Exploring a therapeutic role for IGF1R inhibitors in triple-negative breast cancer

EXPLORING A THERAPEUTIC ROLE FOR IGF1R INHIBITORS IN TRIPLE-NEGATIVE BREAST CANCER Onyinye Offor, Catherine Sullivan, Sofya Rodov, Kimberly Lezon-Geyda, Lyndsay Harris. Section of Medical Oncology, Department of Internal Medicine, Yale University, School of Medicine, New Haven, CT There is substantial preclinical and clinical data suggesting that triple-negative breast cancer (TNBC), a breast cancer subtype that lacks HER-2, estrogen- and progesterone-receptor expression is associated with obesity, insulin resistance and metabolic derangements involving the insulin-like growth factor (IGF) pathway. We hypothesized that IGF-1 receptor (IGF1R) targeted therapy will be active in TNBC and will enhance the activity of chemotherapeutic agents used for breast cancer. We aimed (1) to determine if AG1024, an experimental tyrosine kinase inhibitor of IGF-1R, or Figitumumab, a human anti-IGF1R antibody, has a cytotoxic effect on TNBC cell lines as a single agent and (2) to determine if combining AG1024 or Figitumumab with conventional chemotherapeutic agents, doxorubicin or paclitaxel, in TNBC cell lines would enhance their cytotoxic effects. To evaluate the effect of these agents, cytotoxicity assays were conducted using four TNBC cell lines (MDA-MB-231, MDA-MB-468, SUM149 and BT20) and a non-TNBC cell line, MCF7, for comparison. Our results showed that AG1024 caused a dose-dependent decrease in cell viability in TNBC cell lines and that TNBC cell lines were more sensitive to AG1024 than non-TNBC cell lines. Also, the cytotoxic effects of AG1024 were enhanced in all TNBC cell lines by the addition of paclitaxel and in three out of four TNBC cell lines upon adding doxorubicin. Figitumumab monotherapy failed to have cytotoxic effects on TNBC cell lines but the anti-IGF1R antibody cytotoxic effects were enhanced by addition of doxorubicin in two TNBC cell lines and by addition of paclitaxel in one TNBC cell line. This study suggests that therapies targeting the IGF1R may have clinical application in the treatment of TNBC and tyrosine kinase inhibitors, such as AG1024, may be better suited for treating TNBC than monoclonal antibodies

Community Policing and Insecurity in Rivers State (2015-2019)

The main goal of the Nigeria Police Force is to protect life and property of its citizens but the recent trend of insecurity in Rivers State shows the inability of the Nigeria Police Force in performing these essential functions. These issues can be attributed to inadequate manpower, poor understanding of the environment they are posted to fight insecurity in Rivers State. This issue has created the need for community policing in order to reduce insecurity in Rivers State. This prompted the study to examine the prospect of community policing as a panacea to the problem of insecurity in Rivers State. Therefore, the study developed the following research questions: What is the role of community policing in reducing insecurity in various communities? What is the core principle of community policing in reducing insecurity? What are the challenges of community policing in reducing insecurity in Rivers State? The study adopted the broken windows theory by James Wilson and George Kelling as its framework of analysis. A self-designed structured questionnaire was used to collect data from respondents, while purposive and simple random sampling techniques were employed to select three (3) communities out of two hundred and thirty-four (234) and three (3) local government areas out of twenty-three (23) in Rivers State, with a total sample size of three hundred (300), while two hundred and eighty (280) questionnaires were retrieved. Mean and rank order statistical methods were used to analyse the data. The study revealed that the major role of community policing is to protect life and property, covering and curbing the nooks and cronies in the communities, rapid response to security threats to prevent the breakdown of law and order. The core values of community policing are transparency and openness in their policing function, demonstrate commitment at all times to deliver best quality services. The challenges facing community policing in Rivers State are lack of trust between the police, vigilante groups and the members of the communities, poor public image of the police. The study thus recommends that there is a need for the Nigerian Police to strengthen their cooperation with the members of the various communities in Rivers State. This cooperation will endear them to the people instead of the present mutual suspicion and distrust which alienate people from them. In other words, it will improve community relations with the police, as well as increase information sharing, intelligence, crime detection and prevention

