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1.  A Phase II Trial of a Combination Herbal Supplement for Men with Biochemically Recurrent Prostate Cancer 
Background
Men with biochemical recurrence (BCR) of prostate cancer are typically observed or treated with androgen deprivation therapy. Non-hormonal, non-toxic treatments to slow the rise of PSA are desirable. We studied a combination herbal supplement, Prostate Health Cocktail (PHC), in prostate cancer cell lines and in a population of men with BCR.
Methods
PC3, LAPC3, and LNCaP cells were incubated with increasing concentrations of PHC suspension. Men previously treated for prostate cancer with surgery, radiation, or both with rising PSA but no radiographic metastases were treated with 3 capsules of PHC daily; the primary endpoint was 50% PSA decline. Circulating tumor cells (CTCs) were identified using parylene membrane filters.
Results
PHC showed a strong dose-dependent anti-proliferative effect in androgen-sensitive and independent cell lines in vitro and suppression of androgen receptor expression. 40 eligible patients were enrolled in the clinical trial. Median baseline PSA was 2.8 ng/mL (1.1-84.1) and 15 men (38%) had a PSA decline on study (1%-55% reduction) ; 25 (62%) had rising PSA on study. The median duration of PSA stability was 6.4 months. Two patients had grade 2/3 transaminitis; the only other grade 2 toxicities were hyperglycemia, hypercalcemia and flatulence. There were no significant changes in testosterone or dihydrotestosterone. CTCs were identified in 19 men (47%).
Conclusion
Although the primary endpoint was not met, Prostate Health Cocktail was well tolerated and was associated with PSA declines and stabilization in a significant number of patients. This is the first report of detecting CTCs in men with BCR prostate cancer. Randomized studies are needed to better define the effect of PHC in men with BCR.
doi:10.1038/pcan.2014.37
PMCID: PMC4234307  PMID: 25245366
2.  COMT Associations with Disordered Gambling and Drinking Measures 
Disordered gambling and alcohol dependence are influenced by unique and shared genetic factors. Although the evidence is mixed, some research has linked COMT rs4680 (or COMT Val158Met) to the development of gambling or drinking problems; however, no molecular genetic study has jointly examined gambling and drinking problems. Furthermore, the majority of past studies examined gambling or drinking problems using a case-control design. The purpose of the current study was to examine associations of COMT rs4680 with dimensionally and categorically measured gambling and drinking problems in a nonclinical sample (139 Caucasian adults). The current study found that COMT rs4680 was related to both dimensionally and categorically measured gambling and drinking problems. It appears that the COMT Met/Met genotype may be a genetic risk factor that contributes to the development of both gambling and drinking problems.
doi:10.1007/s10899-013-9434-1
PMCID: PMC4082478  PMID: 24390676
alcohol use; COMT gene; gambling; South Oaks Gambling Screen; Michigan Alcoholism Screening Test
3.  The role of primary care in cancer diagnosis via emergency presentation: qualitative synthesis of significant event reports 
British Journal of Cancer  2015;112(Suppl 1):S50-S56.
Background:
Patients diagnosed with cancer in the context of an emergency presentation (EP) have poorer outcomes. It is often assumed that such patients present to the emergency department without consulting their general practitioner (GP). Little work has been done to identify primary care involvement before hospital attendance.
Methods:
Participating primary care practices completed a significant event audit (SEA) report for the last patient diagnosed with cancer as a result of an EP. Accounts were synthesised and a qualitative approach to analysis undertaken.
Results:
SEAs for 222 patients were analysed. A range of cancers were included, the most common being lung (32.4%) and upper gastrointestinal (19.8%). In most cases, patients had contact with their practice before diagnosis, primarily in the period immediately before admission. In only eight cases had there been no input from primary care. Accounts of protracted primary care contact generally demonstrated complexity, often related to comorbidity, patient-mediated factors or reassurance provided by negative investigations. Learning points identified by practices centred on the themes of presentation and diagnosis, consultation and safety-netting, communication and system issues, patient factors and referral guidelines.
Conclusions:
There is extensive primary care input into patients whose diagnosis results from EP, and for the most part potential ‘delay' in referral can be reasonably explained by the complexity of the presentation or by coexisting patient factors.
doi:10.1038/bjc.2015.42
PMCID: PMC4385976  PMID: 25734395
emergency presentation; significant event; primary care; qualitative
4.  Is increased time to diagnosis and treatment in symptomatic cancer associated with poorer outcomes? Systematic review 
British Journal of Cancer  2015;112(Suppl 1):S92-S107.
Background:
It is unclear whether more timely cancer diagnosis brings favourable outcomes, with much of the previous evidence, in some cancers, being equivocal. We set out to determine whether there is an association between time to diagnosis, treatment and clinical outcomes, across all cancers for symptomatic presentations.
Methods:
Systematic review of the literature and narrative synthesis.
Results:
We included 177 articles reporting 209 studies. These studies varied in study design, the time intervals assessed and the outcomes reported. Study quality was variable, with a small number of higher-quality studies. Heterogeneity precluded definitive findings. The cancers with more reports of an association between shorter times to diagnosis and more favourable outcomes were breast, colorectal, head and neck, testicular and melanoma.
