Reliability and validity of the Atopic Dermatitis Symptom Score (ADSS).

BACKGROUND: We have developed the Atopic Dermatitis Symptom Score (ADSS) by which patients or parents can easily assess and record AD symptoms on a daily basis in a smartphone application. The aim of this study was to evaluate the reliability and validity of the ADSS. METHODS: We enrolled 307 children and adolescents with AD. Parents or caregivers were asked to record daily symptoms of the patients (itching, sleep disturbance, erythema, dryness, oozing, and edema) using a scale of 0-4. Statistical analyses consisted of the test-retest reliability, concurrent validity, minimal clinically important difference (MCID), responsiveness, floor or ceiling effects, and screening accuracy. Receiver-operating characteristic analyses were conducted to evaluate the ADSS cutoff point for predicting severe AD (SCORing AD [SCORAD] ≥40). RESULTS: Test-retest reliability between daytime and night-time ADSS was good (intraclass correlation coefficient, 0.82 [95% CI: 0.70-0.90]). An increase in ADSS was significantly associated with an increase in SCORAD (r = 0.64, P < .0001) (concurrent validity). The MCID was 4.1 points for the ADSS. There was a significant association between changes in ADSS and SCORAD (r = 0.56, P < .0001), indicating good responsiveness. At the optimal ADSS cutoff value of 7.0, sensitivity, specificity, and positive and negative predictive values were 88.4%, 78.6%, 21.1%, and 99.1%, respectively (screening accuracy). CONCLUSIONS: The ADSS can be a useful tool for self-assessment of skin symptoms in children with AD.

Detecting selection signatures between Duroc and Duroc synthetic pig populations using high-density SNP chip.

The development of high throughput genotyping techniques has facilitated the identification of selection signatures of pigs. The detection of genomic selection signals in a population subjected to differential selection pressures may provide insights into the genes associated with economically and biologically important traits. To identify genomic regions under selection, we genotyped 488 Duroc (D) pigs and 155 D × Korean native pigs (DKNPs) using the Porcine SNP70K BeadChip. By applying the FST and extended haplotype homozygosity (EHH-Rsb) methods, we detected genes under directional selection associated with growth/stature (DOCK7, PLCB4, HS2ST1, FBP2 and TG), carcass and meat quality (TG, COL14A1, FBXO5, NR3C1, SNX7, ARHGAP26 and DPYD), number of teats (LOC100153159 and LRRC1), pigmentation (MME) and ear morphology (SOX5), which are all mostly near or at fixation. These results could be a basis for investigating the underlying mutations associated with observed phenotypic variation. Validation using genome-wide association analysis would also facilitate the inclusion of some of these markers in genetic evaluation programs.

Reliability of tumour grade 1 and endometrioid cell type on preoperative endometrial biopsy.

The aim of this study was to evaluate the reliability of using tumour grade and cell type on preoperative endometrial biopsy for the selection of patients for conservative hormone treatment. We retrospectively reviewed results of 643 patients with endometrial carcinoma for tumour grade and 817 for tumour cell type who underwent endometrial biopsy followed by surgery. Of the 357 patients with a grade 1 tumour on preoperative endometrial biopsy, 58 (16.2%) were upgraded based on a final pathology report from hysterectomy specimens. For grade 1, the preoperative endometrial biopsy showed a sensitivity of 80.4%, a specificity of 78.6%, a positive predictive value (PPV) of 83.8% and a negative predictive value (NPV) of 74.5%. Of the 672 patients with the endometrioid cell type on preoperative biopsy, 46 (5.6%) showed a different cell type on final pathology. For the endometrioid cell type, preoperative endometrial biopsy had a sensitivity of 91.3%, a specificity of 64.9%, a PPV of 93.2% and an NPV of 58.6%. This weak predictive value should be considered when selecting patients for conservative hormone treatment.

Metabolic tumour volume and total lesion glycolysis, measured using preoperative 18F-FDG PET/CT, predict the recurrence of endometrial cancer.

