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2.  Screening for Hepatitis C as a Prevention Enhancement (SHAPE) for HIV: An Integration Pilot Initiative in a Massachusetts County Correctional Facility 
Public Health Reports  2014;129(Suppl 1):5-11.
Objectives
The Massachusetts Department of Public Health (MDPH) and the Barnstable County Sheriff's Department (BCSD) in Massachusetts initiated a pilot program in July 2009 offering education and hepatitis C virus (HCV) antibody testing to inmates and detainees, concurrent with routine HIV testing. The initiative was implemented to assess the feasibility of integrating HCV screening into an HIV screening program in a correctional setting and the efficacy of linking HCV antibody-positive inmates to clinical care upon release.
Methods
Through the Screening for Hepatitis C as a Prevention Enhancement initiative, HCV and HIV testing were offered to inmates and detainees shortly after admission, and by request at any time during incarceration. In preparation for release, referrals were made to community-based medical providers for HCV follow-up care. Data from BCSD were compared with routine surveillance data received by MDPH. Confirmatory HCV test results received by April 15, 2012, were considered indicators of appropriate post-release clinical care.
Results
From July 2009 through December 2011, 22% (n=596) and 25% (n=667) of 2,716 inmates/detainees accepted HCV and HIV testing, respectively. Of those tested for HCV antibody, 20.5% (n=122) were positive. Of those tested for HIV antibody, 0.8% (n=5) were positive. Of the inmates who tested HCV positive at BCSD and had been released, 37.8% were identified as receiving post-release medical care.
Conclusions
We determined that integration of HCV education and screening into correctional facilities is feasible and reveals high rates of HCV infection. Although this model presupposes programmatic infrastructure, elements of the service design and integration could inform a range of correctional programs. Effective linkage to care, while substantial, was not routine based on our analysis, and may require additional resources given its cost and complexity.
PMCID: PMC3862988  PMID: 24385643
3.  Association Between Body Mass Index, Sexually Transmitted Infections, and Contraceptive Compliance 
Journal of Women's Health  2013;22(12):1062-1068.
Abstract
Background
Recent studies have examined the relationship between body mass index (BMI) and sexual behaviors, but little information exists on this relationship among racially diverse, low-income women using objectively measured clinical data. The purpose of this study was to examine the association between BMI and sexual behaviors, rates of sexually transmitted infections (STIs) and unintended pregnancy, and contraceptive adherence among adolescent and young adult women.
Methods
As part of a larger study, 1,015 Hispanic (54.2%), Black (18.6%) and White (24.8%) women aged 16 to 24 years seeking family planning services at publicly funded reproductive health clinics provided data on their baseline sexual behaviors, and contraceptive use and pregnancy history over 12 months. Objective clinical data were available from medical records at baseline (i.e., height, weight, and Papanicolaou [Pap] smear results), and over a 12-month period (i.e., STI results). Multivariable analyses were used to compare sexual behaviors, STI rates, contraceptive compliance, and unintended pregnancy rates between obese, overweight, and normal weight participants after adjusting for age, race/ethnicity, and other confounders.
Results
Overall, 423 (36.6%), 304 (26.3%), and 288 (24.9%) participants were classified as normal weight, overweight, and obese, respectively. No statistically significant association was observed between BMI and sexual behaviors, STI rates (overweight odds ratio [OR] 0.67; 95% confidence interval [95% CI] [0.4, 1.08]; obese OR 0.68; 95% CI [0.42, 1.10]); contraceptive compliance (overweight OR 0.89; 95% CI [0.69, 1.16]; obese OR 0.89; 95% CI 0.68, 1.16]), or unintended pregnancy (overweight OR 1.08 95% CI [0.73, 1.60]; obese OR 1.09; 95% CI [0.72, 1.63]).
Conclusion
STI history and contraceptive compliance did not vary by BMI. Therefore, all women should receive equal contraceptive counseling (including condoms) to reduce the risk of unplanned pregnancy and STIs.
doi:10.1089/jwh.2012.4116
PMCID: PMC3852604  PMID: 24093760
4.  An Abscopal Response to Radiation and Ipilimumab in a Patient with Metastatic Non-Small Cell Lung Cancer 
Cancer immunology research  2013;1(6):365-372.
