Myocardial Infarction as a Complication of Bronchial Artery Embolization

CardioVascular and Interventional Radiology - Bronchial artery embolization is now a common treatment for massive pulmonary hemoptysis if flexible bronchoscopy at the bedside failed to control the...     

Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model

Disablement of cell death programs in cancer cells contributes to drug resistance and in some cases has been associated with altered translational control. As eukaryotic translation initiation factor 4E (eIF4E) cooperates with c-Myc during lymphomagenesis, induces drug resistance, and is a genetic modifier of the rapamycin response, we have investigated the effect of dysregulation of the ribosome recruitment phase of translation initiation on tumor progression and chemosensitivity. eIF4E is a subunit of eIF4F, a complex that stimulates ribosome recruitment during translation initiation by delivering the DEAD-box RNA helicase eIF4A to the 5' end of mRNAs. eIF4A is thought to prepare a ribosome landing pad on mRNA templates for incoming 40S ribosomes (and associated factors). Using small molecule screening, we found that cyclopenta[b]benzofuran flavaglines, a class of natural products, modulate eIF4A activity and inhibit translation initiation. One member of this class of compounds, silvestrol, was able to enhance chemosensitivity in a mouse lymphoma model in which carcinogenesis is driven by phosphatase and tensin homolog (PTEN) inactivation or elevated eIF4E levels. These results establish that targeting translation initiation can restore drug sensitivity in vivo and provide an approach to modulating chemosensitivity.     

Tissue stiffness regulates serine/arginine-rich protein-mediated splicing of the extra domain B-fibronectin isoform in tumors

Alternative splicing of proteins gives rise to different isoforms that play a crucial role in regulating several cellular processes. Notably, splicing profiles are altered in several cancer types, and these profiles are believed to be involved in driving the oncogenic process. Although the importance of alternative splicing alterations occurring during cancer is increasingly appreciated, the underlying regulatory mechanisms remain poorly understood. In this study, we use both biochemical and physical tools coupled with engineered models, patient samples, and a murine model to investigate the role of the mechanical properties of the tumor microenvironment in regulating the production of the extra domain-B (EDB) splice variant of fibronectin (FN), a hallmark of tumor angiogenesis. Specifically, we show that the amount of EDB-FN produced by endothelial cells increases with matrix stiffness both in vitro and within mouse mammary tumors. Matrix stiffness regulates splicing through the activation of serine/arginine rich (SR) proteins, the splicing factors involved in the production of FN isoforms. Activation of the SR proteins by matrix stiffness and the subsequent production of EDB-FN are dependent on intracellular contractility and PI3K-AKT signaling. Notably, matrix stiffness-mediated splicing is not limited to EDB-FN, but also affects splicing in the production of PKC βII and the VEGF 165b splice variant. Together, these results demonstrate that the mechanical properties of the microenvironment regulate alternative splicing and establish a previously unidentified mechanism by which cells can adapt to their microenvironment.Differential expression of protein isoforms through alternative splicing is a key element to generating protein diversity and can result in widely different cell phenotypes and behaviors (1–3). Interestingly, tumors exhibit several major differences in protein isoform expression patterns compared with healthy tissue (2, 4), and some of these changes are thought to favor oncogenesis (1). Notably, splicing events are regulated at the pre-mRNA level by splicing regulatory factors that include a family of serine/arginine rich (SR) proteins (5). Elevated SR protein levels have been associated with cancer (5); however, the physiological cues that drive splicing are not well defined.Among the various alternatively spliced proteins present in tumors, the splice variant of fibronectin (FN) that includes the extra domain-B (EDB) type III repeat has been of particular interest in the cancer community because inclusion of the EDB fragment has been proposed as a way to identify and target tumor vasculature (6). EDB-FN is produced by endothelial cells (ECs) in tumors and may favor angiogenesis (7–9). Splicing of FN is regulated by several SR proteins, including SRp40 and SRp20, in several different cell types (10–12). Although the presence of EDB-FN is fairly unique to tumor vasculature, the mechanisms governing its expression within the tumor microenvironment are not clear.The splicing activity of SR proteins that leads to the expression of various protein isoforms including EDB-FN is tightly regulated by phosphorylation (13–15), and this phosphorylation has been shown to be mediated by AKT (14, 16). Interestingly, matrix stiffness can regulate AKT phosphorylation state (17–19). More specifically, recent data indicate that AKT activation and downstream phosphorylation of AKT substrates can occur through changes in the mechanical properties of the tissue in the tumor microenvironment (17). Importantly, tumor tissue stiffens during cancer due to increased collagen deposition and the action of cell-secreted enzymes that cross-link collagen fibrils (20, 21), and this stiffening is believed to be correlated with tumor aggressiveness and metastatic potential (18, 22–25). Elevated extracellular matrix (ECM) stiffness affects several cell behaviors associated with tumors including enhanced cell contractility, response to growth factors, and cell migration (18, 22, 24, 26, 27). Although stiffness has been shown to drive greater AKT activation, AKT activity drives SR protein phosphorylation, and SR proteins mediate splicing, it has not yet been determined whether stiffness-driven signaling can result in SR protein-mediated splicing events during tumorigenesis.In this study, we used a multidisciplinary approach, with in vitro and in vivo models and biochemical and physical tools, to study the relationship between matrix stiffness and FN splicing in ECs. Here, we demonstrate, for the first time to our knowledge, that EDB-FN expression increases with matrix stiffness, both in vitro and in mouse mammary tumors. Our data indicate that matrix stiffness regulates the dynamics of EDB-FN splicing through Rho-associated protein kinase (ROCK) mediated contractility and downstream SR protein phosphorylation. Moreover, phosphorylation of SR proteins correlates with in vivo PI3K/AKT pathway activity in response to tissue stiffness, whereas in vitro inhibition of PI3K prevents SR protein phosphorylation and EDB-FN splicing. Taken together, our data show, for the first time to our knowledge, that the stiffness of the tumor microenvironment modulates intracellular splicing events.     

