Early Disease Development Research Articles

Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.

AimsFamilial hypercholesterolaemia (FH) is a vastly under-diagnosed genetic disorder, associated with early development of coronary heart disease and premature mortality which can be substantially reduced by effective treatment. Patents have recently expired on high-intensity statins, reducing FH treatment costs. We build a model using UK data to estimate the cost effectiveness of DNA testing of relatives of those with monogenic FH.Methods and ResultsA Markov model was used to estimate the cost effectiveness of cascade testing, using data from UK cascade services. The estimated incremental cost effectiveness ratio (ICER) was £5806 and the net marginal lifetime cost per relative tested was £2781. More than 80% of lifetime costs were diagnosis-related and incurred in the 1st year. In UK services, 23% of 6396 index cases were mutation-positive. For each mutation-positive index case, 1.33 relatives were tested, resulting overall in a rate of 0.31 tested relatives per tested index case. If the number of relatives tested per tested index case rose to 3.2 (projected by National Institute for Health and Care Excellence in 2008) the ICER would reduce to £2280 and lifetime costs to £1092.ConclusionCascade testing of relatives of those with suspected FH is highly cost effective. The current Europe-wide high levels of undiagnosed FH, and associated morbidity and mortality, mean adoption of cascade services should yield substantial quality of life and survival gains.

The Potential Role of Acetaminophen and Alcohol in Early Stage Renal Disease: A Bayesian Perspective

In earlier studies, both acetaminophen [AAM] and ethanol [EtOH] have been implicated in renal dysfunction when ingested in variable quantities over a prolonged duration. To determine the potential role of AAM and EtOH on Early Stage Renal Disease [ErSRD], the contribution of threshold dosages of AAM and of light to moderate intakes of EtOH were investigated, and the results analyzed by Bayesian Statistical Methods based on Baye's Theorem. The results of information obtained from the US National Health Examination Survey [2003–3004] were examined, and the data updated with data from a newly designed hospital based case control study conducted in the sub‐Saharan African Region. The results of this study found that renal disease, as determined by measurements of serum creatinine [CTNE], blood urea nitrogen [BUN], Glomerular Filtration Rate [GFR], albumin/creatinine ratios [A/CTNE ratio] values of 0.70 mg/dl, 10.0 mg/dl, 17.0 mg/g, and 135.0 ml/minute/1.73m2, respectively, may occur, marked by statistically significant odds ratios among those who concomitantly ingested therapeutic doses of AAM and ingested light to moderate amounts of EtOH when compared to those who did not ingest the above agents. While light to moderate ingestion of EtOH may not by itself play a significant role, the combination of the two agents appeared to have a synergistic effect on the early development of renal disease in his population. This this study provided both methodological and non‐methodological factors to be considered in the design and implementation of larger scale epidemiologic studies on the interaction of AAM and EtOH on the development of ErSRD.Support or Funding InformationSupported by Institutional Resources of USAT College of Medicine and the Einstein Institute

Serum uric acid and the relationship with subclinical organ damage in adults.

Elevated serum uric acid (SUA) is often present in conditions associated with increased cardiovascular risk yet it is not recognized as a marker of risk. We evaluated whether SUA was associated with evidence of early markers of cardiovascular risk factor including subclinical early organ damage, sympathetic tone and metabolic profile in a healthy population with a high prevalence of obesity. Data from 281 patients (175 women and 106 men, mean age: 35.5 ± 0.8 years, mean BMI: 33.2 ± 0.5 kg/m) were retrieved from a database. All participants were healthy, nonsmoker and free of medication. Available data included metabolic profile, muscle sympathetic nervous activity (MSNA, microneurography), endothelial function (pulse amplitude tonometry, augmentation index), estimated glomerular filtration rate (eGFR) and echocardiography. With participants grouped into sex-adjusted tertiles of SUA, those in the third tertile of SUA had increased waist circumference, worse metabolic profile (fasting glucose, total cholesterol, triglycerides and HDL), elevated MSNA, decreased endothelial function, increased augmentation index and decreased eGFR compared with those in the first tertile of SUA. In multiple regression analysis adjusted for age, sex, BMI and ethnicity, SUA was independently associated with waist circumference, low-density lipoprotein, triglycerides, augmentation index, MSNA and eGFR, providing a combined adjusted R = 0.599 or 60% of the overall variance. In a healthy population with a high proportion of obesity, SUA is associated with measures of metabolic, end-organ damage and sympathetic tone indicating the potential value of SUA as a marker of early cardiovascular disease development.