A posteriori evidence suggests that radiotherapy to a targeted tumor can elicit an immune-mediated abscopal (ab-scopus, away from the target) effect in non-targeted tumors, when combined with an anti-cytotoxic T-lymphocyte antigen-4 monoclonal (CTLA-4) antibody. Concurrent radiotherapy and ipilimumab (a human monoclonal anti-CTLA-4 antibody) induced immune-mediated abscopal effects in poorly immunogenic pre-clinical tumor models and metastatic melanoma patients. However, no such reports exist for patients with metastatic lung adenocarcinoma. We report the first abscopal response in a treatment-refractory lung cancer patient treated with radiotherapy and ipilimumab. A post-treatment increase in tumor-infiltrating cytotoxic lymphocytes, tumor regression, and normalization of tumor markers was observed. One year after treatment with concurrent radiotherapy and ipilimumab the patient is without evidence of disease.
doi:10.1158/2326-6066.CIR-13-0115
PMCID: PMC3930458  PMID: 24563870
9.  Invariant natural killer T cells regulate anti-tumor immunity by controlling the population of dendritic cells in tumor and draining lymph nodes 
Background
Invariant natural killer T (iNKT) cells are CD1d-restricted T cells, which respond rapidly to antigen recognition and promote development of anti-tumor immunity in many tumor models. Surprisingly, we previously found that mice deficient in iNKT cells developed spontaneous CD8+ T cells responses partially effective at inhibiting metastases in mice bearing the 4T1 mammary carcinoma, and showed a markedly improved response to treatment with local radiotherapy and anti-CTLA-4 antibody compared to wild type (WT) mice.
Methods
To understand the mechanisms of the immunosuppressive function of iNKT cells, dendritic cells (DCs) were analyzed by immunohistochemistry and flow cytometry in WT and iNKT-deficient (iNKT−/−) mice. The effects of antibody-mediated blockade of CD1d on DC number and phenotype, priming of anti-tumor T cells, and tumor response to treatment with local radiotherapy and anti-CTLA-4 antibody were evaluated. To determine if the improved response to treatment in the absence of iNKT cells was independent from the immunotherapy employed, 4T1-tumor bearing WT and iNKT−/− mice were treated with local radiotherapy in combination with antibody-mediated CD137 co-stimulation.
Results
DCs in 4T1 tumors and tumor-draining lymph nodes but not distant lymph nodes were significantly reduced in WT mice compared to iNKT−/− mice (p < 0.05), suggesting the selective elimination of DCs cross-presenting tumor-associated antigens by iNKT cells. Consistently, priming of T cells to a tumor-specific CD8 T cell epitope in mice treated with radiotherapy and anti-CTLA-4 or anti-CD137 was markedly enhanced in iNKT−/− compared to WT mice. CD1d blockade restored the number of DC in WT mice, improved T cell priming in draining lymph nodes and significantly enhanced response to treatment.
Conclusions
Here we describe a novel mechanism of tumor immune escape mediated by iNKT cells that limit priming of anti-tumor T cells by controlling DC in tumors and draining lymph nodes. These results have important implications for the design of immunotherapies targeting iNKT cells.
Electronic supplementary material
The online version of this article (doi:10.1186/s40425-014-0037-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s40425-014-0037-x
PMCID: PMC4206765  PMID: 25349699
Breast cancer; CD1d; CD137; CTLA-4; CD8+ T-cells; Dendritic cells; Immunoregulation; Invariant NKT cells; Radiotherapy
10.  The Optimal Partnership of Radiation and Immunotherapy: from Preclinical Studies to Clinical Translation 
Radiation research  2014;182(2):170-181.