Electrocardiography for diagnosis and control of efficacy of oral quinidine sulfate in a case of atrial fibrillation in a Holstein cow

Atrial fibrillation and its treatment in a five year old purebred Holstein cow was explored with electrocardiography. Conversion of atrial fibrillation to a normal sinus rhythm was accomplished with the oral administration of a cumulated total of 125 gm of quinidine sulfate over a period of five days.     

Azobenzene residues from aniline-based herbicides; Evidence for labile intermediates

Summary Formation of asymmetric azobenzenes from variously substituted aniline pairs in soil and by peroxidase pointed to the existence of labile intermediates. These were tentatively identified as the respective phenylhydroxylamines.     

Pharmacoeconomics of Systemic Therapies for Lung Cancer

The purpose of this article is to review the economics of systemic therapies for the treatment of lung cancer. Lung cancer treatment is moderately expensive. The overall cost to society is significant given its high incidence. Most analyses in patients with small cell lung cancer focus on supportive care measures. The economics of chemotherapy in patients with advanced small cell lung cancer, as assessed in one study, shows alternating chemotherapy to be cost effective. Numerous economic analyses of chemotherapy in patients with non-small cell lung cancer (NSCLC) have been completed using varying methodologies in a number of countries. In patients with advanced NSCLC, third generation chemotherapy in the first-line setting can be administered within reasonable incremental cost effectiveness. Single-agent docetaxel chemotherapy in the second-line setting has also been shown to fall within a reasonable cost-effective range. Based on this review, systemic therapies for lung cancer are, for the most part, cost effective. Information on the cost-utility of systemic therapies is more limited. In a population of cancer patients with poor prognosis, the inclusion of quality indicators in the calculation of costs (i.e. cost-utility analyses) will be of great importance to refine our understanding of costs and benefits using a more global approach. Future economic analyses of adjuvant chemotherapy and novel targeted therapies will be of great interest.     

Cut-off phenomenon in the protective effect of alcohols against lysophosphatidylcholine-induced calcium overload

We studied the effect of chain length on the protective effect of alcohols against lysophosphatidylcholine (LPC)-induced Ca²⁺ overload in neonatal rat cardiomyocytes. We previously found that ethanol retards Ca²⁺ elevation. Cells were loaded with the Ca²⁺-sensitive fluorophore fura-2, and changes in fluorescence were followed. The addition of 10 M LPC increased Ca²⁺, which reached a plateau after an 8–10 min delay. The presence of 88 mM n-propanol, n-butanol, tert-butanol, or 2,2-dimethylpropanol significantly increased the delay by 94–213%. However, n-pentanol at 2 mM or 88 mM had no protective effect. Among n-alcohols, the increase in lag time was inversely proportional to the length of the carbon chain. Chain length, rather than molecular weight determines the effect, because 2,2-dimethylpropanol had a protective effect. The influence of alcohols on LPC micelle formation was estimated from the increase in octadecyl rhodamine B fluorescence; the increase by n-alcohols was directly proportional to chain length, indicating that micelle formation was not involved in the extension of lag time. The absence of the protective effect when the alcohol aliphatic chain exceeds four carbons suggests that the effect of ethanol may be mediated via a small lipophilic pocket on a protein, or to lateral pressure perturbation in the membrane.