Showing papers by "Bo Lu published in 2009"

Ambient Air Pollution Exaggerates Adipose Inflammation and Insulin Resistance in a Mouse Model of Diet-Induced Obesity

Abstract: Background—There is a strong link between urbanization and type 2 diabetes mellitus. Although a multitude of mechanisms have been proposed, there are no studies evaluating the impact of ambient air pollutants and the propensity to develop type 2 diabetes mellitus. We hypothesized that exposure to ambient fine particulate matter (2.5 m; PM2.5) exaggerates diet-induced insulin resistance, adipose inflammation, and visceral adiposity. Methods and Results—Male C57BL/6 mice were fed high-fat chow for 10 weeks and randomly assigned to concentrated ambient PM2.5 or filtered air (n14 per group) for 24 weeks. PM2.5-exposed C57BL/6 mice exhibited marked whole-body insulin resistance, systemic inflammation, and an increase in visceral adiposity. PM2.5 exposure induced signaling abnormalities characteristic of insulin resistance, including decreased Akt and endothelial nitric oxide synthase phosphorylation in the endothelium and increased protein kinase C expression. These abnormalilties were associated with abnormalities in vascular relaxation to insulin and acetylcholine. PM2.5 increased adipose tissue macrophages (F4/80 cells) in visceral fat expressing higher levels of tumor necrosis factor-/interleukin-6 and lower interleukin-10/N-acetyl-galactosamine specific lectin 1. To test the impact of PM2.5 in eliciting direct monocyte infiltration into fat, we rendered FVBN mice expressing yellow fluorescent protein (YFP) under control of a monocyte-specific promoter (c-fms ,c -fms YFP ) diabetic over 10 weeks and then exposed these mice to PM2.5 or saline intratracheally. PM2.5 induced YFP cell accumulation in visceral fat and potentiated YFP cell adhesion in the microcirculation. Conclusion—PM2.5 exposure exaggerates insulin resistance and visceral inflammation/adiposity. These findings provide a new link between air pollution and type 2 diabetes mellitus. (Circulation. 2009;119:538-546.)

Combined Bcl-2/Mammalian Target of Rapamycin Inhibition Leads to Enhanced Radiosensitization via Induction of Apoptosis and Autophagy in Non-Small Cell Lung Tumor Xenograft Model

Abstract: Purpose: Radiotherapy has a central role in the treatment of non–small cell lung cancer. Effectiveness of this modality, however, is often limited as resistance results from defects in cell death. Experimental Design: We investigated whether simultaneous up-regulation of apoptosis, via Bcl-2 inhibitor ABT-737, and autophagy, via mammalian target of rapamycin inhibitor rapamycin, can be used to enhance radiosensitivity of H460 cells in vitro and growth delay in a xenograft model. Results:In vitro studies confirmed that ABT-737 and rapamycin induce apoptosis and autophagy, respectively. ABT-737 induced cleaved caspase-3, a marker of apoptosis, and rapamycin correlated with an increase in punctate localization of green fluorescent protein-LC3, characteristic of autophagy. The combination ABT-737/rapamycin markedly enhanced sensitivity of H460 cells to radiation (dose enhancement ratio = 2.47; P = 0.002) in clonogenic assay. In addition, the combination ABT-737/rapamycin/radiation showed a dramatic tumor growth delay in a mouse xenograft model. In vivo immunohistochemistry staining showed that combination therapy yielded over a 100% increase in caspase-3 activity (apoptosis) and a 6-fold decrease in p62 protein level (indicative of autophagic flux) compared with radiation alone control group. Moreover, cell proliferation (Ki-67 staining) was reduced by 77% (P = 0.001) and vascular density (von Willebrand factor staining) by 67.5% (P = 0.09) compared with radiation alone. Additional in vitro studies in human umbilical vein endothelial cells indicated that combined therapy also significantly decreases tubule formation. Conclusion: These results suggest that concurrent induction of apoptosis and autophagy enhances radiation therapy both in vitro and in lung cancer xenograft models. Further investigations are warranted to assess the clinical potential of such strategy in lung cancer patients. (Clin Cancer Res 2009;15(19):6096–105)

