Proline Hydroxylation Primes Protein Kinases for Autophosphorylation and Activation.

Activation of dual-specificity tyrosine-phosphorylation-regulated kinases 1A and 1B (DYRK1A and DYRK1B) requires prolyl hydroxylation by PHD1 prolyl hydroxylase. Prolyl hydroxylation of DYRK1 initiates a cascade of events leading to the release of molecular constraints on von Hippel-Lindau (VHL) ubiquitin ligase tumor suppressor function. However, the proline residue of DYRK1 targeted by hydroxylation and the role of prolyl hydroxylation in tyrosine autophosphorylation of DYRK1 are unknown. We found that a highly conserved proline in the CMGC insert of the DYRK1 kinase domain is hydroxylated by PHD1, and this event precedes tyrosine autophosphorylation. Mutation of the hydroxylation acceptor proline precludes tyrosine autophosphorylation and folding of DYRK1, resulting in a kinase unable to preserve VHL function and lacking glioma suppression activity. The consensus proline sequence is shared by most CMGC kinases, and prolyl hydroxylation is essential for catalytic activation. Thus, formation of prolyl-hydroxylated intermediates is a novel mechanism of kinase maturation and likely a general mechanism of regulation of CMGC kinases in eukaryotes.

Determinants of Meal-Induced Changes in Circulating FFA Epoxides, Diols, and Diol-to-Epoxide Ratios as Indices of Soluble Epoxide Hydrolase Activity.

Soluble epoxide hydrolase (sEH) is an important enzyme for metabolic and cardiovascular health. sEH converts FFA epoxides (EpFAs), many of which are regulators of various cellular processes, to biologically less active diols. In human studies, diol (sEH product) to EpFA (sEH substrate) ratios in plasma or serum have been used as indices of sEH activity. We previously showed these ratios profoundly decreased in rats during acute feeding, possibly reflecting decreases in tissue sEH activities. The present study was designed to test which tissue(s) these measurements in the blood represent and if factors other than sEH activity, such as renal excretion or dietary intake of EpFAs and diols, significantly alter plasma EpFAs, diols, and/or their ratios. The results show that postprandial changes in EpFAs and diols and their ratios in plasma were very similar to those observed in the liver but not in other tissues, suggesting that the liver is largely responsible for these changes in plasma levels. EpFAs and diols were excreted into the urine, but their levels were not significantly altered by feeding, suggesting that renal excretion of EpFAs and diols may not play a major role in postprandial changes in circulating EpFAs, diols, or their ratios. Diet intake had significant impacts on circulating EpFA and diol levels but not on diol-to-EpFA (D-to-E) ratios, suggesting that these ratios, reflecting sEH activities, may not be significantly affected by the availability of sEH substrates (i.e., EpFAs). In conclusion, changes in FFA D-to-E ratios in plasma may reflect those in the liver, which may in turn represent sEH activities in the liver, and they may not be significantly affected by renal excretion or the dietary intake of EpFAs and diols.

Effects of Individual Circulating FFAs on Plasma and Hepatic FFA Epoxides, Diols, and Epoxide-Diol Ratios as Indices of Soluble Epoxide Hydrolase Activity.

Oxylipins, oxidation products of unsaturated free fatty acids (FFAs), are involved in various cellular signaling systems. Among these oxylipins, FFA epoxides are associated with beneficial effects in metabolic and cardiovascular health. FFA epoxides are metabolized to diols, which are usually biologically less active, by soluble epoxide hydrolase (sEH). Plasma epoxide-diol ratios have been used as indirect measures of sEH activity. This study was designed to examine the effects of acute elevation of individual plasma FFAs on a variety of oxylipins, particularly epoxides, diols, and their ratios. We tested if FFA epoxide-diol ratios are altered by circulating FFA levels (i.e., substrate availability) independent of sEH activity. Wistar rats received a constant intravenous infusion of olive (70% oleic acid (OA)), safflower seed (72% linoleic acid (LA)), and fish oils (rich in ω-3 FFAs) as emulsions to selectively raise OA, LA, and ω-3 FFAs (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), respectively. As expected, olive, safflower seed, and fish oil infusions selectively raised plasma OA (57%), LA (87%), EPA (70%), and DHA (54%), respectively (p < 0.05 for all). Raising plasma FFAs exerted substrate effects to increase hepatic and plasma epoxide and diol levels. These increases in epoxides and diols occurred to similar extents, resulting in no significant changes in epoxide-diol ratios. These data suggest that epoxide-diol ratios, often used as indices of sEH activity, are not affected by substrate availability or altered plasma FFA levels and that epoxide-diol ratios may be used to compare sEH activity between conditions of different circulating FFA levels.