The main role of the immune system is to restore tissue homeostasis when altered by pathogenic processes, including neoplastic transformation. Immune-mediated tumor rejection has been recognized as an extrinsic tumor suppressor mechanism that tumors need to overcome to progress. By the time a tumor becomes clinically apparent it has successfully escaped immune control by establishing an immunosuppressive microenvironment. Ionizing radiation applied locally to a tumor alters these tumor-host interactions. Accumulating evidence indicates that standard therapeutic doses of radiation have the potential to recover tumor immunogenicity and convert the tumor into an in situ personalized vaccine. Radiotherapy induces an immunogenic tumor cell death promoting cross-presentation of tumor-derived antigens by dendritic cells to T cells. In addition, radiotherapy stimulates chemokine-mediated recruitment of effector T cells to the tumor, and cellular recognition and killing by T cells that is facilitated by upregulation of major histocompatibility antigens, NKG2D ligands, adhesion molecules and death receptors. Despite these effects, radiotherapy alone is only rarely capable of generating enough proinflammatory signals to sufficiently overcome suppression, as it can also activate immunosuppressive factors. However, our group and others have shown that when combined with targeted immunotherapy agents radiotherapy significantly contributes to a therapeutically effective anti-tumor immune response. To illustrate this partnership between radiation and immunotherapy we will discuss as an example our experience in preclinical models and the molecular mechanisms identified. Additionally, the clinical translation of these combinations will be discussed.
doi:10.1667/RR13500.1
PMCID: PMC4184032  PMID: 24937779
11.  Quality of care and health status in Ukraine 
Background
We conducted a national level assessment of the quality of clinical care practice in the Ukrainian healthcare system for two important causes of death and chronic disease conditions. We tested two hypotheses: a) quality of care is predicted by physician and facility characteristics and b) health status is predicted by quality of care.
Methods
During 2009–2010 in Ukraine, we collected nationally-representative data from clinical facilities, physicians, Clinical Performance and Value (CPV®) vignettes, patient surveys from the facilities, and from the general population. Each physician completed a written CPV® vignette—a simulated case scenario of a typical patient visit—for each of two clinical cases, congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD). CPV® vignette scores, calculated as a percentage of all care criteria completed by the physician, were used as the measure of clinical quality of care. Self-reported health measures were collected from exit and household survey respondents. Regression models were developed to test the two study hypotheses.
Results
136 hospitals and 125 polyclinics were surveyed; 1,044 physicians were interviewed and completed CPV® vignettes. On average physicians scored 47.4% on the vignettes. Younger, female physicians provide a higher quality of care—as well as those that have had recent continuing medical education (CME) in chronic disease or health behaviors. Higher quality was associated with better health outcomes.
Conclusions
As low- and middle-income countries around the world are challenged by non-communicable diseases, higher quality of care provided to these populations may result in better outcomes, such as improved health status and life expectancy, and overcome regional shortfalls. Policy efforts that serially evaluate quality may improve chronic disease care.
doi:10.1186/1472-6963-14-446
PMCID: PMC4263055  PMID: 25269470
Quality of care; Health care delivery; Non-communicable diseases; Health policy; Ukraine; Eastern Europe
12.  Senescent Cells and Their Secretory Phenotype as Targets for Cancer Therapy 
Cancer is a devastating disease that increases exponentially with age. Cancer arises from cells that proliferate in an unregulated manner, an attribute that is countered by cellular senescence. Cellular senescence is a potent tumor-suppressive process that halts the proliferation, essentially irreversibly, of cells at risk for malignant transformation. A number of anti-cancer drugs have emerged that induce tumor cells to undergo cellular senescence. However, although a senescence response can halt the proliferation of cancer cells, the presence of senescent cells in tissues has been associated with age-related diseases, including, ironically, late-life cancer. Thus, anti-cancer therapies that can induce senescence might also drive aging phenotypes and age-related pathology. The deleterious effects of senescent cells most likely derive from their senescence-associated secretory phenotype or SASP. The SASP entails the secretion of numerous inflammatory cytokines, growth factors and proteases that can render the tissue microenvironment favorable for tumor growth. Here, we discuss the beneficial and detrimental effects of inducing cellular senescence, and propose strategies for targeting senescent cells as a means to fight cancer.
doi:10.1159/000343572
PMCID: PMC4167737  PMID: 23503512
13.  Assessment of left atrial volume before and after pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension 
Background
Impaired left ventricular diastolic filling is common in chronic thromboembolic pulmonary hypertension (CTEPH), and recent studies support left ventricular underfilling as a cause. To investigate this further, we assessed left atrial volume index (LAVI) in patients with CTEPH before and after pulmonary thromboendarterectomy (PTE).