Regulated cell death pathways: New twists in modulation of BCL2 family function

Abstract: A number of cell death pathways have been recognized. Though apoptosis and autophagy have been well characterized, programmed necrosis has recently received attention and may provide clinical alternatives to suppress resistant tumors. Necrosis is primarily characterized by large-scale permeabilization, swelling, and rupture of cell membranes and the release of pro-inflammatory cytokines. Traditionally, necrosis in cancer cells has been indicative of poor prognoses, as chronic inflammation was found to encourage tumor growth. Yet, many antitumor effects associated with necrosis have been discovered in certain settings, such as the formation of an effective antitumor immune response. In this way, finding ways to attenuate the pro-tumor effects of necrosis while engaging the antitumor pathways via drugs, radiation, and sensitization may prove valuable as a clinical focus for the future. We hypothesize that the use of Bcl-2 inhibitors may enhance necrotic death characterized by inflammation and antitumor immunity. In this article, we briefly review apoptosis and autophagy and reason how necrosis may be a suitable alternative therapeutic endpoint. We then highlight novel inhibitors of Bcl-2 that may provide clinical application of our hypothesis in the future.

A phase II study of celecoxib in combination with paclitaxel, carboplatin, and radiotherapy for patients with inoperable stage IIIA/B non-small cell lung cancer.

Abstract: Purpose: Cyclooxygenase (COX)-2 up-regulation plays an important role in the pathogenesis of lung cancer. Selective COX-2 inhibitors have promoted chemosensitivity and radiosensitivity of tumor cells in preclinical trials. Experimental Design: In a single-institution phase II study, we sought to determine the effectiveness of concurrent chemoradiation given with celecoxib and examined biomarkers to predict response to COX-2 inhibition. Results: Seventeen patients with stage IIIA or IIIB non–small cell lung cancer (NSCLC) were enrolled in the study. All received 400 mg celecoxib twice daily continuously while on trial in addition to concurrent chemoradiation therapy with paclitaxel and carboplatin. Celecoxib was continued until disease progression. The overall objective response rate was 42.9%, and the median overall survival time was 203 days. In contrast to nonresponders, those patients with complete and partial responses had a significant decrease in the level of urinary 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of prostaglandin E2, after 1 week of celecoxib administration. Patients with very high levels of PGE-M before initiation of therapy also responded poorly to therapy. Serum vascular endothelial growth factor levels did not predict response or survival. Conclusion: The trial was terminated because it did not meet the predetermined goal of 80% overall response rate. In unselected patients, the addition of celecoxib to concurrent chemoradiotherapy with inoperable stage IIIA/B NSCLC does not improve survival. Urinary PGE-M is a promising biomarker for predicting response to COX-2 inhibition in NSCLC.

Synergy between phosphatidylinositol 3-kinase/Akt pathway and Bcl-xL in the control of apoptosis in adenocarcinoma cells of the lung

Abstract: Adenocarcinomas of the lung commonly show an increase in the activity of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, yet many are resistant to apoptosis induced by the inhibition of PI3K. We hypothesized that Bcl-xL would have a synergistic effect on the apoptotic response induced by inhibition of the PI3K/Akt pathway in lung adenocarcinoma. To test this, we examined the effect of the PI3K inhibitor (LY294002) on lung adenocarcinoma cell lines expressing varying levels of Bcl-xL. We found that cells that overexpress Bcl-xL are resistant to LY294002-induced apoptosis, whereas cells that express little Bcl-xL readily are not. Restoring Bcl-xL expression in cells that express low level of Bcl-xL conferred resistance to apoptosis in response to LY294002. The simultaneous inhibition of the PI3K/Akt pathway by LY294002 or Akt1 small interfering RNA and Bcl-xL function by ABT-737 or Bcl-xL small interfering RNA greatly enhanced the apoptotic response. Moreover, this response was associated with the induction of proapoptotic BH3-only Bcl-2 family member Bim. Our data suggest that PI3K/Akt and Bcl-xL pathways control cell death in lung adenocarcinoma cells in a synergistic manner. Modulation of Bcl-xL expression may represent one important strategy to optimize the efficacy of therapeutic agents targeting the PI3K/Akt pathway in adenocarcinoma of the lung.

