bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA25: Targeting cancers with deletion of the p16/p14 tumor suppressor locus
Authors: Marks Kevin 
Published: May 2017

Abstract
Mutations in tumor suppressor genes are a hallmark of cancer and contribute substantially to the molecular pathogenesis of the disease. Particularly prevalent are homozygous deletions of the CDKN2A tumor suppressor locus on chromosome 9p21, which occur in at least 15% of all cancer and lead to loss of the dual tumor suppressors p16(INK4A) and p14(ARF). Targeted therapies selective for loss of CDKN2A have proven elusive, and it may be necessary to identify alternate approaches to target tumors with this deletion. Notably, Chr9p21 deletions frequently involve co-deletion of genes proximal to CDKN2A. Foremost among these is the methylthioadenosine phosphorylase (MTAP) gene, which resides within 100 kb of CDKN2A, and is co-deleted in 80-90% of tumors with CDKN2A deletion. We sought therefore to evaluate whether the frequent co-deletion of the adjacent metabolic gene methylthioadenosine phosphorylase (MTAP) creates targetable vulnerabilities. We conducted an shRNA screen in isogenic cells that varied only in their MTAP-deletion status, and identified the metabolic enzyme, methionine adenosyltransferase II, alpha (MAT2A), and the arginine methyltransferase, PRMT5, as vulnerable enzymes in cells with MTAP deletion. Metabolomic and biochemical studies revealed a mechanistic basis for this synthetic lethality. MTAP substrate methylthioadenosine (MTA) accumulates upon MTAP loss, and biochemical profiling of a methyltransferase enzyme panel revealed that MTA is a potent and selective inhibitor of PRMT5. MTAP-deletion leads to reduced basal PRMT5 methylation activity and increased sensitivity to PRMT5 targeting. MAT2A produces PRMT5 substrate S-adenosylmethionine (SAM), and targeting of MAT2A reduces growth and PRMT5 methylation activity selectively in MTAP-deleted cells. Further, this vulnerability extends to PRMT5 co-complex proteins such as the atypical kinase Rio Kinase 1 (RIOK1). Thus, MAT2A, PRMT5, and RIOK1 comprise an unappreciated axis of targets that is selectively vulnerable in CDKN2A/MTAP-deleted tumors. Unique biochemical features of PRMT5 create this vulnerability, which presents a promising new avenue for targeted therapy.
Citation Format: Kevin Marks. Targeting cancers with deletion of the p16/p14 tumor suppressor locus. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA25.
Abstract IA29: Targeting undruggable proteins for degradation with small molecules
Authors: Kaelin William G. 
Published: May 2017

Abstract
Many well-studied oncoproteins are currently viewed to be “undruggable”. The infamous teratogen thalidomide was serendipitously discovered to be a potent antimyeloma drug in the 1990s but its mechanism of action was unknown. In 2010 thalidomide was shown by Handa and coworkers to bind to cereblon, which is the substrate-recognition subunit of a cullin-dependent ubiquitin ligase. Moreover, thalidomide was found to inhibit this ligase in vitro, suggesting that thalidomide is a cereblon antagonist. However, it soon became apparent that loss of cereblon rendered myeloma cells resistant to thalidomide (and related drugs such as lenalidomide, collectively referred to as IMiDs). This suggested to us that cereblon, once bound to an IMiD, acquires a new (neomorphic) ability to target a myeloma-relevant protein for destruction. To look for such a protein we built a bicistronic expression vector that encodes both a protein open reading frame (ORF)-firefly luciferase fusion protein and, from the same mRNA, renilla luciferase for normalization purposes, with both proteins under the control of an internal ribosomal entry site (IRES). We then made a library of ~12,000 such ORF-luciferase fusions and introduced them into 293T cells in quadruplicate in multiwell plate format (1 ORF/well), treated the cells with lenalidomide or vehicle, and monitored changes in firefly luciferase/renilla luciferase as a surrogate for changes in ORF stability. In this way we discovered that cereblon, once bound to lenalidomide, destabilizes IKZF1 and IKZF3. We went on to show that downregulation of IKZF1 and IKZF3 is intimately linked to the antimyeloma activity of the IMiDs. Ben Ebert and his group working in parallel and using complimentary approaches reached the same conclusion. Published and unpublished work from investigators such as Jay Bradner and Craig Crews suggests IMiDs can be reengineered to serve as molecular matchmakers between cereblon and novel targets. We are currently developing new screening methodologies to identify chemicals and genetic perturbants that directly or indirectly destabilize proteins of interest.
Citation Format: William G. Kaelin, Jr. Targeting undruggable proteins for degradation with small molecules. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA29.
Abstract IA31: Phthalimide conjugation as a strategy for targeted protein degradation
Authors: Winter Georg E. , Buckley Dennis L. , Bradner James E. 
Published: May 2017