Conclusions:
This is the first review encompassing many cancer types, and we have demonstrated those cancers in which more evidence of an association between shorter times to diagnosis and more favourable outcomes exists, and where it is lacking. We believe that it is reasonable to assume that efforts to expedite the diagnosis of symptomatic cancer are likely to have benefits for patients in terms of improved survival, earlier-stage diagnosis and improved quality of life, although these benefits vary between cancers.
doi:10.1038/bjc.2015.48
PMCID: PMC4385982  PMID: 25734382
systematic review; diagnosis; delays; survival; stage
5.  Psychopharmacological characterisation of the successive negative contrast effect in rats 
Psychopharmacology  2015;232(15):2697-2709.
Rationale
Successive negative contrast (SNC) describes a change in the behaviour of an animal following a downshift in the quantitative or qualitative value of an expected reward. This behavioural response has been hypothesised to be linked to affective state, with negative states associated with larger and/or prolonged shifts in behaviour.
Objective
This study has investigated whether different psychopharmacological treatments have dissociable actions on the SNC effect in rats and related these findings to their actions on different neurotransmitter systems and affective state.
Methods
Animals were trained to perform a nose-poke response to obtain a high-value food reward (four pellets). SNC was quantified during devalue sessions in which the reward was reduced to one pellet. Using a within-subject study design, the effects of acute treatment with anxiolytic, anxiogenic, antidepressant and dopaminergic drugs were investigated during both baseline (four pellets) or devalue sessions (one pellet).
Results
The indirect dopamine agonist, amphetamine, attenuated the SNC effect whilst the D1/D2 antagonist, alpha-flupenthixol, potentiated it. The antidepressant citalopram, anxiolytic buspirone and anxiogenic FG7142 had no specific effects on SNC, although FG7142 induced general impairments at higher doses. The α2-adrenoceptor antagonist, yohimbine, increased premature responding but had no specific effect on SNC. Results for the anxiolytic diazepam were mixed with one group showing an attenuation of the SNC effect whilst the other showed no effect.
Conclusions
These data suggest that the SNC effect is mediated, at least in part, by dopamine signalling. The SNC effect may also be attenuated by benzodiazepine anxiolytics.
doi:10.1007/s00213-015-3905-2
PMCID: PMC4502301  PMID: 25791190
Anxiety; Antidepressant; Affective state; Behaviour; Monoamine transmitters
6.  Aggregate Risk of Cardiovascular Disease among Adolescents Perinatally Infected with the Human Immunodeficiency Virus 
Circulation  2013;129(11):1204-1212.
Background
Perinatally HIV-infected adolescents may be susceptible to aggregate atherosclerotic cardiovascular disease (CVD) risk, as measured by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries (CA) and abdominal aorta (AA) risk scores, due to prolonged exposure to HIV and antiretroviral therapy.
Methods and Results
CA and AA PDAY scores were calculated for 165 perinatally HIV-infected adolescents, using a weighted combination of modifiable risk factors: dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. Demographic and HIV-specific predictors of scores ≥ 1 were identified and trends in scores over time were assessed. 48% and 24% of the perinatally HIV-infected adolescents had CA and AA scores ≥ 1, representing increased CVD risk factor burden. Significant predictors of CA scores ≥ 1 included male sex, history of an AIDS-defining condition, longer duration of use of a ritonavir-boosted protease inhibitor, and no prior use of tenofovir. Significant predictors of AA scores ≥ 1 included suppressed viral load, history of an AIDS-defining condition, and longer duration of boosted protease inhibitor use. No significant changes in CA and AA risk scores were observed over the 4-year study period.
Conclusions
A substantial proportion of perinatally HIV-infected youth have high PDAY scores reflecting increased aggregate atherosclerotic CVD risk factor burden. High scores were predicted by HIV disease severity and boosted protease inhibitor use. PDAY scores may be useful in identifying high-risk youth who may benefit from early lifestyle or clinical interventions.
doi:10.1161/CIRCULATIONAHA.113.001978
PMCID: PMC3991841  PMID: 24366631
Perinatally HIV-infected adolescents; cardiovascular disease; boosted protease inhibitor use
7.  Setting Up the JBrowse Genome Browser 
JBrowse is a web-based tool for visualizing genomic data. Unlike most other web-based genome browsers, JBrowse exploits the capabilities of the user's web browser to make scrolling and zooming fast and smooth. It supports the browsers used by almost all internet users, and is relatively simple to install. JBrowse can utilize multiple types of data in a variety of common genomic data formats, including genomic feature data in bioperl databases, GFF files, and BED files, and quantitative data in wiggle files. This unit describes how to obtain the JBrowse software, set it up on a Linux or Mac OS X computer running as a web server and incorporate genome annotation data from multiple sources into JBrowse. After completing the protocols described in this unit, the reader will have a web site that other users can visit to browse the genomic data.
doi:10.1002/0471250953.bi0913s32
PMCID: PMC4350995  PMID: 21154710
genome browser; visualization; jbrowse; gff; bed; wiggle; genbank
8.  Genetically Engineered Mice as Experimental Tools to Dissect the Critical Events in Breast Cancer 
Advances in cancer research  2014;121:331-382.
