ABSTRACT
Decrease in processing speed due to increased resistance and capacitance delay is a major obstacle for the down-scaling of electronics1-3. Minimizing the dimensions of interconnects (metal wires that connect different electronic components on a chip) is crucial for the miniaturization of devices. Interconnects are isolated from each other by non-conducting (dielectric) layers. So far, research has mostly focused on decreasing the resistance of scaled interconnects because integration of dielectrics using low-temperature deposition processes compatible with complementary metal-oxide-semiconductors is technically challenging. Interconnect isolation materials must have low relative dielectric constants (κ values), serve as diffusion barriers against the migration of metal into semiconductors, and be thermally, chemically and mechanically stable. Specifically, the International Roadmap for Devices and Systems recommends4 the development of dielectrics with κ values of less than 2 by 2028. Existing low-κ materials (such as silicon oxide derivatives, organic compounds and aerogels) have κ values greater than 2 and poor thermo-mechanical properties5. Here we report three-nanometre-thick amorphous boron nitride films with ultralow κ values of 1.78 and 1.16 (close to that of air, κ = 1) at operation frequencies of 100 kilohertz and 1 megahertz, respectively. The films are mechanically and electrically robust, with a breakdown strength of 7.3 megavolts per centimetre, which exceeds requirements. Cross-sectional imaging reveals that amorphous boron nitride prevents the diffusion of cobalt atoms into silicon under very harsh conditions, in contrast to reference barriers. Our results demonstrate that amorphous boron nitride has excellent low-κ dielectric characteristics for high-performance electronics.
ABSTRACT
Gastrointestinal stromal tumors arising from gastric cardia are uncommon in dogs. A few studies have shown the effectiveness of tyrosine kinase inhibitors in the treatment of canine gastrointestinal stromal tumors, but no standardized protocols are currently available. An 11-year-old spayed female Maltese dog was diagnosed with a gastrointestinal stromal tumor using histopathological and immunohistochemical analyses. An adenosine triphosphate-based tumor chemosensitivity assay revealed that imatinib at lower concentrations had a stronger inhibitory effect than toceranib. Based on the results of the assay, the dog was treated with imatinib after surgery. After 28 mo of therapy, there was no recurrence of the tumor. Key clinical message: Adenosine triphosphate-based tumor chemosensitivity assays may help clinicians to select appropriate postoperative chemotherapeutic drugs for incompletely resected gastrointestinal stromal tumors in dogs.
Gestion réussie à la suite d'une résection incomplète d'une tumeur stromale gastro-intestinale à l'aide de l'imatinib basée sur un test de sensibilité tumorale à base d'adénosine triphosphate chez un chien. Les tumeurs stromales gastro-intestinales résultant du cardia gastrique sont rares chez le chien. Quelques études ont montré l'efficacité des inhibiteurs de la tyrosine kinase dans le traitement des tumeurs stromales gastrointestinales canines, mais aucun protocole standardisé n'est actuellement disponible. Une chienne maltaise stérilisée de 11 ans a reçu un diagnostic de tumeur stromale gastro-intestinale à l'aide d'analyses histopathologiques et immunohistochimiques. Un test de chimiosensibilité tumorale à base d'adénosine triphosphate a révélé que l'imatinib à des concentrations plus faibles avait un effet inhibiteur plus fort que le tocéranib. Sur la base des résultats du test, le chien a été traité avec de l'imatinib après l'opération. Après 28 mois de traitement, il n'y a eu aucune récidive de la tumeur.Message clinique clé :Les tests de chimiosensibilité tumorale à base d'adénosine triphosphate peuvent aider les cliniciens à sélectionner les médicaments chimiothérapeutiques postopératoires appropriés pour les tumeurs stromales gastro-intestinales incomplètement réséquées chez le chien.(Traduit par Dr Serge Messier).
