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1.  Homologous recombination mediates S-phase-dependent radioresistance in cells deficient in DNA polymerase eta 
Carcinogenesis  2012;33(11):2026-2034.
DNA polymerase eta (pol η) is the only DNA polymerase causally linked to carcinogenesis in humans. Inherited deficiency of pol η in the variant form of xeroderma pigmentosum (XPV) predisposes to UV-light-induced skin cancer. Pol η-deficient cells demonstrate increased sensitivity to cisplatin and oxaliplatin chemotherapy. We have found that XP30R0 fibroblasts derived from a patient with XPV are more resistant to cell kill by ionising radiation (IR) than the same cells complemented with wild-type pol η. This phenomenon has been confirmed in Burkitt’s lymphoma cells, which either expressed wild-type pol η or harboured a pol η deletion. Pol η deficiency was associated with accumulation of cells in S-phase, which persisted after IR. Cells deficient in pol η demonstrated increased homologous recombination (HR)-directed repair of double strand breaks created by IR. Depletion of the HR protein, X-ray repair cross-complementing protein 3 (XRCC3), abrogated the radioresistance observed in pol η-deficient cells as compared with pol η-complemented cells. These findings suggest that HR mediates S-phase-dependent radioresistance associated with pol η deficiency. We propose that pol η protein levels in tumours may potentially be used to identify patients who require treatment with chemo-radiotherapy rather than radiotherapy alone for adequate tumour control.
doi:10.1093/carcin/bgs239
PMCID: PMC3584963  PMID: 22822095
2.  The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy 
Cancer Biology & Therapy  2012;13(11):1072-1081.
DNA damaging agents such as radiotherapy and gemcitabine are frequently used for the treatment of pancreatic cancer. However, these treatments typically provide only modest benefit. Improving the low survival rate for pancreatic cancer patients therefore remains a major challenge in oncology. Inhibition of the key DNA damage response kinase ATR has been suggested as an attractive approach for sensitization of tumor cells to DNA damaging agents, but specific ATR inhibitors have remained elusive. Here we investigated the sensitization potential of the first highly selective and potent ATR inhibitor, VE-821, in vitro. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 led to inhibition of radiation-induced G2/M arrest in cancer cells. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively. These findings support ATR inhibition as a novel approach to improve the efficacy and therapeutic index of standard cancer treatments across a large proportion of pancreatic cancer patients.
doi:10.4161/cbt.21093
PMCID: PMC3461814  PMID: 22825331
ATR; chemotherapy; hypoxia; inhibitor; radiosensitivity
3.  Targeting radiation-resistant hypoxic tumour cells through ATR inhibition 
British Journal of Cancer  2012;107(2):291-299.
Background:
Most solid tumours contain regions of sub-optimal oxygen concentration (hypoxia). Hypoxic cancer cells are more resistant to radiotherapy and represent the most aggressive fraction of a tumour. It is therefore essential that strategies continue to be developed to target hypoxic cancer cells. Inhibition of the DNA damage response (DDR) might be an effective way of sensitising hypoxic tumour cells to radiotherapy.
Methods:
Here, we describe the cellular effects of pharmacological inhibition of the apical DDR kinase ATR (Ataxia Telangiectasia and Rad 3 related) with a highly selective inhibitor, VE-821, in hypoxic conditions and its potential as a radiosensitiser.
Results:
VE-821 was shown to inhibit ATR-mediated signalling in response to replication arrest induced by severe hypoxia. In these same conditions, VE-821 induced DNA damage and consequently increased Ataxia Telangiectasia Mutated-mediated phosphorylation of H2AX and KAP1. Consistently, ATR inhibition sensitised tumour cell lines to a range of oxygen tensions. Most importantly, VE-821 increased radiation-induced loss of viability in hypoxic conditions. Using this inhibitor we have also demonstrated for the first time a link between ATR and the key regulator of the hypoxic response, HIF-1. HIF-1 stabilisation and transcriptional activity were both decreased in response to ATR inhibition.
