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1.  Quantifying and monitoring overdiagnosis in cancer screening: a systematic review of methods 
Objective To determine the optimal method for quantifying and monitoring overdiagnosis in cancer screening over time.
Design Systematic review of primary research studies of any design that quantified overdiagnosis from screening for nine types of cancer. We used explicit criteria to critically appraise individual studies and assess strength of the body of evidence for each study design (double blinded review), and assessed the potential for each study design to accurately quantify and monitor overdiagnosis over time.
Data sources PubMed and Embase up to 28 February 2014; hand searching of systematic reviews.
Eligibility criteria for selecting studies English language studies of any design that quantified overdiagnosis for any of nine common cancers (prostate, breast, lung, colorectal, melanoma, bladder, renal, thyroid, and uterine); excluded case series, case reports, and reviews that only reported results of other studies.
Results 52 studies met the inclusion criteria. We grouped studies into four methodological categories: (1) follow-up of a well designed randomized controlled trial (n=3), which has low risk of bias but may not be generalizable and is not suitable for monitoring; (2) pathological or imaging studies (n=8), drawing conclusions about overdiagnosis by examining biological characteristics of cancers, a simple design limited by the uncertain assumption that the measured characteristics are highly correlated with disease progression; (3) modeling studies (n=21), which can be done in a shorter time frame but require complex mathematical equations simulating the natural course of screen detected cancer, the fundamental unknown question; and (4) ecological and cohort studies (n=20), which are suitable for monitoring over time but are limited by a lack of agreed standards, by variable data quality, by inadequate follow-up time, and by the potential for population level confounders. Some ecological and cohort studies, however, have addressed these potential weaknesses in reasonable ways.
Conclusions Well conducted ecological and cohort studies in multiple settings are the most appropriate approach for quantifying and monitoring overdiagnosis in cancer screening programs. To support this work, we need internationally agreed standards for ecological and cohort studies and a multinational team of unbiased researchers to perform ongoing analysis.
doi:10.1136/bmj.g7773
PMCID: PMC4332263  PMID: 25569206
2.  Mechanistic Consequences of Chiral Radical Clock Probes: Analysis of the Mononuclear Non-Heme Iron Enzyme HppE with 2-Hydroxy-3-methylenecyclopropyl Radical Clock Substrates 
(S)-2-Hydroxypropylphosphonic acid [(S)-HPP] epoxidase (HppE) is a mononuclear iron enzyme that catalyzes the last step in the biosynthesis of the antibiotic fosfomycin. HppE also processes the (R)-enantiomer of HPP but converts it to 2-oxo-propylphosphonic acid. In this study, all four stereoisomers of 3-methylenecyclopropyl-containing substrate analogues, (2R, 3R)-8, (2R, 3S)-8, (2S, 3R)-8, and (2S, 3S)-8, were synthesized and used as radical probes to investigate the mechanism of the HppE-catalyzed reaction. Upon treatment with HppE, (2S, 3R)-8 and (2S, 3S)-8 were converted via a C1 radical intermediate to the corresponding epoxide products, as anticipated. In contrast, incubation of HppE with (2R, 3R)-8 led to enzyme inactivation, and incubation of HppE with (2R, 3S)-8 yielded the 2-keto product. The former finding is consistent with the formation of a C2 radical intermediate, where the inactivation is likely triggered by radical-induced ring cleavage of the methylenecyclopropyl group. Reaction with (2R, 3S)-8 is predicted to also proceed via a C2 radical intermediate, but no enzyme inactivation and no ring-opened product were detected. These results strongly suggest that an internal electron transfer to the iron center subsequent to C–H homolysis competes with ring-opening in the processing of the C2 radical intermediate. The different outcomes of the reactions with (2R, 3R)-8 and (2R, 3S)-8 demonstrate the need to carefully consider the chirality of substituted cyclopropyl groups as radical reporting groups in studies of enzymatic mechanisms.
doi:10.1021/ja4100035
PMCID: PMC4004275  PMID: 24512048
3.  Faster Replication and Higher Expression Levels of Viral Glycoproteins Give the Vesicular Stomatitis Virus/Measles Virus Hybrid VSV-FH a Growth Advantage over Measles Virus 
Journal of Virology  2014;88(15):8332-8339.
ABSTRACT
VSV-FH is a hybrid vesicular stomatitis virus (VSV) with a deletion of its G glycoprotein and encoding the measles virus (MV) fusion (F) and hemagglutinin (H) envelope glycoproteins. VSV-FH infects cells expressing MV receptors and is fusogenic and effective against myeloma xenografts in mice. We evaluated the fusogenic activities of MV and VSV-FH in relationship to the density of receptor on the target cell surface and the kinetics of F and H expression in infected cells. Using a panel of cells expressing increasing numbers of the MV receptor CD46, we evaluated syncytium size in MV- or VSV-FH-infected cells. VSV-FH is not fusogenic at low CD46 density but requires less CD46 for syncytium formation than MV. The size of each syncytium is larger in VSV-FH-infected cells at a specific CD46 density. While syncytium size reached a plateau and did not increase further in MV-infected CHO cells expressing ≥4,620 CD46 copies/cell, there was a corresponding increase in syncytium size with increases in CD46 levels in VSV-FH-infected CD46-expressing CHO (CHO-CD46) cells. Further analysis in VSV-FH-infected cell lines shows earlier and higher expression of F and H mRNAs and protein. However, VSV-FH cytotoxic activity was reduced by pretreatment of the cells with type I interferon. In contrast, the cytopathic effects are not affected in MV-infected cells. In summary, VSV-FH has significant advantages over MV as an oncolytic virus due to its higher viral yield, faster replication kinetics, and larger fusogenic capabilities but should be used in cancer types with defective interferon signaling pathways.
