Low muscle glycogen concentration does not suppress the anabolic response to resistance exercise

We determined the effect of muscle glycogen concentration and postexercise nutrition on anabolic signaling and rates of myofibrillar protein synthesis after resistance exercise (REX). Sixteen young, healthy men matched for age, body mass, peak oxygen uptake (VO2peak) and strength (one repetition maximum; 1RM) were randomly assigned to either a nutrient or placebo group. After 48 h diet and exercise control, subjects undertook a glycogen-depletion protocol consisting of one-leg cycling to fatigue (LOW), whereas the other leg rested (NORM). The next morning following an overnight fast, a primed, constant infusion of L-[ring-13C6] phenylalanine was commenced and subjects completed 8 sets of 5 unilateral leg press repetitions at 80% 1RM. Immediately after REX and 2 h later, subjects consumed a 500 ml bolus of a protein/CHO (20 g whey + 40 g maltodextrin) or placebo beverage. Muscle biopsies from the vastus lateralis of both legs were taken at rest and 1 and 4 h after REX. Muscle glycogen concentration was higher in the NORM than LOW at all time points in both nutrient and placebo groups (P < 0.05). Postexercise Akt-p70S6K-rpS6 phosphorylation increased in both groups with no differences between legs (P < 0.05). mTORSer2448 phosphorylation in placebo increased 1 h after exercise in NORM (P < 0.05), whereas mTOR increased ?4-fold in LOW (P < 0.01) and ?11 fold in NORM with nutrient (P < 0.01; different between legs P < 0.05). Post-exercise rates of MPS were not different between NORM and LOW in nutrient (0.070 ± 0.022 vs. 0.068 ± 0.018 %/h) or placebo (0.045 ± 0.021 vs. 0.049 ± 0.017 %/h). We conclude that commencing high-intensity REX with low muscle glycogen availability does not compromise the anabolic signal and subsequent rates of MPS, at least during the early (4 h) postexercise recovery period.

The molecular bases of training adaptation

Skeletal muscle is a malleable tissue capable of altering the type and amount of protein in response to disruptions to cellular homeostasis. The process of exercise-induced adaptation in skeletal muscle involves a multitude of signalling mechanisms initiating replication of specific DNA genetic sequences, enabling subsequent translation of the genetic message and ultimately generating a series of amino acids that form new proteins. The functional consequences of these adaptations are determined by training volume, intensity and frequency, and the half-life of the protein. Moreover, many features of the training adaptation are specific to the type of stimulus, such as the mode of exercise. Prolonged endurance training elicits a variety of metabolic and morphological changes, including mitochondrial biogenesis, fast-to-slow fibre-type transformation and substrate metabolism. In contrast, heavy resistance exercise stimulates synthesis of contractile proteins responsible for muscle hypertrophy and increases in maximal contractile force output. Concomitant with the vastly different functional outcomes induced by these diverse exercise modes, the genetic and molecular mechanisms of adaptation are distinct. With recent advances in technology, it is now possible to study the effects of various training interventions on a variety of signalling proteins and early-response genes in skeletal muscle. Although it cannot presently be claimed that such scientific endeavours have influenced the training practices of elite athletes, these new and exciting technologies have provided insight into how current training techniques result in specific muscular adaptations, and may ultimately provide clues for future and novel training methodologies. Greater knowledge of the mechanisms and interaction of exercise-induced adaptive pathways in skeletal muscle is important for our understanding of the aetiology of disease, maintenance of metabolic and functional capacity with aging, and training for athletic performance. This article highlights the effects of exercise on molecular and genetic mechanisms of training adaptation in skeletal muscle.

Smart grid-demand side response model to mitigate prices and peak impact on the electrical system

The aims of this project is to develop demand side response model which assists electricity consumers who are exposed to the market price through aggregator to manage the air-conditioning peak electricity demand. The main contribution of this research is to show how consumers can optimise the energy cost caused by the air-conditioning load considering the electricity market price and network overload. The model is tested with selected characteristics of the room, Queensland electricity market data from Australian Energy Market Operator and data from the Bureau of Statistics on temperatures in Brisbane, during weekdays on hot days from 2011 - 2012.

