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Background: Cell death induced by poly(ADP-ribose) (PAR) and mediated by apoptosis-inducing factor (AIF) is well-characterized in models of ischemic tissue injury, but their roles in cancer cell death after chemotherapy are less understood. Methods: Here we investigated the roles of PAR and AIF by RNA interference (RNAi) in MDA-MB-231 and MCF-7 breast adenocarcinoma cells after chemotherapy. Differences in effects were statistically tested by analysis-ofvariance and unpaired student’s t-test. Results: Silencing of AIF by RNAi led to decreased MDA-MB-231 and MCF-7 breast cancer cell death after chemotherapy, which demonstrates a critical role for AIF. RNAi silencing of PAR glycohydrolase (PARG), the primary enzyme that catalyzes the hydrolysis of PAR, led to increased PAR levels but decreased cell death. Further investigation into the possible role of PAR in apoptosis revealed decreased caspase-3/7/8/9 activity in PARG-null cells. Interestingly, the pharmacologic inhibition of caspase activity in PARG-silenced breast cancer cells led to increased cell death after chemotherapy, which indicates that an alternative cell death pathway is activated due to elevated PAR levels and caspase inhibition. AIF silencing in these cells led to profound protection from chemotherapy, which demonstrates that the increased cell death after PARG silencing and caspase inhibition was mediated by AIF. Conclusions: The results show a role for AIF in breast cancer cell death after chemotherapy, the ability of PAR to regulate caspase activity, and the ability of AIF to substitute as a primary mediator of breast cancer cell death in the absence of caspases. Thus, the induction of cell death by PAR/AIF may represent a novel strategy to optimize the eradication of breast tumors by activating an alternative cell death pathway. [ABSTRACT FROM AUTHOR]

Background: A critical therapeutic challenge in epithelial ovarian carcinoma is the development of chemoresistance among tumor cells following exposure to first line chemotherapeutics. The molecular and genetic changes that drive the development of chemoresistance are unknown, and this lack of mechanistic insight is a major obstacle in preventing and predicting the occurrence of refractory disease. We have recently shown that Regulators of G-protein Signaling (RGS) proteins negatively regulate signaling by lysophosphatidic acid (LPA), a growth factor elevated in malignant ascites fluid that triggers oncogenic growth and survival signaling in ovarian cancer cells. The goal of this study was to determine the role of RGS protein expression in ovarian cancer chemoresistance. Results: In this study, we find that RGS2, RGS5, RGS10 and RGS17 transcripts are expressed at significantly lower levels in cells resistant to chemotherapy compared with parental, chemo-sensitive cells in gene expression datasets of multiple models of chemoresistance. Further, exposure of SKOV-3 cells to cytotoxic chemotherapy causes acute, persistent downregulation of RGS10 and RGS17 transcript expression. Direct inhibition of RGS10 or RGS17 expression using siRNA knock-down significantly reduces chemotherapy-induced cell toxicity. The effects of cisplatin, vincristine, and docetaxel are inhibited following RGS10 and RGS17 knock-down in cell viability assays and phosphatidyl serine externalization assays in SKOV-3 cells and MDR-HeyA8 cells. We further show that AKT activation is higher following RGS10 knock-down and RGS 10 and RGS17 overexpression blocked LPA mediated activation of AKT, suggesting that RGS proteins may blunt AKT survival pathways. Conclusions: Taken together, our data suggest that chemotherapy exposure triggers loss of RGS10 and RGS17 expression in ovarian cancer cells, and that loss of expression contributes to the development of chemoresistance, possibly through amplification of endogenous AKT signals. Our results establish RGS10 and RGS17 as novel regulators of cell survival and chemoresistance in ovarian cancer cells and suggest that their reduced expression may be diagnostic of chemoresistance. [ABSTRACT FROM AUTHOR]

