Search

PDF file - 59K, PKCK2 activity dependent stabilization of exogenous Snail. A, MCF-7 cells that have low PKCK2 activity were co-transfected with Flag tagged Snail expression vector along either with empty vector or with Myc tagged PKCK2� expression vector. B, HCE4 cells were transfected with Flag-Snail and then were treated or un-treated with TBB, a pharmacologic inhibitor of PKCK2. C, PKCK2 activity was measured for each condition. S92 represents a vector expressing wild type snail, S92A (serine 92 replaced with alanine) mutant represents a vector expressing non-phosphorylatable form of snail, and S92E (serine 92 replaced with glutamic acid) represents a vector expressing mutant snail to mimic constitutive phosphorylation

PDF file - 71K, Western blot analysis for type of cadherin expressed in TE2, TE3, HCE4, and HCE7 (A) and for epithelial or mesenchymal markers and PKB/Akt activation in TE3 and HCE7 cells (B)

PDF file - 79K, Expression level of molecules involved in E-cadherin down-regulation. Western blot analysis was performed using total cell lysates (A) or lysates from cytoplasmic or nuclear fraction (B). The indicated Abs were used. RT-PCR was performed to examine mRNA expression level of Axin2 in TE2 and HCE4 cells and GAPDH was used as an internal control

Background SB3 has been developed as a trastuzumab biosimilar, a therapeutic monoclonal antibody targeted to human epidermal growth factor receptor 2 (HER2), and approved by the European Commission and United States (US) Food and Drug Administration (FDA). During the developmental period of a biosimilar, setting an appropriate quality target is critical for assessing the similarity of the biosimilar product to the reference product. A stepwise approach should be taken to assessing similarity, beginning with extensive characterization of the reference product to establish the quality target. Objective In this study, we evaluated the similarity of SB3 to the reference product and the impact of changes in the biological profile of the reference product on similarity assessment. Methods Analytical similarity was assessed with defined test procedures in terms of critical quality attributes (CQAs) that could affect efficacy, potency, and safety, as well as for the non-CQAs that are related to process consistency. The quality target was established using up to 154 lots of European Union (EU)- and US-sourced Herceptin® (reference product), analyzed during the developmental period of SB3. Results Trends of the EU- and US-sourced reference product showed that the biological profile exhibited two marked changes for Fc-related attributes, and then recovered to pre-change quality level. Since the similarity range set by pre-change lots was considered most relevant, the changed lots were excluded from establishing the similarity range, which resulted in tightened acceptance criteria. As shown in the results of similarity assessment using the stringent quality target ranges, SB3 exhibits highly similar functional activities compared to the reference product in terms of both CQAs and non-CQAs. Conclusion SB3 has been developed as a trastuzumab biosimilar approved in the EU and USA, and its manufacturing process is deemed to be robust and well-controlled within stringent quality target ranges.

Epidermal growth factor receptor (EGFR) supports colorectal cancer progression via oncogenic signaling. Anti-EGFR therapy is being investigated as a clinical option for colorectal cancer, and an observed interaction between EGFR and Prion protein has been detected in neuronal cells. We hypothesized that PrPC expression levels may regulate EGFR signaling and that detailed understanding of this signaling pathway may enable identification of resistance mechanisms and new actionable targets in colorectal cancer. We performed molecular pathway analysis following knockdown of PrPC or inhibition of EGFR signaling via gefitinib to identify changes in expression of key signaling proteins that determine cellular sensitivity or resistance to cisplatin. Expression of these proteins was examined in matched primary and metastatic patient samples and was correlated for resistance to therapy and progression of disease. Utilizing three colorectal cancer cell lines, we observed a correlation between high expression of PrPC and resistance to cisplatin. Investigation of molecular signaling in a resistant cell line revealed that PrPC contributed to signaling via colocalization with EGFR, which could be overcome by targeting p38 mitogen-activated protein kinases (p38 MAPK). We revealed that the level of Kruppel-like factor 5 (KLF5), a target downstream of p38 MAPK, was predictive for cell line and patient response to platinum agents. Further, high KLF5 expression was observed in BRAF-mutant colorectal cancer. Our study indicates that the EGFR to KLF5 pathway is predictive of patient progression on platinum-based therapy.