Abstract
Ligand-induced target protein destabilization is an efficacious therapeutic strategy in cancer, but discovery in this field has historically been serendipitous given the lack of rational design principles. Building on the molecular logic of immunomodulatory drugs (“IMiDs”), we innovated a facile chemical solution for targeted protein degradation using bifunctional small molecules capable of recruiting the E3 ligase cereblon (CRBN). These bifunctional molecules induce immediate, and complete proteasomal degradation of their target proteins and thus represent a novel class of small molecule therapeutics with an entirely uncharted and unique molecular pharmacology.
Focusing our initial efforts on degraders of the BET family of proteins, we observed that they exhibit superior efficacy than BET inhibitors through unknown mechanisms. In order to dissect and mechanistically explain that differential molecular pharmacology, we used optimized small-molecule degraders and kinetic measures of chromatin structure and function to unveil an unrecognized, essential role for BRD4 in global control of transcriptional pause-release. Targeted BET degradation nucleates a collapse in the transcriptional core regulatory circuitry and thus enabled us to exploit transcriptional addictions in T-Cell acute lymphoblastic leukemia (T-ALL) that were intractable using competitive BET bromodomain inhibitors.
Citation Format: Georg E. Winter, Dennis L. Buckley, James E. Bradner. Phthalimide conjugation as a strategy for targeted protein degradation. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA31.
Abstract PR03: Molecular characterization of in vitro exhausted T cells
Authors: Hastings William , MacIsaac Kenzie , Guan Wei , Shaw Pamela , Dranoff Glenn , Cao Z Alexander 
Published: May 2017

Abstract
In previous work we observed that restimulating human PBMCs with anti-CD3/28 beads 4 days after a primary stimulation resulted in an exhausted phenotype, as characterized by loss of T cells' ability to secrete IL-2, TNFa, and IFNg. To further characterize the molecular phenotype of these cells, we isolated CD4+ and CD8+ T cells from our exhausted and non-exhausted samples and performed Nanostring gene expression analysis. Both exhausted CD4+ and CD8+ T cells exhibited upregulation of a 25-gene exhaustion gene signature, as compared to non-exhausted control cells. In addition, a number of immunologically important molecules are modulated in the exhausted cells. For example, MIF (macrophage migration inhibitory factor) mRNA is induced in the exhausted T cells. Closer examination of MIF expression in TCGA suggests that MIF level is inversely correlated to survival in indications such as HCC and H/N cancer. Furthermore, pathway analysis of differential gene expression revealed the JAK/STAT signaling pathway as significantly upregulated in the exhausted cells. Treatment of exhausted cells with a JAK inhibitor resulted in a partial reversal of the exhausted phenotype, as shown by restored cytokine secretion. Thus we show for the first time the involvement of JAK signaling in human T cell exhaustion, which may provide rationale for combining JAK inhibitors with other immune therapies for cancer. In summary, the in vitro T cell exhaustion model system has yielded intriguing activity nodes during T cell function. Future exploration in such immunological states may identify novel therapeutic targets and combination opportunities for immuno-oncology.
This abstract is also being presented as Poster B17.
Citation Format: William Hastings, Kenzie MacIsaac, Wei Guan, Pamela Shaw, Glenn Dranoff, Z Alexander Cao. Molecular characterization of in vitro exhausted T cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr PR03.
Chronological Development of Terrestrial Mean Precipitation
Authors: Park Kylie J. , Yoshimura Kei , Kim Hyungjun , Oki Taikan 
Published: May 2017

