Human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine: Immunogenicity and safety in healthy Chinese women from Hong Kong

Objective To assess the immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine in Chinese women aged 18 to 35 years enrolled from Hong Kong. Design Double-blind, randomised controlled trial with vaccine and placebo groups. Setting Single-centre study in Hong Kong. Participants Three hundred women enrolled (150 per group) between March 2006 and June 2007. Interventions Subjects received three doses of human papillomavirus-16/18 vaccine or placebo (aluminium hydroxide), administered intramuscularly at 0, 1, and 6 months. Main outcome measures Human papillomavirus-16/18 seroconversion rates and geometric mean titres at month 7 (in human papillomavirus-16/18 recipients); reactogenicity and safety (in all subjects). Results A total of 294 women completed the study (148 in the vaccine group, 146 in placebo group). All initially seronegative subjects in the vaccine group had seroconverted for human papillomavirus-16/18 antibodies by month 7. Anti-human papillomavirus-16 and anti-human papillomavirus-18 antibody geometric mean titres were 10 422 (95% confidence interval, 8730-12 442) EL.U/mL and 4649 (3975-5437) EL.U/mL, respectively. High compliance (99% in both groups) was observed for the three-vaccination course. The frequencies of local injection site reactions were higher in the vaccine than placebo group; pain being the most common symptom in both groups. Regarding solicited symptoms, fatigue and myalgia were the most frequent in both groups. Five serious adverse events (four in vaccine group, one in placebo group) were reported, but all were considered unrelated to the vaccinations. Conclusion The human papillomavirus-16/18 AS04-adjuvanted vaccine was highly immunogenic, safe, and generally well tolerated in Chinese women from Hong Kong.published_or_final_versio

DLX1 acts as a crucial target of FOXM1 to promote ovarian cancer aggressiveness by enhancing TGF-β/SMAD4 signaling

Recent evidence from a comprehensive genome analysis and functional studies have revealed that FOXM1 is a crucial metastatic regulator that drives cancer progression. However, the regulatory mechanism by which FOXM1 exerts its metastatic functions in cancer cells remains obscure. Here, we report that DLX1 acts as a FOXM1 downstream target, exerting pro-metastatic function in ovarian cancers. Both FOXM1 isoforms (FOXM1B or FOXM1C) could transcriptionally upregulate DLX1 through two conserved binding sites, located at +61 to +69bp downstream (TFBS1) and -675 to -667bp upstream (TFBS2) of the DLX1 promoter, respectively. This regulation was further accentuated by the significant correlation between the nuclear expression of FOXM1 and DLX1 in high-grade serous ovarian cancers. Functionally, the ectopic expression of DLX1 promoted ovarian cancer cell growth, cell migration/invasion and intraperitoneal dissemination of ovarian cancer in mice, whereas small interfering RNA-mediated DLX1 knockdown in FOXM1-overexpressing ovarian cancer cells abrogated these oncogenic capacities. In contrast, depletion of FOXM1 by shRNAi only partially attenuated tumor growth and exerted almost no effect on cell migration/invasion and the intraperitoneal dissemination of DLX1-overexpressing ovarian cancer cells. Furthermore, the mechanistic studies showed that DLX1 positively modulates TGF- signaling by upregulating PAI-1 and JUNB through direct interaction with SMAD4 in the nucleus upon TGF-1 induction. Taken together, these data strongly suggest that DLX1 plays a pivotal role in FOXM1 signaling to promote cancer aggressiveness through intensifying TGF-/SMAD4 signaling in high-grade serous ovarian cancer cells.published_or_final_versio

GRO-α and IL-8 enhance ovarian cancer metastatic potential via the CXCR2-mediated TAK1/NFκB signaling cascade

Intraperitoneal metastasis is a common occurrence and is usually involved in the poor prognosis of ovarian cancer. Its specific metastatic pattern implies that certain indispensable microenvironmental factors secreted in the peritoneal cavity can direct metastatic ovarian cancer cells to permissive niches for secondary lesion formation. However, the underlying molecular mechanisms are ill defined. Herein, we report that GRO-α and IL-8 are predominately upregulated in culture media derived from either normal or cancerous omenta and are associated with increased ovarian cancer aggressiveness. Methods: OCM was established from culture medium of fresh human omental tissues. Primary and metastatic ovarian cancer cell lines were generated from human tumor tissues and verified by specific antibodies. The functional roles of GRO-α, IL-8, and their specific receptor CXCR2 were examined by neutralizing antibodies, shRNA gene knockdown, CRISPR/Cas9 gene knockout and pharmaceutical CXCR2 inhibitor SB225002. The oncogenic properties of ovarian cancer cells were examined by in vitro and in vivo mouse models. Results: Both GRO-α and IL-8 can activate TAK1/NFκB signaling via the CXCR2 receptor. Intriguingly, TAK1/NFκB signaling activity was higher in metastatic ovarian cancer cells; this higher activity makes them more susceptible to OCM-induced tumor aggressiveness. Treatment of ovarian cancer cells with GRO-α and IL-8 neutralizing antibodies or ablation of CXCR2 by shRNA gene knockdown, CRISPR/Cas9 gene knockout, or CXCR2 inhibitor SB225002 treatment significantly attenuated TAK1/NFκB signaling and decreased in vitro and in vivo oncogenic and metastatic potential, suggesting CXCR2 plays a key role in the GRO-α and IL-8-governed metastatic spreading of ovarian cancer cells in the intraperitoneal cavity. Conclusion: This study highlights the significance of GRO-α and IL-8 as the key chemokines in the peritoneal tumor microenvironment and suggests the utility of targeting their receptor CXCR2 as a potential target-based therapy for peritoneal metastases of ovarian cancer.published_or_final_versio

Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways

Human growth factor receptor-bound protein-7 (GRB7) is a pivotal mediator involved in receptor tyrosine kinase signaling and governing diverse cellular processes. Aberrant upregulation of GRB7 is frequently associated with the progression of human cancers. However, the molecular mechanisms leading to the upregulation of GRB7 remain largely unknown. Here, we propose that the epigenetic modification of GRB7 at the post-transcriptional level may be a crucial factor leading to GRB7 upregulation in ovarian cancers. Methods: The upstream miRNA regulators were predicted by in silico analysis. Expression of GRB7 was examined by qPCR, immunoblotting and immunohistochemical analyses, while miR-193a-3p levels were evaluated by qPCR and in situ hybridization in ovarian cancer cell lines and clinical tissue arrays. MS-PCR and pyrosequencing analyses were used to assess the methylation status of miR-193a-3p. Stable overexpression or gene knockdown and Tet-on inducible approaches, in combination with in vitro and in vivo tumorigenic assays, were employed to investigate the functions of GRB7 and miR-193a-3p in ovarian cancer cells. Results: Both miR-193a-3p and its isoform, miR-193b-3p, directly targeted the 3' UTR of GRB7. However, only miR-193a-3p showed a significantly inverse correlation with GRB7-upregulated ovarian cancers. Epigenetic studies revealed that methylation-mediated silencing of miR-193a-3p led to a stepwise decrease in miR-193a-3p expression from low to high-grade ovarian cancers. Intriguingly, miR-193a-3p not only modulated GRB7 but also ERBB4, SOS2 and KRAS in the MAPK/ERK signaling pathway to enhance the oncogenic properties of ovarian cancer cells in vitro and in vivo. Conclusion: These findings suggest that epigenetic silencing of miR-193a-3p by DNA hypermethylation is a dynamic process in ovarian cancer progression, and miR-193a-3p may be explored as a promising miRNA replacement therapy in this disease.published_or_final_versio

Exploring the usability of a connected autonomous vehicle human machine interface designed for older adults

Users of Level 4–5 connected autonomous vehicles (CAVs) should not need to intervene with the dynamic driving task or monitor the driving environment, as the system will handle all driving functions. CAV human-machine interface (HMI) dashboards for such CAVs should therefore offer features to support user situation awareness (SA) and provide additional functionality that would not be practical within non-autonomous vehicles. Though, the exact features and functions, as well as their usability, might differ depending on factors such as user needs and context of use. The current paper presents findings from a simulator trial conducted to test the usability of a prototype CAV HMI designed for older adults and/or individuals with sensory and/or physical impairments: populations that will benefit enormously from the mobility afforded by CAVs. The HMI was developed to suit needs and requirements of this demographic based upon an extensive review of HMI and HCI principles focused on accessibility, usability and functionality [1, 2], as well as studies with target users. Thirty-one 50-88-year-olds (M 67.52, three 50–59) participated in the study. They experienced four seven-minute simulated journeys, involving inner and outer urban settings with mixed speed-limits and were encouraged to explore the HMI during journeys and interact with features, including a real-time map display, vehicle status, emergency stop, and arrival time. Measures were taken pre-, during- and post- journeys. Key was the System Usability Scale [3] and measures of SA, task load, and trust in computers and automation. As predicted, SA decreased with journey experience and although cognitive load did not, there were consistent negative correlations. System usability was also related to trust in technology but not trust in automation or attitudes towards computers. Overall, the findings are important for those designing, developing and testing CAV HMIs for older adults and individuals with sensory and/or physical impairments

Cancer Genomics Identifies Regulatory Gene Networks Associated with the Transition from Dysplasia to Advanced Lung Adenocarcinomas Induced by c-Raf-1

