Nm23 and breast cancer metastasis

Summary The majority of breast cancer patients succumb to metastatic disease. We summarize published and recent research concerning thenm23 gene in breast cancer metastasis. In a murine developmental study, nm23 expression increased with the functional differentiation of the mammary gland in nulliparous and pregnant animals. In human breast cancer, five studies have now demonstrated a significant association between reduced nm23 expression, at the RNA or protein levels, and aggressive tumor behavior. Nm23-negative tumor cells have been observed in comedo ductal carcinoma in situ lesions in two independent studies, indicating that decreases innm23 expression begin prior to actual histologically identifiable invasion. Transfection studies, in which humannm23-H1 cDNA was expressed in the metastatic human MDA-MB-435 breast carcinoma cell line, indicate thatnm23-H1 suppresses in vivo metastatic potential by 50-90%. Finally, our data in melanoma and breast carcinoma transfection systems suggest that the biochemical mechanism of nm23 suppressive activity is likely not due to its nucleoside diphosphate kinase activity, association with GAP proteins, or secretion from cells.Supported by an educational grant from CIBA-GEIGY Corp., at the San Antonio Breast Cancer Symposium, Dec. 8, 1992.     

Genetic analysis of breast cancer progression

At the histological level, breast tumors display a variety of morphologic lesions which suggest the existence of an increasingly aberrant pathway of intermediate steps leading to the invasive primary tumor and its metastatic dissemination. In order to obtain direct evidence for this presumed progression, underlying genetic changes must be identified. Analyses of primary breast tumors have revealed a large number of dominant and recessive gene alterations encompassing several cellular attributes and activities. It is quite likely that some of these alterations are of a causal nature and thus enable the tumor to attain distinctive malignant phenotypes, such as, dysregulated proliferation, invasion, angiogenesis, and ability to metastasize. Considerable heterogeneity has been observed in the sequence of acquisition of these genetic changes, which is substantiated by recent comparative analyses between carefully microdissected preinvasive and invasive tumor. The data are evaluated here in the context of existing models of breast cancer progression. Implications and prospects for translational application to the clinic are also discussed.     

Modeling cystic fibrosis disease progression in patients with the rare CFTR mutation P67L

Background

The progression of cystic fibrosis (CF) in patients with the rare mutation P67L was examined to determine if it induced a milder form of CF compared to the common severe ΔF508 mutation.

Use of FEV1 in cystic fibrosis epidemiologic studies and clinical trials: A statistical perspective for the clinical researcher

Background

Forced expiratory volume in 1 s (FEV₁) is an established marker of cystic fibrosis (CF) disease progression that is used to capture clinical course and evaluate therapeutic efficacy. The research community has established FEV₁ surveillance data through a variety of observational data sources such as patient registries, and there is a growing pipeline of new CF therapies demonstrated to be efficacious in clinical trials by establishing improvements in FEV₁.

Alkaline phosphatase velocity predicts overall survival and bone metastasis in patients with castration-resistant prostate cancer

Introduction and objectives

Identifying patients with prostate cancer (CaP) who will ultimately develop bone metastasis (BM) or die of disease is essential. Alkaline phosphatase velocity (APV) has been shown to predict overall survival (OS) and bone metastasis–free survival (BMFS) in an earlier study of an equal access military patient cohort of patients with castrate-resistant prostate cancer (CRPC). To confirm these findings, we examined a cohort of patients from a high-volume cancer center to validate a previous observation that faster alkaline phosphatase (AP) kinetics are predictive of OS and BMFS in this second cohort of patients.

Liposomal doxorubicin: Effective treatment for pediatric desmoid fibromatosis

Efficacy of liposomal doxorubicin (LD) in treating desmoid fibromatosis (DF) in children has not been well evaluated. This retrospective case series examines five children with progressive DF, treated with LD. We report progression‐free intervals (PFIs) and radiographic as well as clinical responses for each medication received. LD was well tolerated, with an average 4.5% reduction in tumor size and median PFI of 29 months. Treatment with LD conferred the longest PFI of all medical therapies pursued. Thus, LD is an important treatment option for DF in pediatrics.     

