Circular RNA ZNF800 (hsa_circ_0082096) regulates cancer stem cell properties and tumor growth in colorectal cancer.

BACKGROUND: Cancer stem cells form a rare cell population in tumors that contributes to metastasis, recurrence and chemoresistance in cancer patients. Circular RNAs (circRNAs) are post-transcriptional regulators of gene expression that sponge targeted microRNA (miRNAs) to affect a multitude of downstream cellular processes. We previously showed in an expression profiling study that circZNF800 (hsa_circ_0082096) was up-regulated in cancer stem cell-enriched spheroids derived from colorectal cancer (CRC) cell lines. METHODS: Spheroids were generated in suspension spheroidal culture. The ZNF800 mRNA, pluripotency stem cell markers and circZNF800 levels were determined by quantitative RT-PCR. CircZNF800-miRNA interactions were shown in RNA pulldown assays and the miRNA levels determined by stem-loop qRT-PCR. The effects of circZNF800 on cell proliferation were tested by EdU staining followed by flowcytometry. Expression of stem cell markers CD44/CD133, Lgr5 and SOX9 was demonstrated in immunofluorescence microscopy. To manipulate the cellular levels of circZNF800, circZNF800 over-expression was achieved via transfection of in vitro synthesized and circularized circZNF800, and knockdown attained using a CRISPR-Cas13d-circZNF800 vector system. Xenografted nude mice were used to demonstrate effects of circZNF800 over-expression and knockdown on tumor growth in vivo. RESULTS: CircZNF800 was shown to be over-expressed in late-stage tumor tissues of CRC patients. Data showed that circZNF800 impeded expression of miR-140-3p, miR-382-5p and miR-579-3p while promoted the mRNA levels of ALK/ACVR1C, FZD3 and WNT5A targeted by the miRNAs, as supported by alignments of seed sequences between the circZNF800-miRNA, and miRNA-mRNA paired interactions. Analysis in CRC cells and biopsied tissues showed that circZNF800 positively regulated the expression of intestinal stem cell, pluripotency and cancer stem cell markers, and promoted CRC cell proliferation, spheroid and colony formation in vitro, all of which are cancer stem cell properties. In xenografted mice, circZNF800 over-expression promoted tumor growth, while circZNF800 knockdown via administration of CRISPR Cas13d-circZNF800 viral particles at the CRC tumor sites impeded tumor growth. CONCLUSIONS: CircZNF800 is an oncogenic factor that regulate cancer stem cell properties to lead colorectal tumorigenesis, and may be used as a predictive marker for tumor progression and the CRISPR Cas13d-circZNF800 knockdown strategy for therapeutic intervention of colorectal cancer.

MicroRNA-362 negatively and positively regulates SMAD4 expression in TGF-ß/SMAD signaling to suppress cell migration and invasion.

Cell migration and invasion are modulated by epithelial-to-mesenchymal transition (EMT) and the reverse MET process. Despite the detection of microRNA-362 (miR-362, both the miR-362-5p and -3p species) in cancers, none of the identified miR-362 targets is a mesenchymal or epithelial factor to link miR-362 with EMT/MET and metastasis. Focusing on the TGF-ß/SMAD signaling pathway in this work, luciferase assays and western blot data showed that miR-362 targeted and negatively regulated expression of SMAD4 and E-cadherin, but not SNAI1, which is regulated by SMAD4. However, miR-362 knockdown also down-regulated SMAD4 and SNAI1, but up-regulated E-cadherin expression. Wound-healing and transwell assays further showed that miR-362 knockdown suppressed cell migration and invasion, effects which were reversed by over-expressing SMAD4 or SNAI1, or by knocking down E-cadherin in the miR-362 knockdown cells. In orthotopic mice, miR-362 knockdown inhibited metastasis, and displayed the same SMAD4 and E-cadherin expression profiles in the tumors as in the in vitro studies. A scheme is proposed to integrate miR-362 negative regulation via SMAD4, and to explain miR-362 positive regulation of SMAD4 via miR-362 targeting of known SMAD4 suppressors, BRK and DACH1, which would have resulted in SMAD4 depletion and annulment of subsequent involvement in TGF-ß signaling actions. Hence, miR-362 both negatively and positively regulates SMAD4 expression in TGF-ß/SMAD signaling pathway to suppress cell motility and invasiveness and metastasis, and may explain the reported clinical association of anti-miR-362 with suppressed metastasis in various cancers. MiR-362 knockdown in miR-362-positive cancer cells may be used as a therapeutic strategy to suppress metastasis.