Subject(s)
Antineoplastic Agents , Dog Diseases , Gastrointestinal Stromal Tumors , Imatinib Mesylate , Animals , Gastrointestinal Stromal Tumors/veterinary , Gastrointestinal Stromal Tumors/surgery , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/pathology , Dogs , Imatinib Mesylate/therapeutic use , Dog Diseases/drug therapy , Dog Diseases/surgery , Female , Antineoplastic Agents/therapeutic use , Adenosine Triphosphate/therapeutic use , Indoles , PyrrolesABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastation to human society through its high virulence, infectivity, and genomic mutations, which reduced the efficacy of vaccines. Here, we report the development of aptamers that effectively interfere with SARS-CoV-2 infection by targeting its spike protein, which plays a pivotal role in host cell entry of the virus through interaction with the viral receptor angiotensin-converting enzyme 2 (ACE2). To develop highly effective aptamers and to understand their mechanism in inhibiting viral infection, we determined the three-dimensional (3D) structures of aptamer/receptor-binding domain (RBD) complexes using cryogenic electron microscopy (cryo-EM). Moreover, we developed bivalent aptamers targeting two distinct regions of the RBD in the spike protein that directly interact with ACE2. One aptamer interferes with the binding of ACE2 by blocking the ACE2-binding site in RBD, and the other aptamer allosterically inhibits ACE2 by binding to a distinct face of RBD. Using the 3D structures of aptamer-RBD complexes, we minimized and optimized these aptamers. By combining the optimized aptamers, we developed a bivalent aptamer that showed a stronger inhibitory effect on virus infection than the component aptamers. This study confirms that the structure-based aptamer-design approach has a high potential in developing antiviral drugs against SARS-CoV-2 and other viruses.
Subject(s)
COVID-19 , Humans , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Binding Sites , Protein BindingABSTRACT
BACKGROUND: A population-based study would be useful to identify the association between chronic kidney disease (CKD) or acute kidney injury (AKI) and prognosis of coronavirus disease 2019 (COVID-19) patients. METHODS: This retrospective study utilized the claim data from Korea. Patients who underwent COVID-19 testing and were confirmed to be positive were included and divided into the following three groups based on the presence of CKD or requirement of maintenance dialysis: Non-CKD (participants without CKD), non-dialysis CKD (ND-CKD), and dialysis-dependent CKD (DD-CKD) patients. We collected data on the development of severe clinical outcomes and death during follow-up. Severe clinical outcomes were defined as the use of inotropics, conventional oxygen therapy, high-flow nasal cannula, mechanical ventilation, or extracorporeal membrane oxygenation and the development of AKI, cardiac arrest, myocardial infarction, or acute heart failure after the diagnosis of COVID-19. AKI was defined as the initiation of renal replacement therapy after the diagnosis of COVID-19 in patients not requiring maintenance dialysis. Death was evaluated according to survival at the end of follow-up. RESULTS: Altogether, 7,341 patients were included. The median duration of data collection was 19 (interquartile range, 11-28) days. On multivariate analyses, odds ratio (OR) for severe clinical outcomes in the ND-CKD group was 0.88 (95% confidence interval [CI], 0.64-1.20; P = 0.422) compared to the Non-CKD group. The DD-CKD group had ORs of 7.32 (95% CI, 2.14-33.90; P = 0.004) and 8.32 (95% CI, 2.37-39.21; P = 0.002) compared to the Non-CKD and ND-CKD groups, respectively. Hazard ratio (HR) for death in the ND-CKD group was 0.79 (95% CI, 0.49-1.26; P = 0.318) compared to the Non-CKD group. The DD-CKD group had HRs of 2.96 (95% CI, 1.09-8.06; P = 0.033) and 3.77 (95% CI, 1.29-11.06; P = 0.016) compared to the Non-CKD and ND-CKD groups, respectively. DD-CKD alone was associated with severe clinical outcomes and higher mortality. There was no significant difference in frequency of severe clinical outcomes or mortality rates between the Non-CKD and ND-CKD groups. In patients not requiring maintenance dialysis, AKI was associated with old age, male sex, and high Charlson's comorbidity index score but not with the presence of CKD. HRs for patients with AKI were 11.26 (95% CI, 7.26-17.45; P < 0.001) compared to those for patients without AKI in the multivariate analysis. AKI was associated with severe clinical outcomes and patient survival, rather than underlying CKD. CONCLUSION: CKD requiring dialysis is associated with severe clinical outcomes and mortality in patients with COVID-19; however, the development of AKI is more strongly associated with severe clinical outcomes and mortality.