IMPORTANCE We studied the cytotoxic activity of a vesicular stomatitis/measles hybrid virus (VSV-FH), which is superior to that of measles virus (MV), in different cancer cell lines. We determined that viral RNA and protein were produced faster and in higher quantities in VSV-FH-infected cells. This resulted in the formation of larger syncytia, higher production of infectious particles, and a more potent cytopathic effect in permissive cells. Importantly, VSV-FH, similar to MV, can discriminate between low- and high-expressing CD46 cells, a phenotype important for cancer therapy as the virus will be able to preferentially infect cancer cells that overexpress CD46 over low-CD46-expressing normal cells.
doi:10.1128/JVI.03823-13
PMCID: PMC4135973  PMID: 24829351
4.  Spatial frequency analysis of anisotropic drug transport in tumor samples 
Journal of Biomedical Optics  2014;19(1):015005.
Abstract.
Directional Fourier spatial frequency analysis was used on standard histological sections to identify salient directional bias in the spatial frequencies of stromal and epithelial patterns within tumor tissue. This directional bias is shown to be correlated to the pathway of reduced fluorescent tracer transport. Optical images of tumor specimens contain a complex distribution of randomly oriented aperiodic features used for neoplastic grading that varies with tumor type, size, and morphology. The internal organization of these patterns in frequency space is shown to provide a precise fingerprint of the extracellular matrix complexity, which is well known to be related to the movement of drugs and nanoparticles into the parenchyma, thereby identifying the characteristic spatial frequencies of regions that inhibit drug transport. The innovative computational methodology and tissue validation techniques presented here provide a tool for future investigation of drug and particle transport in tumor tissues, and could potentially be used a priori to identify barriers to transport, and to analyze real-time monitoring of transport with respect to therapeutic intervention.
doi:10.1117/1.JBO.19.1.015005
PMCID: PMC4019416  PMID: 24395585
spatial frequencies; image analysis; pattern recognition; Fourier spectroscopy; backgrounds; anisotropy
5.  Television's Cultivation of American Adolescents' Beliefs about Alcohol and the Moderating Role of Trait Reactance 
Cultivation research has shown that heavy television viewing is linked to audiences' generalized, and often skewed, views of reality. This research investigates whether television viewing is related to adolescents' views about the consequences of drinking and whether psychological trait reactance moderates this cultivation effect. Results from a survey of 445 American teenagers show that cumulative exposure to television is linked to reduced beliefs about alcohol's negative consequences and greater intentions to drink. These effects were greater for adolescents low on trait reactance. This research adds to the general psychological research on trait reactance as a moderator of media influences and makes a substantive contribution towards furthering our understanding of the media and public health concerns that surround risky adolescent behaviors.
doi:10.1080/17482798.2014.863475
PMCID: PMC3963162  PMID: 24678341
cultivation; adolescence; psychological reactance; persuasion; television
6.  The Twist Box Domain is Required for Twist1-induced Prostate Cancer Metastasis 
Molecular cancer research : MCR  2013;11(11):10.1158/1541-7786.MCR-13-0218-T.
Twist1, a basic helix-loop-helix transcription factor, plays a key role during development and is a master regulator of the epithelial-mesenchymal transition (EMT) that promotes cancer metastasis. Structure-function relationships of Twist1 to cancer-related phenotypes are underappreciated, so we studied the requirement of the conserved Twist box domain for metastatic phenotypes in prostate cancer (PCa). Evidence suggests that Twist1 is overexpressed in clinical specimens and correlated with aggressive/metastatic disease. Therefore, we examined a transactivation mutant, Twist1-F191G, in PCa cells using in vitro assays which mimic various stages of metastasis. Twist1 overexpression led to elevated cytoskeletal stiffness and cell traction forces at the migratory edge of cells based on biophysical single-cell measurements. Twist1 conferred additional cellular properties associated with cancer cell metastasis including increased migration, invasion, anoikis resistance, and anchorage-independent growth. The Twist box mutant was defective for these Twist1 phenotypes in vitro. Importantly, we observed a high frequency of Twist1-induced metastatic lung tumors and extra-thoracic metastases in vivo using the experimental lung metastasis assay. The Twist box was required for PCa cells to colonize metastatic lung lesions and extra-thoracic metastases. Comparative genomic profiling revealed transcriptional programs directed by the Twist box that were associated with cancer progression, such as Hoxa9. Mechanistically, Twist1 bound to the Hoxa9 promoter and positively regulated Hoxa9 expression in PCa cells. Finally, Hoxa9 was important for Twist1-induced cellular phenotypes associated with metastasis. These data suggest that the Twist box domain is required for Twist1 transcriptional programs and PCa metastasis.
doi:10.1158/1541-7786.MCR-13-0218-T
PMCID: PMC3833995  PMID: 23982216
Twist1; Twist box; epithelial-mesenchymal transition; prostate cancer; metastasis; Hoxa9
7.  Frequent mutations in chromatin-remodeling genes in pulmonary carcinoids 
Nature communications  2014;5:3518.
