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A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned for its suitability in kinase inhibitor discovery, offers at least three distinct pharmacophore access points. Insights from molecular modeling studies guided hit-to-lead optimization, which revealed that the 1,3-diketone side chain hybridized with furanopyrimidine scaffold that respectively combined amino-type substituent and 1 H -pyrazol-4-yl substituent on the top and bottom of the aryl regions to produce 22 and 33 , exhibiting potent antitumor activities in various syngeneic and xenograft models. More importantly, 33 demonstrated remarkable immune-modulating activity by upregulating the expression of total T-cells, cytotoxic CD8 + T-cells, and helper CD4 + T-cells in the spleen. These findings underscored the bifunctional capabilities of 33 ( BPR5K230 ) with excellent oral bioavailability ( F = 54.6%), inhibiting both MER and AXL while modulating the tumor microenvironment and highlighting its diverse applicability for further studies to advance its therapeutic potential.

Epithelial cell adhesion molecules (EpCAM) are highly expressed in many carcinomas and regulate the epithelial-mesenchymal transition, which is required for tumor metastasis. Furthermore, EpCAM overexpression induces tumor cells to develop a stem cell-like phenotype and promotes tumor progression. Targeting EpCAM may be a promising approach for inhibiting tumor metastasis and progression. Salmonella treatment suppresses tumor growth and reduces metastatic nodules in tumor-bearing mice. Based on these results, we hypothesized that Salmonella-based treatments could inhibit the expression of metastasis-associated proteins. The dose-dependent Salmonella treatment significantly downregulated the levels of EpCAM and decreased the phosphorylation of protein kinase-B (AKT)/mTOR (mammalian target of rapamycin) pathway, as shown by immunoblotting. In addition, Salmonella treatment increased the levels of epithelial markers and decreased the levels of mesenchymal markers in a dose-dependent manner. Wound-healing and Transwell assays showed that Salmonella treatment significantly reduced tumor cell migration. The mice were intravenously injected with B16F10 and CT26 cells pre-incubated with or without Salmonella, and the survival of tumor-bearing mice in the Salmonella group increased, indicating an antimetastatic effect. Our findings demonstrate that Salmonella plays a role in inhibiting tumor metastasis by downregulating EpCAM via the AKT/mTOR signaling pathway and has great potential for cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Oral squamous cell carcinoma (OSCC) is the predominant histological type of the head and neck squamous cell carcinoma (HNSCC). By comparing the differentially expressed genes (DEGs) in OSCC-TCGA patients with copy number variations (CNVs) that we identify in OSCC-OncoScan dataset, we herein identified 37 dysregulated candidate genes. Among these potential candidate genes, 26 have been previously reported as dysregulated proteins or genes in HNSCC. Among 11 novel candidates, the overall survival analysis revealed that melanotransferrin (MFI2) is the most significant prognostic molecular in OSCC-TCGA patients. Another independent Taiwanese cohort confirmed that higher MFI2 transcript levels were significantly associated with poor prognosis. Mechanistically, we found that knockdown of MFI2 reduced cell viability, migration and invasion via modulating EGF/FAK signaling in OSCC cells. Collectively, our results support a mechanistic understanding of a novel role for MFI2 in promoting cell invasiveness in OSCC., (© 2023. The Author(s).)

Globally, oral cavity squamous cell carcinoma (OSCC) is one of the most common fatal illnesses. Its high mortality is ascribed to the fact that the disease is often diagnosed at a late stage, which indicates an urgent need for approaches for the early detection of OSCC. The use of salivary autoantibodies (autoAbs) as OSCC biomarkers has numerous advantages such as easy access to saliva samples and efficient detection of autoAbs using well-established secondary reagents. To improve OSCC screening, we identified OSCC-associated autoAbs with the enrichment of salivary autoAbs combined with affinity mass spectrometry (MS). The salivary IgA of healthy individuals and OSCC patients was purified with peptide M-conjugated beads and then applied to immunoprecipitated antigens (Ags) in OSCC cells. Using tandem MS analysis and spectral counting-based quantitation, the level of 10 Ags increased in the OSCC group compared with the control group. Moreover, salivary levels of autoAbs to the 10 Ags were determined by a multiplexed bead-based immunoassay. Among them, seven were significantly higher in early-stage OSCC patients than in healthy individuals. A marker panel consisting of autoAbs to LMAN2, PTGR1, RAB13, and UQCRC2 was further developed to improve the early diagnosis of OSCC., (© 2023 Wiley-VCH GmbH.)

Background: Oral cavity squamous cell carcinoma (OSCC) is an aggressive malignant tumor with high recurrence and poor prognosis in the advanced stage. Patient-derived xenografts (PDXs) serve as powerful preclinical platforms for drug testing and precision medicine for cancer therapy. We assess which molecular signatures affect tumor engraftment ability and tumor growth rate in OSCC PDXs., Methods: Treatment-naïve OSCC primary tumors were collected for PDX models establishment. Comprehensive genomic analysis, including whole-exome sequencing and RNA-seq, was performed on case-matched tumors and PDXs. Regulatory genes/pathways were analyzed to clarify which molecular signatures affect tumor engraftment ability and the tumor growth rate in OSCC PDXs., Results: Perineural invasion was found as an important pathological feature related to engraftment ability. Tumor microenvironment with enriched hypoxia, PI3K-Akt, and epithelial-mesenchymal transition pathways and decreased inflammatory responses had high engraftment ability and tumor growth rates in OSCC PDXs. High matrix metalloproteinase-1 (MMP1) expression was found that have a great graft advantage in xenografts and is associated with pooled disease-free survival in cancer patients., Conclusion: This study provides a panel with detailed genomic characteristics of OSCC PDXs, enabling preclinical studies on personalized therapy options for oral cancer. MMP1 could serve as a biomarker for predicting successful xenografts in OSCC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yen, Chang, Chang, Ouyang, Liu, Tsai, Zhang, Wang, Wang, Yu, Liu, Wu, Chang, Yu and Yang.)

Background: Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and has a high mortality rate worldwide. Sorafenib is the only systemic treatment demonstrating a statistically significant but modest overall survival benefit. We previously have identified the aurora kinases (AURKs) and FMS-like tyrosine kinase 3 (FLT3) multikinase inhibitor DBPR114 exhibiting broad spectrum anti-tumor effects in both leukemia and solid tumors. The purpose of this study was to evaluate the therapeutic potential of DBPR114 in the treatment of advanced HCC., Methods: Human HCC cell lines with histopathology/genetic background similar to human HCC tumors were used for in vitro and in vivo studies. Human umbilical vein endothelial cells (HUVEC) were used to evaluate the drug effect on endothelial tube formation. Western blotting, immunohistochemical staining, and mRNA sequencing were employed to investigate the mechanisms of drug action. Xenograft models of sorafenib-refractory and sorafenib-acquired resistant HCC were used to evaluate the tumor response to DBPR114., Results: DBPR114 was active against HCC tumor cell proliferation independent of p53 alteration status and tumor grade in vitro. DBPR114-mediated growth inhibition in HCC cells was associated with apoptosis induction, cell cycle arrest, and polyploidy formation. Further analysis indicated that DBPR114 reduced the phosphorylation levels of AURKs and its substrate histone H3. Moreover, the levels of several active-state receptor tyrosine kinases were downregulated by DBPR114, verifying the mechanisms of DBPR114 action as a multikinase inhibitor in HCC cells. DBPR114 also exhibited anti-angiogenic effect, as demonstrated by inhibiting tumor formation in HUVEC cells. In vivo, DBPR114 induced statistically significant tumor growth inhibition compared with the vehicle control in multiple HCC tumor xenograft models. Histologic analysis revealed that the DBPR114 treatment reduced cell proliferation, and induced apoptotic cell death and multinucleated cell formation. Consistent with the histological findings, gene expression analysis revealed that DBPR114-modulated genes were mostly related to the G2/M checkpoint and mitotic spindle assembly. DBPR114 was efficacious against sorafenib-intrinsic and -acquired resistant HCC tumors. Notably, DBPR114 significantly delayed posttreatment tumor regrowth and prolonged survival compared with the regorafenib group., Conclusion: Our results indicated that targeting AURK signaling could be a new effective molecular-targeted agent in the treatment of patients with HCC., (© 2022. The Author(s).)

