New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer

A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naïve and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies

Weaned age variation in the Virunga mountain gorillas (Gorilla beringei beringei)

The final publication is available at Springer via http://dx.doi.org/10.1007/s00265-016-2066-6Weaning marks an important milestone during life history in mammals indicating nutritional independence from the mother. Age at weaning is a key measure of maternal investment and care, affecting female reproductive rates, offspring survival and ultimately the viability of a population. Factors explaining weaned age variation in the endangered mountain gorilla are not yet well understood. This study investigated the impact of group size, group type (one-male versus multi-male), offspring sex, as well as maternal age, rank, and parity on weaned age variation in the Virunga mountain gorilla population. The status of nutritional independence was established in 69 offspring using long-term suckling observations. A Cox-regression with mixed effects was applied to model weaned age and its relationship with covariates. Findings indicate that offspring in one-male groups are more likely to be weaned earlier than offspring in multi-male groups, which may reflect a female reproductive strategy to reduce higher risk of infanticide in one-male groups. Inferior milk production capacity and conflicting resource allocation between their own and offspring growth may explain later weaning in primiparous mothers compared to multiparous mothers. Sex-biased weaned age related to maternal condition defined by parity, rank, and maternal age will be discussed in the light of the Trivers-Willard hypothesis. Long-term demographic records revealed no disadvantage of early weaning for mother or offspring. Population growth and two peaks in weaned age within the Virunga population encourage future studies on the potential impact of bamboo shoots as a weaning food and other environmental factors on weaning

Identifying Individual T Cell Receptors of Optimal Avidity for Tumor Antigens.

Cytotoxic T cells recognize, via their T cell receptors (TCRs), small antigenic peptides presented by the major histocompatibility complex (pMHC) on the surface of professional antigen-presenting cells and infected or malignant cells. The efficiency of T cell triggering critically depends on TCR binding to cognate pMHC, i.e., the TCR-pMHC structural avidity. The binding and kinetic attributes of this interaction are key parameters for protective T cell-mediated immunity, with stronger TCR-pMHC interactions conferring superior T cell activation and responsiveness than weaker ones. However, high-avidity TCRs are not always available, particularly among self/tumor antigen-specific T cells, most of which are eliminated by central and peripheral deletion mechanisms. Consequently, systematic assessment of T cell avidity can greatly help distinguishing protective from non-protective T cells. Here, we review novel strategies to assess TCR-pMHC interaction kinetics, enabling the identification of the functionally most-relevant T cells. We also discuss the significance of these technologies in determining which cells within a naturally occurring polyclonal tumor-specific T cell response would offer the best clinical benefit for use in adoptive therapies, with or without T cell engineering

Acute Pain and a Motivational Pathway in Adult Rats: Influence of Early Life Pain Experience

The importance of neonatal experience upon behaviour in later life is increasingly recognised. The overlap between pain and reward pathways led us to hypothesise that neonatal pain experience influences reward-related pathways and behaviours in adulthood

Evidence for a “Wattle and Daub” Model of the Cyst Wall of Entamoeba

The cyst wall of Entamoeba invadens (Ei), a model for the human pathogen Entamoeba histolytica, is composed of fibrils of chitin and three chitin-binding lectins called Jacob, Jessie3, and chitinase. Here we show chitin, which was detected with wheat germ agglutinin, is made in secretory vesicles prior to its deposition on the surface of encysting Ei. Jacob lectins, which have tandemly arrayed chitin-binding domains (CBDs), and chitinase, which has an N-terminal CBD, were each made early during encystation. These results are consistent with their hypothesized roles in cross-linking chitin fibrils (Jacob lectins) and remodeling the cyst wall (chitinase). Jessie3 lectins likely form the mortar or daub of the cyst wall, because 1) Jessie lectins were made late during encystation; 2) the addition to Jessie lectins to the cyst wall correlated with a marked decrease in the permeability of cysts to nucleic acid stains (DAPI) and actin-binding heptapeptide (phalloidin); and 3) recombinant Jessie lectins, expressed as a maltose-binding proteins in the periplasm of Escherichia coli, caused transformed bacteria to agglutinate in suspension and form a hard pellet that did not dissociate after centrifugation. Jessie3 appeared as linear forms and rosettes by negative staining of secreted recombinant proteins. These findings provide evidence for a “wattle and daub” model of the Entamoeba cyst wall, where the wattle or sticks (chitin fibrils likely cross-linked by Jacob lectins) is constructed prior to the addition of the mortar or daub (Jessie3 lectins)