Subject(s)
Acute Kidney Injury/complications , COVID-19/mortality , Logistic Models , Renal Insufficiency, Chronic/complications , SARS-CoV-2 , Adult , Aged , COVID-19/complications , Female , Humans , Male , Middle Aged , Renal Dialysis , Retrospective StudiesABSTRACT
BACKGROUND: New biological prognostic predictors have been studied; however, some factors have limited clinical application due to tissue-specific expression and high cost. There is the need for a promising predictive factor that is simple to detect and that is closely linked to oncological outcomes in patients with urothelial bladder cancer (BC) who have undergone radical cystectomy (RC). Therefore, we investigated the clinical prognostic value of the preoperative De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) on oncological outcomes in patients with urothelial BC after RC. METHODS: We retrospectively evaluated clinicopathological data of 118 patients with non-metastatic urothelial BC after RC between 2008 and 2013 at a single center. The association between the De Ritis ratio and clinicopathological findings was assessed. The potential prognostic value of the De Ritis ratio was analyzed using the Kaplan-Meier method, and multivariate Cox analyses were performed to identify the independent predictors of metastasis-free survival, cancer-specific survival, and overall survival. RESULTS: According to the receiver operating curve of the De Ritis ratio for metastasis, we stratified the patients into 2 groups using a threshold of 1.3. A high De Ritis ratio was more likely to be associated with old age and the female sex. Kaplan-Meier estimates revealed that patients with a high De Ritis ratio had inferior metastasis-free survival, cancer-specific survival, and overall survival outcomes (P = 0.012, 0.024, and 0.022, respectively). Multivariate analysis revealed that a high De Ritis ratio was an independent prognostic factor for metastasis (hazard ratio [HR], 2.389; 95% confidence interval [CI], 1.161-4.914; P = 0.018), cancer-related death (HR, 2.755; 95% CI, 1.214-6.249; P = 0.015), and overall death (HR, 2.761; 95% CI, 1.257-6.067; P = 0.011). CONCLUSIONS: An elevated De Ritis ratio was significantly associated with worse prognosis in patients who underwent RC for urothelial BC. This ratio might further improve the predictive accuracy for prognosis in BC.
Subject(s)
Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Biomarkers, Tumor/blood , Cystectomy/trends , Urinary Bladder Neoplasms/blood , Urinary Bladder Neoplasms/surgery , Aged , Cystectomy/methods , Female , Humans , Male , Middle Aged , Neoplasm Grading/methods , Neoplasm Grading/trends , Postoperative Care/trends , Retrospective Studies , Treatment Outcome , Urinary Bladder Neoplasms/diagnosisABSTRACT
BACKGROUND: Venous thromboembolism (VTE) is very rare in childhood. Nevertheless, its incidence has increased recently. This study aimed to identify risk factors for developing thrombosis in childhood cancers and other childhood diseases through the Korean Health Insurance Review and Assessment Service database. METHODS: Data were extracted from the Korean Health Insurance Review and Assessment Service database. Children and young adults from 1 month to 29 years of age were eligible, and 21,747 cases of VTE between January 2008 and December 2016 were identified. RESULTS: The VTE incidence was high in children younger than 1 year of age. After 1 year of age, its incidence decreased rapidly and gradually increased. The VTE incidence for children between 0 and 1 year of age was 10.23-fold higher than that for those between 1 and 5 years of age. Annual VTE incidence increased by year. The age-standardized annual incidence rates were 9.98 per 100,000 population in 2008 and 22.53 per 100,000 population in 2016. The age-standardized annual incidence rate increased 2.25-fold during the 8 years. The lower extremity was the most common site of venous thrombosis. CONCLUSION: The incidence of VTE in a population younger than 30 years was 13.11 per 100,000 persons in Korea. We found a bimodal age distribution of the VTE incidence with peaks at infancy and again after 16 years. The incidence of portal vein thrombosis was high in infants, and infection and malignancy were the most common comorbidities in patients with VTE.
