Metformin and erlotinib synergize to inhibit basal breast cancer

Basal-like breast cancers (BBCs) are enriched for increased EGFR expression and decreased expression of PTEN. We found that treatment with metformin and erlotinib synergistically induced apoptosis in a subset of BBC cell lines. The drug combination led to enhanced reduction of EGFR, AKT, S6 and 4EBP1 phosphorylation, as well as prevented colony formation and inhibited mammosphere outgrowth. Our data with other compounds suggested that biguanides combined with EGFR inhibitors have the potential to outperform other targeted drug combinations and could be employed in other breast cancer subtypes, as well as other tumor types, with activated EGFR and PI3K signaling. Analysis of BBC cell line alterations led to the hypothesis that loss of PTEN sensitized cells to the drug combination which was confirmed using isogenic cell line models with and without PTEN expression. Combined metformin and erlotinib led to partial regression of PTEN-null and EGFR-amplified xenografted MDAMB- 468 BBC tumors with evidence of significant apoptosis, reduction of EGFR and AKT signaling, and lack of altered plasma insulin levels. Combined treatment also inhibited xenografted PTEN null HCC-70 BBC cells. Measurement of trough plasma drug levels in xenografted mice and a separately performed pharmacokinetics modeling study support possible clinical translation

The predictive value of G8 and the Cancer and aging research group chemotherapy toxicity tool in treatment-related toxicity in older Chinese patients with cancer

Introduction: Older patients experience a higher risk of treatment-related toxicity (TRT). The G8 screening tool was developed to separate cancer older patients fit to receive standard treatment from those who are frail and experiencing functional decline due to reduced organ function and multiple comorbidities. The Cancer and Aging Research Group chemotherapy toxicity tool (CARG-tt) questionnaire was developed to predict chemotherapy toxicity in geriatric patients. This prospective observational study evaluated the performance of G8 and CARG-tt in predicting severe TRT in older Chinese cancer patients. Methods: Chinese patients aged ≥65 with a diagnosis of solid malignancy and scheduled to receive anti-cancer treatment (chemotherapy or targeted therapy) were enrolled from March 2016 to July 2017 at the Department of Clinical Oncology at Queen Mary Hospital in Hong Kong. All patients completed the G8 and CARG-tt screening and pre-treatment assessments before starting treatment. Patients were monitored for any severe TRT, which was defined by grades 3–5 using the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.03, treatment discontinuation, or unexpected hospitalization from starting to 30 days after treatment. Results: A total of 259 patients (male: 154, 59.5%; median age: 73.4, age range: 65–93) were enrolled in the study. Two hundred and ten (81.1%) patients received chemotherapy while the rest (n = 49, 18.9%) received targeted therapy. Overall, 146 patients (56.8%) experienced severe TRT. The mean G8 score was 12.4 (SD: 2.8). The G8 score had a significant association with unexpected admission (cutoff: 14, 41.3% vs. 26.5%, p = 0.03) but not significant in other types of TRTs. The mean CARG-tt score was 7.67 (SD: 3.7); it was not associated with severe TRTs. Conclusions: The G8 and CARG-tt demonstrated a weak prediction of severe TRT in older Chinese cancer patients. Future studies need to develop predictive tools for TRT in patients receiving novel antineoplastic therapies, with a focus on subgroup analysis for different populations

Will the community nurse continue to function during H1N1 influenza pandemic: a cross-sectional study of Hong Kong community nurses?

