Citations

Abstract We recently showed that atypical protein kinase Cι (PKCι) is required for transformed growth of human non–small-cell lung cancer (NSCLC) cells by activating Rac1. Genetic disruption of PKCι signaling blocks Rac1 activity and transformed growth, indicating that PKCι is a viable target for development of novel therapeutics for NSCLC. Here, we designed and implemented a novel fluorescence resonance energy transfer–based assay to identify inhibitors of oncogenic PKCι signaling. This assay was used to identify compounds that disrupt the interaction between PKCι and its downstream effector Par6, which links PKCι to Rac1. We identified aurothioglucose (ATG), a gold compound used clinically to treat rheumatoid arthritis, and the related compound, aurothiomalate (ATM), as potent inhibitors of PKCι-Par6 interactions in vitro (IC50 ∼1 μmol/L). ATG blocks PKCι-dependent signaling to Rac1 and inhibits transformed growth of NSCLC cells. ATG-mediated inhibition of transformation is relieved by expression of constitutively active Rac1, consistent with a mechanism at the level of the interaction between PKCι and Par6. ATG inhibits A549 cell tumor growth in nude mice, showing efficacy against NSCLC in a relevant preclinical model. Our data show the utility of targeting protein-protein interactions involving PKCι for antitumor drug development and provide proof of concept that chemical disruption of PKCι signaling can be an effective treatment for NSCLC. ATG and ATM will be useful reagents for studying PKCι function in transformation and represent promising new agents for the clinical treatment of NSCLC. (Cancer Res 2006; 66(3): 1767-74)

Abstract The ability of cancers to evade immune surveillance and resist immunotherapy raises a fundamental question of how tumor cells survive in the presence of a competent immune system. Studies to address this question have primarily focused on mechanisms by which tumor cells avoid recognition by or induce tolerance in the immune system. However, little is known about whether cancer cells also acquire an intrinsic ability to resist killing by immune effectors. We find that cancer cells enhance their ability to withstand an attack by cytotoxic immune effector cells via acquisition of specific genetic alterations that interfere with the shared mitochondrial death signaling pathway entrained by granzyme B, IFN-γ, and Apo2 ligand/tumor necrosis factor–related apoptosis inducing ligand (Apo2L/TRAIL), three key mediators of immunologic cell–mediated cytotoxicity. We show that the coexistence of specific mitochondrial signaling defects (either deletion of Bax, overexpression of Bcl-xL, or deletion of Smac) with expression of X-linked inhibitor of apoptosis protein decreases the sensitivity of cancer cells to IFN-γ/Apo2L/TRAIL– or granzyme B–induced apoptosis, lymphocyte-mediated cytotoxicity in vitro, and adoptive cellular immunotherapy in vivo. Conversely, negating X-linked inhibitor of apoptosis protein expression or function in tumor cells with defective mitochondrial signaling enables direct activation of caspase-3/-7 by granzyme B or Apo2L/TRAIL, and restores their susceptibility to immunologic cytotoxicity. These findings identify an important mechanism by which cancers evade elimination by immune effector cells and suggest that cancer immunotherapy might be improved by concurrent strategies to alleviate or circumvent the intrinsic mitochondrial death signaling defects that help cancer cells resist immunologic cytotoxicity. (Cancer Res 2006; 66(3): 1730-9)

Abstract Lapatinib (GW572016) is a selective inhibitor of both epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases. Here, we explore the therapeutic potential of lapatinib by testing its effect on tumor cell growth in a panel of 31 characterized human breast cancer cell lines, including trastuzumab-conditioned HER-2-positive cell lines. We further characterize its activity in combination with trastuzumab and analyze whether EGFR and HER-2 expression or changes induced in the activation of EGFR, HER-2, Raf, AKT, or extracellular signal-regulated kinase (ERK) are markers of drug activity. We report that concentration-dependent antiproliferative effects of lapatinib were seen in all breast cancer cell lines tested but varied significantly between individual cell lines with up to 1,000-fold difference in the IC50s (range, 0.010-18.6 μmol/L). Response to lapatinib was significantly correlated with HER-2 expression and its ability to inhibit HER-2, Raf, AKT, and ERK phosphorylation. Long-term in vivo lapatinib studies were conducted with human breast cancer xenografts in athymic mice. Treatment over 77 days resulted in a sustained and significant reduction in xenograft volume compared with untreated controls. For the combination of lapatinib plus trastuzumab, synergistic drug interactions were observed in four different HER-2-overexpressing cell lines. Moreover, lapatinib retained significant in vitro activity against cell lines selected for long-term outgrowth (>9 months) in trastuzumab-containing (100 μg/mL) culture medium. These observations provide a clear biological rationale to test lapatinib as a single agent or in combination with trastuzumab in HER-2-overexpressing breast cancer and in patients with clinical resistance to trastuzumab. (Cancer Res 2006; 66(3): 1630-9)