Subject(s)
Venous Thromboembolism/diagnosis , Adolescent , Adult , Child , Child, Preschool , Comorbidity , Databases, Factual , Female , Humans , Incidence , Infant , Male , Republic of Korea/epidemiology , Venous Thromboembolism/epidemiology , Young AdultABSTRACT
PURPOSE: The present study aimed to determine whether sarcopenia after radical cystectomy (RC) could predict overall survival (OS) in patients with urothelial bladder cancer (UBC). MATERIALS AND METHODS: The lumbar skeletal muscle index (SMI) of 80 patients was measured before and 1 year after RC. The prognostic signifi cance of sarcopenia and SMI decrease after RC were evaluated using Kaplan-Meier analysis and a multivariable Cox regression model. RESULTS: Of 80 patients, 26 (32.5%) experienced sarcopenia before RC, whereas 40 (50.0%) experienced sarcopenia after RC. The median SMI change was -2.2 cm2/m2. Patients with sarcopenia after RC had a higher pathological T stage and tumor grade than patients without sarcopenia. Furthermore, the overall mortality rate was signifi - cantly higher in patients with sarcopenia than in those without sarcopenia 1 year after RC. The median follow-up time was 46.2 months, during which 22 patients died. Kaplan-Meier estimates showed a signifi cant difference in OS rates based on sarcopenia (P=0.012) and SMI decrease (P=0.025). Multivariable Cox regression analysis showed that SMI decrease (≥2.2 cm2/m2) was an independent predictor of OS (hazard ratio: 2.68, confi dence interval: 1.007-7.719, P = 0.048). CONCLUSIONS: The decrease in SMI after surgery might be a negative prognostic factor for OS in patients who underwent RC to treat UBC.
Subject(s)
Carcinoma in Situ/surgery , Cystectomy/adverse effects , Sarcopenia/etiology , Urinary Bladder Neoplasms/surgery , Aged , Body Mass Index , Carcinoma in Situ/complications , Carcinoma in Situ/mortality , Cystectomy/methods , Cystectomy/mortality , Female , Humans , Kaplan-Meier Estimate , Male , Multivariate Analysis , Muscle, Skeletal/physiopathology , Proportional Hazards Models , Retrospective Studies , Sarcopenia/physiopathology , Time Factors , Urinary Bladder Neoplasms/complications , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/physiopathologyABSTRACT
Neuroinflammation is an important pathological feature in neurodegenerative diseases. Accumulating evidence has suggested that neuroinflammation is mainly aggravated by activated microglia, which are macrophage like cells in the central nervous system. Therefore, the inhibition of microglial activation may be considered for treating neuroinflammatory diseases. p38 mitogen-activated protein kinase (MAPK) has been identified as a crucial enzyme with inflammatory roles in several immune cells, and its activation also relates to neuroinflammation. Considering the proinflammatory roles of p38 MAPK, its inhibitors can be potential therapeutic agents for neurodegenerative diseases relating to neuroinflammation initiated by microglia activation. This study was designed to evaluate whether NJK14047, a recently identified novel and selective p38 MAPK inhibitor, could modulate microglia-mediated neuroinflammation by utilizing lipopolysaccharide (LPS)-stimulated BV2 cells and an LPS-injected mice model. Our results showed that NJK14047 markedly reduced the production of nitric oxide and prostaglandin E2 by downregulating the expression of various proinflammatory mediators such as nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α and interleukin-1ß in LPS-induced BV2 microglia. Moreover, NJK14047 significantly reduced microglial activation in the brains of LPS-injected mice. Overall, these results suggest that NJK14047 significantly reduces neuroinflammation in cellular/vivo model and would be a therapeutic candidate for various neuroinflammatory diseases.
Subject(s)
Inflammation Mediators/metabolism , Lipopolysaccharides/toxicity , Microglia/metabolism , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Cell Line , Dose-Response Relationship, Drug , Imidazoles/pharmacology , Imidazoles/therapeutic use , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Inflammation Mediators/antagonists & inhibitors , Male , Mice , Mice, Inbred C57BL , Microglia/drug effects , Protein Kinase Inhibitors/therapeutic use , Pyridines/pharmacology , Pyridines/therapeutic useABSTRACT
BACKGROUND: This study investigated the role of hyperthermia combined with preoperative concurrent chemoradiotherapy (CCRT) for locally advanced rectal cancer (LARC) according to hypoxic marker expression. METHODS: One hundred and nine LARC patients with tissue blocks available for immunohistochemical assessment of carbonic anhydrase 9 (CA9) expression were reviewed. CA9 expression was considered positive when the staining percentage of tumor cells was >25% (n = 31). Pelvic radiotherapy with a total dose of 39.6-45 Gy was delivered concurrently with fluorouracil-based chemotherapy. Hyperthermia was administered to 52 patients twice a week during CCRT. Treatment response and outcomes were compared between hyperthermochemoradiotherapy (HCRT) and CCRT groups. RESULTS: In patients with positive CA9 expression, the rates of downstaging (p = 0.060) and pathologic complete response (p = 0.064) tended to be higher in the HCRT group than in the CCRT group. Distant metastasis-free survival (p = 0.029) and cancer-specific survival (p = 0.020) were significantly worse in tumors with both positive CA9 expression and poor tumor response. Negative CA9 expression, presence of major tumor response, and the use of hyperthermia were significant favorable prognostic factors for cancer-specific survival after the first recurrence in multivariate analysis. CONCLUSIONS: Hyperthermia might selectively enhance the preoperative treatment response in LARC with positive CA9 expression and offset the negative effect of hypoxia on prognosis. Pretreatment evaluation of hypoxia could aid in the selection of patients who might benefit from hyperthermia.