HSP90 inhibitors: multi-targeted antitumor effects and novel combinatorial therapeutic approaches in cancer therapy.

Abstract: With the rapid rise of tumor resistance, combinatorial anticancer therapies have gained favor over single-molecule inhibition to maximize the suppression of oncogenic pathways. In this regard, HSP90 inhibitors have rapidly emerged as a class of promising drugs that can target multiple oncogenic pathways simultaneously. HSP90 is a highly conserved protein chaperone involved in essential cellular functions such as protein folding and cell signaling in both stressed and unstressed cells. In the last decade, a large number of oncogenic client proteins have been identified to associate with HSP90 and contribute to malignant transformation. Development of HSP90 inhibitors, derived from the natural compound geldanamycin that mimics the ATP binding site of HSP90, was designed to target HSP90 and allow degradation of these client proteins. Preclinical and clinical data with HSP90 inhibitors in various cancer models are promising, and evidences also hint at the potential for tumor-selective cytotoxicity as well as enhanced sensitization to chemo- and radiotherapy. This review will discuss the effects of HSP90 inhibition in cancer, the known mechanistic basis for the oncogenic toxicity and selectivity, as well as the current progress on single or combinatorial therapies with HSP90 inhibitors.

Calibration of a novel four-dimensional diode array.

Abstract: Purpose: The aim of this work is to develop effective calibration methods for a novel four-dimensional (4D) diode array for pretreatment verification of intensity-modulated radiation therapy (IMRT) and rotational therapy. Methods: A novel 4D diode array (ArcCHECK, Sun Nuclear, Melbourne, FL) was developed to meet the needs of appropriate and efficient quality assurance for IMRT and especially rotational radiotherapy. The diode array presents a consistent detector image in beam's eye view at arbitrary gantry angles due to isotropic arrangement of diodes in a three-dimensional (3D) cylindrical phantom. The 50 ms simultaneous update of all diodes on the detector array (fourth dimension) makes it capable of time-resolved beam delivery analysis with any rotational delivery techniques. The calibration procedure consisted of delivering and measuring a series of calibration beams with 5.8 deg. angular spacing surrounding the cylindrical diode array. Correction factors for diode intrinsic sensitivity and directional response dependence were derived from these measurements. A real-time algorithm to derive gantry angles based on the detector signal was developed to interpolate and apply the corresponding angular correction factors. Results: The calibration was validated with ion chamber scanned beam profiles in a 3D water tank. Excellent agreement was observed between diode array measurement andmore » treatment planning system calculation. The accuracy of the gantry angle derivation algorithm was within 1 deg. which caused a less than 0.2% dosimetric uncertainty. Conclusions: With the proposed calibration method and the automatic gantry angle derivation algorithm, the 4D diode array achieved isotropic detector response and is suitable for both IMRT and rotational therapy pretreatment verification.« less

Modular Synthesis of Thermosensitive P(NIPAAm‐co‐HEMA)/β‐CD Based Hydrogels via Click Chemistry

Abstract: Two kinds of representative polymers, poly(N-isopropylacrylamide) (PNIPAAm) and β-cyclo-dextrin (β-CD) were selected and modified with azide and alkyne fucntional groups, respectively. When the solutions of these two modified polymers were mixed together, a cross-linking reaction, a type of Huisgen's 1,3-dipolar azide-alkyne cycloaddition, occurred in the presence of Cu(I) catalyst. The strategy described here provides several advantages for the hydrogel formation including mild reaction conditions and controllable gelation rate. The resulted hydrogels were studied in terms of scanning electric microscopy (SEM), equilibrium swelling ratio and swelling/shrinking kinetics. The data obtained demonstrated the hydrogels had a porous structure as well as favorable thermosensitivity.