Pulmonary carcinoids are rare neuroendocrine tumors of the lung. The molecular alterations underlying the pathogenesis of these tumors have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodeling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40% and 22.2% of the cases respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine tumors, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumors but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin remodeling genes is sufficient to drive transformation in pulmonary carcinoids.
doi:10.1038/ncomms4518
PMCID: PMC4132974  PMID: 24670920
8.  Ablation of Nectin4 Binding Compromises CD46 Usage by a Hybrid Vesicular Stomatitis Virus/Measles Virus 
Journal of Virology  2014;88(4):2195-2204.
Measles virus (MV) immunosuppression is due to infection of SLAM-positive immune cells, whereas respiratory shedding and virus transmission are due to infection of nectin4-positive airway epithelial cells. The vaccine lineage MV strain Edmonston (MV-Edm) acquired an additional tropism for CD46 which is the basis of its oncolytic specificity. VSVFH is a vesicular stomatitis virus (VSV) encoding the MV-Edm F and H entry proteins in place of G. The virus spreads faster than MV-Edm and is highly fusogenic and a potent oncolytic. To determine whether ablating nectin4 tropism from VSVFH might prevent shedding, increasing its safety profile as an oncolytic, or might have any effect on CD46 binding, we generated VSVFH viruses with H mutations that disrupt attachment to SLAM and/or nectin4. Disruption of nectin4 binding reduced release of VSVFH from the basolateral side of differentiated airway epithelia composed of Calu-3 cells. However, because nectin4 and CD46 have substantially overlapping receptor binding surfaces on H, disruption of nectin4 binding compromised CD46 binding and greatly diminished the oncolytic potency of these viruses on human cancer cells. Thus, our results support continued preclinical development of VSVFH without ablation of nectin4 binding.
doi:10.1128/JVI.02628-13
PMCID: PMC3911550  PMID: 24335299
9.  Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC 
Cancer discovery  2013;3(12):1404-1415.
Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond to first generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR T790M mutation. CO-1686 is a novel, irreversible and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR including T790M while exhibiting minimal activity towards the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition (EMT) and demonstrated increased sensitivity to AKT inhibitors. These results suggest CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC.
doi:10.1158/2159-8290.CD-13-0314
PMCID: PMC4048995  PMID: 24065731
NSCLC; EGFR; drug resistance; T790M; EMT
10.  An Initial Investigation of Sexual Minority Youth Involvement in School-Based Extracurricular Activities 
Sexual minority youth are at risk for negative school-based experiences and poor academic outcomes. Yet, little is known about their experiences in positive school-based contexts. Using the National Longitudinal Study of Adolescent Health (1,214 sexual minority and 11,427 heterosexual participants), this study compared participation rates in, predictors of, and outcomes associated with three types of school-based extracurricular activities - sports, arts, and school clubs - by sexual orientation and gender. Findings revealed several significant sexual orientation and gender differences in participation rates in school-based sports, clubs, and arts activities. Further, findings suggested that the outcomes associated with extracurricular activity involvement do not differ by sexual orientation and gender; however, predictors of participation in these domains varied across groups.
doi:10.1111/j.1532-7795.2012.00830.x
PMCID: PMC3811967  PMID: 24187476
Extracurricular activities; sexual minority youth; school belonging; academic achievement
11.  Randomised controlled trial. Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: Trial design and protocol (CONSTRUCT) 
BMJ Open  2014;4(4):e005091.
Introduction
Many patients with ulcerative colitis (UC) present with acute exacerbations needing hospital admission. Treatment includes intravenous steroids but up to 40% of patients do not respond and require emergency colectomy. Mortality following emergency colectomy has fallen, but 10% of patients still die within 3 months of surgery. Infliximab and ciclosporin, both immunosuppressive drugs, offer hope for treating steroid-resistant UC as there is evidence of their short-term effectiveness. As there is little long-term evidence, this pragmatic randomised trial, known as Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: a Trial (CONSTRUCT), aims to compare the clinical and cost-effectiveness of infliximab and ciclosporin for steroid-resistant UC.
Methods and analysis
Between May 2010 and February 2013, 52 UK centres recruited 270 patients admitted with acute severe UC who failed to respond to intravenous steroids but did not need surgery. We allocated them at random in equal proportions between infliximab and ciclosporin.The primary clinical outcome measure is quality-adjusted survival, that is survival weighted by Crohn's and Colitis Questionnaire (CCQ) participants’ scores, analysed by Cox regression. Secondary outcome measures include: the CCQ—an extension of the validated but community-focused UK Inflammatory Bowel Disease Questionnaire (IBDQ) to include patients with acute severe colitis and stoma; two general quality of life measures—EQ-5D and SF-12; mortality; survival weighted by EQ-5D; emergency and planned colectomies; readmissions; incidence of adverse events including malignancies, serious infections and renal disorders; disease activity; National Health Service (NHS) costs and patient-borne costs. Interviews investigate participants’ views on therapies for acute severe UC and healthcare professionals’ views on the two drugs and their administration.
Ethics and dissemination
The Research Ethics Committee for Wales has given ethical approval (Ref. 08/MRE09/42); each participating Trust or Health Board has given NHS Reseach & Development approval. We plan to present trial findings at international and national conferences and publish in high-impact peer-reviewed journals.
