG effectively suppressed the inflammatory response by inhibiting ROS production. Our results suggest that KRG may have the potential to alleviate asthma. [ABSTRACT FROM AUTHOR]

Background: Previous studies have suggested a close link between sleep disturbances and diabetic retinopathy (DR). However, to date, no confirmatory findings have been reported. We aimed to explore the risk of insomnia in DR by considering demographic factors and diabetes mellitus (DM)-related variables. Methods: A nationwide population-based cohort of 2,206,619 patients with type 2 diabetes from the Korean National Insurance Service Database was followed up for insomnia incidence. DR, non-proliferative DR (NPDR), and proliferative DR (PDR) were defined according to ICD-10 codes. The interactive effects of sex, age, and DM-related variables were analyzed to evaluate their impact on insomnia risk in DR. Results: Compared with the non-DR group, insomnia risk was increased in the DR [(adjusted hazard ratio (aHR): 1.125, 95% confidence interval (CI):1.108-1.142), NPDR (aHR:1.117, 95% CI:1.099-1.134), and PDR (aHR:1.205, 95% CI: 1.156-1.256), even after controlling for comorbidities, lifestyle factors, and DM-related variables. The men and youngest age groups (<40 years) were most vulnerable to insomnia risk. Sex, age, DM duration, and chronic kidney disease (CKD) status exerted interactive effects with DR status in increasing the insomnia risk. In the PDR group, sex, age, DM duration, insulin therapy status, and CKD status exerted interactive effects that increased the risk of insomnia. Conclusion: Insomnia risk is significantly higher in patients with DR, and clinical attention is warranted. [ABSTRACT FROM AUTHOR]

Purpose This study aimed to compare the treatment outcomes of radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) for colorectal cancer liver metastases (CRLM) and to determine the favorable treatment modality according to tumor characteristics. Materials and Methods We retrospectively analyzed the records of 222 colorectal cancer patients with 330 CRLM who underwent RFA (268 tumors in 178 patients) or SBRT (62 tumors in 44 patients) between 2007 and 2014. Kaplan-Meier method and Cox models were used by adjusting with inverse probability of treatment weighting (IPTW). Results The median follow-up duration was 30.5 months. The median tumor size was significantly smaller in the RFA group than in the SBRT group (1.5 cm vs 2.3 cm, p < 0.001). In IPTW-adjusted analysis, difference in treatment modality was not associated with significant differences in 1-year and 3-year recurrence-free survival (35% vs. 43%, 22% vs. 23%; p=0.198), overall survival (96% vs. 91%, 58% vs. 56%; p=0.508), and freedom from local progression (FFLP; 90% vs. 72%, 78% vs. 60%; p=0.106). Significant interaction effect between the treatment modality and tumor size was observed for FFLP (p=0.001). In IPTW-adjusted subgroup analysis of patients with tumor size > 2 cm, the SBRT group had a higher FFLP compared with the RFA group (hazard ratio, 0.153; p < 0.001). Conclusion SBRT and RFA showed similar local control in the treatment of patients with CRLM. Tumor size was an independent prognostic factor for local control and SBRT may be preferred for larger tumors. [ABSTRACT FROM AUTHOR]

In real-time contents, such as games and interactive simulators, it is very important to reduce the amount of simulation computation of 3D deformable objects. Although position-based dynamics has been proposed to reduce the amount of computation, the number of nodes for the tetrahedral model to represent a volumetric deformable object has to be increased, which makes the real-time simulation difficult. Therefore, this paper proposes an Internal shape preserving constraint(ISPC) generation algorithm integrated into the positionbased dynamics to represent the physical properties of the 3D volumetric deformable object, while reducing the number of nodes filling the interior of the object. The proposed algorithm not only provides motion behavior similar to the tetrahedral model by using a surface model, but also enables real-time simulation by reducing the number of nodes constituting the 3D virtual object. It showed high FPS with reduced computation time compared to the tetrahedral model, and the volume maintenance and physical properties of model were expressed similarly to the tetrahedral model. [ABSTRACT FROM AUTHOR]

