Showing papers by "Bo Lu published in 2013"

Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma

Abstract: A growing number of agents targeting ligand-induced Wnt/β-catenin signaling are being developed for cancer therapy. However, clinical development of these molecules is challenging because of the lack of a genetic strategy to identify human tumors dependent on ligand-induced Wnt/β-catenin signaling. Ubiquitin E3 ligase ring finger 43 (RNF43) has been suggested as a negative regulator of Wnt signaling, and mutations of RNF43 have been identified in various tumors, including cystic pancreatic tumors. However, loss of function study of RNF43 in cell culture has not been conducted, and the functional significance of RNF43 mutations in cancer is unknown. Here, we show that RNF43 inhibits Wnt/β-catenin signaling by reducing the membrane level of Frizzled in pancreatic cancer cells, serving as a negative feedback mechanism. Inhibition of endogenous Wnt/β-catenin signaling increased the cell surface level of Frizzled. A panel of 39 pancreatic cancer cell lines was tested for Wnt dependency using LGK974, a selective Porcupine inhibitor being examined in a phase 1 clinical trial. Strikingly, all LGK974-sensitive lines carried inactivating mutations of RNF43. Inhibition of Wnt secretion, depletion of β-catenin, or expression of wild-type RNF43 blocked proliferation of RNF43 mutant but not RNF43–wild-type pancreatic cancer cells. LGK974 inhibited proliferation and induced differentiation of RNF43-mutant pancreatic adenocarcinoma xenograft models. Our data suggest that mutational inactivation of RNF43 in pancreatic adenocarcinoma confers Wnt dependency, and the presence of RNF43 mutations could be used as a predictive biomarker for patient selection supporting the clinical development of Wnt inhibitors in subtypes of cancer.

The association of red blood cell n-3 and n-6 fatty acids with bone mineral density and hip fracture risk in the women's health initiative.

Abstract: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFA) in red blood cells (RBCs) are an objective indicator of PUFA status and may be related to hip fracture risk The primary objective of this study was to examine RBC PUFAs as predictors of hip fracture risk in postmenopausal women A nested case-control study (n = 400 pairs) was completed within the Women's Health Initiative (WHI) using 201 incident hip fracture cases from the Bone Mineral Density (BMD) cohort, along with 199 additional incident hip fracture cases randomly selected from the WHI Observational Study Cases were 1:1 matched on age, race, and hormone use with non–hip fracture controls Stored baseline RBCs were analyzed for fatty acids using gas chromatography After removing degraded samples, 324 matched pairs were included in statistical analyses Stratified Cox proportional hazard models were constructed according to case-control pair status; risk of fracture was estimated for tertiles of RBC PUFA In adjusted hazard models, lower hip fracture risk was associated with higher RBC α-linolenic acid (tertile 3 [T3] hazard ratio [HR]: 044; 95% confidence interval [CI], 023–085; p for linear trend 00154), eicosapentaenoic acid (T3 HR: 046; 95% CI, 024–087; p for linear trend 00181), and total n-3 PUFAs (T3 HR: 055; 95% CI, 030–101; p for linear trend 00492) Conversely, hip fracture nearly doubled with the highest RBC n-6/n-3 ratio (T3 HR: 196; 95% CI, 103–370; p for linear trend 00399) RBC PUFAs were not associated with BMD RBC PUFAs were indicative of dietary intake of marine n-3 PUFAs (Spearman's rho = 045, p < 00001), total n-6 PUFAs (rho = 017, p < 00001) and linoleic acid (rho = 009, p < 005) These results suggest that higher RBC α-linolenic acid, as well as eicosapentaenoic acid and total n-3 PUFAs, may predict lower hip fracture risk Contrastingly, a higher RBC n-6/n-3 ratio may predict higher hip fracture risk in postmenopausal women © 2013 American Society for Bone and Mineral Research

ALK Inhibitor PF02341066 (Crizotinib) Increases Sensitivity to Radiation in Non–Small Cell Lung Cancer Expressing EML4-ALK