Trial registration number
ISRCTN: 22663589; EudraCT number: 2008-001968-36
doi:10.1136/bmjopen-2014-005091
PMCID: PMC4010821  PMID: 24785401
Ulcerative colitis; Acute severe; Steroid refractory; Ciclosporin; Infliximab; Randomised controlled trial
12.  microRNA-145 restores contractile vascular smooth muscle phenotype and coronary collateral growth in the metabolic syndrome 
Objective
Transient, repetitive occlusion stimulates collateral growth (CCG) in normal animals. Vascular smooth muscle cells (VSMCs) switch to synthetic phenotype early in CCG then return to contractile phenotype. CCG is impaired in the metabolic syndrome. We determined whether impaired CCG was due to aberrant VSMC phenotypic modulation by miR-145-mediated mechanisms and if restoration of physiological miR-145 levels in metabolic syndrome (JCR rat) improved CCG.
Approach/Results
CCG was stimulated by transient, repetitive LAD occlusion and evaluated after 9 days by coronary blood flow measurements (microspheres). miR-145 was delivered to JCR VSMCs via adenoviral vector (miR-145-Adv). In JCR rats, miR-145 was decreased late in CCG (~2 fold day 6; ~4 fold day 9 vs. SD), which correlated with decreased expression of SM-specific contractile proteins (~5 fold day 6; ~10 fold day 9 vs. SD) indicative of VSMCs’ failure to return to the contractile phenotype late in CCG. miR-145 expression in JCR rats (miR-145-Adv) on days 6–9 of CCG completely restored VSMCs contractile phenotype and CCG (CZ/NZ flow ratio was 0.93±0.09 JCR+miR-145-Adv vs. 0.12±0.02 JCR vs. 0.87±0.02 SD).
Conclusions
Restoration of VSMC contractile phenotype through miR-145 delivery is a highly promising intervention for restoration of CCG in the metabolic syndrome.
doi:10.1161/ATVBAHA.112.301116
PMCID: PMC3628919  PMID: 23393394
collateral circulation; metabolic syndrome; microRNA; vascular smooth muscle phenotype
13.  Novel Hsp90 inhibitor NVP-AUY922 radiosensitizes prostate cancer cells 
Cancer Biology & Therapy  2013;14(4):347-356.
Outcomes for poor-risk localized prostate cancers treated with radiation are still insufficient. Targeting the “non-oncogene” addiction or stress response machinery is an appealing strategy for cancer therapeutics. Heat-shock-protein-90 (Hsp90), an integral member of this machinery, is a molecular chaperone required for energy-driven stabilization and selective degradation of misfolded “client” proteins, that is commonly overexpressed in tumor cells. Hsp90 client proteins include critical components of pathways implicated in prostate cancer cell survival and radioresistance, such as androgen receptor signaling and the PI3K-Akt-mTOR pathway. We examined the effects of a novel non-geldanamycin Hsp90 inhibitor, AUY922, combined with radiation (RT) on two prostate cancer cell lines, Myc-CaP and PC3, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γ-H2AX foci kinetics and client protein expression in pathways important for prostate cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined treatment (RT-AUY922) on the PI3K-Akt-mTOR and AR pathways in a hind-flank tumor graft model. We observed that AUY922 caused supra-additive radiosensitization in both cell lines at low nanomolar doses with enhancement ratios between 1.4–1.7 (p < 0.01). RT-AUY922 increased apoptotic cell death compared with either therapy alone, induced G2-M arrest and produced marked changes in client protein expression. These results were confirmed in vivo, where RT-AUY922 combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in Myc-CaP and PC3 tumor grafts (both p < 0.0001). Our data suggest that combined RT-AUY922 therapy exhibits promising activity against prostate cancer cells, which should be investigated in clinical studies.
doi:10.4161/cbt.23626
PMCID: PMC3667875  PMID: 23358469
prostate cancer; Hsp90; NVP-AUY922; radiosensitizer; DNA damage response
14.  Mindfulness-Based Cognitive Therapy for Preventing Relapse in Recurrent Depression: A Randomized Dismantling Trial 
Objective: We compared mindfulness-based cognitive therapy (MBCT) with both cognitive psychological education (CPE) and treatment as usual (TAU) in preventing relapse to major depressive disorder (MDD) in people currently in remission following at least 3 previous episodes. Method: A randomized controlled trial in which 274 participants were allocated in the ratio 2:2:1 to MBCT plus TAU, CPE plus TAU, and TAU alone, and data were analyzed for the 255 (93%; MBCT = 99, CPE = 103, TAU = 53) retained to follow-up. MBCT was delivered in accordance with its published manual, modified to address suicidal cognitions; CPE was modeled on MBCT, but without training in meditation. Both treatments were delivered through 8 weekly classes. Results: Allocated treatment had no significant effect on risk of relapse to MDD over 12 months follow-up, hazard ratio for MBCT vs. CPE = 0.88, 95% CI [0.58, 1.35]; for MBCT vs. TAU = 0.69, 95% CI [0.42, 1.12]. However, severity of childhood trauma affected relapse, hazard ratio for increase of 1 standard deviation = 1.26 (95% CI [1.05, 1.50]), and significantly interacted with allocated treatment. Among participants above median severity, the hazard ratio was 0.61, 95% CI [0.34, 1.09], for MBCT vs. CPE, and 0.43, 95% CI [0.22, 0.87], for MBCT vs. TAU. For those below median severity, there were no such differences between treatment groups. Conclusion: MBCT provided significant protection against relapse for participants with increased vulnerability due to history of childhood trauma, but showed no significant advantage in comparison to an active control treatment and usual care over the whole group of patients with recurrent depression.
doi:10.1037/a0035036
PMCID: PMC3964149  PMID: 24294837
mindfulness-based cognitive therapy; major depression; relapse prevention; suicidality; childhood trauma
15.  Embedded Alcohol Messages in Television Series: The Interactive Effect of Warnings and Audience Connectedness on Viewers' Alcohol Beliefs* 
Objective
This research investigates whether warning viewers about the presence of embedded messages in the content of a television episode affects viewers' drinking beliefs and whether audi ence connectedness moderates the warning's impact.