Background: Although the incidence of melanoma in the U.S. is rising faster than any other cancer, the FDA-approved chemotherapies lack efficacy for advanced disease, which results in poor overall survival. Lysophosphatidic acid (LPA), autotaxin (ATX), the enzyme that produces LPA, and the LPA receptors represent an emerging group of therapeutic targets in cancer, although it is not known which of these is most effective. Results: Herein we demonstrate that thio-ccPA 18:1, a stabilized phosphonothionate analogue of carba cyclic phosphatidic acid, ATX inhibitor and LPA1/3 receptor antagonist, induced a marked reduction in the viability of B16F10 metastatic melanoma cells compared with PBS-treated control by 80-100%. Exogenous LPA 18:1 or D-sn-1-O-oleoyl-2- O-methylglyceryl-3-phosphothioate did not reverse the effect of thio-ccPA 18:1. The reduction in viability mediated by thio-ccPA 18:1 was also observed in A375 and MeWo melanoma cell lines, suggesting that the effects are generalizable. Interestingly, siRNA to LPA3 (siLPA3) but not other LPA receptors recapitulated the effects of thio-ccPA 18:1 on viability, suggesting that inhibition of the LPA3 receptor is an important dualistic function of the compound. In addition, siLPA3 reduced proliferation, plasma membrane integrity and altered morphology of A375 cells. Another experimental compound designed to antagonize the LPA1/3 receptors significantly reduced viability in MeWo cells, which predominantly express the LPA3 receptor. Conclusions: Thus the ability of thio-ccPA 18:1 to inhibit the LPA3 receptor and ATX are key to its molecular mechanism, particularly in melanoma cells that predominantly express the LPA3 receptor. These observations necessitate further exploration and exploitation of these targets in melanoma. [ABSTRACT FROM AUTHOR]

Background: The Elders Mentoring Program (EMP) is part of a strengths-based community-based participatory research partnership with the Cree communities of Maskwacîs, Alberta, Canada. The EMP objective is to promote maternal and child health through traditional Cree teachings and support from community Elders to pregnant women and their partners. During the COVID-19 pandemic, the Elders decided to shift the program to an online format in early 2021. The Elders continued to offer mentorship to program participants virtually by Zoom and telephone, and online workshops. The objective of this study was to qualitatively explore the experiences of women that took part in the virtual EMP., Methods: We utilized qualitative description as our method, informed by our overarching community-led research partnership. Semi-structured phone interviews were conducted by Maskwacîs research assistants (RAs) with 11 women who participated in the virtual program. Interviews were conducted between December 2021 and June 2022. The participants were asked about their perceptions of the program and its benefits. The interviews were recorded, transcribed, and coded by four RAs using thematic analysis., Results: Although cultural teachings are traditionally offered in person, the shift to the virtual platform was greatly appreciated by all the women. Technology can be a useful tool for cultural teachings and language to be shared among community members when they cannot be physically together. Four main themes emerged from the data, representing the participants' experiences, and learning through their interactions with the Elders from the EMP. The themes are: Ohpikihâwasowin (grounding and guiding on the path to be a healthy parent); Indigenous ways of healing; On the path of cultural learning; and Identity for self and baby., Conclusion: The virtual adaptation of the EMP allowed a space for Elders to offer support to women living in and out of the community to provide guidance with their pregnancies and into motherhood. The workshops and one-on-one calls allowed for cultural revitalization which is critical for Indigenous well-being. All the participants found that the teachings and interactions positively impacted their pregnancy and parenthood. Overall, the virtual program demonstrated a venue for intergenerational healing and resilience., (© 2024. The Author(s).)

Background: Family carers face challenges that could significantly affect their health and the health of those they care for. However, these challenges are not well documented in low-income settings, including Uganda. We explored the challenges of caring for someone with chronic non-communicable disease (NCD) in Uganda., Methods: We conducted a qualitative exploratory study at Hospice Africa, Uganda (an urban setting) and Hampton Health Center (a rural setting) in Uganda in February and March 2021. Family carers (n = 44) were recruited using snowball and purposive sampling techniques. Data were collected using focus group discussions and in-depth interviews, gathering family carer perspectives of (a) their caring role (b) their support needs, and (c) attitudes of the wider community. In total, four focus group discussions and 10 individual interviews were completed., Results: The average age of carers was 46 years old. The majority of family care was provided by female relatives, who also experienced intersectional disadvantages relating to economic opportunities and employment. Family carers carried a huge burden of care, experiencing significant challenges that affected their physical health, and material and emotional well-being. These challenges also affected the quality of care of the patients for whom they cared. Carers struggled to provide for the basic needs of the patient including the provision of medication and transport to health facilities. Carers received no formal training and limited support to carry out the caring role. They reported that they had little understanding of the patient's illness, or how best to provide care., Conclusions: As NCDs continue to rise globally, the role of family caregivers is becoming more prominent. The need to support carers is an urgent concern. Family carer needs should be prioritised in policy and resource allocation. The need for a carer's toolkit of resources, and the enhancement of community support, have been identified., (© 2023. The Author(s).)