A better understanding of the effects of preoperative chemoradiotherapy (CRT) on tumor immune microenvironment (TIME) is essential to improve the treatment outcomes of patients with locally advanced rectal cancer (LARC). In this context, we performed a multiplex immunofluorescence staining to evaluate the TIME in 158 patients with LARC who underwent preoperative CRT followed by surgery and adjuvant chemotherapy in the ADORE trial. We found that higher levels of T-cell subsets (CD3+, CD4+, and CD8+) and dendritic cells in the tumor compartment of pretreatment biopsy samples were associated with good response to preoperative CRT. After CRT, there was a significant increase in the densities of CD3+ T cells, CD8+ T cells, and dendritic cells, while that of CD4+FoxP3+ regulatory T cells decreased, indicating that CRT changed the TIME into a more immune-active status. However, CRT also conferred an immunosuppressive effect by polarizing the tumor-associated macrophages from pro-inflammatory M1 macrophage to immune-suppressive M2 macrophages and decreasing the density of B cells. High delta values of CD3+ T cells and PD-L1+ lymphocytes after CRT were associated with good disease-free survival (DFS), while that of CD4+FoxP3+ regulatory T cells was associated with poor DFS. These findings provide a framework for future studies incorporating strategies to modulate the TIME in patients with LARC. [ABSTRACT FROM AUTHOR]

Anthropogenic CO2 emissions to the atmosphere have increased not only air temperature, but also precipitation, which has intensified freshening of the sea surface in some parts of the ocean. As a result, many regions, including the Yellow Sea, have been confronted with a decrease in salinity. In this study we investigated the effects of low salinity on the number of dead individuals and behaviour of Haustorioides koreanus, a gammarid amphipod living in the upper and sandy regions of the tidal flats of the west and south coasts of South Korea. The experiment was conducted over 32 days with four different salinity conditions: 30 (control), 27, 24 and 21 psu (n = 8 each). Although the number of dead individuals, the moulting frequency and burrowing and swimming behaviours of H. koreanus did not significantly differ, the time taken for food detection was increased significantly by low salinity (21 psu). A decrease in the speed of food detection suggests that low salinity can reduce the amphipod’s ability to detect chemical cues. [ABSTRACT FROM AUTHOR]

Aim: The aim of the study is to analyze prognostic factors for tumor control, survival, and late toxicity in patients with anal cancer treated with chemoradiation. Materials and Methods: Anal cancer patients treated between 1996 and 2010 were analyzed. Patients received radiotherapy and concurrent 5‑fluorouracil and mitomycin‑C. Results: Data from 70 patients were analyzed. With a median follow‑up of 6.4 years, 5‑year overall survival and progression‑free survival were 88% and 84%, respectively. Female gender and total radiation dose (≥54 Gy) were significantly associated with better local control. For survival, female gender, patient age, and tumor size were significant prognostic factors. The most common late toxicity was lymphedema. Possible prognosticators were examined, and only radiation dose to the inguinal area was significant. Conclusion: Despite moderately high radiation doses, local recurrence, and late complications were problems in treating anal cancer. In the intensity‑modulated radiotherapy era, consensus on accurate target volume based on the pattern of failure analysis is required. [ABSTRACT FROM AUTHOR]