Method
Two hun dred fifty college students participated in a laboratory experiment approximating a real-life television viewing experience. They viewed an actual television series episode containing embedded alcohol messages, and their subsequent beliefs about alcohol consequences were measured. Experimental conditions differed based on a 2 (Connectedness Level: low vs high) × 2 (Timing of the Warning: before or after the episode) × 2 (Emphasis of Warning: advertising vs health message) design. Connectedness was measured, and the timing and emphasis of the warnings were manipulated. The design also included a control condition where there was no warning.
Results
The findings indicate that warning view ers about embedded messages in the content of a program can yield sig nificant differences in viewers' beliefs about alcohol. However, the warning's impact differs depending on the viewers' level of connectedness to the program. In particular, in comparison with the no-warning control condition, the advertising prewarning produced lower positive beliefs about alcohol and its consequences but only for the low-connected viewers. Highly connected viewers were not affected by a warning emphasizing advertising messages embedded in the program, but a warning emphasizing health produced significantly higher negative be liefs about drinking than in the control condition.
Conclusions
The presence of many positive portrayals of drinking and alcohol product placements in television series has led many to suggest ways to counter their influence. However, advocates of warnings should be conscious of their differential impact on high- and low-connected viewers.
PMCID: PMC3894051  PMID: 18432390
16.  Optimal Timing of Systemic Therapy in Resectable Colorectal Liver Metastases 
The American surgeon  2013;79(4):414-421.
Perioperative chemotherapy has been shown to improve disease-free survival compared with surgery alone for resectable colorectal liver metastases (CLM). We examined our experience with systemic chemotherapy in this clinical setting. A prospectively collected liver surgery database identified 210 patients treated for resectable CLM from 1996 to 2010. Results were correlated to four treatment groups: posthepatectomy adjuvant only, prehepatectomy preoperative only, perioperative (preoperative and adjuvant), and surgery only. Seventy-nine (37.6%) patients received posthepatectomy adjuvant only treatment, 33 (15.7%) received prehepatectomy preoperative only treatment, 46 (21.9%) received perioperative (preoperative and adjuvant) treatment, whereas 52 (24.8%) received surgery alone. Preoperative and adjuvant systemic chemotherapy regimens were as follows: 23 (29.1%) and 18 (14.4%) received a 5-fluorouracil monotherapy regimen, 19 (24.1%) and 31 (24.8%) received an irinotecan-based regimen, and 28 (35.4%) and 37 (29.6%) received an oxaliplatin-based regimen. Nine (11.4%) and 12 (9.6%) received some other unknown combination. Treatment groups showed no difference in gender, mean tumor size, number of tumors, margin status, or postoperative complications with the only difference being a higher incidence of metachronous tumors in the preoperative only and perioperative groups (P = 0.01). Median follow-up and overall survival were 25 and 41 months, respectively. The adjuvant, preoperative, perioperative, and surgery only groups had a median survival time of 48, 35, 39, and 29 months, respectively (log-rank P = 0.04). Independent predictors of overall survival on multivariate analysis included treatment algorithm used and postoperative complication status. Adjuvant only systemic therapy was associated with an improved survival in resectable CLM. Prospective randomized trials are needed to confirm these findings.
PMCID: PMC3888812  PMID: 23574853
17.  A Facile Method to Synthesize Histones with Posttranslational Modification Mimics 
Biochemistry  2012;51(26):5232-5234.
Using an evolved pyrrolysyl-tRNA synthetase-tRNAPyl pair, a Se-alkylselenocysteine was genetically incorporated into histone H3 with a high protein expression yield. Quantitative oxidative elimination of Se-alkylselenocysteine followed by Michael addition reactions with various thiol nucleophiles generated biologically active mimics of H3 with posttranslational modifications including lysine methylation, lysine acetylation, and serine phosphorylation.
doi:10.1021/bi300535a
PMCID: PMC3448024  PMID: 22697363
18.  Concurrent versus Sequential Sorafenib Therapy in Combination with Radiation for Hepatocellular Carcinoma 
PLoS ONE  2013;8(6):e65726.