Mapping a Circular RNA-microRNA-mRNA-Signaling Regulatory Axis That Modulates Stemness Properties of Cancer Stem Cell Populations in Colorectal Cancer Spheroid Cells.

Spheroidal cancer cell cultures have been used to enrich cancer stem cells (CSC), which are thought to contribute to important clinical features of tumors. This study aimed to map the regulatory networks driven by circular RNAs (circRNAs) in CSC-enriched colorectal cancer (CRC) spheroid cells. The spheroid cells established from two CRC cell lines acquired stemness properties in pluripotency gene expression and multi-lineage differentiation capacity. Genome-wide sequencing identified 1503 and 636 circRNAs specific to the CRC parental and spheroid cells, respectively. In the CRC spheroids, algorithmic analyses unveiled a core network of mRNAs involved in modulating stemness-associated signaling pathways, driven by a circRNA-microRNA (miRNA)-mRNA axis. The two major circRNAs, hsa_circ_0066631 and hsa_circ_0082096, in this network were significantly up-regulated in expression levels in the spheroid cells. The two circRNAs were predicted to target and were experimentally shown to down-regulate miR-140-3p, miR-224, miR-382, miR-548c-3p and miR-579, confirming circRNA sponging of the targeted miRNAs. Furthermore, the affected miRNAs were demonstrated to inhibit degradation of six mRNA targets, viz. ACVR1C/ALK7, FZD3, IL6ST/GP130, SKIL/SNON, SMAD2 and WNT5, in the CRC spheroid cells. These mRNAs encode proteins that are reported to variously regulate the GP130/Stat, Activin/Nodal, TGF-ß/SMAD or Wnt/ß-catenin signaling pathways in controlling various aspects of CSC stemness. Using the CRC spheroid cell model, the novel circRNA-miRNA-mRNA axis mapped in this work forms the foundation for the elucidation of the molecular mechanisms of the complex cellular and biochemical processes that determine CSC stemness properties of cancer cells, and possibly for designing therapeutic strategies for CRC treatment by targeting CSC.

COVID-19 Vaccine Booster Hesitancy among the Elderly in Malaysian Residential Care Homes: A Cross-Sectional Study in Klang Valley.

The elderly are considered a high-risk group for severe outcomes and death from COVID-19 infection. Given the emergence of new COVID variants and the immunity provided by vaccines waning over time, booster doses of the vaccine have been advocated for those at risk to stay protected. This study aimed to determine the factors associated with hesitancy toward the second booster of the COVID-19 vaccine among the elderly residing in residential care homes. A cross-sectional study was conducted in 24 residential care homes in the Klang Valley using a face-to-face interview questionnaire. The study population included individuals aged 60 and above who had been fully vaccinated against COVID-19 up to the first booster dose. Second-booster hesitancy was assessed using the Oxford Vaccine Hesitancy Scale with seven items, the aggregate score of which ranges from seven to thirty-five; the higher the score, the greater the level of hesitancy. Multivariate linear regression was employed to determine factors associated with second-booster hesitancy, and a p-value < 0.05 was considered statistically significant. Data from 401 elderly individuals were included for analysis. The mean score of the Oxford Vaccine Hesitancy Scale was 21.6 ± 7.2. Predictors of second booster hesitancy were identified. Age, Indian ethnicity, being a recipient of the Sinovac vaccine as the first COVID-19 booster, experiencing the death of close friends or immediate family members following COVID-19 vaccination, and negative messages (indicating that taking a booster dose is harmful) from caregivers, friends, or family members were found to be associated with an increased second-booster-hesitancy score. Conversely, positive messages (indicating that taking a booster is helpful) from the government and caregivers, friends, or family members were identified as predictors associated with a reduction in the second-booster-hesitancy score. While vaccines effectively combat severe COVID-19, the majority of the elderly hesitate before taking the second booster. Their hesitancy, rooted in the perception of a low self risk and reliance on protection from the initial doses, emphasizes the need for intervention by relevant bodies. Taking into consideration the risk, albeit relatively low, of potentially serious side effects following COVID-19 vaccinations, it is imperative that transparent, appropriate, and positive messaging regarding booster vaccines, particularly in the context of the elderly from residential care homes, be available. Encouraging this high-risk group to embrace the second booster aligns with the goal of maximizing protection within the vulnerable elderly population.