Subject(s)
Antigens, Neoplasm/analysis , Carbonic Anhydrase IX/analysis , Patient Selection , Rectal Neoplasms/pathology , Rectal Neoplasms/therapy , Aged , Chemoradiotherapy/methods , Combined Modality Therapy , Female , Fluorouracil/therapeutic use , Humans , Hyperthermia, Induced/methods , Male , Middle Aged , Neoplasm Recurrence, Local , Preoperative Care , Prognosis , Rectal Neoplasms/mortality , Survival Rate , Treatment Failure , Treatment OutcomeABSTRACT
Based on sonographic findings, colovesical fistula was diagnosed in a 71-year-old man with sigmoid colon cancer. Gray-scale sonography revealed an irregular thickening of the sigmoid colon wall abutting the urinary bladder which also showed thickening in the region of contact. Color Doppler sonography showed a twinkling artifact within the thickened bladder wall. Contrast-enhanced computed tomography scan showed luminal communication between the sigmoid colon and the bladder in the region of thickening.
ABSTRACT
Despite recent advances in therapeutic strategies against hepatitis B virus (HBV) infection, chronic hepatitis B remains a major global health burden. Recent studies have shown that targeting host factors instead of viral factors can be an effective antiviral strategy with low risk of the development of resistance. Efforts to identify host factors affecting viral replication have identified p38 mitogen-activated protein kinase (MAPK) as a possible target for antiviral strategies against various viruses, including HBV. Here, a series of biphenyl amides were synthesized as novel p38 MAPK selective inhibitors and assessed for their anti-HBV activities. The suppression of HBV surface antigen (HBsAg) production by these compounds was positively correlated with p38 MAPK-inhibitory activity. The selected compound NJK14047 displayed significant anti-HBV activity, as determined by HBsAg production, HBeAg secretion, and HBV production. NJK14047 efficiently suppressed the secretion of HBV antigens and HBV particles from HBV genome-transfected cells and HBV-infected sodium taurocholate cotransporting polypeptide-expressing human hepatoma cells. Furthermore, NJK14047 treatment resulted in a significant decrease of pregenomic RNA and covalently closed circular DNA (cccDNA) of HBV in HBV-harboring cells, indicating its ability to inhibit HBV replication. Considering that suppression of HBsAg secretion and elimination of cccDNA of HBV are the major aims of anti-HBV therapeutic strategies, the results suggested the potential use of these compounds as a novel class of anti-HBV agents targeting host factors critical for viral infection.