OBJECTIVE: To investigate the prognostic value of metabolic tumour volume (MTV) and total lesion glycolysis (TLG), measured by preoperative positron emission tomography and computerised tomography (PET/CT), in women with endometrial cancer. DESIGN: Retrospective cohort study. SETTING: A tertiary referral centre. POPULATION: Women with endometrial cancer who underwent preoperative (18)F-FDG PET/CT in the period 2004-2009. METHODS: Clinicopathological data for 84 women with endometrial cancer were reviewed from medical records. Cox proportional hazards modelling identified recurrence predictors. The receiver operating characteristic (ROC) curve was used to determine the cut-off value for predicting recurrence. MAIN OUTCOME MEASURE: Disease-free survival (DFS). RESULTS: The number of patients with International Federation of Gynecology and Obstetrics (FIGO) stages were: I (58); II (11); III (13); and IV (2). The median DFS was 48 (1-85) months. By univariate analysis, DFS was significantly associated with FIGO stage, histology, peritoneal cytology, myometrial invasion, nodal metastasis, serum CA-125, MTV, and TLG. Using multivariate analysis, the MTV (P = 0.010; hazard ratio, HR = 1.010; 95% confidence interval, 95% CI = 1.002-1.018) and TLG (P = 0.024; HR = 1.001; 95% CI = 1.000-1.002) were associated with DFS. The area under the ROC curve was 0.679 (95% CI = 0.505-0.836) after discriminating for recurrence using an MTV cut-off value of 17.15 ml. Regarding TLG, the cut-off value was 56.43 g and the area under the ROC plot was 0.661 (95% CI = 0.501-0.827). Kaplan-Meier survival graphs demonstrated a significant difference in DFS between groups categorised using the cut-off values for MTV and TLG (P < 0.022 for MTV and P < 0.047 for TLG, by log-rank test). CONCLUSIONS: Preoperative MTV and TLG could be independent prognostic factors predicting the recurrence of endometrial cancer.

An important role of tumor necrosis factor receptor-2 on natural killer T cells on the development of dsRNA-enhanced Th2 cell response to inhaled allergens.

BACKGROUND: Recent evidence indicates that TNF-α is a key mediator of the development of dsRNA-enhanced Th2 cell response to inhaled allergens. Natural killer T (NKT) cells may be a candidate source of Th2-polarizing cytokines. OBJECTIVE: The objective of this study was to evaluate the role of lung NKT cells on the development of TNF-α-mediated Th2 cell response. METHODS: A virus-associated asthma mouse model was generated by the administration of ovalbumin (OVA, 75 µg) and poly[I:C] (0.1 µg). Role of NKT and type I NKT cells was evaluated using CD1d- and Jα18-deficient mice. TNF-α receptors (TNFRs) were antagonized by using TNFR blocking peptides. RESULTS: The number of infiltrated NKT cells was increased in a virus-associated asthma mouse model. Increase in Th2 and Th17 cytokine levels in wild-type mice were abolished in both CD1d- and Jα18-deficient mice. In vitro co-culture experiments with alveolar macrophages and NKT cells showed that TNF-α produced by macrophages in the presence of poly[I:C] acts on NKT cells, inducing production of Th2-polarizing cytokines. Moreover, the induction of Th2-polarizing cytokines by poly[I:C] or recombinant TNF-α was impaired in both CD1d- and Jα18-deficient mice and that the above effect was reversed by a TNF-α receptor-2 (TNFR2) blocking peptide, but not by a TNFR1 blocker. CONCLUSIONS: These findings suggest that NKT cells play a key role in the development of Th2 cell response to inhaled allergens and that TNF-α produced by alveolar macrophages induces Th2 cell response, via TNFR2 on NKT cells.

Preoperative nomogram for the identification of lymph node metastasis in early cervical cancer.

BACKGROUND: The objective of this study is to construct a preoperative nomogram predicting lymph node metastasis (LNM) in early-cervical cancer patients. METHODS: Between 2009 and 2012, 493 early-cervical cancer patients received hysterectomy and pelvic/para-aortic lymphadenectomy. Patients who were diagnosed during 2009-2010 were assigned to a model-development cohort (n=304) and the others were assigned to a validation cohort (n=189). A multivariate logistic model was created from preoperative clinicopathologic data, from which a nomogram was developed and validated. A predicted probability of LNM<5% was defined as low risk. RESULTS: Age, tumour size assessed by magnetic resonance imaging, and LNM assessed by positron emission tomography/computed tomography were independent predictors of nodal metastasis. The nomogram incorporating these three predictors demonstrated good discrimination and calibration (concordance index=0.878; 95% confidence interval (CI), 0.833-0.917). In the validation cohort, the discrimination accuracy was 0.825 (95% CI, 0.736-0.895). In the model-development cohort, 34% of them were classified as low risk and negative predictive value (NPV) was 99.0%. In the validation cohort, 38% were identified as low risk and NPV was 95.8%. Integrating the model-development and validation cohorts, negative likelihood ratio was 0.094 (95% CI, 0.036-0.248). CONCLUSION: A robust nomogram predicting LNM in early cervical cancer was developed. This model may improve clinical trial design and help physicians to decide whether lymphadenectomy should be performed.

Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia.

Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia; however, little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CREB-binding protein (CBP)) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300 leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small-molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1-110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/ß- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using chromatin immunoprecipitation assay, we demonstrate occupancy of the survivin promoter by CBP that is decreased by ICG-001 in primary ALL. CBP mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL.

Enhanced tunnelling electroresistance effect due to a ferroelectrically induced phase transition at a magnetic complex oxide interface.

The range of recently discovered phenomena in complex oxide heterostructures, made possible owing to advances in fabrication techniques, promise new functionalities and device concepts. One issue that has received attention is the bistable electrical modulation of conductivity in ferroelectric tunnel junctions (FTJs) in response to a ferroelectric polarization of the tunnelling barrier, a phenomenon known as the tunnelling electroresistance (TER) effect. Ferroelectric tunnel junctions with ferromagnetic electrodes allow ferroelectric control of the tunnelling spin polarization through the magnetoelectric coupling at the ferromagnet/ferroelectric interface. Here we demonstrate a significant enhancement of TER due to a ferroelectrically induced phase transition at a magnetic complex oxide interface. Ferroelectric tunnel junctions consisting of BaTiO3 tunnelling barriers and La(0.7)Sr(0.3)MnO3 electrodes exhibit a TER enhanced by up to ~10,000% by a nanometre-thick La(0.5)Ca(0.5)MnO3 interlayer inserted at one of the interfaces. The observed phenomenon originates from the metal-to-insulator phase transition in La(0.5)Ca(0.5)MnO3, driven by the modulation of carrier density through ferroelectric polarization switching. Electrical, ferroelectric and magnetoresistive measurements combined with first-principles calculations provide evidence for a magnetoelectric origin of the enhanced TER, and indicate the presence of defect-mediated conduction in the FTJs. The effect is robust and may serve as a viable route for electronic and spintronic applications.

Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells.

The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of epithelial-mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity in vitro and tumorigenicity in vivo. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance in vitro and exhibited stronger tumorigenic potential in vivo than CXCR4- cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.

Proposed mechanism in the change of cellular composition in the outer medullary collecting duct during potassium homeostasis.

Potassium depletion (K⁺-D) induces hypertrophy and hyperplasia of collecting duct cells, and potassium repletion (K⁺-R) induces regression of these changes. The purpose of this study was to examine the time courses of the changes in cellular composition, the origin of intercalated cells (ICs) and the mechanism responsible for these changes. SD rats received K⁺-depleted diets for 1, 7, or 14 days. After K⁺-D for 14 days some of the rats received normal diets for 1, 3, 5, or 7 days. In the inner stripe of the outer medulla, K⁺-D increased significantly the number and proportion of H⁺-ATPase-positive ICs, but decreased the proportion of H⁺-ATPase-negative principal cells (PCs). However, proliferation was limited to H⁺-ATPase-negative PCs. During K⁺-R, the cellular composition was recovered to control level. Apoptosis increased during K⁺-R and exclusively limited in H⁺-ATPase-negative PCs. Double immunolabeling with antibodies to PC and IC markers identified both cells negative or positive for all markers during both K⁺-D and K⁺-R. Electron microscopic observation showed that ultrastructure of AE1-positive some cells were similar to AE1-negative some cells during K⁺-R. LC3 protein expression increased significantly and autophagic vacuoles appeared particularly in PCs on days 14 of K⁺-D and in ICs on days 3 of K⁺-R. These results suggest that PCs and ICs may interconvert in response to changes in dietary K+ availability and that autophagic pathways may be involved in the interconversion.

TNF-alpha is a key mediator in the development of Th2 cell response to inhaled allergens induced by a viral PAMP double-stranded RNA.