Abstract: Crizotinib (PF02341066) is a tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) that has been shown to selectively inhibit growth of cancer cells that harbor the EML4-ALK fusion found in a subset of patients with non-small cell lung cancer (NSCLC). While in clinical trials, PF02341066 has shown a significant therapeutic benefit as a single agent; the effectiveness of combining it with other therapeutic modalities including ionizing radiation remains unknown. To further elucidate the role of PF02341066 in tumor inhibition, we examined its effects alone and in combination with radiation on downstream signaling, apoptosis, and radiosensitivity in two NSCLC cell lines in vitro: H3122, which harbors the EML4-ALK fusion, and H460, which does not. We also examined the in vivo effects of PF02341066 in H3122 mouse xenografts. In the H3122 cell line, PF02341066 inhibited phosphorylation of ALK and its downstream effectors: AKT, ERK, and STAT3. H3122 cells treated with a combination of PF02341066 and radiation showed an increase in cellular apoptosis and were sensitized to radiation therapy (dose enhancement ratio, 1.43; P < 0.0001). Moreover, in an H3122 xenograft model, the combined treatment resulted in greater tumor growth inhibition than either treatment alone (P < 0.05). None of these effects was observed in the EML4-ALK-negative H460 cells. Our findings indicate that PF02341066 acts as a radiation sensitizer in cells harboring the EML4-ALK fusion, providing a rationale for a clinical trial combining ALK inhibitor with radiation in the NSCLCs expressing ALK.

Opportunities and Challenges in the Era of Molecularly Targeted Agents and Radiation Therapy

Abstract: The first annual workshop for preclinical and clinical development of radiosensitizers took place at the National Cancer Institute on August 8–9, 2012. Radiotherapy is one of the most commonly applied and effective oncologic treatments for solid tumors. It is well recognized that improved clinical efficacy of radiotherapy would make a substantive impact in clinical practice and patient outcomes. Advances in genomic technologies and high-throughput drug discovery platforms have brought a revolution in cancer treatment by providing molecularly targeted agents for various cancers. Development of predictive biomarkers directed toward specific subsets of cancers has ushered in a new era of personalized therapeutics. The field of radiation oncology stands to gain substantial benefit from these advances given the concerted effort to integrate this progress into radiation therapy. This workshop brought together expert clinicians and scientists working in various disease sites to identify the exciting opportunities and expected challenges in the development of molecularly targeted agents in combination with radiation therapy.

Safety of varenicline among smokers enrolled in the lung HIV study.

Abstract: INTRODUCTION The prevalence of smoking is high among the human immunodeficiency virus (HIV)-infected population, yet there are few studies of tobacco dependence treatment in this population This paper reports the safety of varenicline versus nicotine replacement therapy (NRT) and describes preliminary results about the effectiveness of varenicline versus NRT in HIV-infected smokers METHODS Participants completed 12 weeks of telephone counseling and either varenicline or NRT Varenicline was encouraged as the preferred intervention; NRT was used for those unable/unwilling to take varenicline Adverse events (AEs), related to pharmacotherapy, were monitored Biochemically confirmed abstinence at 3 months was examined Inverse probability of treatment weighted logistic regression models was fit to compare participants on varenicline to those on NRT RESULTS Among participants on varenicline (n = 118), the most common AEs were nausea, sleep problems, and mood disturbances One person reported suicidal ideation; there were no cardiovascular complications There were no differences in the varenicline AE profile between participants on combination antiretroviral therapy (ART) and those not on ART The percentages of confirmed abstainers were 118% in the NRT group and 256% in the varenicline group The odds of being abstinent were 254 times as great in the varenicline group compared with the NRT group in the propensity weighted model (95% CI 143-449) CONCLUSIONS In this preliminary study, the safety profile of varenicline among HIV-infected smokers resembles findings among smokers without HIV In addition, varenicline may be more effective at promoting abstinence in this population Future randomized clinical trials are warranted

Efficiency of study designs in diagnostic randomized clinical trials

Abstract: From the patients' management perspective, a good diagnostic test should contribute to both reflecting the true disease status and improving clinical outcomes. The diagnostic randomized clinical trial is designed to combine both diagnostic tests and therapeutic interventions. Evaluation of diagnostic tests is carried out with therapeutic outcomes as the primary endpoint rather than test accuracy. We lay out the probability framework for evaluating such trials. We compare two commonly referred designs-the two-arm design and the paired design-in a formal statistical hypothesis testing setup and identify the causal connection between the two tests. The paired design is shown to be more efficient than the two-arm design. The efficiency gains vary depending on the discordant rates of test results. We derive sample size formulas for both binary and continuous endpoints. We derive estimation of important quantities under the paired design and also conduct simulation studies to verify the theoretical results. We illustrate the method with an example of designing a randomized study on preoperative staging of bladder cancer.

