bluuebunny/crossref_metadata_2025 huggingface dataset:
Dosimetric Comparison of Volumetric Modulated Arc Therapy, Static Field Intensity Modulated Radiation Therapy, and 3D Conformal Planning for the Treatment of a Right-Sided Reconstructed Chest Wall and Regional Nodal Case
Authors: Dumane Vishruta A. , Hunt Margie A. , Green Sheryl , Lo Yeh-Chi , Bakst Richard L.
Published: February 2014

We compared 3D conformal planning, static field intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT) to investigate the suitable treatment plan and delivery method for a right-sided reconstructed chest wall and nodal case. The dose prescribed for the reconstructed chest wall and regional nodes was 50.4 Gy. Plans were compared for target coverage and doses of the lungs, heart, contralateral breast, and healthy tissue. All plans achieved acceptable coverage of the target and IMNs. The best right lung sparing achieved with 3D was a V20 Gy of 31.09%. Compared to it, VMAT reduced the same by 10.85% and improved the CI and HI over 3D by 18.75% and 2%, respectively. The ipsilateral lung V5 Gy to V20 Gy decreased with VMAT over IMRT by as high as 17.1%. The contralateral lung V5 Gy was also lowered with VMAT compared to IMRT by 16.22%. The MU and treatment beams were lowered with VMAT over IMRT by 30% and 10, respectively, decreasing the treatment time by >50%. VMAT was the treatment plan and delivery method of choice for this case due to a combination of improved lung sparing and reduced treatment time without compromising target coverage.
The Relationship between Health Promoting Behaviors and Quality of Life in Nursing Home Residents in Kayseri
Authors: Şenol Vesile , Ünalan Demet , Soyuer Ferhan , Argün Mahmut
Published: February 2014

Background and Aims. Healthy lifestyle behaviors are the major determinant of both prevention health and health related quality of life. The aim of this study was to examine the relationship between health-promoting behaviors and quality of life of elderly individuals living in nursing homes.Methods. The study was performed between October 2008 and 2009, in the city of Kayseri in Turkey, upon 136 individuals, aged 65 and above, living in the Gazioglu Nursing Home. A sociodemographic questionnaire, Standardized Mini Mental Test, Health Promoting Lifestyle Behaviors Profile (HPLP), and WHOQOL-OLD module were used for the gathering of data.Results. The overall HPLP and quality of life (QoL) scores were118.06±20.54and43.45±10.30, respectively. More than half of the participants have higher points than the mean QoL scores. The HPLP scores of these subjects were significantly higher compared to those with lower points than mean QoL scores. There was a positive relationship between the overall HPLP and WHOQOL-OLD mean scores, except for the autonomy and sensorial function domains.Conclusions. The study result showed that health-promoting behaviors are positively associated with better quality of life scores in the elderly subjects living in a nursing home.
Congenital Central Hypoventilation Syndrome: A Comprehensive Review and Future Challenges
Authors: Ljubič Karin , Fister Iztok , Fister Iztok
Published: February 2014

Congenital central hypoventilation syndrome is a disorder predisposed by a paired-like homebox PHOX2B gene. A mutation in the PHOX2B gene is a requisite when diagnosing congenital central hypoventilation syndrome. This mutation is identified in 93–100% of diagnosed patients. The mutation regarding this disorder affects the sensors, the central controller, and the integration of the signals within the central nervous system. This, inter alia, leads to insufficient ventilation and a decrease in PaO2, as well as an increase in PaCO2. Affected children are at risk during and after the neonatal period. They suffer from hypoventilation periods which may be present whilst sleeping only or in more severe cases when both asleep and awake. It is important for clinicians to perform an early diagnosis of congenital central hypoventilation in order to prevent the deleterious effects of hypoxaemia, hypercapnia, and acidosis on the neurocognitive and cardiovascular functions. Patients need long-term management and appropriate ventilatory support for improving the qualities of their lives. This paper provides a detailed review of congenital central hypoventilation syndrome, a congenital disorder that is genetic in origin. We describe the genetic basis, the wider clinical picture, and those challenges during the diagnosis and management of patients with this condition.
Colicin E2 Expression inLactobacillus brevisDT24, A Vaginal Probiotic Isolate, against UropathogenicEscherichia coli
Authors: Trivedi Disha , Jena Prasant Kumar , Seshadri Sriram
Published: February 2014