AbstractOver 150 years of investigations into global terrestrial precipitation are revisited to reveal how researchers estimated annual means from in situ observations before the age of digitization. After introducing early regional efforts to measure precipitation, the pioneering estimates of terrestrial mean precipitation from the late nineteenth and early twentieth centuries are compared to successive estimates, including those using the latest gridded precipitation datasets available. The investigation reveals that the range of the early estimates is comparable to the interannual variation in terrestrial mean precipitation derived from the latest Climatic Research Unit (CRU) dataset. In-depth revisions of the estimates were infrequent up to the 1970s, due in part to difficulty obtaining and maintaining up-to-date datasets with global coverage. This point is illustrated in a “family tree” that identifies the key publications that subsequent authors referenced, sometimes decades after the original publication. Significant efforts to collate global observations facilitated new investigations and improved data exchange, for example, in the International Hydrological Decade (1965–74) and following the establishment of the Global Telecommunication System under the World Weather Watch Programme of the World Meteorological Organization. Also in the 1970s were the first attempts to adjust in situ observations on a global scale to account for gauge undercatch, and this had a noticeable impact on mean annual estimates. There remains no single satisfactory approach to gauge bias adjustment. Echoing the repeated message of past researchers, today’s authors cite poor spatial coverage, temporal inhomogeneity, and inadequate sharing of in situ observations as the key obstacles to obtaining more accurate estimates of terrestrial mean precipitation.
Effect of alcohol consumption and smoking on disease damage in systemic lupus erythematosus: data from the Korean Lupus Network (KORNET) registry
Authors: Kim S-K , Lee S-S , Choe J-Y , Park S-H , Lee H 
Published: May 2017

Background We assessed correlations of smoking habits and alcohol consumption with disease activity or damage in patients with systemic lupus erythematosus (SLE). Methods A total of 505 patients with SLE were enrolled in the Korean Lupus Network (KORNET) SLE registry from January 2014 to January 2016. Disease activity and organ damage were measured by the SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index, respectively. Multivariate logistic regression analysis was used to analyze associations with cutaneous lesions. Results There were no differences in SLEDAI-2K and SLICC/ACR damage indices according to either smoking status or alcohol consumption. More frequent cutaneous damage was observed in current alcohol drinkers compared with non-current alcohol drinkers ( p = 0.020). Cutaneous damage was significantly associated with alcohol consumption (odds ratio (OR) 4.048, 95% confidence interval (CI) 1.251–12.102, p = 0.020). Both low (1–5 glasses/week) and high (≥6 glasses/week) amounts of alcohol consumption had a significant impact on cutaneous damage compared with the absence of current alcohol consumption ( p = 0.033 and p = 0.027, respectively). Pairwise comparison of alcohol consumption and smoking status with cutaneous damage showed that only alcohol consumption was significantly associated with the presence of cutaneous damage, compared with non-current alcohol consumption and non-current smoking (OR 3.513, 95% CI 1.130–10.920, p =0.030). Conclusions Current alcohol consumption, but not smoking, might influence the development of cutaneous damage in patients with SLE.
Perception of futile care and caring behaviors of nurses in intensive care units
Authors: Rostami Somaye , Esmaeali Ravanbakhsh , Jafari Hedayat , Cherati Jamshid Yazdani 
Published: May 2017