Predictive markers for early conversion of iRBD to neurodegenerative synucleinopathy diseases.

To determine the predictive value of clinical assessment and dopamine transporter (DAT) uptake for the early development of neurodegenerative synucleinopathy diseases from idiopathic REM sleep behavior disorder (iRBD) over 5 years in a Chinese population. Forty-three patients with iRBD were administered clinical assessment tests, and 35 were examined by DAT-SPECT imaging during 2011. Cox proportional hazard and Kaplan-Meier analyses were used to evaluate the predictive value of the markers in a follow-up study over 5 years. Eighteen patients (41.9%) developed neurodegenerative synucleinopathy diseases after a median of 4.1 years of prospective follow-up (median interval of 10.5 years from the estimated onset of iRBD symptoms). Patients with higher scores on the Nonmotor Symptom Questionnaire (hazard ratio [HR] 3.11, 95% confidence interval [CI] 1.15-8.40, p = 0.026) and Scale for Outcomes in Parkinson Disease-Autonomic questionnaire (HR 4.46, 95% CI 1.64-12.10, p = 0.003) were more likely to develop neurodegenerative synucleinopathy diseases. Furthermore, the population with decreased 99mTc-TRODAT-1 binding in the left striatum (HR 2.7, 95% CI 1.02-7.14, p = 0.046) and putamen (HR 3.23, 95% CI 1.16-8.33, p = 0.024) had a relatively higher risk of developing neurodegenerative synucleinopathy diseases. Our findings elucidate the predictive value of autonomic dysfunction and DAT uptake in identifying patients with iRBD at a high risk of progressing into neurodegenerative synucleinopathy diseases and could form a basis for future disease-prevention trials.

TMJ energy densities in healthy men and women.

Cartilage fatigue, due to mechanical work, may account for the early development of degenerative joint disease (DJD) in the temporomandibular joint (TMJ), and why women are three times more likely to be afflicted. This study tested for gender differences in mechanical energy densities in women and men with healthy TMJs. Eighteen women and eighteen men gave informed consent. Research diagnostic criteria including imaging were used to ensure that subjects' TMJs were normal, without disc displacement or signs of DJD. Numerical modeling determined TMJ loads (Fnormal). Jaw tracking and three-dimensional dynamic stereometry characterized individual-specific data of stress-field dynamic mechanics during 10 symmetrical jaw closing cycles. These data were used to estimate tractional forces (Ftraction). Energy densities were then calculated, where: Energy Density=W/Q (W=work done or mechanical energy input=Ftraction*distance of stress-field translation, Q=volume of cartilage). Two-way analysis of variance (ANOVA) and follow-up two-group comparisons tested mean energy densities for ipsilateral and contralateral TMJs in women vs men. Mean energy densities ± standard deviations in ipsilateral and contralateral TMJs in women were 9.0±9.7 and 8.4±5.5mJ/mm3, respectively, and were significantly larger (P=0.004 and 0.001, respectively) compared to ipsilateral and contralateral TMJs in men, which were 5.6±4.2 and 6.3±4.2mJ/mm3, respectively. Energy densities were significantly larger in healthy TMJs of women than men. Larger TMJ energy densities during normal jaw functions could predispose earlier mechanical fatigue of the TMJ disc.

Relationship among macronutrient intake and overweight/obesity in school children from Celaya, Mexico.

Objective: Excessive intake of macronutrients in schoolchildren is associated with obesity and then with early development of chronic degenerative diseases and young death. Methods: 225 school-age children were evaluated in Celaya, Guanajuato. Anthropometric measures were performed and individual interviews with parents and children were conducted to collect information on the frequency of food consumption using a validated questionnaire (SNUT) from which the intake of macronutrients (carbohydrates, proteins and fats) and fat subtypes. Chi squared, and p value was calculated to identify the association of macronutrient intake with overweight/obesity in schoolchildren. Results: There are not relationship between macronutrient intake (proteins, carbohydrates and lipids) and overweight/obesity in this sample of schoolchildren from Celaya, Mexico. Conclusion: It is possible that there are other strong factors in relationship with overweight/ obesity as physical activity.

Autoantibodies other than Anti-desmogleins in Pemphigus Vulgaris Patients.