Novel therapeutic approaches are needed to combat the urinary tract infection in women. During menstruation elevated protein concentration and increase in oxygen and carbon dioxide concentrations with decrease in vaginal Lactobacilli all together contribute to urinary tract infections.Lactobacillusspecies are a predominant member of the vaginal microflora and are critical in the prevention of a number of urogenital diseases. In order to increase antimicrobial potential of vaginal Lactobacilli, bacteriocin colicin E2 which has specific activity against uropathogenicEscherichia colihas been overexpressed in vaginal probioticLactobacillus brevisDT24. RecombinantLactobacillus brevisDT24 expressing colicin E2 showed much higher inhibitory activity against uropathogenicEscherichia colithan wild typeL. brevisDT24in vitro. Efficacy of probioticLactobacillus brevisDT24 expressing colicin E2 protein is required for furtherin vivoevaluation.
Modeling and Testing Landslide Hazard Using Decision Tree
Authors: Alkhasawneh Mutasem Sh. , Ngah Umi Kalthum , Tay Lea Tien , Mat Isa Nor Ashidi , Al-Batah Mohammad Subhi
Published: February 2014

This paper proposes a decision tree model for specifying the importance of 21 factors causing the landslides in a wide area of Penang Island, Malaysia. These factors are vegetation cover, distance from the fault line, slope angle, cross curvature, slope aspect, distance from road, geology, diagonal length, longitude curvature, rugosity, plan curvature, elevation, rain perception, soil texture, surface area, distance from drainage, roughness, land cover, general curvature, tangent curvature, and profile curvature. Decision tree models are used for prediction, classification, and factors importance and are usually represented by an easy to interpret tree like structure. Four models were created using Chi-square Automatic Interaction Detector (CHAID), Exhaustive CHAID, Classification and Regression Tree (CRT), and Quick-Unbiased-Efficient Statistical Tree (QUEST). Twenty-one factors were extracted using digital elevation models (DEMs) and then used as input variables for the models. A data set of 137570 samples was selected for each variable in the analysis, where 68786 samples represent landslides and 68786 samples represent no landslides. 10-fold cross-validation was employed for testing the models. The highest accuracy was achieved using Exhaustive CHAID (82.0%) compared to CHAID (81.9%), CRT (75.6%), and QUEST (74.0%) model. Across the four models, five factors were identified as most important factors which are slope angle, distance from drainage, surface area, slope aspect, and cross curvature.
Comparison of Matrix Pencil Extracted Features in Time Domain and in Frequency Domain for Radar Target Classification
Authors: Khodjet-Kesba Mahmoud , Drissi Khalil El Khamlichi , Lee Sukhan , Kerroum Kamal , Faure Claire , Pasquier Christophe
Published: February 2014

Feature extraction is a challenging problem in radar target identification. In this paper, we propose a new approach of feature extraction by using Matrix Pencil Method in Frequency Domain (MPMFD). The proposed method takes into account not only the magnitude of the signal, but also its phase, so that all the physical characteristics of the target will be considered. With this method, the separation between the early time and the late time is not necessary. The proposed method is compared to Matrix Pencil Method in Time Domain (MPMTD). The methods are applied on UWB backscattered signal from three canonical targets (thin wire, sphere, and cylinder). MPMFD is applied on a complex field (real and imaginary parts of the signal). To the best of our knowledge, this comparison and the reconstruction of the complex electromagnetic field by MPMFD have not been done before. We show the effect of the two extraction methods on the accuracy of three different classifiers: Naïve bayes (NB), K-Nearest Neighbor (K-NN), and Support Vector Machine (SVM). The results show that the accuracy of classification is better when using extracted features by MPMFD with SVM.
Monosomy 21 Seen in Live Born Is Unlikely to Represent True Monosomy 21: A Case Report and Review of the Literature
Authors: Burgess Trent , Downie Lilian , Pertile Mark D. , Francis David , Glass Melissa , Nouri Sara , Pszczola Rosalynn
Published: February 2014

