Quantifying residents' exposure to agricultural pesticides using new geospatial approaches.

A better understanding of environmental exposure to agricultural pesticides is crucial for public health, regulatory and management purposes. Residents in close vicinity to agricultural fields are likely to be more exposed to pesticides. In that context, an innovative geospatial approach for mapping estimates of agricultural pesticide exposure was developed in this study.

An integrative network-based approach to identify driving gene communities in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is an etiologically complex disease characterized by acute exacerbations and stable phases. We aimed to identify biological functions modulated in specific COPD conditions, using whole blood samples collected in the AERIS clinical study (NCT01360398). Considered conditions were exacerbation onset, severity of airway obstruction, and presence of respiratory pathogens in sputum samples.

Establishing Correlates of Maternal-Fetal Cytomegalovirus Transmission-One Step Closer Through Predictive Modeling.

Background: Determinants of maternal-fetal cytomegalovirus (CMV) transmission and factors influencing the severity of congenital CMV (cCMV) infection are not well understood.

Methods: We conducted a descriptive, multicenter study in pregnant women ≥18 years old with primary CMV infection and their newborns to explore maternal immune responses to CMV and determine potential immunologic/virologic correlates of cCMV following primary infection during pregnancy. We developed alternative approaches looking into univariate/multivariate factors associated with cCMV, including a participant clustering/stratification approach and an interpretable predictive model-based approach using trained decision trees for risk prediction (post hoc analyses).

Innate Immune Responses to Chimpanzee Adenovirus Vector 155 Vaccination in Mice and Monkeys.

Replication-deficient chimpanzee adenovirus (ChAd) vectors represent an attractive vaccine platform and are thus employed as vaccine candidates against several infectious diseases. Since inducing effective immunity depends on the interplay between innate and adaptive immunity, a deeper understanding of innate immune responses elicited by intramuscularly injected ChAd vectors in tissues can advance the platform's development. Using different candidate vaccines based on the Group C ChAd type 155 (ChAd155) vector, we characterized early immune responses in injected muscles and draining lymph nodes (dLNs) from mice, and complemented these analyses by evaluating cytokine responses and gene expression patterns in peripheral blood from ChAd155-injected macaques.

Transcriptional profiles of adjuvanted hepatitis B vaccines display variable interindividual homogeneity but a shared core signature.

The current routine use of adjuvants in human vaccines provides a strong incentive to increase our understanding of how adjuvants differ in their ability to stimulate innate immunity and consequently enhance vaccine immunogenicity. Here, we evaluated gene expression profiles in cells from whole blood elicited in naive subjects receiving the hepatitis B surface antigen formulated with different adjuvants. We identified a core innate gene signature emerging 1 day after the second vaccination and that was shared by the recipients of vaccines formulated with adjuvant systems AS01, AS01, or AS03.

Fitter Mitochondria Are Associated With Radioresistance in Human Head and Neck SQD9 Cancer Cells.

The clinical management of head and neck squamous cell carcinoma (HNSCC) commonly involves chemoradiotherapy, but recurrences often occur that are associated with radioresistance. Using human SQD9 laryngeal squamous cell carcinoma cancer cells as a model, we aimed to identify metabolic changes associated with acquired radioresistance. In a top-down approach, matched radiosensitive and radioresistant SQD9 cells were generated and metabolically compared, focusing on glycolysis, oxidative phosphorylation (OXPHOS) and ROS production.

Immune cell infiltration in head and neck squamous cell carcinoma and patient outcome: a retrospective study.

Background: Human papillomavirus (HPV) prevalence in oropharynx squamous cell carcinoma (OPSCC) is on the rise. HPV-linked OPSCCs represent a distinct clinical entity with a better treatment response and patient survival compared to tumors not linked to HPV. An emerging role in treatment response has been attributed to immune cell infiltration in human tumors.

Lack of differences in radiation-induced immunogenicity parameters between HPV-positive and HPV-negative human HNSCC cell lines.

Background And Purpose: Clinical studies indicate that patients with HPV/p16-associated head & neck squamous cell carcinoma (HNSCC) represent a subgroup with a better prognosis and improved response to conventional radiotherapy. Involvement of immune-based factors has been hypothesized. In the present study, we investigated radiation-induced differences in release of damage associated molecular patterns (DAMPs), cytokines and activation of dendritic cells (DCs) in HPV-positive and negative HNSCC cancer cell lines.