ALDH7A1 expression is associated with recurrence in patients with surgically resected non-small-cell lung carcinoma

Abstract: Aim: The purpose of this study was to describe the prognostic significance of ALDH7A1 in surgically treated non-small-cell lung carcinoma. (NSCLC). Materials & methods: We immunohistochemically analyzed ALDH7A1 expression in surgically resected NSCLC from 89 patients using a tissue microarray. Results: ALDH7A1 staining was positive in 43 patients and negative in 44 patients, with two tumor sections missing. For stage I NSCLC patients, ALDH7A1 positivity was associated with decreased recurrence-free and overall survival. Multivariate analysis demonstrated that ALDH7A1-expressing NSCLC tumors had a significantly higher incidence of lung cancer recurrence compared with patients with ALDH7A1-negative tumors, although there was no association with overall survival. Conclusion: For patients with NSCLC, low ALDH7A1 expression was associated with a decreased incidence of cancer recurrence. Specifically in stage I patients, negative staining for ALDH7A1 was associated with improved recurrence-free and overall surv...

Ambiguity-free optical tracking system

Abstract: An ambiguity-free optical tracking system ( 100 ) includes a position sensor unit ( 104 ), a control box ( 106 ), a computer ( 110 ) and software. The position sensor unit includes two cameras ( 121 and 122 ) that track a plurality of individual infra-red reflecting markers ( 160 ) affixed on a patient's skin. Coordinates of the cameras in a coordinate system of the cameras are determined as part of a system calibration process by intentionally creating ambiguous markers with two true markers. Using this information, an ambiguity elimination algorithm automatically identifies and eliminates ambiguous markers. A recursive backtracking algorithm builds a one-to-one correspondence between reference markers and markers optically observed during treatment. By utilizing a concept of null markers, the backtracking algorithm deals with missing, misplaced and occluded markers.

A study of IMRT planning parameters on planning efficiency, delivery efficiency, and plan quality

Abstract: Purpose: To improve planning and delivery efficiency of head and neck IMRT without compromising planning quality through the evaluation of inverse planning parameters.Methods: Eleven head and neck patients with pre-existing IMRT treatment plans were selected for this retrospective study. The Pinnacle treatment planning system (TPS) was used to compute new treatment plans for each patient by varying the individual or the combined parameters of dose/fluence grid resolution, minimum MU per segment, and minimum segment area. Forty-five plans per patient were generated with the following variations: 4 dose/fluence grid resolution plans, 12 minimum segment area plans, 9 minimum MU plans, and 20 combined minimum segment area/minimum MU plans. Each plan was evaluated and compared to others based on dose volume histograms (DVHs) (i.e., plan quality), planning time, and delivery time. To evaluate delivery efficiency, a model was developed that estimated the delivery time of a treatment plan, and validated through measurements on an Elekta Synergy linear accelerator. Results: The uncertainty (i.e., variation) of the dose-volume index due to dose calculation grid variation was as high as 8.2% (5.5 Gy in absolute dose) for planning target volumes (PTVs) and 13.3% (2.1 Gy in absolute dose) for planning at risk volumes (PRVs). Comparisonmore » results of dose distributions indicated that smaller volumes were more susceptible to uncertainties. The grid resolution of a 4 mm dose grid with a 2 mm fluence grid was recommended, since it can reduce the final dose calculation time by 63% compared to the accepted standard (2 mm dose grid with a 2 mm fluence grid resolution) while maintaining a similar level of dose-volume index variation. Threshold values that maintained adequate plan quality (DVH results of the PTVs and PRVs remained satisfied for their dose objectives) were 5 cm{sup 2} for minimum segment area and 5 MU for minimum MU. As the minimum MU parameter was increased, the number of segments and delivery time were decreased. Increasing the minimum segment area parameter decreased the plan MU, but had less of an effect on the number of segments and delivery time. Our delivery time model predicted delivery time to within 1.8%. Conclusions: Increasing the dose grid while maintaining a small fluence grid allows for improved planning efficiency without compromising plan quality. Delivery efficiency can be improved by increasing the minimum MU, but not the minimum segment area. However, increasing the respective minimum MU and/or the minimum segment area to any value greater than 5 MU and 5 cm{sup 2} is not recommended because it degrades plan quality.« less

Prevention of gross setup errors in radiotherapy with an efficient automatic patient safety system