Background:Pemphigus vulgaris (PV) is an immunoglobulin G-mediated autoimmune bullous skin disease. Nonorgan-specific antibodies were detected in Tunisian and Brazilian pemphigus patients with different prevalence.Materials and Methods:Fifty PV patients and fifty controls were screened for antinuclear antibodies (ANAs), anti-smooth muscle antibodies (ASMAs), anti-parietal antibodies (APAs), anti-mitochondrial antibodies, and Anti-nuclear cytoplasmic antibodies (ANCA) by indirect immunofluorescence.Results:Thirty-nine patients were female and 11 were male. Fifteen patients did not receive treatment before while 35 patients were on systemic steroid treatment ± azathioprine. Twenty (40%) of the PV patients and 1 (2%) control had positive ANA. ANA was significantly higher in PV patients than controls, P < 0.0001. ASMAs were detected in 20 (40%) PV patients and none of the controls. ASMA was significantly higher in PV patients than controls, P < 0.0001. No significant difference was detected between treated and untreated regarding ANA, P - 0.11. However, there was a significant difference between treated and untreated regarding ASMA, P - 0.03. Six patients (12%) and none of the controls had positive APA. There was a significant difference between the patients and the controls in APA. P - 0.027.Conclusion:Egyptian PV patients showed more prevalent ANA, ASMA, and APA than normal controls. Follow-up of those patients is essential to detect the early development of concomitant autoimmune disease. Environmental factors might account for the variability of the nonorgan-specific antibodies among different populations.

Relationship among macronutrient intake and overweight/obesity in school children from Celaya, Mexico.

Objective: Excessive intake of macronutrients in schoolchildren is associated with obesity and then with early development of chronic degenerative diseases and young death. Methods: 225 school-age children were evaluated in Celaya, Guanajuato. Anthropometric measures were performed and individual interviews with parents and children were conducted to collect information on the frequency of food consumption using a validated questionnaire (SNUT) from which the intake of macronutrients (carbohydrates, proteins and fats) and fat subtypes. Chi squared, and p value was calculated to identify the association of macronutrient intake with overweight/obesity in schoolchildren. Results: There are not relationship between macronutrient intake (proteins, carbohydrates and lipids) and overweight/obesity in this sample of schoolchildren from Celaya, Mexico. Conclusion: It is possible that there are other strong factors in relationship with overweight/ obesity as physical activity.

Vascular Disease Is Associated With the Expression of Genes for Intestinal Cholesterol Transport and Metabolism.

Intestinal cholesterol metabolism is important in influencing postprandial lipoprotein concentrations, and might be important in the development of vascular disease. This study evaluated associations between expression of intestinal cholesterol metabolism genes, postprandial lipid metabolism, and endothelial function/early vascular disease in human subjects. One hundred patients undergoing routine oesophago-gastro-duodenoscopy were recruited. mRNA levels of Nieman-Pick C1-like 1 protein (NPC1L1), ABC-G5, ABC-G8, ABC-A1, microsomal tissue transport protein (MTTP), and sterol-regulatory element-binding protein (SREBP)-2 were measured in duodenal biopsies using quantitative reverse transcription polymerase chain reaction. Postprandially, serum lipid and glycemic profiles were measured, endothelial function was assessed using fasting, and postprandial flow-mediated dilatation (FMD) and carotid intima-media thickness (IMT). Subjects were divided into those above and below the median value of relative expression of each gene, and results were compared between the groups. There were no between-group differences in demographic variables or classical cardiovascular risks. For all genes, the postprandial triglyceride incremental area under the curve was greater (P < 0.05) in the group with greater expression. Postprandial apolipoprotein B48 (ApoB48) levels were greater (P < 0.05) in groups with greater expression of NPC1L1, ABC-G8, and SREBP-2. For all genes, postprandial but not fasting FMD was lower (P < 0.01) in the group with greater expression. Triglyceride and ApoB48 levels correlated significantly with postprandial FMD. Carotid artery IMT was greater (P < 0.05) in groups with greater expression of MTTP, ABC-A1, and SREBP-2. Intestinal cholesterol metabolism gene expression is significantly associated with postprandial increment in triglycerides, intestinal ApoB48, and reduced postprandial FMD. Some genes were also associated with increased IMT. These findings suggest a role of intestinal cholesterol metabolism in development of early vascular disease.

