bluuebunny/crossref_metadata_2025_split huggingface dataset:
Realistic respiratory motion margins for external beam partial breast irradiation
Authors: Conroy Leigh , Quirk Sarah , Smith Wendy L. 
Published: August 2015

Purpose:Respiratory margins for partial breast irradiation (PBI) have been largely based on geometric observations, which may overestimate the margin required for dosimetric coverage. In this study, dosimetric population‐based respiratory margins and margin formulas for external beam partial breast irradiation are determined.Methods:Volunteer respiratory data and anterior–posterior (AP) dose profiles from clinical treatment plans of 28 3D conformal radiotherapy (3DCRT) PBI patient plans were used to determine population‐based respiratory margins. The peak‐to‐peak amplitudes (A) of realistic respiratory motion data from healthy volunteers were scaled from A = 1 to 10 mm to create respiratory motion probability density functions. Dose profiles were convolved with the respiratory probability density functions to produce blurred dose profiles accounting for respiratory motion. The required margins were found by measuring the distance between the simulated treatment and original dose profiles at the 95% isodose level.Results:The symmetric dosimetric respiratory margins to cover 90%, 95%, and 100% of the simulated treatment population were 1.5, 2, and 4 mm, respectively. With patient set up at end exhale, the required margins were larger in the anterior direction than the posterior. For respiratory amplitudes less than 5 mm, the population‐based margins can be expressed as a fraction of the extent of respiratory motion. The derived formulas in the anterior/posterior directions for 90%, 95%, and 100% simulated population coverage were 0.45A/0.25A, 0.50A/0.30A, and 0.70A/0.40A. The differences in formulas for different population coverage criteria demonstrate that respiratory trace shape and baseline drift characteristics affect individual respiratory margins even for the same average peak‐to‐peak amplitude.Conclusions:A methodology for determining population‐based respiratory margins using real respiratory motion patterns and dose profiles in the AP direction was described. It was found that the currently used respiratory margin of 5 mm in partial breast irradiation may be overly conservative for many 3DCRT PBI patients. Amplitude alone was found to be insufficient to determine patient‐specific margins: individual respiratory trace shape and baseline drift both contributed to the dosimetric target coverage. With respiratory coaching, individualized respiratory margins smaller than the full extent of motion could reduce planning target volumes while ensuring adequate coverage under respiratory motion.
Coverage‐based treatment planning to accommodate delineation uncertainties in prostate cancer treatment
Authors: Xu Huijun , Gordon J. James , Siebers Jeffrey V. 
Published: August 2015

Purpose:To compare two coverage‐based planning (CP) techniques with fixed margin‐based (FM) planning for high‐risk prostate cancer treatments, with the exclusive consideration of the dosimetric impact of delineation uncertainties of target structures and normal tissues.Methods:In this work, 19‐patient data sets were involved. To estimate structure dose for each delineated contour under the influence of interobserver contour variability and CT image quality limitations, 1000 alternative structures were simulated by an average‐surface‐of‐standard‐deviation model, which utilized the patient‐specific information of delineated structure and CT image contrast. An IMRT plan with zero planning‐target‐volume (PTV) margin on the delineated prostate and seminal vesicles [clinical‐target‐volume (CTVprostate) and CTVSV] was created and dose degradation due to contour variability was quantified by the dosimetric consequences of 1000 alternative structures. When D98 failed to achieve a 95% coverage probability objective D98,95 ≥ 78 Gy (CTVprostate) or D98,95 ≥ 66 Gy (CTVSV), replanning was performed using three planning techniques: (1) FM (PTVprostate margin = 4,5,6 mm and PTVSV margin = 4,5,7 mm for RL, PA, and SI directions, respectively), (2) CPOM which optimized uniform PTV margins for CTVprostate and CTVSV to meet the D98,95 objectives, and (3) CPCOP which directly optimized coverage‐based objectives for all the structures. These plans were intercompared by computing percentile dose‐volume histograms and tumor‐control probability/normal tissue complication probability (TCP/NTCP) distributions.Results:Inherent contour variability resulted in unacceptable CTV coverage for the zero‐PTV‐margin plans for all patients. For plans designed to accommodate contour variability, 18/19 CP plans were most favored by achieving desirable D98,95 and TCP/NTCP values. The average improvement of probability of complication free control was 9.3% for CPCOP plans and 3.4% for CPOM plans.Conclusions:When the delineation uncertainties need to be considered for prostate patients, CP techniques can produce more desirable plans than FM plans for most patients. The relative advantages between CPCOP and CPOM techniques are patient specific.
Widening inequalities in self-rated health by material deprivation? A trend analysis between 2001 and 2011 in Germany
Authors: Pförtner Timo-Kolja , Elgar Frank J 
Published: August 2015

