From condemnation to normalisation: Young Africans' narratives about same-sex attraction and implications for communication and advocacy efforts.

Narrative is a primary tool in human meaning-making and communication. Frequently value-laden, it plays an important role in global public health communication and advocacy efforts. State-endorsed homophobia is widespread across much of sub-Saharan Africa, severely restricting access to sexual health services and undermining human rights and mental health for sexual minorities. Young Africans' narratives about same-sex attraction (SSA) can both inform message framing and provide a source of creative ideas for communication and advocacy efforts. We conducted an analysis of 56 narratives about SSA submitted by young people aged 13-24 years from 10 African countries to a spring 2013 scriptwriting competition in response to a prompt inviting participants to 'Tell a story about someone who is attracted to people of the same sex.' We categorised the narratives across a spectrum of attitudinal perspectives vis-à-vis SSA and identified characteristics of each category, ranging from condemnation (including characterising SSA as satanic), through ambivalence (e.g. 'love the sinner, hate the sin'), to acceptance, activism (including petitioning for same-sex marriage), and normalisation. The texts shed light on potential message frames and cultural narratives that can be countered or leveraged in communication efforts to improve the health and human rights of sexual minority Africans.

Young Africans' representations of the origins of same-sex attraction and implications for sexual and mental health.

Sexual minorities are stigmatised in much of sub-Saharan Africa, restricting their access to sexual health services and undermining their mental health. Although public attitudes and social representations inform the experience of sexual stigma, little is known about how young Africans make sense of sexual diversity. We conducted a thematic analysis of 56 texts contributed by young people from 10 countries in response to a prompt in a scriptwriting competition inviting participants to 'tell a story about someone who is attracted to people of the same sex'. We analysed accounts of the origins of same-sex attraction, a prominent theme in the narratives. Two-thirds of the texts provide an explicit or implicit explanation, presenting same-sex attraction as innate (15/38) and/or the consequence of environmental influences (32/38), including parental behaviour, gender separation, trauma, foreign influences and evil spirits. Expressions of the potential to avert or cure same-sex attraction are common. Young people's sense-making around sexual diversity draws on available sociocultural and symbolic resources, some of which may be highly stigmatising, and reflects local, national and transnational influences. The need to explain same-sex attraction and the preponderance of harmful explanatory frameworks compounds sexual minority youth's vulnerability to sexual stigma, harmful coping strategies and mental health challenges.

Guiding and supporting adolescents living with HIV in sub-Saharan Africa: The development of a curriculum for family and community members.

Although HIV-related deaths declined globally by 30% between 2005 and 2012, those among adolescents living with HIV (ALHIV) rose by 50%. This discrepancy is primarily due to failure to address the specific needs of ALHIV and resulting poor clinical outcomes related to late diagnosis and poor adherence to antiretroviral therapy. The Families Matter! Program (FMP) is an evidence-based intervention for parents and caregivers of 9-12 year-olds that promotes positive parenting practices and effective parent-child communication about sexuality and sexual risk reduction. It is delivered to groups of participants at the community level through a series of six weekly three-hour sessions. Recognizing family and community members' need for guidance on issues specific to ALHIV, we developed a seventh FMP session to address their needs. Key themes treated in the curriculum for this session include: stigma and mental health, disclosure, ART adherence and self-care, and responsible sexual relationships. In developing the curriculum, we drew on narratives about growing up with HIV contributed by young Africans to a 2013 scriptwriting competition. We describe the data-driven process of developing this curriculum with a view to informing the development of much-needed interventions to serve this vulnerable population.

Breast Cancer Cause Beliefs: Chinese, Korean, and Mexican American Breast Cancer Survivors.

This study examined causal attribution beliefs about breast cancer and the influence that these beliefs exert on health behavior change among breast cancer survivors (BCS). Focus groups with Chinese (n = 21), Korean (n = 11), and Mexican American (n = 9) BCS recruited through community- and hospital-based support groups were conducted. Interviews were audio-recorded, transcribed verbatim, and translated into English for thematic content analysis. Three themes concerning beliefs about breast cancer cause common to all three groups included (a) stress, (b) diet, and (c) fatalism. Causal beliefs corresponded to behavioral changes with women describing efforts to improve their diet and manage their stress. Ethnic minority BCS adhere to beliefs about what caused their cancer that influence their health behaviors. Providing quality health care to ethnically diverse cancer survivors requires cultural sensitivity to patients' beliefs about the causes of their cancer and awareness of how beliefs influence patients' health behaviors post diagnosis.

Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition.

Malignant peripheral nerve sheath tumours (MPNST) are rare, hereditary cancers associated with neurofibromatosis type I. MPNSTs lack effective treatment options as they often resist chemotherapies and have high rates of disease recurrence. Aurora kinase A (AURKA) is an emerging target in cancer and an aurora kinase inhibitor (AKI), termed MLN8237, shows promise against MPNST cell lines in vitro and in vivo. Here, we test MLN8237 against two primary human MPNST grown in vivo as xenotransplants and find that treatment results in tumour cells exiting the cell cycle and undergoing endoreduplication, which cumulates in stabilized disease. Targeted therapies can often fail in the clinic due to insufficient knowledge about factors that determine tumour susceptibilities, so we turned to three MPNST cell-lines to further study and modulate the cellular responses to AKI. We find that the sensitivity of cell-lines with amplification of AURKA depends upon the activity of the kinase, which correlates with the expression of the regulatory gene products TPX2 and HMMR/RHAMM. Silencing of HMMR/RHAMM, but not TPX2, augments AURKA activity and sensitizes MPNST cells to AKI. Furthermore, we find that AURKA activity is critical to the propagation and self-renewal of sphere-enriched MPNST cancer stem-like cells. AKI treatment significantly reduces the formation of spheroids, attenuates the self-renewal of spheroid forming cells, and promotes their differentiation. Moreover, silencing of HMMR/RHAMM is sufficient to endow MPNST cells with an ability to form and maintain sphere culture. Collectively, our data indicate that AURKA is a rationale therapeutic target for MPNST and tumour cell responses to AKI, which include differentiation, are modulated by the abundance of HMMR/RHAMM.

Hedgehog signaling pathway molecules and ALDH1A1 expression in early-stage non-small cell lung cancer.

INTRODUCTION: The Hedgehog Signaling Pathway (HHSP) has been implicated in the development of multiple cancers. HHSP activation may primarily be hedgehog ligand-dependent in non-small cell lung cancer (NSCLC); while a subset may be ligand-independent. In this study NSCLC primary tumors were used to identify correlations between multiple biomarkers thought to be involved in the HHSP and the clinical outcomes of patients with NSCLC. Identification of such correlations could be used to aid in NSCLC treatment and predicting patient prognosis. METHODS: A tissue microarray representing 248 clinically annotated stage I-II NSCLC cases was stained using immunohistochemistry (IHC) and scored for HHSP proteins namely, SHH, PTCH1, SMO, GLI1, and GLI2; as well as, ALDH1A1, a putative cancer stem cell marker. Data was analyzed for correlation between IHC staining, EGFR and KRAS mutations, and clinical characteristics including relapse-free survival (RFS) and overall survival (OS). RESULTS: In adenocarcinoma, there were significant correlations of IHC expression between SHH and downstream HHSP receptor SMO (p=0.017) and transcription factor GLI1 (p=0.001), while SMO correlated with GLI1 (p=0.007). In squamous cell carcinoma, SHH significantly correlated with GLI2 protein expression (p=0.003). After multiple testing correction, there was no significant correlation between any of the six markers and RFS or OS. CONCLUSIONS: Key downstream components of the HHSP show correlation with sonic hedgehog ligand (SHH) expression, suggesting that ligand-dependent signaling is more prevalent in primary NSCLC tumors. Surprisingly, in early-stage NSCLC, there were no significant correlations between HHSP proteins or ALDH1A1 and RFS or OS.

A novel pathway for human endothelial cell activation by antiphospholipid/anti-ß2 glycoprotein I antibodies.