Elucidating the mechanism of pathogenesis of breast cancer has greatly benefited from breakthrough advances in both genetically engineered mouse (GEM) models and xenograft transplantation technologies. The vast array of breast cancer mouse models currently available is testimony to the complexity of mammary tumorigenesis and attempts by investigators to accurately portray the heterogeneity and intricacies of this disease. Distinct molecular changes that drive various aspects of tumorigenesis, such as alterations in tumor cell proliferation and apoptosis, invasion and metastasis, angiogenesis, and drug resistance have been evaluated using the currently available GEM breast cancer models. GEM breast cancer models are also being exploited to evaluate and validate the efficacy of novel therapeutics, vaccines, and imaging modalities for potential use in the clinic. This review provides a synopsis of the various GEM models that are expanding our knowledge of the nuances of breast cancer development and progression and can be instrumental in the development of novel prevention and therapeutic approaches for this disease.
doi:10.1016/B978-0-12-800249-0.00008-1
PMCID: PMC4349377  PMID: 24889535
9.  Molecular-Genetic Imaging of Cancer 
Advances in cancer research  2014;124:131-169.
Molecular-genetic imaging of cancer using nonviral delivery systems has great potential for clinical application as a safe, efficient, noninvasive tool for visualization of various cellular processes including detection of cancer, and its attendant metastases. In recent years, significant effort has been expended in overcoming technical hurdles to enable clinical adoption of molecular-genetic imaging. This chapter will provide an introduction to the components of molecular-genetic imaging and recent advances on each component leading to safe, efficient clinical applications for detecting cancer. Combination with therapy, namely, generating molecular-genetic theranostic constructs, will provide further impetus for clinical translation of this promising technology.
doi:10.1016/B978-0-12-411638-2.00004-5
PMCID: PMC4339000  PMID: 25287688
10.  Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24 
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis and modulation of antitumor immune responses. In our study, we elucidated the role of MDA-7/IL-24 in inhibiting growth of breast cancer-initiating/stem cells. Ad.mda-7 infection decreased proliferation of breast cancer-initiating/stem cells without affecting normal breast stem cells. Ad.mda-7 induced apoptosis and endoplasmic reticulum stress in breast cancer-initiating/stem cells similar to unsorted breast cancer cells and inhibited the self-renewal property of breast cancer-initiating/stem cells by suppressing Wnt/β-catenin signaling. Prevention of inhibition of Wnt signaling by LiCl increased cell survival upon Ad.mda-7 treatment, suggesting that Wnt signaling inhibition might play a key role in MDA-7/IL-24-mediated death of breast cancer-initiating/stem cells. In a nude mouse subcutaneous xenograft model, Ad.mda-7 injection profoundly inhibited growth of tumors generated from breast cancer-initiating/stem cells and also exerted a potent “bystander” activity inhibiting growth of distant uninjected tumors. Further studies revealed that tumor growth inhibition by Ad.mda-7 was associated with a decrease in proliferation and angiogenesis, two intrinsic features of MDA-7/IL-24, and a reduction in vivo in the percentage of breast cancer-initiating/stem cells. Our findings demonstrate that MDA-7/IL-24 is not only nontoxic to normal cells and normal stem cells but also can kill both unsorted cancer cells and enriched populations of cancer-initiating/stem cells, providing further documentation that MDA-7/IL-24 might be a safe and effective way to eradicate cancers and also potentially establish disease-free survival.
doi:10.1002/ijc.28289
PMCID: PMC4334374  PMID: 23720015
MDA-7/IL-24; apoptosis; Wnt signaling; cancer-initiating/stem cells; breast cancer
11.  Expression and Functional Role of Orphan Receptor GPR158 in Prostate Cancer Growth and Progression 
PLoS ONE  2015;10(2):e0117758.
Prostate cancer (PCa) is the second-leading cause of cancer-related mortality, after lung cancer, in men from developed countries. In its early stages, primary tumor growth is dependent on androgens, thus generally can be controlled by androgen deprivation therapy (ADT). Eventually however, the disease progresses to castration-resistant prostate cancer (CRPC), a lethal form in need of more effective treatments. G-protein coupled receptors (GPCRs) comprise a large clan of cell surface proteins that have been implicated as therapeutic targets in PCa growth and progression. The findings reported here provide intriguing evidence of a role for the newly characterized glutamate family member GPR158 in PCa growth and progression. We found that GPR158 promotes PCa cell proliferation independent of androgen receptor (AR) functionality and that this requires its localization in the nucleus of the cell. This suggests that GPR158 acts by mechanisms different from other GPCRs. GPR158 expression is stimulated by androgens and GPR158 stimulates AR expression, implying a potential to sensitize tumors to low androgen conditions during ADT via a positive feedback loop. Further, we found GPR158 expression correlates with a neuroendocrine (NE) differentiation phenotype and promotes anchorage-independent colony formation implying a role for GPR158 in therapeutic progression and tumor formation. GPR158 expression was increased at the invading front of prostate tumors that formed in the genetically defined conditional Pten knockout mouse model, and co-localized with elevated AR expression in the cell nucleus. Kaplan-Meier analysis on a dataset from the Memorial Sloan Kettering cancer genome portal showed that increased GPR158 expression in tumors is associated with lower disease-free survival. Our findings strongly suggest that pharmaceuticals targeting GPR158 activities could represent a novel and innovative approach to the prevention and management of CRPC.
