Melanoma-Derived Extracellular Vesicles Induce CD36-Mediated Pre-Metastatic Niche.

CD36 expression in both immune and non-immune cells is known to be directly involved in cancer metastasis. Extracellular vesicles (EVs) secreted by malignant melanocytes play a vital role in developing tumor-promoting microenvironments, but it is unclear whether this is mediated through CD36. To understand the role of CD36 in melanoma, we first analyzed the SKCM dataset for clinical prognosis, evaluated the percentage of CD36 in lymphatic fluid-derived EVs (LEVs), and tested whether melanoma-derived EVs increase CD36 expression and induce M2-macrophage-like characteristics.

Carcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma: a phase 1 trial.

Measles virus (MV) vaccine strains have shown significant preclinical antitumor activity against glioblastoma (GBM), the most lethal glioma histology. In this first in human trial (NCT00390299), a carcinoembryonic antigen-expressing oncolytic measles virus derivative (MV-CEA), was administered in recurrent GBM patients either at the resection cavity (Group A), or, intratumorally on day 1, followed by a second dose administered in the resection cavity after tumor resection on day 5 (Group B). A total of 22 patients received study treatment, 9 in Group A and 13 in Group B.

Host immunity and KLF 11 deficiency together promote fibrosis in a mouse model of endometriosis.

Background: Endometriosis is a debilitating disease typically characterized by prolific fibrotic scarring. Earlier we reported downregulation of two transcription factors belonging TGF-βR signaling pathway Sp/Krüppel-like factor 11 (KLF11) and 10 (KLF10) in human endometriosis lesions. Here we investigated the role of these nuclear factors and immunity in the scaring fibrosis associated with endometriosis.

Quantitative spatial evaluation of tumor-immune interactions in the immunotherapy setting of metastatic melanoma lymph nodes.

Introduction: Immune cell infiltration into the tumor microenvironment is generally associated with favorable clinical outcomes in solid tumors. However, the dynamic interplay among distinct immune cell subsets within the tumor-immune microenvironment as it relates to clinical responses to immunotherapy remains unresolved. In this study, we applied multiplex immunofluorescence (MxIF) to spatially characterize tumor-immune interactions within the metastatic melanoma lymph node.

Are Baseball Statistics an Appropriate Tool for Assessing Return to Play in Injured Pitchers? Analysis of Statistical Variability in Healthy Players.

Background: Basic pitcher statistics have been used to assess performance in pitchers after injury or surgery without being validated. Even among healthy pitchers, the normal variability of these parameters has not yet been established.

Purpose: To determine (1) the normal variability of basic and advanced pitcher statistics in healthy professional baseball pitchers and (2) the minimum pitches needed to predict these parameters.

Cancer immune control dynamics: a clinical data driven model of systemic immunity in patients with metastatic melanoma.

Background: Recent clinical advances in cancer immuno-therapeutics underscore the need for improved understanding of the complex relationship between cancer and the multiple, multi-functional, inter-dependent, cellular and humoral mediators/regulators of the human immune system. This interdisciplinary effort exploits engineering analysis methods utilized to investigate anomalous physical system behaviors to explore immune system behaviors. Cancer Immune Control Dynamics (CICD), a systems analysis approach, attempts to identify differences between systemic immune homeostasis of 27 healthy volunteers versus 14 patients with metastatic malignant melanoma based on daily serial measurements of conventional peripheral blood biomarkers (15 cell subsets, 35 cytokines).

Intratumoral Injection of -NT Spores in Patients with Treatment-refractory Advanced Solid Tumors.

Purpose: Intratumorally injected -NT (nontoxic; lacking the alpha toxin), an attenuated strain of , replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation.

Patients And Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of -NT across 6 dose cohorts (1 × 10 to 3 × 10 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose.

Results: Among 24 patients, a single intratumoral injection of -NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses.

Upregulation of HLA-Class I and II in Placentas Diagnosed with Villitis of Unknown Etiology.

The placenta utilizes many mechanisms to protect the haploidentical fetus from recognition by the maternal immune system. However, in cases of villitis of unknown etiology (VUE), maternal lymphocytes gain access into the placenta, causing significant health risks for the fetus. Evidence suggests that VUE is a rejection response between the mother and the haploidentical fetus.