The present study aimed to compare the pattern of distant recurrence between patients with non-metastatic rectal cancer treated with pre-operative (OP) and those treated with post-operative (post-OP) chemoradiotherapy (CRT). A total of 631 patients with newly diagnosed non-metastatic rectal cancer who had received pre-OP or post-OP CRT with curative intent surgery between August 2008 and April 2015 were identified. Inverse probability of treatment weighting (IPTW) was performed to account for baseline differences between the two arms. Overall, 449 and 182 patients were treated with pre-OP and post-OP CRT, respectively. Sex, tumor location, clinical tumor stage, CRT regimen and adjuvant chemotherapy regimen were significantly different between the two arms. The median follow-up duration was 55.4 months (range, 53.7-57.1). The 5-year distant recurrence-free survival (RFS) rates and 5-year overall survival (OS) rates were not significantly different between the pre-OP and post-OP CRT arms (RFS, 67.5 vs. 71.6%, P=0.595 and OS, 81.9 vs. 77.0%, P=0.449), and no difference was observed in the distant recurrence patterns. Following IPTW, there was still no difference in distant RFS (pre-OP vs. post-OP CRT; hazard ratio (HR)=0.62; P=0.911), but pre-OP CRT was significantly associated with lower peritoneal recurrence (pre-OP vs. post-OP CRT; HR, 0.13; P=0.032). In addition, there was no significant difference in OS between the two arms (pre-OP vs. post-OP CRT; HR, 0.85; P=0.665). In conclusion, although distant RFS was not significantly different between the two arms, pre-OP CRT was significantly associated with a lower risk of peritoneal recurrence than post-OP CRT in patients non-metastatic rectal cancer. [ABSTRACT FROM AUTHOR]

Purpose We evaluated the efficacy and safety of avelumab, an anti--PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations. Materials and Methods In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLE mutations after failure of ≥ 1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H was confirmed with immunohistochemical staining (IHC) by loss of expression of MMR proteins or polymerase chain reaction (PCR) for micro-satellite sequences. POLE mutation was confirmed by next-generation sequencing (NGS). The primary endpoint was the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors ver. 1.1. Results The median age was 60 years, and 78.8% were male. Thirty patients were dMMR/MSIH and three had POLE mutations. The ORR was 24.2%, and all of the responders were dMMR/MSI-H. For 21 patients with MSI-H by PCR or NGS, the ORR was 28.6%. At a median follow-up duration of 16.3 months, median progression-free survival and overall survival were 3.9 and 13.2 months in all patients, and 8.1 months and not reached, respectively, in patients with MSI-H by PCR or NGS. Dose interruption and discontinuation due to treatment-related adverse events occurred in four and two patients, respectively, with no treatment-related deaths. Conclusion Avelumab displayed antitumor activity with manageable toxicity in patients with previously treated mCRC harboring dMMR/MSI-H. Diagnosis of dMMR/MSI-H with PCR or NGS could be complementary to IHC to select patients who would benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose Simvastatin has demonstrated anti-tumor activity in preclinical studies via tumor cell senescence, apoptosis, and anti-angiogenesis. This phase II trial evaluated the efficacy and toxicity profile of conventional XELOX and bevacizumab chemotherapy plus simvastatin in metastatic colorectal cancer patients (MCRC). Materials and Methods Patients with MCRC received first-line XELOX in 3-week treatment cycles of intravenous xaliplatin 130 mg/m² plus bevacizumab 7.5 mg/kg (day 1), followed by oral capecitabine 1,000 mg/m² twice daily (day 1-14). Simvastatin 80 mg tablets were taken orally once daily every day during the period of chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, duration of response, overall survival (OS), time to progression, and toxicity. Results From January 2014 to April 2015, 60 patients were enrolled and 55 patients were evaluable for tumor response. The median follow-up duration was 30.1 months (range, 28.5 to 31.7 months). The median PFS was 10.4 months (95% confidence interval [CI], 9.6 to 11.1). The median OS of all patients was 19.0 months (95% CI, 11.9 to 26.0). The disease-control rate and overall response rate were 88.3% (95% CI, 74 to 96) and 58.3% (95% CI, 44 to 77), respectively, by intent-to-treat protocol analysis. There was one complete response and 34 partial responses. One patient experienced grade 3 creatine kinase elevation and liver enzyme elevation. Conclusion Based on the current study, the addition of 80 mg simvastatin to XELOX and bevacizumab showed comparable clinical efficacy in patients with MCRC as first-line chemotherapy and did not increase toxicity. [ABSTRACT FROM AUTHOR]