Federalism and National Development in Nigeria An Assessment of former President Goodluck Jonathan’s Administration

The background to this study comprehensively captured the usefulness and unavoidability of social relations to human existence. Hence, it impressed that the desire to live in a society where the socio-economic needs, rights and privileges of humans who are drawn from diverse ethnic and socio-cultural affiliations are advanced and protected, gave rise to the formation of a sovereign union. Using the administration of former President Goodluck Jonathan as a case study, this research work holistically appraised the impact of federalism on national development in Nigeria; it investigated the extent to which some inherent problems in Nigerian federalism impinged on the successful realisation of national developmental objectives in Nigeria during the period under study and beyond. The study developed two research questions bordering on what constitutes the problems of Nigerian federalism as it pertains to national development, as well as the strategies to combat them. The study was anchored on the theory of Distributive Justice by John Rawls. The study adopted the review research design. The source of data for this study was exclusively the secondary source, using the instruments of textbooks, journals, official documents and internet materials. The study equally used the content analysis method for data presentation and analysis. At the end of the study, it was revealed that problems associated with agitations and complaints over revenue sharing formular, agitation for state autonomy, resource control, etc. constituted the problems of Nigerian federalism as they pertain to national development during the administration of former President Jonathan. The study therefore recommended among other things for an improved regional autonomy to achieve a maximum degree of widespread national development

Vote Buying and Electoral Credibility in the 2019 and 2023 General Elections in Rivers State, Nigeria A Study of Emohua Local Government Area

This study critically examined the negative impact of vote buying on electoral credibility, during the 2019 and 2023 general elections in Rivers State, Nigeria. Using Emohua local government area as a case study, this study made an attempt at identifying the factors that were responsible for the upsurge in the activities of vote buying in the periods under study, as well as their attendant consequences. The 2019 and 2023 general elections in Rivers State, Nigeria, were characterised by massive irregularities in the form of reckless acts of voter-inducement, as well as other aspects of rampant electoral malpractices, hence, the quest for this study. This study was guided by three research questions and three objectives. The study was anchored on the theory of Economic Determinism by Karl Marx. The study used the survey design method. Data for this study were generated through the primary and secondary sources. While the primary source involved the use of questionnaires, the secondary source involved the use of textbooks, journals and internet materials. At the end of the study, it was revealed that high rate of poverty, the systemic tolerance and adoption of money politics and the lack of stringent laws and penalties against vote buying constituted the factors that gave rise to the activities of vote buying, thus, compromising the integrity and credibility of the 2019 and 2023 general elections in Rivers State, Nigeria. Consequently, the situation gave rise to series of post-election litigations and widespread criticisms of the entire electoral process. The study therefore recommended among other things, the application of stringent laws and penalties against the perpetrators of vote buying, so as to achieve an appreciable degree of credibility in future elections

Vote Buying and Electoral Credibility in the 2019 and 2023 General Elections in Rivers State, Nigeria A Study of Emohua Local Government Area

This study critically examined the negative impact of vote buying on electoral credibility, during the 2019 and 2023 general elections in Rivers State, Nigeria. Using Emohua local government area as a case study, this study made an attempt at identifying the factors that were responsible for the upsurge in the activities of vote buying in the periods under study, as well as their attendant consequences. The 2019 and 2023 general elections in Rivers State, Nigeria, were characterised by massive irregularities in the form of reckless acts of voter-inducement, as well as other aspects of rampant electoral malpractices, hence, the quest for this study. This study was guided by three research questions and three objectives. The study was anchored on the theory of Economic Determinism by Karl Marx. The study used the survey design method. Data for this study were generated through the primary and secondary sources. While the primary source involved the use of questionnaires, the secondary source involved the use of textbooks, journals and internet materials. At the end of the study, it was revealed that high rate of poverty, the systemic tolerance and adoption of money politics and the lack of stringent laws and penalties against vote buying constituted the factors that gave rise to the activities of vote buying, thus, compromising the integrity and credibility of the 2019 and 2023 general elections in Rivers State, Nigeria. Consequently, the situation gave rise to series of post-election litigations and widespread criticisms of the entire electoral process. The study therefore recommended among other things, the application of stringent laws and penalties against the perpetrators of vote buying, so as to achieve an appreciable degree of credibility in future elections