Subject(s)
Antiviral Agents/pharmacology , Hepatitis B virus/drug effects , Hepatitis B, Chronic/drug therapy , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Amides/chemistry , Amides/pharmacology , Antiviral Agents/chemistry , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Cell Survival , DNA, Circular/analysis , Hepatitis B Surface Antigens/drug effects , Hepatitis B e Antigens/drug effects , Hepatitis B virus/physiology , Hepatitis B, Chronic/virology , Humans , Protein Kinase Inhibitors/chemistry , Virus Replication/drug effectsABSTRACT
PURPOSE: Treatment outcomes of patients with pelvic recurrence after hysterectomy alone for uterine cervical cancer who received salvage radiotherapy (RT) with or without concurrent chemotherapy were investigated. METHODS: Salvage RT for recurrent cervical cancer confined to the pelvic cavity after hysterectomy alone was received by 33 patients. The median interval between initial hysterectomy and recurrence was 26 months. Whole-pelvic irradiation was delivered to median dose of 45 Gy, followed by a boost with a median dose of 16 Gy to the gross tumor volume. Cisplatin-based concurrent chemotherapy was administered to 29 patients. RESULTS: The median follow-up period was 53 months for surviving patients. Most patients (97.0%) completed salvage RT of ≥45 Gy. Complete response (CR) was achieved in 23 patients (69.7%). Pelvic sidewall involvement and evaluation with positron-emission tomography-computed tomography were significantly associated with CR. The 5year progression-free survival (PFS), local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) rates were 62.7, 79.5, 72.5, and 60.1%, respectively. Initial International Federation of Gynecology and Obstetrics stage, pelvic sidewall involvement, and CR status were significant factors for PFS and OS rates in multivariate analysis. The incidence of severe acute and late toxicities (≥grade 3) was 12.1 and 3.0%, respectively. CONCLUSION: Aggressive salvage RT with or without concurrent chemotherapy for recurrent cervical cancer confined to the pelvic cavity was feasible, with promising treatment outcomes and acceptable toxicities. However, even more intensive novel treatment strategies should be investigated for patients with unfavorable prognostic factors.
Subject(s)
Chemoradiotherapy , Hysterectomy , Neoplasm Recurrence, Local/therapy , Re-Irradiation , Salvage Therapy , Uterine Cervical Neoplasms/therapy , Adult , Aged , Female , Follow-Up Studies , Humans , Magnetic Resonance Imaging , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Positron Emission Tomography Computed Tomography , Prognosis , Propensity Score , Radiotherapy Dosage , Survival Rate , Uterine Cervical Neoplasms/mortality , Uterine Cervical Neoplasms/pathologyABSTRACT
BACKGROUND: The aim of the present study was to investigate the long-term survival outcomes and toxicities associated with our experienced early administration of adjuvant concurrent chemoradiotherapy (CCRT). METHODS: Ninety-eight patients with pelvic lymph node metastasis, positive resection margin, and/or parametrial invasion who received adjuvant CCRT between 1995 and 2011 were analyzed retrospectively. The first cycle of platinum-based adjuvant chemotherapy was initiated within 2-3 weeks after surgery (median, 12 days) and continued every 4 weeks for a total of 4 cycles. Adjuvant radiotherapy was performed during the second and third cycles of chemotherapy. RESULTS: After a median follow-up period of 119 months for survivors, 13 patients (13.3%) experienced recurrence and 11 patients died of cancer during the follow-up period. The 5-year recurrence-free survival and cancer specific survival rates were 87.6% and 90.6%, respectively. Ninety-four patients (95.9%) received ≥3 cycles of chemotherapy. Total radiation dose of ≥45 Gy was delivered in 91 patients (92.9%). Grade 3-4 hematologic and gastrointestinal toxicities developed in 37 (37.8%) and 14 (14.3%) patients during CCRT, respectively. CONCLUSION: The present study confirmed the long-term safety and encouraging survival outcomes of early administration of adjuvant CCRT, suggesting the benefits of early time to initiation of adjuvant treatments.
Subject(s)
Hysterectomy/methods , Outcome Assessment, Health Care/methods , Uterine Cervical Neoplasms/surgery , Uterine Cervical Neoplasms/therapy , Adult , Aged , Chemoradiotherapy, Adjuvant/adverse effects , Chemoradiotherapy, Adjuvant/methods , Diarrhea/etiology , Female , Humans , Hysterectomy/adverse effects , Kaplan-Meier Estimate , Leukopenia/etiology , Lymphatic Metastasis , Middle Aged , Multivariate Analysis , Neoplasm Staging , Outcome Assessment, Health Care/statistics & numerical data , Time Factors , Uterine Cervical Neoplasms/pathologyABSTRACT
In an effort to identify novel anti-inflammatory compounds, a series of flavone derivatives were synthesized and biologically evaluated for their inhibitory effects on the production of nitric oxide (NO) and prostaglandin E2 (PGE2), representative pro-inflammatory mediators, in LPS-induced RAW 264.7 cells. Their structure-activity relationship was also investigated. In particular, we found that compound 3g displayed more potent inhibitory activities on PGE2 production, similar inhibitory activities on NO production and less weak cytotoxicity than luteolin, a natural flavone known as a potent anti-inflammatory agent.