Purpose: Goserelin is a drug used for chemical castration. In a rat model, we investigated whether surgical and chemical castration affected memory ability through the protein kinase A (PKA)/cyclic adenosine monophosphate response elementbinding protein (CREB)/brain-derived neurotrophic factor (BDNF) and c-Raf/mitogen-activated protein kinases-extracellular signal-regulated kinases (MEK)/extracellular signal-regulated kinases (ERK) pathways in the hippocampus. Methods: Orchiectomy was performed for surgical castration and goserelin acetate was subcutaneously transplanted into the anterior abdominal wall for chemical castration. Immunohistochemistry was done to quantify neurogenesis. To assess the involvement of the PKA/CREB/BDNF and c-Raf/MEK/ERK pathways in the memory process, western blots were used. Results: The orchiectomy group and the goserelin group showed less neurogenesis and impaired short-term and spatial memory. Phosphorylation of PKA/CREB/BDNF and phosphorylation of c-Raf/MEK/ERK decreased in the orchiectomy and goserelin groups. Conclusions: Short-term memory and spatial memory were affected by surgical and chemical castration via the PKA/CREB/BDNF and c-Raf/MEK/ERK signaling pathways. [ABSTRACT FROM AUTHOR]

Purpose: This study was to evaluate changes of the mechanical loading pattern after anatomic anterior cruciate ligament (ACL) reconstruction by analyzing uptake patterns using combined single-photon emission computerized tomography and conventional computerized tomography (SPECT/CT). Materials and Methods: On SPECT/CT, high signal intensity of the articular surface which shows biological activity and mean increase of mechanical loading was compared with that of the tibiofemoral shaft as a comparative signal. The proportion of positive signals was evaluated in all compartments of the operated knee. Analysis was performed according to combined injury. Results: A relatively high proportion of positive signals was detected in the posterior zone of the lateral tibial plateau (23.5%) and trochlear groove (23.5%) although increased signal intensity was detected in all compartments. There was no statistical difference depending on the presence of combined injury and between single-bundle and double-bundle ACL reconstruction. Conclusions: Following anatomic ACL reconstruction, higher signal intensity was detected, particularly in the posterior part of the lateral tibial plateau and trochlear groove. Close observation for further signal changes or osteoarthritic changes would be required even if there was no combined injury and anatomic reconstruction was performed. [ABSTRACT FROM AUTHOR]

Purpose With the emergence of next-generation sequencing (NGS) technology, profiling a wide range of genomic alterations has become a possibility resulting in improved implementation of targeted cancer therapy. In Asian populations, the prevalence and spectrum of clinically actionable genetic alterations has not yet been determined because of a lack of studies examining high-throughput cancer genomic data. Materials and Methods To address this issue, 1,071 tumor samples were collected from five major cancer institutes in Korea and analyzed using targeted NGS at a centralized laboratory. Samples were either fresh frozen or formalin-fixed, paraffin embedded (FFPE) and the quality and yield of extracted genomic DNA was assessed. In order to estimate the effect of sample condition on the quality of sequencing results, tissue preparation method, specimen type (resected or biopsied) and tissue storage time were compared. Results We detected 7,360 non-synonymous point mutations, 1,164 small insertions and deletions, 3,173 copy number alterations, and 462 structural variants. Fifty-four percent of tumors had one or more clinically relevant genetic mutation. The distribution of actionable variants was variable among different genes. Fresh frozen tissues, surgically resected specimens, and recently obtained specimens generated superior sequencing results over FFPE tissues, biopsied specimens, and tissues with long storage duration. Conclusion In order to overcome, challenges involved in bringing NGS testing into routine clinical use, a centralized laboratory model was designed that could improve the NGS workflows, provide appropriate turnaround times and control costs with goal of enabling precision medicine. [ABSTRACT FROM AUTHOR]