Systemically delivered measles virus-infected mesenchymal stem cells can evade host immunity to inhibit liver cancer growth.

BACKGROUND & AIMS: Although attenuated measles virus (MV) has demonstrated potent oncolytic activities towards human cancers, it has not yet been widely adopted into clinical practice. One of the major hurdles is the presence of pre-existing anti-MV immunity in the recipients. In this study, we have evaluated the combination of the potent oncolytic activity of the attenuated MV with the unique immunoprivileged and tumor-tropic biological properties of human bone marrow-derived mesenchymal stem cells (BM-hMSCs) to combat human hepatocellular carcinoma (HCC), orthotopically implanted in SCID mice, passively immunized with human neutralizing antibodies against MV as a preclinical model. METHODS: SCID mice were orthotopically implanted with patient-derived HCC tissues and established HCC cell lines. SCID mice were passively immunized with human neutralizing anti-measles antibodies. Bioluminescence and fluorescence imaging were employed to monitor the ability of systemically delivered MV-infected BM-hMSCs to infiltrate the implanted tumors and their effects on tumor growth. RESULTS: Systemically delivered MV-infected BM-hMSCs homed to the HCC tumors implanted orthotopically in the liver and it was evidenced that BM-hMSCs could transfer MV infectivity to HCC via heterofusion. Furthermore, therapy with MV-infected BM-hMSCs resulted in significant inhibition of tumor growth in both measles antibody-naïve and passively-immunized SCID mice. By contrast, when cell-free MV viruses were delivered systemically, antitumor activity was evident only in measles antibody-naïve SCID mice. CONCLUSIONS: MV-infected BM-hMSCs cell delivery system provides a feasible strategy to elude the presence of immunity against MV in most of the potential cancer patients to be treated with the oncolytic MV viruses.

COVID-19 Vaccine Booster Hesitancy in Malaysia: A Web-Based Cross-Sectional Study.

Vaccination is a key public health strategy that is known to be effective in mitigating the risk of infection and severe disease. However, in the context of the COVID-19 pandemic, the percentage (<50%) of Malaysians who have received a booster for the COVID-19 vaccine has remained stagnant over a year. This study aimed to determine the prevalence of and the factors associated with hesitancy toward the second dose of booster for the COVID-19 vaccine. A web-based cross-sectional study was conducted from August to November 2022. The Oxford Vaccine Hesitancy Scale was used to assess the hesitancy toward the second dose of booster for the COVID-19 vaccine. Simple and multiple factors logistic regressions were used to determine the predictors of hesitancy. A p-value less than 0.05 was considered to be statistically significant. Data from 798 respondents were included in the analysis. The prevalence of hesitancy toward the second booster of the COVID-19 vaccine was 26.7%. The predictors of second-booster hesitancy were older age (AOR = 1.040, 95 CI = 1.022, 1.058), having received the third dose (first booster) because of instruction by the government (AOR = 2.125, 95% CI = 1.380, 3.274), concern about serious long term side effects of the vaccine (AOR = 4.010, 95% CI = 2.218, 7.250), and opinions of close friends and immediate family members that the booster is harmful (AOR = 2.201, 95% CI = 1.280, 3.785). Conversely, factors that appear to reduce vaccine booster hesitancy were acceptance of the third dose due to the high number of cases and the increasing rate of infection (AOR = 0.548, 95% CI = 0.317, 0.947), the belief that the vaccine will decrease the risk of getting the infection (AOR = 0.491, 95% CI = 0.277, 0.870), and opinions of close friends and immediate family members that the booster is helpful (AOR = 0.479, 95% CI = 0.273, 0.840). In conclusion, more than one-fifth of Malaysians were hesitant to take the second booster of the COVID-19 vaccine. This suggests that appropriate steps that increase vaccine acceptance, taking into consideration the findings of the present study, are needed to address this issue and to foster more positive attitudes toward vaccination. The survey was available in three main languages but limited to people with internet access; hence, it would likely be biased toward younger adults and social media users and exclude those with limited or no internet access, in particular older people. Therefore, the results are not representative of the Malaysian population at large and caution should be exercised when interpreting the findings.