doi:10.1371/journal.pone.0117758
PMCID: PMC4333349  PMID: 25693195
12.  Reduced-Intensity Allogeneic Transplantation Using Alemtuzumab from HLA-Matched Related, Unrelated, or Haploidentical Related Donors for Patients with Hematologic Malignancies 
We present a comparative study on 124 patients with hematologic malignancies who had undergone reduced-intensity conditioning and then received a transplant from an HLA-matched related (MRD), an HLA-matched unrelated (MUD), or an HLA-haploidentical related (HAPLO) donor. The conditioning regimen, which consisted of fludarabine, melphalan or busulfan, and alemtuzumab was administered to patients with lymphoid (n = 62) or myeloid disease (n = 62). Mycophenolate mofetil was used as prophylaxis for graft-versus-host disease (GVHD), and 38, 58, and 33 patients received transplants from MRD, MUD, and HAPLO donors, respectively. Only 2 patients experienced primary graft failure (GF) after melphalan-based regimen, whereas 8 of the 17 patients who received a transplant from HAPLO donors experienced a primary GF after busulfan-based regimen. The cumulative incidence of grade III to IV acute GVHD in engrafted patients who had received transplants from MRD, MUD, or HAPLO donors was 3%, 11%, and 27%, respectively, and the 2-year overall survival (OS) rates were 51%, 22%, and 23%, respectively. According to multivariate analysis, transplantation from either MUD or HAPLO donors compared with MRD were adverse factors that affected the OS (P = .006 and P = .002, respectively). In conclusion, the reduced-intensity regimen that included fludarabine, busulfan, or melphalan and alemtuzumab using only mycophenolate mofetil as the GVHD prophylaxis conferred favorable outcomes in the MRD group but lower survival rates in the MUD and HAPLO groups. The busulfan-based regimen led to a high incidence of GF in the HAPLO group, suggesting the need for modification or intensification of immunosuppression.
doi:10.1016/j.bbmt.2013.11.010
PMCID: PMC4140655  PMID: 24269380
Reduced-intensity; Alemtuzumab; Matched-related; Matched-unrelated; Haploidentical
13.  MDA-9/syntenin is a key regulator of glioma pathogenesis 
Neuro-Oncology  2013;16(1):50-61.
Background
The extraordinary invasiveness of human glioblastoma multiforme (GBM) contributes to treatment failure and the grim prognosis of patients diagnosed with this tumor. Consequently, it is imperative to define further the cellular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene–9 (MDA-9/syntenin) is a highly conserved PDZ domain–containing scaffolding protein that promotes invasion and metastasis in vitro and in vivo in human melanoma models. To determine whether MDA-9/syntenin is a relevant target in GBM, we investigated its expression in tumor samples and involvement in GBM invasion and angiogenesis.
Materials
We assessed MDA-9/syntenin levels in available databases, patient tumor samples, and human-derived cell lines. Through gain-of-function and loss-of-function studies, we analyzed changes in invasion, angiogenesis, and signaling in vitro. We used orthotopic xenografts with GBM6 cells to demonstrate the role of MDA-9/syntenin in GBM pathogenesis in vivo.
Results
MDA-9/syntenin expression in high-grade astrocytomas is significantly higher than normal tissue counterparts. Forced overexpression of MDA-9/syntenin enhanced Matrigel invasion, while knockdown inhibited invasion, migration, and anchorage-independent growth in soft agar. Moreover, overexpression of MDA-9/syntenin increased activation of c-Src, p38 mitogen-activated protein kinase, and nuclear factor kappa-B, leading to elevated expression of matrix metalloproteinase 2 and secretion of interleukin-8 with corresponding changes observed upon knockdown. GBM6 cells that stably express small hairpin RNA for MDA-9/syntenin formed smaller tumors and had a less invasive phenotype in vivo.
Conclusions
Our findings indicate that MDA-9/syntenin is a novel and important mediator of invasion in GBM and a key regulator of pathogenesis, and we identify it as a potential target for anti-invasive treatment in human astrocytoma.
doi:10.1093/neuonc/not157
PMCID: PMC3870820  PMID: 24305713
MDA-9/syntenin; GBM; glioma; invasion; intracranial injection
14.  DTI measures track and predict motor function outcomes in stroke rehabilitation utilizing BCI technology 
Tracking and predicting motor outcomes is important in determining effective stroke rehabilitation strategies. Diffusion tensor imaging (DTI) allows for evaluation of the underlying structural integrity of brain white matter tracts and may serve as a potential biomarker for tracking and predicting motor recovery. In this study, we examined the longitudinal relationship between DTI measures of the posterior limb of the internal capsule (PLIC) and upper-limb motor outcomes in 13 stroke patients (median 20-month post-stroke) who completed up to 15 sessions of intervention using brain–computer interface (BCI) technology. Patients’ upper-limb motor outcomes and PLIC DTI measures including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were assessed longitudinally at four time points: pre-, mid-, immediately post- and 1-month-post intervention. DTI measures and ratios of each DTI measure comparing the ipsilesional and contralesional PLIC were correlated with patients’ motor outcomes to examine the relationship between structural integrity of the PLIC and patients’ motor recovery. We found that lower diffusivity and higher FA values of the ipsilesional PLIC were significantly correlated with better upper-limb motor function. Baseline DTI ratios were significantly correlated with motor outcomes measured immediately post and 1-month-post BCI interventions. A few patients achieved improvements in motor recovery meeting the minimum clinically important difference (MCID). These findings suggest that upper-limb motor recovery in stroke patients receiving BCI interventions relates to the microstructural status of the PLIC. Lower diffusivity and higher FA measures of the ipsilesional PLIC contribute toward better motor recovery in the stroke-affected upper-limb. DTI-derived measures may be a clinically useful biomarker in tracking and predicting motor recovery in stroke patients receiving BCI interventions.