BackgroundResearch on inequalities in health has shown a strong association between the lack of standard of living (defined as material deprivation) and self-rated health (SRH). In this study, we sought to further examine this association in a trend analysis of relative and absolute inequalities in SRH as defined by material deprivation in Germany.MethodsData were obtained from the German Socio-Economic Panel (GSOEP) between 2001 and 2011. Material deprivation was measured on the basis of 11 living standard items missing due to financial reasons. We used the relative index of inequality (RII) and slope index of inequality (SII) to measure inequalities in SRH by material deprivation, calculating pooled interval logistic regression with robust SEs. Stepwise models were estimated, including demographic and socioeconomic variables, to assess their inter-relation with inequalities in SRH by material deprivation.ResultsThe results showed a steady increase in poor SRH over the 10-year duration of the study. A quadratic (inverted U-shaped) trend was observed in material deprivation in the standards of living, which rose from 2001 to 2005, and then declined in 2011. A similar but non-significant trend was found in relative and absolute inequalities in SRH by material deprivation, which increased from 2001 to 2005 and then declined.ConclusionsInequality in SRH by material deprivation was relatively stable; however, an observed quadratic trend coincided with active and passive labour market reforms in Germany in early 2005.
Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53
Authors: Zhang Shengliang , Zhou Lanlan , Hong Bo , van den Heuvel A. Pieter J. , Prabhu Varun V. , Warfel Noel A. , Kline Christina Leah B. , Dicker David T. , Kopelovich Levy , El-Deiry Wafik S. 
Published: August 2015

Abstract
The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or antiangiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small-molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin–proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation, specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity toward normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anticancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anticancer therapy that acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling. Cancer Res; 75(18); 3842–52. ©2015 AACR.
Antitumor Effects and Mechanisms of AZD4547 on FGFR2-Deregulated Endometrial Cancer Cells
Authors: Kwak Yeonui , Cho Hanna , Hur Wooyoung , Sim Taebo 
Published: August 2015

AbstractUncontrolled activation of FGFRs induces the progression of various cancers. It was recently reported that FGFR2-activating mutants are implicated in about 12% of endometrial carcinomas. AZD4547, a potent pan-FGFR inhibitor, is currently being evaluated in clinical trials for several FGFR-driven cancers. However, AZD4547 has not been examined yet against FGFR2 mutant–driven endometrial cancers. Thus, we evaluated the activity of AZD4547 against four different endometrial cancer cells, including AN3-CA, MFE296, MFE280, and HEC1A, where all but HEC1A cells express distinctive FGFR2 mutations. We found that AZD4547 exhibits potent antiproliferative activity (EC50 = 31 nmol/L) against AN3-CA cells harboring FGFR2-K310R/N550K mutant. Analysis using a phospho-kinase array revealed that AZD4547 blocks FGFR2 downstream signaling, such as p38, ERK1/2, JNK, p70S6K, and PLCγ. Moreover, oral administration of AZD4547 (30 mg/kg, every day) remarkably delayed tumor growth in a mouse xenograft model of AN3-CA cells. Unbiased reporter gene assay showed that AZD4547 antagonizes the aFGF-induced activation of several transcription factors, including EGR1, ELK-1/SRF, AP-1, and NFκB. Genome-wide transcriptome analysis revealed that AZD4547 perturbs a number of transcriptions, and EGR1 was identified as one of the major targets of AZD4547. The significance of the FGFR2–EGR1 axis in endometrial cancer progression has not been reported. In addition, using kinome-wide inhibition profiling analysis, we first identified potential new target kinases of AZD4547, including MAP4K3, MAP4K5, IRR, RET, and FLT3. Our study demonstrated that AZD4547 exhibits its therapeutic activity against endometrial cancer cells by perturbing various regulatory mechanisms related to FGFR signaling. Mol Cancer Ther; 14(10); 2292–302. ©2015 AACR.
Abstract A07: Loss of Rpl22 promotes tumor progression through regulation of angiogenesis and dissemination.
Authors: Rao Shuyun , Stadanlick Jason E. , Cai Kathy Q. , David Wiest L. 
Published: August 2015

