Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma

Interference with inhibitory immunological checkpoints controlling T cell activation provides new opportunities to augment cancer immunotherapies. Whereas cytotoxic T lymphocyte–associated antigen-4 blockade has shown promising preclinical and clinical results, therapeutic CD4+CD25+ T reg cell depletion has failed to consistently enhance immune-based therapies. Using B16/BL6, a transplantable murine melanoma model, we show a dichotomy between the effects of T reg cell depletion on tumor rejection dependent on whether depletion occurs before (prophylactic) or after (therapeutic) tumor engraftment. Failure to promote rejection with therapeutic depletion is not related to lack of T reg cell depletion, to elimination of CD25+ effector T cells, or to a failure to enhance systemic antitumor T cell responses, but correlates with failure of effector cells to infiltrate the tumor and increase the intratumor ratio of effector T cell/T reg cell. Finally, systemic antitumor responses generated upon therapeutic T reg cell depletion are significantly stronger than those generated in the presence of T reg cells, and are capable of eliciting rejection of established tumors after transfer into immunoablated recipients receiving combination immunotherapy. The data demonstrate a dissociation between measurable systemic responses and tumor rejection during CD25-directed T reg cell depletion, and suggest an alternative, clinically applicable strategy for the treatment of established tumors

Experimental probing of exchange interactions between localized spins in the dilute magnetic insulator (Ga,Mn)N

The sign, magnitude, and range of the exchange couplings between pairs of Mn ions is determined for (Ga,Mn)N and (Ga,Mn)N:Si with x < 3%. The samples have been grown by metalorganic vapor phase epitaxy and characterized by secondary-ion mass spectroscopy; high-resolution transmission electron microscopy with capabilities allowing for chemical analysis, including the annular dark-field mode and electron energy loss spectroscopy; high-resolution and synchrotron x-ray diffraction; synchrotron extended x-ray absorption fine-structure; synchrotron x-ray absorption near-edge structure; infra-red optics and electron spin resonance. The results of high resolution magnetic measurements and their quantitative interpretation have allowed to verify a series of ab initio predictions on the possibility of ferromagnetism in dilute magnetic insulators and to demonstrate that the interaction changes from ferromagnetic to antiferromagnetic when the charge state of the Mn ions is reduced from 3+ to 2+.Comment: 12 pages, 14 figures; This version contains the detailed characterization of the crystal structure as well as of the Mn distribution and charge stat

Novel, bilateral, two-bellied muscles span the extensor forearm, thenar eminence to insert on the proximal phalanx of the thumb: clinical and embryological significance

Muscle and tendon variations in the forearm, wrist and hand are commonly reported in the anatomical and surgical literature. They are frequently the source of inflammatory conditions such as de Quervain’s tenosynovitis or carpal tunnel syndrome. During academic dissection, a cadaver presented with bilateral, additional muscles running parallel to the abductor pollicis longus muscles (APL) in the extensor compartment of the forearm. Both additional muscles had two bellies, one proximal and one distal, with an intervening tendon. The proximal bellies were separate and distinct from the adjacent APLs. The tendons traversed the first dorsal compartments with the tendons of the APLs and the extensor pollicis brevis muscles (EPB). The distal bellies lay adjacent to the abductor pollicis brevis (APB) muscles in the thenar compartments, and inserted onto the volar base of the proximal phalanges of the thumbs. Following a thorough search of the literature, we determined that these additional muscles constitute a previously unreported variation. This report details the variation, compares it with other reported variations, presents the related embryology, and reviews the significance of this variation as it relates to inflammatory conditions and surgical procedures

Repetitive mild traumatic brain injury causes optic nerve and retinal damage in a mouse model

There is increasing evidence that long-lasting morphologic and functional consequences can be present in the human visual system after repetitive mild traumatic brain injury (r-mTBI). The exact lo- cation and extent of the damage in this condition are not well un- derstood. Using a recently developed mouse model of r-mTBI, we assessed the effects on the retina and optic nerve using histology and immunohistochemistry, electroretinography (ERG), and spectral- domain optical coherence tomography (SD-OCT) at 10 and 13 weeks after injury. Control mice received repetitive anesthesia alone (r-sham). We observed decreased optic nerve diameters and increased cellularity and areas of demyelination in optic nerves in r-mTBI versus r-sham mice. There were concomitant areas of decreased cellularity in the retinal ganglion cell layer and approximately 67% decrease in brain- specific homeobox/POU domain protein 3AYpositive retinal ganglion cells in retinal flat mounts. Furthermore, SD-OCT demonstrated a de- tectable thinning of the inner retina; ERG demonstrated a decrease in the amplitude of the photopic negative response without any change in a- or b-wave amplitude or timing. Thus, the ERG and SD-OCT data correlated well with changes detected by morphometric, histologic, and immunohistochemical methods, thereby supporting the use of these noninvasive methods in the assessment of visual function and morphology in clinical cases of mTBI