doi:10.3389/fnhum.2015.00195
PMCID: PMC4410488  PMID: 25964753
DTI; fractional anisotropy; axial diffusivity; radial diffusivity; mean diffusivity; motor recovery; stroke rehabilitation; brain-computer interface
15.  Dose-response relationships using brain–computer interface technology impact stroke rehabilitation 
Brain–computer interfaces (BCIs) are an emerging novel technology for stroke rehabilitation. Little is known about how dose-response relationships for BCI therapies affect brain and behavior changes. We report preliminary results on stroke patients (n = 16, 11 M) with persistent upper extremity motor impairment who received therapy using a BCI system with functional electrical stimulation of the hand and tongue stimulation. We collected MRI scans and behavioral data using the Action Research Arm Test (ARAT), 9-Hole Peg Test (9-HPT), and Stroke Impact Scale (SIS) before, during, and after the therapy period. Using anatomical and functional MRI, we computed Laterality Index (LI) for brain activity in the motor network during impaired hand finger tapping. Changes from baseline LI and behavioral scores were assessed for relationships with dose, intensity, and frequency of BCI therapy. We found that gains in SIS Strength were directly responsive to BCI therapy: therapy dose and intensity correlated positively with increased SIS Strength (p ≤ 0.05), although no direct relationships were identified with ARAT or 9-HPT scores. We found behavioral measures that were not directly sensitive to differences in BCI therapy administration but were associated with concurrent brain changes correlated with BCI therapy administration parameters: therapy dose and intensity showed significant (p ≤ 0.05) or trending (0.05 < p < 0.1) negative correlations with LI changes, while therapy frequency did not affect LI. Reductions in LI were then correlated (p ≤ 0.05) with increased SIS Activities of Daily Living scores and improved 9-HPT performance. Therefore, some behavioral changes may be reflected by brain changes sensitive to differences in BCI therapy administration, while others such as SIS Strength may be directly responsive to BCI therapy administration. Data preliminarily suggest that when using BCI in stroke rehabilitation, therapy frequency may be less important than dose and intensity.
doi:10.3389/fnhum.2015.00361
PMCID: PMC4477141  PMID: 26157378
dose-response; brain–computer interface; stroke rehabilitation; BCI therapy; UE motor recovery; fMRI
17.  Systemic insecticides (neonicotinoids and fipronil): trends, uses, mode of action and metabolites 
Since their discovery in the late 1980s, neonicotinoid pesticides have become the most widely used class of insecticides worldwide, with large-scale applications ranging from plant protection (crops, vegetables, fruits), veterinary products, and biocides to invertebrate pest control in fish farming. In this review, we address the phenyl-pyrazole fipronil together with neonicotinoids because of similarities in their toxicity, physicochemical profiles, and presence in the environment. Neonicotinoids and fipronil currently account for approximately one third of the world insecticide market; the annual world production of the archetype neonicotinoid, imidacloprid, was estimated to be ca. 20,000 tonnes active substance in 2010. There were several reasons for the initial success of neonicotinoids and fipronil: (1) there was no known pesticide resistance in target pests, mainly because of their recent development, (2) their physicochemical properties included many advantages over previous generations of insecticides (i.e., organophosphates, carbamates, pyrethroids, etc.), and (3) they shared an assumed reduced operator and consumer risk. Due to their systemic nature, they are taken up by the roots or leaves and translocated to all parts of the plant, which, in turn, makes them effectively toxic to herbivorous insects. The toxicity persists for a variable period of time—depending on the plant, its growth stage, and the amount of pesticide applied. A wide variety of applications are available, including the most common prophylactic non-Good Agricultural Practices (GAP) application by seed coating. As a result of their extensive use and physicochemical properties, these substances can be found in all environmental compartments including soil, water, and air. Neonicotinoids and fipronil operate by disrupting neural transmission in the central nervous system of invertebrates. Neonicotinoids mimic the action of neurotransmitters, while fipronil inhibits neuronal receptors. In doing so, they continuously stimulate neurons leading ultimately to death of target invertebrates. Like virtually all insecticides, they can also have lethal and sublethal impacts on non-target organisms, including insect predators and vertebrates. Furthermore, a range of synergistic effects with other stressors have been documented. Here, we review extensively their metabolic pathways, showing how they form both compound-specific and common metabolites which can themselves be toxic. These may result in prolonged toxicity. Considering their wide commercial expansion, mode of action, the systemic properties in plants, persistence and environmental fate, coupled with limited information about the toxicity profiles of these compounds and their metabolites, neonicotinoids and fipronil may entail significant risks to the environment. A global evaluation of the potential collateral effects of their use is therefore timely. The present paper and subsequent chapters in this review of the global literature explore these risks and show a growing body of evidence that persistent, low concentrations of these insecticides pose serious risks of undesirable environmental impacts.
doi:10.1007/s11356-014-3470-y
PMCID: PMC4284386  PMID: 25233913
Neonicotinoid; Fipronil; Trends; Mechanism of action; Agriculture; Seed treatment; Systemic insecticides; Metabolites
18.  MDA-9/Syntenin regulates differentiation and angiogenesis programs in head and neck squamous cell carcinoma 
Oncoscience  2014;1(11):725-737.