The global pandemic of COVID-19 has caused huge causality and unquantifiable loss of social wealth. The innate immune response is the first line of defense against SARS-CoV-2 infection. However, strong inflammatory response associated with dysregulation of innate immunity causes severe acute respiratory syndrome (SARS) and death. In this review, we update the current knowledge on how SARS-CoV-2 modulates the host innate immune response for its evasion from host defense and its corresponding pathogenesis caused by cytokine storm. We emphasize Type I interferon response and the strategies of evading innate immune defense used by SARS-CoV-2. We also extensively discuss the cells and their function involved in the innate immune response and inflammatory response, as well as the promises and challenges of drugs targeting excessive inflammation for antiviral treatment. This review would help us to figure out the current challenge questions of SARS-CoV-2 infection on innate immunity and directions for future studies., (© 2022. The Author(s).)

Background & Aims: Cancer metastasis into distant organs is an evolutionarily selective process. A better understanding of the driving forces endowing proliferative plasticity of tumor seeds in distant soils is required to develop and adapt better treatment systems for this lethal stage of the disease. To this end, we aimed to utilize transcript expression profiling features to predict the site-specific metastases of primary tumors and second, to identify the determinants of tissue specific progression., Methods: We used statistical machine learning for transcript feature selection to optimize classification and built tree-based classifiers to predict tissue specific sites of metastatic progression., Results: We developed a novel machine learning architecture that analyzes 33 types of RNA transcriptome profiles from The Cancer Genome Atlas (TCGA) database. Our classifier identifies the tumor type, derives synthetic instances of primary tumors metastasizing to distant organs and classifies the site-specific metastases in 16 types of cancers metastasizing to 12 locations., Conclusions: We have demonstrated that site specific metastatic progression is predictable using transcriptomic profiling data from primary tumors and that the overrepresented biological processes in tumors metastasizing to congruent distant loci are highly overlapping. These results indicate site-specific progression was organotropic and core features of biological signaling pathways are identifiable that may describe proliferative plasticity in distant soils., (© 2021. The Author(s).)

Background: Area-level measures are often used to approximate socioeconomic status (SES) when individual-level data are not available. However, no national studies have examined the validity of these measures in approximating individual-level SES., Methods: Data came from ~ 3,471,000 participants in the Mortality Disparities in American Communities study, which links data from 2008 American Community Survey to National Death Index (through 2015). We calculated correlations, specificity, sensitivity, and odds ratios to summarize the concordance between individual-, census tract-, and county-level SES indicators (e.g., household income, college degree, unemployment). We estimated the association between each SES measure and mortality to illustrate the implications of misclassification for estimates of the SES-mortality association., Results: Participants with high individual-level SES were more likely than other participants to live in high-SES areas. For example, individuals with high household incomes were more likely to live in census tracts (r = 0.232; odds ratio [OR] = 2.284) or counties (r = 0.157; OR = 1.325) whose median household income was above the US median. Across indicators, mortality was higher among low-SES groups (all p < .0001). Compared to county-level, census tract-level measures more closely approximated individual-level associations with mortality., Conclusions: Moderate agreement emerged among binary indicators of SES across individual, census tract, and county levels, with increased precision for census tract compared to county measures when approximating individual-level values. When area level measures were used as proxies for individual SES, the SES-mortality associations were systematically underestimated. Studies using area-level SES proxies should use caution when selecting, analyzing, and interpreting associations with health outcomes.