Validity of dietary questionnaires in Sri Lankan adults and the association of dietary intake with obesity

Traditionally, infectious diseases and under-nutrition have been considered major health problems in Sri Lanka with little attention paid to obesity and associated non-communicable diseases (NCDs). However, the recent Sri Lanka Diabetes and Cardiovascular Study (SLDCS) reported the epidemic level of obesity, diabetes and metabolic syndrome. Moreover, obesity-associated NCDs is the leading cause of death in Sri Lanka and there is an exponential increase in hospitalization due to NCDs adversely affecting the development of the country. Despite Sri Lanka having a very high prevalence of NCDs and associated mortality, little is known about the causative factors for this burden. It is widely believed that the global NCD epidemic is associated with recent lifestyle changes, especially dietary factors. In the absence of sufficient data on dietary habits in Sri Lanka, successful interventions to manage these serious health issues would not be possible. In view of the current situation the dietary survey was undertaken to assess the intakes of energy, macro-nutrients and selected other nutrients with respect to socio demographic characteristics and the nutritional status of Sri Lankan adults especially focusing on obesity. Another aim of this study was to develop and validate a culturally specific food frequency questionnaire (FFQ) to assess dietary risk factors of NCDs in Sri Lankan adults. Data were collected from a subset of the national SLDCS using a multi-stage, stratified, random sampling procedure (n=500). However, data collection in the SLDCS was affected by the prevailing civil war which resulted in no data being collected from Northern and Eastern provinces. To obtain a nationally representative sample, additional subjects (n=100) were later recruited from the two provinces using similar selection criteria. Ethical Approval for this study was obtained from the Ethical Review Committee, Faculty of Medicine, University of Colombo, Sri Lanka and informed consent was obtained from the subjects before data were collected. Dietary data were obtained using the 24-h Dietary Recall (24HDR) method. Subjects were asked to recall all foods and beverages, consumed over the previous 24-hour period. Respondents were probed for the types of foods and food preparation methods. For the FFQ validation study, a 7-day weight diet record (7-d WDR) was used as the reference method. All foods recorded in the 24 HDR were converted into grams and then intake of energy and nutrients were analysed using NutriSurvey 2007 (EBISpro, Germany) which was modified for Sri Lankan food recipes. Socio-demographic details and body weight perception were collected from interviewer-administrated questionnaire. BMI was calculated and overweight (BMI ≥23 kg.m-2), obesity (BMI ≥25 kg.m-2) and abdominal obesity (Men: WC ≥ 90 cm; Women: WC ≥ 80 cm) were categorized according to Asia-pacific anthropometric cut-offs. The SPSS v. 16 for Windows and Minitab v10 were used for statistical analysis purposes. From a total of 600 eligible subjects, 491 (81.8%) participated of whom 34.5% (n=169) were males. Subjects were well distributed among different socio-economic parameters. A total of 312 different food items were recorded and nutritionists grouped similar food items which resulted in a total of 178 items. After performing step-wise multiple regression, 93 foods explained 90% of the variance for total energy intake, carbohydrates, protein, total fat and dietary fibre. Finally, 90 food items and 12 photographs were selected. Seventy-seven subjects completed (response rate = 65%) the FFQ and 7-day WDR. Estimated mean energy intake (SD) from FFQ (1794±398 kcal) and 7DWR (1698±333 kcal, P<0.001) was significantly different due to a significant overestimation of carbohydrate (~10 g/d, P<0.001) and to some extent fat (~5 g/d, NS). Significant positive correlations were found between the FFQ and 7DWR for energy (r = 0.39), carbohydrate (r = 0.47), protein (r = 0.26), fat (r =0.17) and dietary fiber (r = 0.32). Bland-Altman graphs indicated fairly good agreement between methods with no relationship between bias and average intake of each nutrient examined. The findings from the nutrition survey showed on average, Sri Lankan adults consumed over 14 portions of starch/d; moreover, males consumed 5 more portions of cereal than females. Sri Lankan adults consumed on average 3.56 portions of added sugars/d. Moreover, mean daily intake of fruit (0.43) and vegetable (1.73) portions was well below minimum dietary recommendations (fruits 2 portions/d; vegetables 3 portions/d). The total fruit and vegetable intake was 2.16 portions/d. Daily consumption of meat or alternatives was 1.75 portions and the sum of meat and pulses was 2.78 portions/d. Starchy foods were consumed by all participants and over 88% met the minimum daily recommendations. Importantly, nearly 70% of adults exceeded the maximum daily recommendation for starch (11portions/d) and a considerable proportion consumed larger numbers of starch servings daily, particularly men. More than 12% of men consumed over 25 starch servings/d. In contrast to their starch consumption, participants reported very low intakes of other food groups. Only 11.6%, 2.1% and 3.5% of adults consumed the minimum daily recommended servings of vegetables, fruits, and fruits and vegetables combined, respectively. Six out of ten adult Sri Lankans sampled did not consume any fruits. Milk and dairy consumption was extremely low; over a third of the population did not consume any dairy products and less than 1% of adults consumed 2 portions of dairy/d. A quarter of Sri Lankans did not report consumption of meat and pulses. Regarding protein consumption, 36.2% attained the minimum Sri Lankan recommendation for protein; and significantly more men than women achieved the recommendation of ≥3 servings of meat or alternatives daily (men 42.6%, women 32.8%; P<0.05). Over 70% of energy was derived from carbohydrates (Male:72.8±6.4%, Female:73.9±6.7%), followed by fat (Male:19.9±6.1%, Female:18.5±5.7%) and proteins (Male:10.6±2.1%, Female:10.9±5.6%). The average intake of dietary fiber was 21.3 g/day and 16.3 g/day for males and females, respectively. There was a significant difference in nutritional intake related to ethnicities, areas of residence, education levels and BMI categories. Similarly, dietary diversity was significantly associated with several socio-economic parameters among Sri Lankan adults. Adults with BMI ≥25 kg.m-2 and abdominally obese Sri Lankan adults had the highest diet diversity values. Age-adjusted prevalence (95% confidence interval) of overweight, obesity, and abdominal obesity among Sri Lankan adults were 17.1% (13.8-20.7), 28.8% (24.8-33.1), and 30.8% (26.8-35.2), respectively. Men, compared with women, were less overweight, 14.2% (9.4-20.5) versus 18.5% (14.4-23.3), P = 0.03, less obese, 21.0% (14.9-27.7) versus 32.7% (27.6-38.2), P < .05; and less abdominally obese, 11.9% (7.4-17.8) versus 40.6% (35.1-46.2), P < .05. Although, prevalence of obesity has reached to epidemic level body weight misperception was common among Sri Lankan adults. Two-thirds of overweight males and 44.7% of females considered themselves as in "about right weight". Over one third of both male and female obese subjects perceived themselves as "about right weight" or "underweight". Nearly 32% of centrally obese men and women perceived that their waist circumference is about right. People who perceived overweight or very overweight (n = 154) only 63.6% tried to lose their body weight (n = 98), and quarter of adults seek advices from professionals (n = 39). A number of important conclusions can be drawn from this research project. Firstly, the newly developed FFQ is an acceptable tool for assessing the nutrient intake of Sri Lankans and will assist proper categorization of individuals by dietary exposure. Secondly, a substantial proportion of the Sri Lankan population does not consume a varied and balanced diet, which is suggestive of a close association between the nutrition-related NCDs in the country and unhealthy eating habits. Moreover, dietary diversity is positively associated with several socio-demographic characteristics and obesity among Sri Lankan adults. Lastly, although obesity is a major health issue among Sri Lankan adults, body weight misperception was common among underweight, healthy weight, overweight, and obese adults in Sri Lanka. Over 2/3 of overweight and 1/3 of obese Sri Lankan adults believe that they are in "right weight" or "under-weight" categories.

Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer

Purpose: Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non-small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy. Patients and Methods: Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. Results: Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients. Conclusion: Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC. © 2005 by American Society of Clinical Oncology.

Response to chemotherapy is predictive in relation to longer overall survival in an individual patient combined-analysis with pleural mesothelioma

Background: There is currently no early predictive marker of survival for patients receiving chemotherapy for malignant pleural mesothelioma (MPM). Tumour response may be predictive for overall survival (OS), though this has not been explored. We have thus undertaken a combined-analysis of OS, from a 42 day landmark, of 526 patients receiving systemic therapy for MPM. We also validate published progression-free survival rates (PFSRs) and a progression-free survival (PFS) prognostic-index model. Methods: Analyses included nine MPM clinical trials incorporating six European Organisation for Research and Treatment of Cancer (EORTC) studies. Analysis of OS from landmark (from day 42 post-treatment) was considered regarding tumour response. PFSR analysis data included six non-EORTC MPM clinical trials. Prognostic index validation was performed on one non-EORTC data-set, with available survival data. Results: Median OS, from landmark, of patients with partial response (PR) was 12·8 months, stable disease (SD), 9·4 months and progressive disease (PD), 3·4 months. Both PR and SD were associated with longer OS from landmark compared with disease progression (both p < 0·0001). PFSRs for platinum-based combination therapies were consistent with published significant clinical activity ranges. Effective separation between PFS and OS curves provided a validation of the EORTC prognostic model, based on histology, stage and performance status. Conclusion: Response to chemotherapy is associated with significantly longer OS from landmark in patients with MPM. © 2012 Elsevier Ltd. All rights reserved.