Little is known about the molecular pathways regulating poor differentiation and invasion of head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to determine the role of MDA-9/Syntenin, a metastasis associated molecule in HNSCC tumorigenesis. Elevated MDA-9/Syntenin expression was evident in 67% (54/81) primary HNSCC tumors (p=0.001-0.002) and 69% (9/13) pre-neoplastic tissues (p=0.02-0.03). MDA-9/Syntenin overexpression was associated with the stage (p=0.001), grade (p=0.001) and lymph node metastasis (p=0.0001). Silencing of MDA-9/Syntenin in 3 poorly differentiated HNSCC cell lines induced squamous epithelial cell differentiation, disrupted angiogenesis and reduced tumor growth in vitro and in vivo. We confirmed SPRR1B and VEGFR1 as the key molecular targets of MDA-9/Syntenin on influencing HNSCC differentiation and angiogenesis respectively. MDA-9/Syntenin disrupted SPRR1B expression interacting through its PDZ1 domain and altered VEGFR1 expression in vitro and in vivo. VEGFR1 co-localized with MDA-9/Syntenin in HNSCC cell lines and primary tumor. Downregulation of growth regulatory molecules CyclinD1, CDK4, STAT3, PI3K and CTNNB1 was also evident in the MDA-9/Syntenin depleted cells, which was reversed following over-expression of MDA-9/Syntenin in immortalized oral epithelial cells. Our results suggest that early induction of MDA-9/Syntenin expression influences HNSCC progression and should be further evaluated for potential biomarker development.
PMCID: PMC4278274  PMID: 25593999
Head and neck suqamous cell carcinoma; MDA-9/Syntenin; differentiation; SPRR1B; VEGFR1
19.  Bone Mineral Density in Children and Adolescents with Perinatal HIV Infection 
AIDS (London, England)  2013;27(2):211-220.
Objective
To estimate prevalence of low bone mineral density (BMD) in perinatally HIV infected (HIV+) and HIV-exposed but uninfected (HEU) children, and to determine predictors of BMD in HIV+.
Design
Cross-sectional analysis within a 15-site United States and Puerto Rico cohort study.
Methods
Total body (TB) and lumbar spine (LS) BMD were measured using dual energy-xray absorptiometry. BMD Z-scores accounted for bone age and sex. Multiple linear regression was used to evaluate differences in Z-scores by HIV status and for predictors of BMD in HIV+.
Results
350 HIV+ and 160 HEU were enrolled. Mean age was 12.6 and 10.7 years for HIV+ and HEU, respectively. Most (87%) HIV+ were receiving highly active antiretroviral therapy (HAART). More HIV+ than HEU had TB and LS Z-scores < -2.0 (TB: 7% vs. 1%, p=0.008; LS: 4% vs. 1%, p=0.08). Average differences in Z-scores between HIV+ and HEU were attenuated after height and/or weight adjustment. Among HIV+, TB Z-scores were lower in those with higher CD4% and in those who ever used boosted protease inhibitors or lamivudine. LS Z-scores were lower with higher peak viral load and CD4%, more years on HAART, and ever use of indinavir.
Conclusions
Rates of low BMD in HIV+ children were greater than expected based on normal population distributions. These differences were partially explained by delays in growth. Since most HIV+ children in this study had not entered their pubertal growth spurt, prepubertal factors associated with BMD, magnified or carried forward, may result in sub-optimal peak BMD in adulthood.
doi:10.1097/QAD.0b013e32835a9b80
PMCID: PMC4157938  PMID: 23032412
Anti-retroviral agents; Bone age; Bone mineral density; HIV; Children; CD4; Viral load
20.  Novel Role of MDA-9/Syntenin in Regulating Urothelial Cell Proliferation by Modulating EGFR Signaling 
Purpose
Urothelial cell carcinoma (UCC) rapidly progresses from superficial to muscle-invasive tumors. The key molecules involved in metastatic progression and its early detection require clarification. The present study defines a seminal role of the metastasis-associated gene MDA-9/Syntenin in UCC progression.
Experimental Design
Expression pattern of MDA-9/Syntenin was examined in 44 primary UCC and the impact of its overexpression and knock down was examined in multiple cells lines and key findings were validated in primary tumors.