Patient navigation has expanded as a promising approach to improve cancer care coordination and patient adherence. This paper addresses the need to identify the evidence on the economic impact of patient navigation in colorectal cancer, following the Health Economic Evaluation Publication Guidelines. Articles indexed in Medline, Cochrane, CINAHL, and Web of Science between January 2000 and March 2017 were analyzed. We conducted a systematic review of the literature using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality assessment of the included studies was based on the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Inclusion criteria indicated that the paper's subject had to explicitly address patient navigation in colorectal cancer and the study had to be an economic evaluation. The search yielded 243 papers, 9 of which were finally included within this review. Seven out of the nine studies included met standards for high-quality based on CHEERS criteria. Eight concluded that patient navigation programs were unequivocally cost-effective for the health outcomes of interest. Six studies were cost-effectiveness analyses. All studies computed the direct costs of the program, which were defined a minima as the program costs. Eight of the reviewed studies adopted the healthcare system perspective. Direct medical costs were usually divided into outpatient and inpatient visits, tests, and diagnostics. Effectiveness outcomes were mainly assessed through screening adherence, quality of life and time to diagnostic resolution. Given these outcomes, more economic research is needed for patient navigation during cancer treatment and survivorship as well as for patient navigation for other cancer types so that decision makers better understand costs and benefits for heterogeneous patient navigation programs.

[This corrects the article DOI: 10.1186/s12959-017-0157-x.].

Background: An incidental/unsuspected diagnosis of pulmonary embolism (IPE) in cancer patients is a frequent occurrence. This single-institution analysis of uniformly managed patients investigates short and long-term outcomes and proposes a prognostic risk score, aiming to assist clinical decision-making., Methods: Data from a prospectively recorded cohort of 234 consecutive cancer patients with IPE were analysed. Multivariate logistic regression and the Cox regression survival methods were used to identify factors with independent association with early (30-day, 3-month, 6-month) mortality and survival. Receiver operator characteristic analysis (ROC) was used to assess appropriate cut-offs for continuous variables and the fitness of prognostic scoring., Results: 30-day, 3-month and 6-month mortality was 3.4% ( n  = 8), 15% ( n  = 35) and 31% ( n  = 72) respectively. Recurrence during anticoagulation occurred in 2.6% ( n  = 6) and major haemorrhage in 2.1% ( n  = 5) of the patients. A prognostic score incorporating performance status (0 vs 1-2 vs 3-4) and the presence of new or worsening symptoms, with and without the consideration of the presence of incurable malignancy, correlated with overall survival ( p  < .001 respectively) as well as early mortality (AUC = .821, p  = .004 and AUC = .805, p  = 0.006, respectively)., Conclusion: A simple prognostic score incorporating basic oncologic clinical assessment and self-reported symptomatology could reliably stratify the mortality risk of ambulant cancer patients and IPE., Trial Registration: Audit registration No. 2013.287, Hull and East Yorkshire Hospitals Trust, 29/11/2013., Competing Interests: This study was conducted under the UK Health Research Authority regulations as an Audit / Service Evaluation project, not requiring Ethics Approval. Patient consent for anonymised data collection for audit purposes is implicit. Regulatory compliance [as per Data Protection Act (1998), the Caldicott principles (1997) and the NHS Confidentiality code of practice (2003)] was overseen by the Hull and East Yorkshire Hospitals Trust Governance bodies. Audit registration No. 2013.287, Hull and East Yorkshire Hospitals Trust, 29/11/2013.Non-applicable. No individually identifiable data are presented in this work.All authors listed declare that they have no competing interests relevant to this manuscript.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Deep vein thrombosis (DVT) is a common complication of peripherally inserted central catheters (PICCs). PICCs are increasingly utilised in the management of cancer patients, a group which carries both additional risks for vascular thromboembolism as well as for complex morbidity. We analysed a cohort of cancer patients subjected to PICC insertion in a single cancer centre for the incidence of all-type vascular thromboembolism (VTE) and investigated relative risk factors., Methods: In this clinical audit, the records of patients referred for PICC insertion in our centre in the period between 1/1/2011 and 1/4/2014 were retrospectively reviewed. The primary outcomes investigated were a) PICC-related deep vein thrombosis (PRDVT) and b) distant VTE (lower limb DVT and pulmonary embolism). 4Fr single lumen PICCs were placed in all patients. The Kaplan Meier method was used to study time from PICC insertion to PRDVT/VTE. Survival curves were compared using the log rank method. Logistic and Cox regression analyses were used to assess local, distant and combined endpoints., Results: Four hundred ninety patients were included in the analysis of which 27 (5.5%) developed a PRDVT. Statistically significant risk factors for developing PRDVT in multivariate analysis included more than one attempt for insertion (OR 2.61, 95%CI: 1.12-6.05) and the use of fluoropyrimidine containing chemotherapy (OR 4.27, 95%CI 1.3-14.07). Twenty-six patients developed a distant VTE. Male gender was the only significant risk factor for distant VTE. When all-type VTE were considered together fluoropyrimidine containing chemotherapy (OR 4.54, 95% CI 1.63-12.61), male gender (OR 2.03, 95% CI 1.04-3.93) and white cell count (OR 1.12, 95% CI 1.00-1.26) were statistically significant as risk factors in this analysis., Conclusions: This is a large study of VTE following PICC insertion in cancer patients which also looks at the rate of distant VTE. The observed PRDVT incidence is comparable with available literature. Fluoropyrimidine containing chemotherapy and more than one attempt for PICC insertion were independent predictors of PICC-associated VTE whilst the former remained an independent predictor of all-type VTE. Anticoagulation did not prevent thrombotic events in this cohort.

