Impact of Thymectomy on the Peripheral T Cell Pool in the Context of SIV Infection

The thymus is the primary lymphoid organ responsible for T cell production. It is of particular interest in the context of human immunodeficiency virus (HIV)-l infection, in which the progressive loss of CD4+ T cells leads to immunodeficiency and opportunistic infection. CD4+ T cell loss is thought to result from direct and indirect killing of C D 4 cells in the periphery as well as from pathogenic effects of the virus on the thymus. However, it is not fully understood which is the greater factor in viral-induced CD4+ T cell decay. The development of an assay to detect T cell receptor excisional circles (TREC) as a marker for recent T cell receptor (TCR) recombination in the thymus has proved to be an invaluable tool for the study of recent thymic emigrants. Here we describe the development of this technique in the rhesus macaque model and use this method in combination with other techniques to study the role of the thymus in maintenance of the peripheral T cell pool. This study has two major goals: to define the role of the thymus in peripheral T cell homeostasis in the juvenile rhesus macaque (Macaca mulatto) and to assess the significance of thymic output in the context of simian immunodeficiency virus (SIV) infection. To this end, we have studied the impact of surgical thymectomy on the peripheral T cell pool in a cohort of macaques. W e present evidence that thymic output in the juvenile macaque is measurable but quantitatively insignificant in the context of the total T cell pool. While SIV infection does have pathogenic effects on the thymus, these effects play a minimal role in the overall destruction of the peripheral T cell pool

Safety and efficacy of vismodegib in patients aged ≥65 years with advanced basal cell carcinoma.

Because many patients with unresectable basal cell carcinoma (BCC) are aged ≥65 years, this study explores the efficacy and safety of vismodegib in these patients with locally advanced (la) or metastatic (m) basal cell carcinoma (BCC) in the ERIVANCE BCC trial and the expanded access study (EAS).We compared patients aged ≥65 years to patients aged <65 years taking vismodegib 150 mg/day, using descriptive statistics for response and safety. Patients aged ≥65 years (laBCC/mBCC) were enrolled in ERIVANCE BCC (33/14) and EAS (27/26). Investigator-assessed best overall response rate in patients ≥65 and <65 years was 46.7%/35.7% and 72.7%/52.6% (laBCC/mBCC), respectively, in ERIVANCE BCC and 45.8%/33.3% and 46.9%/28.6%, respectively, in EAS. These differences were not clinically meaningful. Safety was similar in both groups, although those aged ≥65 years had a higher percentage of grade 3-5 adverse events than those aged <65 years. Vismodegib demonstrated similar clinical activity and adverse events regardless of age

Transcriptional landscape of epithelial and immune cell populations revealed through FACS-seq of healthy human skin.

Human skin consists of multiple cell types, including epithelial, immune, and stromal cells. Transcriptomic analyses have previously been performed from bulk skin samples or from epithelial and immune cells expanded in cell culture. However, transcriptomic analysis of bulk skin tends to drown out expression signals from relatively rare cells while cell culture methods may significantly alter cellular phenotypes and gene expression profiles. To identify distinct transcriptomic profiles of multiple cell populations without substantially altering cell phenotypes, we employed a fluorescence activated cell sorting method to isolate keratinocytes, dendritic cells, CD4+ T effector cells, and CD8+ T effector cells from healthy skin samples, followed by RNA-seq of each cell population. Principal components analysis revealed distinct clustering of cell types across samples, while differential expression and coexpression network analyses revealed transcriptional profiles of individual cell populations distinct from bulk skin, most strikingly in the least abundant CD8+ T effector population. Our work provides a high resolution view of cutaneous cellular gene expression and suggests that transcriptomic profiling of bulk skin may inadequately capture the contribution of less abundant cell types

Transcriptome Sequencing Demonstrates that Human Papillomavirus Is Not Active in Cutaneous Squamous Cell Carcinoma

β-Human papillomavirus (β-HPV) DNA is present in some cutaneous squamous cell carcinomas (cuSCCs), but no mechanism of carcinogenesis has been determined. We used ultra-high-throughput sequencing of the cancer transcriptome to assess whether papillomavirus transcripts are present in these cancers. In all, 67 cuSCC samples were assayed for β-HPV DNA by PCR, and viral loads were measured with type-specific quantitative PCR. A total of 31 SCCs were selected for whole transcriptome sequencing. Transcriptome libraries were prepared in parallel from the HPV18-positive HeLa cervical cancer cell line and HPV16-positive primary cervical and periungual SCCs. Of the tumors, 30% (20/67) were positive for β-HPV DNA, but there was no difference in β-HPV viral load between tumor and normal tissue (P=0.310). Immunosuppression and age were significantly associated with higher viral load (P=0.016 for immunosuppression; P=0.0004 for age). Transcriptome sequencing failed to identify papillomavirus expression in any of the skin tumors. In contrast, HPV16 and HPV18 mRNA transcripts were readily identified in primary cervical and periungual cancers and HeLa cells. These data demonstrate that papillomavirus mRNA expression is not a factor in the maintenance of cuSCCs

Cutaneous squamous cell carcinoma staging may influence management in users: A survey study.