Breast cancer genome-wide association studies (GWASs) have identified 150 genomic risk regions containing more than 13,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements. However, the genes underlying breast cancer risk associations are largely unknown. Here, we used genetic colocalization analysis to identify loci at which gene expression could potentially explain breast cancer risk phenotypes. Using data from the Breast Cancer Association Consortium (BCAC) and quantitative trait loci (QTL) from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Project (TCGA), we identify shared genetic relationships and reveal novel associations between cancer phenotypes and effector genes. Seventeen genes, including NTN4, were identified as potential mediators of breast cancer risk. For NTN4, we showed the rs61938093 CCV at this region was located within an enhancer element that physically interacts with the NTN4 promoter, and the risk allele reduced NTN4 promoter activity. Furthermore, knockdown of NTN4 in breast cells increased cell proliferation in vitro and tumor growth in vivo. These data provide evidence linking risk-associated variation to genes that may contribute to breast cancer predisposition.

Transforming growth factor β (TGFβ) is overexpressed in advanced cancers and promotes tumorigenesis by inducing epithelial–mesenchymal transition (EMT), which enhances invasiveness and metastasis. Although we previously reported that EMT could be induced by increasing CK2 activity alone, it is not known whether CK2 also plays an essential role in TGFβ‐induced EMT. Therefore, in the present study, we investigated whether TGFβ signaling could activate CK2 and, if so, whether such activation is required for TGFβ‐induced EMT. We found that CK2 is activated by TGFβ treatment, and that activity peaks at 48 h after treatment. CK2 activation is dependent on TGFβ receptor (TGFBR) I kinase activity, but independent of SMAD4. Inhibition of CK2 activation through the use of either a CK2 inhibitor or shRNA against CSNK2A1 inhibited TGFβ‐induced EMT. TGFβ signaling decreased CK2β but did not affect CK2α protein levels, resulting in a quantitative imbalance between the catalytic α and regulatory β subunits, thereby increasing CK2 activity. The decrease in CK2β expression was dependent on TGFBRI kinase activity and the ubiquitin–proteasome pathway. The E3 ubiquitin ligases responsible for TGFβ‐induced CK2β degradation were found to be CHIP and WWP1. Okadaic acid (OA) pretreatment protected CK2β from TGFβ‐induced degradation, suggesting that dephosphorylation of CK2β by an OA‐sensitive phosphatase might be required for CK2 activation in TGFβ‐induced EMT. Collectively, our results suggest CK2 as a therapeutic target for the prevention of EMT and metastasis of cancers.

Hypoxia arises frequently in solid tumors and is a poor prognostic factor as it promotes tumor cell proliferation, invasion, angiogenesis, therapy resistance, and metastasis. Notably, there are two described forms of hypoxia present in a growing tumor: chronic hypoxia, caused by abnormal tumor vasculature, and intermittent hypoxia, caused by transient perfusion facilitated by tumor-supplying blood vessels. Here, we demonstrate that intermittent hypoxia, but not chronic hypoxia, endows breast cancer cells with greater metastatic potential. Using an immunocompetent and syngeneic murine model of breast cancer, we show that intermittent hypoxia enhances metastatic seeding and outgrowth in lungs in vivo. Furthermore, exposing mammary tumor cells to intermittent hypoxia promoted clonal diversity, upregulated metastasis-associated gene expression, induced a pro-tumorigenic secretory profile, increased stem-like cell marker expression, and gave rise to tumor-initiating cells at a relatively higher frequency. This work demonstrates that intermittent hypoxia, but not chronic hypoxia, induces a number of genetic, molecular, biochemical, and cellular changes that facilitate tumor cell survival, colonization, and the creation of a permissive microenvironment and thus enhances metastatic growth.