Background: Incomplete categorical variables with more than two categories are common in public health data. However, most of the existing missing-data methods do not use the information from nonresponse (missingness) probabilities., Methods: We propose a nearest-neighbour multiple imputation approach to impute a missing at random categorical outcome and to estimate the proportion of each category. The donor set for imputation is formed by measuring distances between each missing value with other non-missing values. The distance function is calculated based on a predictive score, which is derived from two working models: one fits a multinomial logistic regression for predicting the missing categorical outcome (the outcome model) and the other fits a logistic regression for predicting missingness probabilities (the missingness model). A weighting scheme is used to accommodate contributions from two working models when generating the predictive score. A missing value is imputed by randomly selecting one of the non-missing values with the smallest distances. We conduct a simulation to evaluate the performance of the proposed method and compare it with several alternative methods. A real-data application is also presented., Results: The simulation study suggests that the proposed method performs well when missingness probabilities are not extreme under some misspecifications of the working models. However, the calibration estimator, which is also based on two working models, can be highly unstable when missingness probabilities for some observations are extremely high. In this scenario, the proposed method produces more stable and better estimates. In addition, proper weights need to be chosen to balance the contributions from the two working models and achieve optimal results for the proposed method., Conclusions: We conclude that the proposed multiple imputation method is a reasonable approach to dealing with missing categorical outcome data with more than two levels for assessing the distribution of the outcome. In terms of the choices for the working models, we suggest a multinomial logistic regression for predicting the missing outcome and a binary logistic regression for predicting the missingness probability.

Background: The period following discharge from a pediatric emergency department (ED) can be a time of significant vulnerability for caregivers who provide ongoing care to their child when they return home. Discharge communication practice varies widely at the individual practitioner and departmental level. At present, there are no nationally accepted guidelines for discharge communication for children and/or their caregivers in the ED.The primary objective of this knowledge synthesis is to understand how and why discharge instructions work and under what conditions. We will also examine the contextual factors and barriers and facilitators associated with discharge communication across varied ED settings., Methods/design: Using an integrated narrative approach, we will synthesize different types of evidence and explore relationships within and between included studies to develop a theory-based and knowledge user-informed discharge communication practice guideline. We will follow key principles for knowledge synthesis including: (1) involvement of a multidisciplinary team (for example, information specialists, statisticians, and content experts); (2) developing focused and answerable questions in collaboration with the knowledge users; (3) using a systematic method including specific tools and techniques appropriate for answering questions concerned with effectiveness and the implementation of interventions; and, (4) involving knowledge users throughout the process in an integrated knowledge translation approach., Discussion: This collaborative and narrative approach will be a determining factor in increasing the reliability, validity and relevance of the study findings for healthcare practice and policy decision-makers., Trial Registration: PROSPERO registration number: CRD42014007106.