Abstract
Mutations in ribosomal proteins (RP) often cause bone marrow syndromes associated with increased risk for cancer development. We have shown that Rpl22 is a haploinsufficient tumor suppressor in T acute lymphoblastic leukemia (T-ALL). Indeed, loss of one Rpl22 allele accelerates T-cell lymphomagenesis in the murine Akt transgenic mouse model, by inducing the stem cell factor Lin28B in an NFκB-dependent manner. Moreover, mice lacking both Rpl22 alleles exhibited significantly increased thymic tumor size, which was associated with poor survival and markedly enhanced angiogenesis relative to Rpl22 heterozygous mice or wild type. The increased angiogenesis in the mediastinal mass was linked to upregulation of VEGFA and downregulation of S1P1. Loss of S1P1 is sufficient to block egress of lymphoma cells from thymus. Rpl22-deficient thymic lymphoma lines also exhibit enhanced growth upon adaptation to growth in vitro, and this is reversed by ectopic expression of Rpl22. Rpl22 expression also represses the expression of proteins that promote traversal of the cell cycle. Collectively, the increased tumor growth and angiogenesis, and the blockade of thymic egress contribute to the enlarged mediastinal masses observed in Rpl22-deficient mice. Rpl22-mutant T-ALL are a molecularly distinct subtype exhibiting increased aggression and treatment resistance. Accordingly, our identification of a number of signaling pathways controlled by Rpl22 may enable the development of novel strategies, such as targeting angiogenesis, in such cases of T-ALL.
Citation Format: Shuyun Rao, Jason E. Stadanlick, Kathy Q. Cai, Wiest L. David. Loss of Rpl22 promotes tumor progression through regulation of angiogenesis and dissemination. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A07.
Abstract A33: Role for the tumor suppressor phf6 in hematopoiesis.
Authors: Moore Finola E. , Esain Virginie , Lobbardi Riadh , Blackburn Jessica S. , North Trista E. , Langenau David M. 
Published: August 2015