Background: Lung cancer is a leading cause of cancer morbidity. To improve an understanding of molecular causes of disease a transgenic mouse model was investigated where targeted expression of the serine threonine kinase c-Raf to respiratory epithelium induced initialy dysplasia and subsequently adenocarcinomas. This enables dissection of genetic events associated with precancerous and cancerous lesions. Methodology/Principal Findings: By laser microdissection cancer cell populations were harvested and subjected to whole genome expression analyses. Overall 473 and 541 genes were significantly regulated, when cancer versus transgenic and non-transgenic cells were compared, giving rise to three distinct and one common regulatory gene network. At advanced stages of tumor growth predominately repression of gene expression was observed, but genes previously shown to be upregulated in dysplasia were also up-regulated in solid tumors. Regulation of developmental programs as well as epithelial mesenchymal and mesenchymal endothelial transition was a hall mark of adenocarcinomas. Additionaly, genes coding for cell adhesion, i.e. the integrins and the tight and gap junction proteins were repressed, whereas ligands for receptor tyrosine kinase such as epi- and amphiregulin were up-regulated. Notably, Vegfr- 2 and its ligand Vegfd, as well as Notch and Wnt signalling cascades were regulated as were glycosylases that influence cellular recognition. Other regulated signalling molecules included guanine exchange factors that play a role in an activation of the MAP kinases while several tumor suppressors i.e. Mcc, Hey1, Fat3, Armcx1 and Reck were significantly repressed. Finally, probable molecular switches forcing dysplastic cells into malignantly transformed cells could be identified. Conclusions/Significance: This study provides insight into molecular pertubations allowing dysplasia to progress further to adenocarcinoma induced by exaggerted c-Raf kinase activity

Technical aspects of checking the driver's working time

W artykule omówiono normy prawne regulujące czas pracy kierowców samochodów o nośności powyżej 3,5 tony oraz urządzenia stosowane do rejestracji czasu ich pracy. Okazuje się, że w praktyce regulacje te stwarzają dla kierowców wiele problemów. Powoduje to, że czasami podejmowane są próby omijania tych przepisów. W pracy przedstawiono przykłady działań związanych z tym procesem. Dotyczą one głównie ingerencji w pracę urządzeń rejestrujących parametry jazdy samochodem. Przykłady te dotyczą typowych działań podejmowanych w stosunku do tachometrów samochodowych. Należy podkreślić, że są one niezgodne z przepisami i podlegają stosownym karom. Nie mniej w praktyce zdarzają się dość często. Głównym celem pracy było przybliżenie zasad i unormowań obowiązujących w transporcie samochodowym oraz problemów technicznych związanych z ich stosowaniem.In the article, there are presented the discussion of the legal standards governing the working time for car drivers with a capacity of over 3.5 tones and the equipment used to record of their work time. In practice, these regulations pose many problems for drivers. This makes that sometimes attempts are made to avoid these rules. The paper presents examples of activities related to this process. These actions mainly concern the interference in the operation of recording equipment the limits of driving the car. These examples illustrate the typical activities undertaken with respect to car tachometers. It is important to point out that they are illegal and subject to appropriate penalties. It is important, that they are illegal and subject to appropriate penalties. Nevertheless, in practice there often occur. The aim of the article was to approximate the rules and regulations governing of car transport and the technical problems related to their use

Role of Has-miR-141 as a therapeutic target and predictive biomarker for ovarian cancer

Poster PresentationConference Theme: Precision Cancer Biology and MedicineAlthough recent advances have improved the treatment of ovarian cancer, this disease is still the most deadly of female malignancies worldwide. The poor prognosis and late diagnosis of ovarian cancer are the primary causes of its high mortality rate. Therefore, understanding the molecular mechanisms of this disease may assist in the development of “targeted” oncologic therapies and the identification of reliable biomarkers to improve the curative rate of this disease. Anoikis resistance is a fundamental feature of metastatic cancer cells, allowing for their survival during cancer invasion and dissemination. Emerging evidence indicates that deregulation of miRNAs has been associated with different aspects of tumorigenesis. Using miRCURY™ LNA Array profiling analysis, we identified the Has-miR-141 (miR-141) as a highly expressed miRNA in ovarian cancer cells with increased capacities in anchorage-independence, anoikis resistance, tumor growth and metastatic colonization in a xenograft mouse model. Further studies demonstrated that a tumor suppressor, Krüppel-related zinc finger protein AP-2rep (KLF12), is a direct target of miR-141. In contrast to miR-141, KLF12 inhibits colony formation and the cell growth potential of ovarian cancer cells exposed to metabolic stress, whereas the depletion of KLF12 augments the anchorage independence of ovarian cancer cells through the upregulation of survival-associated factors. Clinical study revealed the upregulated miR-141 was significantly associated with the advanced and distant metastatic ovarian cancers accompanied with downregulated KLF12. On the other hand, miR-141 was found to be a secretary miRNA and detected in the serum of ovarian cancer patients. Subsequent analysis showed that the circulating miR-141 was correlated to the levels of CA125. Importantly, the serum miR-141 level was significantly correlated with the tumor burden of patients in pre- and post-neoadjuvant chemotherapy. Taken together, miR-141 may play a role in oncogene-enhancing anoikis resistance in ovarian cancer cells through the downregulation of KLF12 and may be used as a non-invasive biomarker for diagnosis and treatment outcome of ovarian cancer