Background: Cell death induced by poly(ADP-ribose) (PAR) and mediated by apoptosis-inducing factor (AIF) is well-characterized in models of ischemic tissue injury, but their roles in cancer cell death after chemotherapy are less understood., Methods: Here we investigated the roles of PAR and AIF by RNA interference (RNAi) in MDA-MB-231 and MCF-7 breast adenocarcinoma cells after chemotherapy. Differences in effects were statistically tested by analysis-of-variance and unpaired student's t-test., Results: Silencing of AIF by RNAi led to decreased MDA-MB-231 and MCF-7 breast cancer cell death after chemotherapy, which demonstrates a critical role for AIF. RNAi silencing of PAR glycohydrolase (PARG), the primary enzyme that catalyzes the hydrolysis of PAR, led to increased PAR levels but decreased cell death. Further investigation into the possible role of PAR in apoptosis revealed decreased caspase-3/7/8/9 activity in PARG-null cells. Interestingly, the pharmacologic inhibition of caspase activity in PARG-silenced breast cancer cells led to increased cell death after chemotherapy, which indicates that an alternative cell death pathway is activated due to elevated PAR levels and caspase inhibition. AIF silencing in these cells led to profound protection from chemotherapy, which demonstrates that the increased cell death after PARG silencing and caspase inhibition was mediated by AIF., Conclusions: The results show a role for AIF in breast cancer cell death after chemotherapy, the ability of PAR to regulate caspase activity, and the ability of AIF to substitute as a primary mediator of breast cancer cell death in the absence of caspases. Thus, the induction of cell death by PAR/AIF may represent a novel strategy to optimize the eradication of breast tumors by activating an alternative cell death pathway.

Background: During pathology of the nervous system, increased extracellular ATP acts both as a cytotoxic factor and pro-inflammatory mediator through P2X(7) receptors. In animal models of amyotrophic lateral sclerosis (ALS), astrocytes expressing superoxide dismutase 1 (SOD1G93A) mutations display a neuroinflammatory phenotype and contribute to disease progression and motor neuron death. Here we studied the role of extracellular ATP acting through P2X(7) receptors as an initiator of a neurotoxic phenotype that leads to astrocyte-mediated motor neuron death in non-transgenic and SOD1G93A astrocytes., Methods: We evaluated motor neuron survival after co-culture with SOD1G93A or non-transgenic astrocytes pretreated with agents known to modulate ATP release or P2X(7) receptor. We also characterized astrocyte proliferation and extracellular ATP degradation., Results: Repeated stimulation by ATP or the P2X(7)-selective agonist BzATP caused astrocytes to become neurotoxic, inducing death of motor neurons. Involvement of P2X(7) receptor was further confirmed by Brilliant blue G inhibition of ATP and BzATP effects. In SOD1G93A astrocyte cultures, pharmacological inhibition of P2X(7) receptor or increased extracellular ATP degradation with the enzyme apyrase was sufficient to completely abolish their toxicity towards motor neurons. SOD1G93A astrocytes also displayed increased ATP-dependent proliferation and a basal increase in extracellular ATP degradation., Conclusions: Here we found that P2X(7) receptor activation in spinal cord astrocytes initiated a neurotoxic phenotype that leads to motor neuron death. Remarkably, the neurotoxic phenotype of SOD1G93A astrocytes depended upon basal activation the P2X(7) receptor. Thus, pharmacological inhibition of P2X(7) receptor might reduce neuroinflammation in ALS through astrocytes.