Frequency of Gestational Diabetes Mellitus Reappearance or Absence during the Second Pregnancy of Women Treated at Mayo Clinic between 2013 and 2018.

The Center for Disease Control and Prevention ranks diabetes mellitus (DM) as the seventh leading cause of death in the USA. The most prevalent forms of DM include Type 2 DM, Type 1 DM, and gestational diabetes mellitus (GDM). While the acute problem of diabetic hyperglycemia can be clinically managed through dietary control and lifestyle changes or pharmacological intervention with oral medications or insulin, long-term complications of the disease are associated with significant morbidity and mortality.

Understanding heterogeneous tumor microenvironment in metastatic melanoma.

A systemic analysis of the tumor-immune interactions within the heterogeneous tumor microenvironment is of particular importance for understanding the antitumor immune response. We used multiplexed immunofluorescence to elucidate cellular spatial interactions and T-cell infiltrations in metastatic melanoma tumor microenvironment. We developed two novel computational approaches that enable infiltration clustering and single cell analysis-cell aggregate algorithm and cell neighborhood analysis algorithm-to reveal and to compare the spatial distribution of various immune cells relative to tumor cell in sub-anatomic tumor microenvironment areas.

NOTCH3 expression is linked to breast cancer seeding and distant metastasis.

Background: Development of distant metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which includes dissemination of cancer cells from the primary tumor to secondary organs. NOTCH developmental signaling plays a critical role in promoting epithelial-to-mesenchymal transition, tumor stemness, and metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive.

Constitutive Interferon Pathway Activation in Tumors as an Efficacy Determinant Following Oncolytic Virotherapy.

Background: Attenuated measles virus (MV) strains are promising agents currently being tested against solid tumors or hematologic malignancies in ongoing phase I and II clinical trials; factors determining oncolytic virotherapy success remain poorly understood, however.

Methods: We performed RNA sequencing and gene set enrichment analysis to identify pathways differentially activated in MV-resistant (n = 3) and -permissive (n = 2) tumors derived from resected human glioblastoma (GBM) specimens and propagated as xenografts (PDX). Using a unique gene signature we identified, we generated a diagonal linear discriminant analysis (DLDA) classification algorithm to predict MV responders and nonresponders, which was validated in additional randomly selected GBM and ovarian cancer PDX and 10 GBM patients treated with MV in a phase I trial.

CD206-positive myeloid cells bind galectin-9 and promote a tumor-supportive microenvironment.

In patients with metastatic melanoma, high blood levels of galectin-9 are correlated with worse overall survival and a bias towards a Th2 inflammatory state supportive of tumor growth. Although galectin-9 signaling through TIM3 on T cells has been described, less is known about the interaction of galectin-9 with macrophages. We aimed to determine whether galectin-9 is a binding partner of CD206 on macrophages and whether the result of this interaction is tumor-supportive.

Survival of cutaneous melanoma based on sex, age, and stage in the United States, 1992-2011.

Women diagnosed with cutaneous melanoma have a survival advantage compared to men, which has been hypothesized to be due to difference in behavior and/or biology (sex hormones). It remains controversial whether this advantage is dependent on age or stage of disease. We sought to compare melanoma-specific survival between females in pre, peri, and postmenopausal age groups to males in the same age group, adjusting for stage of disease.

Effect of the lymphocyte-to-monocyte ratio on the clinical outcome of chemotherapy administration in advanced melanoma patients.

Skin cancer affects more individuals in the USA than any other malignancy and malignant melanoma is particularly deadly because of its metastatic potential. Melanoma has been recognized as one of the most immunogenic malignancies; therefore, understanding the mechanisms of tumor-immune interaction is key for developing more efficient treatments. As the tumor microenvironment shows an immunosuppressive action, immunotherapeutic agents promoting endogenous immune response to cancer have been tested (interleukin-2, anticytotoxic-T-lymphocyte-associated antigen 4, and antiprogrammed cell death protein 1 monoclonal antibodies) as well as combinations of cytotoxic chemotherapy agents and inhibitors of angiogenesis (taxol/carboplatin/avastin).

Galectin-9 modulates immunity by promoting Th2/M2 differentiation and impacts survival in patients with metastatic melanoma.