Prognostic factors for resected non-small cell lung cancer with pN2 status: implications for use of postoperative radiotherapy.

Abstract: Background. For non-small cell lung cancer (NSCLC) patients with pN2 status, the use of postoperative radiotherapy (PORT) remains controversial. Here, we investigated the association between different clinicopathological features and postoperative therapy and local control and survival in patients with resected pN2 NSCLC. Methods. We retrospectively analyzed 83 patients with pN2 NSCLC who underwent resection at Vanderbilt University Medical Center between 1994 and 2004. The relationship between 10 prognostic factors—gender, age at diagnosis, histology, tumor size, number of nodal stations involved, positive node number, surgical margin,extracapsularextension(ECE),anduseofpostoperative chemotherapy and PORT—and 2-year local recurrence-free survival (LRFS), distant recurrencefree survival (DRFS), recurrence-free survival (RFS), and overall survival (OS) rates was evaluated. Univari

Radiosensitization of solid tumors by Z-VAD, a pan-caspase inhibitor

Abstract: Despite recent advances in the management of breast and lung cancer, novel treatment strategies are still needed to further improve patient outcome. The targeting of cell death pathways has therefore been proposed to enhance therapeutic ratio in cancer. In this study, we examined the in vitro and in vivo effects of Z-VAD, a broad-spectrum caspase inhibitor, on breast and lung cancer in association with radiation. Using clonogenic assays, we observed that Z-VAD markedly radiosensitized breast and lung cancer cells, with a radiation dose enhancement ratio of 1.31 (P < 0.003). For both models, the enhanced tumor cytotoxicity was associated with induction of autophagy. Furthermore, we found that administration of Z-VAD with radiation in both breast and lung cancer xenograft produced a significant tumor growth delay compared with radiation alone and was well tolerated. Interestingly, Z-VAD also had dramatic antiangiogenic effect when combined with radiation both in vitro and in vivo and thus represents an attractive anticancer therapeutic strategy. In conclusion, this preclinical study supports the therapeutic potential of Z-VAD as a radiosensitizer in breast and lung cancer. This study also suggests caspase inhibition as a promising strategy to enhance the therapeutic ratio of radiation therapy in solid tumors. Therefore, clinical trials are needed to determine the potential of this combination therapy in cancer patients.

Serious psychological distress among persons with epilepsy based on the 2005 California Health Interview Survey.

Abstract: SUMMARY Purpose: To compare the prevalence of selfreported serious psychological distress using the Kessler 6 (K6) in persons with a history of epilepsy (PWE) to those without epilepsy from a population-based survey. Methods: Data were analyzed from adults aged ‡18 years (n = 43,020) who participated in the 2005 California Health Interview Survey (CHIS). Results: California adults with a history of epilepsy, after controlling for demographics and comorbidities, reported higher rates of feeling nervous [odds ratio (OR) 2.22], feeling hopeless (OR 1.35), feeling restless (OR 2.07), feeling depressed (OR 3.14), and feeling worthless (OR 2.57), and reported that everything has been an effort (OR 2.28) in the last 30 days. The K6 score showed that serious psychological distress is more common in PWE (OR 2.24). After adjusting for demographics, comorbidities, and serious psychological distress, PWE are more likely to report having 14 or more physical, mental, and general unhealthy days in the last 30 days. Discussion: PWE have significantly higher rates of serious psychological distress and poor health-related quality of life after controlling for demographics, comorbidities. These comorbid conditions need to be factored into any comprehensive treatment strategy for managing PWE to achieve optimum quality of life.

