Immunotherapy-induced CD8+ T Cells Instigate Immune Suppression in the Tumor

Despite clear evidence of immunogenicity, cancer vaccines only provide a modest clinical benefit. To evaluate the mechanisms that limit tumor regression following vaccination, we have investigated the weak efficacy of a highly immunogenic experimental vaccine using a murine melanoma model. We discovered that the tumor adapts rapidly to the immune attack instigated by tumor-specific CD8⁺ T cells in the first few days following vaccination, resulting in the upregulation of a complex set of biological networks, including multiple immunosuppressive processes. This rapid adaptation acts to prevent sustained local immune attack, despite continued infiltration by increasing numbers of tumor-specific T cells. Combining vaccination with adoptive transfer of tumor-specific T cells produced complete regression of the treated tumors but did not prevent the adaptive immunosuppression. In fact, the adaptive immunosuppressive pathways were more highly induced in regressing tumors, commensurate with the enhanced level of immune attack. Examination of tumor infiltrating T-cell functionality revealed that the adaptive immunosuppression leads to a progressive loss in T-cell function, even in tumors that are regressing. These novel observations that T cells produced by therapeutic intervention can instigate a rapid adaptive immunosuppressive response within the tumor have important implications for clinical implementation of immunotherapies.     

Penalized least squares regression methods and applications to neuroimaging

The goals of this paper are to review the most popular methods of predictor selection in regression models, to explain why some fail when the number P of explanatory variables exceeds the number N of participants, and to discuss alternative statistical methods that can be employed in this case. We focus on penalized least squares methods in regression models, and discuss in detail two such methods that are well established in the statistical literature, the LASSO and Elastic Net. We introduce bootstrap enhancements of these methods, the BE-LASSO and BE-Enet, that allow the user to attach a measure of uncertainty to each variable selected. Our work is motivated by a multimodal neuroimaging dataset that consists of morphometric measures (volumes at several anatomical regions of interest), white matter integrity measures from diffusion weighted data (fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity) and clinical and demographic variables (age, education, alcohol and drug history). In this dataset, the number P of explanatory variables exceeds the number N of participants. We use the BE-LASSO and BE-Enet to provide the first statistical analysis that allows the assessment of neurocognitive performance from high dimensional neuroimaging and clinical predictors, including their interactions. The major novelty of this analysis is that biomarker selection and dimension reduction are accomplished with a view towards obtaining good predictions for the outcome of interest (i.e., the neurocognitive indices), unlike principal component analysis that are performed only on the predictors' space independently of the outcome of interest.     

Spontaneous activity promotes synapse formation in a cell-type-dependent manner in the developing retina

Spontaneous activity is thought to regulate synaptogenesis in many parts of the developing nervous system. In vivo evidence for this regulation, however, is scarce and comes almost exclusively from experiments in which normal activity was reduced or blocked completely. Thus, whether spontaneous activity itself promotes synaptogenesis or plays a purely permissive role remains uncertain. In addition, how activity influences synapse dynamics to shape connectivity and whether its effects among neurons are uniform or cell-type-dependent is unclear. In mice lacking the cone-rod homeobox gene (Crx), photoreceptors fail to establish normal connections with bipolar cells (BCs). Here, we find that retinal ganglion cells (RGCs) in Crx?/? mice become rhythmically hyperactive around the time of eye opening as a result of increased spontaneous glutamate release from BCs. This elevated neurotransmission enhances synaptogenesis between BCs and RGCs, without altering the overall circuit architecture. Using live imaging, we discover that spontaneous activity selectively regulates the rate of synapse formation, not elimination, in this circuit. Reconstructions of the connectivity patterns of three BC types with a shared RGC target further revealed that neurotransmission specifically promotes the formation of multisynaptic appositions from one BC type without affecting the maintenance or elimination of connections from the other two. Although hyperactivity in Crx?/? mice persists, synapse numbers do not increase beyond 4 weeks of age, suggesting closure of a critical period for synaptic refinement in the inner retina. Interestingly, despite their hyperactivity, RGC axons maintain normal eye-specific territories and cell-type-specific layers in the dorsal lateral geniculate nucleus.     

Epilepsy-associated stigma in Bolivia: A community-based study among the Guarani population: An International League Against Epilepsy/International Bureau for Epilepsy/World Health Organization Global Campaign Against Epilepsy Regional Project

Epilepsy is associated with a significant burden of social stigma that appears to be influenced by psychosocial and cultural factors. Stigma has a negative effect on the management of people with epilepsy (PWE), representing one of the major factors that contribute to the burden of epilepsy. To assess stigma perception among the Guarani population, one hundred thirty-two people living in Guaraní communities in Bolivia were invited to complete the Stigma Scale of Epilepsy questionnaire. The main determinants of stigma identified were: the fear linked to loss of control, the feelings of sadness and pity toward PWE, the difficulties faced by PWE in the professional and relationship fields, the level of education and type of seizure. Our study pointed out that, in this population, PWE face difficulties in everyday life because of epilepsy-associated stigma and the results attest to the importance of promoting community-based educational programs aimed at reducing the stigmatization process.     