Methods
Forty-eight consecutive CTEPH patients had pre- & post-PTE echocardiograms and right heart catheterizations. Parameters included mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, LAVI, & mitral E/A ratio. Echocardiograms were performed 6 ± 3 days pre-PTE and 10 ± 4 days post-PTE. Regression analyses compared pre- and post-PTE LAVI with other parameters.
Results
Pre-op LAVI (mean 19.0 ± 7 mL/m2) correlated significantly with pre-op PVR (R = -0.45, p = 0.001), mPAP (R = -0.28, p = 0.05) and cardiac index (R = 0.38, p = 0.006). Post-PTE, LAVI increased by 18% to 22.4 ± 7 mL/m2 (p = 0.003). This change correlated with change in PVR (765 to 311 dyne-s/cm5, p = 0.01), cardiac index (2.6 to 3.2 L/min/m2, p = 0.02), and E/A (.95 to 1.44, p = 0.002).
Conclusion
In CTEPH, smaller LAVI is associated with lower cardiac output, higher mPAP, and higher PVR. LAVI increases by ~20% after PTE, and this change correlates with changes in PVR and mitral E/A. The rapid increase in LAVI supports the concept that left ventricular diastolic impairment and low E/A pre-PTE are due to left heart underfilling rather than inherent left ventricular diastolic dysfunction.
doi:10.1186/1476-7120-12-32
PMCID: PMC4131478  PMID: 25109313
Left atrial volume; Chronic thromboembolic pulmonary hypertension; Pulmonary thromboendarterectomy
14.  STAT3 Activities and Energy Metabolism: Dangerous Liaisons 
Cancers  2014;6(3):1579-1596.
STAT3 mediates cytokine and growth factor receptor signalling, becoming transcriptionally active upon tyrosine 705 phosphorylation (Y-P). Constitutively Y-P STAT3 is observed in many tumors that become addicted to its activity, and STAT3 transcriptional activation is required for tumor transformation downstream of several oncogenes. We have recently demonstrated that constitutively active STAT3 drives a metabolic switch towards aerobic glycolysis through the transcriptional induction of Hif-1α and the down-regulation of mitochondrial activity, in both MEF cells expressing constitutively active STAT3 (Stat3C/C) and STAT3-addicted tumor cells. This novel metabolic function is likely involved in mediating pre-oncogenic features in the primary Stat3C/C MEFs such as resistance to apoptosis and senescence and rapid proliferation. Moreover, it strongly contributes to the ability of primary Stat3C/C MEFs to undergo malignant transformation upon spontaneous immortalization, a feature that may explain the well known causative link between STAT3 constitutive activity and tumor transformation under chronic inflammatory conditions. Taken together with the recently uncovered role of STAT3 in regulating energy metabolism from within the mitochondrion when phosphorylated on Ser 727, these data place STAT3 at the center of a hub regulating energy metabolism under different conditions, in most cases promoting cell survival, proliferation and malignant transformation even though with distinct mechanisms.
doi:10.3390/cancers6031579
PMCID: PMC4190557  PMID: 25089666
STAT3; metabolism; Warburg effect; aerobic glycolysis; cellular transformation; mitochondrial activity
15.  The Impact of a Massachusetts State Sponsored Educational Program on Antimicrobial Stewardship in Acute Care Hospitals 
Our objective was to characterize barriers to antimicrobial stewardship implementation in acute care hospitals in Massachusetts, as well as to identify successful existing antimicrobial stewardship practices. We show that a statewide antimicrobial stewardship educational program had a significant effect on implementation of antimicrobial stewardship programs and improvement of existing programs.
doi:10.1086/669861
PMCID: PMC4062359  PMID: 23466920
16.  Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure 
The Journal of Clinical Investigation  2014;124(7):3047-3060.