We report a case of a neonate who was shown with routine chromosome analysis on peripheral blood lymphocytes to have full monosomy 21. Further investigation on fibroblast cells using conventional chromosome and FISH analysis revealed two additional mosaic cell lines; one is containing a ring chromosome 21 and the other a double ring chromosome 21. In addition, chromosome microarray analysis (CMA) on fibroblasts showed a mosaic duplication of chromosome region 21q11.2q22.13 with approximately 45% of cells showing three copies of the proximal long arm segment, consistent with the presence of a mosaic ring chromosome 21 with ring instability. The CMA also showed complete monosomy for an 8.8 Mb terminal segment (21q22.13q22.3). Whilst this patient had a provisional clinical diagnosis of trisomy 21, the patient also had phenotypic features consistent with monosomy 21, such as prominent epicanthic folds, broad nasal bridge, anteverted nares, simple ears, and bilateral overlapping fifth fingers, features which can also be present in individuals with Down syndrome. The patient died at 4.5 months of age. This case highlights the need for additional studies using multiple tissue types and molecular testing methodologies in patients provisionally diagnosed with monosomy 21, in particular if detected in the neonatal period.
New Insight into the Molecular Drug Target of Diabetic Nephropathy
Authors: Soetikno Vivian , Arozal Wawaimuli , Louisa Melva , Setiabudy Rianto
Published: February 2014

Diabetic nephropathy (DN) lowered quality of life and shortened life expectancy amongst those affected. Evidence indicates interaction between advanced glycation end products (AGEs), activated protein kinase C (PKC) and angiotensin II exacerbate the progression of DN. Inhibitors of angiotensin-converting enzyme (ACEIs), renin angiotensin aldosterone system (RAAS), AGEs, and PKC have been tested for slowing down the progression of DN. The exact molecular drug targets that lead to the amelioration of renal injury in DN are not well understood. This review summarizes the potential therapeutic targets, based on putative mechanism in the progression of the disease.
Application of Liposomes in Treatment of Rheumatoid Arthritis: Quo Vadis
Authors: Kapoor Bhupinder , Singh Sachin Kumar , Gulati Monica , Gupta Reena , Vaidya Yogyata
Published: February 2014

The most common treatments for rheumatoid arthritis include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, disease modifying antirheumatic drugs (DMARDs), and some biological agents. However, none of the treatments available is able to achieve the ultimate goal of treatment, that is, drug-free remission. This limitation has shifted the focus of treatment to delivery strategies with an ability to deliver the drugs into the synovial cavity in the proper dosage while mitigating side effects to other tissues. A number of approaches like microemulsions, microspheres, liposomes, microballoons, cocrystals, nanoemulsions, dendrimers, microsponges, and so forth, have been used for intrasynovial delivery of these drugs. Amongst these, liposomes have proven to be very effective for retaining the drug in the synovial cavity by virtue of their size and chemical composition. The fast clearance of intra-synovially administered drugs can be overcome by use of liposomes leading to increased uptake of drugs by the target synovial cells, which in turn reduces the exposure of nontarget sites and eliminates most of the undesirable effects associated with therapy. This review focuses on the use of liposomes in treatment of rheumatoid arthritis and summarizes data relating to the liposome formulations of various drugs. It also discusses emerging trends of this promising technology.
Insecticidal Activity of Some Traditionally Used Ethiopian Medicinal Plants against Sheep KedMelophagus ovinus
Authors: Gemeda Negero , Mokonnen Walelegn , Lemma Hirut , Tadele Ashenif , Urga Kelbessa , Addis Getachew , Debella Asfaw , Getachew Mesaye , Teka Frehiwot , Yirsaw Kidist , Mudie Kissi , Gebre Solomon
Published: February 2014

