The NF-B family mediates immune and inflammatory responses. In many cancers, NF-B is constitutively activated and induces the expression of genes that facilitate tumorigenesis. ING4 is a tumor suppressor that is absent or mutated in several cancers. Herein, we demonstrate that in human gliomas, NF-B is constitutively activated, ING4 expression is negligible, and NF-B-regulated gene expression is elevated. We demonstrate that an ING4 and NF-B interaction exists but does not prevent NF-B activation, nuclear translocation, or DNA binding. Instead, ING4 and NF-B bind simultaneously at NF-B-regulated promoters, and this binding correlates with reductions in p65 phosphorylation, p300, and the levels of acetylated histones and H3-Me3K4, while enhancing the levels of HDAC-1 at these promoters. Using a knockdown approach, we correlate reductions in ING4 protein levels with increased basal and inducible NF-B target gene expression. Collectively, these data suggest that ING4 may specifically regulate the activity of NF-B molecules that are bound to target gene promoters.
Downregulation of microRNA-34a by Myc is known to be essential for tumorigenesis and improve tumor-cell survival. Conversely, upregulation of miR-34a by p53 is thought to enhance its acetylation and activity and contribute to the pro-apoptotic effects of this tumor suppressor. We sought to determine whether restoration of miR-34a levels in B-lymphoid cells with Myc overexpression would aid therapeutic apoptosis. Unexpectedly, delivery of miR-34a, which doesn’t target p53 directly, severely compromised steady-state p53 levels. This effect was preceded and mediated by direct targeting of Myc, which sustained p53 protein levels via the Arf–Hdm2 pathway. As a result, in the presence of Myc, miR-34a inhibited p53-dependent bortezomib-induced apoptosis as efficiently as anti-p53 small interfering RNA. Conversely, inhibition of miR-34a using antisense RNA sensitized lymphoma cells to therapeutic apoptosis. Thus, in tumors with deregulated Myc expression, miR-34a confers drug resistance and could be considered a therapeutic target.
Canine melanomas and mast cell tumours (MCTs) frequently metastasize to lymph nodes, worsening prognosis compared with dogs without metastasis. Sentinel lymph node (SLN) evaluation is more specific than evaluation of the lymph node closest to the tumour, which may not be the draining lymph node. Computed tomography lymphangiography (CTL) allows for SLN identification and one study of canine mammary tumours found that CTL was able to assist in determination of the metastatic status of inguinal SLNs prior to extirpation and histopathology. The objective of the present study was to evaluate CTL for use in determining metastasis to the SLN in dogs with a pre-operative diagnosis of melanoma or MCT in various locations by correlating CTL findings with histopathology. The hypothesis was that CTL would not be able to determine the metastatic status of lymph nodes, based on author experience. Dogs were prospectively enrolled and underwent CTL and subsequent SLN extirpation. Histopathology results for the primary tumour, SLN, and additional extirpated lymph nodes were recorded. Fifteen dogs were enrolled and 21 SLN were evaluated. The SLN enhancement pattern (heterogeneous, homogenous or peripheral) was not associated with metastasis, nor was the attenuation value at 1 minute, 5 minutes, or the change in attenuation value. No correlation was found between CTL findings and metastatic status of SLNs. Based on these results, CTL alone cannot be used to diagnose SLN metastasis. Extirpation of the SLN with histopathology is recommended to diagnose lymph node metastasis in dogs with melanoma and MCT.
The stage classification for canine primary pulmonary carcinomas (PPC) was last updated in 1980. In people, the human lung cancer stage classification (HLCSC) (currently in its eighth edition) plays an integral role in diagnostic and therapeutic decision-making and is prognostic despite a heterogeneous population of tumours. The objective of this retrospective case study was to evaluate the prognostic significance of a canine lung carcinoma stage classification (CLCSC) adapted from the HLCSC by removal of substage for ease of application to canine PPC. A secondary objective was to evaluate the effect of adjuvant chemotherapy. Medical records of 71 dogs with histologically confirmed PPC were reviewed. All dogs underwent surgical excision of the primary lung tumour. Primary tumour features (referring to T1-T4 stages) and TNM stages (1-4) were assigned using the CLCSC. Canine lung carcinoma stage was I (n = 7), II (n = 32), III (n = 24) and IV (n = 8). Median survival time was 952, 658, 158 and 52 days for stages I-IV, respectively. Primary tumour features (T1-T4), incomplete surgical excision, presence of lymph node metastasis and tumour grade were independent prognostic indicators for overall survival. Twenty-six dogs received adjuvant chemotherapy; however, no statistically significant benefit was found. The CLCSC primary tumour features and stage classification were highly prognostic for survival in dogs with PPC. We propose further application and evaluation of this update to canine PPC stage classification. Given the poor prognosis of advanced stage canine PPC, novel treatments are needed.
Efficacious therapies for measurable metastatic canine osteosarcoma (OSA) are generally lacking. Preliminary retrospective studies suggested that approximately 50% of dogs with measurable metastatic OSA experienced clinical benefit (objective response or clinically meaningful disease stabilisation) following toceranib (TOC) treatment. The purpose of this clinical trial was to prospectively evaluate the clinical outcome following TOC treatment in dogs with measurable pulmonary metastatic OSA. A secondary goal was to identify potential biomarkers of clinical benefit by measuring changes in plasma vascular endothelial growth factor (VEGF) and circulating regulatory T-cell (Treg) percentage. Twenty-two dogs with pulmonary metastasis from appendicular OSA having undergone previous amputation were treated prospectively with TOC. Adverse events (AEs) were common but predominantly low grade. Nine patients were withdrawn from the study prior to the week 8 assessment of response either due to progressive disease (PD), decreased quality of life or owner perceived unacceptable AEs. Of the patients evaluable for disease progression at week 8 (or earlier), 3/17 (17.6 %) had stable disease with the remainder having PD. The median progression-free survival time for all patients was 57 days (range 7-176 days) with a median overall survival time of 89 days (range 7-574 days). Plasma VEGF concentrations were significantly elevated in patients after 4 weeks of TOC treatment, but no changes were observed in percentage of Treg in peripheral blood. Overall, the results of this clinical trial do not support the use of TOC as single agent therapy for canine metastatic OSA.
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