Silicon (Si) anode materials have attracted substantial interest due to their high theoretical capacity. Here, the growth of helical Si@Cu 3 Si nanorod arrays via glancing angle deposition (GLAD) followed by an annealing process is reported. Pre-deposited Cu atoms were driven into Si-nanorods and successfully reacted with Si to form a Si-Cu alloy at a high temperature. By varying the rotation rate and annealing temperature, the resultant Si@Cu 3 Si nanorod arrays showed a reasonably accessible surface area with precise control spacing behavior in favor of accommodating Si volume expansion. Meanwhile, the Si@Cu 3 Si anode materials showed higher electrical conductivity, facilitating Li + ion diffusion and electron transfer. The Si@Cu 3 Si nanorod arrays in half cells exhibited a volumetric capacity as high as 3350.1 mA h cm -3 at a rate of 0.25 C and could maintain 1706.7 mA h cm -3 after 100 cycles, which are superior to those of pristine Si materials. This facile and innovative technology provided new insights into the development of Si-based electrode materials.

Radioresistance is one of the major factors that contributes to radiotherapy failure in oral cavity squamous cell carcinoma (OSCC). By comparing the prognostic values of 20,502 genes expressed in patients in The Cancer Genome Atlas (TCGA)-OSCC cohort with ( n = 162) and without radiotherapy ( n = 118), herein identified 297 genes positively correlated with poor disease-free survival in OSCC patients with radiotherapy as the potential radioresistance-associated genes. Among the potential radioresistance-associated genes, 36 genes were upregulated in cancerous tissues relative to normal tissues. The bioinformatics analysis revealed that 60S ribosomal protein L36a (RPL36A) was the most frequently detected gene involved in radioresistance-associated gene-mediated biological pathways. Then, two independent cohorts ( n = 162 and n = 136) were assessed to confirm that higher RPL36A transcript levels were significantly associated with a poor prognosis only in OSCC patients with radiotherapy. Mechanistically, we found that knockdown of RPL36A increased radiosensitivity via sensitizing cells to DNA damage and promoted G2/M cell cycle arrest followed by augmenting the irradiation-induced apoptosis pathway in OSCC cells. Taken together, our study supports the use of large-scale genomic data for identifying specific radioresistance-associated genes and suggests a regulatory role for RPL36A in the development of radioresistance in OSCC.

Colony-stimulating factor-1 receptor (CSF1R) is implicated in tumor-associated macrophage (TAM) repolarization and has emerged as a promising target for cancer immunotherapy. Herein, we describe the discovery of orally active and selective CSF1R inhibitors by property-driven optimization of BPR1K871 ( 9 ), our clinical multitargeting kinase inhibitor. Molecular docking revealed an additional nonclassical hydrogen-bonding (NCHB) interaction between the unique 7-aminoquinazoline scaffold and the CSF1R hinge region, contributing to CSF1R potency enhancement. Structural studies of CSF1R and Aurora kinase B (AURB) demonstrated the differences in their back pockets, which inspired the use of a chain extension strategy to diminish the AURA/B activities. A lead compound BPR1R024 ( 12 ) exhibited potent CSF1R activity (IC 50 = 0.53 nM) and specifically inhibited protumor M2-like macrophage survival with a minimal effect on antitumor M1-like macrophage growth. In vivo , oral administration of 12 mesylate delayed the MC38 murine colon tumor growth and reversed the immunosuppressive tumor microenvironment with the increased M1/M2 ratio.

Background and Objectives: Human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) is increasing globally. In Taiwan, HPV-positive OPSCC is obscured by tobacco, alcohol, and betel quid use. We investigated the role of high-risk HPV (hrHPV) in a large retrospective Taiwan OPSCC cohort., Methods and Results: The cohort of 541 OPSCCs treated at Chang Gung Memorial Hospital from 1998-2016 consisted of 507 men (94%) and 34 women (6%). Most used tobacco (81%), alcohol (51%), and betel quid (65%). Formalin-fixed, paraffin-embedded tissue was used for p16 staining (a surrogate marker for HPV) and testing for HPV DNA presence and type by Multiplex HPV PCR-MassArray. HPV DNA and/or p16 staining (HPV-positive) was found in 28.4% (150/528) tumors. p16 and HPV DNA were strongly correlated (F < 0.0001). HPV16 was present in 82.8%, and HPV58 in 7.5% of HPV-positive tumors. HPV was associated with higher age (55.5 vs. 52.7 years, p = 0.004), lower T-stage (p = 0.008) better overall survival (OS) (hazard ratio [HR] 0.58 [95% CI 0.42-0.81], p = 0.001), and disease-free survival (DFS) (HR 0.54 [95% CI 0.40-0.73], p < 0.0001). Alcohol was strongly associated with recurrence and death (OS: HR 2.06 [95% CI 1.54-2.74], p < 0.0001; DFS: HR 1.72 [95% CI 1.33-2.24], p < 0.0001). OS and DFS in HPV-positive cases decreased for alcohol users (p < 0.0001). Obscured by the strong alcohol effect, predictive associations were not found for tobacco or betel quid., Conclusions: As with HPV-positive OPSCC globally, HPV is an increasingly important etiological factor in Taiwanese OPSCC. HPV-positive OPSCC has considerable survival benefit, but this is reduced by alcohol, tobacco, and betel quid use. hrHPV is a cancer risk factor in males and females. Vaccinating both sexes with a multivalent vaccine including HPV58, combined with alcohol and tobacco cessation policies will be effective cancer-prevention public health strategies in Taiwan., Competing Interests: The authors have declared that no competing interests exist.

