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INTRODUCTION: Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells. METHODS: Bulk RNA‐sequencing of blood cells was performed on AD patients of Chinese descent (n = 214 and 26 in the discovery and validation cohorts, respectively) with normal controls (n = 208 and 38 in the discovery and validation cohorts, respectively). Weighted gene co‐expression network analysis (WGCNA) and deconvolution analysis identified AD‐associated gene modules and blood cell types. Regression and unsupervised clustering analysis identified AD‐associated genes, gene modules, cell types, and established AD classification models. RESULTS: WGCNA on differentially expressed genes revealed 15 gene modules, with 6 accurately classifying AD (areas under the receiver operating characteristics curve [auROCs] > 0.90). These modules stratified AD patients into subgroups with distinct disease states. Cell‐type deconvolution analysis identified specific blood cell types potentially associated with AD pathogenesis. DISCUSSION: This study highlights the potential of blood transcriptome for AD diagnosis, patient stratification, and mechanistic studies. Highlights: We comprehensively analyze the blood transcriptomes of a well‐characterized Alzheimer's disease cohort to identify genes, gene modules, pathways, and specific blood cells associated with the disease.Blood transcriptome analysis accurately classifies and stratifies patients with Alzheimer's disease, with some gene modules achieving classification accuracy comparable to that of the plasma ATN biomarkers.Immune‐associated pathways and immune cells, such as neutrophils, have potential roles in the pathogenesis and progression of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Existing blood‐based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood‐based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited. METHODS: We developed a blood‐based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD‐related endophenotypes in three independent cohorts from Chinese or European‐descent populations. RESULTS: The 21‐protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic‐specific dysregulations of biological processes upon AD progression. DISCUSSION: This study demonstrated the utility of a blood‐based, multi‐pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine. Highlights: The authors developed a blood‐based biomarker assay for Alzheimer's disease.The 21‐protein assay classifies AD/MCI and indicates brain amyloid pathology.The 21‐protein assay can simultaneously assess activities of five biological processes.Ethnic‐specific dysregulations of biological processes in AD were revealed. [ABSTRACT FROM AUTHOR]

Abstract: Post‐transplant lymphoproliferative disease (PTLD) has the highest incidence following intestinal transplantation (ITx). Our center has seen a recent increase in PTLD. Our aim was to review a single‐center PTLD experience with a focus on clinical characteristics and outcomes. We completed a retrospective review of biopsy‐proven PTLD cases using a prospectively maintained database of 115 ITx recipients transplanted between 1991 and 2014. Nineteen (17%) ITx recipients developed 25 PTLD cases during a median follow‐up time of 6.4 (1.6‐14.6) years. The incidence of early PTLD was 6% (n = 7). There was a trend toward increased risk of PTLD in children compared with adults (P = .11) and a significantly increased risk of PTLD in re‐ITx compared with primary ITx recipients (P = .03). Most PTLD cases were diagnosed between 2010 and 2014 (n = 14). All early PTLD cases were EBV+ on in situ hybridization. Overall graft and patient survival are 68% and 74%, respectively. Second episodes of PTLD were diagnosed in 43% of surviving pediatric patients. Our program has a low incidence of early PTLD with overall excellent graft and patient survival following diagnosis. However, we have also seen a rising incidence of late PTLD. The cause of the increase is unknown as no major changes in immunosuppression protocols have occurred since 1999. [ABSTRACT FROM AUTHOR]