Abstract: Treatment of the wrong body part due to incorrect setup is among the leading types of errors in radiotherapy The purpose of this paper is to report an efficient automatic patient safety system (PSS) to prevent gross setup errors The system consists of a pair of charge-coupled device (CCD) cameras mounted in treatment room, a single infrared reflective marker (IRRM) affixed on patient or immobilization device, and a set of in-house developed software Patients are CT scanned with a CT BB placed over their surface close to intended treatment site Coordinates of the CT BB relative to treatment isocenter are used as reference for tracking The CT BB is replaced with an IRRM before treatment starts PSS evaluates setup accuracy by comparing real-time IRRM position with reference position To automate system workflow, PSS synchronizes with the record-and-verify (R&V) system in real time and automatically loads in reference data for patient under treatment Special IRRMs, which can permanently stick to patient face mask or body mold throughout the course of treatment, were designed to minimize therapist’s workload Accuracy of the system was examined on an anthropomorphic phantom with a designed end-to-end test Its performance was also evaluated on head and neck as well as abdominalpelvic patients using cone-beam CT (CBCT) as standard The PSS system achieved a seamless clinic workflow by synchronizing with the R&V system By permanently mounting specially designed IRRMs on patient immobilization devices, therapist intervention is eliminated or minimized Overall results showed that the PSS system has sufficient accuracy to catch gross setup errors greater than 1 cm in real time An efficient automatic PSS with sufficient accuracy has been developed to prevent gross setup errors in radiotherapy The system can be applied to all treatment sites for independent positioning verification It can be an ideal complement to complex image-guidance systems due to its advantages of continuous tracking ability, no radiation dose, and fully automated clinic workflow

Aliskiren Effect on Plaque Progression in Established Atherosclerosis Using High Resolution 3D MRI (ALPINE): A Double-Blind Placebo-Controlled Trial

Abstract: Background The renin–angiotensin system is well recognized as a mediator of pathophysiological events in atherosclerosis. The benefits of renin inhibition in atherosclerosis, especially when used in combination with angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) are currently not known. We hypothesized that treatment with the renin inhibitor aliskiren in patients with established cardiovascular disease will prevent the progression of atherosclerosis as determined by high‐resolution magnetic resonance imaging (MRI) measurements of arterial wall volume in the thoracic and abdominal aortas of high‐risk patients with preexisting cardiovascular disease. Methods and Results This was a single‐center, randomized, double‐blind, placebo‐controlled trial in patients with established cardiovascular disease. After a 2‐week single‐blind placebo phase, patients were randomized to receive either placebo (n=37, mean±SD age 64.5±8.9 years, 3 women) or 150 mg of aliskiren (n=34, mean±SD age 63.9±11.5 years, 9 women). Treatment dose was escalated to 300 mg at 2 weeks and maintained during the remainder of the study. Patients underwent dark‐blood, 3‐dimensional MRI assessment of atherosclerotic plaque in the thoracic and abdominal segments at baseline and on study completion or termination (up to 36 weeks of drug or matching placebo). Aliskiren use resulted in significant progression of aortic wall volume (normalized total wall volume 5.31±6.57 vs 0.15±4.39 mm3, P =0.03, and percentage wall volume 3.37±2.96% vs 0.97±2.02%, P =0.04) compared with placebo. In a subgroup analysis of subjects receiving ACEI/ARB therapy, atherosclerosis progression was observed only in the aliskiren group, not in the placebo group. Conclusions MRI quantification of atheroma plaque burden demonstrated that aliskiren use in patients with preexisting cardiovascular disease resulted in an unexpected increase in aortic atherosclerosis compared with placebo. Although preliminary, these results may have implications for the use of renin inhibition as a therapeutic strategy in patients with cardiovascular disease, especially in those receiving ACEI/ARB therapy. Clinical Trial Registration URL: Unique identifier : [NCT01417104][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01417104&atom=%2Fahaoa%2F2%2F3%2Fe004879.atom

Everolimus enhances the cytotoxicity of bendamustine in multiple myeloma cells through a network of pro-apoptotic and cell-cycle-progression regulatory proteins.

Abstract: Bendamustine is a bifunctional alkylating agent with some efficacy in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM) Everolimus, an mammalian target of rapamycin (mTOR) inhibitor, is a additional promising chemotherapeutic agent that has efficacy in a variety of cancers We investigated the individual and combinational cytotoxic effects of these drugs in MM cell lines (RPMI8226 and MM1S) and primary MM cells Our results demonstrated a synergistic effect of these drugs, which was effective for both p53-wild-type and p-53-deleted MM cells, but was minimal in mononuclear cells from a healthy donor Combination treatment with the two agents inhibited proliferation and promoted cytotoxicity and apoptosis as assessed by Annexin-V/PI staining, caspase-3 degradation, and PARP cleavage Cell death was associated with the up-regulation of the pro-apoptotic protein Bax and the down-regulation of the anti-apoptotic proteins Mcl-1 and survivin The combination drug treatment also promoted a decrease in the levels of the downstream target proteins of the mTOR pathway, p70s6k, and 4EBP-1, as well as an increase in the level of phosphorylation of the tumor suppressor protein p53 in MM1S cells p21 was also down-regulated upon treatment with the two drugs, suggesting a mechanism of sensitization through the release of cell cycle arrest Our results demonstrate a network of regulatory factors that may contribute to the synergistic cytotoxicity of everolimus and bendamustine, and provide a rationale for application for the combinatorial treatment of MM with alkylating agents and mTOR inhibitors in future clinical practice