A smoking ban in public places increases the efficacy of bupropion and counseling on cessation outcomes at 1 year

Abstract: INTRODUCTION Legal restrictions have contributed to the decline in smoking prevalence in several European countries. We investigated the impact of the Italian 2005 indoor smoking ban on the efficacy of counseling alone or in combination with bupropion for smoking cessation. METHODS Before and after the introduction of the ban (2001-2006), 550 smokers were enrolled in the smoking cessation program in Rome and were asked to choose between a 6-week group counseling therapy (GCT) given alone or in combination with 7 weeks of daily bupropion. Follow-up was completed 12, 26, and 52 weeks after the quit day. Due to the observational nature of the study, we used propensity scores to match 138 and 290 subjects (pre-/postban) in the bupropion- and GCT-only groups, respectively. RESULTS Covariate balance in the two matched samples was adequate for all variables except "coffee consumption" in the GCT-only group. The regression adjusted odds ratios indicated that the introduction of the ban resulted in 52% reduced odds of continued smoking at 12 months among the GCT + bupropion group and 41% reduced odds in the GCT-only group. We observed that the ban was associated with both increased 12-month abstinence rates and motivation to quit. In a mediation analysis, we determined that the total effect of the smoking ban on the abstinence rate was reduced after controlling for motivation, which confirmed that motivation was a partial mediator. DISCUSSION The introduction of an indoor smoking ban improved the efficacy of smoking cessation treatments by possibly providing a setting that increased the level of motivation to stop smoking.

N-Succinyl-chitosan grafted with low molecular weight polyethylenimine as a serum-resistant gene vector.

Abstract: Low transfection efficiency and inactivation by serum are the major drawbacks for cationic polymers when used as non-viral gene vectors. Here, a series of N-succinyl-chitosan-graft-polyethylenimine (NSC-g-PEI) copolymers with different compositions were synthesized through grafting low molecular weight PEI (800 Da) to N-succinyl-chitosan. An agarose gel electrophoresisassay showed NSC-g-PEIs had good binding capability with DNA and the particle size of the NSC-g-PEI–DNA complexes was between 150 to 300 nm as determined by a Zeta sizer. In vitro transfection of NSC-g-PEI–DNA complexes for 293T, HeLa and CHO cells was investigated. It was found that the transfection efficiency of NSC-g-PEI–DNA complexes was higher than that of DNA combined PEI (25 kDa) and the transfection efficiency increased with the increasing GD of PEI. More importantly, the NSC-g-PEI–DNA complexes were stable and the transfection efficiency was not affected obviously in the presence of serum with different concentrations. In addition, NSC-g-PEIs had a lower cytotoxicity than PEI (25 kDa) and the toxicity increased with increasing GD of PEI. The NSC-g-PEI copolymers will have a good potential as efficient non-viral gene vectors in the presence of serum.

Autophagy in lung cancer.

Abstract: Lung cancer is the leading cause of cancer-related deaths worldwide. The relatively poor cure rate in lung cancer patients has been associated with a resistance to chemotherapy and radiation that is at least in part related to defects in cellular apoptotic machinery. Exploitation of another form of cell death, autophagy, has the capacity to improve the therapeutic gain of current therapies. In an effort to develop novel treatment strategies to enhance the therapeutic ratio for lung cancer, we wish to better understand the role of autophagic cell death for the sensitization of lung cancer. This text reviews the most up to date protocols and techniques for the study of autophagic cell death in lung cancer models. Others may use these techniques as a framework for study within their experimental models.

Serious psychological distress and health outcomes for persons with epilepsy in poverty.

Abstract: Epidemiology literature demonstrates socioeconomic status as an important variable for outcomes in persons with epilepsy. However, no previous studies have analyzed the association between poverty and epilepsy in the United States. Forty-one percent (246/604) of persons with a history of epilepsy (PWHE) in the 2005 California Health Interview Survey ( n =43,020) had an annual income

A prospective randomized comparison of continuous hemihepatic with intermittent total hepatic inflow occlusion in hepatectomy for liver tumors.