The raised source/drain (RSD) structure is one of thin film transistor designs that is often used to improve device characteristics. Many studies have mentioned that the high impact ionization rate occurring at a drain side can be reduced, owing to a raised source/drain area that can disperse the drain electric field. In this study, we will discuss how the electric field at the drain side of an RSD device is reduced by a vertical lightly doped drain (LDD) scheme rather than a RSD structure. We used different raised source/drain forms to simulate the drain side electric field for each device, as well as their output characteristics, using Integrated Systems Engineering (ISE-TCAD) simulators. Different source and drain thicknesses and doping profiles were applied to verify the RSD mechanism. We found that the electric fields of a traditional device and uniform doping RSD structures are almost the same (~2.9 × 10 5 V/cm). The maximum drain electric field could be reduced to ~2 × 10 5 V/cm if a vertical lightly doped drain RSD scheme was adopted. A pure raised source/drain structure did not benefit the device characteristics if a vertical lightly doped drain design was not included in the raised source/drain areas.

Bluetongue is a fatal viral disease in ruminants and has serious economic impacts on the livestock industry. Interactions between bluetongue virus (BTV) and immune cells are interesting because of the unique scenarios in each combination of animal species/breed and viral virulence/serotype. This study investigated the immune response in bovine peripheral blood mononuclear cells (PBMC) infected by the BTV2 Taiwan strain. The replication of the virus was limited in monocytes and monocyte-derived macrophages (MDM), and lymphocytes were less permissive. The cytokine mRNA of IL-4 in PBMC was expressed earlier and in greater quantities than that of innate immunity (TNFα, IL-1β) and cell mediated immunity (CMI) (IFNγ), and the IL-4 protein was stably present in the culture medium until 72 h post-infection (hpi). Even in MDM reconstituted with autologous lymphocyte (MDM-Lymphocyte), the IL-4 still had high mRNA expression level. The level of IgE antibody also increased at 24-72 hpi, suggestive of the engagement of type I hypersensitivity in the pathogenesis. The anti-viral activity contained in the culture supernatant was transferrable to recipient infected PBMC from other cows. However, in infected MDM largely free of lymphocytes, mRNA expressions of IL-1β, TNFα and IL-12p40 were normally expressed from 6 to 48 hpi, supporting the notion that IL-4 elaborated by lymphocytes in PBMC mediated the inhibition of both innate immunity and CMI to BTV2. The sum of responses subsequent to the early IL-4 expression likely constitutes part of the unique scenario in the current BTV2-Cow experimental combination biased toward Th2 response., Competing Interests: Declaration of competing interest On behalf of all authors, the authors declare no conflict of interest. All financial resources are acknowledged., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway that modulates cellular redox homeostasis via the regeneration of NADPH. G6PD-deficient cells have a reduced ability to induce the innate immune response, thus increasing host susceptibility to pathogen infections. An important part of the immune response is the activation of the inflammasome. G6PD-deficient peripheral blood mononuclear cells (PBMCs) from patients and human monocytic (THP-1) cells were used as models to investigate whether G6PD modulates inflammasome activation. A decreased expression of IL-1β was observed in both G6PD-deficient PBMCs and PMA-primed G6PD-knockdown (G6PD-kd) THP-1 cells upon lipopolysaccharide (LPS)/adenosine triphosphate (ATP) or LPS/nigericin stimulation. The pro-IL-1β expression of THP-1 cells was decreased by G6PD knockdown at the transcriptional and translational levels in an investigation of the expression of the inflammasome subunits. The phosphorylation of p38 MAPK and downstream c-Fos expression were decreased upon G6PD knockdown, accompanied by decreased AP-1 translocation into the nucleus. Impaired inflammasome activation in G6PD-kd THP-1 cells was mediated by a decrease in the production of reactive oxygen species (ROS) by NOX signaling, while treatment with hydrogen peroxide (H 2 O 2 ) enhanced inflammasome activation in G6PD-kd THP-1 cells. G6PD knockdown decreased Staphylococcus aureus and Escherichia coli clearance in G6PD-kd THP-1 cells and G6PD-deficient PBMCs following inflammasome activation. These findings support the notion that enhanced pathogen susceptibility in G6PD deficiency is, in part, due to an altered redox signaling, which adversely affects inflammasome activation and the bactericidal response., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Patients with oral cavity squamous cell carcinoma (OSCC) are frequently first diagnosed at an advanced stage, leading to poor prognosis and high mortality rates. Early detection of OSCC using body fluid-accessible biomarkers may improve the prognosis and survival rate of OSCC patients. As tumor interstitial fluid is a proximal fluid enriched with cancer-related proteins, it is a useful reservoir suitable for the discovery of cancer biomarkers and dysregulated biological pathways in tumor microenvironments. Thus, paired interstitial fluids of tumor (TIF) and adjacent noncancerous (NIF) tissues from 10 OSCC patients were harvested and analyzed using one-dimensional gel electrophoresis coupled with liquid chromatography-tandem mass spectrometry (GeLC-MS/MS). Using label-free spectral counting-based quantification, 113 proteins were found to be up-regulated in the TIFs compared with the NIFs. The gene set enrichment analysis (GSEA) revealed that the differentially expressed TIF proteins were highly associated with aminoacyl tRNA biosynthesis pathway. The elevated levels of 4 proteins (IARS, KARS, WARS, and YARS) involved in the aminoacyl tRNA biosynthesis were verified in the OSCC tissues with immunohistochemistry (IHC). In addition, nidogen-1 (NID1) was selected for verification as an OSCC biomarker. Salivary level of NID1 in OSCC patients ( n = 48) was significantly higher than that in the healthy individuals ( n = 51) and subjects with oral potentially malignant disorder (OPMD; n = 53). IHC analysis showed that NID1 level in OSCC tissues was increased compared with adjacent noncancerous epithelium ( n = 222). Importantly, the elevated NID1 level was correlated with the advanced stages of OSCC, as well as the poor survival of OSCC patients. Collectively, the results suggested that TIF analysis facilitates understanding of the OSCC microenvironment and that salivary NID1 may be a useful biomarker for OSCC., (© 2019 Hsu et al.)

The generation of reducing equivalent NADPH via glucose-6-phosphate dehydrogenase (G6PD) is critical for the maintenance of redox homeostasis and reductive biosynthesis in cells. NADPH also plays key roles in cellular processes mediated by redox signaling. Insufficient G6PD activity predisposes cells to growth retardation and demise. Severely lacking G6PD impairs embryonic development and delays organismal growth. Altered G6PD activity is associated with pathophysiology, such as autophagy, insulin resistance, infection, inflammation, as well as diabetes and hypertension. Aberrant activation of G6PD leads to enhanced cell proliferation and adaptation in many types of cancers. The present review aims to update the existing knowledge concerning G6PD and emphasizes how G6PD modulates redox signaling and affects cell survival and demise, particularly in diseases such as cancer. Exploiting G6PD as a potential drug target against cancer is also discussed., Competing Interests: The authors declare no conflict of interest.