Non-small cell lung cancer (NSCLC) is the most common lung cancer type and the most common cause of mortality in lung cancer patients. NSCLC is often associated with resistance to chemotherapeutics and together with rapid metastatic spread, results in limited treatment options and poor patient survival. NSCLCs are heterogeneous, and consist of epithelial and mesenchymal NSCLC cells. Mesenchymal NSCLC cells are thought to be responsible for the chemoresistance phenotype, but if and how this phenotype can be transferred to other NSCLC cells is currently not known. We hypothesised that small extracellular vesicles, exosomes, secreted by mesenchymal NSCLC cells could potentially transfer the chemoresistance phenotype to surrounding epithelial NSCLC cells. To explore this possibility, we used a unique human bronchial epithelial cell (HBEC) model in which the parental cells were transformed from an epithelial to mesenchymal phenotype by introducing oncogenic alterations common in NSCLC. We found that exosomes derived from the oncogenically transformed, mesenchymal HBECs could transfer chemoresistance to the parental, epithelial HBECs and increase ZEB1 mRNA, a master EMT transcription factor, in the recipient cells. Additionally, we demonstrate that exosomes from mesenchymal, but not epithelial HBECs contain the ZEB1 mRNA, thereby providing a potential mechanism for the induction of a mesenchymal phenotype in recipient cells. Together, this work demonstrates for the first time that exosomes derived from mesenchymal, oncogenically transformed lung cells can transfer chemoresistance and mesenchymal phenotypes to recipient cells, likely via the transfer of ZEB1 mRNA in exosomes.

Anthracyclines are amongst the most effective chemotherapeutics ever developed, but they produce grueling side-effects, serious adverse events and resistance often develops over time. We found that these compounds can be sequestered by secreted cellular Prion protein (PrPC), blocking their cytotoxic activity. This effect was dose-dependent using either cell line-conditioned medium or human serum as a source of PrPC. Genetic depletion of PrPC or inhibition of binding via chelation of ionic copper prevented the interaction and restored cytotoxic activity. This was more pronounced for doxorubicin than its epimer, epirubicin. Investigating the relevance to breast cancer management, we found that the levels of PRNP transcript in pre-treatment tumor biopsies stratified relapse-free survival after neoadjuvant treatment with anthracyclines, particularly amongst doxorubicin-treated patients with residual disease at surgery (p=2.8E-08). These data suggest that local sequestration could mediate treatment resistance. Consistent with this, tumor cell expression of PrPC protein correlated with poorer response to doxorubicin but not epirubicin in an independent cohort analyzed by immunohistochemistry, particularly soluble isoforms released into the extracellular environment by shedding (p=0.015). These findings have important potential clinical implications for frontline regimen decision-making. We suggest there is warranted utility for prognostic PrPC/PRNP assays to guide chemo-sensitization strategies that exploit an understanding of PrPC-anthracycline-copper ion complexes.

Fine-mapping of breast cancer GWAS regions has identified 195 high confidence signals containing more than 5,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements and thus may confer the risk by altering gene expression in cis. We analyzed allelic expression imbalance (AEI) of genes surrounding known breast cancer signals, using normal breast and breast tumor transcriptome data and imputed genotypes. Fourteen genes, including NTN4, were identified whose expression was associated with CCV genotype. We showed that CCVs at this signal were located within an enhancer that physically interacts with the NTN4 promoter. Furthermore, knockdown of NTN4 in breast cells increased cell proliferation in vitro and tumor growth in vivo. Here, we present the most comprehensive AEI analysis of breast cancer CCVs resulting in identification of new candidate risk genes.

The activating receptor CD226 is expressed on lymphocytes, monocytes, and platelets and promotes anti-tumor immunity in pre-clinical models. Here, we examined the role of CD226 in the function of tumor-infiltrating lymphocytes (TILs) and resistance to immunotherapy. In murine tumors, a large proportion of CD8+ TILs had decreased surface expression of CD226 and exhibited features of dysfunction, whereas CD226hi TILs were highly functional. This correlation was seen also in TILs isolated from HNSCC patients. Mutation of CD226 at tyrosine 319 (Y319) led to increased CD226 surface expression, enhanced anti-tumor immunity and improved efficacy of immune checkpoint blockade (ICB). Mechanistically, tumor-derived CD155, the ligand for CD226, initiated phosphorylation of Y319 by Src kinases, thereby enabling ubiquitination of CD226 by CBL-B, internalization, and proteasomal degradation. In pre-treatment samples from melanoma patients, CD226+CD8+ T cells correlated with improved progression-free survival following ICB. Our findings argue for the development of therapies aimed at maintaining the expression of CD226.