<p>Abstract</p> <p>Background</p> <p>Healthcare workers have been identified as one of the high risk groups for being infected with influenza during influenza pandemic. Potential levels of absenteeism among healthcare workers in hospital settings are high. However, there was no study to explore the attitudes of healthcare workers in community setting towards the preparedness to the novel H1N1 influenza pandemic. The aim of this study was to explore the willingness of community nurses in Hong Kong to work during H1N1 influenza pandemic.</p> <p>Methods</p> <p>A cross-sectional survey was conducted among all 401 community nurses employed by the Hospital Authority in Hong Kong when the WHO pandemic alert level was 6.</p> <p>Results</p> <p>The response rate of this study was 66.6%. 76.9% participants reported being "not willing" (33.3%) or "not sure" (43.6%) to take care of patients during H1N1 influenza pandemic. The self-reported reasons for being unwilling to report to duty during H1N1 influenza pandemic were psychological stress (55.0%) and fear of being infected H1N1 influenza (29.2%). The reported unwillingness to report to duty was marginally significantly associated with the request for further training of using infection control clinical guideline (OR: 0.057; CI: 0.25-1.02). Those who reported unwillingness or not being sure about taking care of the patients during H1N1 influenza pandemic were more depressed (p < 0.001) and found work more emotionally stressful (p < 0.001).</p> <p>Conclusions</p> <p>Interventions to provide infection control training and address community nurses' psychological needs might increase their willingness to provide care to patients in the community during H1N1 influenza pandemic. This would help to ensure an effective and appropriate health system response during the H1N1 influenza pandemic.</p

Docosahexaenoic Acid Therapy of Experimental Ischemic Stroke

We examined the neuroprotective efficacy of docosahexaenoic acid (DHA), an omega-3 essential fatty acid family member, in acute ischemic stroke; studied the therapeutic window; and investigated whether DHA administration after an ischemic stroke is able to salvage the penumbra. In each series described below, SD rats underwent 2 h of middle cerebral artery occlusion (MCAo). In series 1, DHA or saline was administered i.v. at 3, 4, 5, or 6 h after stroke. In series 2, MRI was conducted on days 1, 3 and 7. In series 3, DHA or saline was administered at 3 h, and lipidomic analysis was conducted on day 3. Treatment with DHA significantly improved behavior and reduced total infarct volume by a mean of 40% when administered at 3 h, by 66% at 4 h, and by 59% at 5 h. Total lesion volumes computed from T2-weighted images were reduced in the DHA group at all time points. Lipidomic analysis showed that DHA treatment potentiates neuroprotectin D1 (NPD1) synthesis in the penumbra 3 days after MCAo. DHA administration provides neurobehavioral recovery, reduces brain infarction and edema, and activates NPD1 synthesis in the penumbra when administered up to 5 h after focal cerebral ischemia in rats

Contributions of Mamu-A*01 Status and TRIM5 Allele Expression, But Not CCL3L Copy Number Variation, to the Control of SIVmac251 Replication in Indian-Origin Rhesus Monkeys

CCL3 is a ligand for the HIV-1 co-receptor CCR5. There have recently been conflicting reports in the literature concerning whether CCL3-like gene (CCL3L) copy number variation (CNV) is associated with resistance to HIV-1 acquisition and with both viral load and disease progression following infection with HIV-1. An association has also been reported between CCL3L CNV and clinical sequelae of the simian immunodeficiency virus (SIV) infection in vivo in rhesus monkeys. The present study was initiated to explore the possibility of an association of CCL3L CNV with the control of virus replication and AIDS progression in a carefully defined cohort of SIVmac251-infected, Indian-origin rhesus monkeys. Although we demonstrated extensive variation in copy number of CCL3L in this cohort of monkeys, CCL3L CNV was not significantly associated with either peak or set-point plasma SIV RNA levels in these monkeys when MHC class I allele Mamu-A*01 was included in the models or progression to AIDS in these monkeys. With 66 monkeys in the study, there was adequate power for these tests if the correlation of CCL3L and either peak or set-point plasma SIV RNA levels was 0.34 or 0.36, respectively. These findings call into question the premise that CCL3L CNV is important in HIV/SIV pathogenesis