Objectives: Futile medical care is considered as the care or treatment that does not benefit the patient. Staff of intensive care units experience moral distress when they perceive the futility of care. Therefore, this study aimed to determine the relationship between perceptions of nurses regarding futile medical care and their caring behaviors toward patients in the final stages of life admitted to intensive care units. Method: This correlation, analytical study was conducted with 181 nursing staff of the intensive care units of health centers affiliated to Mazandaran University of Medical Sciences, Mazandaran, Iran. The data collection tool included a three-part questionnaire containing demographic characteristics form, perception of futile care questionnaire, and caring behaviors inventory. To analyze the data, statistical tests and central indices of tendency and dispersion were investigated using SPSS, version 19. Pearson’s correlation coefficient, partial correlation, t-test, and analysis of variance tests were performed to assess the relationship between the variables. Ethical considerations: The study was reviewed by the ethics committee of the Mazandaran University of Medical Sciences. Informed consent was obtained from participants. Results: Our findings illustrated that the majority of nurses (65.7%) had a moderate perception of futile care, and most of them (98.9%) had desirable caring behaviors in taking care of patients in the final stages of life. The nurses believed that psychosocial aspects of care were of utmost importance. There was a significant negative relationship between perception of futile care and caring behavior. Conclusion: Given the moderate perception of nurses concerning futile care, and its negative impact on caring behaviors toward patients, implementing suitable interventions for minimizing the frequency of futile care and its resulting tension seems to be mandatory. It is imperative to train nurses on adjustment mechanisms and raise their awareness as to situations resulting in futile care.
Dosimetric Evaluation of a Flexible Dual Balloon-Constructed Applicator in Treating Anorectal Cancer
Authors: Kuo Hsiang-Chi , Mehta Keyur J. , Yaparpalvi Ravindra , Lee Alan , Mynampati Dinesh , Bodner William , Garg Madhur , Huang David , Tomé Wolfgang A. , Kalnicki Shalom 
Published: May 2017

Background and Purpose: To assess the dosimetric flexibility of a dual balloon brachytherapy applicator developed for the treatment of anorectal lesions. Materials and Methods: Different amounts of water were infused into the inner and outer balloon separately to study the asymmetrical distribution of the catheter, the radial distance of the active source channel to the inner surface of the global target volume , the space between the active source channels, and their dosimetric impact to target tissues and uninvolved rectum. Results: Increasing inner balloon volume directly increased both the space between the active source channels and the radial distance of the active source channel to the inner surface of the global target volume. The space between the active source channels and the percentage of global target volume received 150% or more of the prescribed dose to target had a strong inverse correlation (−0.881/ P = .007, −0.976/ P = .001, respectively) with the radial distance of the active source channel to the inner surface of the global target volume. Conformity index, dose to 2 cm3 of rectum, and total reference air kerma were strongly correlated with the radial distance of the active source channel to the inner surface of the global target volume, with values of 0.952 ( P = .001), 0.833 ( P = .015), and 0.922 ( P = .002), respectively. Percentage of global target volume received 150% or more of the prescribed dose was significantly correlated with the space between the active source channels (0.81/ P = .022), and conformity index was strongly inversely correlated with the space between the active source channels (−0.833/ P = .015). Conclusion: The dual balloon-constructed Anorectal Applicator offers a flexible way to adjust the distances of the active source positions to the target in relation to uninvolved rectal wall. This flexibility simplifies planning which results in a highly conformal dose distribution to the target lesion while minimizing dose to normal rectal tissue.
CT Angiography of Peripheral Arterial Disease by 256-Slice Scanner: Accuracy, Advantages and Disadvantages Compared to Digital Subtraction Angiography
Authors: Mishra Atul , Jain Narendra , Bhagwat Anand 
Published: May 2017