BACKGROUND: Viral pathogen-associated molecular patterns, such as dsRNA, disrupt airway tolerance to inhaled allergens. Specifically, the Th2 and Th17 cell responses are induced by low-dose dsRNA and the Th1-dominant response by high-dose dsRNA. OBJECTIVE: In this model, we evaluate the role of TNF-α in the development of adaptive immune dysfunction to inhaled allergens induced by airway sensitization with dsRNA-containing allergens. METHODS: A virus-associated asthma mouse model was generated via simultaneous airway administration of ovalbumin (OVA) and low (0.1 µg) or high (10 µg) doses of polyinosine-polycytidylic acid (poly[I:C]). The effect of TNF-α on Th2 airway inflammation was evaluated using TNF-α-deficient mice and recombinant TNF-α. RESULTS: TNF-α production was enhanced by airway exposure to low and high doses of poly[I:C]. After airway sensitization with OVA plus low-dose poly[I:C], TNF-α-deficient mice exhibited less OVA-induced airway inflammation than did wild-type (WT) mice. However, this did not occur upon sensitization with high-dose poly[I:C]. In terms of T-cell response, the production of IL-4 from lung T cells after OVA challenge was enhanced by airway sensitization with OVA plus low-dose poly[I:C] in WT mice, and this phenotype was inhibited by the absence of TNF-α. Moreover, the Th2 cell response induced by sensitization with OVA plus low-dose poly[I:C], which was abolished in TNF-α-deficient mice, was restored in these mice upon addition of recombinant TNF-α. CONCLUSION: The results of this study suggest that TNF-α produced by airway exposure to low-dose dsRNA is a key mediator in the development of Th2 cell response to inhaled allergens.

Smad3 regulates E-cadherin via miRNA-200 pathway.

To identify potential microRNA (miRNA) links between Smad3, a mediator of TGF-ß (transforming growth factor-ß) signaling, and E-cadherin, we characterized the miRNA profiles of two gastric cancer cell lines: SNU484-LPCX, which does not express Smad3, and SNU484-Smad3, in which Smad3 is overexpressed. We found that among differentially expressed miRNAs, miR-200 family members are overexpressed in SNU484-Smad3 cells. Subsequent studies, including analysis of the effects of silencing Smad3 in SNU484-Smad3 cells and a luciferase reporter assay, revealed that Smad3 directly binds to a Smad-binding element located in the promoter region of miR-200b/a, where it functions as a transcriptional activator. TGF-ß did not affect the regulatory role of Smad3 in transcription of miR-200 and expression of epithelial-mesenchymal transition markers. We conclude that Smad3 regulates, at the transcriptional level, miR-200 family members, which themselves regulate ZEB1 and ZEB2, known transcriptional repressors of E-cadherin, at the posttranscriptional level in a TGF-ß-independent manner. This represents a novel link between Smad3 and posttranscriptional regulation by miRNAs in epithelial-mesenchymal transition in gastric cancer cells.

Laparoscopic versus open radical hysterectomy in early-stage cervical cancer: long-term survival outcomes in a matched cohort study.

BACKGROUND: To compare the long-term survival outcomes between laparoscopic radical hysterectomy (LRH) and open radical hysterectomy (ORH). METHOD: We matched patients with stage IA2 to IIA cervical cancer with known risk factors for recurrence who underwent ORH and LRH. RESULTS: Compared with ORH (n = 263), LRH (n = 263) did not have higher risks of recurrence [hazard ratio (HR) = 1.28; 95% confidence interval (CI) 0.62-2.64] or death (HR = 1.46; 95% CI 0.62-3.43). Even in patients with tumors >2 cm in diameter, the risks of recurrence (HR = 0.82; 95% CI 0.31-2.16) or death (HR = 1.01; 95% CI 0.35-2.95) were not higher for LRH than for ORH. The LRH and ORH group had 5-year recurrence-free survival rates of 92.8% and 94.4%, respectively (P = 0.499). LRH resulted in significantly lower estimated blood loss (379.6 versus 541.1 ml, P < 0.001) and shorter postoperative hospital stay (12.5 versus 20.3 days, P < 0.001). Intraoperative complication rates were similar in the two groups (6.8% versus 5.7%, P = 0.711), but postoperative complication rate was lower in the LRH than in the ORH group (9.2% versus 21%, P < 0.001). CONCLUSION: LRH is an oncologically safe alternative to ORH and was associated with fewer postoperative complication and earlier recovery.

Outcomes after radical hysterectomy according to tumor size divided by 2-cm interval in patients with early cervical cancer.