The Role of the Main Risk Factors in the Early Adjacent Segment Disease Development in Patients after Lumbar Fusion

The Role of the Main Risk Factors in the Early Adjacent Segment Disease Development in Patients after Lumbar Fusion

Diagnosis, therapeutic response assessment, and detection of disease recurrence in cardiac sarcoidosis: Integral role of cardiac PET

Sarcoidosis is a systemic disease and recognition of cardiac involvement remains challenging. We report a case and illustrate the integral role of cardiac PET perfusion-metabolic imaging in evaluating various stages of cardiac sarcoidosis. A 61-year-old African-American male presented with a 6-month history of progressive exertional dyspnea, cough, palpitations, and atypical chest pain. Physical exam was consistent with acute heart failure and his baseline EKG showed sinus rhythm with frequent premature ventricular contractions. Chest x-ray showed bilateral hilar adenopathy and telemetry monitoring was significant for multiple runs of nonsustained ventricular tachycardia. Echocardiography showed ejection fraction of 30% with global biventricular hypokinesis. Patient underwent coronary angiogram revealing minimal coronary atherosclerosis. A gadolinium-enhanced cardiac MRI was obtained (Figure 1), and a diagnosis of pulmonary and cardiac sarcoidosis was made following which a dual chamber defibrillator was implanted. Prednisone 20 mg daily and methotrexate 12.5 mg weekly was planned. However, given that treatment response and disease progression assessment could not be achieved with serial cardiac MRI (ICD placed), a baseline rest Rubidium 82/F-18 flourodeoxyglucose (Rb-82/18-FDG) cardiac PET was obtained prior to treatment to be used to then assess treatment response with serial scans as indicated showing pattern consistent with active cardiac sarcoidosis (Figure 2). Treatment was initiated and methotrexate titrated up to 15 mg weekly. He was seen in the clinic five months after medical therapy was initiated. Subjectively reported minimal to no symptoms. A repeat cardiac PET was done (Figure 3) using same protocol to assess response to therapy showed marked improvement. His dose of prednisone was decreased to 10 mg daily and then discontinued. Few months later, amiodarone and methotrexate were discontinued due to early development of interstitial lung disease. Seven months after discontinuation of medical therapy, he developed recurrent heart failure symptoms. Echocardiogram EF was 30%-35%. Repeat cardiac PET was done (Figure 4) showing recurrence of active cardiac sarcoidosis. He was reinitiated on prednisone at 50 mg but refused to take it due to weight gain and did not return for follow-up appointments. This case highlights the role of cardiac PET not only in situations where MRI cannot be used but also following treatment response and disease reactivation which is challenging to assess with cardiac MRI. The emerging importance of cardiac PET in cardiac sarcoidosis is now acknowledged in the recent consensus documents and nuclear societies recommendations 1,2 as an indicator of cardiac sarcoidosis in contrast to prior older imaging criteria for CS which included on SPECT or MRI abnormalities. 3 Whole body imaging to evaluate sarcoid activity in other extra cardiac organs apart from the heart and quantitation of standardized uptake values (SUVmax) to enhance diagnosis of disease activity and response to therapy were not available in our study but are key methods to better evaluate and assess sarcoidosis as shown in recent studies. 4

Periodontitis is associated with the risk of subclinical atherosclerosis and peripheral arterial disease in Korean adults

Background and aimsWe aimed to evaluate the association of periodontitis with the development of early atherosclerotic vascular disease in Korean adults. MethodsIn this cross-sectional study, a total of 1343 adults aged over 40 years were recruited from a community-based cohort of Yangpyeong county, Korea, during the period 2010–2014. Only dentate individuals were included in the study. Subclinical atherosclerosis (SA) was defined as carotid intima-media thickness (cIMT)≥0.754 mm, as assessed bilaterally by B-mode ultrasound. Peripheral arterial disease (PAD) was defined as ankle-brachial index (ABI)≤1.0, as measured by Doppler. History of periodontitis was assessed by measuring the radiographic alveolar bone loss (RABL) on a digital dental panorama and was classified into three groups: normal, moderate and severe periodontitis (≥2 non-adjacent interproximal sites with RABL≥4 mm and 6 mm, respectively). The associations of periodontitis with SA and PAD were evaluated by multivariable logistic regression analysis and analysis of covariance, adjusted for age, sex, education level, tooth loss, smoking, drinking, exercise, obesity, triglycerides, HDL, LDL, hs-CRP, diabetes and hypertension. Stratified analyses were performed to identify specific risk groups. ResultsAfter controlling for confounders, severe periodontitis was associated with SA [adjusted odds ratio (aOR) = 1.55; 95% confidence interval (CI): 1.07–2.24] and PAD (aOR = 2.03; 95% CI: 1.05–3.93). These associations were highlighted in never-smokers. For increasing severity of periodontitis, the adjusted mean cIMT increased (p = 0.011) while that of ABI decreased (p = 0.033). ConclusionsOur data showed that periodontitis is a substantially important risk factor for atherosclerotic vascular disease among Korean adults.