Factorial structure, reliability, and construct validity of the Generalized Anxiety Disorder 7-item (GAD-7): Evidence from Malaysia.

Generalized anxiety disorder (GAD) is one of the most common mental disorders in Malaysia. Psychometrically sound measurements are urgently needed to assess anxiety symptoms. The extensively used Generalized Anxiety Disorder 7-item (GAD-7) is a promising candidate. However, studies on its factorial validity show mixed findings. While the one-factor solution has been replicated in different cultural contexts, some studies found different factorial structures instead. This study aimed to clarify the factorial validity of the English version of the GAD-7 in the Malaysian context. The responses collected from 1272 emerging to older adults in Malaysia were randomly divided into two halves and submitted to exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) respectively. Four acceptable models were explored in EFA ranging from unidimensional factor with 7 items to 3-factor models with 6 items. The four models revealed in EFA and the other competing models found in past studies were then examined and compared using CFA. The 6-item second-order model with a general factor of anxiety and three first-order factors with two items respectively (i.e., GAD-6) showed a more harmonic result and hence, is preferable. Moreover, the GAD-6 and its three subscales also showed satisfactory internal consistency and construct validity. This study uncovers a new and unique factorial structure of the GAD screening tool that fits in the Malaysian context. The scale may reveal GAD symptomatic dimensions that guide clinical interventions.

Anxiety and coping strategies during the COVID-19 pandemic: A cross-sectional study of staff and students from a tertiary education center in Malaysia.

Aim: We examined the anxiety levels and coping strategies among staff and students of a tertiary educational institution during the COVID-19 pandemic and determined the association between anxiety level and coping strategies. Method: Through an online survey, we used Coronavirus Anxiety Scale (CAS) to measure the level of anxiety associated with the COVID-19 crisis and Brief Coping Orientation to Problems Experienced (COPE) to assess the coping responses adopted to handle stressful life events. Coping strategies were classified as adaptive and maladaptive, for which the aggregate sores were calculated. Multiple linear regression was used to determine the predictors of anxiety adjusted for potentially confounding variables. Results from 434 participants were available for analysis. Results: The mean score (SD) of the CAS was 1.1 (1.8). The mean scores of adaptive and maladaptive coping strategies were 35.69 and 19.28, respectively. Multiple linear regression revealed that maladaptive coping [Adjusted B coefficient = 4.106, p-value < 0.001] and presence of comorbidities [Adjusted B coefficient = 1.376, p-value = 0.025] significantly predicted anxiety. Conclusion: Maladaptive coping and presence of comorbidities were the predictors of coronavirus anxiety. The apparent lack of anxiety in relation to COVID-19 and movement restriction is reflective of the reported high level of satisfaction with the support and services provided during the COVID-19 outbreak in Malaysia. Adaptive coping strategies were adopted more frequently than maladaptive. Nevertheless, public education on positive coping strategies and anxiety management may be still be relevant to provide mental health support to address the needs of the general population.

Knowledge, Perceptions and Behaviors Related to COVID-19 in a University Setting in Malaysia.