Results
Significantly higher (p= 0.002–0.003) expression of MDA-9/Syntenin was observed in 64% (28/44) of primary tumors and an association was evident with stage (p=0.01), grade (p=0.03) and invasion status (p=0.02). MDA-9/Syntenin overexpression in non-tumorigenic HUC-1 cells increased proliferation (p=0.0012), invasion (p=0.0001) and EGFR, AKT, PI3K and c-Src expression. Alteration of Beta-catenin, E-Cadherin, Vimentin, Claudin-1, ZO-1 and TCF4 expression were also observed. MDA-9/Syntenin knock down in 3 UCC cell lines reversed phenotypic and molecular changes observed in the HUC-1 cells and reduced in vivo metastasis. Key molecular changes observed in the cell lines were confirmed in primary tumors. A physical interaction and co-localization of MDA-9/Syntenin and EGFR was evident in UCC cell lines and primary tumors. A logistic regression model analysis revealed a significant correlation between MDA-9/Syntenin:EGFR and MDA-9/Syntenin: AKT expressions with stage (p=0.04, EGFR), (p=0.01, AKT). A correlation between MDA-9/Syntenin: β-catenin co-expression with stage (p=0.03) and invasion (p=0.04) was also evident.
Conclusions
Our findings indicate that MDA-9/Syntenin might provide an attractive target for developing detection, monitoring and therapeutic strategies for managing UCC.
doi:10.1158/1078-0432.CCR-13-0585
PMCID: PMC3872137  PMID: 23873690
Urothelial cancer; MDA-9/Syntenin; invasion; EGFR signaling
21.  Pubertal Onset in HIV-infected Children in the Era of Combination Antiretroviral Treatment 
AIDS (London, England)  2013;27(12):1959-1970.
Objective
To evaluate associations of perinatal HIV infection (PHIV), HIV disease severity, and combination antiretroviral treatment with age at pubertal onset.
Design
Analysis of data from two U.S. longitudinal cohort studies [IMPAACT 219C and PHACS AMP], conducted 2000–2012, including PHIV and HIV-exposed uninfected (HEU) youth. Tanner stage assessments of pubertal status (breast and pubic hair in girls; genitalia and pubic hair in boys) were conducted annually.
Methods
We compared the timing of pubertal onset (Tanner stage ≥2) between PHIV and HEU youth using interval-censored models. For PHIV youth, we evaluated associations of HIV disease severity and combination antiretroviral treatment with age at pubertal onset, adjusting for race/ethnicity and birth cohort.
Results
The mean age at pubertal onset was significantly later for the 2086 PHIV youth compared to 453 HEU children (10.3 vs 9.6, 10.5 vs 10.0, 11.3 vs 10.4, and 11.5 vs 10.7 years according to female breast, female pubic hair, male genitalia, and male pubic hair staging, respectively, all p<0.001). PHIV youth with HIV-1 RNA viral load >10,000 copies/mL (vs ≤10,000 copies/mL) or CD4% <15% (vs ≥15%) had significantly later pubertal onset (by 4–13 months). Each additional year of combination antiretroviral treatment was associated with a 0.6- to1.2-month earlier mean age at pubertal onset, but this trend did not persist after adjustment for birth cohort.
Conclusions
Pubertal onset occurs significantly later in PHIV than in HEU youth, especially among those with more severe HIV disease. However, in the current era, combination antiretroviral treatment may result in more normal timing of pubertal onset.
doi:10.1097/QAD.0b013e328361195b
PMCID: PMC4143250  PMID: 24145244
puberty; antiretroviral therapy; protease inhibitors; pediatrics; CD4; viral load; statistics; interval-censored; Tanner stage; BMI
22.  Environmental fate and exposure; neonicotinoids and fipronil 
Systemic insecticides are applied to plants using a wide variety of methods, ranging from foliar sprays to seed treatments and soil drenches. Neonicotinoids and fipronil are among the most widely used pesticides in the world. Their popularity is largely due to their high toxicity to invertebrates, the ease and flexibility with which they can be applied, their long persistence, and their systemic nature, which ensures that they spread to all parts of the target crop. However, these properties also increase the probability of environmental contamination and exposure of nontarget organisms. Environmental contamination occurs via a number of routes including dust generated during drilling of dressed seeds, contamination and accumulation in arable soils and soil water, runoff into waterways, and uptake of pesticides by nontarget plants via their roots or dust deposition on leaves. Persistence in soils, waterways, and nontarget plants is variable but can be prolonged; for example, the half-lives of neonicotinoids in soils can exceed 1,000 days, so they can accumulate when used repeatedly. Similarly, they can persist in woody plants for periods exceeding 1 year. Breakdown results in toxic metabolites, though concentrations of these in the environment are rarely measured. Overall, there is strong evidence that soils, waterways, and plants in agricultural environments and neighboring areas are contaminated with variable levels of neonicotinoids or fipronil mixtures and their metabolites (soil, parts per billion (ppb)-parts per million (ppm) range; water, parts per trillion (ppt)-ppb range; and plants, ppb-ppm range). This provides multiple routes for chronic (and acute in some cases) exposure of nontarget animals. For example, pollinators are exposed through direct contact with dust during drilling; consumption of pollen, nectar, or guttation drops from seed-treated crops, water, and consumption of contaminated pollen and nectar from wild flowers and trees growing near-treated crops. Studies of food stores in honeybee colonies from across the globe demonstrate that colonies are routinely and chronically exposed to neonicotinoids, fipronil, and their metabolites (generally in the 1–100 ppb range), mixed with other pesticides some of which are known to act synergistically with neonicotinoids. Other nontarget organisms, particularly those inhabiting soils, aquatic habitats, or herbivorous insects feeding on noncrop plants in farmland, will also inevitably receive exposure, although data are generally lacking for these groups. We summarize the current state of knowledge regarding the environmental fate of these compounds by outlining what is known about the chemical properties of these compounds, and placing these properties in the context of modern agricultural practices.