Orthodontic treatment as a possible trigger of periodontal disease

Background: Periodontal disease leads to the deterioration of oral health, including loss of teeth and its supporting structures. It has been established that the cause of this disease is multifactorial, indicating that both genes and environmental factors are intertwined with the formation and progression of periodontal disease. Case Description: Here we discuss the possibility of orthodontic treatment serving as a trigger to an early development of periodontal disease in a patient who has a family history of periodontitis. Between debonding at age 17.5 years and age 28, the patient experienced gradual general loss of attachment on the mandibular arch with the left mandibular canine having exaggerated attachment loss. Between age 28 and 29 years, the patient experienced exacerbated loss of attachment at both mandibular canines. Practical Implications: The occurrence of attachment loss during and after orthodontic treatment should not be overlooked. It is crucial for orthodontists to obtain a family history of periodontal disease and carefully monitor patient’s periodontal conditions throughout the treatment.

Serum Cortisol and BMI in Chronic Diseases and Increased Early Cardiovascular Diseases

The purpose of this study was to examine the role of cortisol, and it is related to BMI in the chronic diseases which may increase early cardiovascular disease (CVD) in old Iraqi. The subjects were 116 adults, aged 51-71 years. Body Mass Index (BMI), Waist Circumferences (WC) and Waist Hip Ratio (WHR) were used as a measure of adiposity. Investigation showed highly significant difference between patients in BMI ranges, most of male were in an obese weight range (48.5%), as well in women. There were no significant correlations between serum cortisol concentration and age both gender groups. While there were highly significant correlations between cortisol level and BMI, waist, and WHR (except in female subjects), also there were highly significant correlations between cortisol level and SBP,DBP (mmHg)only in male. In both groups, total cholesterol concentration, FBS, and A1C were significantly correlated with serum cortisol. Negatively correlated has been observed between serum cortisol and HDL-C in men but not in women. In men, the results of cortisol with CV risk factors (dyslipidemia, D.M, hypertension, at least 2 risk factors and three risk factors) show significant differences (p&gt;0.0). In summary, there is a major association between cortisol levels, obese, and chronic diseases. These conclusions promote the hypothesis that the opposing effect of adiposity on the chronic diseases might be mediated by cortisol. This association could cause early development of cardiovascular diseases even in males.

STAT3 Establishes an Immunosuppressive Microenvironment during the Early Stages of Breast Carcinogenesis to Promote Tumor Growth and Metastasis.

Immunosurveillance constitutes the first step of cancer immunoediting in which developing malignant lesions are eliminated by antitumorigenic immune cells. However, the mechanisms by which neoplastic cells induce an immunosuppressive state to evade the immune response are still unclear. The transcription factor STAT3 has been implicated in breast carcinogenesis and tumor immunosuppression in advanced disease, but its involvement in early disease development has not been established. Here, we genetically ablated Stat3 in the tumor epithelia of the inducible PyVmT mammary tumor model and found that Stat3-deficient mice recapitulated the three phases of immunoediting: elimination, equilibrium, and escape. Pathologic analyses revealed that Stat3-deficient mice initially formed hyperplastic and early adenoma-like lesions that later completely regressed, thereby preventing the emergence of mammary tumors in the majority of animals. Furthermore, tumor regression was correlated with massive immune infiltration into the Stat3-deficient lesions, leading to their elimination. In a minority of animals, focal, nonmetastatic Stat3-deficient mammary tumors escaped immune surveillance after a long latency or equilibrium period. Taken together, our findings suggest that tumor epithelial expression of Stat3 plays a critical role in promoting an immunosuppressive tumor microenvironment during breast tumor initiation and progression, and prompt further investigation of Stat3-inhibitory strategies that may reactivate the immunosurveillance program.

Proteomic profiling change during the early development of silicosis disease.

