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Purpose Manocept™ constructs are mannosylated amine dextrans (MADs) that bind with high affinity to the mannose receptor, CD206. Tumor-associated macrophages (TAMs) are the most numerous immune cells in the tumor microenvironment and a recognized target for tumor imaging and cancer immunotherapies. Most TAMs express CD206, suggesting utility of MADs to deliver imaging moieties or therapeutics to TAMs. The liver Kupffer cells also express CD206, making them an off-target localization site when targeting CD206 on TAMs. We evaluated TAM targeting strategies using two novel MADs differing in molecular weight in a syngeneic mouse tumor model to determine how varying MAD molecular weights would impact tumor localization. Increased mass dose of the non-labeled construct or a higher molecular weight (HMW) construct were also used to block liver localization and enhance tumor to liver ratios. Procedures Two MADs, 8.7 kDa and 22.6 kDa modified with DOTA chelators, were synthesized and radiolabeled with 68Ga. A HMW MAD (300 kDa) was also synthesized as a competitive blocking agent for Kupffer cell localization. Balb/c mice, with and without CT26 tumors, underwent dynamic PET imaging for 90 min followed by biodistribution analyses in selected tissues. Results The new constructs were readily synthesized and labeled with 68Ga with ≥ 95% radiochemical purity in 15 min at 65 °C. When injected at doses of 0.57 nmol, the 8.7 kDa MAD provided 7-fold higher 68Ga tumor uptake compared to the 22.6 kDa MAD (2.87 ± 0.73%ID/g vs. 0.41 ± 0.02%ID/g). Studies with increased mass of unlabeled competitors showed reduced liver localization of the [68Ga]MAD-8.7 to varying degrees without significant reductions in tumor localization, resulting in enhanced tumor to liver signal ratios. Conclusion Novel [68Ga]Manocept constructs were synthesized and studied in in vivo applications, showing that the smaller MAD localized to CT26 tumors more effectively than the larger MAD and that the unlabeled HMW construct could selectively block liver binding of [68Ga]MAD-8.7 without diminishing the localization to tumors. Promising results using the [68Ga]MAD-8.7 show a potential path to clinical applications. Graphical Abstract

One in eight women will be diagnosed with breast cancer in their lifetime and approximately 25% of those cases will be HER2-positive. Current methods for diagnosing HER2-positive breast cancer involve using IHC and FISH from suspected cancer biopsies to quantify HER2 expression. HER2 PET imaging could potentially increase accuracy and improve the diagnosis of lesions that are not available for biopsies. Using two previously discovered HER2-targeting peptides, we modified each peptide with the chelator DOTA and a PEG

Antigen-specific multifunctional T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α simultaneously after activation are important for the control of many infections. It is unclear if these CD8(+) T cells are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multi-parameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen-specific CD8(+) T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow-FISH). The end-stage/senescent CD8(+) CD45RA(+) CD27(-) T-cell subset increases significantly during ageing and this is exaggerated in CMV immune-responsive subjects. However, these end-stage cells do not have the shortest telomeres, implicating additional non-telomere-related mechanisms in inducing their senescence. The telomere lengths in total and CMV (NLV)-specific CD8(+) T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared with young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple-cytokine-producing cells are found in CD8(+) T cells at all stages of differentiation in both age groups. Furthermore, these multi-functional cells had intermediate telomere lengths compared with cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific CD8(+) T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion.

Introduction: Stress suffered by adolescents is often neglected. In fact, there are very few measuring instruments that have been translated into Spanish for the assessment of stress manifestations in teenagers. Method: The main purpose of this work was to analyze the psychometric properties of the Student Stress Inventory-Stress Manifestations (SSI-SM) in Spanish adolescents. The final sample comprised a total of 708 students, 308 were male, with a mean age of 13.61 years (SD = 1.08). Results: The results indicated that the SSI-SM scores presented adequate psychometric properties. Cronbach's alpha coefficient for the subscales ranged between 0.69 and 0.90. Analysis of the internal structure of the SSI-SM scores, through confirmatory factorial analysis, showed that the three dimensional structure solution was the most satisfactory model. A total of 6 items of the SSI-SM showed differential item functioning by gender. SSI-SM subscales were correlated with emotional and behavioural symptoms and schizotypal traits. Statistically significant differences were found between mean scores of SSI-SM by gender and age. Conclusions: These results provided new sources of validity evidence for the SSI-SM scores in an independent sample of non-clinical adolescents. The SSI-SM seems to be a useful, brief and easy to apply self-report instrument for the screening of stress manifestations in this sector of the population. © 2015 Education & Psychology I+D+i and Ilustre Colegio Oficial de la Psicología de Andalucía Oriental (Spain).