Anti-Inflammatory and Antiatopic Effects of Rorippa cantoniensis (Lour.) Ohwi in RAW 264.7 and HaCaT Cells.

This study evaluated the effects of Rorippa cantoniensis (Lour.) ohwi extract (RCE) on factors associated with inflammation-related skin lesions in RAW 264.7 and HaCaT cells. RCE inhibited the levels of proinflammatory mediators and cytokines such as nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL)-6, and tumor necrosis factor (TNF)-α in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In addition, RCE significantly inhibited the expression of chemokines and cytokines such as MDC/CCL22, TARC/CCL17, RANTES/CCL5, CTSS, IL-6, IL-1ß, and TNF-α in HaCaT cells costimulated by TNF-α and interferon (IFN)-γ in a concentration-dependent manner. These results suggest that RCE attenuated the TNF-α- and IFN-γ-induced release of proinflammatory chemokines and cytokines probably by suppressing the activation of MAPK (JNK and p38), NF-κB, and STAT1 signaling. Moreover, RCE significantly increased the expression of skin components such as hyaluronic acid and aquaporin, which play important roles in the physical and chemical barriers of the skin. These results suggest that RCE has significant anti-inflammatory and antiatopic activities, which may be beneficial for the topical treatment of inflammatory skin disorders.

Estimating in vivo potassium distribution and fluxes with stable potassium isotopes.

Extracellular potassium (K+) homeostasis is achieved by a concerted effort of multiple organs and tissues. A limitation in studies of K+ homeostasis is inadequate techniques to quantify K+ fluxes into and out of organs and tissues in vivo. The goal of the present study was to test the feasibility of a novel approach to estimate K+ distribution and fluxes in vivo using stable K+ isotopes. 41K was infused as KCl into rats consuming control or K+-deficient chow (n = 4 each), 41K-to-39K ratios in plasma and red blood cells (RBCs) were measured by inductively coupled plasma mass spectrometry, and results were subjected to compartmental modeling. The plasma 41K/39K increased during 41K infusion and decreased upon infusion cessation, without altering plasma total K+ concentration ([K+], i.e., 41K + 39K). The time course of changes was analyzed with a two-compartmental model of K+ distribution and elimination. Model parameters, representing transport into and out of the intracellular pool and renal excretion, were identified in each rat, accurately predicting decreased renal K+ excretion in rats fed K+-deficient vs. control diet (P < 0.05). To estimate rate constants of K+ transport into and out of RBCs, 41K/39K were subjected to a simple model, indicating no effects of the K+-deficient diet. The findings support the feasibility of the novel stable isotope approach to quantify K+ fluxes in vivo and sets a foundation for experimental protocols using more complex models to identify heterogeneous intracellular K+ pools and to answer questions pertaining to K+ homeostatic mechanisms in vivo.

Modulation of Nogo receptor 1 expression orchestrates myelin-associated infiltration of glioblastoma.

As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.

Chemoradiation in elderly patients with glioblastoma from the multi-institutional GBM-molRPA cohort: is short-course radiotherapy enough or is it a matter of selection?

BACKGROUND: The optimal radiotherapy regimen in elderly patients with glioblastoma treated by chemoradiation needs to be addressed. We provide the results of a comparison between conventionally fractionated standard radiotherapy (CRT) and short-course radiotherapy (SRT) in those patients treated by temozolomide-based chemoradiation. METHODS: Patients aged 65 years or older from the GBM-molRPA cohort were included. Patients who were planned for a ≥ 6-week or ≤ 4-week radiotherapy were regarded as being treated by CRT or SRT, respectively. The median RT dose in the CRT and SRT group was 60 Gy in 30 fractions and 45 Gy in 15 fractions, respectively. RESULTS: A total of 260 and 134 patients aged older than 65 and 70 years were identified, respectively. CRT- and SRT-based chemoradiation was applied for 192 (73.8%) and 68 (26.2%) patients, respectively. Compared to SRT, CRT significantly improved MS from 13.2 to 17.6 months and 13.3 to 16.4 months in patients older than 65 years (P < 0.001) and 70 years (P = 0.002), respectively. Statistical significance remained after adjusting for age, performance status, surgical extent, and MGMT promoter methylation in both age groups. The benefit was clear in all subgroup analyses for patients with Karnofsky performance score 70-100, Karnofsky performance score ≤ 60, gross total resection, biopsy, methylated MGMT promoter, and unmethylated MGMT promoter (all P < 0.05). CONCLUSION: CRT significantly improved survival compared to SRT in elderly glioblastoma patients treated with chemoradiation in selected patients amenable for chemoradiation. This study is hypothesis-generating and a prospective randomized trial is urgently warranted.