Conclusion:
These findings suggest that ATR inhibition represents a novel strategy to target tumour cells in conditions relevant to pathophysiology and enhance the efficacy of radiotherapy.
doi:10.1038/bjc.2012.265
PMCID: PMC3394988  PMID: 22713662
ATR; hypoxia; replication; radiation; VE-821
4.  Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation 
Cell Death & Disease  2012;3(12):e441-.
Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC.
doi:10.1038/cddis.2012.181
PMCID: PMC3542617  PMID: 23222511
ATR; novel inhibitor; radiosensitiser; pancreatic cancer; tumor selectivity
5.  Guidelines for preclinical and early phase clinical assessment of novel radiosensitisers 
British Journal of Cancer  2011;105(5):628-639.
doi:10.1038/bjc.2011.240
PMCID: PMC3188925  PMID: 21772330
assessment; novel radiosensitisers; early; preclinical; clinical
6.  NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity 
Background
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated in tumor cells and promotes tumor cell survival after radiation-induced DNA damage. Because the pathway may not be completely inhibited after blockade of PI3K itself, due to feedback through mammalian target of rapamycin (mTOR), more effective inhibition might be expected by targeting both PI3K and mTOR inhibition.
Materials and methods
We investigated the effect of two dual PI3K/mTOR (both mTORC1 and mTORC2) inhibitors, NVP-BEZ235 and NVP-BGT226, on SQ20B laryngeal and FaDu hypopharyngeal cancer cells characterised by EGFR overexpression, on T24 bladder tumor cell lines with H-Ras mutation and on endothelial cells. Analysis of target protein phosphorylation, clonogenic survival, number of residual γH2AX foci, cell cycle and apoptosis after radiation was performed in both tumor and endothelial cells. In vitro angiogenesis assays were conducted as well.
Results
Both compounds effectively inhibited phosphorylation of Akt, mTOR and S6 target proteins and reduced clonogenic survival in irradiated tumor cells. Persistence of DNA damage, as evidenced by increased number of γH2AX foci, was detected after irradiation in the presence of PI3K/mTOR inhibition, together with enhanced G2 cell cycle delay. Treatment with one of the inhibitors, NVP-BEZ235, also resulted in decreased clonogenicity after irradiation of tumor cells under hypoxic conditions. In addition, NVP-BEZ235 blocked VEGF- and IR-induced Akt phosphorylation and increased radiation killing in human umbilical venous endothelial cells (HUVEC) and human dermal microvascular dermal cells (HDMVC). NVP-BEZ235 inhibited VEGF-induced cell migration and capillary tube formation in vitro and enhanced the antivascular effect of irradiation. Treatment with NVP-BEZ235 moderately increased apoptosis in SQ20B and HUVEC cells but not in FaDu cells, and increased necrosis in both tumor and endothelial all cells tumor.
Conclusions
The results of this study demonstrate that PI3K/mTOR inhibitors can enhance radiation-induced killing in tumor and endothelial cells and may be of benefit when combined with radiotherapy.
doi:10.1186/1748-717X-7-48
PMCID: PMC3348043  PMID: 22452803
PI3K; mTOR; Radiosensitization; Endothelial cells; VEGF
7.  A siRNA Screen of Genes Involved in DNA Repair Identifies Tumour Specific Radiosensitisation by POLQ Knockdown 
Cancer research  2010;70(7):2984-2993.