Tumor-derived exosomes are being recognized as essential mediators of intercellular communication between cancer and immune cells. It is well established that bone marrow-derived macrophages (BMDMs) take up tumor-derived exosomes. However, the functional impact of these exosomes on macrophage phenotypes is controversial and not well studied. Here, we show that breast cancer-derived exosomes alter the phenotype of macrophages through the interleukin-6 (IL-6) receptor beta (glycoprotein 130, gp130)-STAT3 signaling pathway. Addition of breast cancer-derived exosomes to macrophages results in the activation of the IL-6 response pathway, including phosphorylation of the key downstream transcription factor STAT3. Exosomal gp130, which is highly enriched in cancer exosomes, triggers the secretion of IL-6 from BMDMs. Moreover, the exposure of BMDMs to cancer-derived exosomes triggers changes from a conventional toward a polarized phenotype often observed in tumor-associated macrophages. All of these effects can be inhibited through the addition of a gp130 inhibitor to cancer-derived exosomes or by blocking BMDMs exosome uptake. Collectively, this work demonstrates that breast cancer-derived exosomes are capable of inducing IL-6 secretion and a pro-survival phenotype in macrophages, partially via gp130/STAT3 signaling. CA extern

A biosimilar product needs to demonstrate biosimilarity to the originator reference product, and the quality profile of the latter should be monitored throughout the period of the biosimilar's development to match the quality attributes of the 2 products that relate to efficacy and safety. For the development of a biosimilar version of trastuzumab, the reference product, Herceptin®, was extensively characterized for the main physicochemical and biologic properties by standard or state-of-the-art analytical methods, using multiple lots expiring between March 2015 and December 2019. For lots with expiry dates up to July 2018, a high degree of consistency was observed for all the tested properties. However, among the lots expiring in August 2018 or later, a downward drift was observed in %afucose (G0+G1+G2). Furthermore, the upward drift of %high mannose (M5+M6) was observed in the lots with expiry dates from June 2019 to December 2019. As a result, the combination of %afucose and %high mannose showed 2 marked drifts in the lots with expiry dates from August 2018 to December 2019, which was supported by the similar trend of biologic data, such as FcγRIIIa binding and antibody-dependent cell-mediated cytotoxicity (ADCC) activity. Considering that ADCC is one of the clinically relevant mechanisms of action for trastuzumab, the levels of %afucose and %high mannose should be tightly monitored as critical quality attributes for biosimilar development of trastuzumab.

Non-small cell lung cancer (NSCLC) is the most common lung cancer type and the most common cause of mortality in lung cancer patients. NSCLC is often associated with resistance to chemotherapeutics and together with rapid metastatic spread, results in limited treatment options and poor patient survival. NSCLCs are heterogeneous, and consist of epithelial and mesenchymal NSCLC cells. Mesenchymal NSCLC cells are thought to be responsible for the chemoresistance phenotype, but if and how this phenotype can be transferred to other NSCLC cells is currently not known. We hypothesised that small extracellular vesicles, exosomes, secreted by mesenchymal NSCLC cells could potentially transfer the chemoresistance phenotype to surrounding epithelial NSCLC cells. To explore this possibility, we used a unique human bronchial epithelial cell (HBEC) model in which the parental cells were transformed from an epithelial to mesenchymal phenotype by introducing oncogenic alterations common in NSCLC. We found that exosomes derived from the oncogenically transformed, mesenchymal HBECs could transfer chemoresistance to the parental, epithelial HBECs and increase ZEB1 mRNA, a master EMT transcription factor, in the recipient cells. Additionally, we demonstrate that exosomes from mesenchymal, but not epithelial HBECs contain the ZEB1 mRNA, thereby providing a potential mechanism for the induction of a mesenchymal phenotype in recipient cells. Together, this work demonstrates for the first time that exosomes derived from mesenchymal, oncogenically transformed lung cells can transfer chemoresistance and mesenchymal phenotypes to recipient cells, likely via the transfer of ZEB1 mRNA in exosomes.