Twelve medicinal plants and a commercially used drug Ivermectin were examined for insecticidal activity againstMelophagus ovinussheep ked at different time intervals usingin vitroadult immersion test. The findings show that at 3.13 µL/mL, 6.25 µL/mL and 12.5 µL/mL concentration ofCymbopogon citratus,Foeniculum vulgareandEucalyptus globulusessential oils respectively, recorded 100% mortalities againstM. ovinuswithin 3 hour of exposure. Significantly higher insecticidal activity of essential oils was recorded (P=0.00) when compared to 10 μg/mL Ivermectin after 3-hour exposure ofM. ovinusat a concentration of ≥1.57 μL/mL, ≥3 μL/mL, and ≥12.7 μL/mL essential oils ofC. citratus,F. vulgare, andE. globulus, respectively. Among essential oils,C. citratushas showed superior potency at a three-hour exposure of the parasite (P=0.00) at a concentration of ≥0.78 μL/mL. Strong antiparasitic activity was recorded by aqueous extract ofCalpurnia aurea(80% mortality) at a concentration of 200 mg/mL within 24 h among aqueous extracts of 9 medicinal plants. The results indicated all the four medicinal plants, particularly those tested essential oils, can be considered as potential candidates for biocontrol ofM. ovinussheep ked.
Activation of the Glutamate Receptor GRM1 Enhances Angiogenic Signaling to Drive Melanoma Progression
Authors: Wen Yu , Li Jiadong , Koo Jasmine , Shin Seung-Shick , Lin Yong , Jeong Byeong-Seon , Mehnert Janice M. , Chen Suzie , Cohen-Sola Karine A. , Goydos James S.
Published: February 2014

Glutamate-triggered signal transduction is thought to contribute widely to cancer pathogenesis. In melanoma, overexpression of the metabotropic glutamate receptor (GRM)-1 occurs frequently and its ectopic expression in melanocytes is sufficient for neoplastic transformation. Clinical evaluation of the GRM1 signaling inhibitor riluzole in patients with advanced melanoma has demonstrated tumor regressions that are associated with a suppression of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathways. Together, these results prompted us to investigate the downstream consequences of GRM1 signaling and its disruption in more detail. We found that melanoma cells with enhanced GRM1 expression generated larger tumors in vivo marked by more abundant blood vessels. Media conditioned by these cells in vitro contained relatively higher concentrations of interleukin-8 and VEGF due to GRM1-mediated activation of the AKT–mTOR–HIF1 pathway. In clinical specimens from patients receiving riluzole, we confirmed an inhibition of MAPK and PI3K/AKT activation in posttreatment as compared with pretreatment tumor specimens, which exhibited a decreased density of blood vessels. Together, our results demonstrate that GRM1 activation triggers proangiogenic signaling in melanoma, offering a mechanistic rationale to design treatment strategies for the most suitable combinatorial use of GRM1 inhibitors in patients. Cancer Res; 74(9); 2499–509. ©2014 AACR.
CBP Loss Cooperates with PTEN Haploinsufficiency to Drive Prostate Cancer: Implications for Epigenetic Therapy
Authors: Ding Liya , Chen Shuai , Liu Ping , Pan Yunqian , Zhong Jian , Regan Kevin M. , Wang Liguo , Yu Chunrong , Rizzardi Anthony , Cheng Liang , Zhang Jun , Schmechel Stephen C. , Cheville John C. , Van Deursen Jan , Tindall Donald J. , Huang Haojie
Published: February 2014

Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−; Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1, and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer. Cancer Res; 74(7); 2050–61. ©2014 AACR.
miR-28-5p Promotes Chromosomal Instability in VHL-Associated Cancers by Inhibiting Mad2 Translation
Authors: Hell Michael P. , Thoma Claudio R. , Fankhauser Niklaus , Christinat Yann , Weber Thomas C. , Krek Wilhelm
Published: February 2014