Green turtles (Chelonia mydas) are observed year-round in the Sea of Jeju Island, Republic of Korea; however, there is limited information on their migration and seasonal distribution outside of Korean waters. To investigate their spatial and temporal movement, we tracked 8 green turtles (straight carapace length range, 49.7-85.9 cm; mean ± SD, 63.36 ± 10.99 cm), taken as bycatch in pound nets near Jeju Island, using satellite transmitters from August 2015 to January 2017. Turtles were mainly juveniles and were tracked for 17-314 d. Three turtles traveled more than 400 km from their release site in 2 different directions: one individual moved westward to China within 17 d of release, and 2 individuals traveled eastward to Japan. One turtle that moved to Japan had been flipper-tagged at Kagoshima, Japan, 1 mo prior to its capture at Jeju Island. The other 5 individuals remained near the coast of Jeju Island. The individual tracked for the longest period (314 d) overwintered (water temperature, 12°-14°C) in the eastern area of Jeju Island. These results indicate that green turtles from different regions, including China and Japan, may use the areas around Jeju Island for foraging, for overwintering, and/or as a migratory corridor. To fortify the conservation of green turtles in the region, international cooperation and expanded research efforts, such as genetic studies, are needed. [ABSTRACT FROM AUTHOR]

Purpose Although gemcitabine plus cisplatin has been established as the standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC), overall prognosis remains poor. We investigated the efficacy of a novel triplet combination of oxaliplatin, irinotecan, and S-1 (OIS) for advanced BTC. Materials and Methods Chemotherapy-naive patients with histologically documented unresectable or metastatic BTC were eligible for this multicenter, single-arm phase II study. Patients received 65 mg/m2 oxaliplatin (day 1), 135 mg/m2 irinotecan (day 1), and 40 mg/m2 S-1 (twice a day, days 1-7) every 2 weeks. Primary endpoint was objective response rate. Targeted exome sequencing for biomarker analysis was performed using archival tissue. Results In total, 32 patients were enrolled between October 2015 and June 2016. Median age was 64 years (range, 40 to 76 years), with 24 (75%) male patients; 97% patients had metastatic or recurrent disease. Response rate was 50%, and median progression-free survival and overall survival (OS) were 6.8 months (95% confidence interval [CI], 4.8 to 8.8) and 12.5 months (95% CI, 7.0 to 18.0), respectively. The most common grade 3-4 adverse events were neutropenia (32%), diarrhea (6%), and peripheral neuropathy (6%). TP53 and KRAS mutations were the most frequent genomic alterations (42% and 32%, respectively), and KRAS mutations showed a marginal relationship with worse OS (p=0.07). Conclusion OIS combination chemotherapy was feasible and associated with favorable efficacy outcomes as a first-line treatment in patients with advanced BTC. Randomized studies are needed to compare OIS with gemcitabine plus cisplatin. [ABSTRACT FROM AUTHOR]

Background: In metastatic colorectal cancer, the location of the primary tumor has been suggested to have biological significance. In this study, we investigated whether primary tumor location affects cetuximab efficacy in patients with RAS wild-type metastatic colorectal cancer.Methods: Genotyping by the SequenomMassARRAY technology platform (OncoMap) targeting KRAS, NRAS, PIK3CA, and BRAF was performed in tumors from 307 patients who had been given cetuximab as salvage treatment. Tumors with mutated RAS (KRAS or NRAS; n = 127) and those with multiple primary location (n = 10) were excluded. Right colon cancer was defined as a tumor located in the proximal part to splenic flexure.Results: A total of 170 patients were included in the study (right versus left, 23 and 147, respectively). Patients with right colon cancer showed more mutated BRAF (39.1% vs. 5.4%), mutated PIK3CA (13% vs. 1.4%), poorly differentiated tumor (17.4% vs. 3.4%), and peritoneal involvement (26.1% vs. 8.8%) than those with left colon and rectal cancer. Right colon cancer showed poorer progression-free survival (2.0 vs.5.0 months, P = 0.002) and overall survival (4.1 months and 13.0 months, P < 0.001) than the left colon and rectal cancer. By multivariable analysis, BRAF mutation, right colon primary, poorly differentiated histology, and peritoneal involvement were associated with risk of death.Conclusions: In RAS wild-type colon cancer treated with cetuximab as salvage treatment, right colon primary was associated with poorer survival outcomes than left colon and rectal cancer. [ABSTRACT FROM AUTHOR]