PURPOSE: This study aims to determine whether there is consensus regarding staging and management of cutaneous squamous cell carcinoma (CSCC) across the various specialties that manage this disease. MATERIALS AND METHODS: A survey regarding CSCC high-risk features, staging, and management was created and emailed to cutaneous oncology experts including dermatology, head and neck surgery/surgical oncology, radiation oncology, and medical oncology. RESULTS: One hundred fifty-six (46%) of 357 invited physicians completed the survey. Depth of invasion (92%), perineural invasion (99%), histologic differentiation (85%), and patient immunosuppression (90%) achieved consensus (\u3e80%) as high-risk features of CSCC. Dermatologists were more likely to also choose clinical tumor diameter (79% vs. 54%) and histology (99% vs. 66%) as a high-risk feature. Dermatologists were also more likely to utilize the Brigham and Women\u27s Hospital (BWH) staging system alone or in conjunction with American Joint Committee on Cancer (AJCC) (71%), whereas other cancer specialists (OCS) tend to use only AJCC (71%). Respondents considered AJCC T3 and higher (90%) and BWH T2b and higher (100%) to be high risk and when they consider radiologic imaging, sentinel lymph node biopsy, post-operative radiation therapy, and increased follow-up. Notably, a large number of respondents do not use staging systems or tumor stage to determine treatment options beyond surgery in high-risk CSCC. CONCLUSION: This survey study highlights areas of consensus and differences regarding the definition of high-risk features of CSCC, staging approaches, and management patterns between dermatologists and OCS. High-risk CSCC is defined as, but not limited to, BWH T2b and higher and AJCC T3 and higher, and these thresholds can be used to identify cases for which treatment beyond surgery may be considered. Dermatologists are more likely to utilize BWH staging, likely because BWH validation studies showing advantages over AJCC were published in dermatology journals and discussed at dermatology meetings. Additional data are necessary to develop a comprehensive risk-based management approach for CSCC

Validation of a Diagnostic Microarray for Human Papillomavirus: Coverage of 102 Genotypes

Papillomaviruses have been implicated in a variety of human diseases ranging from common warts to invasive carcinoma of the anogenital mucosa. Existing assays for genotyping human papillomavirus are restricted to a small number of types. Here, we present a comprehensive, accurate microarray strategy for detection and genotyping of 102 human papillomavirus types and validate its use in a panel of 91 anal swabs. This array has equal performance to traditional dot blot analysis with the benefits of added genotype coverage and the ability to calibrate readout over a range of sensitivity or specificity values

Attention-Related Brain Activation Is Altered in Older Adults With White Matter Hyperintensities Using Multi-Echo fMRI

Cognitive decline is often undetectable in the early stages of accelerated vascular aging. Attentional processes are particularly affected in older adults with white matter hyperintensities (WMH), although specific neurovascular mechanisms have not been elucidated. We aimed to identify differences in attention-related neurofunctional activation and behavior between adults with and without WMH. Older adults with moderate to severe WMH (n = 18, mean age = 70 years), age-matched adults (n = 28, mean age = 72), and healthy younger adults (n = 19, mean age = 25) performed a modified flanker task during multi-echo blood oxygenation level dependent functional magnetic resonance imaging. Task-related activation was assessed using a weighted-echo approach. Healthy older adults had more widespread response and higher amplitude of activation compared to WMH adults in fronto-temporal and parietal cortices. Activation associated with processing speed was absent in the WMH group, suggesting attention-related activation deficits that may be a consequence of cerebral small vessel disease. WMH adults had greater executive contrast activation in the precuneous and posterior cingulate gyrus compared to HYA, despite no performance benefits, reinforcing the network dysfunction theory in WMH

Repetitive Behavior in Rubinstein–Taybi Syndrome: Parallels with Autism Spectrum Phenomenology

Background. Syndrome specific repetitive behavior profiles have been described previously. A detailed profile is absent for Rubinstein-Taybi syndrome (RTS). Method. The Repetitive Behaviour Questionnaire and Social Communication Questionnaire (SCQ) were completed for children and adults RTS (N = 87), Fragile-X (N = 196) and Down (N = 132) syndromes, and individuals reaching cut-off for Autism Spectrum Disorder (ASD) (N = 228). Results. Total and matched group analyses were conducted. A phenotypic profile of repetitive behavior was found in RTS. The majority of behaviors in RTS were not associated with social-communication deficits or degree of disability. Conclusions. Repetitive behavior should be studied at a fine-grained level. A dissociation of the triad of impairments might be evident in RTS