Drug-resistant tuberculosis (TB) is a global crisis and a threat to health security. Since conventional drug susceptibility testing (DST) takes several weeks, we herein described a molecular assay to rapidly identify multidrug-resistant (MDR) and extensively drug-resistant (XDR) and reveal transmission associated-mutations of Mycobacterium tuberculosis complex (MTBC) isolates in 6 to 7 hours. An array was designed with 12 pairs of primers and 60 single nucleotide polymorphisms of 9 genes: rpoB, katG, inhA, ahpC, embB, rpsL, gyrA, rrs and eis. We assessed the performance of the array using 176 clinical MTBC isolates. The results of culture-based DST were used as the gold standard, the GenoType MTBDRplus and MTBDRsl tests were used for parallel comparison, and gene sequencing was performed to resolve the discordance. The sensitivities and specificities of the array are comparable to those of the MTBDRplus test for resistance to isoniazid (INH) (100.0%, 96.7%) and rifampicin (RIF) (99.4%, 96.7%) and of the MTBDRsl test for resistance to fluoroquinolones (FQs) (100%, 100%) and second-line injectable drugs (SLIDs) (98.3%, 100%). The sensitivities of the array for detecting resistance to ethambutol and streptomycin were 79.3% and 64.9%, respectively. The array has potential as a powerful tool for clinical diagnosis and epidemiological investigations.

Background and Objectives: Information on the growth status of indigenous children is useful for developing intervention strategies, but the data are limited. This study determined the prevalence of undernutrition among under-five indigenous children (Orang Asli) and tracked the growth status of Orang Asli children aged 0-3 years., Methods and Study Design: This study had two phases: a cross-sectional growth study of under-five Orang Asli children (N=304; Phase 1) and a 2-year prospective cohort growth study of Orang Asli children aged 0-3 years (N=214; Phase 2) in the Temerloh district of Pahang, Malaysia. Weight-for-age, length/height-for-age, weight-for-length/height, and body mass index-for-age were determined., Results: The prevalence rates of stunting, underweight, wasting, and thinness in under-five Orang Asli children (Phase 1) were 64%, 49%, 14%, and 12%, respectively. In the cohort of 214 children (Phase 2), weight-for-age was initially documented and maintained closely at -1.50 standard deviations (SD) in the first 6 months, but it declined to approximately -2.00 SD at 15 months and remained close to -2.00 SD thereafter. Length/height-for-age declined rapidly to approximately -2.50 SD at 18 months and fluctuated between -2.30 and -2.50 SD thereafter. Weight-for-length/height increased sharply to -0.40 SD at 2-3 months, declined gradually to less than -1.00 SD at 12 months, and plateaued between -1.00 and -1.30 SD thereafter., Conclusions: Undernutrition is prevalent among Orang Asli children, with length rather than weight faltering being more pronounced in the first 2 years of life. Identifying the causes of early growth retardation in this population is required to inform future preventive strategies.

Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient-derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, β-catenin, or RNF43. In these latter types of tumors that represent over 90% of CRC, RSPO3 is produced by stromal cells in the tumor microenvironment and the activating mutations appear to sensitize the tumors to Wnt-Rspo synergy. The combination of RSPO3 inhibition and taxane treatment provides an approach to effectively target oncogenic WNT signaling in a significant number of patients with colorectal and other intestinal cancers.

The WNT pathway mediates intercellular signaling that regulates cell fate in both normal development and cancer. It is widely appreciated that the WNT pathway is frequently dysregulated in human cancers through a variety of genetic and epigenetic mechanisms. Targets in the WNT pathway are being extensively pursued for the development of new anticancer therapies, and we have advanced two WNT antagonists for clinical development: vantictumab (anti-FZD) and ipafricept (FZD8-Fc). We examined the antitumor efficacy of these WNT antagonists in combination with various chemotherapies in a large set of patient-derived xenograft models. In responsive models, WNT blockade led to profound synergy with taxanes such as paclitaxel, and the combination activity with taxanes was consistently more effective than with other classes of chemotherapy. Taxane monotherapy increased the frequency of cells with active WNT signaling. This selection of WNT-active chemotherapy-resistant tumorigenic cells was prevented by WNT-antagonizing biologics and required sequential dosing of the WNT antagonist followed by the taxane. The WNT antagonists potentiated paclitaxel-mediated mitotic blockade and promoted widespread mitotic cell death. By blocking WNT/β-catenin signaling before mitotic blockade by paclitaxel, we found that this treatment effectively sensitizes cancer stem cells to taxanes. This combination strategy and treatment regimen has been incorporated into ongoing clinical testing for vantictumab and ipafricept.

Development of broadband photodetectors is of great importance for applications in high-capacity optical communication, night vision, and biomedical imaging systems. While heterostructured photodetectors can expand light detection range, fabrication of heterostructures via epitaxial growth or wafer bonding still faces significant challenges because of problems such as lattice and thermal mismatches. Here, a transfer printing technique is used for the heterogeneous integration of InGaAs nanomembranes on silicon semiconductors and thus the formation of van der Waals heterojunction photodiodes, which can enhance the spectral response and photoresponsivity of Si photodiodes. Transfer-printed InGaAs nanomembrane/Si heterojunction photodiode exhibits a high rectification ratio (7.73 × 10 4 at ±3 V) and low leakage current (7.44 × 10 -5 A/cm 2 at -3 V) in a dark state. In particular, the photodiode shows high photoresponsivities (7.52 and 2.2 A W -1 at a reverse bias of -3 V and zero bias, respectively) in the broadband spectral range (400-1250 nm) and fast rise-fall response times (13-16 ms), demonstrating broadband and fast photodetection capabilities. The suggested III-V/Si van der Waals heterostructures can be a robust platform for the fabrication of high-performance on-chip photodetectors compatible with Si integrated optical chips.

Glucose-6-phosphate dehydrogenase (G6PD) provides the reducing agent NADPH to meet the cellular needs for reductive biosynthesis and the maintenance of redox homeostasis. G6PD-deficient cells experience a high level of oxidative stress and an increased susceptibility to viral infections. Cyclooxygenase-2 (COX-2) is a key mediator in the regulation of viral replication and inflammatory response. In the current study, the role of G6PD on the inflammatory response was determined in both scramble control and G6PD-knockdown (G6PD-kd) A549 cells upon tumor necrosis factor-α (TNF-α) stimulation. A decreased expression pattern of induced COX-2 and reduced production of downstream PGE2 occurred upon TNF-α stimulation in G6PD-kd A549 cells compared with scramble control A549 cells. TNF-α-induced antiviral activity revealed that decreased COX-2 expression enhanced the susceptibility to coronavirus 229E infection in G6PD-kd A549 cells and was a result of the decreased phosphorylation levels of MAPK (p38 and ERK1/2) and NF-κB. The impaired inflammatory response in G6PD-kd A549 cells was found to be mediated through NADPH oxidase (NOX) signaling as elucidated by cell pretreatment with a NOX2-siRNA or NOX inhibitor, diphenyleneiodonium chloride (DPI). In addition, NOX activity with TNF-α treatment in G6PD-kd A549 cells was not up-regulated and was coupled with a decrease in NOX subunit expression at the transcriptional level, implying that TNF-α-mediated NOX signaling requires the participation of G6PD. Together, these data suggest that G6PD deficiency affects the cellular inflammatory response and the decreased TNF-α-mediated antiviral response in G6PD-kd A549 cells is a result of dysregulated NOX/MAPK/NF-κB/COX-2 signaling.

Deregulation of the β-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and β-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate β-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate β-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited β-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of β-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis., (©2015 American Association for Cancer Research.)