Galectin-9, a β-galactoside-binding protein, is defined as a negative regulator of T helper 1 (Th1) immune responses, favoring Th2 bias. Systemic immunity in patients with metastatic melanoma is predominantly Th2 biased. We hypothesized that galectin-9 can modulate systemic immunity toward Th2 polarization in patients with advanced melanoma.

The synovial microenvironment of osteoarthritic joints alters RNA-seq expression profiles of human primary articular chondrocytes.

Osteoarthritis (OA) is a disabling degenerative joint disease that prompts pain and has limited treatment options. To permit early diagnosis and treatment of OA, a high resolution mechanistic understanding of human chondrocytes in normal and diseased states is necessary. In this study, we assessed the biological effects of OA-related changes in the synovial microenvironment on chondrocytes embedded within anatomically intact cartilage from joints with different pathological grades by next generation RNA-sequencing (RNA-seq).

Epigenetic Studies Point to DNA Replication/Repair Genes as a Basis for the Heritable Nature of Long Term Complications in Diabetes.

Metabolic memory (MM) is defined as the persistence of diabetic (DM) complications even after glycemic control is pharmacologically achieved. Using a zebrafish diabetic model that induces a MM state, we previously reported that, in this model, tissue dysfunction was of a heritable nature based on cell proliferation studies in limb tissue and this correlated with epigenetic DNA methylation changes that paralleled alterations in gene expression. In the current study, control, DM, and MM excised fin tissues were further analyzed by MeDIP sequencing and microarray techniques.

Evidence of Th2 polarization of the sentinel lymph node (SLN) in melanoma.

Melanoma has a propensity for lymphatogenous metastasis. Improved understanding of the sentinel lymph node (SLN) immunological environment may improve outcomes. The immune phenotype of fresh melanoma SLNs ( = 13) were compared to fresh control lymph nodes ( = 13) using flow cytometry.

Use of zebrafish as a model to investigate the role of epigenetics in propagating the secondary complications observed in diabetes mellitus.

Diabetes mellitus (DM) is classified as a disease of metabolic dysregulation predicted to affect over 400 million individuals world-wide by 2030. The debilitating aspects of this disease are the long term complications involving microvascular and macrovascular pathologies. These long term complications are related to the clinical phenomenon of metabolic memory (MM) that is defined as the persistence of diabetic complications even after glycemic control has been pharmacologically achieved.

Subfractionation, characterization, and in-depth proteomic analysis of glomerular membrane vesicles in human urine.

Urinary exosome-like vesicles (ELVs) are a heterogenous mixture (diameter 40-200 nm) containing vesicles shed from all segments of the nephron including glomerular podocytes. Contamination with Tamm-Horsfall protein (THP) oligomers has hampered their isolation and proteomic analysis. Here we improved ELV isolation protocols employing density centrifugation to remove THP and albumin, and isolated a glomerular membranous vesicle (GMV)-enriched subfraction from 7 individuals identifying 1830 proteins and in 3 patients with glomerular disease identifying 5657 unique proteins.

The immunomodulatory effects of bevacizumab on systemic immunity in patients with metastatic melanoma.

Metastatic melanoma is near-to-invariably a fatal disease. As novel therapeutic strategies against metastatic melanoma are urgently needed, we have tested a combinatorial regimen consisting of conventional chemotherapy coupled to bevacizumab, a monoclonal antibody that inhibit angiogenesis, demonstrating some clinical benefit. A preliminary assessment of one of our clinical trials points to a previously unrecognized immunomodulatory effect of bevacizumab.

Inhibition of Cdk2 activity decreases Aurora-A kinase centrosomal localization and prevents centrosome amplification in breast cancer cells.

Centrosome amplification plays a key role in the origin of chromosomal instability (CIN) during cancer development and progression. In this study, MCF-7 breast cancer cell lines harboring abrogated p53 function (vMCF-7DNp53) were employed to investigate the relationship between induction of genotoxic stress, activation of cyclin-A/Cdk2 and Aurora-A oncogenic signalings and development of centrosome amplification. Introduction of genotoxic stress in the vMCF-7DNp53 cell line by treatment with hydroxyurea (HU) induced centrosome amplification that was mechanistically linked to Aurora-A kinase activity.