Sorafenib (SOR) is the only systemic agent known to improve survival for hepatocellular carcinoma (HCC). However, SOR prolongs survival by less than 3 months and does not alter symptomatic progression. To improve outcomes, several phase I-II trials are currently examining SOR with radiation (RT) for HCC utilizing heterogeneous concurrent and sequential treatment regimens. Our study provides preclinical data characterizing the effects of concurrent versus sequential RT-SOR on HCC cells both in vitro and in vivo. Concurrent and sequential RT-SOR regimens were tested for efficacy among 4 HCC cell lines in vitro by assessment of clonogenic survival, apoptosis, cell cycle distribution, and γ-H2AX foci formation. Results were confirmed in vivo by evaluating tumor growth delay and performing immunofluorescence staining in a hind-flank xenograft model. In vitro, concurrent RT-SOR produced radioprotection in 3 of 4 cell lines, whereas sequential RT-SOR produced decreased colony formation among all 4. Sequential RT-SOR increased apoptosis compared to RT alone, while concurrent RT-SOR did not. Sorafenib induced reassortment into less radiosensitive phases of the cell cycle through G1-S delay and cell cycle slowing. More double-strand breaks (DSBs) persisted 24 h post-irradiation for RT alone versus concurrent RT-SOR. In vivo, sequential RT-SOR produced the greatest tumor growth delay, while concurrent RT-SOR was similar to RT alone. More persistent DSBs were observed in xenografts treated with sequential RT-SOR or RT alone versus concurrent RT-SOR. Sequential RT-SOR additionally produced a greater reduction in xenograft tumor vascularity and mitotic index than either concurrent RT-SOR or RT alone. In conclusion, sequential RT-SOR demonstrates greater efficacy against HCC than concurrent RT-SOR both in vitro and in vivo. These results may have implications for clinical decision-making and prospective trial design.
doi:10.1371/journal.pone.0065726
PMCID: PMC3675179  PMID: 23762417
19.  Activity enhances dopaminergic long-duration response in Parkinson disease 
Jung Kang, Un | Auinger, Peggy | Fahn, Stanley | Oakes, David | Shoulson, Ira | Kieburtz, Karl | Rudolph, Alice | Marek, Kenneth | Seibyl, John | Lang, Anthony | Olanow, C. Warren | Tanner, Caroline | Schifitto, Giovanni | Zhao, Hongwei | Reyes, Lydia | Shinaman, Aileen | Comella, Cynthia L. | Goetz, Christopher | Blasucci, Lucia M. | Samanta, Johan | Stacy, Mark | Williamson, Kelli | Harrigan, Mary | Greene, Paul | Ford, Blair | Moskowitz, Carol | Truong, Daniel D. | Pathak, Mayank | Jankovic, Joseph | Ondo, William | Atassi, Farah | Hunter, Christine | Jacques, Carol | Friedman, Joseph H. | Lannon, Margaret | Russell, David S. | Jennings, Danna | Fussell, Barbara | Standaert, David | Schwarzschild, Michael A. | Growdon, John H. | Tennis, Marsha | Gauthier, Serge | Panisset, Michel | Hall, Jean | Gancher, Stephen | Hammerstad, John P. | Stone, Claudia | Alexander-Brown, Barbara | Factor, Stewart A. | Molho, Eric | Brown, Diane | Evans, Sharon | Clark, Jeffrey | Manyam, Bala | Simpson, Patricia | Wulbrecht, Brian | Whetteckey, Jacqueline | Martin, Wayne | Roberts, Ted | King, Pamela | Hauser, Robert | Zesiewicz, Theresa | Gauger, Lisa | Trugman, Joel | Wooten, G. Frederick | Rost-Ruffner, Elke | Perlmutter, Joel | Racette, Brad A. | Suchowersky, Oksana | Ranawaya, Ranjit | Wood, Susan | Pantella, Carol | Kurlan, Roger | Richard, Irene | Pearson, Nancy | Caviness, John N. | Adler, Charles | Lind, Marlene | Simuni, Tanya | Siderowf, Andrew | Colcher, Amy | Lloyd, Mary | Weiner, William | Shulman, Lisa | Koller, William | Lyons, Kelly | Feldman, Robert G. | Saint-Hilaire, Marie H. | Ellias, Samuel | Thomas, Cathi-Ann | Juncos, Jorge | Watts, Ray | Partlow, Anna | Tetrud, James | Togasaki, Daniel M. | Stewart, Tracy | Mark, Margery H. | Sage, Jacob I. | Caputo, Debbie | Gould, Harry | Rao, Jayaraman | McKendrick, Ann | Brin, Mitchell | Danisi, Fabio | Benabou, Reina | Hubble, Jean | Paulson, George W. | Reider, Carson | Birnbaum, Alex | Miyasaki, Janis | Johnston, Lisa | So, Julie | Pahwa, Rajesh | Dubinsky, Richard M. | Wszolek, Zbigniew | Uitti, Ryan | Turk, Margaret | Tuite, Paul | Rottenberg, David | Hansen, Joy | Ramos, Serrano | Waters, Cheryl | Lew, Mark | Welsh, Mickie | Kawai, Connie | O'Brien, Christopher | Kumar, Rajeev | Seeberger, Lauren | Judd, Deborah | Barclay, C. Lynn | Grimes, David A. | Sutherland, Laura | Dawson, Ted | Reich, Stephen | Dunlop, Rebecca | Albin, Roger | Frey, Kirk | Wernette, Kristine | Fahn, Stanley | Oakes, David | Shoulson, Ira | Kieburtz, Karl | Rudolph, Alice | Marek, Kenneth | Seibyl, John | Lang, Anthony | Olanow, C. Warren | Tanner, Caroline | Schifitto, Giovanni | Zhao, Hongwei | Reyes, Lydia | Shinaman, Aileen | Comella, Cynthia L. | Goetz, Christopher | Blasucci, Lucia M. | Samanta, Johan | Stacy, Mark | Williamson, Kelli | Harrigan, Mary | Greene, Paul | Ford, Blair | Moskowitz, Carol | Truong, Daniel D. | Pathak, Mayank | Jankovic, Joseph | Ondo, William | Atassi, Farah | Hunter, Christine | Jacques, Carol | Friedman, Joseph H. | Lannon, Margaret | Russell, David S. | Jennings, Danna | Fussell, Barbara | Standaert, David | Schwarzschild, Michael A. | Growdon, John H. | Tennis, Marsha | Gauthier, Serge | Panisset, Michel | Hall, Jean | Gancher, Stephen | Hammerstad, John P. | Stone, Claudia | Alexander-Brown, Barbara | Factor, Stewart A. | Molho, Eric | Brown, Diane | Evans, Sharon | Clark, Jeffrey | Manyam, Bala | Simpson, Patricia | Wulbrecht, Brian | Whetteckey, Jacqueline | Martin, Wayne | Roberts, Ted | King, Pamela | Hauser, Robert | Zesiewicz, Theresa | Gauger, Lisa | Trugman, Joel | Wooten, G. Frederick | Rost-Ruffner, Elke | Perlmutter, Joel | Racette, Brad A. | Suchowersky, Oksana | Ranawaya, Ranjit | Wood, Susan | Pantella, Carol | Kurlan, Roger | Richard, Irene | Pearson, Nancy | Caviness, John N. | Adler, Charles | Lind, Marlene | Simuni, Tanya | Siderowf, Andrew | Colcher, Amy | Lloyd, Mary | Weiner, William | Shulman, Lisa | Koller, William | Lyons, Kelly | Feldman, Robert G. | Saint-Hilaire, Marie H. | Ellias, Samuel | Thomas, Cathi-Ann | Juncos, Jorge | Watts, Ray | Partlow, Anna | Tetrud, James | Togasaki, Daniel M. | Stewart, Tracy | Mark, Margery H. | Sage, Jacob I. | Caputo, Debbie | Gould, Harry | Rao, Jayaraman | McKendrick, Ann | Brin, Mitchell | Danisi, Fabio | Benabou, Reina | Hubble, Jean | Paulson, George W. | Reider, Carson | Birnbaum, Alex | Miyasaki, Janis | Johnston, Lisa | So, Julie | Pahwa, Rajesh | Dubinsky, Richard M. | Wszolek, Zbigniew | Uitti, Ryan | Turk, Margaret | Tuite, Paul | Rottenberg, David | Hansen, Joy | Ramos, Serrano | Waters, Cheryl | Lew, Mark | Welsh, Mickie | Kawai, Connie | O'Brien, Christopher | Kumar, Rajeev | Seeberger, Lauren | Judd, Deborah | Barclay, C. Lynn | Grimes, David A. | Sutherland, Laura | Dawson, Ted | Reich, Stephen | Dunlop, Rebecca | Albin, Roger | Frey, Kirk | Wernette, Kristine | Mendis, Tilak
Neurology  2012;78(15):1146-1149.
Objective:
We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined.
Methods:
We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks.
Results:
The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands.
Conclusions:
Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during “off” medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects.
doi:10.1212/WNL.0b013e31824f8056
PMCID: PMC3466780  PMID: 22459675
20.  Endothelial-derived neuregulin is an important mediator of ischaemia-induced angiogenesis and arteriogenesis 
Cardiovascular Research  2011;93(3):516-524.
Aims
Neuregulins (NRG) are growth factors that are synthesized by endothelial cells (ECs) and bind to erbB receptors. We have shown previously that NRG is proangiogenic in vitro, and that NRG/erbB signalling is important for autocrine endothelial angiogenic signalling in vitro. However, the role of NRG in the angiogenic response to ischaemia is unknown. We hypothesized that endothelial NRG is required for ischaemia-induced angiogenesis in vivo and that exogenous administration of NRG will enhance angiogenic responses after ischaemic insult.
Methods and results
An endothelial-selective inducible NRG knockout mouse was created and subjected to femoral artery ligation. Endothelial NRG deletion significantly decreased blood flow recovery (by 40%, P < 0.05), capillary density, αvβ3 integrin activation, and arteriogenesis after ischaemic injury. Isolated ECs from knockout mice demonstrated significantly impaired cord formation in vitro, suggesting that NRG signalling performs an important cell autonomous function. Recombinant human NRG (rNRG) has not only reversed the angiogenic defect in knockout mice but also accelerated blood flow recovery in wild-type mice.
Conclusion
Endothelial production of NRG is required for angiogenesis and arteriogenesis induced by ischaemic injury. Furthermore, exogenous administration of rNRG can enhance this process, suggesting a potential role for NRG in vascular disease.
doi:10.1093/cvr/cvr352
PMCID: PMC3282578  PMID: 22200588
Endothelium; Angiogenesis; Ischaemia; Genetically altered mice; Growth factors
22.  High School Gay-Straight Alliances (GSAs) and Young Adult Well-Being: An Examination of GSA Presence, Participation, and Perceived Effectiveness 
Applied developmental science  2011;15(4):175-185.