Background: In Malaysia the COVID-19 disease (COVID-19) has continued to escalate since its first detection in late January 2020, despite widespread implementation of control measures. This study aims to determine the knowledge, perception and behaviors with respect to COVID-19 in the midst of the third wave of the infection. Methods: A cross-sectional study was carried out among staffs and students of Universiti Tunku Abdul Rahman (UTAR). The survey consists of basic sociodemographic information, 22 items on knowledge on COVID-19, 3 items on perceived self-risk, 2 items on preparedness & perceived self-efficacy, 10 items on preventive (own) measures, 9 items assessing unwanted and desirable behaviors during the pandemic. Simple and multiple linear regression were performed to determine the factors associated with knowledge, preventive measures adopted, self-risk perception, preparedness & perceived self-efficacy, and behaviors. Results: A total of 434 responded to the survey of whom the majority (85.1%) had high scores for knowledge (mean score of 18.72 out of 22). A significant positive association was found between knowledge and older age (adjusted B coefficient (SE) = 0.046 (0.022), p = 0.039), those from medical faculty (adjusted B coefficient (SE) = 0.870 (0.420), p = 0.039) and residence in high-risk areas (adjusted B coefficient (SE) = 0.831 (0.295), p = 0.005). Predictors for higher perception of COVID-19 risk included presence of COVID-19 cases among social contacts (adjusted B coefficient (SE) = 0.751 (0.308), p = 0.015) and living with elderly (adjusted B coefficient (SE) = 1.137 (0.296), p < 0.001), while that for perception of preparedness and self-efficacy were living with children (adjusted Beta coefficient (SE) = 0.440 (0.173), p = 0.011) and absence of positive cases among social contacts (adjusted B coefficient (SE) = 0.418 (0.183), p = 0.023). Good preventive measures among the respondents were positively associated with knowledge (adjusted B coefficient (SE) = 0.116 (0.025), p < 0.001), as well as with female gender (adjusted B coefficient (SE) = 0.348 (0.142), p = 0.014). Unwanted behavior was significantly associated with male gender (adjusted B coefficient (SE) = 0.664 (0.321), p = 0.039) and COVID-19 positive status (adjusted B coefficient (SE) = 9.736 (3.297), p = 0.003). Knowledge of COVID-19 (adjusted B coefficient (SE) = 0.069 (0.035), p = 0.048) and being married (adjusted B coefficient (SE) = 0.917 (0.462), p = 0.048) were the predictors of desirable behavior. Conclusion: Overall, the UTAR community had demonstrated a good level of knowledge and preventive behaviors, albeit with some areas for improvement.

Intravascularly administered RGD-displaying measles viruses bind to and infect neovessel endothelial cells in vivo.

Systemically administered vectors must cross the endothelial lining of tumor blood vessels to access cancer cells. Vectors that interact with markers on the lumenal surface of these endothelial cells might have enhanced tumor localization. Here, we generated oncolytic measles viruses (MVs) displaying alpha(v)beta(3) integrin-binding peptides, cyclic arginine-glycine-aspartate (RGD) or echistatin, on the measles hemagglutinin protein. Both viruses had expanded tropisms, and efficiently entered target cells via binding to integrins, but also retained their native tropisms for CD46 and signaling lymphocyte activation molecule (SLAM). When fluorescently labeled and injected intravascularly into chick chorioallantoic membranes (CAMs), in contrast to unmodified viruses, the integrin-binding viral particles bound to the lumenal surface of the developing chick neovessels and infected the CAM vascular endothelial cells. In a mouse model of VEGF-induced angiogenesis in the ear pinna, the integrin-binding viruses, but not the parental virus, infected cells at sites of new blood vessel formation. When given intravenously to mice bearing tumor xenografts, the integrin-binding virus infected endothelial cells of tumor neovessels in addition to tumor parenchyma. To our knowledge, this is the first report demonstrating that oncolytic MVs can be engineered to target the lumenal endothelial surface of newly formed blood vessels when administered intravenously in living animals.

Oncolytic measles virus targets high CD46 expression on multiple myeloma cells.