Background: In metastatic colorectal cancer, the location of the primary tumor has been suggested to have biological significance. In this study, we investigated whether primary tumor location affects cetuximab efficacy in patients with RAS wild-type metastatic colorectal cancer. Methods: Genotyping by the SequenomMassARRAY technology platform (OncoMap) targeting KRAS, NRAS, PIK3CA, and BRAF was performed in tumors from 307 patients who had been given cetuximab as salvage treatment. Tumors with mutated RAS (KRAS or NRAS; n = 127) and those with multiple primary location (n = 10) were excluded. Right colon cancer was defined as a tumor located in the proximal part to splenic flexure. Results: A total of 170 patients were included in the study (right versus left, 23 and 147, respectively). Patients with right colon cancer showed more mutated BRAF (39.1% vs. 5.4%), mutated PIK3CA (13% vs. 1.4%), poorly differentiated tumor (17.4% vs. 3.4%), and peritoneal involvement (26.1% vs. 8.8%) than those with left colon and rectal cancer. Right colon cancer showed poorer progression-free survival (2.0 vs.5.0 months, P = 0.002) and overall survival (4.1 months and 13.0 months, P < 0.001) than the left colon and rectal cancer. By multivariable analysis, BRAF mutation, right colon primary, poorly differentiated histology, and peritoneal involvement were associated with risk of death. Conclusions: In RAS wild-type colon cancer treated with cetuximab as salvage treatment, right colon primary was associated with poorer survival outcomes than left colon and rectal cancer. [ABSTRACT FROM AUTHOR]

Purpose: The concentration of capecitabine peaks at 1-2 hours after administration. We therefore assumed that proper timing of capecitabine administration and radiotherapy would maximize radiosensitization and influence survival among patients with locally advanced rectal cancer. Materials and Methods: We retrospectively reviewed 223 patients with locally advanced rectal cancer who underwent preoperative chemoradiation, followed by surgery from January 2002 to May 2006. All patients underwent pelvic radiotherapy (50 Gy/25 fractions) and received capecitabine twice daily at 12-hour intervals (1,650 mg/m2/day). Patients were divided into two groups according to the time interval between capecitabine intake and radiotherapy. Patients who took capecitabine 1 hour before radiotherapy were classified as Group A (n = 109); all others were classified as Group B (n = 114). Results: The median follow-up period was 72 months (range, 7 to 149 months). Although Group A had a significantly higher rate of good responses (44% vs. 25%; p = 0.005), the 5-year local recurrence-free survival rates of 93% in Group A and 97% in Group B did not differ significantly (p = 0.519). The 5-year disease-free survival and overall survival rates were also comparable between the groups. Conclusions: Despite the better pathological response in Group A, the time interval between capecitabine and radiotherapy administration did not have a significant effect on survivals. Further evaluations are needed to clarify the interaction of these treatment modalities. [ABSTRACT FROM AUTHOR]