The pathogenesis of mucoinfective lung disease in cystic fibrosis (CF) patients likely involves poor mucus clearance. A recent model of mucus clearance predicts that mucus flow depends on the relative mucin concentration of the mucus layer compared with that of the periciliary layer; however, mucin concentrations have been difficult to measure in CF secretions. Here, we have shown that the concentration of mucin in CF sputum is low when measured by immunologically based techniques, and mass spectrometric analyses of CF mucins revealed mucin cleavage at antibody recognition sites. Using physical size exclusion chromatography/differential refractometry (SEC/dRI) techniques, we determined that mucin concentrations in CF secretions were higher than those in normal secretions. Measurements of partial osmotic pressures revealed that the partial osmotic pressure of CF sputum and the retained mucus in excised CF lungs were substantially greater than the partial osmotic pressure of normal secretions. Our data reveal that mucin concentration cannot be accurately measured immunologically in proteolytically active CF secretions; mucins are hyperconcentrated in CF secretions; and CF secretion osmotic pressures predict mucus layer–dependent osmotic compression of the periciliary liquid layer in CF lungs. Consequently, mucin hypersecretion likely produces mucus stasis, which contributes to key infectious and inflammatory components of CF lung disease.
doi:10.1172/JCI73469
PMCID: PMC4072023  PMID: 24892808
18.  Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson’s disease? 
Journal of internal medicine  2013;273(5):429-436.
Exposure to environmental toxins is associated with a variety of age-related diseases including cancer and neurodegeneration. For example, in Parkinson’s disease (PD), chronic environmental exposure to certain toxins has been linked to the age-related development of neuropathology. Neuronal damage is believed to involve the induction of neuroinflammatory events as a consequence of glial cell activation. Cellular senescence is a potent anti-cancer mechanism that occurs in a number of proliferative cell types and causes the arrest of proliferation of cells at risk of malignant transformation following exposure to potentially oncogenic stimuli. With age, senescent cells accumulate and express a senescence-associated secretory phenotype (SASP; i.e. the robust secretion of many inflammatory cytokines, growth factors and proteases). Whereas cell senescence in peripheral tissues has been causally linked to a number of age-related pathologies, little is known about the induction of cellular senescence and the SASP in the brain. Based on recently reported findings, we propose that environmental stressors associated with PD may act in part by eliciting senescence and the SASP within non-neuronal glial cells in the ageing brain, thus contributing to the characteristic decline in neuronal integrity that occurs in this disorder.
doi:10.1111/joim.12029
PMCID: PMC3633085  PMID: 23600398
19.  Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death 
Oncoimmunology  2014;3:e28518.
Established tumors are typified by an immunosuppresive microenvironment. Countering this naturally occurring phenomenon, emerging evidence suggests that radiation promotes a proimmunogenic milieu within the tumor capable of stimulating host cancer-specific immune responses. Three cryptic immunogenic components of cytotoxic-agent induced cell death—namely, calreticulin cell surface exposure, the release of high mobility group box 1 (HMGB1) protein, and the liberation of ATP—have been previously shown to be critical for dendritic cell (DC) activation and effector T-cell priming. Thus, these immune-mobilizing components commonly presage tumor rejection in response to treatment. We initially set out to address the hypothesis that radiation-induced immunogenic cell death (ICD) is dose-dependent. Next, we hypothesized that radiation would enhance chemotherapy-induced ICD when given concomitantly, as suggested by the favorable clinical outcomes observed in response to analogous concurrent chemoradiation regimens. Thus, we designed an in vitro assay to examine the 3 hallmark features of ICD at clinically relevant doses of radiation. We then tested the immunogenic-death inducing effects of radiation combined with carboplatin or paclitaxel, focusing on these combinations to mimic chemoradiation regimens actually used in clinical trials of early stage triple negative [NCT0128953/NYU-10–01969] and locally advanced [NYU-06209] breast cancer patients, respectively. Despite the obvious limitations of an in vitro model, radiotherapy produced both a dose-dependent induction and chemotherapeutic enhancement of ICD. These findings provide preliminary evidence that ICD stimulated by either high-dose radiotherapy alone, or concurrent chemoradiation regimens, may contribute to the establishment of a peritumoral proimmunogenic milieu.
doi:10.4161/onci.28518
PMCID: PMC4106151  PMID: 25071979
Immunogenic cell death; ionizing radiation; oxaliplatin; carboplatin; paclitaxel
20.  Hospitalization Records as a Tool for Evaluating Performance of Food- and Water-Borne Disease Surveillance Systems: A Massachusetts Case Study 
PLoS ONE  2014;9(4):e93744.