OBJECTIVE: Multiple myeloma (MM) is an incurable B cell malignancy and novel therapeutics are urgently needed. Live attenuated measles virus (MV) has potent oncolytic activity against MM tumor xenografts. The virus is tumor selective and preferentially targets cells that express high levels of CD46 receptors. However, CD46 levels on MM have not previously been evaluated. In this study, we investigated the potential of CD46 as a target for MM therapy and correlated surface levels of CD46 on MM cells with their susceptibility to MV-induced cytopathic effects. MATERIALS AND METHODS: CD46 expression on neoplastic plasma cells (PCs) and nonplasma cells (NPCs) from 38 MM patients was analyzed by flow cytometry and receptor numbers were quantitated using BD QuantiBRITE PE beads. RESULTS: Results showed that malignant PCs expressed significantly higher levels of CD46 receptors compared to NPCs (p < 0.0001). The mean CD46 receptor numbers on PCs and NPCs were 49,130/cell and 7,340/cell, respectively. Potent cytopathic effects of extensive intercellular fusion were observed in measles-infected PCs but not in NPCs. The extent of MV-induced cytopathic effects of cell fusion correlated with CD46 expression levels on the MM cells. Normal plasma cells do not overexpress CD46 and colony-forming assays demonstrated that MV was not cytotoxic to normal bone marrow progenitor cells. CONCLUSION: The present study establishes CD46 as a surface antigen that is expressed more abundantly on primary MM cells compared to normal hematopoietic cells of various lineages in the bone marrow, making CD46 a promising surface marker for targeted cytoreductive therapy of MM.

Genotyping of hepatitis B virus in Malaysia based on the nucleotide sequence of preS and S genes.

Hepatitis B virus (HBV) has been classified into eight genotypes, designated A-H. These genotypes are known to have distinct geographic distributions. The clinical importance of genotype-related differences in the pathogenicity of HBV has been revealed recently. In Malaysia, the current distribution of HBV remains unclear. The aim of this study was to determine the genotypes and subtypes of HBV by using PCR, followed by DNA sequencing, as well as to analyse the mutations in the immunodominant region of preS and S proteins. The S gene sequence was determined from HBV DNA of four apparently healthy blood donors' sera and three sera from asymptomatic chronic hepatitis B carriers. Of this batch of sera, the preS gene sequence was obtained from HBV DNA from three out of the four blood donors and two out of the three chronic carriers. Due to insufficient sera, we had to resort to using sera from another blood donor to make up for the sixth DNA sequence of the preS gene. Based on the comparative analysis of the preS sequences with the reported sequences in the GenBank database, HBV DNA from two normal carriers was classified as genotype C. Genotype B was assigned to HBV from one blood donor and two hepatitis B chronic carriers, whereas HBV of one chronic carrier was of genotype D. Based on the S gene sequences, HBV from three blood donors was of genotype C, that of one blood donor and one chronic carrier was of genotype B, and the remaining, of genotype D. In the five cases where both preS and S gene sequences were determined, the genotypes assigned based on either the preS or S gene sequences were in concordance. The nature of the deduced amino acid (aa) sequences at positions 125, 127, 134, 143, 159, 161 and 168 of the S gene enabled the classification of these sequences into subtypes, namely, adrq+, adw2 and ayw2. The clustering of our DNA sequences into genotype groups corresponded to their respective subtype, that is, adw2 in genotype B, adrq in genotype C and ayw in genotype D. Analysis of the point mutations revealed that five of the sequences contained aa substitutions at immunodominant epitopes involved in B or/and T cell recognition. In conclusion, despite the low numbers of samples studied, due to budget constraints, these data are still worthwhile reporting, as it is important for the control of HBV infections. In addition, the genotype and mutational data obtained in this study may be useful for designing new treatment regimes for HBV patients.

Benzylidene-indolinones are effective as multi-targeted kinase inhibitor therapeutics against hepatocellular carcinoma.