High atmospheric CO2 dissolves into the surface of the ocean and lowers the pH of seawater and is thus expected to pose a potential threat to various marine organisms. We investigated the physiological and behavioural responses of adult Manila clams, Venerupis philippinarum (n=96, shell length 25.3261.66mm and total wet weight 3.1060.54 g), to three levels (400, 700, and 900 latm) of C O2 partial pressure (pCO2) for 48 days. There were no significant differences in mortality, growth, respiration rate, or emergence from the sediment between the three levels, indicating that near future atmospheric levels of CO2 do not seem to have a serious effect on the physiology and behaviour of adult Manila clams. However, Manila clams could be exposed to notably higher pCO2 and lower pH levels at local conditions due to the other issues, including eutrophication. Thus, the younger clams (n=240, shell length 16.7160.96mm and total wet weight 0.7060.13 g) were exposed to pCO2 levels of 900 latm (pH 7.8) and higher, such as 1300 and 2300 latm (pH 7.7 and 7.5, respectively), for 39 days. Although mortality and growth were not significantly different between treatments, the emergence rates at the two higher pCO2 levels were higher than that at the lowest level during the last 10 days of the experiment. The oxygen consumption rate (OCR) was reduced after 39 days of exposure to 2300 latm of pCO2. The increase in emerging behaviour and the decrease in the rate of oxygen consumption indicated worse physiological conditions of the clams; the population may be negatively influenced due to worse conditions or increased probability of predation. [ABSTRACT FROM AUTHOR]

Dendrobium genus was reported to contain alkaloid, bibenzyl, fluorenone, phenanthrene, sesquiterpenoid, and phenolic acid, which have biological properties. Our aim was to investigate the protective effect of an aqueous extract of Dendrobium nobile Lindl (DNE) against cisplatininduced acute kidney injury (AKI). Quantification of four phenolic acids (4-hydroxybenzoic, vanillic, syringic, and ferulic acid) in DNE was determined using the HPLC-photodiode array method. Possible protective effects against cisplatin-induced nephrotoxicity were investigated using in-vitro (porcine kidney cells; PK15) and in-vivo (Sprague Dawley rat) studies. Among the four phenolic acids, 4-hydroxybenzoic acid was the most abundant. In the in-vitro study, DNE pretreatment partially prevented decrement of viability after cisplatin (15 µg/mL) treatment in the both the MTT and crystal violet assays. Moreover, relative to cells treated with cisplatin alone, the DNE (50 µg/mL)-pretreated cells showed a ~30% increase in glutathione levels and a ~15% decrease in reactive oxygen species. The expression of p53 was also decreased in DNEpretreated cells (p < 0.05). In the in-vivo study, the renal function index decreased to normal levels in groups pretreated with DNE (300 and 500 mg/kg); histopathological alterations and apoptotic cells were also attenuated. Moreover, DNE pretreatment ameliorated oxidative stress in the kidney, as evidenced by recovered antioxidant enzyme levels and decreased lipid peroxidation. DNE, by decreasing oxidative stress, was found to have a protective effect against cisplatin-induced nephrotoxicity. Based on these findings, DNE might be beneficial when treating cisplatin-induced AKI. [ABSTRACT FROM AUTHOR]

Purpose: Cetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS exon 2. Resistance to cetuximab is mediated by activating less frequent mutations in the RAS genes beyond KRAS exon 2. We performed extended RASmutational analysis using a high -throughput genotyping platform (OncoMap) and evaluated extended RAS analysis for predicting cetuximab efficacy in patients harboring wild-type KRAS exon 2 tumors following Sanger sequencing. Materials and Methods: Extended RAS analysis was performed on 227 wild-type KRAS exon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0. Targeted genes included exon 2, exon 3, and exon 4, both in KRAS and NRAS, and included BRAF exon 15. We assessed efficacy by the new RAS mutation status. Results: The OncoMap detected 57 additional mutations (25.1%): 25 (11%) in KRAS exon 2 and 32 (14.1%) beyond KRAS exon 2. Survival differences were observed after dividing patients into the wild-type RAS group (n=170) and mutant RAS group (n=57) using OncoMap. Progression-free survival was 4.8 months versus 1.8 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.32 to 0.61), and overall survival was 11.9 months versus 8.4 months (HR, 0.65; 95% CI, 0.47 to 0.88). Conclusion: Sanger sequencing is not sufficient for selecting candidates for cetuximab treatment. High - throughput extended RAS genotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment. [ABSTRACT FROM AUTHOR]

