White Matter Deterioration May Foreshadow Impairment of Emotional Valence Determination in Early-Stage Dementia of the Alzheimer Type

In Alzheimer Disease (AD), non-verbal skills often remain intact for far longer than verbally mediated processes. Four (1 female, 3 males) participants with early-stage Clinically Diagnosed Dementia of the Alzheimer Type (CDDAT) and eight neurotypicals (NTs; 4 females, 4 males) completed the emotional valence determination test (EVDT) while undergoing BOLD functional magnetic resonance imaging (fMRI). We expected CDDAT participants to perform just as well as NTs on the EVDT, and to display increased activity within the bilateral amygdala and right anterior cingulate cortex (r-ACC). We hypothesized that such activity would reflect an increased reliance on these structures to compensate for on-going neuronal loss in frontoparietal regions due to the disease. We used diffusion tensor imaging (DTI) to determine if white matter (WM) damage had occurred in frontoparietal regions as well. CDDAT participants had similar behavioral performance and no differences were observed in brain activity or connectivity patterns within the amygdalae or r-ACC. Decreased fractional anisotropy (FA) values were noted, however, for the bilateral superior longitudinal fasciculi and posterior cingulate cortex (PCC). We interpret these findings to suggest that emotional valence determination and non-verbal skill sets are largely intact at this stage of the disease, but signs foreshadowing future decline were revealed by possible WM deterioration. Understanding how non-verbal skill sets are altered, while remaining largely intact, offers new insights into how non-verbal communication may be more successfully implemented in the care of AD patients and highlights the potential role of DTI as a presymptomatic biomarker

Diagnostic Accuracy of Fine Needle Biopsy for Metastatic Melanoma and Its Implications for Patient Management

The use of fine needle biopsy (FNB) for the diagnosis of metastatic melanoma can lead to the early removal and treatment of metastases, reduce the frequency of unnecessary surgery, and facilitate the staging of patients enrolled in clinical trials of adjuvant therapies. In this study, the accuracy of FNB for the diagnosis of metastatic melanoma was investigated. A retrospective cohort study was performed with 2204 consecutive FNBs performed on 1416 patients known or suspected to have metastatic melanoma. Almost three-quarters (1582) of these FNBs were verified by either histopathologic diagnosis following surgical resection or clinical follow-up. FNB for metastatic melanoma was found to have an overall sensitivity of 92.1% and a specificity of 99.2%, with 69 false-negative and 5 false-positive findings identified. The sensitivity of the procedure was found to be influenced by six factors. The use of immunostains, reporting of the specimen by a cytopathologist who had reported >500 cases, lesions located in the skin and subcutis, and patients with ulcerated primary melanomas were factors associated with a significant improvement in the sensitivity of the test. However, FNBs performed in masses located in lymph nodes of the axilla and FNBs that required more than one needle pass to obtain a sample were far more likely to result in false-negative results. FNB is a rapid, accurate, and clinically useful technique for the assessment of disease status in patients with suspected metastatic melanoma

Confirmed adult dengue deaths in Singapore: 5-year multi-center retrospective study

10.1186/1471-2334-11-123BMC Infectious Diseases11-BIDM

Tissue-Specific Features of the T Cell Repertoire After Allogeneic Hematopoietic Cell Transplantation in Human and Mouse

T cells are the central drivers of many inflammatory diseases, but the repertoire of tissue-resident T cells at sites of pathology in human organs remains poorly understood. We examined the site-specificity of T cell receptor (TCR) repertoires across tissues (5 to 18 tissues per patient) in prospectively collected autopsies of patients with and without graft-versus-host disease (GVHD), a potentially lethal tissue-targeting complication of allogeneic hematopoietic cell transplantation, and in mouse models of GVHD. Anatomic similarity between tissues was a key determinant of TCR repertoire composition within patients, independent of disease or transplant status. The T cells recovered from peripheral blood and spleens in patients and mice captured a limited portion of the TCR repertoire detected in tissues. Whereas few T cell clones were shared across patients, motif-based clustering revealed shared repertoire signatures across patients in a tissue-specific fashion. T cells at disease sites had a tissue-resident phenotype and were of donor origin based on single-cell chimerism analysis. These data demonstrate the complex composition of T cell populations that persist in human tissues at the end stage of an inflammatory disorder after lymphocyte-directed therapy. These findings also underscore the importance of studying T cell in tissues rather than blood for tissue-based pathologies and suggest the tissue-specific nature of both the endogenous and posttransplant T cell landscape

A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia

Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL)1–3, but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A (p.Gly183Ser), affecting the octapeptide domain of PAX5 that was found to segregate with disease in two unrelated kindreds with autosomal dominant B-ALL. Leukemic cells from all affected individuals in both families exhibited 9p deletion, with loss of heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss harbored somatic PAX5 substitutions affecting Gly183. Functional and gene expression analysis of the PAX5 mutation demonstrated that it had significantly reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B cell ALL and implicate PAX5 in a new syndrome of susceptibility to pre-B cell neoplasia

Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

Purpose:; Resistance to platinum-based chemotherapy or PARP inhibition in germline; BRCA1; or; BRCA2; mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function. We assessed whether; BRCA1/2; reversion mutations could be identified in circulating cell-free DNA (cfDNA) of patients with ovarian or breast cancer previously treated with platinum and/or PARP inhibitors.; Experimental Design:; cfDNA from 24 prospectively accrued patients with germline; BRCA1; or; BRCA2; mutations, including 19 patients with platinum-resistant/refractory ovarian cancer and five patients with platinum and/or PARP inhibitor pretreated metastatic breast cancer, was subjected to massively parallel sequencing targeting all exons of 141 genes and all exons and introns of; BRCA1; and; BRCA2; Functional studies were performed to assess the impact of the putative; BRCA1/2; reversion mutations on BRCA1/2 function.; Results:; Diverse and often polyclonal putative; BRCA1; or; BRCA2; reversion mutations were identified in cfDNA from four patients with ovarian cancer (21%) and from two patients with breast cancer (40%).; BRCA2; reversion mutations were detected in cfDNA prior to PARP inhibitor treatment in a patient with breast cancer who did not respond to treatment and were enriched in plasma samples after PARP inhibitor therapy. Foci formation and immunoprecipitation assays suggest that a subset of the putative reversion mutations restored BRCA1/2 function.; Conclusions:; Putative; BRCA1/2; reversion mutations can be detected by cfDNA sequencing analysis in patients with ovarian and breast cancer. Our findings warrant further investigation of cfDNA sequencing to identify putative; BRCA1/2; reversion mutations and to aid the selection of patients for PARP inhibition therapy.; Clin Cancer Res; 23(21); 6708-20. ©2017 AACR;