It has been reported that extracts from Asian traditional/medical herbs possess therapeutic agents against cancers, metabolic diseases, inflammatory diseases, and other intractable diseases. In this study, we assessed the molecular mechanisms involved in the anticancer effects of A1E, the extract of Korean medicinal herbs. We examined the role of the cytotoxic and apoptotic pathways in the cancer chemopreventive activity in non-small-cell lung cancer (NSCLC) cell lines NCI-H460 and NCI-H1299. A1E inhibited the proliferation of NCI-H460 more efficiently than NCI-H1299 (p53(-/-)) cells. The apoptosis was detected by nuclear morphological changes, annexin V-FITC/PI staining, cell cycle analysis, western blot, RT-PCR, and measurement of mitochondrial membrane potential. A1E induced cellular morphological changes and nuclear condensation at 24 h in a dose-dependent manner. A1E also perturbed cell cycle progression at the sub-G1 stage and altered cell cycle regulatory factors in NCI-H460 cells. Furthermore, A1E inhibited the PI3K/Akt and NF-κB survival pathways, and it activated apoptotic intrinsic and extrinsic pathways. A1E increased the expression levels of members of the extrinsic death receptor complex FasL and FADD. In addition, A1E treatment induced cleavage of caspase-8, caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP), whereas the expression levels of Bcl-2 and Bcl-xl were downregulated. A1E induced mitochondrial membrane potential collapse and cytochrome C release. Our results suggest that A1E induces apoptosis via activation of both extrinsic and intrinsic pathways and inhibition of PI3K/Akt survival signaling pathways in NCI-H460 cells. In conclusion, these data demonstrate the potential of A1E as a novel chemotherapeutic agent in NSCLC.

This study focuses on the preparation of CdSe/ZnO composite by combining three techniques, namely, electrodeposition, galvanic displacement, and photocathodic deposition. Thus ZnO nanowire array was first electrodeposited on Sn-doped indium oxide (ITO) or polycrystalline Au electrode; then, the metallic zinc codeposited with ZnO was galvanically replaced with Se from a Se4+ containing aqueous solution, which resulted in a Se/ZnO composite nanowire array. Finally, the Se component in Se/ZnO was photoelectrochemically reduced to Se2– by irradiation. The Se species reacted with Cd2+ in the electrolyte phase to produce CdSe/ZnO composite in situ. The deposition details were elucidated in situ by a combination of stripping voltammetry and electrochemical quartz crystal microgravimetry. The composite sample was subsequently characterized by scanning electron microscopy, X-ray powder diffraction, energy-dispersive X-ray analyses, and photoelectrochemical (PEC) measurements. The PEC experiments revealed that the ...

Previously, we reported that high PKCK2 activity could protect cancer cells from death receptor–mediated apoptosis through phosphorylation of procaspase-2. Because anoikis is another form of apoptosis, we asked whether PKCK2 could similarly confer resistance to anoikis on cancer cells. Human esophageal squamous cancer cell lines with high PKCK2 activity (HCE4 and HCE7) were anoikis-resistant, whereas cell lines with low PKCK2 activity (TE2 and TE3) were anoikis-sensitive. Because the cells showed different sensitivity to anoikis, we compared the expression of cell adhesion molecules between anoikis-sensitive TE2 and anoikis-resistant HCE4 cells using cDNA microarray. We found that E-cadherin is expressed only in TE2 cells; whereas N-cadherin is expressed instead of E-cadherin in HCE4 cells. To examine whether PKCK2 activity could determine the type of cadherin expressed, we first increased intracellular PKCK2 activity in TE2 cells by overexpressing the PKCK2α catalytic subunit using lentivirus and found that high PKCK2 activity could switch cadherin expression from type E to N and confer anoikis resistance. Conversely, a decrease in PKCK2 activity in HCE4 cells by knockdown of PKCK2α catalytic subunit using shRNA induced N- to E-cadherin switching and the anoikis-resistant cells became sensitive. In addition, N-cadherin expression correlated with PKB/Akt activation and increased invasiveness. We conclude that high intracellular PKCK2 activity confers anoikis resistance on esophageal cancer cells by inducing E- to N-cadherin switching. Mol Cancer Res; 10(8); 1032–8. ©2012 AACR.

during stripping analysis of Te(IV) or Se(IV). Therefore in this study, the conventional HgFE was also deployed to investigate whether alloy formation is a general phenomenon (like in the BiFE instance above) or not. Finally, comparative aspects of Te determination at BiFE and HgFE will be briefly discussed.