Background: Although the incidence of melanoma in the U.S. is rising faster than any other cancer, the FDA-approved chemotherapies lack efficacy for advanced disease, which results in poor overall survival. Lysophosphatidic acid (LPA), autotaxin (ATX), the enzyme that produces LPA, and the LPA receptors represent an emerging group of therapeutic targets in cancer, although it is not known which of these is most effective., Results: Herein we demonstrate that thio-ccPA 18:1, a stabilized phosphonothionate analogue of carba cyclic phosphatidic acid, ATX inhibitor and LPA1/3 receptor antagonist, induced a marked reduction in the viability of B16F10 metastatic melanoma cells compared with PBS-treated control by 80-100%. Exogenous LPA 18:1 or D-sn-1-O-oleoyl-2-O-methylglyceryl-3-phosphothioate did not reverse the effect of thio-ccPA 18:1. The reduction in viability mediated by thio-ccPA 18:1 was also observed in A375 and MeWo melanoma cell lines, suggesting that the effects are generalizable. Interestingly, siRNA to LPA3 (siLPA3) but not other LPA receptors recapitulated the effects of thio-ccPA 18:1 on viability, suggesting that inhibition of the LPA3 receptor is an important dualistic function of the compound. In addition, siLPA3 reduced proliferation, plasma membrane integrity and altered morphology of A375 cells. Another experimental compound designed to antagonize the LPA1/3 receptors significantly reduced viability in MeWo cells, which predominantly express the LPA3 receptor., Conclusions: Thus the ability of thio-ccPA 18:1 to inhibit the LPA3 receptor and ATX are key to its molecular mechanism, particularly in melanoma cells that predominantly express the LPA3 receptor. These observations necessitate further exploration and exploitation of these targets in melanoma.

Background: Lethal yellow (LY; C57BL/6J Ay/a) mice exhibit adult-onset obesity, altered metabolic regulation, and early reproductive senescence. The present study was designed to test the hypothesis that obese LY mice possess differences in expression of ovarian genes relative to age-matched lean mice., Methods: 90- and 180-day-old LY and lean black (C57BL/6J a/a) mice were suppressed with GnRH antagonist (Antide(R)), then stimulated with 5 IU eCG. cRNA derived from RNA extracts of whole ovarian homogenates collected 36 h post-eCG were run individually on Codelink Mouse Whole Genome Bioarrays (GE Healthcare Life Sciences)., Results: Fifty-two genes showed >/= 2-fold differential (p < 0.05) expression between 180-day-old obese LY and lean black mice. LY mice exhibited elevated ovarian expression of agouti (350x), leptin (6.5x), and numerous genes involved in cholesterol/lipid transport and metabolism, e.g. lanosterol synthase, Cyp51, and steroidogenic acute regulatory protein (Star). Fewer genes showed lower expression in LY mice, e.g. angiotensinogen. In contrast, none of these genes showed differential expression in 90-day-old LY and black mice, which are of similar body weight. Interestingly, 180-day-old LY mice had a 2-fold greater expression of 11beta-hydroxysteroid dehydrogenase type 1 (Hsd11b1) and a 2-fold lesser expression of 11beta-hydroxysteroid dehydrogenase type 2 (Hsd11b2), differences not seen in 90-day-old mice. Consistent with altered Hsd11b gene expression, ovarian concentrations of corticosterone (C) were elevated in aging LY mice relative to black mice, but C levels were similar in young LY and black mice., Conclusion: The data suggest that reproductive dysfunction in aging obese mice is related to modified intraovarian gene expression that is directly related to acquired obesity.

In the landmark 1990 publication Scholarship Reconsidered, Boyer challenged the 'teaching verses research debates' by advocating for the scholarship of discovery, teaching, integration, and application. The scholarship of discovery considers publications and research as the yardstick in the merit, promotion and tenure system the world over. But this narrow view of scholarship does not fully support the obligations of universities to serve global societies and to improve health and health equity. Mechanisms to report the scholarship of teaching have been developed and adopted by some universities. In this article, we contribute to the less developed areas of scholarship, i.e. integration and application. We firstly situate the scholarship of discovery, teaching, integration and application within the interprofessional and knowledge exchange debates. Second, we propose a means for health science scholars to report the process and outcomes of the scholarship of integration and application with other disciplines, decision-makers and communities. We conclude with recommendations for structural and process change in faculty merit, tenure, and promotion systems so that health science scholars with varied academic portfolios are valued and many forms of academic scholarship are sustained. It is vital academic institutions remain relevant in an era when the production of knowledge is increasingly recognized as a social collaborative activity.