Analysis of acute-phase proteins, AHSG, C3, CLI, HP and SAA, reveals distinctive expression patterns associated with breast, colorectal and lung cancer

Early detection, clinical management and disease recurrence monitoring are critical areas in cancer treatment in which specific biomarker panels are likely to be very important in each of these key areas. We have previously demonstrated that levels of alpha-2-heremans-schmid-glycoprotein (AHSG), complement component C3 (C3), clusterin (CLI), haptoglobin (HP) and serum amyloid A (SAA) are significantly altered in serum from patients with squamous cell carcinoma of the lung. Here, we report the abundance levels for these proteins in serum samples from patients with advanced breast cancer, colorectal cancer (CRC) and lung cancer compared to healthy controls (age and gender matched) using commercially available enzyme-linked immunosorbent assay kits. Logistic regression (LR) models were fitted to the resulting data, and the classification ability of the proteins was evaluated using receiver-operating characteristic curve and leave-one-out cross-validation (LOOCV). The most accurate individual candidate biomarkers were C3 for breast cancer [area under the curve (AUC) = 0.89, LOOCV = 73%], CLI for CRC (AUC = 0.98, LOOCV = 90%), HP for small cell lung carcinoma (AUC = 0.97, LOOCV = 88%), C3 for lung adenocarcinoma (AUC = 0.94, LOOCV = 89%) and HP for squamous cell carcinoma of the lung (AUC = 0.94, LOOCV = 87%). The best dual combination of biomarkers using LR analysis were found to be AHSG + C3 (AUC = 0.91, LOOCV = 83%) for breast cancer, CLI + HP (AUC = 0.98, LOOCV = 92%) for CRC, C3 + SAA (AUC = 0.97, LOOCV = 91%) for small cell lung carcinoma and HP + SAA for both adenocarcinoma (AUC = 0.98, LOOCV = 96%) and squamous cell carcinoma of the lung (AUC = 0.98, LOOCV = 84%). The high AUC values reported here indicated that these candidate biomarkers have the potential to discriminate accurately between control and cancer groups both individually and in combination with other proteins. Copyright © 2011 UICC.

Receptor tyrosine kinases and their activation in melanoma

Receptor tyrosine kinases (RTKs) and their downstream signalling pathways have long been hypothesized to play key roles in melanoma development. A decade ago, evidence was derived largely from animal models, RTK expression studies and detection of activated RAS isoforms in a small fraction of melanomas. Predictions that overexpression of specific RTKs implied increased kinase activity and that some RTKs would show activating mutations in melanoma were largely untested. However, technological advances including rapid gene sequencing, siRNA methods and phospho-RTK arrays now give a more complete picture. Mutated forms of RTK genes including KIT, ERBB4, the EPH and FGFR families and others are known in melanoma. Additional over- or underexpressed RTKs and also protein tyrosine phosphatases (PTPs) have been reported, and activities measured. Complex interactions between RTKs and PTPs are implicated in the abnormal signalling driving aberrant growth and survival in malignant melanocytes, and indeed in normal melanocytic signalling including the response to ultraviolet radiation. Kinases are considered druggable targets, so characterization of global RTK activity in melanoma should assist the rational development of tyrosine kinase inhibitors for clinical use. © 2011 John Wiley & Sons A/S.