Short sleep duration and obesity among Australian children

Extent: 6p.Background: There is limited information on sleep duration and obesity among Australian children. The objective of the study is to cross-sectionally examine the relationship between sleep duration and obesity in Australian children aged 5 to 15 years. Methods: Data were collected using the South Australian Monitoring and Surveillance System between January 2004 and December 2008. Each month a representative random sample of South Australians are selected from the Electronic White Pages with interviews conducted using Computer Assisted Telephone Interviewing (CATI). Within each household, the person who was last to have a birthday was selected for interview. Parents reported the number of hours their children slept each day. Obesity was defined according to the International Obesity Task Force (IOTF) definition based on BMI calculated from reported body weight and height. Results: Overall, parents of 3495 children aged 5-15 years (mean 10.7 years, 50.3% boys) were interviewed. The prevalence of obesity was 7.7% (8.9% in boys, 6.6% in girls). In multivariate analysis after adjusting for sociodemographic variables, intake of fruit and vegetables, physical activity and inactivity, the odds ratio (OR) for obesity comparing sleeping <9 hours with ≥10 hours was 2.23 (95% CI 1.04-4.76) among boys, 1.70(0.78-3.73) among girls, and 1.97(1.15-3.38) in both genders. The association between short sleep (<9 hours) and obesity was stronger in the younger age group. No significant association between short sleep and obesity was found among children aged 13-15. There was also an additive interaction between short sleep and low level of physical activity. Conclusion: Short sleep duration is associated with increased obesity in children especially among younger age groups and boys.Zumin Shi, Anne W Taylor, Tiffany K Gill, Jane Tuckerman, Robert Adams and James Marti

Lipocalin-7 Is a Matricellular Regulator of Angiogenesis

Matricellular proteins are extracellular regulators of cellular adhesion, signaling and performing a variety of physiological behaviors such as proliferation, migration and differentiation. Within vascular microenvironments, matricellular proteins exert both positive and negative regulatory cues to vascular endothelium. The relative balance of these matricellular cues is believed to be critical for vascular homeostasis, angiogenesis activation or angiogenesis resolution. However, our knowledge of matricellular proteins within vascular microenvironments and the mechanisms by which these proteins impact vascular function remain largely undefined. The matricellular protein lipocalin-7 (LCN7) is found throughout vascular microenvironments, and circumstantial evidence suggests that LCN7 may be an important regulator of angiogenesis. Therefore, we hypothesized that LCN7 may be an important regulator of vascular function.To test this hypothesis, we examined the effect of LCN7 overexpression, recombinant protein and gene knockdown in a series of in vitro and in vivo models of angiogenesis. We found that overexpression of LCN7 in MB114 and SVEC murine endothelial cell lines or administration of highly purified recombinant LCN7 protein increased endothelial cell invasion. Similarly, LCN7 increased angiogenic sprouting from quiescent endothelial cell monolayers and ex vivo aortic rings. Moreover, LCN7 increased endothelial cell sensitivity to TGF-β but did not affect sensitivity to other pro-angiogenic growth factors including bFGF and VEGF. Finally, morpholino based knockdown of LCN7 in zebrafish embryos specifically inhibited angiogenic sprouting but did not affect vasculogenesis within injected embryos.No functional analysis has previously been performed to elucidate the function of LCN7 in vascular or other cellular processes. Collectively, our results show for the first time that LCN7 is an important pro-angiogenic matricellular protein of vascular microenvironments

Basonuclin-2 Requirements for Zebrafish Adult Pigment Pattern Development and Female Fertility

Relatively little is known about the generation of adult form. One complex adult trait that is particularly amenable to genetic and experimental analysis is the zebrafish pigment pattern, which undergoes extensive remodeling during post-embryonic development to form adult stripes. These stripes result from the arrangement of three classes of neural crest-derived pigment cells, or chromatophores: melanophores, xanthophores, and iridophores. Here, we analyze the zebrafish bonaparte mutant, which has a normal early pigment pattern but exhibits a severe disruption to the adult stripe pattern. We show that the bonaparte mutant phenotype arises from mutations in basonuclin-2 (bnc2), encoding a highly conserved, nuclear-localized zinc finger protein of unknown function. We show that bnc2 acts non-autonomously to the melanophore lineage and is expressed by hypodermal cells adjacent to chromatophores during adult pigment pattern formation. In bonaparte (bnc2) mutants, all three types of chromatophores differentiate but then are lost by extrusion through the skin. We further show that while bnc2 promotes the development of two genetically distinct populations of melanophores in the body stripes, chromatophores of the fins and scales remain unaffected in bonaparte mutants, though a requirement of fin chromatophores for bnc2 is revealed in the absence of kit and colony stimulating factor-1 receptor activity. Finally, we find that bonaparte (bnc2) mutants exhibit dysmorphic ovaries correlating with infertility and bnc2 is expressed in somatic ovarian cells, whereas the related gene, bnc1, is expressed within oocytes; and we find that both bnc2 and bnc1 are expressed abundantly within the central nervous system. These findings identify bnc2 as an important mediator of adult pigment pattern formation and identify bonaparte mutants as an animal model for dissecting bnc2 functions