Chromosomal instability enables tumor development, enabled in part by aberrant expression of the mitotic checkpoint protein Mad2. Here we identify a novel regulatory mechanism for Mad2 expression involving miR-28-5p-mediated inhibition of Mad2 translation, and we demonstrate that this mechanism is triggered by inactivation of the tumor suppressor VHL, the most common event in clear cell renal cell carcinoma (ccRCC). In VHL-positive cancer cells, enhanced expression of miR-28-5p diminished Mad2 levels and promoted checkpoint weakness and chromosomal instability. Conversely, in checkpoint-deficient VHL-negative renal carcinoma cells, inhibition of miR-28-5p function restored Mad2 levels, mitotic checkpoint proficiency, and chromosomal stability. Notably, chromosome missegregation errors and aneuploidy that were produced in a mouse model of acute renal injury (as a result of kidney-specific ablation of pVHL function) were reverted in vivo also by genetic inhibition of miR-28-5p. Finally, bioinformatic analyses in human ccRCC associated loss of VHL with increased miR-28-5p expression and chromosomal instability. Together, our results defined miR-28-5p as a critical regulator of Mad2 translation and mitotic checkpoint function. By identifying a potential mediator of chromosomal instability in VHL-associated cancers, our work also suggests a novel microRNA-based therapeutic strategy to target aneuploid cells in VHL-associated cancers. Cancer Res; 74(9); 2432–43. ©2014 AACR.
Noninvasive Quantification of Solid Tumor Microstructure Using VERDICT MRI
Authors: Panagiotaki Eletheria , Walker-Samuel Simon , Siow Bernard , Johnson S. Peter , Rajkumar Vineeth , Pedley R. Barbara , Lythgoe Mark F. , Alexander Daniel C.
Published: February 2014

There is a need for biomarkers that are useful for noninvasive imaging of tumor pathophysiology and drug efficacy. Through its use of endogenous water, diffusion-weighted MRI (DW-MRI) can be used to probe local tissue architecture and structure. However, most DW-MRI studies of cancer tissues have relied on simplistic mathematical models, such as apparent diffusion coefficient (ADC) or intravoxel incoherent motion (IVIM) models, which produce equivocal results on the relation of the model parameter estimate with the underlying tissue microstructure. Here, we present a novel technique called VERDICT (Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumors) to quantify and map histologic features of tumors in vivo. VERDICT couples DW-MRI to a mathematical model of tumor tissue to access features such as cell size, vascular volume fraction, intra- and extracellular volume fractions, and pseudo-diffusivity associated with blood flow. To illustrate VERDICT, we used two tumor xenograft models of colorectal cancer with different cellular and vascular phenotypes. Our experiments visualized known differences in the tissue microstructure of each model and the significant decrease in cell volume resulting from administration of the cytotoxic drug gemcitabine, reflecting the apoptotic volume decrease. In contrast, the standard ADC and IVIM models failed to detect either of these differences. Our results illustrate the superior features of VERDICT for cancer imaging, establishing it as a noninvasive method to monitor and stratify treatment responses. Cancer Res; 74(7); 1902–12. ©2014 AACR.
Phase I Dose-Escalation Study of Onartuzumab as a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies
Authors: Salgia Ravi , Patel Premal , Bothos John , Yu Wei , Eppler Steve , Hegde Priti , Bai Shuang , Kaur Surinder , Nijem Ihsan , Catenacci Daniel V.T. , Peterson Amy , Ratain Mark J. , Polite Blase , Mehnert Janice M. , Moss Rebecca A.
Published: February 2014

Purpose: This first-in-human study evaluated the safety, immunogenicity, pharmacokinetics, and antitumor activity of onartuzumab, a monovalent antibody against the receptor tyrosine kinase MET.

Experimental Design: This 3+3 dose-escalation study comprised three stages: (i) phase Ia dose escalation of onartuzumab at doses of 1, 4, 10, 20, and 30 mg/kg intravenously every 3 weeks; (ii) phase Ia cohort expansion at the recommended phase II dose (RP2D) of 15 mg/kg; and (iii) phase Ib dose escalation of onartuzumab at 10 and 15 mg/kg in combination with bevacizumab (15 mg/kg intravenously every 3 weeks). Serum samples were collected for evaluation of pharmacokinetics, potential pharmacodynamic markers, and antitherapeutic antibodies.