GABAergic agents modify the response of chick scleral fibroblasts to myopic and hyperopic eye cup tissues

Purpose: GABA antagonists inhibit experimental myopia in chick and GABA receptors have been localized to chick sclera and the retinal pigment epithelium (RPE). The RPE and the choroid alter scleral DNA and glycosaminoglycan (GAG) content in vitro; opposite effects have been observed for tissues from myopic and hyperopic eyes. The aim was to determine the effect of GABAergic agents on the DNA and GAG content of chick scleral fibroblasts directly and in co-culture with ocular tissues from myopic and hyperopic chick eyes. Materials and Methods: Primary cultures of fibroblastic cells expressing vimentin and α-smooth muscle actin were established. GABAergic agents were added separately (i) to the culture medium of the scleral cells and (ii) to the culture medium of the scleral cells with the addition of posterior eye cup tissue (retina, RPE, retina + RPE, choroid + RPE) to cell culture inserts. Ocular tissues were obtained from chick eyes wearing + 15D (lens-induced hyperopia, LIH) or −15D lenses (lens-induced myopia, LIM) for three days (post-hatch day 5–8) (n = 12). GAG and DNA content of scleral fibroblasts were measured. Results: GABA agents had a small direct effect on scleral cell GAG and DNA content but a larger effect was measured when GABA agents were added to the culture medium with myopic and hyperopic RPE and choroid + RPE tissues. GABA agonists increased (p = 0.002) whereas antagonists decreased (p = 0.0004) DNA content of scleral cells; effects were opposite for scleral GAG content. GABA agents significantly altered the effect of both LIM and LIH tissues (p = 0.0005) compared to control; the effects were greater for LIM tissue versus LIH tissue co-culture (p = 0.0004). Conclusion: GABAergic agents affect the DNA and GAG content of scleral fibroblasts both directly and when co-cultured with ocular tissues. GABA antagonists that prevent myopia development in chick model could act via a scleral mechanism utilizing the RPE/choroid.

Phase II clinical trial of first or second-line treatment with bortezomib in patients with malignant pleural mesothelioma

Based on promising preclinical efficacy of bortezomib in mesothelioma, a single-arm phase II trial (Ireland Cooperative Oncology Research Group 05-10 study), with Simon's two-stage design, was undertaken to assess efficacy of bortezomib monotherapy in the first-line (poor performance status) and second-line settings. The Bcl-2 homology domain 3-only protein Noxa has been implicated as a key inducer of apoptosis by bortezomib. Thus, in a biomarker research substudy, we hypothesized that deficiency in Noxa expression might correlate with resistance. In the second-line setting, 23 patients were enrolled. Partial response was confirmed in one patient (4.8%) who received four cycles of bortezomib. One patient had stable disease; however, progression occurred in the majority of patients within the first two cycles. Median progression-free survival and overall survival were 2.1 and 5.8 months, respectively. In the first-line setting, ten patients were accrued, and there was no evidence of objective response. In the tumor analysis, expression of Noxa was seen in all biopsies. Bortezomib monotherapy exhibits insufficient activity to warrant further investigation in unselected patients with mesothelioma. © 2012 by the International Association for the Study of Lung.

Platelet-derived endothelial cell growth factor (thymidine phosphorylase) expression in lung cancer

Platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) is an enzyme with angiogenic and cell motility properties. Moreover, it is involved in the transformation of fluoropyrimidines into active cytotoxic metabolites, In the present study, the expression of PD-ECGF in normal lung and lung cancer was immunohistochemically evaluated using the P-GF.44C monoclonal antibody. Alveolar and tumoural macrophages mere invariably stained and mere used as an internal control for assessment of the staining. Alveolar epithelium was always negative, whilst bronchiolar epithelium showed occasional positive reactivity. Normal lung and tumour endothelium was occasionally positive, Positive staining in more than 50 per cent of cells was observed in 23/71 squamous carcinomas (32 per cent), 16/38 (42 per cent) adenocarcinomas, and 2/6 (33 per cent) adenosquamous carcinomas. Differentiated areas and areas of squamous metaplasia mere more strongly positive than other tumour areas. All 22 small cell carcinomas and one carcinoid tumour were negative. The present study provides a baseline for future studies in non-small cell lung cancer to correlate PD-ECGF expression with tumour vascularization, prognosis, and response to chemotherapy.