Despite the vast progress in chemical vapor deposition (CVD) graphene grown on metals, the transfer process is still a major bottleneck, being not devoid of wrinkles and polymer residues. In this paper, a structure is introduced to directly synthesize few layer graphene on insulating substrates by a laser irradiation heating process. The segregation of graphene layers can be manipulated by tuning the metal layer thickness and laser power at different scanning rates. Graphene deposition and submicrometer patterning resolution can be achieved by patterning the intermediate metal layer using standard lithography methods in order to overcome the scalability issue regardless the resolution of the laser beam. The systematic analysis of the process based on the formation of carbon microchannels by the laser irradiation process can be extended to several materials, thicknesses, and methods. Furthermore, hole and electron mobilities of 500 and 950 cm(2) V(-1) s(-1) are measured. The laser-synthesized graphene is a step forward along the direct synthesis route for graphene on insulators that meets the criteria for photonics and electronics., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: The Notch pathway plays an important role in both stem cell biology and cancer. Dysregulation of Notch signaling has been reported in several human tumor types. In this report, we describe the development of an antibody, OMP-59R5 (tarextumab), which blocks both Notch2 and Notch3 signaling., Experimental Design: We utilized patient-derived xenograft tumors to evaluate antitumor effect of OMP-59R5. Immunohistochemistry, RNA microarray, real-time PCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts., Results: We found that anti-Notch2/3, either as a single agent or in combination with chemotherapeutic agents was efficacious in a broad spectrum of epithelial tumors, including breast, lung, ovarian, and pancreatic cancers. Notably, the sensitivity of anti-Notch2/3 in combination with gemcitabine in pancreatic tumors was associated with higher levels of Notch3 gene expression. The antitumor effect of anti-Notch2/3 in combination with gemcitabine plus nab-paclitaxel was greater than the combination effect with gemcitabine alone. OMP-59R5 inhibits both human and mouse Notch2 and Notch3 function and its antitumor activity was characterized by a dual mechanism of action in both tumor and stromal/vascular cells in xenograft experiments. In tumor cells, anti-Notch2/3 inhibited expression of Notch target genes and reduced tumor-initiating cell frequency. In the tumor stroma, OMP-59R5 consistently inhibited the expression of Notch3, HeyL, and Rgs5, characteristic of affecting pericyte function in tumor vasculature., Conclusions: These findings indicate that blockade of Notch2/3 signaling with this cross-reactive antagonist antibody may be an effective strategy for treatment of a variety of tumor types., (©2015 American Association for Cancer Research.)

The loss of overlying enamel or cementum exposes dentinal tubules and increases the risk of several dental diseases, such as dentin hypersensitivity (causing sharp pain and anxiety), caries, and pulp inflammation. This paper presents a fast-reacting, more reliable and biocompatible biomaterial that effectively occludes exposed dentinal tubules by forming a biomimetic crystalline dentin barrier. To generate this biomaterial, a gelatin-templated mesoporous silica biomaterial (CaCO3@mesoporous silica, CCMS) containing nanosized calcium carbonate particles is mixed with 30% H3PO4 at a 1/1 molar ratio of Ca/P (denoted as CCMS-HP), which enables Ca2+ and PO4(3-)/HPO4(2-) ions to permeate the dentinal tubules and form dicalcium phosphate dihydrate (DCPD), tricalcium phosphate (TCP) or hydroxyapatite (HAp) crystals at a depth of approximately 40 μm (sub-μ-CT and nano-SEM/EDS examinations). In vitro biocompatibility tests (WST-1 and lactate dehydrogenase) and ALP assays show high cell viability and mineralization ability in a transwell dentin disc model treated with CCMS-HP (p<0.05). The in vivo efficacy and biocompatibility analyses of the biomaterial in an animal model reveal significant crystal growth (DCPD, TCP or HAp-like) and no pulp irritation after 70 days (p<0.05). The developed CCMS-HP holds great promise for treating exposed dentin by growing biomimetic crystals within dentinal tubules. These findings demonstrate that the mesoporous silica biomaterials presented here have great potential for serving as both a catalyst and carrier in the repair or regeneration of dental hard tissue.

We report on the presence, distribution and numbers of diatoms within specific organs as a result of drowning in fresh, treated and seawater. Specimens of sphenoid sinus fluid and lung tissue from 100 cases of suspected drowning and 20 cases where death was by natural causes, to act as a control, were examined for the presence of diatoms. In the 100 cases where the deceased was suspected to have drowned, 94 were confirmed as a death by drowning after autopsy with the other six being reported as death by another cause. No diatoms were found in cases confirmed as death by causes unrelated to drowning, with the exception of possible contamination via open wounds and through decomposition. In 94 cases, where all fatalities were confirmed as death by drowning, there were 81 cases in which diatoms were detected in samples taken from the sphenoid sinus fluid and/or lung tissue. No, or only few, diatoms were observed from the samples where the deceased drowned in treated waters such as spa or swimming pools. A significantly higher number of diatoms were detected in the sphenoid sinus fluid and lung tissue of confirmed drowning cases in fresh water compared to seawater. More diatoms were observed in sphenoid sinus fluid compared to lung tissue regardless of the water in which the deceased drowned. This study illustrates the potential use of diatom screening using both sphenoid sinus fluid and lung tissue to determine the cause of death in suspected cases of drowning. This report also highlights specific variables that need to be considered prior to such as conclusion being reached., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Temporal profile distortions reduce excitation efficiency and image quality in temporal focusing-based multiphoton microscopy. In order to compensate the distortions, a wavefront sensorless adaptive optics system (AOS) was integrated into the microscope. The feedback control signal of the AOS was acquired from local image intensity maximization via a hill-climbing algorithm. The control signal was then utilized to drive a deformable mirror in such a way as to eliminate the distortions. With the AOS correction, not only is the axial excitation symmetrically refocused, but the axial resolution with full two-photon excited fluorescence (TPEF) intensity is also maintained. Hence, the contrast of the TPEF image of a R6G-doped PMMA thin film is enhanced along with a 3.7-fold increase in intensity. Furthermore, the TPEF image quality of 1μm fluorescent beads sealed in agarose gel at different depths is improved.

A directly self-crystallized graphene layer with transfer-free process on arbitrary insulator by Ni vapor-assisted growth at growth temperatures between 950 to 1100 °C via conventional chemical vapor deposition (CVD) system was developed and demonstrated. Domain sizes of graphene were confirmed by Raman spectra from ~12 nm at growth temperature of 1000 °C to ~32 nm at growth temperature of 1100 °C, respectively. Furthermore, the thickness of the graphene is controllable, depending on deposition time and growth temperature. By increasing growth pressure, the growth of graphite nano-balls was preferred rather than graphene growth. The detailed formation mechanisms of graphene and graphite nanoballs were proposed and investigated in detail. Optical and electrical properties of graphene layer were measured. The direct growth of the carbon-based materials with free of the transfer process provides a promising application at nanoelectronics.