The effectiveness of radiotherapy treatment could be significantly improved if tumour cells could be rendered more sensitive to ionizing radiation without altering the sensitivity of normal tissues. However many of the key, therapeutically exploitable mechanisms that determine intrinsic tumour radiosensitivity are largely unknown. We have conducted a siRNA screen of 200 genes involved in DNA damage repair aimed at identifying genes whose knockdown increased tumour radiosensitivity. Parallel siRNA screens were conducted in irradiated and unirradiated tumour cells (SQ20B) and irradiated normal tissue cells (MRC5). Using γH2AX foci at 24 hours after ionising radiation we identified several genes such as BRCA2, Lig IV and XRCC5, whose knockdown is known to cause increased cell radiosensitivity thereby validating the primary screening endpoint. In addition we identified POLQ (DNA polymerase theta) as a potential tumour-specific target. Subsequent investigations demonstrated that POLQ knockdown resulted in radiosensitisation of a panel of tumour cell lines from different primary sites, whilst having little or no effect on normal tissue cell lines. These findings raise the possibility that POLQ inhibition might be used clinically to cause tumour specific radiosensitisation.
doi:10.1158/0008-5472.CAN-09-4040
PMCID: PMC2848966  PMID: 20233878
High-throughput Screen; siRNA; DNA-repair; POLQ; Tumour Radiosensitivity
8.  Overexpression Of POLQ Confers a Poor Prognosis In Early Breast Cancer Patients 
Oncotarget  2010;1(3):175-184.
Depletion of POLQ (DNA polymerase theta) has recently been shown to render tumour cells more sensitive to radiotherapy whilst having little or no effect on normal tissues. This finding led us to investigate whether tumours that overexpress POLQ are associated with an adverse outcome. We therefore correlated the clinical outcomes of two retrospective series of patients with early breast cancer with the expression levels of POLQ, as determined by microarray gene expression analysis. We found that a significant number of tumours overexpressed POLQ and that overexpression was correlated with ER negative disease (p=0.047) and high tumour grade (p=0.004), both of which are associated with poor clinical outcomes. POLQ overexpression was associated with poor relapse free survival rates on both univariate (HR 5.80; 95% CI, 2.220 to 15.159; p<0.001) and multivariate analysis (HR 8.086; 95% CI 2.340 to 27.948 p=0.001). Analysis of other published clinical series confirmed that POLQ overexpression is associated with adverse clinical outcomes. The poor prognosis associated with POLQ is independent of other clinical or pathological features. The mechanism that causes this adverse outcome remains to be elucidated but may in part arise from resistance to adjuvant treatment. These findings, combined with the limited normal tissue expression of POLQ, make it a very appealing target for possible clinical exploitation.
PMCID: PMC2917771  PMID: 20700469
Translational research; POLQ; breast cancer; prognosis; radiotherapy
9.  Overexpression of POLQ Confers a Poor Prognosis in Early Breast Cancer Patients 
Oncotarget  2010;1(3):175-184.
Depletion of POLQ (DNA polymerase theta) has recently been shown to render tumour cells more sensitive to radiotherapy whilst having little or no effect on normal tissues. This finding led us to investigate whether tumours that overexpress POLQ are associated with an adverse outcome. We therefore correlated the clinical outcomes of two retrospective series of patients with early breast cancer with the expression levels of POLQ, as determined by microarray gene expression analysis. We found that a significant number of tumours overexpressed POLQ and that overexpression was correlated with ER negative disease (p=0.047) and high tumour grade (p=0.004), both of which are associated with poor clinical outcomes. POLQ overexpression was associated with poor relapse free survival rates on both univariate (HR 5.80; 95% CI, 2.220 to 15.159; p<0.001) and multivariate analysis (HR 8.086; 95% CI 2.340 to 27.948 p=0.001). Analysis of other published clinical series confirmed that POLQ overexpression is associated with adverse clinical outcomes. The poor prognosis associated with POLQ is independent of other clinical or pathological features. The mechanism that causes this adverse outcome remains to be elucidated but may in part arise from resistance to adjuvant treatment. These findings, combined with the limited normal tissue expression of POLQ, make it a very appealing target for possible clinical exploitation.
PMCID: PMC2917771  PMID: 20700469
Translational research; POLQ; breast cancer; prognosis; radiotherapy
10.  Sudden arrhythmic death syndrome: a national survey of sudden unexplained cardiac death 
Heart  2007;93(5):601-605.