Biomarkers in T cell therapy clinical trials

T cell therapy represents an emerging and promising modality for the treatment of both infectious disease and cancer. Data from recent clinical trials have highlighted the potential for this therapeutic modality to effect potent anti-tumor activity. Biomarkers, operationally defined as biological parameters measured from patients that provide information about treatment impact, play a central role in the development of novel therapeutic agents. In the absence of information about primary clinical endpoints, biomarkers can provide critical insights that allow investigators to guide the clinical development of the candidate product. In the context of cell therapy trials, the definition of biomarkers can be extended to include a description of parameters of the cell product that are important for product bioactivity

Protocol for the ROSE sustainment (ROSES) study, a sequential multiple assignment randomized trial to determine the minimum necessary intervention to maintain a postpartum depression prevention program in prenatal clinics serving low-income women

Background: More research on sustainment of interventions is needed, especially return on investment (ROI) studies to determine cost-benefit trade-offs for effort required to sustain and how much is gained when effective programs are sustained. The ROSE sustainment (ROSES) study uses a sequential multiple assignment randomized (SMART) design to evaluate the effectiveness and cost-effectiveness of a stepwise approach to sustainment of the ROSE postpartum depression prevention program in 90 outpatient clinics providing prenatal care to pregnant women on public assistance. Postpartum depression (PPD) is common and can have lasting consequences. Outpatient clinics offering prenatal care are an opportune place to provide PPD prevention because most women visit while pregnant. The ROSE (Reach Out, Stay Strong, Essentials for mothers of newborns) program is a group educational intervention to prevent PPD, delivered during pregnancy. ROSE has been found to reduce cases of PPD in community prenatal settings serving low-income pregnant women. Methods: All 90 prenatal clinics will receive enhanced implementation as usual (EIAU; initial training + tools for sustainment). At the first time at which a clinic is determined to be at risk for failure to sustain (i.e., at 3, 6, 9, 12, and 15 months), that clinic will be randomized to receive either (1) no additional implementation support (i.e., EIAU only), or (2) low-intensity coaching and feedback (LICF). If clinics receiving LICF are still at risk at subsequent assessments, they will be randomized to either (1) EIAU + LICF only, or (2) high-intensity coaching and feedback (HICF). Additional follow-up interviews will occur at 18, 24, and 30 months, but no implementation intervention will occur after 18 months. Outcomes include (1) percent sustainment of core program elements at each time point, (2) health impact (PPD rates over time at each clinic) and reach, and (3) ROI (costs and cost-effectiveness) of each sustainment step. Hypothesized mechanisms include sustainment of capacity to deliver core elements and engagement/ownership. Discussion: This study is the first randomized trial evaluating the ROI of a stepped approach to sustainment, a critical unanswered question in implementation science. It will also advance knowledge of implementation mechanisms and clinical care for an at-risk population

An Estimate of Avian Mortality at Communication Towers in the United States and Canada

Avian mortality at communication towers in the continental United States and Canada is an issue of pressing conservation concern. Previous estimates of this mortality have been based on limited data and have not included Canada. We compiled a database of communication towers in the continental United States and Canada and estimated avian mortality by tower with a regression relating avian mortality to tower height. This equation was derived from 38 tower studies for which mortality data were available and corrected for sampling effort, search efficiency, and scavenging where appropriate. Although most studies document mortality at guyed towers with steady-burning lights, we accounted for lower mortality at towers without guy wires or steady-burning lights by adjusting estimates based on published studies. The resulting estimate of mortality at towers is 6.8 million birds per year in the United States and Canada. Bootstrapped subsampling indicated that the regression was robust to the choice of studies included and a comparison of multiple regression models showed that incorporating sampling, scavenging, and search efficiency adjustments improved model fit. Estimating total avian mortality is only a first step in developing an assessment of the biological significance of mortality at communication towers for individual species or groups of species. Nevertheless, our estimate can be used to evaluate this source of mortality, develop subsequent per-species mortality estimates, and motivate policy action

Palladium–mediated organofluorine chemistry

Producción CientíficaThe substitution of fluorine for hydrogen in a molecule may result in profound changes in its properties and behaviour. Fluorine does not introduce special steric constraints since the F atom has a small size. However, the changes in bond polarity and the possibility of forming hydrogen bonds with other hydrogen donor fragments in the same or other molecules, may change the solubility and physical properties of the fluorinated compound when compared to the non-fluorinated one. Fluorine forms strong bonds to other elements and this ensures a good chemical stability. Altogether, fluorinated compounds are very attractive in materials chemistry and in medicinal chemistry, where many biologically active molecules and pharmaceuticals do contain fluorine in their structure and this has been shown to be essential for their activityJunta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA302U13)Junta de Castilla y León (programa de apoyo a proyectos de investigación – Ref. VA256U13