Federalism and National Development in Nigeria An Assessment of former President Goodluck Jonathan’s Administration

The background to this study comprehensively captured the usefulness and unavoidability of social relations to human existence. Hence, it impressed that the desire to live in a society where the socio-economic needs, rights and privileges of humans who are drawn from diverse ethnic and socio-cultural affiliations are advanced and protected, gave rise to the formation of a sovereign union. Using the administration of former President Goodluck Jonathan as a case study, this research work holistically appraised the impact of federalism on national development in Nigeria; it investigated the extent to which some inherent problems in Nigerian federalism impinged on the successful realisation of national developmental objectives in Nigeria during the period under study and beyond. The study developed two research questions bordering on what constitutes the problems of Nigerian federalism as it pertains to national development, as well as the strategies to combat them. The study was anchored on the theory of Distributive Justice by John Rawls. The study adopted the review research design. The source of data for this study was exclusively the secondary source, using the instruments of textbooks, journals, official documents and internet materials. The study equally used the content analysis method for data presentation and analysis. At the end of the study, it was revealed that problems associated with agitations and complaints over revenue sharing formular, agitation for state autonomy, resource control, etc. constituted the problems of Nigerian federalism as they pertain to national development during the administration of former President Jonathan. The study therefore recommended among other things for an improved regional autonomy to achieve a maximum degree of widespread national development

Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy.

Triple negative breast cancer (TNBC) is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African American (AA) patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA). It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, gene expression profiling and immunohistochemistry were used to elucidate potential differences between TNBC tumors of EA and AA patients on a molecular level. In a retrospective cohort of 136 TNBC patients, a major transcriptional signature of proliferation was found to be significantly upregulated in samples of AA ethnicity. Furthermore, transcriptional profiles of AA tumors showed differential activation of insulin-like growth factor 1 (IGF1) and a signature of BRCA1 deficiency in this cohort. Using signatures derived from the meta-analysis of TNBC gene expression carried out by Lehmann et al., tumors from AA patients were more likely of basal-like subtypes whereas transcriptional features of many EA samples corresponded to mesenchymal-like or luminal androgen receptor driven subtypes. These results were validated in The Cancer Genome Atlas mRNA and protein expression data, again showing enrichment of a basal-like phenotype in AA tumors and mesenchymal subtypes in EA tumors. In addition, increased expression of VEGF-activated genes together with elevated microvessel area determined by the AQUA method suggest that AA patients exhibit higher tumor vascularization. This study confirms the existence of distinct transcriptional programs in triple negative breast cancer in two separate cohorts and that these programs differ by racial group. Differences in TNBC subtypes and levels of tumor angiogenesis in AA versus EA patients suggest that targeted therapy choices should be considered in the context of race

Association of ethnicity with TNBC subtypes [<b>9</b>].

<p>Correlations of gene expression with the mesenchymal stem cell (A), luminal androgen receptor positive (B) and basal 1 (C) subtypes were compared between African American (AA) and European American (EA) patient samples.</p

Gene sets negatively associated with principal component 4 by enrichment analysis.

<p>Enrichment of gene sets from the Broad Molecular Signature Database (MSigDB) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071915#pone.0071915-Subramanian1" target="_blank">[34]</a>, Gene Ontology <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0071915#pone.0071915-Ashburner1" target="_blank">[33]</a> and selected publications was assessed using Fisher's Exact test for 250 probes with the lowest projection scores on principal component 4. P-values were FDR-adjusted for multiple testing.</p