An age-related decline in immune responses in the elderly results in greater susceptibility to infection and reduced responses to vaccination. This decline in immune function affects both innate and adaptive immune systems. A meeting of experts in immunology and gerontology in Paris, France, in April 2008, considered current understanding of immunosenescence and its clinical consequences. Essential features of immunosenescence include: reduced natural killer cell cytotoxicity on a per cell basis; reduced number and function of dendritic cells in blood; decreased pools of naive T and B cells; and increases in the number of memory and effector T and B cells. In particular, an accumulation of late differentiated effector T cells, commonly associated with cytomegalovirus infection, contributes to a decline in the capacity of the adaptive immune system to respond to novel antigens. Consequently, vaccine responsiveness is compromised in the elderly, especially frail patients. Strategies to address the effects of immunosenescence include ensuring that seroprotective antibody levels against preventable infectious diseases are maintained throughout adulthood, and improving diet and exercise to address the effects of frailty. New vaccines are being developed, such as intradermal and high-dose vaccines for influenza, to improve the efficacy of immunization in the elderly. In the future, the development and use of markers of immunosenescence to identify patients who may have impaired responses to vaccination, as well as the use of end-points other than antibody titers to assess vaccine efficacy, may help to reduce morbidity and mortality due to infections in the elderly.

Background. Renal artery stenosis (RAS) causes renal injury partly via microvascular (MV) endothelial dysfunction and damage. Vascular endothelial growth factor (VEGF) is crucial for preservation of microvasculature and promotes vascular proliferation and endothelial repair. We have previously shown that MV rarefaction is associated with decreased VEGF in the kidney exposed to chronic RAS, accompanied by deteriorated renal function and fibrosis. We hypothesized that preserving the renal microcirculation in the stenotic kidney will halt the progression of renal damage. Methods. Unilateral RAS was induced in 16 pigs. In eight, VEGF (0.05 micrograms/kg) was infused intra-renally at the onset of RAS. After 6 weeks, single-kidney haemodynamics and function were assessed using in vivo multi-detector computed tomography (CT). Renal microvessels, angiogenic pathways and morphology were investigated ex vivo using micro-CT, real-time PCR and histology. Results. Blood pressure and degree of RAS was similar in RAS and RAS + VEGF pigs. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in RAS compared to Normal (221.1 ± 46.5 and 29.9 ± 3.8 vs. 522.5 ± 60.9 and 49.3 ± 3.4 mL/min, respectively, P < 0.05), accompanied by decreased cortical MV density and increased renal fibrosis. Pre-emptive administration of VEGF preserved MV architecture, attenuated fibrosis and normalized RBF and GFR (510.8 ± 50.9 and 39.9.1 ± 4.1 mL/min, P = not significant vs. Normal). Conclusions. This study underscores the importance of the renal microcirculation in renovascular disease. Intra-renal administration of VEGF preserved renal MV architecture and function of the stenotic kidney, which in turn preserved renal haemodynamics and function and decreased renal fibrosis. These observations suggest that preventing renal MV loss may be a potential target for therapeutic approaches for patients with chronic renovascular disease.

We have identified a new point mutation in the myelin protein zero (P0) gene in two genetically identical twins with a demyelinating neuropathy. The G to A transition at nucleotide position 382 caused an aspartic acid to asparagine substitution in exon 3. Moreover, we found clear clinical differences which were most evident at an early age. These observations suggest that the expression of this P0 mutation may be susceptible to external, non-genetic influences that may act early in the course of the disease to alter the phenotype.