A selective retinoid X receptor agonist bexarotene (Targretin) prevents and overcomes acquired paclitaxel (Taxol) resistance in human non-small cell lung cancer.

PURPOSE: Paclitaxel is an important anticancer agent for the treatment of non-small cell lung cancer (NSCLC). However, its use in cancer therapy is limited by development of acquired drug resistance. The goal of this study was to determine the effect of bexarotene on development of acquired paclitaxel resistance in NSCLC. EXPERIMENTAL DESIGN: Human NSCLC Calu3 cells were repeatedly treated in culture with intermittent paclitaxel alone or in combination with continuous bexarotene for 3 months. Thereafter, cells were isolated and characterized for their drug sensitivity in vitro and in vivo. RESULTS: Repeat exposure to paclitaxel alone resulted in development of paclitaxel resistance with cross-resistance to multidrug resistance P-glycoprotein substrates, whereas the bexarotene/paclitaxel combination prevented the development of drug resistance and the cells remained chemosensitive. Furthermore, paclitaxel resistance could be overcome when the resistant cells were treated with the combination regimen. Fluctuation analysis showed that treatment with bexarotene decreased the rate of spontaneous development of paclitaxel resistance. In vivo, the bexarotene/paclitaxel combination regimen produced a statistically significant decrease in tumor growth in a Calu3 NSCLC xenograft model compared with the single agents (two-tailed, P < 0.05). In addition, paclitaxel-resistant Calu3 tumors treated with the bexarotene/paclitaxel combination showed greater delay in tumor growth compared with those treated with paclitaxel alone. CONCLUSIONS: Our results suggest that bexarotene may offer a novel approach to prevent and overcome paclitaxel resistance in patients with NSCLC.     

Undifferentiated (embryonal) sarcoma of the liver: radiologic- pathologic correlation

Undifferentiated (embryonal) sarcoma (UES) is an uncommon malignant mesenchymal hepatic tumor that occurs in older children and young adults. Fourteen cases are correlated with radiologic and pathologic findings. Radiologic findings reflect the spectrum of solid to cystic appearances observed in the gross specimens. Sonography typically demonstrates a large mass that may be predominantly solid with many small anechoic spaces or may be cystic. Computed tomography reveals a hypodense mass with hyperdense septa of variable thickness and a dense peripheral rim corresponding to the fibrous pseudocapsule of the tumor. Angiographically, UES is usually hypovascular with tumoral vessels, although hypervascular and avascular patterns occur. Prognosis of UES is poor, with a median survival of less than 1 year. Radiologists should be familiar with this malignant tumor since it may present as a large cystic hepatic mass, suggestive of a benign lesion.     

Prevention and treatment of experimental estrogen receptor-negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl Ester and the rexinoid LG100268

PURPOSE: To test whether the triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) and the rexinoid LG100268 (268) prevent the formation of estrogen receptor (ER)-negative mammary tumors or either arrest the growth or cause regression of established tumors in MMTV-neu mice. EXPERIMENTAL DESIGN: For prevention, mice were fed control diet, CDDO-Me (60 mg/kg diet), 268 (20 mg/kg diet), or the combination for 45 weeks. For treatment, mice with established tumors at least 4 mm in diameter were fed control diet, CDDO-Me (100 mg/kg diet), 268 (60 mg/kg diet), or the combination for 4 weeks. RESULTS: CDDO-Me and 268 significantly delayed the development of ER-negative tumors, with a 14- and 24-week delay, respectively, compared with the control group for the time required to reach 50% tumor incidence. The combination of CDDO-Me and 268 was significantly more potent than the individual drugs, as only one tumor was found in the combination group, after 45 weeks on diet, at which time all control animals had tumors. Treating established tumors with CDDO-Me arrested the growth of 86% of the tumors, and 268 induced tumor regression in 85% of tumors. CDDO-Me and 268 target different signaling pathways and cell types. CDDO-Me inhibited constitutive STAT3 phosphorylation and the degradation of IKBalpha in ER-negative breast cancer cells, whereas 268 blocked IKBalpha degradation and the release of interleukin-6 in RAW264.7 macrophage-like cells, inhibited the ability of endothelial cells to organize into networks, and blocked angiogenesis in vivo. CONCLUSIONS: CDDO-Me and 268 are useful as individual drugs to prevent ER-negative mammary tumorigenesis and to treat established tumors. They synergize when used in combination for prevention.     