Genetic analysis of porcine circovirus type 2 from pigs affected with PMWS in Chile reveals intergenotypic recombination

Background: Porcine circovirus type 2 (PCV2) is a very small, non-enveloped and icosahedral virus, with circular single stranded DNA genome. This virus is the most ubiquitous and persistent pathogen currently affecting the swine industry worldwide. PCV2 has been implicated as the major causative agent of postweaning multisystemic wasting syndrome (PMWS), a disease which is characterized by severe immunosuppressive effects in the porcine host. Worldwide PCV2 isolates have been classified into four different genotypes, PCV2a, PCV2b, PCV2c and PCVd. The goal of this work was to conduct the first phylogenetic analysis of PCV2 in Chile. Methods: PCV2 partial ORF2 sequences (462 nt) obtained from 29 clinical cases of PMWS in 22 Chilean intensive swine farms, covering over the 90% of the local pork-production, were analyzed. Results: 14% and 52% of sequences belonged to the genotypes PCV2a and PCV2b, respectively. Surprisingly, 34% of sequences were PCV2a/PCV2d recombinant viruses. Conclusions: Our findings suggested that a novel cluster of Chilean sequences emerged resulting from intergenotypic recombination between PCV2a and PCV2d

Genetic differentiation in the Agave deserti (Agavaceae) complex of the Sonoran desert

The Agave deserti complex, comprising A. deserti, A. cerulata and A. subsimplex, represents a group of species and subspecies with a near allopatric distribution and clear differences in morphology. Genetic differentiation and taxonomic status with respect to spatial distribution of 14 populations of the complex were analyzed in an effort to understand the evolution and speciation process within the genus. Allelic frequencies, levels of genetic variation, expected heterozygosity (H S ), proportion of polymorphic loci (P), and genetic differentiation (y and Nei&apos;s genetic distance) were estimated using 41 putative RAPD loci. All three species show high levels of genetic variation (H S ¼ 0.12-0.29, P ¼ 63.4-95.1), and low genetic differentiation between populations and species (y populations ¼ 0.1470.02 (SE); G st ¼ 0.1170.02). Accordingly, gene flow among populations was estimated as high by three different methods (N m ¼ 2.91-6.14). Nei&apos;s genetic distances between the three species were low compared to the values obtained from other Agavaceae, and there was no clear correlation with taxonomic divisions. In a UPGMA analysis, A. subsimplex and A. cerulata formed exclusive monospecific clusters, whereas the A. deserti populations appear in more than one cluster together with other species. The results were consistent with a pattern of genetic isolation by distance

The Fe-Mg interplay and the effect of deposition mode in (Ga,Fe)N doped with Mg

The effect of Mg codoping and its deposition mode on the Fe distribution in (Ga,Fe)N layers grown by metalorganic vapor phase epitaxy is investigated. Both homogeneously- and digitally-Mg codoped samples are considered and contrasted to the case of (Ga,Fe)N layers obtained without any codoping by shallow impurities. The structural analysis of the layers by high-resolution transmission electron microscopy and by high-resolution- and synchrotron x-ray diffraction gives evidence of the fact that in the case of homogenous-Mg doping, Mg and Fe competitively occupy the Ga-substitutional cation sites, reducing the efficiency of Fe incorporation. Accordingly, the character of the magnetization is modified from ferromagnetic-like in the non-codoped films to paramagnetic in the case of homogeneous Mg codoping. The findings are discussed vis-`a-vis theoretical results obtained by ab initio computations, showing only a weak effect of codoping on the pairing energy of two Fe cations in bulk GaN. However, according to these computations, codoping reverses the sign of the paring energy of Fe cations at the Ga-rich surface, substantiating the view that the Fe aggregation occurs at the growth surface. In contrast to the homogenous deposition mode, the digital one is found to remarkably promote the aggregation of the magnetic ions. The Fe-rich nanocrystals formed in this way are distributed non-uniformly, giving reason for the observed deviation from a standard superparamagnetic behavior.Comment: 13 pages, 14 figure