Correction to: Chemoradiation in elderly patients with glioblastoma from the multi­institutional GBM­molRPA cohort: is short­course radiotherapy enough or is it a matter of selection?

The name of author Do Hoon Lim was incorrect in the initial online publication. The original article has been corrected.

Guanosine tetra- and pentaphosphate increase antibiotic tolerance by reducing reactive oxygen species production in Vibrio cholerae.

The pathogen Vibrio cholerae is the causative agent of cholera. Emergence of antibiotic-resistant V. cholerae strains is increasing, but the underlying mechanisms remain unclear. Herein, we report that the stringent response regulator and stress alarmone guanosine tetra- and pentaphosphate ((p)ppGpp) significantly contributes to antibiotic tolerance in V. cholerae We found that N16961, a pandemic V. cholerae strain, and its isogenic (p)ppGpp-overexpressing mutant ΔrelAΔspoT are both more antibiotic-resistant than (p)ppGpp0 (ΔrelAΔrelVΔspoT) and ΔdksA mutants, which cannot produce or utilize (p)ppGpp, respectively. We also found that additional disruption of the aconitase B-encoding and tricarboxylic acid (TCA) cycle gene acnB in the (p)ppGpp0 mutant increases its antibiotic tolerance. Moreover, expression of TCA cycle genes, including acnB, was increased in (p)ppGpp0, but not in the antibiotic-resistant ΔrelAΔspoT mutant, suggesting that (p)ppGpp suppresses TCA cycle activity, thereby entailing antibiotic resistance. Importantly, when grown anaerobically or incubated with an iron chelator, the (p)ppGpp0 mutant became antibiotic-tolerant, suggesting that reactive oxygen species (ROS) are involved in antibiotic-mediated bacterial killing. Consistent with that hypothesis, tetracycline treatment markedly increased ROS production in the antibiotic-susceptible mutants. Interestingly, expression of the Fe(III) ABC transporter substrate-binding protein FbpA was increased 10-fold in (p)ppGpp0, and fbpA gene deletion restored viability of tetracycline-exposed (p)ppGpp0 cells. Of note, FbpA expression was repressed in the (p)ppGpp-accumulating mutant, resulting in a reduction of intracellular free iron, required for the ROS-generating Fenton reaction. Our results indicate that (p)ppGpp-mediated suppression of central metabolism and iron uptake reduces antibiotic-induced oxidative stress in V. cholerae.

Psychiatric comorbidities among ovarian cancer survivors in South Korea: A nationwide population-based, longitudinal study.

PURPOSE: The aim of this time-dependent study was to analyze the prevalence of mental disorders in ovarian cancer survivors using claims data in South Korea. MATERIALS AND METHODS: We confirmed mental disorders in a nationwide cohort of 9763 patients who were diagnosed with ovarian cancer between January 1, 2010 and December 31, 2014. We categorized the prevalence of mental disorders based on the age and the time of diagnosis. RESULTS: A total of 821 ovarian cancer patients were diagnosed with a mental disorder, 1 year prior to the cancer diagnosis. Of those patients, 311 were diagnosed with depression (37.9%) and 245 with anxiety (29.8%) during their first visit. The overall frequency of mental disorders peaked within 2 months after the cancer diagnosis. The highest rate of increase after diagnosis was noted in stress reaction/adjustment disorders. While depression was relatively high (40.4%) in the younger age group under 60 years, anxiety was higher (39.4%) in the elderly group over 60 years old. Age was a significant predictive factor for mental disorders (P = 0.002), and patients over 50 years were at a higher risk for mental disorders (hazard ratio: 1.29, P = 0.002). CONCLUSION: Mental disorders in ovarian cancer survivors showed different patterns of prevalence depending on age at the time of diagnosis and the nature of disease. Timely diagnosis and intervention for psychological distress could increase the quality of life for ovarian cancer survivors.