Objective
To describe the characteristics of sudden arrhythmic death syndrome (SADS) and compare its incidence with official national mortality statistics for unascertained deaths.
Design and setting
Sudden unexplained deaths were prospectively surveyed through 117 coroners' jurisdictions in England. Consecutive cases meeting the following criteria were included: white Caucasian, aged 4–64 years, no history of cardiac disease, last seen alive within 12 h of death, normal coroner's autopsy, cardiac pathologist's confirmation of a normal heart and negative toxicology.
Main outcome measures
The estimated mortality from SADS was calculated and the official mortality statistics for unascertained causes of deaths in 4–64‐year‐olds was identified for the same time period.
Results
115 coroner's cases were reported and 56 (49%) SADS victims were identified: mean age 32 years, range 7–64 years and 35 (63%) male. 7 of 39 cases (18%) had a family history of other premature sudden deaths (<45). The estimated mortality from SADS was 0.16/100 000 per annum (95% CI 0.12 to 0.21), compared with an official mortality of 0.10/100 000 per annum for International Classification of Diseases 798.1 (sudden death, cause unknown—instantaneous death) or 1.34/100 000 per annum for unascertained causes of death.
Conclusions
Deaths from SADS occur predominantly in young males. When compared with official mortality, the incidence of SADS may be up to eight times higher than estimated: more than 500 potential SADS cases per annum in England. Families with SADS carry genetic cardiac disease, placing them at risk of further sudden deaths. SADS should therefore be a certifiable cause of death prompting specialised cardiological evaluation of families.
doi:10.1136/hrt.2006.099598
PMCID: PMC1955564  PMID: 17237131
11.  Tumor Vascular Changes Mediated by Inhibition of Oncogenic Signaling 
Cancer research  2009;69(15):6347-6354.
Many inhibitors of the EGFR-RAS-PI3 kinase-AKT signaling pathway are in clinical use or under development for cancer therapy. Here we show that treatment of mice bearing human tumor xenografts with inhibitors that block EGFR, RAS, PI3 kinase or AKT resulted in prolonged and durable enhancement of tumor vascular flow, perfusion and decreased tumor hypoxia. The vessels in the treated tumors had decreased tortuosity and increased internodal length accounting for the functional alterations. Inhibition of tumor growth cannot account for these results as the drugs were given at doses that did not alter tumor growth. The tumor cell itself was an essential target as HT1080 tumors that lack EGFR did not respond to an EGFR inhibitor, but did respond with vascular alterations to RAS or PI3 Kinase inhibition. We extended these observations to spontaneously arising tumors in MMTV-neu mice. These tumors also responded to PI3 kinase inhibition with decreased tumor hypoxia, increased vascular flow and morphological alterations of their vessels including increased vascular maturity and acquisition of pericyte markers. These changes are similar to the vascular normalization that has been described after anti-angiogenic treatment of xenografts. One difficulty in the use of vascular normalization as a therapeutic strategy has been its limited duration. In contrast, blocking tumor cell RAS-PI3K-AKT signaling led to persistent vascular changes that might be incorporated into clinical strategies based on improvement of vascular flow or decreased hypoxia. These results indicate that vascular alterations must be considered as a consequence of signaling inhibition in cancer therapy.