Antiphospholipid Abs (APLAs) are associated with thrombosis and recurrent fetal loss. These Abs are primarily directed against phospholipid-binding proteins, particularly ß(2)GPI, and activate endothelial cells (ECs) in a ß(2)GPI-dependent manner after binding of ß(2)GPI to EC annexin A2. Because annexin A2 is not a transmembrane protein, the mechanisms of APLA/anti-ß(2)GPI Ab-mediated EC activation are uncertain, although a role for a TLR4/myeloid differentiation factor 88-dependent pathway leading to activation of NF-κB has been proposed. In the present study, we confirm a critical role for TLR4 in anti-ß(2)GPI Ab-mediated EC activation and demonstrate that signaling through TLR4 is mediated through the assembly of a multiprotein signaling complex on the EC surface that includes annexin A2, TLR4, calreticulin, and nucleolin. An essential role for each of these proteins in cell activation is suggested by the fact that inhibiting the expression of each using specific siRNAs blocked EC activation mediated by APLAs/anti-ß(2)GPI Abs. These results provide new evidence for novel protein-protein interactions on ECs that may contribute to EC activation and the pathogenesis of APLA/anti-ß(2)GPI-associated thrombosis and suggest potential new targets for therapeutic intervention in antiphospholipid syndrome.

Endothelial cell activation by antiphospholipid antibodies is modulated by Kruppel-like transcription factors.

Antiphospholipid syndrome is characterized by thrombosis and/or recurrent pregnancy loss in the presence of antiphospholipid antibodies (APLAs). The majority of APLAs are directed against phospholipid-binding proteins, particularly ß2-glycoprotein I (ß2GPI). Anti-ß2GPI antibodies activate endothelial cells in a ß2GPI-dependent manner through a pathway that involves NF-κB. Krüppel-like factors (KLFs) play a critical role in regulating the endothelial response to inflammatory stimuli. We hypothesized that activation of endothelial cells by APLA/anti-ß2GPI antibodies might be associated with decreased expression of KLFs, which in turn might facilitate cellular activation mediated through NF-κB. Our experimental results confirmed this hypothesis, demonstrating markedly decreased expression of KLF2 and KLF4 after incubation of cells with APLA/anti-ß2GPI antibodies. Restoration of KLF2 or KLF4 levels inhibited NF-κB transcriptional activity and blocked APLA/anti-ß2GPI-mediated endothelial activation despite NF-κB p65 phosphorylation. Chromatin immunoprecipitation analysis demonstrated that inhibition of NF-κB transcriptional activity by KLFs reflects sequestration of the cotranscriptional activator CBP/p300, making this cofactor unavailable to NF-κB. These findings suggest that the endothelial response to APLA/anti-ß2GPI antibodies reflects competition between KLFs and NF-κB for their common cofactor, CBP/p300. Taken together, these observations are the first to implicate the KLFs as novel participants in the endothelial proinflammatory response to APLA/anti-ß2GPI antibodies.

miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer.

INTRODUCTION: The ability to diagnose non-small cell lung cancer (NSCLC) at an early stage may lead to improved survival. The aim of this study was to identify differentially expressed serum-based microRNAs (miRNAs) between patients with early-stage NSCLC and controls. These miRNAs may serve as biomarkers for NSCLC early detection. METHODS: miRNA profiling was performed on total RNA extracted from serum obtained from 22 individuals (11 controls and 11 patients with early-stage NSCLC). Quantitative polymerase chain reaction (qPCR) was used to validate the profiling results in the discovery set and in a validation set of 31 controls and 22 patients with early-stage NSCLC. Additionally, six matched plasma samples (four NSCLC cases and two controls) and three serum mesothelioma samples were analyzed by qPCR. Receiver operating characteristic curves were generated for each possible combination of the miRNAs measured by qPCR. RESULTS: The expression of hsa-miR-1254 and hsa-miR-574-5p was significantly increased in the early-stage NSCLC samples with respect to the controls. Receiver operating characteristic curves plotting these two miRNAs were able to discriminate early-stage NSCLC samples from controls with 82% and 77% of sensitivity and specificity, respectively, in the discovery cohort and with 73% and 71% of sensitivity and specificity, respectively, in the validation cohort. The mesothelioma and plasma samples did not seem to classify into either NSCLC or control groups. CONCLUSIONS: Serum miRNAs are differentially expressed between patients with early-stage NSCLC and controls. The utility of miR-1254 and miR-574-5p serum-based biomarkers as minimally invasive screening and triage tools for subsequent diagnostic evaluation warrants additional validation.