Cancer risk after renal transplantation in South Korea: a nationwide population-based study.

BACKGROUND: This study aimed to evaluate patterns of posttransplant malignancies among renal transplant recipients (RTRs) in South Korea using nationwide data. METHODS: The nationwide cohort assessed in this study included RTRs from January 1, 2010, to December 31, 2014. We analyzed cancer incidence during the time course after renal transplantation. Additionally, we calculated standardized incidence ratios (SIRs) to evaluate the risk of malignancies in RTRs. RESULTS: A total of 1343 RTRs (871 males and 472 females, mean age 48.5 ± 11.6 years) were assessed. Among them, 104 (7.7%) developed malignancies after transplantation, most commonly in the thyroid cancer (23.1%). The SIR for all cancers was 3.54; particularly, the SIRs for renal cancer, myeloma, and non-Hodgkin lymphoma were 16.31, 24.02, and 28.64, respectively. Females showed a higher risk of malignancy than males (SIRs: 4.04 for women and 3.26 for men). The median interval between transplantation and malignancy diagnosis was 27.2 months (range 12.3-54.8 months). CONCLUSIONS: RTRs in South Korea demonstrated a high risk of malignancy after transplantation compared with the general population. This indicates that close surveillance and routine screening for cancer in RTRs are needed.

Psychiatric comorbidities among breast cancer survivors in South Korea: a nationwide population-based study.

PURPOSE: The aim of this study was to analyze the prevalence of mental disorders in breast cancer survivors using claims data from the Health Insurance Review and Assessment Service in South Korea. We also analyzed patterns of mental disorders with respect to the time of diagnosis and age. MATERIALS AND METHODS: We confirmed mental disorders in a nationwide cohort of 87,843 people who were diagnosed with invasive breast cancer and underwent surgery between January 1, 2010 and December 31, 2014. We investigated the prevalence of mental disorders according to the time of diagnosis and age group. We also examined the utilization patterns of medical institutions and medical departments. RESULT: From one year before a breast cancer diagnosis, 8430 patients were diagnosed with a mental disorder. Of those patients, 3256 were diagnosed with depression (38.6%) and 2739 with anxiety (32.5%). The overall frequency of mental disorders peaked within one month after the cancer diagnosis. The highest rate of increase after diagnosis was noted in stress reaction/adjustment disorders. Depression was relatively high in the young age group, and anxiety was high in the elderly group. In total, there were 59,111 claims for mental disorders. Over 70% (43,788) of claims for mental disorder treatment were from a psychiatry medical department. CONCLUSION: Mental disorders in breast cancer survivors showed different patterns of prevalence according to time, age, and disease. Early intervention could be effective in controlling symptoms of mental disorder and could increase the quality of life for cancer survivors.

Hematological parameters during concurrent chemoradiotherapy as potential prognosticators in patients with stage IIB cervical cancer.

We hypothesized that hemoglobin levels, absolute neutrophil count, and absolute lymphocyte count were associated with radiotherapy response and cancer progression and that they might reflect tumor repopulation during concurrent chemoradiotherapy. This study aimed to investigate these hematological parameters as prognosticators of cervical cancer. We analyzed 105 stage IIB cervical cancer patients treated with concurrent chemoradiotherapy, using log-rank tests and multivariate analyses. Hazard ratios were calculated weekly to evaluate changes in hemoglobin, absolute neutrophil count, and absolute lymphocyte count that were associated with disease-specific survival. Patients were categorized into the high hematological risk (patients with low hemoglobin plus high absolute neutrophil count and/or low absolute lymphocyte count) and the low hematological risk (others) groups according to the median cutoff values. During the second week of concurrent chemoradiotherapy, hematological factors were significantly associated with survival. In multivariate analysis, hematological risk was independently associated with disease-specific survival and progression-free survival. The 5-year disease-specific survival and progression-free survival rates in the high hematological risk group were significantly lower compared with those in the low hematological risk group (81.6% vs 92.6%, p = 0.0297; 73.7% vs 89.3%, p = 0.0163, respectively). During the second week of concurrent chemoradiotherapy, the hematological parameters could predict treatment outcome in stage IIB cervical cancer.

Prognostic implication of simultaneous anemia and lymphopenia during concurrent chemoradiotherapy in cervical squamous cell carcinoma.