BACKGROUND: this study investigated the outcomes after radical hysterectomy according to tumor size divided by 2-cm interval in patients with International Federation of Obstetrics and Gynecology stage IA2-IIA cervical cancer. PATIENTS AND METHODS: a total of 1415 patients were eligible for participation in the study and were retrospectively analyzed. Patients were divided into four groups according to tumor size (i.e. ≤ 2, 2-4, 4-6 and >6 cm). The relationships between tumor size and other clinicopathologic risk factors, the probability of adjuvant therapy, survival parameters, recurrence-free survival (RFS) and overall survival (OS) were analyzed. RESULTS: the incidence of intermediate- and high-risk factors gradually increased with increasing tumor size. Adjuvant therapy was required in 13.6%, 34.0%, 56.7% and 92.9% of patients with tumor sizes of ≤ 2, 2-4, 4-6 and >6 cm, respectively (P < 0.001). The risks of recurrence and death gradually increased with increasing tumor size, after adjusting for other significant prognostic factors in multivariate analysis (P < 0.001 and < 0.001, respectively). Even in patients with no intermediate- or high-risk factors, tumor size was a significant predictor of RFS and OS (P < 0.001 and < 0.001, respectively). Immediate surgical parameters did not significantly differ according to tumor size. CONCLUSIONS: tumor size divided by a 2-cm interval was an independent prognostic factor and correlated well with other risk factors and with the need for adjuvant therapy.

The effect of ketamine with remifentanil for improving the quality of anaesthesia and recovery in paediatric patients undergoing middle-ear ventilation tube insertion.

This prospective randomized study evaluated the effects of ketamine with remifentanil to improve the quality of anaesthesia and postoperative recovery, following brief procedures, in 60 paediatric patients undergoing middle-ear ventilation tube insertion (MEVTI). Patients were randomly assigned to either ketamine 2 mg/kg intravenous [i.v.] bolus plus normal saline by i.v. infusion (K group, n = 30) or ketamine 2 mg/kg i.v. bolus, plus remifentanil 0.15 µg/kg per min i.v. infusion (KR group, n = 30). Parameters that were assessed included intraoperative patient movement, surgeon satisfaction, anaesthesia time, total ketamine dose, postoperative recovery time, agitation and side-effects. Intraoperative patient movement scores were significantly lower, and surgeon satisfaction scores were significantly higher, in the KR group than in the K group. Time to recovery was significantly shorter in the KR group than in the K group. In conclusion, remifentanil was a good adjuvant to ketamine, improving the quality of anaesthesia and postoperative recovery in children undergoing MEVTI.

Outcomes after radical hysterectomy in patients with early-stage adenocarcinoma of uterine cervix.

BACKGROUND: To determine the prognostic factors and treatment outcomes of patients with early-stage adenocarcinoma (AdCa) of uterine cervix who underwent radical hysterectomy (RH). METHODS: Patients with early-stage squamous cell carcinoma (SCCa) of the uterine cervix who underwent RH were compared with patients with AdCa by multivariate analysis. RESULTS: A total of 1218 patients were eligible, of which 996 (81.8%) had SCCa and 222 (18.2%) had AdCa. In multivariate analysis, parametrial involvement and lymph node metastasis were significant factors for both recurrence-free survival(RFS) and overall survival (OS) of patients with AdCa, whereas age, tumour size, parametrial involvement and lymph node metastasis were significant factors for both RFS and OS of patients with SCCa. After adjusting for significant prognostic factors, patients with AdCa had significantly poorer RFS (odds ratio (OR)=2.07, 95% confidence interval (CI)=1.37-3.12, P=0.001) and OS (OR=2.56, 95% CI=1.65-3.96, P<0.001) than patients with SCCa. Recurrence outside the pelvis was more frequent in AdCa than in those with SCCa (75 vs 57.8%, P=0.084). CONCLUSION(S): Although RH is still acceptable for treatment of patients with AdCa, a more effective systemic adjuvant therapy is required.

Self-assembled growth and luminescence of crystalline Si/SiOx core-shell nanowires.

Crystalline Si/SiOx core/shell nanowires (NWs) are self-assembled by annealing Ni-coated hydrogenated Si-rich SiOx (SRO:H) films at 1100 degrees C in the presence of Si powder. Plasma-enhanced chemical vapor deposition is used to grow 100 nm SRO:H thin films with varying silicon concentration (n(Si)). The NWs vary from SiOx nanowires to Si/SiOx core/shell structures depending on the composition of the SRO:H substrate, with the fraction of core/shell structures increasing with increasing Si concentration. As n(Si) increases from 37 to 43 at.%, the average diameter of the NWs also increases from 48 to 157 nm. A growth model based on the diffusion-assisted vapor-liquid-solid mechanism is proposed to explain how the core/shell structures are self-assembled. Photoluminescence (PL) spectra of the individual NWs have two major emission bands in the near UV (381 nm) and blue (423 nm) ranges at n(Si) = 43 at.%, named as UV and BL PL bands, respectively. In contrast, only the BL PL band is observed at n(Si) < or = 39 at.%. These results suggest that the BL and UV PL bands can be attributed to the defect states in the SiOx shell and at the Si core/SiOx shell interface, respectively, and that the BL band is closely related to the growth process of the NWs.

Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia.

Dasatinib is a potent dual Abl/Src inhibitor approved for treatment of Philadelphia chromosome-positive (Ph-positive) leukemias. At a once-daily dose and a relatively short half-life of 3-5 h, tyrosine kinase inhibition is not sustained. However, transient inhibition of K562 leukemia cells with a high-dose pulse of dasatinib or long-term treatment with a lower dose was reported to irreversibly induce apoptosis. Here, the effect of dasatinib on treatment of Bcr/Abl-positive acute lymphoblastic leukemia (ALL) cells was evaluated in the presence of stromal support. Dasatinib eradicated Bcr/Abl ALL cells, caused significant apoptosis and eliminated tyrosine phosphorylation on Bcr/Abl, Src, Crkl and Stat-5. However, treatment of mouse ALL cells with lower doses of dasatinib over an extended period of time allowed the emergence of viable drug-resistant cells. Interestingly, dasatinib treatment increased cell-surface expression of CXCR4, which is important for survival of B-lineage cells, but this did not promote survival. Combined treatment of cells with dasatinib and a CXCR4 inhibitor resulted in enhanced cell death. These results do not support the concept that long-term treatment with low-dose dasatinib monotherapy will be effective in causing irreversible apoptosis in Ph-positive ALL, but suggest that combined treatment with dasatinib and drugs such as AMD3100 may be effective.

The HTLV-1 tax protein cooperates with phosphorylated CREB, TORC2 and p300 to activate CRE-dependent cyclin D1 transcription.

Adult T-cell leukemia/lymphoma is a fatal malignancy etiologically linked to infection with the human T-cell leukemia virus (HTLV-1). The virally encoded oncoprotein Tax activates the transcription of HTLV-1 and cellular genes by cooperating with cellular transcription factors. Cyclin D1 is a pivotal regulator of cell cycle progression, and increased expression strongly correlates with malignant transformation. Here, we characterize the mechanism of Tax transactivation of cyclin D1. We find that cyclin D1 transcript levels are elevated in HTLV-1 infected cells and that Tax physically associates with the cyclin D1 gene in vivo. Tax binds the cyclin D1 promoter-proximal cyclic AMP response element (CRE) in the presence of phosphorylated CREB (pCREB) in vitro, and together the Tax-pCREB complex recruits the cellular co-activator p300 to the promoter through this unconventional Tax-responsive element. We further show that the transducer of regulated CREB 2 (TORC2) cooperates with Tax to further enhance p300 recruitment to the cyclin D1 promoter in vitro. Tax and TORC2 in combination stimulate cyclin D1 expression in vivo, demonstrating the functional outcome of the binding interactions. Together, our findings support a model in which Tax-induced accumulation of cyclin D1 shortens the G1 phase of the cell cycle, promotes mitotic replication of the virus, and drives selection and expansion of malignant T-cells.

Management of occult invasive cervical cancer found after simple hysterectomy.

BACKGROUND: To estimate safety and efficacy of radical parametrectomy (RP) and radiation therapy (RT) or concurrent chemoradiation therapy (CCRT) for patients with occult invasive cervical cancer found after simple hysterectomy. MATERIALS AND METHODS: We retrospectively evaluated outcomes in 147 patients with occult invasive cervical cancer. RESULTS: Forty-eight patients with IA1 lesions (IA1 group) did not receive further treatment. Of the 99 patients with IA2-IIA lesions, 26 received no definitive treatment (observation group), 44 received RT or CCRT (RT/CCRT group), and 29 underwent RP (RP group). After a median follow-up of 116 months (range 3-235 months), recurrent disease was observed in 0%, 34.6%, 6.8%, and 0% of patients in the IA1, observation, RT/CCRT, and RP groups, respectively. In the RT/CCRT group, treatment was delayed due to severe diarrhea in 4 patients (9%) and 12 patients (27%) had late complications related to RT requiring further management (including two surgical interventions). Five patients in the RP group (17%) experienced perioperative complications which were easily managed, intraoperatively or conservatively. Late complications were not observed in the RP group. CONCLUSION: Although RP and RT/CCRT had similar therapeutic efficacy, the lower rate of late complications observed with RP makes it preferable to RT/CCRT.