Gay-Straight Alliances (GSAs) are student-led, school-based clubs that aim to provide a safe environment in the school context for lesbian, gay, bisexual, and transgender (LGBT) students, as well as their straight allies. The present study examines the potential for GSAs to support positive youth development and to reduce associations among LGBT-specific school victimization and negative young adult well-being. The sample includes 245 LGBT young adults, ages 21–25, who retrospectively reported on the presence of a GSA in their high school, their participation in their school’s GSA, and their perceptions of whether or not their GSA was effective in improving school safety. Findings revealed that the presence of a GSA, participation in a GSA, and perceived GSA effectiveness in promoting school safety were differentially associated with young adult well-being and in some cases, buffered the negative association between LGBT-specific school victimization and well-being. Implications for future research and schools are discussed.
doi:10.1080/10888691.2011.607378
PMCID: PMC3217265  PMID: 22102782
23.  Enhancing ventilation in homes of children with asthma: pragmatic randomised controlled trial 
The British Journal of General Practice  2011;61(592):e724-e732.
Background
Few robust studies have tested whether enhancing housing also improves health.
Aim
To evaluate the effectiveness of installing ventilation systems, and central heating where necessary, in the homes of children with moderate or severe asthma.
Design and setting
Pragmatic randomised controlled trial (RCT) in homes within Wrexham County Borough, Wales, UK.
Method
A pragmatic RCT was carried out, of a tailored package of housing improvements providing adequate ventilation and temperature, following inspection by a housing officer. One hundred and ninety-two children with asthma aged 5 to 14 years, identified from general practice registers, were randomised to receive this package, either immediately or a year after recruitment. At baseline, and after 4 and 12 months, parents reported their child's asthma-specific and generic quality of life, and days off school.
Results
The package improved parent-reported asthma-specific quality of life significantly at both 4 and 12 months. At 12 months, this showed an adjusted mean difference between groups of 7.1 points (95% confidence interval [CI] = 2.8 to 11.4, P= 0.001): a moderate standardised effect size of 0.42. The generic quality-of-life scale showed reported physical problems were significantly reduced at 4 months, but not quite at 12 months, when the mean difference was 4.5 (95% CI = -0.2 to 9.1, P= 0.061). The improvement in psychosocial quality of life at 12 months was not significant, with a mean difference of 2.2 (95% CI = -1.9 to 6.4, P= 0.292). Parent-reported school attendance improved, but not significantly
Conclusion
This novel and pragmatic trial, with integrated economic evaluation, found that tailored improvement of the housing of children with moderate to severe asthma significantly increases parent-reported asthma-related quality of life and reduces physical problems. Collaborative housing initiatives have potential to improve health.
doi:10.3399/bjgp11X606636
PMCID: PMC3207090  PMID: 22054336
asthma; children; general practice health; housing; quality of life; clinical trials, randomised
24.  Enhancing ventilation in homes of children with asthma: cost-effectiveness study alongside randomised controlled trial 
The British Journal of General Practice  2011;61(592):e733-e741.
Background
There has been little rigorous economic analysis of the relationship between asthma and improved housing.
Aim
To evaluate the cost-effectiveness of installing ventilation systems, and central heating if necessary, in homes of children with ‘moderate’ or ‘severe’ asthma.
Design and setting
An incremental cost-effectiveness analysis alongside a pragmatic randomised controlled trial of a tailored package of housing modifications designed to improve ventilation and household heating in homes within Wrexham County Borough, Wales, UK.
Method
A total of 177 children aged between 5 and 14 years, identified from general practice registers, were studied. Parents reported on the quality of life of their children over a 12-month period. General practices reported on health-service resources used by those children, and their asthma-related prescriptions, over the same period.
Results
The tailored package shifted 17% of children in the intervention group from ‘severe’ to ‘moderate’ asthma, compared with a 3% shift in the control group. The mean cost of these modifications was £1718 per child treated or £12300 per child shifted from ‘severe’ to ‘moderate’. Healthcare costs over 12 months following randomisation did not differ significantly between intervention and control groups. Bootstrapping gave an incremental cost-effectiveness ratio (ICER) of £234 per point improvement on the 100-point PedsQL™ asthma-specific scale, with 95% confidence interval (CI) = £140 to £590. The ICER fell to £165 (95% CI = £84 to £424) for children with ‘severe’ asthma.
Conclusion
This novel and pragmatic trial, with integrated economic evaluation, reported that tailored improvement of the housing of children with moderate to severe asthma is likely to be a cost-effective use of public resources. This is a rare example of evidence for collaboration between local government and the NHS.
doi:10.3399/bjgp11X606645
PMCID: PMC3207091  PMID: 22054337
asthma; children; general practice; health; housing; quality of life; clinical trials, randomised
25.  Clinical Vignettes: Integrated Care of Cancer Patients by Oncologists and Cardiologists 
Current Cardiology Reviews  2011;7(4):258-261.
Because of the paucity of large, randomized trials concerning the cardiac care of patients with cancer, treatment and prevention of chemotherapy-induced cardiotoxicity must rely on insights gained from small trials and case reports as well as the application of guidelines developed for the general population. In these clinical vignettes, we present patients referred by their oncologists to a cardiologist for specialized evaluation and management of cardiotoxicity with the goal of emphasizing the importance of identifying risk factors for cardiotoxicity, initiating evidence-based therapy, and establishing a close collaboration between oncologists and cardiologists.
doi:10.2174/157340311799960654
PMCID: PMC3322444  PMID: 22758627
Cardiotoxicity; anthracyclines; trastuzumab; left ventricular ejection fraction.

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