Radioresistance often leads to poor survival in concurrent chemoradiotherapy-treated cervical squamous cell carcinoma, and reliable biomarkers can improve prognosis. We compared the prognostic potential of hemoglobin, absolute neutrophil count, and absolute lymphocyte count with that of squamous cell carcinoma antigen in concurrent chemoradiotherapy-treated squamous cell carcinoma. We analyzed 152 patients with concurrent chemoradiotherapy and high-dose-rate intracavitary brachytherapy-treated cervical squamous cell carcinoma. Hemoglobin, absolute neutrophil count, absolute lymphocyte count, and squamous cell carcinoma antigen were quantitated and correlated with survival, using Cox regression, receiver operating characteristic curve analysis, and Kaplan-Meier plots. Both hemoglobin and absolute lymphocyte count in the second week of concurrent chemoradiotherapy (Hb2 and ALC2) and squamous cell carcinoma antigen in the third week of concurrent chemoradiotherapy (mid-squamous cell carcinoma antigen) correlated significantly with disease-specific survival and progression-free survival. The ratio of high-dose-rate intracavitary brachytherapy dose to total dose (high-dose-rate intracavitary brachytherapy ratio) correlated significantly with progression-free survival. Patients with both low Hb2 (≤11 g/dL) and ALC2 (≤639 cells/µL) showed a lower 5-year disease-specific survival rate than those with high Hb2 and/or ALC2, regardless of mid-squamous cell carcinoma antigen (mid-squamous cell carcinoma antigen: ≤4.7 ng/mL; 5-year disease-specific survival rate: 85.5% vs 94.6%, p = 0.0096, and mid-squamous cell carcinoma antigen: >4.7 ng/mL; 5-year disease-specific survival rate: 43.8% vs 66.7%, p = 0.192). When both Hb2 and ALC2 were low, the low high-dose-rate intracavitary brachytherapy ratio (≤0.43) subgroup displayed significantly lower 5-year disease-specific survival rate compared to the subgroup high high-dose-rate intracavitary brachytherapy ratio (>0.43) (62.5% vs 88.2%, p = 0.0067). Patients with both anemia and lymphopenia during concurrent chemoradiotherapy showed poor survival, independent of mid-squamous cell carcinoma antigen, and escalating high-dose-rate intracavitary brachytherapy ratio might improve survival.

Salvage radiotherapy with or without concurrent chemotherapy for pelvic recurrence after hysterectomy alone for early-stage uterine cervical cancer.

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.

Long-term results of early adjuvant concurrent chemoradiotherapy for high-risk, early stage uterine cervical cancer patients after radical hysterectomy.

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.

Chemoradiotherapy versus surgery followed by postoperative radiotherapy in tonsil cancer: Korean Radiation Oncology Group (KROG) study.

BACKGROUND: Treatment of tonsil cancer, a subset of oropahryngeal cancer, varies between surgery and radiotherapy. Well-designed studies in tonsil cancer have been rare and it is still controversial which treatment is optimal. This study aimed to assess the outcome and failure patterns in tonsil cancer patients treated with either approaches. METHODS: We retrospectively reviewed medical records of 586 patients with tonsil cancer, treated between 1998 and 2010 at 16 hospitals in Korea. Two hundred and one patients received radiotherapy and chemotherapy (CRT), while 385 patients received surgery followed by radiotherapy and/or chemotherapy (SRT). Compared with the SRT group, patients receiving CRT were older, with more advanced T stage and received higher radiotherapy dose given by intensity modulation techniques. Overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and clinicopathologic factors were analyzed. RESULTS: At follow-up, the 5-year OS, DFS, LRRFS and DMFS rates in the CRT group were 82, 78, 89, and 94%, respectively, and in the SRT group were 81, 73, 87, and 89%, respectively. Old age, current smoking, poor performance status, advanced T stage, nodal involvement, and induction chemotherapy were associated with poor OS. Induction chemotherapy had a negative prognostic impact on OS in both treatment groups (p = 0.001 and p = 0.033 in the CRT and SRT groups, respectively). CONCLUSIONS: In our multicenter, retrospective study of tonsil cancer patients, the combined use of radiotherapy and chemotherapy resulted in comparable oncologic outcome to surgery followed by postoperative radiotherapy, despite higher-risk patients having been treated with the definitive radiotherapy. Induction chemotherapy approaches combined with either surgery or definitive radiotherapy were associated with unfavorable outcomes.