doi:10.1158/0008-5472.CAN-09-0657
PMCID: PMC2825046  PMID: 19622766
Signaling inhibition; tumor vasculature; hypoxia; EGFR; RAS; PI3 Kinase; AKT
12.  Arrhythmogenic right ventricular dysplasia, a cell adhesion cardiomyopathy: insights into disease pathogenesis from preliminary genotype—phenotype assessment 
Heart  2006;92(12):1720-1723.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetically determined heart muscle disorder presenting clinically with even lethal ventricular arrhythmias, particularly in the young and athletes. It is reported familial with recessive and most commonly dominant inheritance. Disease‐causing genes are increasingly recognised among desmosomal proteins plakoglobin, desmoplakin, plakophilin2, and desmoglein2 displaying phenotypic heterogeneity. Mutations in the plakoglobin and desmoplakin genes have been identified to underlie recessive ARVC associated with woolly hair and palmoplantar keratoderma (Naxos disease), while mutations in plakophilin2, desmoglein2 as well as desmoplakin have been identified to underlie the dominant non‐syndromic form. Preliminary genotype–phenotype assessment indicates that mutations affecting the outer dense plaque of desmosome (desmoglein2, plakoglobin, plakophilin2 and the N‐terminal of desmoplakin) result in ARVC with the ordinary described phenotype. However, mutations at the inner dense plaque, particularly affecting the desmin‐binding site of desmoplakin, may result in ARVC with predominantly left ventricular involvement and clinical overlapping with dilated cardiomyopathy. The interesting finding of abnormal distribution of plakoglobin, independently of the primarily affected protein, might suggest a common pathway for plakoglobin in ARVC pathogenesis.
doi:10.1136/hrt.2005.081679
PMCID: PMC1861281  PMID: 16698823
arrhythmogenic right ventricular dysplasia/cardiomyopathy; Naxos disease; cell‐adhesions; desmosomal proteins; sudden death
13.  Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy 
Heart  2005;92(6):785-791.
Objective
To determine the range of survival rates of patients with hypertrophic cardiomyopathy (HCM) by comparing and contrasting the natural history of a cohort of patients seen between 1988 and 2002 with that of other published series.
Methods
956 adult (⩾ 16 years old) patients with HCM (572 men, mean (SD) age 42 (15) years, range 16–88) were evaluated by ECG, Holter, exercise testing, and echocardiography. Patient characteristics and survival data were compared with those in natural history studies from referral and non‐referral centres published between 1960 and January 2003.
Results
The duration of follow up was 69 (45) months. 120 (12.6%) patients died or underwent cardiac transplantation. Sudden cardiac death (n  =  48) was the most common mode of death. The annual rate of sudden death or implantable cardioverter‐defibrillator discharge was 1.02 (95% confidence interval (CI) 0.76 to 1.26). Annual rates for heart failure death or transplantation and stroke related death were 0.55% (95% CI 0.37% to 0.78%) and 0.07% (95% CI 0.02% to 0.19%), respectively. When studies published within the last 10 years of the study period were compared with earlier reports, the size of individual study cohorts was larger (309 (240.6) v 136.5 (98.8), p  =  0.058) and the proportion with severe functional limitation NYHA class III/IV lower (12.4% v 24.8%, p < 0.0001), and fewer patients underwent septal myotomy‐myectomy (5.2% v 18.7%, p < 0.0001). Published sudden death rates over the last 10 years were lower than previously published figures (median 1.0% (range 0.1–1.7) v 2.0% (0–3.5)).
Conclusion
Published survival rates in HCM cohorts have improved progressively over the past 40 years. In the modern era the prevalence of disease related complications is similar in all reporting centres.
doi:10.1136/hrt.2005.068577
PMCID: PMC1860645  PMID: 16216855
prognosis; hypertrophic cardiomyopathy; referral bias
14.  Familial dilated cardiomyopathy: assessment of left ventricular systolic and diastolic function using Doppler tissue imaging in asymptomatic relatives with left ventricular enlargement 
Heart  2006;92(3):405-406.
doi:10.1136/hrt.2005.065474
PMCID: PMC1860825  PMID: 16501207
dilated cardiomyopathy; left ventricular enlargement; Doppler tissue imaging; ventricular function
15.  Coronary microvascular dysfunction in male patients with Anderson‐Fabry disease and the effect of treatment with α galactosidase A 
Heart  2005;92(3):357-360.
