The vestibular contribution to the head direction signal and navigation.

Spatial learning and navigation depend on neural representations of location and direction within the environment. These representations, encoded by place cells and head direction (HD) cells, respectively, are dominantly controlled by visual cues, but require input from the vestibular system. Vestibular signals play an important role in forming spatial representations in both visual and non-visual environments, but the details of this vestibular contribution are not fully understood.

Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy.

Purpose: Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization.

Experimental Design: Patients (N = 41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens.

BRAF pyrosequencing analysis aided by a lookup table.

Objectives: BRAF mutations have substantial therapeutic, diagnostic, and prognostic significance, so detecting and specifying them is an important part of the workload of molecular pathology laboratories. Pyrosequencing assays are well suited for this analysis but can produce complex results. Therefore, we introduce a pyrosequencing lookup table based on Pyromaker that assists the user in generating hypotheses for solving complex pyrosequencing results.

Expression profile and in vitro blockade of programmed death-1 in human papillomavirus-negative head and neck squamous cell carcinoma.

Background: Treatment with a blocking programmed death-1 (αPD-1) antibody recently showed clinical efficacy for various tumor types. In this study, we characterized the expression profile of PD-1/programmed death-ligand-1 (PD-L1) and the potential of PD-1 blockade in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC).

Methods: Lymphocytes from peripheral blood, draining lymph nodes, and the tumor were phenotyped for PD-1 expression, and their proliferative activity was assessed in the presence of blocking αPD-1 treatment.

Resolving the active versus passive conundrum for head direction cells.

Head direction (HD) cells have been identified in a number of limbic system structures. These cells encode the animal's perceived directional heading in the horizontal plane and are dependent on an intact vestibular system. Previous studies have reported that the responses of vestibular neurons within the vestibular nuclei are markedly attenuated when an animal makes a volitional head turn compared to passive rotation.

Self-motion improves head direction cell tuning.

Head direction (HD) cells respond when an animal faces a particular direction in the environment and form the basis for the animal's perceived directional heading. When an animal moves through its environment, accurate updating of the HD signal is required to reflect the current heading, but the cells still maintain a representation of HD even when the animal is motionless. This finding suggests that the HD system holds its current state in the absence of input, a view that we tested by rotating a head-restrained rat in the presence of a prominent visual landmark and then stopping it suddenly when facing the cell's preferred firing direction (PFD).

Emerging immunologic biomarkers: setting the (TNM-immune) stage.

The cooperation of tumor-infiltrating lymphocytes and tertiary lymphoid tissue in early-stage colorectal carcinoma further corroborates the strong immune influences on tumor progression and patient outcome. Immune factors in the tumor microenvironment may warrant inclusion in pathology reports and staging systems for prognostication and prediction of therapeutic response.

Basal cell carcinomas of the vulva: high-risk human papillomavirus DNA detection, p16 and BerEP4 expression.

Basal cell carcinoma (BCC) of the vulva is rare and may be confused with the much more commonly encountered high-risk human papillomavirus (HPV)-related basaloid squamous cell carcinoma (SCC). The HPV status of BCCs is not well established. This study assesses the utility of p16 and BerEP4 expression patterns and high-risk HPV detection for distinction of these tumors.

Tumor cellularity as a quality assurance measure for accurate clinical detection of BRAF mutations in melanoma.

Background: Detection of BRAF mutations is an established standard of care to predict small-molecule inhibitor (vemurafenib) response in metastatic melanoma. Molecular assays should be designed to detect not only the most common p.V600E mutation, but also p.

HHV-8-positive and EBV-positive intravascular lymphoma: an unusual presentation of extracavitary primary effusion lymphoma.

Intravascular lymphomas are rare and aggressive hematolymphoid tumors. Here, we describe a human herpesvirus type-8 (HHV-8)/Kaposi sarcoma-associated herpesvirus-positive and Epstein-Barr virus (EBV)-positive intravascular lymphoma. The patient was a 59-year-old human immunodeficiency virus-positive man who presented with diarrhea, abdominal pain, fevers, night sweats, and weight loss.

PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival.

Merkel cell carcinoma (MCC) is a lethal, virus-associated cancer that lacks effective therapies for advanced disease. Agents blocking the PD-1/PD-L1 pathway have demonstrated objective, durable tumor regressions in patients with advanced solid malignancies and efficacy has been linked to PD-L1 expression in the tumor microenvironment. To investigate whether MCC might be a target for PD-1/PD-L1 blockade, we examined MCC PD-L1 expression, its association with tumor-infiltrating lymphocytes (TILs), Merkel cell polyomavirus (MCPyV), and overall survival.

Architecture of epigenetic reprogramming following Twist1-mediated epithelial-mesenchymal transition.

Background: Epithelial-mesenchymal transition (EMT) is known to impart metastasis and stemness characteristics in breast cancer. To characterize the epigenetic reprogramming following Twist1-induced EMT, we characterized the epigenetic and transcriptome landscapes using whole-genome transcriptome analysis by RNA-seq, DNA methylation by digital restriction enzyme analysis of methylation (DREAM) and histone modifications by CHIP-seq of H3K4me3 and H3K27me3 in immortalized human mammary epithelial cells relative to cells induced to undergo EMT by Twist1.