Abstract: Background/aims To evaluate whether continuous hemihepatic inflow occlusion (HHO) during hepatectomy can be safer than and be as effective as intermittent total hepatic inflow occlusion (THO) in reducing blood loss. Methodology Eighty patients undergoing liver resections were included in a prospective randomized study comparing the intra- and postoperative course under THO (n=40) or HHO (n=40). THO was performed with periods of 20 minutes of occlusion and 5 minutes of releasing, while HHO was performed with continuous occlusion. The surface area of liver transection, amount of blood loss, measurements of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and postoperative evolution were recorded. Results The two groups were similar at entry in terms of preoperative liver function and in the proportion of patients experiencing major hepatectomy. The total ischemic time of the two groups was similar (p=0.37), but the operative time in the THO group was longer than in the HHO group (p=0.02). No significant difference was found between the HHO and THO group in blood loss during liver parenchyma transection (p=0.14), the elevations of ALT and AST on the first postoperative day (ALT: p=0.12; AST: p=0.66) and postoperative morbidity (p=0.35). Conclusions On the basis of our findings, if it is feasible, continuous HHO is recommended for complex liver resection.

The effect of intravenous contrast on photon radiation therapy dose calculations for lung cancer.

Abstract: Objective: The aim of this study was to evaluate the effect of intravenous contrast-enhanced computed tomography (CT) scans on the photon radiation dose calculations for lung cancer treatment planning. Materials and Methods: Nonionic iodinated intravenous contrast (Iohexol) was administered during the treatment planning CT scan of 9 patients with node-positive non―small-cell lung cancer (NSCLC). The potential effect of intravenous contrast was studied by changing the density of the contrast-enhanced vessels. A total of 9 patients were treated in this study: 5 patients with intensity-modulated radiation therapy (IMRT), and 4 patients with three-dimensional (3D) conformal radiation therapy. A treatment plan was generated from an unmanipulated "normal contrast" planning scan. The same planning parameters were then applied to a "no contrast" planning scan. The effect of intravenous contrast was quantified by calculating the percent change of dose in a variety of target and normal structures. To evaluate a worst-case scenario, the comparison between "normal contrast" and "no contrast" planning scans was repeated, assigning each vessel the artificial high density of 1.3 g/cm 3 . Results: Dose differences between the planning image set using intravenous contrast and the image set without contrast were less than 2.5% for planning target volumes. A worst-case scenario in which normal contrast was overridden with an artificially high density of 1.3 g/cm 3 led to small dose differences of less than 3%. Conclusions: Planning lung radiation therapy treatment using CT scans that contain intravenous contrast does not result in clinically significant errors in dose delivery.

Chemoradiotherapy in locally advanced, unresectable non-small cell lung cancer.

Abstract: Chemoradiation is the major treatment option in unresectable, locally advanced non-small cell lung cancer. Many clinical trials have evaluated the efficacy of different combinations of chemotherapy and radiotherapy in this heterogeneous patient population. Early clinical trials showed a survival advantage of sequential chemo-RT compared to radiation alone. Subsequent trials demonstrated that concurrent chemo-RT improved survival over sequential chemo-RT. More recent studies have suggested that there is no advantage to adding induction chemotherapy prior to concurrent chemo-RT, or to adding consolidation chemotherapy after concurrent chemo-RT. Various clinical trials have used different chemotherapy regimens, though there is still no consensus about those which are most effective. Additionally, different radiotherapeutic strategies have included hyperfractionation vs. standard fractionation, use of 3-dimensional techniques, and altering total radiation dose. As these methods are being perfected, much attention has turned toward the use of molecularly targeted therapies. This review summarizes recent clinical trials examining the role of chemo-RT in locally advanced non-small cell lung cancer and the movement toward personalized medicine.