Objective
To measure coronary flow reserve (CFR), an index of microvascular function, in Anderson‐Fabry disease (AFD) at baseline and after enzyme replacement therapy (ERT).
Methods and results
Mean (SD) myocardial blood flow (MBF) at rest and during hyperaemia (adenosine 140 μg/kg/min) was measured in 10 male, non‐smoking patients (53.8 (10.9) years, cholesterol 5.5 (1.3) mmol/l) and in 24 age matched male, non‐smoking controls (52.0 (7.6) years, cholesterol 4.5 (0.6) mmol/l) by positron emission tomography (PET). Resting and hyperaemic MBF and CFR (hyperaemic/resting MBF) were reduced in patients compared with controls (0.99 (0.17) v 1.17 (0.25) ml/g/min, p < 0.05; 1.37 (0.32) v 3.44 (0.78) ml/g/min, p < 0.0001; and 1.41 (0.39) v 3.03 (0.85), p < 0.0001, respectively). This coronary microvascular dysfunction was independent of cholesterol concentrations. PET was repeated in five patients after 10.1 (2.3) months of ERT; resting and hyperaemic MBF and CFR were unchanged after ERT (0.99 (0.16) v 0.99 (0.16) ml/g/min; 1.56 (0.29) v 1.71 (0.3) ml/g/min; and 1.6 (0.37) v 1.74 (0.28), respectively; all not significant).
Conclusions
The results of the present study show that patients with AFD have very abnormal coronary microvascular function. These preliminary data suggest that ERT has no effect on coronary microvascular dysfunction. Further work is necessary to determine whether treatment at an earlier stage in the course of the disease may improve coronary microvascular function in patients with AFD.
doi:10.1136/hrt.2004.054015
PMCID: PMC1860797  PMID: 16085718
cardiomyopathy; coronary circulation; myocardial blood flow; myocardial ischaemia; cardiac imaging
16.  Myocardial late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy caused by mutations in troponin I 
Heart  2005;91(8):1036-1040.
Objective: To examine the influence of genotype on late gadolinium enhancement (LGE) and the potential of cardiovascular magnetic resonance (CMR) to detect preclinical hypertrophic cardiomyopathy.
Design: Prospective, blinded cohort study of myocardial LGE in a genetically homogeneous population.
Patients: 30 patients with disease causing mutations in the recognised hypertrophic cardiomyopathy gene for cardiac troponin I (TNNI3): 15 with echocardiographically determined left ventricular hypertrophy (LVH+) and 15 without (LVH−).
Main outcome measures: CMR measures of regional left ventricular function, wall thickness, and mass, and the extent and distribution of LGE.
Results: LGE was found in 12 (80%) LVH+ patients but with variable extent (mean 15%, range 3–48%). LGE was also found in two (13%) LVH− patients but the extent was limited (3.6%) and both patients were found to have an abnormal ECG and regional hypertrophy by cine CMR. The extent of LGE was positively associated with clinical markers of sudden death risk (21% with ⩾ 2 risk factors v 7% with ⩽ 1 risk factor, p  =  0.02) and left ventricular mass (r  =  0.56, p < 0.001) and was inversely associated with ejection fraction (r  =  −0.58, p < 0.001). Segmental analysis showed that as regional wall thickness increased, LGE was more prevalent (p < 0.0001) and more extensive (r  =  0.98, p  =  0.001).
Conclusion: In patients with disease causing mutations in TNNI3, focal fibrosis was not detected by LGE CMR before LVH and ECG abnormalities were present. Once LVH is present, LGE is common and the extent correlates with adverse clinical parameters. This suggests that focal fibrosis is closely linked to disease development.
doi:10.1136/hrt.2004.041384
PMCID: PMC1769031  PMID: 16020591
hypertrophic cardiomyopathy; magnetic resonance imaging; fibrosis; gadolinium
18.  Prevalence and clinical significance of systolic impairment in hypertrophic cardiomyopathy 
Heart  2005;91(7):920-925.