Results: EMT is accompanied by focal hypermethylation and widespread global DNA hypomethylation, predominantly within transcriptionally repressed gene bodies.

Genomic copy number imbalances associated with bone and non-bone metastasis of early-stage breast cancer.

The aim of this study is to identify and validate copy number aberrations in early-stage primary breast tumors associated with bone or non-bone metastasis. Whole-genome molecular inversion probe arrays were used to evaluate copy number imbalances (CNIs) in breast tumors from 960 early-stage patients with information about site of metastasis. The CoxBoost algorithm was used to select metastasis site-related CNIs and to fit a Cox proportional hazards model.

Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine.

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses.

A case of infraorbital lichen sclerosus.

We present a 57-year-old man with erosive lichen sclerosus isolated to the infraorbital area.

Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties.

The epithelial-mesenchymal transition (EMT) imparts metastatic competence on otherwise non-metastatic cancer cells through decreased inter-cellular adhesions, increased migratory capacity, stem cell properties and anoikis and chemotherapy resistance. In this study, we profiled changes in microRNA expression during EMT in conjunction with changes in DNA methylation at microRNA promoters to discover essential mediators of EMT-imparted stemness properties. MicroRNA-203 (miR-203) expression is repressed following EMT induced by multiple different stimuli and in established claudin-low cell lines as well as the CD44hi/CD24lo stem cell-enriched fraction.

The head-direction signal is critical for navigation requiring a cognitive map but not for learning a spatial habit.

Head-direction (HD) cells fire as a function of an animal's directional heading in the horizontal plane during two-dimensional navigational tasks [1]. The information from HD cells is used with place and grid cells to form a spatial representation (cognitive map) of the environment [2, 3]. Previous studies have shown that when rats are inverted (upside down), they have difficulty learning a task that requires them to find an escape hole from one of four entry points but that they can learn it when released from one or two start points [4].

B7-H5 costimulates human T cells via CD28H.

The B7/CD28 family has profound modulatory effects in immune responses and constitutes an important target for the development of novel therapeutic drugs against human diseases. Here we describe a new CD28 homologue (CD28H) that has unique functions in the regulation of the human immune response and is absent in mice. CD28H is constitutively expressed on all naive T cells.

Investigating the link between molecular subtypes of glioblastoma, epithelial-mesenchymal transition, and CD133 cell surface protein.

In this manuscript, we use genetic data to provide a three-faceted analysis on the links between molecular subclasses of glioblastoma, epithelial-to-mesenchymal transition (EMT) and CD133 cell surface protein. The contribution of this paper is three-fold: First, we use a newly identified signature for epithelial-to-mesenchymal transition in human mammary epithelial cells, and demonstrate that genes in this signature have significant overlap with genes differentially expressed in all known GBM subtypes. However, the overlap between genes up regulated in the mesenchymal subtype of GBM and in the EMT signature was more significant than other GBM subtypes.

Lesions of the dorsal tegmental nuclei disrupt control of navigation by distal landmarks in cued, directional, and place variants of the Morris water task.

Navigation depends on a network of neural systems that accurately monitor an animal's spatial orientation in an environment. Within this navigation system are head direction (HD) cells which discharge as a function of an animal's directional heading, providing an animal with a neural compass to guide ongoing spatial behavior. Experiments were designed to test this hypothesis by damaging the dorsal tegmental nucleus (DTN), a midbrain structure that plays a critical role in the generation of the rodent HD cell signal, and evaluating landmark based navigation using variants of the Morris water task.

Locally invasive dermal squamomelanocytic tumor with matrical differentiation: a peculiar case with review of the literature.

Dermal-based combined squamous and melanocytic neoplasms are emerging clinicopathologic entities that tend to appear on sun-exposed areas of elderly patients. The biologic behavior of such cutaneous neoplasms remains uncertain because of their rarity. Histopathologic differential includes the following diagnostic entities: (1) dermal squamomelanocytic tumor, (2) melanocytic matricoma, and (3) rare histologic variant of pilomatrical carcinoma, the so-called pilomatrical carcinoma with intralesional melanocytes.

Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling.

Tissue progenitor cells are an attractive target for regenerative therapy. In various organs, bone marrow cell (BMC) therapy has shown promising preliminary results, but to date no definite mechanism has been demonstrated to account for the observed benefit in organ regeneration. Tissue injury and regeneration is invariably accompanied by macrophage infiltration, but their influence upon the progenitor cells is incompletely understood, and direct signaling pathways may be obscured by the multiple roles of macrophages during organ injury.

The C-terminal domain of A1/Bfl-1 regulates its anti-inflammatory function in human endothelial cells.

A1/Bfl-1 is a NF-κB dependent, anti-apoptotic Bcl-2 family member that contains four Bcl-2 homology domains (BH) and an amphipathic C-terminal domain, and is expressed in endothelial cells (EC). Based on NF-κB reporter assays in bovine aortic EC, we have previously demonstrated that A1, like Bcl-2 and Bcl-xL, inhibits NF-κB activation. These results, however, do not fully translate when evaluating the cell's own NF-κB machinery in human EC overexpressing A1 by means of recombinant adenovirus (rAd.