doi:10.1007/s11356-014-3332-7
PMCID: PMC4284396  PMID: 25096486
Neonicotinoid; Fipronil; Water; Soil; Dust; Plant; Guttation; Pollen; Nontarget; Bee; Invertebrates; Vertebrates
23.  Rapid Phenotypic and Genomic Change in Response to Therapeutic Pressure in Prostate Cancer Inferred by High Content Analysis of Single Circulating Tumor Cells 
PLoS ONE  2014;9(8):e101777.
Timely characterization of a cancer's evolution is required to predict treatment efficacy and to detect resistance early. High content analysis of single Circulating Tumor Cells (CTCs) enables sequential characterization of genotypic, morphometric and protein expression alterations in real time over the course of cancer treatment. This concept was investigated in a patient with castrate-resistant prostate cancer progressing through both chemotherapy and targeted therapy. In this case study, we integrate across four timepoints 41 genome-wide copy number variation (CNV) profiles plus morphometric parameters and androgen receptor (AR) protein levels. Remarkably, little change was observed in response to standard chemotherapy, evidenced by the fact that a unique clone (A), exhibiting highly rearranged CNV profiles and AR+ phenotype was found circulating before and after treatment. However, clinical response and subsequent progression after targeted therapy was associated with the drastic depletion of clone A, followed by the sequential emergence of two distinct CTC sub-populations that differed in both AR genotype and expression phenotype. While AR- cells with flat or pseudo-diploid CNV profiles (clone B) were identified at the time of response, a new tumor lineage of AR+ cells (clone C) with CNV altered profiles was detected during relapse. We showed that clone C, despite phylogenetically related to clone A, possessed a unique set of somatic CNV alterations, including MYC amplification, an event linked to hormone escape. Interesting, we showed that both clones acquired AR gene amplification by deploying different evolutionary paths. Overall, these data demonstrate the timeframe of tumor evolution in response to therapy and provide a framework for the multi-scale analysis of fluid biopsies to quantify and monitor disease evolution in individual patients.
doi:10.1371/journal.pone.0101777
PMCID: PMC4118839  PMID: 25084170
24.  Classification of Thyroid Nodules Using a Resonance-Frequency–Based Electrical Impedance Spectroscopy: A Preliminary Assessment 
Thyroid  2013;23(7):854-862.
Background
Ultrasound and ultrasound-guided fine-needle aspiration biopsy are considered the most effective approaches for both identifying and classifying thyroid nodules. However, despite continuing improvements in scanner technology and refinements in ultrasound/cytological classification guidelines, indeterminate findings still lead to diagnostic lobectomy under general anesthesia. This study aims to investigate the feasibility of applying a modified noninvasive electrical impedance spectroscopy (EIS) approach to classifying thyroid nodules.
Method
To increase nodule classification sensitivity, we developed a new EIS-based model that introduces an optimized inductance component, which increases the measured signal-to-noise ratio of capacitance variation in and about thyroid nodules. Our model then measures the change of resonance frequency when the positive reactance of the system inductor cancels out the negative reactance of the nodule capacitance in a multi-frequency electrical signal scan. The system is termed “resonance-frequency–based electrical impedance spectroscopy” (REIS). A portable REIS system with multiple probes was assembled and preliminarily tested in our clinical facility. From an ongoing prospective study, an initial data set of 160 REIS examinations including 27 verified cancer cases was used. From the data set, a number of EIS signal features was extracted and analyzed. A multi-feature–based Bayesian Belief Network was built to classify the detected thyroid nodules. A receiver operating characteristic data analysis method was applied to evaluate classification performance.
Results
The results showed that (i) the median resonance frequency measured by the probe nearest to malignant nodules was in general lower than that measured in benign cases, and (ii) the median descending slope of EIS signal sweep curves computed from cancer cases was larger than that computed from benign cases. The Bayesian Belief Network yielded a classification performance as measured by the area under the receiver operating characteristic curve of 0.794 [with a 95% confidence interval of 0.709–0.863].
Conclusions
The study demonstrates that noninvasive measurement of REIS signal features may potentially provide useful supplementary information to assist in classifying between malignant and benign thyroid nodules. Such an approach may ultimately lead to a reduction in the number of unnecessary thyroid surgeries.
doi:10.1089/thy.2012.0413
PMCID: PMC3704105  PMID: 23259723
25.  Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment 
The Journal of Clinical Investigation  2014;124(7):3121-3128.
BACKGROUND. Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo–expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment.
METHODS. In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls.
RESULTS. No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively.
CONCLUSION. UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell–containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation.
TRIAL REGISTRATION. Clinicaltrials.gov NCT01221857.
FUNDING. Gamida Cell Ltd.
doi:10.1172/JCI74556
PMCID: PMC4071379  PMID: 24911148

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