Tunable surface morphology in III-V semiconductor nanomembranes provides opportunities to modulate electronic structures and light interactions of semiconductors. Here, we introduce a vacuum-induced wrinkling method for the formation of ordered wrinkles in InGaAs nanomembranes (thickness, 42 nm) on PDMS microwell arrays as a strategy for deterministic and multidirectional wrinkle engineering of semiconductor nanomembranes. In this approach, a vacuum-induced pressure difference between the outer and inner sides of the microwell patterns covered with nanomembranes leads to bulging of the nanomembranes at the predefined microwells, which, in turn, results in stretch-induced wrinkle formation of the nanomembranes between the microwells. The direction and geometry of the nanomembrane wrinkles are well controlled by varying the PDMS modulus, depth, and shape of microwells, and the temperature during the transfer printing of nanomembrane onto heterogeneous substrates. The wrinkling method shown here can be applied to other semiconductor nanomembranes and may create an important platform to realize unconventional electronic devices with tunable electronic properties.

Solution processing of π-conjugated polymers constitutes a major low-cost manufacturing method for the fabrication of many new organic optoelectronic devices. The solution self-assembly kinetics of π-conjugated rod-coil block copolymers of symmetric poly(3-hexyl thiophene)-b-poly(2-vinyl pyridine) (P3HT-P2VP) during drying and the phase transformations of the subsequently dried samples were studied by using a combination of TEM, SAXS, WAXS and DSC measurements. During solution drying in chlorobenzene, a good solvent for the copolymer, P3HT-P2VP first formed nanoseed aggregates followed by the directional growth of nanofibrils driven by the formation of prevailing form II P3HT crystals within its nanofibril core confined by the surrounding domain of P2VP blocks. This result was in sharp contrast when a similar molecular weight P3HT homopolymer was solution self-assembled in chlorobenzene, nearly free from confinement, in which case the resulting nanofibrils consisted of a mixture of majority form I and form II crystals. Solvent-cast films of P3HT-P2VP nanofibrils with form II crystals were heat-/cold-treated and showed solid-state phase transformations from form II crystals to form I crystals, both within nanofibrils with annealing, indicating the metastability of the form II crystals with temperature. A disordered state followed with increasing temperatures which, when cooled, induced the formation of a thermodynamically stable lamellar phase with only form I P3HT crystals. Correspondingly, the study provides new strategies for controlling polymorphs and nanostructures of π-conjugated block copolymers for future applications using solution processing and subsequent heat treatment.

This cross-sectional study examined the relationship between household food insecurity and the metabolic syndrome (MetS) among reproductive-aged women (n=625) in low income communities. The Radimer/Cornell Hunger and Food Insecurity instrument was utilized to assess food insecurity. Anthropometry, diet diversity, blood pressure and fasting venous blood for lipid and glucose profile were also obtained. MetS was defined as having at least 3 risk factors and is in accordance with the Harmonized criteria. The prevalence of food insecurity and MetS was 78.4% (household food insecure, 26.7%; individual food insecure, 25.3%; child hunger, 26.4%) and 25.6%, respectively. While more food secure than food insecure women had elevated glucose (food secure, 54.8% vs food insecure, 37.3-46.1%), total cholesterol (food secure, 54.1% vs food insecure, 32.1-40.7%) and LDL-cholesterol (food secure, 63.7% vs food insecure, 40.6-48.7%), the percentage of women with overweight/ obesity, abdominal obesity, hypertension, high triglyceride, low HDL-cholesterol and MetS did not vary significantly by food insecurity status. However, after controlling for demographic and socioeconomic covariates, women in food insecure households were less likely to have MetS (individual food insecure and child hunger) (p<0.05), abdominal obesity (individual food insecure and child hunger) (p<0.01), elevated glucose (household food insecure), total cholesterol (child hunger) (p<0.05) and LDL-cholesterol (household food insecure and child hunger) (p<0.05) compared to food secure women. Efforts to improve food insecurity of low income households undergoing nutrition transition should address availability and accessibility to healthy food choices and nutrition education that could reduce the risk of diet-related chronic diseases.

In this paper, an easily implementable adaptive optics system (AOS) based on a real-time field programmable gate array (FPGA) platform with state-space multichannel control programmed by LabVIEW has been developed, and also integrated into a laser focusing system successfully. To meet the requirements of simple programming configuration and easy integration with other devices, the FPGA-based AOS introduces a standard operation procedure including AOS identification, computation, and operation. The overall system with a 32-channel driving signal for a deformable mirror (DM) as input and a Zernike polynomial via a lab-made Shack-Hartmann wavefront sensor (SHWS) as output is optimally identified to construct a multichannel state-space model off-line. In real-time operation, the FPGA platform first calculates the Zernike polynomial of the optical wavefront measured from the SHWS as the feedback signal. Then, a state-space multichannel controller according to the feedback signal and the identified model is designed and implemented in the FPGA to drive the DM for phase distortion compensation. The current FPGA-based AOS is capable of suppressing low-frequency thermal disturbances with a steady-state phase error of less than 0.1 π within less than 10 time steps when the control loop is operated at a frequency of 30 Hz.

Colloid TiO(2) nanorods are used for solution-processable poly(3-hexyl thiophene): TiO(2) hybrid solar cell. The nanorods were covered by insulating ligand of oleic acid (OA) after sol-gel synthesis. Three more conducting pyridine type ligands: pyridine, 2,6-lutidine (Lut) and 4-tert-butylpyridine (tBP) were investigated respectively to replace OA. The power conversion efficiency (PCE) of the solar cell was increased because the electronic mobility of pyridine-type ligand-modified TiO(2) is higher than that of TiO(2)-OA. The enhancement of PCE is in the descending order of Lut > pyridine > tBP because of the effective replacement of OA by Lut. The PCE of solar cell can be further enhanced by ligand exchange of pyridine type ligand with conjugating molecule of 2-cyano-3-(5-(7-(thiophen-2-yl)-benzothiadiazol-4-yl) thiophen-2-yl) acrylic acid (W4) on TiO(2) nanorods because W4 has aligned bandgap with P3HT and TiO(2) to facilitate charge separation and transport. The electronic mobility of two-stage ligand exchanged TiO(2) is improved furthermore except Lut, because it adheres well and difficult to be replaced by W4. The amount of W4 on TiO(2)-tBP is 3 times more than that of TiO(2)-Lut (0.20 mol % vs. 0.06 mol %). Thus, the increased extent of PCE of solar cell is in the decreasing order of tBP > pyridine > Lut. The TiO(2)-tBP-W4 device has the best performance with 1.4 and 2.6 times more than TiO(2)-pyridine-W4 and TiO(2)-Lut-W4 devices, respectively. The pKa of the pyridine derivatives plays the major role to determine the ease of ligand exchange on TiO(2) which is the key factor mandating the PCE of P3HT:TiO(2) hybrid solar cell. The results of this study provide new insights of the significance of acid-base reaction on the TiO(2) surface for TiO(2)-based solar cells. The obtained knowledge can be extended to other hybrid solar cell systems.

All-solid-state flexible supercapacitors based on a carbon/MnO(2) (C/M) core-shell fiber structure were fabricated with high electrochemical performance such as high rate capability with a scan rate up to 20 V s(-1), high volume capacitance of 2.5 F cm(-3), and an energy density of 2.2 × 10(-4) Wh cm(-3). By integrating with a triboelectric generator, supercapacitors could be charged and power commercial electronic devices, such as a liquid crystal display or a light-emitting-diode, demonstrating feasibility as an efficient storage component and self-powered micro/nanosystems.