Prevention of setup errors in radiotherapy

Abstract: A patient safety system (PSS) (100) uses optical tracking in a linear accelerator treatment room to prevent gross setup errors. A patient (150) undergoes a computed tomography (CT) treatment-simulation scan while a CT ball bearing (BB) is on patient's surface. The CT BB is replaced with an infrared reflective marker (IRRM) (160) before radiotherapy treatment starts. Coordinates of the CT BB relative to an isocenter of the treatment room are used as reference for tracking. The coordinate system of an optical tracking system is converted to a coordinate system of the treatment room. The PSS evaluates setup accuracy for a radiotherapy session by comparing real-time position of the single IRRM determined by the optical tracking technology with a predicted reference position, and displays results on a graphical user interface. The PSS stops radiation when a deviation between real-time coordinates and predicted coordinates of the IRRM (160) exceeds a predefined threshold.

Identification of a KRAS mutation in a patient with non-small cell lung cancer treated with chemoradiotherapy and panitumumab

Abstract: RTOG 0839 is a Phase II study of pre-operative chemoradiotherapy with or without panitumumab in potentially operable locally advanced non-small cell lung cancer (NSCLC). The investigational agent, panitumumab, is an anti-epithelial growth factor receptor (EGFR) antibody that improves progression-free survival in chemorefractory metastatic colorectal cancer (mCRC). Recently, both KRAS mutational status (i.e., mutated or not) and subtype (i.e., activating or inactivating) have been shown to be predictive of response to anti-EGFR therapy in mCRC. However, in NSCLC, it is unknown if KRAS mutational status or subtype predict benefit to anti-EGFR therapies because of unique genetic and epigenetic factors unique to each cancer. We present a patient with stage III NSCLC containing a KRAS G12D activating mutation who had a partial pathologic response, with disappearance of a minor KRAS mutant clone. This case suggests possible eradication of the G12D KRAS lung cancer clones by concurrent chemoradiation with panitumumab.

Design and analysis of dual-frame telephone surveys for health policy research

Abstract: Large-scale health surveys are major data sources for health policy research, and telephone survey is the major mode for national or state health surveys. With the dramatic increase of cell phone use over the past decade, large telephone surveys need to employ the dual-frame design, which greatly improves the representativeness of the sample. From a practical perspective, it is not clear how to optimally implement the dual-frame sampling design. This article studies the impact of different design and analytical strategies of dual-frame surveys on the estimation of population quantities via both simulation studies and using data from the Ohio Family Health Survey (OFHS). Results imply that cell-only design is less biased than the cell-any design with no or poor post-stratification. If accurate post-stratification information is available for different phone use patterns, all estimation techniques provide similar results and the cell-any supplemental sampling is more cost efficient. Practical recommendations for health policy researchers are provided based on applying different analytical methods to the OFHS data.

Estimation bias of different design and analytical strategies in dual-frame telephone surveys: an empirical evaluation

Abstract: Dual-frame survey designs have become increasingly popular in large-scale telephone surveys. This is due to the lack of coverage of the traditional landline survey design and the escalating use of cell phones in recent years. Several estimation strategies have been proposed and their properties have been discussed under ideal scenarios, including pseudo-maximum-likelihood estimation, single-frame estimation, and simple composite estimation [C.J. Skinner and J.N.K. Rao, Estimation in dual frame surveys with complex designs, J. Am. Statist. Assoc. 91 (1996), pp. 349–356; S.L. Lohr and J.N.K. Rao, Inference from dual frame surveys, J. Am. Statist. Assoc. 95 (2000), pp. 271–280]. In practice, estimation in dual-frame telephone surveys is vulnerable to biases and errors (e.g. inaccessibility, topic/mode salience, and measurement error). The investigation of the performance of popular dual-frame estimation methods is scarce in real and less ideal scenarios. Through an innovatively designed simulation study, we ...