The mechanistic aspects of a two-step method for the electrodeposition of a BiVO4 semiconductor (previously developed in the Rajeshwar/Tacconi laboratory) were elaborated by the combined application of voltammetry and EQCM. The electrosynthesized films were also characterized ex situ using SEM, EDX, XRD, and XPS. Stripping of pre-electrodeposited bismuth films, followed by reaction either with VO43− (formed by hydrolysis from the initially added VO3− species) or with hydroxide ions, produced BiVO4 or Bi2O3 thin films in situ on the Pt electrode. The deposition potential, pH of the electrolyte, and choice of vanadium precursor were shown to be crucial variables in the composition of the electrodeposited film. When a more positive potential than 0.5 V (vs Ag/AgCl reference) was applied to the Bi-modified electrode in VO3−-containing electrolyte, the content of Bi2O3 in the film increased instead of BiVO4. Stripping efficiency of the predeposited bismuth layer was increased at acidic electrolytes and resulte...

Silver sulfide nanowire precursor was prepared at room temperature by simple mixing of mercaptoacetic acid (MAA) and silver nitrate solutions for 10–20 min duration. The MAA concentration in the chemical reaction bath was varied from 1 to 10 mM to afford nanowire precursors ranging in length from 800 nm to 42 μm and diameters ranging from 53 to 210 nm. The chemical identity of the precursor was established as a Ag+–−SCH2COOH complex by a variety of spectroscopic probes. It could be converted into crystalline Ag2S nanowires (with no alteration in nanowire dimensions) by a thermal anneal at ∼300 °C. Reverse cation exchange of the Ag2S nanowire precursor in a Cd2+-containing medium afforded CdS nanowires (with some alterations in morphology) whose chemical identity was confirmed by Raman spectroscopy and photoluminescence. Finally the dual role of MAA as a capping agent and reducing agent in the formation of the Ag2S nanowire precursor complex is briefly discussed.

Combined stripping voltammetry and electrochemical quartz crystal microgravimetry were employed for the compositional analysis of electrodeposited bismuth selenide (Bi–Se) thin films. Electrodeposited films contain free Bi and free Se in addition to the targeted Bi2Se3 compound and the amount of these “impurity” phases depends on the electrodeposition variables. Thus the free Se content was determined using the reduction peak of Se to Se2− obtained during the cathodic scan of films in 0.1 M Na2SO4 blank electrolyte. The Se content obtained during the cathodic stripping of Bi2Se3 to Bi + Se2− was used for the determination of Bi2Se3 content using the assumption of 2:3 compound stoichiometry. Finally, the total Bi content was obtained from the anodic scan and the free Bi content was calculated from the difference between total Bi and the Bi present in Bi2Se3. The compositional assays thus obtained from the combined use of stripping voltammetry and EQCM are presented as a function of electrodeposition potential and electrolyte composition. The Bi2Se3 content decreased as the deposition potential was decreased (made more negative) and was highest when the electrolyte contained the same molar ratio of Bi3+ and Se4+ species. Unlike the Bi2Te3 previously studied by us, electrodeposition of Bi2Se3 was not efficient at potentials more negative than −0.5 V because of Se stripping and hydrogen evolution.

Photoelectrochemical deposition of CdZnSe thin films on the Se-modified Au electrode using electrochemical quartz crystal microgravimetry (EQCM) and voltammetry is described. Corrosion of pre-deposited Se electrodes by illumination at a fixed potential resulted in species, which was manifest from the EQCM frequency changes. species generated from the photocorrosion reacted with and ions in the electrolyte to form CdZnSe films on the Au electrode. The effect of electrolyte composition on the composition and band gap of CdZnSe films was studied in detail. Also, photoelectrochemistry, EDX, Raman spectroscopy were used for the characterization of CdZnSe thin films.

Photocathodic stripping of a pre-deposited tellurium film on a gold electrode in 0.1 M Na2SO4 electrolyte containing Cd2+ ions and poly(vinyl pyrrolidone) (PVP) was used as a route to the photoelectrosynthesis of CdTe nanoparticles. Thus illumination of a Te-modified gold surface generated Te2− species, which were removed from the surface into the bulk electrolyte containing Cd2+and PVP by vigorous stirring. The reaction of Te2−and Cd2+ produced PVP-protected nanosized CdTe particles dispersed in solution in the size range 20–40 nm. In this approach, PVP played a critical role as a stabilizer to form discrete CdTe particles instead of larger (agglomerated) ones. Electrochemical quartz crystal microgravimetry was used to monitor stripping of Te films during the light illumination and the synthesized CdTe nanoparticles were characterized by scanning electron microscopy, energy dispersive X-ray analyses and laser Raman spectroscopy.