Purpose: We previously showed that targeting Delta-like ligand 4 (DLL4) in colon and breast tumors inhibited tumor growth and reduced tumor initiating cell frequency. In this report, we have extended these studies to pancreatic cancer and probed the mechanism of action in tumor and stromal cells involved in antitumor efficacy., Experimental Design: Patient-derived pancreatic xenograft tumor models were used to evaluate the antitumor effect of anti-DLL4. To investigate the mechanism of action, we compared the activity of targeting DLL4 in tumor cells with an anti-human DLL4 antibody (anti-hDLL4) and in the host stroma/vasculature with an anti-mouse DLL4 antibody (anti-mDLL4). The effect of these antibodies on cancer stem cell frequency was examined by in vivo limiting dilution assays., Results: The combination of anti-hDLL4 and anti-mDLL4 was efficacious in a broad spectrum of pancreatic tumor xenografts and showed additive antitumor activity together with gemcitabine. Treatment with either anti-hDLL4 or anti-mDLL4 delayed pancreatic tumor recurrence following termination of gemcitabine treatment, and the two together produced an additive effect. Anti-hDLL4 had a pronounced effect in reducing the tumorigenicity of pancreatic cancer cells based on serial transplantation and tumorsphere assays. In contrast, disruption of tumor angiogenesis with anti-mDLL4 alone or with anti-VEGF had minimal effects on tumorigenicity. Gene expression analyses indicated that anti-DLL4 treatment regulated genes that participate in Notch signaling, pancreatic differentiation, and epithelial-to-mesenchymal transition., Conclusions: Our findings suggest a novel therapeutic approach for pancreatic cancer treatment through antagonism of DLL4/Notch signaling.

The Wnt/β-catenin pathway, which signals through the Frizzled (Fzd) receptor family and several coreceptors, has long been implicated in cancer. Here we demonstrate a therapeutic approach to targeting the Wnt pathway with a monoclonal antibody, OMP-18R5. This antibody, initially identified by binding to Frizzled 7, interacts with five Fzd receptors through a conserved epitope within the extracellular domain and blocks canonical Wnt signaling induced by multiple Wnt family members. In xenograft studies with minimally passaged human tumors, this antibody inhibits the growth of a range of tumor types, reduces tumor-initiating cell frequency, and exhibits synergistic activity with standard-of-care chemotherapeutic agents.

In this study, a microscope based on spatiotemporal focusing offering widefield multiphoton excitation has been developed to provide fast optical sectioning images. Key features of this microscope are the integrations of a 10 kHz repetition rate ultrafast amplifier featuring high instantaneous peak power (maximum 400 μJ/pulse at a 90 fs pulse width) and a TE-cooled, ultra-sensitive photon detecting, electron multiplying charge-coupled camera into a spatiotemporal focusing microscope. This configuration can produce multiphoton images with an excitation area larger than 200 × 100 μm² at a frame rate greater than 100 Hz (current maximum of 200 Hz). Brownian motions of fluorescent microbeads as small as 0.5 μm were observed in real-time with a lateral spatial resolution of less than 0.5 μm and an axial resolution of approximately 3.5 μm. Furthermore, second harmonic images of chicken tendons demonstrate that the developed widefield multiphoton microscope can provide high resolution z-sectioning for bioimaging.

Taiwan's multicultural population requires that nursing educators address and effectively manage trans-cultural healthcare issues. A longstanding lack of self-reflection on cultural issues has caused a gap between community nursing and the health needs of Taiwan's indigenous people. Taiwan's newer immigrant populations from Southeast Asia, Mainland China and elsewhere have added further cultural complexity to Taiwan's community healthcare landscape. In this paper, the authors apply their practical experience in community nursing to derive the special healthcare needs of indigenous and new immigrant populations based on the unique cultural attributes and health concepts of these populations. We hope to help nursing staff develop cultural self-awareness and sensitivity by admiring, respecting, and learning from their own culture while empathizing with and appreciating the cultures of their healthcare clients. By doing so, healthcare providers can further examine the cultural characteristics of the professional nursing system and conduct trans-cultural evaluations.

KRAS mutations are frequent in colorectal cancer (CRC) and are associated with clinical resistance to treatment with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway and mediates stem cell self-renewal and vascular development. DLL4 inhibition in colon tumor cells reduces tumor growth and stem cell frequency. Considering the need for new drugs to treat colon cancers with oncogenic KRAS mutations, we examined in this study the efficacy of anti-DLL4 antibodies in KRAS mutant tumors in a panel of early passage colon tumor xenograft models derived from patients. Consistent with clinical findings, mutant KRAS colorectal xenograft tumors were insensitive to the EGFR therapeutic antibody cetuximab, whereas KRAS wild-type tumors responded to cetuximab. In contrast, anti-DLL4 was efficacious against both wild-type and mutant KRAS colon tumors as a single agent and in combination with irinotecan. Further analysis of mutant KRAS tumors indicated that the anti-DLL4/irinotecan combination produced a significant decrease in colon cancer stem cell frequency while promoting apoptosis in tumor cells. Our findings provide a rationale for targeting DLL4-Notch signaling for improved treatment of CRC patients with activating KRAS mutations., (©2010 AACR.)

An ordered nanostructure can be created from the hybrid materials of self-assembly poly(3-hexyl thiophene-b-2-vinyl pyridine) and nicotinic acid-modified titanium dioxide nanoparticles (P3HT-b-P2VP/TiO(2)). TEM and XRD analyses reveal that the TiO(2) nanoparticles (NPs) are preferentially confined in the P2VP domain of P3HT-b-P2VP whereas TiO(2) NPs interact with either pure P3HT or a blend of P3HT and P2VP to produce microsized phase segregation. The morphologies of lamellar and cylindrical structures are disturbed when the loading of TiO(2) NPs is 40 wt % or higher. Cylindrical P3HT-b-P2VP/TiO(2) exhibits a small blue shift in absorption and photoluminescence spectra with increasing TiO(2) loading as compared to P3HT/TiO(2). The NPs cause a slightly misaligned P3HT domain in the copolymer. Furthermore, the PL quenching of P3HT-b-P2VP/TiO(2) becomes very large as a result of efficient charge separation in the ordered nanodomain at 16 nm. Solar cells fabricated from self-assembly P3HT-b-P2VP/TiO(2) hybrid materials exhibit a >30 fold improvement in power conversion efficiency as compared to the corresponding 0.3P3HT-0.7P2VP/TiO(2) polymer blend hybrid. This study paves the way for the further development of high-efficiency polymer-inorganic nanoparticle hybrid solar cells using a self-assembled block copolymer.