Purpose: Although the mutation status of KRAS is highly concordant in primary and metastatic lesions, it has not been generalized to other major pathway genes. Materials and Methods: In this study, 41 genes were evaluated and the mutational profiles were compared in 46 colorectal cancer patients with paired surgical specimens of primary and metastatic lesions: synchronous (n=27) and metachronous (n=19) lesions. A high-throughput mass spectrometry- based genotyping platform validated by orthogonal chemistry, OncoMap v.4.4, was used to evaluate the formalin-fixed, paraffin-embedded surgical specimens. The patients' demographics, tumor characteristics, and microsatellite instability status were analyzed by a retrospective chart review. Results: In this study, with OncoMap, mutations were identified in 80.4% of patients with the following frequency: KRAS (39.1%), TP53 (28.3%), APC (28.3%), PIK3CA (6.5%), BRAF (6.5%), and NRAS (4.3%). Although 19.6% (9/46) of the patients showed no gene mutations, 43.5% (20/46) and 37.0% (17/46) had mutations in one and two or more genes, respectively. The synchronous and metachronous lesions showed similar mutational profiles. Paired samples between primary and metastatic tumors differed in 7.4% (2/27) and 10.5% (2/19) for synchronous and metachronous according to OncoMap. Conclusion: These findings indicate the major pathway genes, including KRAS, TP53, APC, PIK3CA, BRAF, and NRAS, are often concordant between the primary and metastatic lesions regardless of the temporal relationship of metastasis. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to evaluate compartmental changes using combined single-photon emission computerized tomography and conventional computerized tomography (SPECT/CT) after open wedge high tibial osteotomy (OWHTO) for providing clinical guidance for proper correction. Materials and Methods: Analysis was performed using SPECT/CT from around 1 year after surgery on 22 patients who underwent OWHTO. Postoperative mechanical axis was measured and classified into 3 groups: group I (varus), group II (0°-3° valgus), and group III (>3° valgus). Patella location was evaluated using Blackburne-Peel (BP) ratio. On SPECT/CT, the knee joint was divided into medial, lateral, and patellofemoral compartments and the brighter signal was marked as a positive signal. Results: Increased signal activity in the medial compartment was observed in 12 cases. No correlation was observed between postoperative mechanical axis and medial signal increase. Lateral increased signal activity was observed in 3 cases, and as valgus degree increased, lateral compartment's signal activity increased. Increased signal activity of the patellofemoral joint was observed in 7 cases, and significant correlation was observed between changes in BP ratio and increased signal activity. Conclusions: For the treatment of medial osteoarthritis, OWHTO requires overcorrection that does not exceed 3 valgus. In addition, the possibility of a patellofemoral joint problem after OWHTO should be kept in mind. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether preoperative chemoradiotherapy (PCRT) followed by local excision (LE) is feasible approach in clinical T2N0 rectal cancer patients. Materials and Methods: Patients who received PCRT and LE because of clinical T2 rectal cancer within 7 cm from anal verge between January 2006 and June 2014 were retrospectively analyzed. LE was performed in case of a good clinical response after PCRT. Patients' characteristics, treatment record, tumor recurrence, and treatment-related complications were reviewed at a median follow-up of 49 months. Results: All patients received transanal excision or transanal minimally invasive surgery. Of 34 patients, 19 patients (55.9%) presented pathologic complete response (pCR). The 3-year local recurrence-free survival and disease free-survival were 100.0% and 97.1%, respectively. There was no recurrence among the patients with pCR. Except for 1 case of grade 4 enterovesical fistula, all other late complications were mild and self-limiting. Conclusion: PCRT followed by an LE might be feasible as an alternative to total mesorectal excision in good responders with clinical T2N0 distal rectal cancer. [ABSTRACT FROM AUTHOR]