We outline a framework for evaluating food- and water-borne surveillance systems using hospitalization records, and demonstrate the approach using data on salmonellosis, campylobacteriosis and giardiasis in persons aged ≥65 years in Massachusetts. For each infection, and for each reporting jurisdiction, we generated smoothed standardized morbidity ratios (SMR) and surveillance to hospitalization ratios (SHR) by comparing observed surveillance counts with expected values or the number of hospitalized cases, respectively. We examined the spatial distribution of SHR and related this to the mean for the entire state. Through this approach municipalities that deviated from the typical experience were identified and suspected of under-reporting. Regression analysis revealed that SHR was a significant predictor of SMR, after adjusting for population age-structure. This confirms that the spatial “signal” depicted by surveillance is in part influenced by inconsistent testing and reporting practices since municipalities that reported fewer cases relative to the number of hospitalizations had a lower relative risk (as estimated by SMR). Periodic assessment of SHR has potential in assessing the performance of surveillance systems.
doi:10.1371/journal.pone.0093744
PMCID: PMC3989214  PMID: 24740304
21.  Role of a Ubiquitously Expressed Receptor in the Vertebrate Olfactory System 
The Journal of Neuroscience  2013;33(38):15235-15247.
Odorant cues are recognized by receptors expressed on olfactory sensory neurons, the primary sensory neurons of the olfactory epithelium. Odorant receptors typically obey the “one receptor, one neuron” rule, in which the receptive field of the olfactory neuron is determined by the singular odorant receptor that it expresses. Odor-evoked receptor activity across the population of olfactory neurons is then interpreted by the brain to identify the molecular nature of the odorant stimulus. In the present study, we characterized the properties of a C family G-protein-coupled receptor that, unlike most other odorant receptors, is expressed in a large population of microvillous sensory neurons in the zebrafish olfactory epithelium and the mouse vomeronasal organ. We found that this receptor, OlfCc1 in zebrafish and its murine ortholog Vmn2r1, is a calcium-dependent, low-sensitivity receptor specific for the hydrophobic amino acids isoleucine, leucine, and valine. Loss-of-function experiments in zebrafish embryos demonstrate that OlfCc1 is required for olfactory responses to a diverse mixture of polar, nonpolar, acidic, and basic amino acids. OlfCc1 was also found to promote localization of other OlfC receptor family members to the plasma membrane in heterologous cells. Together, these results suggest that the broadly expressed OlfCc1 is required for amino acid detection by the olfactory system and suggest that it plays a role in the function and/or intracellular trafficking of other olfactory and vomeronasal receptors with which it is coexpressed.
doi:10.1523/JNEUROSCI.2339-13.2013
PMCID: PMC3776066  PMID: 24048853
22.  Systems biology perspectives on the carcinogenic potential of radiation 
Journal of Radiation Research  2014;55(Suppl 1):i145-i154.
This review focuses on recent experimental and modeling studies that attempt to define the physiological context in which high linear energy transfer (LET) radiation increases epithelial cancer risk and the efficiency with which it does so. Radiation carcinogenesis is a two-compartment problem: ionizing radiation can alter genomic sequence as a result of damage due to targeted effects (TE) from the interaction of energy and DNA; it can also alter phenotype and multicellular interactions that contribute to cancer by poorly understood non-targeted effects (NTE). Rather than being secondary to DNA damage and mutations that can initiate cancer, radiation NTE create the critical context in which to promote cancer. Systems biology modeling using comprehensive experimental data that integrates different levels of biological organization and time-scales is a means of identifying the key processes underlying the carcinogenic potential of high-LET radiation. We hypothesize that inflammation is a key process, and thus cancer susceptibility will depend on specific genetic predisposition to the type and duration of this response. Systems genetics using novel mouse models can be used to identify such determinants of susceptibility to cancer in radiation sensitive tissues following high-LET radiation. Improved understanding of radiation carcinogenesis achieved by defining the relative contribution of NTE carcinogenic effects and identifying the genetic determinants of the high-LET cancer susceptibility will help reduce uncertainties in radiation risk assessment.