A combination of photocathodic stripping and precipitation was used to prepare CdTe nanoparticles (size range: 30–60 nm) that were immobilized on a polycrystalline Au substrate. Thus visible light irradiation of a Te modified Au surface generated Te2− species in situ followed by interfacial reaction with added Cd2+ ions in 0.1 M Na2SO4 electrolyte. The resultant CdTe compound semiconductor deposited as nanosized particles uniformly dispersed on the Au substrate surface. This approach to CdTe nanoparticle deposition was monitored by a combination of electrochemical methods (voltammetry, chronoamperometry) and quartz crystal microgravimetry in the “dark” and under illumination. The synthesized CdTe nanoparticles were characterized by scanning electron microscopy and energy dispersive X-ray analyses and laser Raman spectroscopy. Keywords: Photoelectrochemistry, Photoexcitation, Compound semiconductor, Electrochemistry

A novel two-step approach for the cathodic electrodeposition of CdTe films, based on the initial electrochemical modification of polycrystalline gold substrates with elemental tellurium, is described. This Te-modified Au electrode is subjected to electroreduction (to generate Te 2− species) in a separate, Te-free medium containing Cd 2+ species. In situ precipitation results in the formation of a CdTe semiconductor film. For this two-step approach to work, the electroreduction of Cd 2+ species will have to be shifted to more negative potentials past the Te 0 → Te 2− conversion regime. This was accomplished in the present study by complexation of Cd 2+ species with ethylenediaminetetraacetic acid (EDTA). The CdTe films thus obtained were characterized by linear sweep voltammetry, electrochemical quartz crystal microgravimetry, energy-dispersive X-ray analysis, X-ray photoelectron spectroscopy, and photoelectrochemical experiments.

This paper describes a two-step electrosynthesis approach for the preparation of CdS semiconductor layers on polycrystalline Au substrates. The sulfide ion precursor required for in situ CdS precipitation can be electrogenerated (via cathodic stripping) either from a pre-formed sulfur layer or a thiol-based self-assembled monolayer on the Au surface. The morphology of CdS formed in the two cases and the corresponding photoelectrochemical behavior are compared and contrasted.

Luteolin, a flavonoid extracted from a number of plants with recognized anticancer, anti-inflammatory and anti-oxidative activities, inhibits angiogenic processes and modulates multidrug resistance. However, the efficacy and mechanisms of action of this flavonoid agent are still undergoing study. In order to elucidate whether luteolin exhibits an anticancer effect in cervical cancer cells, HeLa cells were incubated with luteolin and apoptosis was assessed by observing nuclear morphological changes, and performing Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. Cell cycle analysis, western blotting, RT-PCR and mitochondrial membrane potential measurements were also carried out. Luteolin showed a significant dose-dependent cytotoxic effect only in human papillomavirus (HPV)-positive cervical cancer cells, when compared to its effect on HPV-negative cervical cancer C33A cells. Expression levels of human papilloma virus E6 and E7 oncogenes were suppressed, those of related factors pRb and p53 were recovered and E2F5 was increased by luteolin treatment. Furthermore, luteolin enhanced the expression of death receptors and death receptor downstream factors such as Fas/FasL, DR5/TRAIL and FADD in HeLa cells, and activated caspase cascades. In particular, luteolin enhanced the activity of caspase-3 and -8 in a dose-dependent manner. Activation of caspase-3 induced caspase-8 activity and vice versa. Luteolin also induced mitochondrial membrane potential collapse and cytochrome c release, and inhibited Bcl-2 and Bcl-xL expression. In conclusion, luteolin exerts anticarcinogenic activity through inhibition of E6 and E7 expression and cross-activation of caspase-3 and -8. Taken together, these results suggest that luteolin induces inactivation of HPV-18 oncogene expression and apoptosis by activating the intrinsic and extrinsic pathways.