Abstract
Plant Home domain Finger 6 (PHF6) is a tumor suppressor of unknown function for blood malignancies such as T-cell Acute Lymphoblastic Leukemia (T-ALL), Acute Myeloid leukemia (AML), and Chronic Myeloid Leukemia (CML). PHF6 contains two zinc finger-like PH domains and interacts with the Nucleosome Remodeling and Deacetylation (NuRD) complex, suggesting a role in chromatin remodeling. Although PHF6 loss-of-function mutations are found in nearly 40% of T-ALL patients, little is known about how PHF6 mutations contribute to blood development and leukemogenesis. To understand the function of PHF6, beginning with its role in hematopoiesis, we have undertaken developmental studies in zebrafish to discover how loss of phf6 affects blood development and to determine which pathways are regulated by phf6. Zebrafish will be used to study hematopoiesis due to the remarkable conservation of molecular pathways that regulate blood development, genetic tractability, and ability to observe embryonic development over a short window of time. RNA in situ hybridization studies of zebrafish embryos showed that phf6 is expressed broadly during zebrafish development, and especially in the dorsal aorta, a site analogous to the aorta-gonad-mesonephros (AGM) in mammals, from which hematopoietic stem cells (HSCs) arise. Further, phf6 is highly expressed in lymphocytes of adult zebrafish, reminiscent of the expression patterns found in human and mouse. To determine the effect of phf6 loss on hematopoiesis, phf6 expression was knocked down by morpholino injection. We find that phf6 morphants have increased numbers of HSCs by RNA in situ hybridization of runx1/cmyb in the AGM and caudal hematopoietic tissue ((CHT) analogous to mammalian fetal liver), sites of HSC emergence and migration. Later in development, phf6 morphants demonstrate increased lymphocytes by RNA in situ hybridization of rag1 at the thymus. Similar phenotypes were observed in homozygous phf6-null mutants generated by TALEN-mediated knockout. Phf6-null mutant zebrafish survive to Mendelian ratios and are fertile as adults. In total, we found a new role for phf6 in regulation of HSC formation.
Citation Format: Finola E. Moore, Virginie Esain, Riadh Lobbardi, Jessica S. Blackburn, Trista E. North, David M. Langenau. Role for the tumor suppressor phf6 in hematopoiesis. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A33.
Abstract A45: Osteoblastic niche supports the growth of quiescent multiple myeloma cells.
Authors: Chen Zheng , Orlowski Robert Z. , Wang Michael , Kwak Larry , McCarty Nami 
Published: August 2015

Abstract
The heterogeneity of multiple myeloma (MM) contributes to variable responses to therapy. In this study, we aim to correlate the heterogeneity of MM to the presence of quiescent cells using the PKH26 dye. We tracked the rare quiescent cells in different niches of the bone marrow by allowing the cells to cycle in vivo. Surprisingly, quiescent PKH+ MM cells prefer to reside within the osteoblastic niches of the bone marrow (PKH+/OS) rather than the vascular niches or the spleen. These cells (PKH+/OS) displayed enhanced stem-like properties by forming colonies in semi-solid medium. PKH+ cells were highly tumorigenic, as compared to PKH- cells, and were resistant to a variety of drugs. However, the levels of drug resistance were somewhat similar regardless of where the PKH+ cells were isolated. Our data indicate that osteoblastic niches support the growth of quiescent PKH+ cells and allow them to have stem-like functions.
Citation Format: Zheng Chen, Robert Z. Orlowski, Michael Wang, Larry Kwak, Nami McCarty. Osteoblastic niche supports the growth of quiescent multiple myeloma cells. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A45.
Abstract B14: Hematopoietic RIPK1 deficiency results in bone marrow failure due to apoptosis and RIPK3-mediated necroptosis.
Authors: Roderick Justine R. , Hermance Nicole C. , Zelic Matija , Polykratis Apostolos , Pasparakis Manolis , Kelliher Michelle A. 
Published: August 2015

Abstract
The serine/threonine kinase RIPK1 is recruited to the TNF receptor 1 to mediate pro-inflammatory signaling and to regulate TNF-induced apoptosis and necroptosis. The kinase activity of RIPK1 is required for RIPK3 activation and induction of necroptosis, an inflammatory form of cell death. Although Ripk3-/- mice are viable, a RIPK1 deficiency results in postnatal lethality. To identify the lineages and cell types that depend on RIPK1 for survival, we generated conditional Ripk1 mice. Tamoxifen administration to adult RosaCreERT2Ripk1fl/fl mice results in lethality due to cell death in the intestinal and hematopoietic lineages. Similarly, Ripk1 deletion in cells of the hematopoietic lineage stimulates pro-inflammatory cytokine and chemokine production and hematopoietic cell death, resulting in bone marrow failure. The cell death reflects cell intrinsic survival roles for RIPK1 in hematopoietic stem and progenitor cells, as Vav-iCre Ripk1fl/fl fetal liver cells failed to reconstitute hematopoiesis in lethally irradiated recipients. We demonstrate that a RIPK3 deficiency partially rescues hematopoiesis in Vav-iCre Ripk1fl/fl mice, revealing that RIPK1 mediates survival by preventing RIPK3-mediated necroptosis. However, Vav-iCre Ripk1fl/fl Ripk3-/- progenitors remain TNF sensitive in vitro and fail to repopulate irradiated mice. These genetic studies reveal that a hematopoietic RIPK1 deficiency triggers both apoptotic and necroptotic death that is partially prevented by a RIPK3 deficiency. Thus, in contrast to in vitro studies, RIPK1 functions in hematopoietic cells to negatively regulate RIPK3 and prevent inflammation.
Citation Format: Justine R. Roderick, Nicole C. Hermance, Matija Zelic, Apostolos Polykratis, Manolis Pasparakis, Michelle A. Kelliher. Hematopoietic RIPK1 deficiency results in bone marrow failure due to apoptosis and RIPK3-mediated necroptosis. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B14.
Abstract B21: Identifying mechanisms of resistance to BET bromodomain inhibition.
Authors: Centore Richard C. , Hatton Charlie , Bryant Barbara , Sims Robert J. 
Published: August 2015