Abstract: The significance of post‐transplant HLA DSA and chronic AMR in LT is an emerging field of study. Although OPV has previously been described as a histopathologic finding in DSA‐positive adult LT recipients, it was not included in the recent Banff criteria for chronic AMR. Our aim was to describe the association between OPV and chronic AMR in pediatric LT recipients. A retrospective review of 67 liver biopsies performed between November 2014 and April 2016 in 45 pediatric LT recipients identified four patients with OPV. Clinical status, liver biochemistry, the presence of DSA, and available non‐HLA antibody testing, as well as histopathologic features of chronic AMR, were assessed. All four patients with OPV had class II DSA and histopathologic features of chronic AMR based on the Banff criteria. Two patients were noted to have non‐HLA antibodies. Three patients are undergoing treatment with IVIG but have persistent DSA. Two patients have graft failure and are awaiting retransplantation. In conclusion, OPV is a histopathologic finding associated with chronic AMR in pediatric LT recipients. Further studies are needed to elucidate whether OPV is reversible and/or amenable to medical therapy. [ABSTRACT FROM AUTHOR]

BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of a novel BRAF mutation that confers resistance to PLX4032 employing whole-exome sequencing of drug-resistant BRAF V600K melanoma cells. We further describe a new screening approach, a genome-wide piggy Bac mutagenesis screen that revealed clinically relevant aberrations ( N-terminal BRAF truncations and CRAF overexpression). The novel BRAF mutation, a Leu505 to His substitution ( BRAF L505H), is the first resistance-conferring second-site mutation identified in BRAF mutant cells. The mutation replaces a small nonpolar amino acid at the BRAF- PLX4032 interface with a larger polar residue. Moreover, we show that BRAF L505H, found in human prostate cancer, is itself a MAPK-activating, PLX4032-resistant oncogenic mutation. Lastly, we demonstrate that the PLX4032-resistant melanoma cells are sensitive to novel, next-generation BRAF inhibitors, especially the 'paradox-blocker' PLX8394, supporting its use in clinical trials for treatment of melanoma patients with BRAF-mutations. [ABSTRACT FROM AUTHOR]

Background Renal transplant outcomes in Hispanics have been conflicting regarding acute rejection ( AR) and allograft survival. Additionally, the feasibility of early corticosteroid withdrawal ( ECW) regimens among Hispanics has not been adequately addressed. The purpose of this study is to report outcomes following ECW among Hispanic renal transplant recipients. Methods We retrospectively reviewed 498 consecutive renal transplants performed at our institution between July 2005 and October 2007, including 73 Hispanic and 146 white recipients who had ECW (median follow-up 49 months). Demographics, transplant data, and outcomes of Hispanic and white recipients ( WR) were analyzed. Results Hispanics had a higher incidence of diabetes mellitus and hypertension (p = 0.007), a higher proportion of blood type O (p = 0.006), and a higher serum panel reactive antibody at the time of transplantation (p = 0.02) compared with WR. Additionally, Hispanics were on dialysis longer than WR prior to transplantation (p = 0.03). Nevertheless, the incidence of AR, patient, and graft survival rates was similar (p > 0.05) between Hispanics and WR. Ethnicity was not an independent predictor of inferior patient and graft outcomes in multivariate analyses. Conclusion Our single-center experience indicates that ECW can be performed in Hispanic renal transplant recipients, with patient and allograft outcomes comparable with those observed in WR. [ABSTRACT FROM AUTHOR]

BRAFV600E/K is a frequent mutationally active tumor-specific kinase in melanomas that is currently targeted for therapy by the specific inhibitor PLX4032. Our studies with melanoma tumor cells that are BRAFV600E/K and BRAFWT showed that, paradoxically, while PLX4032 inhibited ERK1/2 in the highly sensitive BRAFV600E/K, it activated the pathway in the resistant BRAFWT cells, via RAF1 activation, regardless of the status of mutations in NRAS or PTEN. The persistently active ERK1/2 triggered downstream effectors in BRAFWT melanoma cells and induced changes in the expression of a wide-spectrum of genes associated with cell cycle control. Furthermore, PLX4032 increased the rate of proliferation of growth factor-dependent NRAS Q61L mutant primary melanoma cells, reduced cell adherence and increased mobility of cells from advanced lesions. The results suggest that the drug can confer an advantage to BRAFWT primary and metastatic tumor cells in vivo and provide markers for monitoring clinical responses. [ABSTRACT FROM AUTHOR]