Subject(s)
Anti-Inflammatory Agents/chemistry , Dinoprostone/metabolism , Flavones/chemistry , Nitric Oxide/metabolism , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/toxicity , Flavones/chemical synthesis , Flavones/toxicity , Lipopolysaccharides/toxicity , Macrophages/drug effects , Mice , RAW 264.7 Cells , Structure-Activity RelationshipABSTRACT
Respiratory syncytial virus (RSV) and influenza A virus are leading causes of acute lower respiratory infectious disease. Respiratory diseases caused by RSV and influenza A virus result in serious economic burden and life-threatening disease for immunocompromised people. With the revelation that p38 mitogen-activated protein kinase (MAPK) activity in host cells is crucial for infection and replication of RSV and influenza A virus, inhibition of p38 MAPK activity has been suggested as a potential antiviral therapeutic strategy. However, the low selectivity and high toxicity of the p38 MAPK inhibitors necessitate the development of better inhibitors. Herein, we report the synthesis of a novel p38 MAPK inhibitor, NJK14047, with high kinase selectivity. In this work, it was demonstrated that NJK14047 inhibits RSV- and influenza A-mediated p38 MAPK activation in epithelial cells. Subsequently, NJK14047 treatment resulted in decreased viral replication and viral mRNA synthesis. In addition, secretion of interleukin-6 from infected cells was greatly diminished by NJK14047, suggesting that it can ameliorate immunopathological responses to RSV and influenza A. Collectively, the results suggest that NJK14047 has therapeutic potential to treat respiratory viral infection through the suppression of p38 MAPK activation, which is suggested to be an essential step for respiratory virus infection.
Subject(s)
Antiviral Agents/pharmacology , Influenza A virus/drug effects , Protein Kinase Inhibitors/pharmacology , Respiratory Syncytial Viruses/drug effects , Virus Replication/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Cell Line , Enzyme Activation , Influenza A virus/growth & development , Influenza A virus/physiology , Mice , RNA, Viral/antagonists & inhibitors , RNA, Viral/biosynthesis , Respiratory Syncytial Viruses/growth & development , Respiratory Syncytial Viruses/physiology , Viral Plaque Assay , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
High-density lipoprotein (HDL) cholesterol levels are associated with a decreased risk of coronary artery disease. Several genome-wide association studies that have examined HDL cholesterol levels have implicated myosin light chain 2 regulatory cardiac slow (MYL2) as a possible causal factor. Herein, the association between the rs3782889 single-nucleotide polymorphism (SNP) in the MYL2 gene and HDL cholesterol levels was tested in the Korean population. A total of 4294 individuals were included in a replication study with MYL2 SNP rs3782889. SNP rs3782889 in the MYL2 gene was associated with mean HDL cholesterol level (effect per allele, -1.055 mg dl(-1), P=0.0005). Subjects with the CT/CC genotype had a 1.43-fold (range 1.19-1.73-fold) higher risk of an abnormal HDL cholesterol level (<40 mg dl(-1)) than subjects with the TT genotype. When analyzed by sex, the MYL2 association was stronger in men than that in women. When analyzed by body mass index (BMI), the MYL2 association was much stronger in male subjects with BMI ⩾26.44 kg m(-2) (odds ratio (OR)=2.68; 95% confidence interval (CI)=1.87-3.84; P<0.0001) than that in male subjects with BMI <26.44 kg m(-2). When compared with subjects having the TT genotype and BMI <26.44 kg m(-2), ORs (95% CI) were 3.30 (2.41-4.50) in subjects having the CT/CC genotype and BMI ⩾26.44 kg m(-2) (P for interaction <0.0001). Our results clearly demonstrate that genetic variants in MYL2 influence HDL cholesterol levels in Korean obese male subjects.