Silicosis is one of several severe occupational diseases for which effective diagnostic tools during early development are currently unavailable. In this study we focused on proteomic profiling during the early stages of silicosis to investigate the pathophysiology and identify the proteins involved. Two-dimensional (2D) gel electrophoresis and MALDI-TOF-MS were used to assess the proteomic differences between healthy individuals (HI), dust-exposed workers without silicosis (DEW) and silicosis patients (SP). Proteins abundances that differed by a factor of two-fold or greater were subjected to more detailed analysis, and enzyme linked to immunosorbent assay (ELISA) was employed to correlate with protein expression data. Compared with HI, 42 proteins were more abundant and 8 were less abundant in DEW, and these were also differentially accumulated in SP. Closer inspection revealed that serine protease granzyme A, alpha-1-B-glycoprotein (A1BG) and the T4 surface glycoprotein precursor (TSGP) were among the up-regulated proteins in DEW and SP. Significant changes in serine proteases, glycoproteins and proto-oncogenes may be associated with the response to cytotoxicity and infectious pathogens by activation of T cells, positive regulation of extracellular matrix structural constituents and immune response, and fibroblast proliferation. Up-regulation of cytokines included TNFs, interferon beta precursor, interleukin 6, atypical chemokine receptor 2, TNFR13BV, and mutant IL-17F may be involved in the increased and persistent immune response and fibrosis that occurred during silicosis development. Granzymes, glycoproteins, cytokines and immune factors were dramatically involved in the immune response, metabolism, signal regulation and fibrosis during the early development of silicosis. Proteomic profiling has expanded our understanding of the pathogenesis of silicosis, and identified a number of targets that may be potential biomarkers for early diagnosis of this debilitating disease.

Year in review 2015: Interstitial lung disease, pulmonary vascular disease, pulmonary function, sleep and ventilation, cystic fibrosis and paediatric lung disease.

Keywords: interstitial lung disease; lung function; paediatric lung disease; pulmonary vascular disease; sleep

Dietary Protein Intake and Lean Muscle Mass in Survivors of Childhood Acute Lymphoblastic Leukemia: Report From the St. Jude Lifetime Cohort Study.

Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for low lean muscle mass and muscle weakness, which may contribute to inactivity and early development of chronic diseases typically seen in older adults. Although increasing protein intake, in combination with resistance training, improves lean muscle mass in other populations, it is not known whether muscular tissue among survivors of ALL, whose impairments are treatment-related, will respond similarly. The aim of this study was to evaluate associations among dietary protein intake, resistance training, and lean muscle mass in survivors of ALL and age-, sex-, and race-matched controls. This was a cross-sectional study. Lean muscle mass was determined with dual-energy x-ray absorptiometry, dietary information with 24-hour recalls, and participation in resistance training with a questionnaire. Participants were 365 survivors of ALL (52% male; 87% white; median age=28.5 years, range=23.6-31.7) and 365 controls with no previous cancer. Compared with controls, survivors of ALL had lower lean muscle mass (55.0 versus 57.2 kg, respectively) and lower percentage of lean muscle mass (68.6% versus 71.4%, respectively) than controls. Similar proportions of survivors (71.1%) and controls (69.7%) met recommended dietary protein intake (0.8 g/kg/d). Survivors (45.4%) were less likely to report resistance training than controls (53.8%). In adjusted models, 1-g higher protein intake per kilogram of body mass per day was associated with a 7.9% increase and resistance training ≥1×wk, with a 2.8% increase in lean muscle mass. The cross-sectional study design limits temporal evaluation of the association between protein intake and lean muscle mass. The findings suggest that survivors of childhood ALL with low lean muscle mass may benefit from optimizing dietary protein intake in combination with resistance training. Research is needed to determine whether resistance training with protein supplementation improves lean muscle mass in survivors of childhood ALL.

Serum Cortisol and BMI in Chronic Diseases and Increased Early Cardiovascular Diseases

The purpose of this study was to examine the role of cortisol, and it is related to BMI in the chronic diseases which may increase early cardiovascular disease (CVD) in old Iraqi. The subjects were 116 adults, aged 51-71 years. Body Mass Index (BMI), Waist Circumferences (WC) and Waist Hip Ratio (WHR) were used as a measure of adiposity. Investigation showed highly significant difference between patients in BMI ranges, most of male were in an obese weight range (48.5%), as well in women. There were no significant correlations between serum cortisol concentration and age both gender groups. While there were highly significant correlations between cortisol level and BMI, waist, and WHR (except in female subjects), also there were highly significant correlations between cortisol level and SBP,DBP (mmHg)only in male. In both groups, total cholesterol concentration, FBS, and A1C were significantly correlated with serum cortisol. Negatively correlated has been observed between serum cortisol and HDL-C in men but not in women. In men, the results of cortisol with CV risk factors (dyslipidemia, D.M, hypertension, at least 2 risk factors and three risk factors) show significant differences (p&gt;0.0). In summary, there is a major association between cortisol levels, obese, and chronic diseases. These conclusions promote the hypothesis that the opposing effect of adiposity on the chronic diseases might be mediated by cortisol. This association could cause early development of cardiovascular diseases even in males.

