Biomarkers in solid organ transplantation: establishing personalized transplantation medicine.

Technological advances in molecular and in silico research have enabled significant progress towards personalized transplantation medicine. It is now possible to conduct comprehensive biomarker development studies of transplant organ pathologies, correlating genomic, transcriptomic and proteomic information from donor and recipient with clinical and histological phenotypes. Translation of these advances to the clinical setting will allow assessment of an individual patient's risk of allograft damage or accommodation. Transplantation biomarkers are needed for active monitoring of immunosuppression, to reduce patient morbidity, and to improve long-term allograft function and life expectancy. Here, we highlight recent pre- and post-transplantation biomarkers of acute and chronic allograft damage or adaptation, focusing on peripheral blood-based methodologies for non-invasive application. We then critically discuss current findings with respect to their future application in routine clinical transplantation medicine. Complement-system-associated SNPs present potential biomarkers that may be used to indicate the baseline risk for allograft damage prior to transplantation. The detection of antibodies against novel, non-HLA, MICA antigens, and the expression of cytokine genes and proteins and cytotoxicity-related genes have been correlated with allograft damage and are potential post-transplantation biomarkers indicating allograft damage at the molecular level, although these do not have clinical relevance yet. Several multi-gene expression-based biomarker panels have been identified that accurately predicted graft accommodation in liver transplant recipients and may be developed into a predictive biomarker assay

WHEN DOES NEGATIVE BRAND PUBLICITY HURT? The Moderating Influence of Analytic Versus Holistic Thinking

Negative publicity can diminish positive consumer perceptions of a brand. We explore the impact of processing style on mitigating the effects of negative publicity. We hypothesize that holistic thinkers are less susceptible to negative publicity information than are analytic thinkers. Holistic thinkers are more likely to consider external context-based explanations for the negative publicity, resulting in little or no revision of beliefs about the parent brand. Analytic thinkers, in contrast, are less likely to consider contextual factors, attributing negative information to the parent brand and updating their brand beliefs accordingly. Across three studies, we find support for our predictions.Brand publicity, holistic thinking

Identification of common blood gene signatures for the diagnosis of renal and cardiac acute allograft rejection.

To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR) and with cytomegalovirus (CMV) infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score >37%  = AR) and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV) irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection

Noble gases in diamonds: Occurrences of solarlike helium and neon

We have measured noble gases in 17 diamond samples, mostly inclusion free, from diverse, known locations. The ^3He/^4He ratios are characterized by a large spread (10^4), ranging from values below atmospheric to close to the solar ratio. Highest ratios were seen for an Australian colorless diamond composite and an Arkansas diamond. These samples also have imprecise but intriguing neon isotopic ratios, which are close to the solar value. An origin for the solarlike He and Ne in the diamond samples is unlikely to be accounted for by the presence of nucleogenic or spallogenic components. For single diamond stones a positive correlation is found between ^3He/^4He and ^(13)C/^(12)C, possibly indicating that heavy carbon is accompanied by primordial helium. However, the He result for the Australian colorless diamond composite with low δ^(13)C value requires another explanation, possibly sedimentary carbon contaminated with cosmic dust. The wide variation in ^4He/^(40)_*Ar ratios observed from diamond samples suggests a complex history for the source regions and the diamond crystallization processes. Results for two Australian diamond composites (colorless and colored), which came from the same kimberlite pipe, are especially notable: the colorless stones contain no radiogenic components but solarlike He and Ne isotopic ratios, whereas the colored stones are enriched in radiogenic and fissiogenic components. Seemingly the Australian diamonds crystallized in a heterogeneous environment in the mantle source region. A pair of Arkansas diamonds, believed to be from a single pipe, exhibits similar anomalies

Magmatic inclusions in the search for natural silicate-salt melt immiscibility: methodology and examples

Immiscible phase separation during the cooling and crystallisation of magmas is an inherently fugitive phenomenon and melt inclusions may provide the only remaining evidence of this process. We detail those features of such inclusions that can both prove the existence of immiscible phase separation, and constrain the compositional signature of the process. To do so requires the combination of traditional methods (petrographic examination, microthermometry, etc.) with state of the art microbeam analytical techniques (laser Raman spectroscopy and proton-induced X-ray emission). Examples of inclusions in phenocrysts from barren and mineralised rocks are provided to illustrate the approach and validate the interpretations

Experimental strategies for the investigation of low temperature properties in granitic and pegmatitic melts

The physical behavior of silicate melts during the final stages of intrusion in the earth's crust are poorly understood. In particular, the low temperature limit of igneous petrogenesis is poorly constrained. The extreme differentiates of granitic magmatism that lead to pegmatite genesis span a very large range of composition not normally considered to be within the domain of igneous melt compositions. This combination of very low petrogenetic temperatures and extreme chemistries requires a concentrated effort for the determination of melt properties under conditions of pressure, temperature and composition appropriate to these systems. An experimental strategy for the determination of melt properties under appropriate conditions is presented. The determination of individual melt properties at very low temperatures is described with the aid of three examples, heat capacity, volume and viscosity. In this way the physical behavior of an important component of the earth's crust will become accessible

A computational gene expression score for predicing immune injury in renal allografts

Background Whole genome microarray meta-analyses of 1030 kidney, heart, lung and liver allograft biopsies identified a common immune response module (CRM) of 11 genes that define acute rejection (AR) across different engrafted tissues. We evaluated if the CRM genes can provide a molecular microscope to quantify graft injury in acute rejection (AR) and predict risk of progressive interstitial fibrosis and tubular atrophy (IFTA) in histologically normal kidney biopsies. Methods Computational modeling was done on tissue qPCR based gene expression measurements for the 11 CRM genes in 146 independent renal allografts from 122 unique patients with AR (n = 54) and no-AR (n = 92). 24 demographically matched patients with no-AR had 6 and 24 month paired protocol biopsies; all had histologically normal 6 month biopsies, and 12 had evidence of progressive IFTA (pIFTA) on their 24 month biopsies. Results were correlated with demographic, clinical and pathology variables. Results The 11 gene qPCR based tissue CRM score (tCRM) was significantly increased in AR (5.68 ± 0.91) when compared to STA (1.29 ± 0.28; p < 0.001) and pIFTA (7.94 ± 2.278 versus 2.28 ± 0.66; p = 0.04), with greatest significance for CXCL9 and CXCL10 in AR (p <0.001) and CD6 (p<0.01), CXCL9 (p<0.05), and LCK (p<0.01) in pIFTA. tCRM was a significant independent correlate of biopsy confirmed AR (p < 0.001; AUC of 0.900; 95% CI = 0.705-903). Gene expression modeling of 6 month biopsies across 7/11 genes (CD6, INPP5D, ISG20, NKG7, PSMB9, RUNX3, and TAP1) significantly (p = 0.037) predicted the development of pIFTA at 24 months. Conclusions Genome-wide tissue gene expression data mining has supported the development of a tCRM-qPCR based assay for evaluating graft immune inflammation. The tCRM score quantifies injury in AR and stratifies patients at increased risk of future pIFTA prior to any perturbation of graft function or histology