Subject(s)
Cardiac Myosins/genetics , Cholesterol, HDL/blood , Genetic Association Studies , Myosin Light Chains/genetics , Obesity/blood , Obesity/genetics , Adult , Alleles , Biomarkers , Comorbidity , Female , Genotype , Humans , Male , Middle Aged , Obesity/epidemiology , Odds Ratio , Polymorphism, Single Nucleotide , Republic of Korea/epidemiology , Risk FactorsABSTRACT
PURPOSE: This study compared a tablet PC questionnaire with a paper method for reliability and patient preferences in the acquisition of patient-reported outcomes (PROs) for patients treated with radiotherapy. By comparing the two modes of PRO administration, we aimed to evaluate the adequacy of using tablet PC questionnaires in future clinical use. METHODS: Patients were randomized in a crossover study design using two different methods for PRO entry. A group of 89 patients answered a paper questionnaire followed by the tablet PC version, whereas 89 patients in another group completed the tablet PC questionnaire followed by the paper version. Surveys were performed four times per patient throughout the course of the radiotherapy. The Korean versions of the M.D. Anderson Symptom Inventory (MDASI-K) and the Brief Fatigue Inventory (BFI-K) were used. The primary endpoint of our current study was an assessment of patient preference for the survey method. The proportions of patients preferring each mode of questionnaire were evaluated. RESULTS: The proportion of patients who preferred the tablet PC version, paper form, or who had no preference was 52.2, 22.1, and 25.7 %, respectively. More than half of the patients preferred the tablet PC to the paper version in all four surveys. Age, gender, educational status, prior experience of using a tablet PC, and the order of paper to tablet PC administration did not impact patient preferences. Inter-class correlation coefficients (ICCs) between the modes were 0.92 for MDASI-K and 0.94 for BFI-K and ranged from 0.91 to 0.96 on both instruments during the four surveys. CONCLUSIONS: A tablet PC-based PRO is an acceptable and reliable method compared with paper-based data collection for Korean patients receiving radiotherapy.
Subject(s)
Internet/statistics & numerical data , Neoplasms/radiotherapy , Quality of Life/psychology , Adolescent , Adult , Aged , Cross-Over Studies , Female , Humans , Male , Middle Aged , Paper , Prospective Studies , Surveys and Questionnaires , Young AdultABSTRACT
PURPOSE: The aims of the study were to evaluate the usefulness of low-dose (LD) nonenhanced CT (NECT) with coronal reformation in diagnosing acute appendicitis and to compare LD NECT with standard-dose (SD) NECT and SD contrast-enhanced CT (CECT). METHODS: A total of 452 patients suspected of having acute appendicitis underwent CT using a scan 1 (SD NECT and SD CECT1, n = 182) or a scan 2 protocol (LD NECT and SD CECT2, n = 270). The diagnostic performance and interobserver agreement for diagnosing acute appendicitis were compared. RESULTS: Although the area under the curves of both reviewers of LD NECT were lower than those of SD CECT2, area under the curves of both reviewers for SD NECT were not significantly different for SD CECT1 and LD NECT (all P > 0.05). The interobserver agreements within each scan were excellent (all κ > 0.8). CONCLUSIONS: Low-dose NECT with coronal reformation showed high diagnostic performance and can be used as the first-line imaging tool in the work-up of patients with suspected acute appendicitis.
Subject(s)
Appendicitis/diagnostic imaging , Image Interpretation, Computer-Assisted/methods , Radiation Exposure/analysis , Radiation Exposure/prevention & control , Tomography, X-Ray Computed/methods , Adolescent , Adult , Aged , Female , Humans , Image Enhancement/methods , Male , Middle Aged , Observer Variation , Radiation Dosage , Radiation Protection/methods , Radiography, Abdominal/methods , Reproducibility of Results , Sensitivity and Specificity , Young AdultABSTRACT
We investigate how the electrical conductance of microfibers (made of polymers and conductive nanofillers) decreases upon uniaxial deformation by performing both experiments and simulations. Even though various elastic conductors have been developed due to promising applications for deformable electronic devices, the mechanism at a molecular level for electrical conductance change has remained elusive. Previous studies proposed that the decrease in electrical conductance would result from changes in either distances or contact numbers between conductive fillers. In this work, we prepare microfibers of single walled carbon nanotubes (SWCNTs)/polyvinyl alcohol composites and investigate the electrical conductance and the orientation of SWCNTs upon uniaxial deformation. We also perform extensive Monte Carlo simulations, which reproduce experimental results for the relative decrease in conductance and the SWCNTs orientation. We investigate the electrical networks of SWCNTs in microfibers and find that the decrease in the electrical conductance upon uniaxial deformation should be attributed to a subtle change in the topological structure of the electrical network.