In vitro controlled release of antihypertensive drugs intercalated into unmodified SBA-15 and MgO modified SBA-15 matrices

The aim of the present study was two-fold: (1) to investigate the effect of pH and presence of surfactant sodium lauryl sulphate (SLS) on the solubility and dissolution rate of two solid-state forms of piroxicam (PRX), anhydrate (PRXAH) and monohydrate (PRXMH), and (2) to quantitatively assess the solid-phase transformation of PRXAH to PRXMH in slurry with a special interest to the impact on the solubility and dissolution behavior of the drug. X-ray powder diffractometry (XRPD), Raman spectroscopy and scanning electron microscopy (SEM) were used for characterization of the solid-state forms. Phase transformation was monitored in slurry by means of in-line Raman spectroscopy, and the partial least squares (PLS) regression model was used for predicting the amount of PRXMH. The results showed that the solubility and dissolution rate of PRXAH were higher compared to PRXMH at different pHs. The pH and presence of SLS together affected the solubility and dissolution rate of different PRX forms. The lowest solubility values and dissolution rates for PRX forms were observed in distilled water (pH 5.6) at 37 °C. The changes in the dissolution rate could be explained by the hydrate formation during solubility testing. The rate of hydrate formation was also dependent on the pH of the dissolution medium.     

NK cell immunotherapy for high-risk neuroblastoma relapse after haploidentical HSCT

Little is known on strategies to prevent or to treat relapses occurring after haploidentical stem cell transplantation (haplo-HSCT) performed for the high-risk neuroblastoma (NB). We describe a 6-year-old male with refractory NB who relapsed 22 months after haplo-HSCT. A complete remission was obtained with a combination of immuno-chemotherapy based on donor NK cells transplants, IL2 infusions and temozolomide/topotecan. This case is an incentive to explore both the immediate therapeutic effect of haplo-graft provided via haplo-NK cells and the immunogenic platform that haplo-HSCT offers for future treatment. Our post-relapse strategy shows that chemo- and bio-treatment should be viewed as complementary therapeutic options.     

Long-Term Corrosion Testing of Zy-4 in a LiOH Solution under High Pressure and Temperature Conditions

The fuel cladding is one of the most important structural components for maintaining the integrity of a fuel channel and for safely exploitation of a nuclear power plant. The corrosion behavior of a fuel cladding material, Zy-4, under high pressure and temperatures conditions, was analyzed in a static isothermal autoclave under simulated primary water conditions—a LiOH solution at 310 °C and 10 MPa for up to 3024 h. After this, the oxides grown on the Zy-4 sample surface were characterized using electrochemical measurements, gravimetric analysis, metallographic analysis, SEM and XPS. The maximum oxide thicknesses evaluated by gravimetric and SEM measurements were in good agreement; both values were around 1.2 µm. The optical light microscopy (OLM) investigations identified the presence of small hydrides uniformly distributed horizontally across the alloy. EIS impedance spectra showed an increase in the oxide impedance for the samples oxidized for a long time. EIS plots has the best fit with an equivalent circuit which illustrated an oxide model that has two oxide layers: an inner oxide layer and outer layer. The EIS results showed that the inner layer was a barrier layer, and the outer layer was a porous layer. Potentiodynamic polarization results demonstrated superior corrosion resistance of the samples tested for longer periods of time. By XPS measurements we identified all five oxidation states of zirconium: Zr⁰ located at 178.5 eV; Zr⁴⁺ at 182.8 eV; and the three suboxides, Zr⁺, Zr²⁺ and Zr³⁺ at 179.7, 180.8 and 181.8 eV, respectively. The determination of Vickers microhardness completed the investigation.     

Analysis of genetic and serology of hepatitis A virus infection during and after outbreak in two junior high schools in Surabaya,Indonesia

Outbreaks of hepatitis A have occurred in some cities in Indonesia. In Surabaya, the capital city of East Java province, Indonesia, hepatitis A outbreaks have been reported since2013, with a marked increase in the number of cases in 2015. The aim of the present study was to analyze the genetic and serology of acute symptomatic cases (early infection) during a hepatitis A outbreak and asymptomatic cases after the outbreak in two junior high schools in Surabaya in 2015 to 2016. Students with acute symptomatic hepatitis A during the outbreak and other students who were asymptomatic 3 to 4 months after the outbreak were enrolled. Asymptomatic students had no symptoms from the outbreak until they were enrolled. Sera were collected to identify anti-hepatitis A virus (HAV) IgM (by enzyme-linked immunosorbent assay) and HAV genetic variations/genotypes (using polymerase chain reaction [PCR]-sequencing and phylogenetic analysis). A total of 33 (97.1%) out of 34 sera of students with acute symptoms were positive for anti-HAV IgM and 18% of them were positive by PCR, identified as HAV subgenotype IA. No prominent amino acid variations were observed from reported HAV sequences from Indonesia. Among 38 sera of asymptomatic students, most (55.3%) were positive for anti-HAV IgM, while none were positive by PCR. In conclusion, HAV-IA was the only subgenotype identified in acute symptomatic cases during the outbreak. The percentage of HAV-specific IgM-positive cases was very high among acute symptomatic students, but that was also high among asymptomatic students, which might contribute as the important source of infection during the outbreak.