Objectives: To determine the frequency of systolic impairment (SI) and its impact on the natural history of hypertrophic cardiomyopathy (HCM).
Methods: 1080 patients (mean (SD) age 43 (15) years, 660 men) with HCM were evaluated. Initial assessment included history, examination, 48 hour Holter monitoring, cardiopulmonary exercise testing, and echocardiography; SI was defined as a fractional shortening (FS) ⩽ 25%. Survival data were collected at clinic visits or by direct communication with patients and their general practitioners. The results of serial echocardiography in 462 patients with normal FS at presentation are also reported.
Results: 26 (2.4%) patients (49 (14) years, 18 men) had SI at the initial visit. During follow up (58 (49) months), nine (34.6%) died or underwent cardiac transplantation compared with 108 (10.2%) patients with normal FS (p  =  0.01). Five year survival from death (any cause) or transplantation was 90.1% (95% confidence interval (CI) 87.8 to 92.4) in patients with normal systolic function versus 52.4% (95% CI 25.2 to 79.6, p < 0.0001) in patients with SI. In patients who underwent serial echocardiography, 22 (4.8%, aged 41 (15) years) developed SI over 66 (40) months; the annual incidence of SI was 0.87% (95% CI 0.54 to 1.31). On initial evaluation patients who developed SI had a higher frequency of syncope (67 (15.2%) v 10 (45.5%) of those who did not develop SI, p  =  0.001), non-sustained ventricular tachycardia (91 (20.6%) v 11 (50%), p  =  0.002), and an abnormal blood pressure response on exercise (131 (29.7%) v 15 (68.2%), p  =  0.001). Patients with SI had greater wall thinning (p  =  0.001), left ventricular cavity enlargement (p < 0.0005), and deterioration in New York Heart Association functional class (p  =  0.001) during follow up. Thirteen (59.1%) patients who progressed to SI died or underwent transplantation compared with 38 (8.6%) patients who maintained normal systolic function.
Conclusions: SI is an infrequent complication of HCM but, when present, is associated with a poor prognosis.
doi:10.1136/hrt.2003.031161
PMCID: PMC1768999  PMID: 15958362
cardiomyopathy; end stage; hypertrophy; systolic impairment
19.  Arrhythmogenic right ventricular cardiomyopathy with fibrofatty atrophy, myocardial oedema, and aneurysmal dilation 
Heart  2005;91(6):784.
doi:10.1136/hrt.2004.043307
PMCID: PMC1768931  PMID: 15894778
Images in cardiology
20.  Physiological upper limits of ventricular cavity size in highly trained adolescent athletes 
Heart  2005;91(4):495-499.
Objectives: To define physiological upper limits of left ventricular (LV) cavity size in trained adolescent athletes.
Design: Cross sectional echocardiographic study.
Setting: British national sports training grounds and Olympic Medical Institute.
Subjects: 900 elite adolescent athletes (77% boys) aged 15.7 (1.2) years participating in ball, racket, and endurance sports and 250 healthy controls matched for age, sex, and size.
Main outcome measures: LV end diastolic cavity size.
Results: Compared with controls, athletes had a larger LV cavity (50.8 (3.7) v 47.9 (3.5) mm), a difference of 6%. The LV cavity was > 54 mm in 18% athletes, whereas none of the controls had an LV cavity > 54 mm. The LV cavity exceeded predicted sizes in 117 (13%) athletes. Among the athletes with LV dilatation, 78% were boys, LV size ranged from 52–60 mm, and left atrial diameter and LV wall thickness were enlarged. Systolic and diastolic function were normal. None of the athletes in the study had an LV cavity size > 60 mm. LV cavity size correlated with age, sex, heart rate, and body surface area.