Microenvironment Tumor Metabolic Interactions Highlighted by qMSI: Application to the Tryptophan-Kynurenine Pathway in Immuno-Oncology.

Inhibition of NK and effector T-cell functions and activation of regulatory cell populations are the main immunosuppressive effects of indoleamine-2,3-dioxygenase1 (IDO1). By converting tryptophan (Trp) into kynurenine (Kyn), IDO1 is involved in the immune response homeostasis, and its dysregulated expression is described in immune-related pathologies, as tumors that hijack it to evade immune destruction. Thereby, IDO1 inhibitors are being developed to stimulate antitumor immune responses.

Targeting DNA repair with aphidicolin sensitizes primary chronic lymphocytic leukemia cells to purine analogs.

Purine analogs are among the most effective chemotherapeutic drugs for the treatment of chronic lymphocytic leukemia (CLL). However, chemoresistance and toxicity limit their clinical use. Here, we report that the DNA polymerase inhibitor aphidicolin, which displayed negligible cytotoxicity as a single agent in primary CLL cells, markedly synergizes with fludarabine and cladribine via enhanced apoptosis.

DW-MRI and (18) F-FLT PET for early assessment of response to radiation therapy associated with hypoxia-driven interventions. Preclinical studies using manipulation of oxygenation and/or dose escalation.

Early markers of treatment response may help in the management of patients by predicting the outcome of a specific therapeutic intervention. Here, we studied the potential value of diffusion-weighted MRI (DW-MRI) and (18)F-fluorothymidine ((18)F-FLT), markers of cell death and cell proliferation respectively, to predict the response to irradiation. In addition, dose escalation and/or carbogen breathing were used to modulate the response to irradiation.

αVβ3 integrin-targeted microSPECT/CT imaging of inflamed atherosclerotic plaques in mice.

Background: αVβ3-integrin is expressed by activated endothelial cells and macrophages in atherosclerotic plaques and may represent a valuable marker of high-risk plaques. We evaluated (99m)Tc-maraciclatide, an integrin-specific tracer, for imaging vascular inflammation in atherosclerotic lesions in mice.

Methods: Apolipoprotein E-negative (ApoE(-/-)) mice on a Western diet (n = 10) and normally fed adult C57BL/6 control mice (n = 4) were injected with (99m)Tc-maraciclatide (51.

Impact of Oxygenation Status on 18F-FDG Uptake in Solid Tumors.

The influence of changes in tumor oxygenation (monitored by EPR oximetry) on the uptake of 18F-FDG tracer was evaluated using micro-PET in two different human tumor models. The 18F-FDG uptake was higher in hypoxic tumors compared to tumors that present a pO2 value larger than 10 mmHg.

Reducing the serine availability complements the inhibition of the glutamine metabolism to block leukemia cell growth.

Leukemia cells are described as a prototype of glucose-consuming cells with a high turnover rate. The role of glutamine in fueling the tricarboxylic acid cycle of leukemia cells was however recently identified confirming its status of major anaplerotic precursor in solid tumors. Here we examined whether glutamine metabolism could represent a therapeutic target in leukemia cells and whether resistance to this strategy could arise.

Digital pathology: elementary, rapid and reliable automated image analysis.

Aims: Slide digitalization has brought pathology to a new era, including powerful image analysis possibilities. However, while being a powerful prognostic tool, immunostaining automated analysis on digital images is still not implemented worldwide in routine clinical practice.

Methods And Results: Digitalized biopsy sections from two independent cohorts of patients, immunostained for membrane or nuclear markers, were quantified with two automated methods.

The increase in tumor oxygenation under carbogen breathing induces a decrease in the uptake of [(18)F]-fluoro-deoxy-glucose.

We investigated the impact of oxygenation status (measured by EPR oximetry) on the uptake of (18)F-FDG (measured by PET) in two different tumor models during a carbogen breathing challenge. We observed a significant drop in (18)F-FDG uptake under carbogen breathing that suggests a rapid metabolic adaptation to the oxygen environment.

Potential role of hypoxia imaging using (18)F-FAZA PET to guide hypoxia-driven interventions (carbogen breathing or dose escalation) in radiation therapy.

Background And Purpose: Hypoxia-driven intervention (oxygen manipulation or dose escalation) could overcome radiation resistance linked to tumor hypoxia. Here, we evaluated the value of hypoxia imaging using (18)F-FAZA PET to predict the outcome and guide hypoxia-driven interventions.