Comparative effectiveness of interferons in relapsing–remitting multiple sclerosis: a meta-analysis of real-world studies

Background: Differences between interferons have been evaluated for over 20 years. While randomized controlled trial (RCT) data is mainly used for assessments and strong data for causal inferences, it does not necessarily reflect everyday practice. Real-world data may provide additional information.

Purpose: To assess the results, quality, and representativeness of observational studies directly comparing interferons (IFNs) in RRMS.

Methods: Medline and Embase were searched for observational studies comparing IFN-beta-1a 30?mcg IM (Avonex¹), IFN-beta-1a 44?mcg SC (Rebif²) and/or IFN-beta-1b 250?mcg SC (Betaseron³). Outcomes included annualized relapse rate (ARR), proportions relapse free, confirmed progression free, treatment persistence, and neutralizing antibodies rates (NABs) measured up to 5 years of treatment. Data was combined using random effects meta-analyses. Categorical values were analyzed using chi-squared and Mann–Whitney tests.

Results: Thirty-six studies examining 32,026 patients (72.5% females, age?=?39.2?±?3.7 years, disease duration?=?5.6?±?2.0 years) were identified. Thirty-three studies investigated IFN-beta-1a IM (N?=?11,925), 30 IFN-beta-1a SC (N?=?10,684) and 34 IFN-beta-1b SC (N?=?9417). Baseline ARRs were similar (1.37?±?0.35, 1.51?±?0.27 and 1.55?±?0.23, respectively; P?=?.101) as were EDSS scores (2.24?±?0.39, 2.33?±?0.30, 2.55?±?0.38; P?=?.070) and >75% were naïve to IFNs. On treatment, ARRs were comparable (IFN-beta-1a IM 0.52?±?0.27, IFN-beta-1a SC 0.51?±?0.24, IFN-beta-1b SC 0.55?±?0.23; P?=?.595). Proportions of relapse-free patients were similar between drugs (P?>?.05 for all data points), except that IFN-beta-1a SC was superior to IFN-beta-1b SC in years 3–5 (all P?≤?.001). After 1 year, EDSS scores were comparable; after 2 years, IFN-beta-1a IM and IFN-beta-1a SC incurred less disease progression than IFN-beta-1b SC (P?progression-free rates and persistence were similar over 5 years. Fewer patients developed NABs with IFN-beta-1a IM (4.7?±?1.5%) versus IFN-beta-1a SC (21.4?±?2.8%) (P?P?Conclusions: In this comprehensive meta-analysis of real-world studies in RRMS, IFN-beta-1a IM, IFN-beta-1a SC and IFN-beta-1b SC had similar clinical profiles. When selecting an IFN, practitioners should consider observational data in their decision making process.     

Autophagy function and its relationship to pathology,clinical applications,drug metabolism and toxicity

Autophagy is a cellular process that facilitates nutrient turnover and removal of expended macromolecules and organelles to maintain homeostasis. The recycling of cytosolic macromolecules and damaged organelles by autophagosomes occurs through the lysosomal degradation pathway. Autophagy can also be upregulated as a prosurvival pathway in response to stress stimuli such as starvation, hypoxia or cell damage. Over the last two decades, there has been a surge in research revealing the basic molecular mechanisms of autophagy in mammalian cells. A corollary of an advanced understanding of autophagy has been a concurrent expansion of research into understanding autophagic function and dysfunction in pathology. Recent studies have revealed a pivotal role for autophagy in drug toxicity, and for utilizing autophagic components as diagnostic markers and therapeutic targets in treating disease and cancer. In this review, advances in understanding the molecular basis of mammalian autophagy, methods used to induce and evaluate autophagy, and the diverse interactions between autophagy and drug toxicity, disease progression and carcinogenesis are discussed. Copyright © 2016 John Wiley & Sons, Ltd.