A novel photoluminescence electron beam resist made from the blend of poly(3-hexylthiophene) (P3HT) and poly(methyl methacrylate) (PMMA) has been successfully developed in this study. In order to optimize the resolution of the electron beam resist, the variations of nanophase separated morphology produced by differing blending ratios were examined carefully. Concave P3HT-rich island-like domains were observed in the thin film of the resist. The size of concave island-like domains decreased from 350 to 100 nm when decreasing the blending ratio of P3HT/PMMA from 1:5 to 1:50 or lower, concurrently accompanied by significant changes in optical properties and morphological behaviors. The lambda(max) of the film absorption is blue-shifted from 520 to 470 nm, and its lambda(max) of photoluminescence (PL) is also shifted from 660 to 550 nm. The radiative lifetime is shorter while the luminescence efficiency is higher when the P3HT/PMMA ratio decreases. These results are attributed to the quantum confinement effect of single P3HT chain isolated in PMMA matrix, which effectively suppresses the energy transfer between the well-separated polymer chains of P3HT. The factors affecting the resolution of the P3HT/PMMA electron beam resists were systematically investigated, including blending ratios and molecular weight. The photoluminescence resist with the best resolution was fabricated by using a molecular weight of 13 500 Da of P3HT and a blending ratio of 1:1000. Furthermore, high-resolution patterns can be obtained on both flat silicon wafers and rough substrates made from 20 nm Au nanoparticles self-assembled on APTMS (3-aminopropyltrimethoxysilane)-coated silicon wafers. Our newly developed electron beam resist provides a simple and convenient approach for the fabrication of nanoscale photoluminescent periodic arrays, which can underpin many optoelectronic applications awaiting future exploration.

This is an in depth study on the surface potential changes of P3HT/TiO(2) nanorod bulk heterojunction thin films. They are affected by interlayer structures, the molecular weight of P3HT, the processing solvents and the surface ligands on the TiO(2). The addition of an electron blocking layer and/or the hole blocking layer to the P3HT/TiO(2) thin film can facilitate charge carrier transport and result in a high surface potential shift. The changes in surface potential of multilayered bulk heterojunction films are closely correlated to their power conversion efficiency of photovoltaic devices. Changing ligand leads to the largest change in surface potential yielding the greatest effect on the power conversion efficiency. Merely changing the P3HT molecular weight is less effective and varying the processing solvents is least effective in increasing power conversion efficiency. The steric effect of the ligand has a large influence on the reduction of charge carrier recombination resulting in a great effect on the power conversion efficiency. By monitoring the changes in the surface potential of bulk heterojunction film of multilayer structures, we have obtained a useful guide for the fabrication of high performance photovoltaic devices.

Previous studies have shown that blocking DLL4 signaling reduced tumor growth by disrupting productive angiogenesis. We developed selective anti-human and anti-mouse DLL4 antibodies to dissect the mechanisms involved by analyzing the contributions of selectively targeting DLL4 in the tumor or in the host vasculature and stroma in xenograft models derived from primary human tumors. We found that each antibody inhibited tumor growth and that the combination of the two antibodies was more effective than either alone. Treatment with anti-human DLL4 inhibited the expression of Notch target genes and reduced proliferation of tumor cells. Furthermore, we found that specifically inhibiting human DLL4 in the tumor, either alone or in combination with the chemotherapeutic agent irinotecan, reduced cancer stem cell frequency, as shown by flow cytometric and in vivo tumorigenicity studies.

We theoretically verify that the threshold of an intracavity optical parametric oscillator pumped by a passively Q-switched laser is entirely controlled by the bleach of the saturable absorber not by the signal output reflectivity. We use a series of different output couplers to optimize the output performance. With a signal output reflectivity of 15%, we experimentally achieve an efficient subnanosecond eye-safe laser with 3.3 mJ pulse energy and 1.5 MW peak power.

Treatment of inflammation is often accomplished through the use of glucocorticoids. However, their use is limited by side effects. We have examined the activity of a novel glucocorticoid receptor ligand that binds the receptor efficiently and strongly represses inflammatory gene expression. This compound has potent antiinflammatory activity in vivo and represses the transcription of the inflammatory cytokine monocyte chemoattractant protein-1 and induces the antiinflammatory cytokine IL-10. The compound demonstrates differential gene regulation, compared with commonly prescribed glucocorticoids, effectively inducing some genes and repressing others in a manner different from the glucocorticoid prednisolone. The separation between the antiinflammatory effects of LGD-5552 and the side effects commonly associated with glucocorticoid treatment suggest that this molecule differs significantly from prednisolone and other steroids and may provide a safer therapeutic window for inflammatory conditions now commonly treated with steroidal glucocorticoids.

We present a compact efficient eye-safe intracavity optical parametric oscillator pumped by a passively Q-switched Nd:YAG laser in a shared cavity configuration. A signal pulse of 3.3 mJ energy at a 1573 nm wavelength with a peak power of 150 kW was achieved. The effective conversion efficiency with respective to the optimized 1064 nm Q-switched pulse energy was as high as 51%.

Acquired drug resistance is a major obstacle in cancer therapy. As for many other drugs, this is also the case for gemcitabine, a nucleoside analogue with activity against non-small cell lung cancer (NSCLC). Here, we evaluate the ability of bexarotene to modulate the acquisition and maintenance of gemcitabine resistance in Calu3 NSCLC models. In the prevention model, Calu3 cells treated repeatedly with gemcitabine alone gradually developed resistance. However, with inclusion of bexarotene, the cells remained chemosensitive. RNA analysis showed a strong increase of rrm1 (ribonucleotide reductase M1) expression in the resistant cells (Calu3-GemR), a gene known to be involved in gemcitabine resistance. In addition, the expression of genes surrounding the chromosomal location of rrm1 was increased, suggesting that resistance was due to gene amplification at the chr11 p15.5 locus. Analysis of genomic DNA confirmed that the rrm1 gene copy number was increased over 10-fold. Correspondingly, fluorescence in situ hybridization analysis of metaphase chromosomes showed an intrachromosomal amplification of the rrm1 locus. In the therapeutic model, bexarotene gradually resensitized Calu3-GemR cells to gemcitabine, reaching parental drug sensitivity after 10 treatment cycles. This was associated with a loss in rrm1 amplification. Corresponding with the in vitro data, xenograft tumors generated from the resistant cells did not respond to gemcitabine but were growth inhibited when bexarotene was added to the cytotoxic agent. The data indicate that bexarotene can resensitize gemcitabine-resistant tumor cells by reversing gene amplification. This suggests that bexarotene may have clinical utility in cancers where drug resistance by gene amplification is a major obstacle to successful therapy.

Objective: This study was designed to investigate the correlation between the irritability of the myofascial trigger point (MTrP) and the prevalence of endplate noise (EPN) in the MTrP region of human skeletal muscle., Design: Twenty normal subjects with latent MTrPs and 12 patients with active MTrPs in the upper trapezius muscles were recruited for this study. The patients reported the subjective pain intensity of the active MTrP (0-10). The MTrP and an adjacent non-MTrP site were confirmed and marked for the measurement of pressure pain threshold (with a pressure algometer) and the prevalence of EPN (with electromyographic recordings)., Results: The prevalence of EPN in the MTrP regions was significantly higher (P < 0.01) in the active MTrPs than in the latent ones. However, no EPN could be found in the non-MTrP region near either the active or the latent MTrPs. The pain intensity and the pressure pain threshold were highly correlated with the prevalence of EPN in the MTrP region (r = 0.742 and -0.716, respectively)., Conclusions: The irritability of an MTrP is highly correlated with the prevalence of EPN in the MTrP region of the upper trapezius muscle. The assessment of EPN prevalence in an MTrP region may be applied to evaluate the irritability of that MTrP.