Resistance may not be futile: microRNA biomarkers for chemoresistance and potential therapeutics.

Chemoresistance to many commercially available cancer therapeutic drugs is a common occurrence and contributes to cancer mortality as it often leads to disease progression. There have been a number of studies evaluating the mechanisms of resistance and the biological factors involved. microRNAs have recently been identified as playing a role in the regulation of key genes implicated as cancer therapeutic targets or in mechanisms of chemoresistance including EGFR, MDR1, PTEN, Bak1, and PDCD4 among others. This article briefly reviews chemoresistance mechanisms, discusses how microRNAs can play a role in those mechanisms, and summarizes current research involving microRNAs as both regulators of key target genes for chemoresistance and biomarkers for treatment response. It is clear from the accumulating literature that microRNAs can play an important role in chemoresistance and hold much promise for the development of targeted therapies and personalized medicine. This review brings together much of this new research as a starting point for identifying key areas of interest and potentials for future study.

Impaired fibrinolysis in the antiphospholipid syndrome.

The antiphospholipid syndrome (APS) is characterized by venous and/or arterial thrombosis, or recurrent fetal loss, in the presence of antiphospholipid antibodies (APL). The pathogenesis of APS is multifaceted and involves numerous mechanisms including activation of endothelial cells, monocytes, and/or platelets; inhibition of natural anticoagulant pathways such as protein C, tissue factor inhibitor, and annexin A5; activation of the complement system; and impairment of the fibrinolytic system. Fibrinolysis--the process by which fibrin thrombi are remodeled and degraded--involves the conversion of plasminogen to plasmin by tissue plasminogen activator (tPA) or urokinase-type plasminogen activator, and is tightly regulated. Although the role of altered fibrinolysis in patients with APS is relatively understudied, several reports suggest that deficient fibrinolytic activity may contribute to the pathogenesis of disease in these patients. This article discusses the function of the fibrinolytic system and reviews studies that have reported alterations in fibrinolytic pathways that may contribute to thrombosis in patients with APL. Some of these mechanisms include elevations in plasminogen activator inhibitor-1 levels, inhibitory antibodies against tPA or other components of the fibrinolytic system, antibodies against annexin A2, and finally, antibodies to beta(2)-glycoprotein-I (beta(2)GPI) that block the ability of beta(2)GPI to stimulate tPA-mediated plasminogen activation.

A plant lignan, 3'-O-methyl-nordihydroguaiaretic acid, suppresses papillomavirus E6 protein function, stabilizes p53 protein, and induces apoptosis in cervical tumor cells.

Persistent infection with oncogenic human papillomaviruses (HPVs) is the most important factor in the induction of uterine cervical cancer, a leading cause of cancer mortality in women worldwide. Upon cell transformation, continual expression of the viral oncogenes is required to maintain the transformed phenotype. The viral E6 protein forms a ternary complex with the cellular E6-AP protein and p53 protein which promotes the rapid degradation of p53. Recent studies have revealed that lignans from the creosote bush (3'-O-methyl-nordihydroguaiaretic acid) can repress the viral promoter responsible for E6 gene expression. Work reported here shows that the lignan can subvert viral oncogene function resulting in stabilized p53 protein within treated HPV-containing tumor cells. The stabilized p53 is transcriptionally active as demonstrated by a luciferase reporter vector and induction of genes for Bax and PUMA proteins. Apoptosis is detected by annexin V binding to treated cells as analyzed by flow cytometry. Programmed cell death is confirmed by the induction of active caspases and TUNEL assay. Initiator caspase-9 is activated first, followed later by the effector caspase-3 enzyme. The stabilization and induced apoptosis are not observed within treated HPV-negative cervical tumor cells. Quantitative real time RT-PCR analysis of endogenous E6 gene transcription from the integrated HPV 16 promoter shows at least a fivefold repression of expression as compared to untreated cells. These results indicate that the loss of E6 protein in treated cells could be, in part, responsible for the stabilization of p53 within the lignan treated cells.