Objective: To review the literature concerning the physiology of the endocannabinoid system, current drug development of cannabinoid agonists, and current clinical research on the use of cannabinoid agonists for analgesia. Data Sources: Articles were identified through a search of MEDLINE (1966–August 2005) using the key words cannabis, cannabinoid, cannabi*, cannabidiol, nabilone, THC, pain, and analgesia. No search limits were included. Additional references were located through review of the bibliographies of the articles identified. Study Selection and Data Extraction: Studies of cannabinoid agonists for treatment of pain were selected and were not limited by pain type or etiology. Studies or reviews using animal models of pain were also included. Articles that related to the physiology and pharmacology of the endocannabinoid system were evaluated. Data Synthesis: The discovery of cannabinoid receptors and endogenous ligands for these receptors has led to increased drug development of cannabinoid agonists. New cannabimimetic agents have been associated with fewer systemic adverse effects than delta-9-tetrahydrocannabinol, including recent development of cannabis medicinal extracts for sublingual use (approved in Canada), and have had promising results for analgesia in initial human trials. Several synthetic cannabinoids have also been studied in humans, including 2 cannabinoid agonists available on the international market. Conclusions: Cannabinoids provide a potential approach to pain management with a novel therapeutic target and mechanism. Chronic pain often requires a polypharmaceutical approach to management, and cannabinoids are a potential addition to the arsenal of treatment options.

Background: The aim of this study was to determine the clinical utility of transthoracic echocardiography (TTE) as a screening method for the detection of abdominal aortic aneurysms (AAA). Patients and methods: Each patient who was referred to the echocardiography laboratory TTE was included into the study. After complete cardiac assessment the abdominal aorta was evaluated. Patients with a known, a clinically suspected, or a previously operated AAA were excluded. Results: During the study period, 14876 patients underwent TTE. 13166 (88.5%) of the patients were 50 years and older. Of these 6953 (52.8%) were men and 6213 (47.2%) were women. A total of 108 (0.82%; 95% confidence interval (CI) 0.67–0.99) clinically unsuspected AAA of at least 3 cm in diameter (range 3 cm – 6.8 cm) were detected. There were 93 (86.1%) men and 15 (13.9%) women with a mean age of 73.8 years (range 59–90). In 7 patients an AAA was suspected by TTE but not verified on subsequent abdominal ultrasound, as the diameter of the abdominal aorta was less than 3 cm. The prevalence of an AAA in patients 50 years and older was 1.34% (95% CI 1.08–1.64) for men and 0.24% (95% CI 0.14–0.40) for women. In patients less than 50 years old no aneurysm was detected. Seventeen patients who were found to have an AAA with a mean diameter of 4.4 cm (range 3–6 cm) underwent successful elective conventional AAA repair after a mean interval of 13.9 months (range 0.2–49 months) following the initial diagnosis. Conclusions: TTE performed in a highly selected cardiac patient group in a tertiary referral center is not a useful tool to screen for clinically unsuspected abdominal aortic aneurysms due to the low prevalence. The detection of an aneurysm should be confirmed by conventional abdominal ultrasound.

Objectives:A prospective randomized trial was designed to test the hypothesis that disease-free survival and overall survival are equivalent regardless of whether patients receive laparoscopic assisted colectomy (LAC) or open colectomy. Secondary and tertiary aims will test the safety of LAC and the impact of LAC on quality of life and costs, respectively. Methods:1200 patients will be accrued and randomly assigned to LAC or open colectomy. Consenting adults with primary colon cancer without previous or concurrent malignancies and with tumors considered resectable for cure are eligible for enrollment. Patients will be followed postoperatively for evidence of recurrence and for survival and perioperatively for morbidity, mortality, quality of life, and cost end points. Results: Over 800 patients have been enrolled to date. Early trial results are available for 408 patients, 203 open and 205 LAC. As anticipated, patients are evenly distributed within the two treatment arms according to age, gender, and anesthesia risk (ASA classification). In the open arm, the mean age is 69 with 52 percent females, 87 percent ASA I/II and 13 percent ASA III. In the laparoscopic arm, the mean age is 67, with 48 percent females, 87 percent ASA I/II, and 13 percent ASA III. A total of 160 right and 117 sigmoid colectomies have been performed. Extent of resection data is also available and all parameters tested show no difference between the LAC and open cases: for the laparoscopic vs open colectomy, total bowel length 26cm vs 27cm; proximal margins 12cm vs 11cm; distal margins 10cm vs 12cm; mesenteric length 9cm vs 8cm. Similarly, the number of nodes resected for laparoscopic colectomy is essentially the same (mean 12 lymph nodes) to that for open surgery (mean 13 nodes). Conclusions: Although this study is ongoing; preliminary results suggest that open and LAC provide for the same extent of resection. The quality of life portion of the study is now complete and data will soon be available.