Semiconductor nanoparticles (NPs) are of fundamental and practical interest due to unique quantum size effects which result in strongly size dependent electronic, optical and electrochemical properties. Among them, CdSe nanoparticles are of much interest because of applications in solar photovoltaic cells, sensors and optoelectronic devices. CdSe NPs have been extensively studied following the development of chemical preparation procedures using hot trioctylphosphine oxide (TOPO) as a capping agent. Unlike the original method which employed toxic dimethyl cadmium as a cadmium source, other researchers have developed a “green synthesis” route and they synthesized CdSe NPs using CdO as a precursor. While hot TOPO-based approaches require rather severe experimental conditions such as toxic chemicals and high temperatures, electrochemical methods can provide much more “green” environments. Recently, CdTe NPs have been electrochemically synthesized using a Te disc electrode. In this method, a Te disc electrode was cathodically polarized in the electrolyte containing Cd and mercaptoacetic acid (MAA), which served as a stabilizer. We have developed a two-step method for the electrochemical synthesis of semiconductor films or particles. This approach is based on initial electrochemical modification of the substrate with the chalcogen. Subsequent electrochemical reduction of chalcogen in an aqueous electrolyte solution dosed with the desired metal generates compound semiconductor films on the substrate surface or particles in bulk solution with stirring. This approach has been successfully used for the synthesis of semiconductor NPs such as CdTe and films such as FeS2, In2S3, CdS, CdSe, CdTe, and ZnTe. Here we report the first example of electrochemical synthesis of CdSe NPs, in which particle size can be tuned by controlling heating time. In this study a RVC electrode was employed for the first time to synthesize CdSe NPs and this approach can be used for the synthesis of NPs in large quantities. Optical properties of NPs with different heating times were studied by absorption and photoluminescence spectroscopy.

Strict semiconductor cleaning demands for shrinking feature size and increased contamination sensitivity have led to projects that improve performance. The sources of contamination are generally the process chemicals themselves, where wafers are exposed to chemicals for etching or cleaning. Concerns over contamination are compounded in wet benches where chemical baths are re-circulated for periods up to 24 hours. Particle and metal impurities can arise from insufficiently pure chemicals/water, or liquid carry contaminants to the tools through plumbing components such as valves and pumps, and chemical containers/lines. Strict chemical, deionized water (DIW) and material specifications have benefited the industry. Currently, typical purity levels are below detection limits. That being said, point of use filtration offers enhanced reduction of contamination for critical cleans. In this paper we investigate particle adsorption on an immersed wafer surface in dilute HF and rinse applications. Particle addition for various immersion times in the tank can probe the contamination concentration in a solution. In this study, point of use filtration with tighter retention rating and cleaner devices is demonstrated to be critical for small particle control. 300mm wafers were processed by immersing a batch of up to 50 at a time in dilute HF and oxidizing agents for several minutes, rinsing and then drying. Inspection was conducted on a Surfscan SP3 system by KLA-Tencor. As shown below, the surface count of defects increases linearly with immersion time in HF for wafers processed normally. This demonstrates that particle contamination is present in the tank. Due to its acidic and etching nature (impact on particle zeta potential and silica concentration), HF processing is difficult in semiconductor processing. There is a need for enhanced particle retention filters with adequate flow rate to remove undesirable particles. The team evaluated tighter and cleaner Torrento® filters. Torrento® devices are polytetrafluoroethylene membrane filters that deliver contaminant protection performance for critical wet etch and cleaning technology. In a wafer manufacturing facility, recirculation filters were upgraded in a dilute HF tank. Tighter and cleaner Torrento® devices replaced the previous filters. Greater than one month of sampling was conducted, before and after the exchange. SP3 data for 32nm particles show that the average decreases >35%, and the standard deviation is reduced as well. Surface metals by VPD-ICPMS confirm no adverse effects. Separately, deionized water point of use purifier + filters were upgraded. Tighter retention Protego devices replaced the previously used purifiers. Protego® Plus ion-exchange purifier + filters are designed to reduce particles and metallic contamination during rinse. The Protego Plus technology is capable of processing DI water applications up to 80°C. Greater than one month of sampling was conducted, before and after the exchange. SP3 data for 26nm particles demonstrate that the average is reduced by >30%, and the standard deviation is lowered in turn. Surface metals by VPD-ICPMS show improvement (e.g. reduction in Na). Particle performance of acidic baths and DIW rinses has been shown to depend strongly on point of use filtration. Systematic studies of immersion time and large quantities of wafer production data are required to isolate the contribution and measure improvements. Figure 1

not Available.

Background Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. Results We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers, and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals and explore the functional mechanism underlying altered risk at the 12q24 risk region. Conclusions Our results demonstrate the power of combining genetics, computational genomics, and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.

Additional file 1. Supplementary figures.

Additional file 1. Supplementary figures.