Background: Peripheral arterial occlusive disease (PAOD) may cause disabling claudication or critical limb ischemia. Multidetector computed tomography (CT) technology has evolved to the level of 256-slice CT scanners which has significantly improved the spatial and temporal resolution of the images. This has provided the capability of chasing the contrast bolus at a fast speed enabling angiographic imaging of long segments of the body. These images can be reconstructed in various planes and various modes for detailed analysis of the peripheral vascular diseases which helps in making treatment decision. Purpose: The aim of this retrospective study was to compare the CT angiograms (CTAs) of all cases of PAOD done by 256-slice CT scanner at a tertiary care vascular center and comparing these images with the digital subtraction angiograms (DSAs) of these patients. Materials and Methods: The retrospective study included 53 patients who underwent both CTA and DSA at our center over a period of 3 years from March 2013 to March 2016. Results: The CTA showed high sensitivity (93%) and specificity (92.7%) for overall assessment of degree of stenosis in a vascular segment in cases of aortic and lower limb occlusive disease. The assessment of lesions of infrapopliteal segment was comparatively inferior (sensitivity 91.6%, accuracy 73.3%, and positive predictive value 78.5%), more so in the presence of significant calcification. The advantages of CTA were its noninvasive nature, ability to image large area of body, almost no adverse effects to the patients, and better assessment of vessel wall disease. However, the CTA assessment of collaterals was inferior with a sensitivity of only 62.7% as compared to DSA. Overall, 256-slice CTA provides fast and accurate imaging of vascular tree which can restrict DSA only in few selected cases as a problem-solving tool where clinico-radiological mismatch is present.
Cost‐effectiveness of biological treatment sequences for fistulising Crohn’s disease across Europe
Authors: Baji Petra , Gulácsi László , Brodszky Valentin , Végh Zsuzsanna , Danese Silvio , Irving Peter M , Peyrin‐Biroulet Laurent , Schreiber Stefan , Rencz Fanni , Lakatos Péter L , Péntek Márta 
Published: May 2017

BackgroundIn clinical practice, treatment sequences of biologicals are applied for active fistulising Crohn’s disease, however underlying health economic analyses are lacking.ObjectiveThe purpose of this study was to analyse the cost‐effectiveness of different biological sequences including infliximab, biosimilar‐infliximab, adalimumab and vedolizumab in nine European countries.MethodsA Markov model was developed to compare treatment sequences of one, two and three biologicals from the payer’s perspective on a five‐year time horizon. Data on effectiveness and health state utilities were obtained from the literature. Country‐specific costs were considered. Calculations were performed with both official list prices and estimated real prices of biologicals.ResultsBiosimilar‐infliximab is the most cost‐effective treatment against standard care across the countries (with list prices: €34684–€72551/quality adjusted life year; with estimated real prices: €24364–€56086/quality adjusted life year). The most cost‐effective two‐agent sequence, except for Germany, is the biosimilar‐infliximab–adalimumab therapy compared with single biosimilar‐infliximab (with list prices: €58533–€133831/quality adjusted life year; with estimated prices: €45513–€105875/quality adjusted life year). The cost‐effectiveness of the biosimilar‐infliximab–adalimumab–vedolizumab three‐agent sequence compared wit biosimilar‐infliximab –adalimumab is €87214–€152901/quality adjusted life year.ConclusionsThe suggested first‐choice biological treatment is biosimilar‐infliximab. In case of treatment failure, switching to adalimumab then to vedolizumab provides meaningful additional health gains but at increased costs. Inter‐country differences in cost‐effectiveness are remarkable due to significant differences in costs.
Targeting the interleukin-1 pathway in patients with hematological disorders
Authors: de Mooij Charlotte E. M. , Netea Mihai G. , van der Velden Walter J. F. M. , Blijlevens Nicole M. A. 
Published: May 2017

Abstract
Interleukin-1α (IL-1α) and IL-1β are potent inflammatory cytokines that activate local and systemic inflammatory processes and are involved in protective immune responses against infections. However, their dysregulated production and signaling can aggravate tissue damage during infection, inflammatory diseases, and chemotherapy-induced intestinal mucositis. Additionally, cytokines of the IL-1 family play an important role in homeostatic as well as “emergency” hematopoiesis and are involved in the pathogenesis of several myeloid and lymphoid hematological malignancies. In the pathogenesis of intestinal mucositis and graft-versus-host disease (GVHD), these cytokines are considered pivotal during the initiation as well as propagation phase, and insights from animal studies suggest that targeting the IL-1 pathway can significantly ameliorate mucositis and GVHD. Moreover, IL-1α and IL-1β might prove to be valuable targets for both prevention and treatment of cancer and cancer therapy–related complications, and the first clinical studies have already been performed in the setting of hematological malignancies. In this review, we will discuss the role of cytokines of the IL-1 family in hematological malignancies, chemotherapy-induced intestinal mucositis, and GVHD, and speculate on possibilities of therapeutically targeting the IL-1 pathway in hematological patients.