Abstract B012: Immunomodulated VTP enables cure of metastatic prostate and breast cancers in animal models

Abstract Vascular-targeted photodynamic therapy with WST11 (VTP) enables safe and efficient non-thermal ablation of solid tumors as demonstrated by recent phase II and III clinical trials with localized prostate cancer. Studies in animal models in our labs revealed that VTP of immunogenic tumors elicits innate/adaptive immune responses and over 80% cures with consequent long-lasting anti-tumor protection. Here we show that local VTP combined with immune modulation in rodents, bearing weakly immunogenic prostate and triple negative breast tumors, results in eradication of remote metastases and animal cure. Methodology: 4T1-luc cells were subcutaneously grafted at the hind leg of Balb/C mice. Colony forming assay confirmed tumor cell spreading to the lungs already by day 7 post grafting when local VTP was delivered to the primary tumor. The study comprised: (i) animals treated by VTP alone or (ii) following 50mg/kg cyclophosphamide (CTX) on day 4 post grafting, or (iii) VTP combined with anti-CTLA4 antibodies administered on days 1, 4, 7 and 10 post VTP according to standard protocol. Appropriate control groups using immunomodulatory agents alone or untreated tumors were utilized. Cure was defined as absence of detectable primary or metastatic tumor by necropsy at 90 days. Mat-Lu-luc prostate cancer cells were grafted orthotopically in Copenhagen rats. Surgical removal of tumor bearing prostate and follow up of disease progression demonstrated that on day 10 post grafting, the day of VTP, metastatic spread has already been initiated in 57% of animals, eventually developing abdominal and visceral metastases. Treatment groups comprised (i) animals treated by VTP with or (ii) without CTX pre-treatment followed by prostate removal three days after VTP or (iii) surgery only. Results: Treatment of primary 4T1-luc tumors with VTP resulted in a complete primary tumor ablation in 50% of treated animals. Less then 10% of animals treated with VTP alone were cured with the rest developing lung metastases, while combination with CTX resulted in 30% cures. CTX induced reduction of total cell counts in tumor draining lymph nodes (LN) and spleens on VTP day followed by cell expansion over the following four days. Significant CTX-mediated reduction of Foxp3+ cells accompanied by increase in CD8+ cells during this period could be responsible for observed anti-metastatic effect of the combined treatment. Moreover, no significant change in total CD4+ cells observed at the same time suggests expansion of T helper cell subsets with concomitant suppression of regulatory population. Anti-CTLA-4 treatment, although significantly improved primary response rates after sub-optimal VTP (56% vs 14% in combined group vs VTP), did not prevent metastases suggesting additional escape mechanisms. VTP of orthotopic prostate tumors followed by whole gland removal resulted in 45% metastatic rate vs 57% in group treated by surgery alone on the same day. Pre-treatment with 50mg/kg CTX three days prior to VTP reduced metastatic rate to 7%. These findings suggest VTP-induced immune response can be augmented by prior immune modulation. Conclusions: Our results demonstrate that immunomodulation combined with local VTP enables systemic anti-tumor effects with impact on the development of early metastatic disease in the setting of poorly immunogenic tumors. The choice of different immune modulatory agents and timing of treatment appears to play a critical role in the treatment outcome. Further studies are in progress to evaluate combination of WST11-VTP with more than one immunomodulating agent to further characterize localized and systemic response and augment treatment success. These studies serve as pre-clinical support for clinical trials, exploiting the immunogenic effects of VTP for tumor ablation, being developed in collaboration with Memorial Sloan Kettering Cancer Center. Note:This abstract was not presented at the conference. Citation Format: Dina Preise, Natasha Kudinova, Uri Lindner, Keren Sasson, Ronny Uzana, Jonathan Coleman, Yoram Salomon, Avigdor Scherz. Immunomodulated VTP enables cure of metastatic prostate and breast cancers in animal models. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B012.