18FDG uptake during induction chemoradiation for oesophageal cancer fails to predict histomorphological tumour response

To determine whether [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) could predict the pathological response in oesophageal cancer after only the first week of neoadjuvant chemoradiation. Thirty-two patients with localised oesophageal cancer had a pretreatment PET scan and a repeat after the first week of chemoradiation. The change in mean maximum standardised uptake value (SUV) and volume of metabolically active tissue (MTV) was compared with the tumour regression grade (TRG) in the final histology. Those who achieved a TRG of 1 and 2 were deemed responders and 3-5 nonresponders. In the responders (28%), the SUV fell from 12.6 (±6.3) to 8.1 (±2.9) after 1 week of chemoradiation (P = 0.070). In nonresponders (72%), the results were 9.7 (±5.4) and 7.1 (±3.8), respectively (P = 0.003). The MTV in responders fell from 36.6 (±22.7) to 22.3 (±10.4) cm3 (P = 0.180), while in nonresponders, this fell from 35.9 (±36.7) to 31.9 (±52.7) cm3 (P = 0.405). There were no significant differences between responders and nonresponders. The hypothesis that early repeat FDG-PET scanning may predict histomorphologic response was not proven. This may reflect an inflammatory effect of radiation that obscures tumour-specific metabolic changes at this time. This assessment may have limited application in predicting response to multimodal regimens for oesophageal cancer. © 2006 Cancer Research UK.

Galectin-1 : a link between tumor hypoxia and tumor immune privilege

Purpose: To identify a 15-KDa novel hypoxia-induced secreted protein in head and neck squamous cell carcinomas (HNSCC) and to determine its role in malignant progression. Methods: We used surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF-MS) and tandem MS to identify a novel hypoxia-induced secreted protein in FaDu cells. We used immunoblots, real-time polymerase chain reaction (PCR), and enzyme-linked immunoabsorbent assay to confirm the hypoxic induction of this secreted protein as galectin-1 in cell lines and xenografts. We stained tumor tissues from 101 HNSCC patients for galectin-1, CA IX (carbonic anhydrase IX, a hypoxia marker) and CDS (a T-cell marker). Expression of these markers was correlated to each other and to treatment outcomes. Results: SELDI-TOF studies yielded a hypoxia-induced peak at 15 kDa that proved to be galectin-1 by MS analysis. Immunoblots and PCR studies confirmed increased galectin-1 expression by hypoxia in several cancer cell lines. Plasma levels of galectin-1 were higher in tumor-bearing severe combined immunodeficiency (SCID) mice breathing 10% O 2 compared with mice breathing room air. In HNSCC patients, there was a significant correlation between galectin-1 and CA IX staining (P = .01) and a strong inverse correlation between galectin-1 and CDS staining (P = .01). Expression of galectin-1 and CDS were significant predictors for overall survival on multivariate analysis. Conclusion: Galectin-1 is a novel hypoxia-regulated protein and a prognostic marker in HNSCC. This study presents a new mechanism on how hypoxia can affect the malignant progression and therapeutic response of solid tumors by regulating the secretion of proteins that modulate immune privilege. © 2005 by American Society of Clinical Oncology.

Gene expression analysis of diagnostic biopsies predicts pathological response to neoadjuvant chemoradiotherapy of esophageal cancer

OBJECTIVE: This study explored gene expression differences in predicting response to chemoradiotherapy in esophageal cancer. PURPOSE:: A major pathological response to neoadjuvant chemoradiation is observed in about 40% of esophageal cancer patients and is associated with favorable outcomes. However, patients with tumors of similar histology, differentiation, and stage can have vastly different responses to the same neoadjuvant therapy. This dichotomy may be due to differences in the molecular genetic environment of the tumor cells. BACKGROUND DATA: Diagnostic biopsies were obtained from a training cohort of esophageal cancer patients (13), and extracted RNA was hybridized to genome expression microarrays. The resulting gene expression data was verified by qRT-PCR. In a larger, independent validation cohort (27), we examined differential gene expression by qRT-PCR. The ability of differentially-regulated genes to predict response to therapy was assessed in a multivariate leave-one-out cross-validation model. RESULTS: Although 411 genes were differentially expressed between normal and tumor tissue, only 103 genes were altered between responder and non-responder tumor; and 67 genes differentially expressed >2-fold. These included genes previously reported in esophageal cancer and a number of novel genes. In the validation cohort, 8 of 12 selected genes were significantly different between the response groups. In the predictive model, 5 of 8 genes could predict response to therapy with 95% accuracy in a subset (74%) of patients. CONCLUSIONS: This study has identified a gene microarray pattern and a set of genes associated with response to neoadjuvant chemoradiation in esophageal cancer. The potential of these genes as biomarkers of response to treatment warrants further investigation. Copyright © 2009 by Lippincott Williams & Wilkins.