Abstract
BET (bromodomain and extra terminal domain) family members are key transcriptional regulators that play an important role driving oncogene expression in hematologic malignancies. Several BET inhibitors (BETi) have recently entered clinical trials, including the optimized BET inhibitor CPI-0610. Understanding mechanisms of resistance to BET inhibition represents an important challenge and will likely provide insight into mechanisms of BET sensitivity. Here, we have developed a model of BETi resistance in AML using the BET inhibitor, CPI-203. Resistant cells demonstrate half-maximal growth inhibition at a concentration of CPI-203 that is greater than 10-fold that of parental cells. When challenged with CPI-203, parental cells undergo apoptosis, a phenomenon that correlates with strong suppression of MYC and the anti-apoptotic gene, BCL2. In resistant cells, transcription of MYC and BCL2 is maintained in the presence of BETi, and the apoptotic effect is severely blunted. Interestingly, withdrawal of BETi from the resistant cells triggers apoptosis, suggesting an acquired dependency on BET inhibition in these cells. To further understand the molecular mechanisms responsible for maintenance of MYC expression in resistant cells, we performed gene expression profiling and functionally interrogated transcriptional co-regulators that may facilitate BET-escape. Despite inhibition of BET proteins, MYC transcription in resistant cells remained dependent on acetyl-lysine signaling and non-BET chromatin adaptors. In summary, our work models resistance to a novel therapy and sheds light on additional targets that may allow cancer cells to bypass BETi-induced cell death.
Citation Format: Richard C. Centore, Charlie Hatton, Barbara Bryant, Robert J. Sims, III. Identifying mechanisms of resistance to BET bromodomain inhibition. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B21.
Abstract B37: The real deal: Using cytochalasin B in sonodynamic therapy to preferentially damage leukemia cells.
Authors: Trendowski Matthew 
Published: August 2015

Abstract
Background/Aim: Sonodynamic therapy (SDT) is a form of ultrasound therapy in which chemotherapeutic agents known as sonosensitizers are administered to increase the efficacy of ultrasound's preferential damage to neoplastic cells. Perhaps one of the most intriguing capabilities of ultrasound is its ability to preferentially lyse cells based on size. Cytochalasin B is a cytokinesis inhibitor that preferentially enlarges and multinucleates malignant cells, making them much more sensitive to ultrasonic irradiation.
Materials and Methods: The present study investigated the extent of preferential damage inflicted by cytochalasin B on U937 leukemia/human blood cell populations. Cell mixtures were treated with cytochalasin B and then sonicated under a relatively low intensity (3W/cm2).
Results: Cytochalasin B preferentially damages U937 cells both before and after sonication. This agent also reduces rapid proliferation as the clonogenicity of U937 cells was considerably reduced following treatment.
Conclusion: Cytochalasin B may have profound therapeutic applications when combined with SDT.
Citation Format: Matthew Trendowski. The real deal: Using cytochalasin B in sonodynamic therapy to preferentially damage leukemia cells. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B37.