A further investigation of the centroid-to-centroid method for stereotactic lung radiotherapy: A phantom study

Abstract: Purpose: Our previous study[B. Lu et al. , “A patient alignment solution for lung SBRT setups based on a deformable registration technique,” Med. Phys.39(12), 7379–7389 (Year: 2012)]10.1118/1.4766875 proposed a deformable-registration-based patient setup strategy called the centroid-to-centroid (CTC) method, which can perform an accurate alignment of internal-target-volume (ITV) centroids between averaged four-dimensional computed tomography and cone-beam computed tomography (CBCT) images. Scenarios with variations between CBCT and simulation CT caused by irregular breathing and/or tumor change were not specifically considered in the patient study [B. Lu et al. , “A patient alignment solution for lung SBRT setups based on a deformable registration technique,” Med. Phys.39(12), 7379–7389 (Year: 2012)]10.1118/1.4766875 due to the lack of both a sufficiently large patient data sample and a method of tumor tracking. The aim of this study is to thoroughly investigate and compare the impacts of breathing pattern and tumor change on both the CTC and the translation-only (T-only) gray-value mode strategies by employing a four-dimensional (4D) lung phantom. Methods: A sophisticated anthropomorphic 4D phantom (CIRS Dynamic Thorax Phantom model 008) was employed to simulate all desired respiratory variations. The variation scenarios were classified into four groups: inspiration to expiration ratio (IE ratio) change, tumor trajectory change, tumor position change, tumor size change, and the combination of these changes. For each category the authors designed several scenarios to demonstrate the effects of different levels of breathing variation on both of the T-only and the CTC methods. Each scenario utilized 4DCT and CBCT scans. The ITV centroid alignment discrepancies for CTC and T-only were evaluated. The dose-volume-histograms (DVHs) of ITVs for two extreme cases were analyzed. Results: Except for some extreme cases in the combined group, the accuracy of the CTC registration was about 2 mm for all cases for both the single and the combined scenarios. The performance of the CTC method was insensitive to region-of-registration (ROR) size selections, as suggested by the comparable accuracy between 1 and 2 cm expansions of the ROR selections for the method. The T-only method was suitable for some single scenarios, such as trajectory variation, position variation, and size variation. However, for combined scenarios and/or a large variation in the IE ratio, the T-only method failed to produce reasonable registration results (within 3 mm). The discrepancy was close to, or even greater than, 1 cm. In addition, unlike the CTC method, the T-only method was sensitive to the ROR size selection. The DVH analysis suggested that a large ITV to PTV margin should be considered if a breathing pattern variation is observed. Conclusions: The phantom study demonstrated that the CTC method was reliable for scenarios in which breathing pattern variation was involved. The T-only gray value method worked for some scenarios, but not for scenarios that involved an IE ratio variation. For scenarios involving position variation, the T-only method worked only with a careful selection of the ROR, whereas the CTC method was independent of ROR size as long as the ITVs were included in the ROR. One indication of the dose consequence analysis was that a large ITV to PTV margin should be considered if a breathing pattern variation is observed.

PM02734 (Elisidepsin) induces caspase-independent cell death associated with features of autophagy, inhibition of the Akt/mTOR signaling pathway, and activation of death-associated protein kinase (Clinical Cancer Research (2011))

Abstract: The authors wish to retract the article titled \"PM02734 (Elisidepsin) Induces Caspase-Independent Cell Death Associated with Features of Autophagy, Inhibition of the Akt/mTOR Signaling Pathway, and Activation of Death-Associated Protein Kinase,\" which was published in the August 15, 2011, issue of Clinical Cancer Research (1). After an unidentified concerned reader made allegations of image mishandling in several figures, the authors requested that their medical school conduct an investigation as per its established protocol. The investigators concluded that there was enhancement of bands in some of the questioned figures and that the changes were subtle and seen only on special analysis. One of the coauthors, who since has returned to his home country, accepted full responsibility for the changes. He never mentioned the enhancements to any of the authors before manuscript submission. In no casewould the conclusions from the experiments have been different if no alterations had been made. Independent repetition of key experiments by another senior investigator showed reproducibility of the major findings. In view of the reproducibility of the original data by a third party, the authors continue to stand by the conclusions of the article. However, because the submission did not meet the standards for manuscript submission to Clinical Cancer Research as described in the Instructions to Authors, the authors voluntarily retract this article. The authors apologize to the readers for the inconvenience that this oversight may have caused.