doi:10.1093/jrr/rrt211
PMCID: PMC3941546
ionizing radiation; breast cancer; heavy ion radiation; modeling; initiation; promotion
23.  Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift 
The therapeutic application of ionizing radiation has been largely based on its cytocidal power combined with the ability to selectively target tumors. Radiotherapy effects on survival of cancer patients are generally interpreted as the consequence of improved local control of the tumor, directly decreasing systemic spread. Experimental data from multiple cancer models have provided sufficient evidence to propose a paradigm shift, whereby some of the effects of ionizing radiation are recognized as contributing to systemic antitumor immunity. Recent examples of objective responses achieved by adding radiotherapy to immunotherapy in metastatic cancer patients support this view. Therefore, the traditional palliative role of radiotherapy in metastatic disease is evolving into that of a powerful adjuvant for immunotherapy. This combination strategy adds to the current anticancer arsenal and offers opportunities to harness the immune system to extend survival, even among metastatic and heavily pretreated cancer patients. We briefly summarize key evidence supporting the role of radiotherapy as an immune adjuvant. A critical appraisal of the current status of knowledge must include potential immunosuppressive effects of radiation that can hamper its capacity to convert the irradiated tumor into an in situ, individualized vaccine. Moreover, we discuss some of the current challenges to translate this knowledge to the clinic as more trials testing radiation with different immunotherapies are proposed.
doi:10.1093/jnci/djs629
PMCID: PMC3576324  PMID: 23291374
24.  Safety and efficacy of an injectable extracellular matrix hydrogel for treating myocardial infarction 
Science translational medicine  2013;5(173):10.1126/scitranslmed.3005503.
New therapies are needed to prevent heart failure after myocardial infarction (MI). As experimental treatment strategies for MI approach translation, safety and efficacy must be established in relevant animal models that mimic the clinical situation. We have developed an injectable hydrogel derived from porcine myocardial extracellular matrix (ECM) as a scaffold for cardiac repair post-MI. In this study, we establish the safety and efficacy of this injectable biomaterial in large-and small-animal studies that simulate the clinical setting. Infarcted pigs were treated with percutaneous transendocardial injections of the myocardial matrix hydrogel two weeks post-MI and evaluated after three months. Echocardiography indicated improvement in cardiac function, ventricular volumes, and global wall motion scores. Furthermore, a significantly larger zone of cardiac muscle was found at the endocardium in matrix-injected pigs compared to controls. In rats, we establish the safety of this biomaterial and explore the host response via direct injection into the left ventricular lumen and in an inflammation study, both of which support the biocompatibility of this material. Hemocompatibility studies with human blood indicate that exposure to the material at relevant concentrations does not affect clotting times or platelet activation. This work therefore provides a strong platform to move forward in clinical studies with this cardiac-specific biomaterial that can be delivered by catheter.
doi:10.1126/scitranslmed.3005503
PMCID: PMC3848875  PMID: 23427245
25.  The Numbers of FoxP3+ Lymphocytes in Sentinel Lymph Nodes of Breast Cancer Patients Correlate With Primary Tumor Size but Not Nodal Status 
Cancer investigation  2011;29(6):10.3109/07357907.2011.585193.
Regulatory T cells, lymphocytes marked by expression of the transcription factor Forkhead Box Protein P3 (FoxP3), inhibit the activation of tumor-specific T cells in tumor-draining lymph nodes. Immunohistochemical analyses of sentinel lymph nodes (SLNs) from 104 breast cancer patients showed a significant association (p = .0028, Pearson correlation) between the number of FoxP3+ cells and the size of primary breast invasive ductal carcinoma. In contrast, there was no correlation between the number of FoxP3+ cells and the presence of SLN metastases, or other clinicopathological parameters. These results suggest the presence of an immune suppressive environment in SLNs of larger tumors.
doi:10.3109/07357907.2011.585193
PMCID: PMC3883568  PMID: 21649468
Breast cancer; Immunology/Immunobiology; Tumor immunology

Results 1-25 (144)