The retinoid X receptor-selective retinoid,LGD1069, prevents the development of estrogen receptor-negative mammary tumors in transgenic mice

Despite the effectiveness of the selective estrogen receptor (ER) modulators in preventing ER-positive breast cancer, chemopreventive agents still need to be developed for the prevention of ER-negative breast cancers. The naturally occurring retinoids are promising agents for the prevention of human cancers but are too toxic for long-term chronic use. We previously demonstrated that the chemopreventive effects of the retinoids could be separated from the toxicity by using an RXR-selective retinoid, LGD1069. The studies described here demonstrate that LGD1069 effectively suppresses ER-negative tumor development in mouse mammary tumor virus-erbB2 transgenic mice with minimal toxicity. These studies suggest that receptor-selective retinoids are promising agents for the prevention of breast cancer and that they may be particularly useful in preventing ER-negative breast cancer.     

The rexinoid, bexarotene, prevents the development of premalignant lesions in MMTV-erbB2 mice

Retinoids, vitamin A analogues that bind to retinoic acid receptor (RAR) or retinoid X receptor (RXR), play important roles in regulating cell proliferation, apoptosis, and differentiation. Recently, RXR-selective ligands, also referred to as rexinoids, have been investigated as potential chemopreventive agents for breast cancer. Our previous studies demonstrated that the rexinoid bexarotene significantly prevented ER-negative mammary tumourigenesis with less toxicity than naturally occurring retinoids in animal models. To determine whether bexarotene prevents cancer at the early stages during the multistage process of mammary carcinogenesis, we treated MMTV-erbB2 mice with bexarotene for 2 or 4 months. The development of preinvasive mammary lesions such as hyperplasias and carcinoma-in-situ was significantly inhibited. This inhibition was associated with reduced proliferation, but no induction of apoptosis. We also examined the regulation of a number of rexinoid-modulated genes including critical growth and cell cycle regulating genes using breast cell lines and mammary gland samples from mice treated with rexinoids. We showed that two of these genes (DHRS3 and DEC2) were modulated by bexarotene both in vitro and in vivo. Identification of these rexinoid-modulated genes will help us understand the mechanism by which rexinoid prevents cancer. Such rexinoid-regulated genes also represent potential biomarkers to assess the response of rexinoid treatment in clinical trials.     

The M694V mutation in Armenian‐Americans: a 10‐year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA

Familial Mediterranean fever (FMF), inherited in an autosomal recessive manner, is a systemic auto‐inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin‐encoding fever (MEFV) gene, located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian‐American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis.     

Motivations for Contributing to Health-Related Articles on Wikipedia: An Interview Study

BackgroundWikipedia is one of the most accessed sources of health information online. The current English-language Wikipedia contains more than 28,000 articles pertaining to health.ObjectiveThe aim was to characterize individuals’ motivations for contributing to health content on the English-language Wikipedia.MethodsA set of health-related articles were randomly selected and recent contributors invited to complete an online questionnaire and follow-up interview (by Skype, by email, or face-to-face). Interviews were transcribed and analyzed using thematic analysis and a realist grounded theory approach.ResultsA total of 32 Wikipedians (31 men) completed the questionnaire and 17 were interviewed. Those completing the questionnaire had a mean age of 39 (range 12-59) years; 16 had a postgraduate qualification, 10 had or were currently studying for an undergraduate qualification, 3 had no more than secondary education, and 3 were still in secondary education. In all, 15 were currently working in a health-related field (primarily clinicians). The median period for which they have been an active editing Wikipedia was 3-5 years. Of this group, 12 were in the United States, 6 were in the United Kingdom, 4 were in Canada, and the remainder from another 8 countries. Two-thirds spoke more than 1 language and 90% (29/32) were also active contributors in domains other than health. Wikipedians in this study were identified as health professionals, professionals with specific health interests, students, and individuals with health problems. Based on the interviews, their motivations for editing health-related content were summarized in 5 strongly interrelated categories: education (learning about subjects by editing articles), help (wanting to improve and maintain Wikipedia), responsibility (responsibility, often a professional responsibility, to provide good quality health information to readers), fulfillment (editing Wikipedia as a fun, relaxing, engaging, and rewarding activity), and positive attitude to Wikipedia (belief in the value of Wikipedia). An additional factor, hostility (from other contributors), was identified that negatively affected Wikipedians’ motivations.ConclusionsContributions to Wikipedia’s health-related content in this study were made by both health specialists and laypeople of varying editorial skills. Their motivations for contributing stem from an inherent drive based on values, standards, and beliefs. It became apparent that the community who most actively monitor and edit health-related articles is very small. Although some contributors correspond to a model of “knowledge philanthropists,” others were focused on maintaining articles (improving spelling and grammar, organization, and handling vandalism). There is a need for more people to be involved in Wikipedia’s health-related content.