Effective pharmacological intervention of advanced hepatocellular carcinoma (HCC) is currently lacking. Despite the use of tyrosine kinase inhibitors (TKIs) for the targeted therapy of several malignancies, no agent has been developed to specifically interfere with the oncogenic tyrosine kinase signaling aberrations found in HCC. Therefore, we adopted an orthogonal biological phenotypic screening approach to uncover candidate compounds: based on a potent cytotoxicity toward HCC-derived cell lines, and minimal toxicity toward normal liver cells. Given the success of indolinone as a chemical scaffold in deriving potent multi-kinase inhibitors (e.g. sunitinib), we screened a group of newly synthesized benzylidene-indolinones. Among the candidates, E/Z 6-Chloro-3-(3-trifluoromethyl-benzyliden)-1,3-dihydroindol-2-one (compound 47) exhibited potent anti-proliferative, anti-migratory, pro-apoptotic properties and good safety profile as compared to known multi-targeted tyrosine kinase inhibitors sunitinib and sorafenib. Additionally, an accompanying suppression of alpha-fetoprotein (AFP) transcription, an HCC tumor marker, implies a favorable selectivity and efficacy on HCC. The in vivo efficacy was demonstrated in an HCC xenograft where 47 was administered once weekly (60 mg/kg) and suppressed tumor burden to the same extent as sorafenib (30 mg/kg daily). A receptor tyrosine kinase (RTK) array study revealed promising inhibition of multiple tyrosine kinases such as IGF-1R, Tyro3 and EphA2 phosphorylation. Gene silencing of these targets ameliorated the cytotoxic potential of 47 on the HuH7 cell line, thereby implicating their contribution to the tumorigenicity of HCC. Hence, 47 exhibits potent anti-cancer effects on HCC cell lines, and is a suitable lead for developing multi-targeted kinase inhibitors of relevance to HCC.

DEAD-box helicase DP103 defines metastatic potential of human breast cancers.

Despite advancement in breast cancer treatment, 30% of patients with early breast cancers experience relapse with distant metastasis. It is a challenge to identify patients at risk for relapse; therefore, the identification of markers and therapeutic targets for metastatic breast cancers is imperative. Here, we identified DP103 as a biomarker and metastasis-driving oncogene in human breast cancers and determined that DP103 elevates matrix metallopeptidase 9 (MMP9) levels, which are associated with metastasis and invasion through activation of NF-κB. In turn, NF-κB signaling positively activated DP103 expression. Furthermore, DP103 enhanced TGF-ß-activated kinase-1 (TAK1) phosphorylation of NF-κB-activating IκB kinase 2 (IKK2), leading to increased NF-κB activity. Reduction of DP103 expression in invasive breast cancer cells reduced phosphorylation of IKK2, abrogated NF-κB-mediated MMP9 expression, and impeded metastasis in a murine xenograft model. In breast cancer patient tissues, elevated levels of DP103 correlated with enhanced MMP9, reduced overall survival, and reduced survival after relapse. Together, these data indicate that a positive DP103/NF-κB feedback loop promotes constitutive NF-κB activation in invasive breast cancers and activation of this pathway is linked to cancer progression and the acquisition of chemotherapy resistance. Furthermore, our results suggest that DP103 has potential as a therapeutic target for breast cancer treatment.

Controlled size and morphology of EDTMP-doped hydroxyapatite nanoparticles as model for 153Samarium-EDTMP doping.

Hydroxyapatite (HA) nanoparticles have been studied as nano-sized carriers for the delivery of therapeutic agents. One important consideration for these carriers to be used effectively is their bio-distribution in vivo, of which particle size has a significant effect. In this work, HA nanoparticles doped with Ethylene-diamine-tetramethylene-phosphonate (EDTMP) were synthesized via co-precipitation as a model for HA doped with (153)Samarium ((153)Sm) EDTMP. EDTMP has high affinity for radioactive (153)Sm isotopes that can emit both gamma and beta radiation. The effects of synthesis temperature, amount of dopant and hydrothermal treatment on the size of HA-EDTMP nanoparticles were therefore studied. The results showed that the EDTMP ligand was successfully incorporated in the nanoparticles without changing the crystal structure as shown from X-ray diffractometer (XRD) analysis. From the Field Emission Scanning Electron Microscopy (FESEM) and Transmission Electron Microscopy (TEM) micrographs, it was observed that shorter rod-like nanoparticles, obtained at low synthesis temperatures, became elongated needle-like nanoparticles with increasing temperature. Increasing dopant amount by five fold increases particle size slightly, while a two fold increase in dopant amount has no significant effect. Hydrothermal treatment increases particle crystallinity and results in smooth elongated rod-like structures. The size of HA nanoparticles doped with EDTMP can therefore be manipulated by controlling synthesis temperature and through hydrothermal treatment.