Material And Methods: Two hypoxic rat tumor models were used: rhabdomyosarcoma and 9L-glioma.

Reprogramming of tumor metabolism by targeting mitochondria improves tumor response to irradiation.

Background: The Warburg phenotype identified decades ago describes tumor cells with increased glycolysis and decreased mitochondrial respiration even in the presence of oxygen. This particular metabolism also termed 'aerobic glycolysis' reflects an adaptation of tumor cells to proliferation in a heterogeneous tumor microenvironment. Although metabolic alterations in cancer cells are common features, their impact on the response to radiotherapy is not yet fully elucidated.

Biological basis for increased sensitivity to radiation therapy in HPV-positive head and neck cancers.

Although development of head and neck squamous cell carcinomas (HNSCCs) is commonly linked to the consumption of tobacco and alcohol, a link between human papillomavirus (HPV) infection and a subgroup of head and neck cancers has been established. These HPV-positive tumors represent a distinct biological entity with overexpression of viral oncoproteins E6 and E7. It has been shown in several clinical studies that HPV-positive HNSCCs have a more favorable outcome and greater response to radiotherapy.

Synthesis of new 18F-radiolabeled silicon-based nitroimidazole compounds.

The syntheses of new nitroimidazole compounds using silicon-[(18)F]fluorine chemistry for the potential detection of tumor hypoxia are described. [(18)F]silicon-based compounds were synthesized by coupling 2-nitroimidazole with silyldinaphtyl or silylphenyldi-tert-butyl groups and labeled by fluorolysis or isotopic exchange. Dinaphtyl compounds (6, 10) were labeled in 56-71% yield with a specific activity of 45 GBq/μmol, however these compounds ([(18)F]7 and [(18)F]11) were not stable in plasma.

Helical tomotherapy for SIB and hypo-fractionated treatments in lung carcinomas: a 4D Monte Carlo treatment planning study.

Purpose: To evaluate the impact of intra-fraction motion induced by regular breathing on treatment quality for helical tomotherapy treatments.

Material And Methods: Four patients treated by simultaneous-integrated boost (SIB) and three by hypo-fractionated stereotactic treatments (hypo-fractionated, 18 Gy/fraction) were included. All patients were coached to ensure regular breathing.

Developmental programming of adult obesity and cardiovascular disease in rodents by maternal nutrition imbalance.

Studies on fetal undernutrition have generated the hypothesis that fetal programming corresponds to an attempt of the fetus to adapt to adverse conditions encountered in utero. These adaptations would be beneficial if these conditions prevail later in life, but they become detrimental in the case of normal or plentiful nutrition and favor the appearance of the metabolic syndrome. In this article, the discussion is limited to the developmental programming of obesity and cardiovascular disorders caused by an early mismatched nutrition, particularly intrauterine growth retardation followed by postnatal catch-up growth.

Does early mismatched nutrition predispose to hypertension and atherosclerosis, in male mice?

Background: A link between early mismatched nutritional environment and development of components of the metabolic syndrome later in life has been shown in epidemiological and animal data. The aim of this study was to investigate whether an early mismatched nutrition produced by catch-up growth after fetal protein restriction could induce the appearance of hypertension and/or atherosclerosis in adult male mice.

Methodology/principal Findings: Wild-type C57BL6/J or LDLr-/- dams were fed a low protein (LP) or a control (C) diet during gestation.

Forced catch-up growth after fetal protein restriction alters the adipose tissue gene expression program leading to obesity in adult mice.

A mismatch between fetal and postnatal environment can permanently alter the body structure and physiology and therefore contribute later to obesity and related disorders, as revealed by epidemiological studies. Early programming of adipose tissue might be central in this observation. Moreover, adipose tissue secretes adipokines that provide a molecular link between obesity and its related disorders.

Postnatal catch-up growth after fetal protein restriction programs proliferation of rat preadipocytes.

We studied the in vitro proliferation and differentiation of rat preadipocytes to investigate whether catch-up growth after prenatal protein restriction may program adipose precursor cells leading to development of increased adipose tissue mass. Pregnant rat dams were fed either an isocaloric low-protein diet (LP-8%) or control diet (C-20%). During lactation, in order to induce catch-up growth, dams from LP group were fed with the C diet and litter size was reduced to four pups instead of eight.