Temperature Dependence According to Grain Boundary Potential Barrier Variation in Vertical NAND Flash Cell with Polycrystalline-Silicon Channel.

We investigate the electrical characteristics according to changing temperature on trap distribution in the energy gap of grain boundary (GB) and interface trap density (D(it)) between polycrystalline-silicon (poly-Si) channel and tunnel oxide in Vertical NAND (VNAND) flash cell with poly-Si channel. We confirmed that there are two factors changing GB potential barrier height such as trap distribution in GB and D(it) using technology computer-aided design (TCAD) simulation. Also, we found that the electrical characteristics according to changing temperature are significantly dependent on height and position of GB potential barrier in VNAND flash cell with poly-Si channel. We expect that it is required to develop more accurate extraction method for trap distribution in each GB and D(it) for better understanding temperature dependence of electrical characteristics in VNAND Flash cell.

Automatic image fusion of real-time ultrasound with computed tomography images: a prospective comparison between two auto-registration methods.

Background A major drawback of conventional manual image fusion is that the process may be complex, especially for less-experienced operators. Recently, two automatic image fusion techniques called Positioning and Sweeping auto-registration have been developed. Purpose To compare the accuracy and required time for image fusion of real-time ultrasonography (US) and computed tomography (CT) images between Positioning and Sweeping auto-registration. Material and Methods Eighteen consecutive patients referred for planning US for radiofrequency ablation or biopsy for focal hepatic lesions were enrolled. Image fusion using both auto-registration methods was performed for each patient. Registration error, time required for image fusion, and number of point locks used were compared using the Wilcoxon signed rank test. Results Image fusion was successful in all patients. Positioning auto-registration was significantly faster than Sweeping auto-registration for both initial (median, 11 s [range, 3-16 s] vs. 32 s [range, 21-38 s]; P < 0.001] and complete (median, 34.0 s [range, 26-66 s] vs. 47.5 s [range, 32-90]; P = 0.001] image fusion. Registration error of Positioning auto-registration was significantly higher for initial image fusion (median, 38.8 mm [range, 16.0-84.6 mm] vs. 18.2 mm [6.7-73.4 mm]; P = 0.029), but not for complete image fusion (median, 4.75 mm [range, 1.7-9.9 mm] vs. 5.8 mm [range, 2.0-13.0 mm]; P = 0.338]. Number of point locks required to refine the initially fused images was significantly higher with Positioning auto-registration (median, 2 [range, 2-3] vs. 1 [range, 1-2]; P = 0.012]. Conclusion Positioning auto-registration offers faster image fusion between real-time US and pre-procedural CT images than Sweeping auto-registration. The final registration error is similar between the two methods.

(p)ppGpp, a Small Nucleotide Regulator, Directs the Metabolic Fate of Glucose in Vibrio cholerae.

When V. cholerae encounters nutritional stress, it activates (p)ppGpp-mediated stringent response. The genes relA and relV are involved in the production of (p)ppGpp, whereas the spoT gene encodes an enzyme that hydrolyzes it. Herein, we show that the bacterial capability to produce (p)ppGpp plays an essential role in glucose metabolism. The V. cholerae mutants defective in (p)ppGpp production (i.e. ΔrelAΔrelV and ΔrelAΔrelVΔspoT mutants) lost their viability because of uncontrolled production of organic acids, when grown with extra glucose. In contrast, the ΔrelAΔspoT mutant, a (p)ppGpp overproducer strain, exhibited better growth in the presence of the same glucose concentration. An RNA sequencing analysis demonstrated that transcriptions of genes consisting of an operon for acetoin biosynthesis were markedly elevated in N16961, a seventh pandemic O1 strain, but not in its (p)ppGpp(0) mutant during glucose-stimulated growth. Transposon insertion in acetoin biosynthesis gene cluster resulted in glucose-induced loss of viability of the ΔrelAΔspoT mutant, further suggesting the crucial role of acetoin production in balanced growth under glucose-rich environments. Additional deletion of the aphA gene, encoding a negative regulator for acetoin production, failed to rescue the (p)ppGpp(0) mutant from the defective glucose-mediated growth, suggesting that (p)ppGpp-mediated acetoin production occurs independent of the presence of AphA. Overall, our results reveal that (p)ppGpp, in addition to its well known role as a stringent response mediator, positively regulates acetoin production that contributes to the successful glucose metabolism and consequently the proliferation of V. cholerae cells under a glucose-rich environment, a condition that may mimic the human intestine.