Protocol for the ROSE sustainment (ROSES) study, a sequential multiple assignment randomized trial to determine the minimum necessary intervention to maintain a postpartum depression prevention program in prenatal clinics serving low-income women

Background: More research on sustainment of interventions is needed, especially return on investment (ROI) studies to determine cost-benefit trade-offs for effort required to sustain and how much is gained when effective programs are sustained. The ROSE sustainment (ROSES) study uses a sequential multiple assignment randomized (SMART) design to evaluate the effectiveness and cost-effectiveness of a stepwise approach to sustainment of the ROSE postpartum depression prevention program in 90 outpatient clinics providing prenatal care to pregnant women on public assistance. Postpartum depression (PPD) is common and can have lasting consequences. Outpatient clinics offering prenatal care are an opportune place to provide PPD prevention because most women visit while pregnant. The ROSE (Reach Out, Stay Strong, Essentials for mothers of newborns) program is a group educational intervention to prevent PPD, delivered during pregnancy. ROSE has been found to reduce cases of PPD in community prenatal settings serving low-income pregnant women. Methods: All 90 prenatal clinics will receive enhanced implementation as usual (EIAU; initial training + tools for sustainment). At the first time at which a clinic is determined to be at risk for failure to sustain (i.e., at 3, 6, 9, 12, and 15 months), that clinic will be randomized to receive either (1) no additional implementation support (i.e., EIAU only), or (2) low-intensity coaching and feedback (LICF). If clinics receiving LICF are still at risk at subsequent assessments, they will be randomized to either (1) EIAU + LICF only, or (2) high-intensity coaching and feedback (HICF). Additional follow-up interviews will occur at 18, 24, and 30 months, but no implementation intervention will occur after 18 months. Outcomes include (1) percent sustainment of core program elements at each time point, (2) health impact (PPD rates over time at each clinic) and reach, and (3) ROI (costs and cost-effectiveness) of each sustainment step. Hypothesized mechanisms include sustainment of capacity to deliver core elements and engagement/ownership. Discussion: This study is the first randomized trial evaluating the ROI of a stepped approach to sustainment, a critical unanswered question in implementation science. It will also advance knowledge of implementation mechanisms and clinical care for an at-risk population

Deficits in Inhibitory Control in Smokers During a Go/NoGo Task: An Investigation Using Event-Related Brain Potentials

Contains fulltext : 119553.pdf (publisher's version ) (Open Access)Introduction: The role of inhibitory control in addictive behaviors is highlighted in several models of addictive behaviors. Although reduced inhibitory control has been observed in addictive behaviors, it is inconclusive whether this is evident in smokers. Furthermore, it has been proposed that drug abuse individuals with poor response inhibition may experience greater difficulties not consuming substances in the presence of drug cues. The major aim of the current study was to provide electrophysiological evidence for reduced inhibitory control in smokers and to investigate whether this is more pronounced during smoking cue exposure. Methods: Participants (19 smokers and 20 non-smoking controls) performed a smoking Go/NoGo task. Behavioral accuracy and amplitudes of the N2 and P3 event-related potential (ERP), both reflecting aspects of response inhibition, were the main variables of interest. Results: Reduced NoGo N2 amplitudes in smokers relative to controls were accompanied by decreased task performance, whereas no differences between groups were found in P3 amplitudes. This was found to represent a general lack of inhibition in smokers, and not dependent on the presence of smoking cues. Conclusions: The current results suggest that smokers have difficulties with response inhibition, which is an important finding that eventually can be implemented in smoking cessation programs. More research is needed to clarify the exact role of cue exposure on response inhibition.7 p