Dieser zweiteilige Artikel stützt sich auf ein vergleichendes und beschreibendes Modell, anhand dessen sich die Wahrnehmungen der Symptombelastung von Lungenkrebspatientinnen und -patienten und die Einschätzungen der sie hauptsächlich pflegenden Angehörigen im familiären Rahmen untersuchen lassen. Der zweite Teil beschreibt die Resultate der qualitativen Komponente dieser Untersuchung. Eine Auswahl von 37 Paaren, die aus Patient/in und pflegendem Familienmitglied bestanden, füllte die McCorkle and Young Symptom Distress Scale (SDS) aus. Die Gesamtresultate der pflegenden Angehörigen korrelierten mäßig1 mit jenen der Patienten (r = 0.71; P < 0.001). Bei 10 der 13 Symptome fanden sich keine bedeutsamen Unterschiede in der Einstufung. Pflegende sollten sich daher bewußt sein, daß die pflegenden Angehörigen die Symptombelastung von Lungenkrebspatienten bei mindestens 10 der 13 auf der SDS aufgeführten Symptome zuverlässig einschätzen. Dies ist vor allem dann von großer Bedeutung, wenn der Patient oder die Patientin selbst nicht in der Lage ist, über seine/ihre Symptombelastung zu sprechen.

Experimental studies have shown the beneficial effects of antioxidant supplementation on endothelial function in the presence of increased endogenous oxidative stress, whereas limited data are available under normal conditions. The present study tested the hypothesis that in normal pigs long-term antioxidants would have deleterious effects on the cardiovascular system. Normal domestic pigs (V, n=6) were studied 12 weeks after dietary supplementation with vitamin E (100 IU/kg per day) and vitamin C (1 g/day) and compared with normal controls (C, n=7). Myocardial perfusion and permeability index were evaluated by electron beam computed tomography after intravenous adenosine and dobutamine. Coronary endothelial function was evaluated in vitro by organ chamber and coronary tissue studied by immunoblotting and staining. Myocardial perfusion response was lower in V than in C after adenosine (10.1±4.5 versus 53.4±5.2%; P <0.01) and dobutamine (V, 78.4±8.1; C, 193.0±39.0%; P <0.05). The permeability index increased in V after adenosine (48.8±5.1%) and dobutamine (59.9±13.6%) and did not change in C. Coronary vasodilation to bradykinin and substance P was lower in V than in C. Moreover, in V, coronary nitrotyrosine and superoxide content was significantly higher than in C. The groups had similar total monomer expression of endothelial nitric oxide synthase, whereas the dimerized form, reflecting coupled enzyme, was lower in V. These findings suggest that long-term experimental antioxidant vitamin supplementation in normal pigs impairs myocardial perfusion and coronary endothelial function via an increased level of oxidative stress in the arterial wall, which may be partly related to the uncoupling of endothelial nitric oxide synthase and/or the direct prooxidant effect of vitamin radicals.

Purpose The primary goal of this study was to evaluate the feasibility and effectiveness of a structured, multidisciplinary intervention targeted to maintain the overall quality of life (QOL), which is more comprehensive than psychosocial distress, of patients undergoing radiation therapy for advanced-stage cancer. Patients and Methods Radiation therapy patients with advanced cancer and an estimated 5-year survival rate of 0% to 50% were randomly assigned to either an eight-session structured multidisciplinary intervention arm or a standard care arm. The eight 90-minute sessions addressed the five domains of QOL including cognitive, physical, emotional, spiritual, and social functioning. The primary end point of maintaining overall QOL was assessed by a single-item linear analog scale (Linear Analog Scale of Assessment or modified Spitzer Uniscale). QOL was assessed at baseline, week 4 (end of multidisciplinary intervention), week 8, and week 27. Results Of the 103 participants, overall QOL at week 4 was maintained by the patients in the intervention (n = 49), whereas QOL at week 4 significantly decreased for patients in the control group (n = 54). This change reflected a 3-point increase from baseline in the intervention group and a 9-point decrease from baseline in the control group (P = .009). Intervention participants maintained their QOL, and controls gradually returned to baseline by the end of the 6-month follow-up period. Conclusion Although intervention participants maintained and actually improved their QOL during radiation therapy, control participants experienced a significant decrease in their QOL. Thus, a structured multidisciplinary intervention can help maintain or even improve QOL in patients with advanced cancer who are undergoing cancer treatment.

Non-exercise activity thermogenesis (NEAT) is the energy expenditure of all physical activities other than volitional sporting-like exercise. NEAT includes all the activities that render us vibrant, unique, and independent beings such as working, playing, and dancing. Because people of the same weight have markedly variable activity levels, it is not surprising that NEAT varies substantially between people by up to 2000 kcal per day. Evidence suggests that low NEAT may occur in obesity but in a very specific fashion. Obese individuals appear to exhibit an innate tendency to be seated for 2.5 hours per day more than sedentary lean counterparts. If obese individuals were to adopt the lean “NEAT-o-type,” they could potentially expend an additional 350 kcal per day. Obesity was rare a century ago and the human genotype has not changed over that time. Thus, the obesity epidemic may reflect the emergence of a chair-enticing environment to which those with an innate tendency to sit, did so, and became obese. To reverse obesity, we need to develop individual strategies to promote standing and ambulating time by 2.5 hours per day and also re-engineer our work, school, and home environments to render active living the option of choice.