Conclusion: Highly trained junior athletes usually have only modest increases in LV cavity size. A proportion of trained adolescent athletes have LV cavity size exceeding predicted values but, in absolute terms, LV cavity rarely exceeds 60 mm as in patients with dilated cardiomyopathy. In highly trained adolescent athletes with an LV cavity size > 60 mm and any impairment of systolic or diastolic function, the diagnosis of dilated cardiomyopathy should be considered.
doi:10.1136/hrt.2004.035121
PMCID: PMC1768829  PMID: 15772210
adolescent; elite athlete; athlete’s heart; cardiomyopathy; ventricular cavity dilatation
21.  Detection of apical hypertrophic cardiomyopathy by cardiovascular magnetic resonance in patients with non-diagnostic echocardiography 
Heart  2004;90(6):645-649.
Objective: To investigate the role of cardiovascular magnetic resonance (CMR) in a series of patients with ECG repolarisation changes and normal echocardiography.
Patients and design: 10 patients with anterolateral T wave inversion for which there was no obvious pathological cause who had normal routine echocardiography without contrast for the exclusion of hypertrophic cardiomyopathy (HCM) also had CMR that was diagnostic of apical HCM.
Results: Apical HCM detected by CMR could be morphologically severe with wall thickness up to 28 mm, or mild. The extent of repolarisation abnormalities did not correlate to the morphological severity.
Conclusions: In patients with unexplained repolarisation abnormalities, a normal routine echocardiogram without contrast does not exclude apical HCM. Further imaging with CMR or contrast echocardiography may be required. The reliance on routine echocardiography to exclude apical HCM may have led to underreporting of this condition.
doi:10.1136/hrt.2003.014969
PMCID: PMC1768283  PMID: 15145868
cardiovascular magnetic resonance; echocardiography; apical hypertrophic cardiomyopathy
22.  Spontaneous atrial fibrillation in a freestyle skier 
doi:10.1136/bjsm.2003.006197
PMCID: PMC1724760  PMID: 15039268
23.  Oncogenic K-Ras Signals through Epidermal Growth Factor Receptor and Wild-Type H-Ras to Promote Radiation Survival in Pancreatic and Colorectal Carcinoma Cells1 
Neoplasia (New York, N.Y.)  2007;9(4):341-348.
Pancreatic and colorectal carcinomas frequently express oncogenic/mutant K-Ras that contributes to both tumorigenesis and clinically observed resistance to radiation treatment. We have previously shown that farnesyltransferase inhibitors (FTI) radiosensitize many pancreatic and colorectal cancer cell lines that express oncogenic K-ras at doses that inhibit the prenylation and activation of H-Ras but not K-Ras. In the present study, we have examined the mechanism of FTI-mediated radiosensitization in cell lines that express oncogenic K-Ras and found that wild-type H-Ras is a contributor to radiation survival in tumor cells that express oncogenic K-Ras. In these experiments, inhibiting the expression of oncogenic K-Ras, wild-type H-Ras, or epidermal growth factor receptor (EGFR) led to similar levels of radiosensitization as treatment with the FTI tipifarnib. Treatment with the EGFR inhibitor gefitinib led to similar levels of radiosensitization, and the combinations of tipifarnib or gefitinib plus inhibition of K-Ras, H-Ras, or EGFR expression did not provide additional radiosensitization compared with tipifarnib or gefitinib alone. Finally, supplementing culture medium with the EGFR ligand transforming growth factor α was able to reverse the radiosensitizing effect of inhibiting K-ras expression. Taken together, these findings suggest that EGFR-activated H-Ras signaling is initiated by oncogenic K-Ras to promote radiation survival in pancreatic and colorectal cancers.
PMCID: PMC1854847  PMID: 17460778
Ras; EGFR; radiosensitivity; signal transduction; cancer
25.  Cardiac abnormalities in patients with Leber’s hereditary optic neuropathy 
Heart  2003;89(7):791-792.
PMCID: PMC1767718  PMID: 12807863
hypertrophic cardiomyopathy; Leber’s hereditary optic atrophy; mitochondria

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