Results: Thirty-four patients with solid tumors were treated in phase Ia and 9 in phase Ib. Onartuzumab was generally well tolerated at all dose levels evaluated; the maximum tolerated dose was not reached. The most frequent drug-related adverse events included fatigue, peripheral edema, nausea, and hypoalbuminemia. In the phase Ib cohort, onartuzumab at the RP2D was combined with bevacizumab and no dose-limiting toxicities were seen. Onartuzumab showed linear pharmacokinetics in the dose range from 4 to 30 mg/kg. The half-life was approximately 8 to 12 days. There were no apparent pharmacokinetic interactions between onartuzumab and bevacizumab, and antitherapeutic antibodies did not seem to affect the safety or pharmacokinetics of onartuzumab. A patient with gastric carcinoma in the 20-mg/kg dose cohort achieved a durable complete response for nearly 2 years.

Conclusions: Onartuzumab was generally well tolerated as a single agent and in combination with bevacizumab in patients with solid tumors. Clin Cancer Res; 20(6); 1666–75. ©2014 AACR.
High-Resolution Array CGH and Gene Expression Profiling of Alveolar Soft Part Sarcoma
Authors: Selvarajah Shamini , Pyne Saumyadipta , Chen Eleanor , Sompallae Ramakrishna , Ligon Azra H. , Nielsen Gunnlaugur P. , Dranoff Glenn , Stack Edward , Loda Massimo , Flavin Richard
Published: February 2014

Purpose: Alveolar soft part sarcoma (ASPS) is a soft tissue sarcoma with poor prognosis, and little molecular evidence exists for its origin, initiation, and progression. The aim of this study was to elucidate candidate molecular pathways involved in tumor pathogenesis.

Experimental Design: We employed high-throughput array comparative genomic hybridization (aCGH) and cDNA-Mediated Annealing, Selection, Ligation, and Extension Assay to profile the genomic and expression signatures of primary and metastatic ASPS from 17 tumors derived from 11 patients. We used an integrative bioinformatics approach to elucidate the molecular pathways associated with ASPS progression. FISH was performed to validate the presence of the t(X;17)(p11.2;q25) ASPL–TFE3 fusion and, hence, confirm the aCGH observations.

Results: FISH analysis identified the ASPL–TFE3 fusion in all cases. aCGH revealed a higher number of numerical aberrations in metastatic tumors relative to primaries, but failed to identify consistent alterations in either group. Gene expression analysis highlighted 1,063 genes that were differentially expressed between the two groups. Gene set enrichment analysis identified 16 enriched gene sets (P < 0.1) associated with differentially expressed genes. Notable among these were several stem cell gene expression signatures and pathways related to differentiation. In particular, the paired box transcription factor PAX6 was upregulated in the primary tumors, along with several genes whose mouse orthologs have previously been implicated in Pax6 DNA binding during neural stem cell differentiation.

Conclusion: In addition to suggesting a tentative neural line of differentiation for ASPS, these results implicate transcriptional deregulation from fusion genes in the pathogenesis of ASPS. Clin Cancer Res; 20(6); 1521–30. ©2014 AACR.
The Impact of EGFR T790M Mutations and BIM mRNA Expression on Outcome in Patients with EGFR-Mutant NSCLC Treated with Erlotinib or Chemotherapy in the Randomized Phase III EURTAC Trial
Authors: Costa Carlota , Molina Miguel Angel , Drozdowskyj Ana , Giménez-Capitán Ana , Bertran-Alamillo Jordi , Karachaliou Niki , Gervais Radj , Massuti Bartomeu , Wei Jia , Moran Teresa , Majem Margarita , Felip Enriqueta , Carcereny Enric , Garcia-Campelo Rosario , Viteri Santiago , Taron Miquel , Ono Mayumi , Giannikopoulos Petros , Bivona Trever , Rosell Rafael
Published: February 2014

Purpose: Concomitant genetic alterations could account for transient clinical responses to tyrosine kinase inhibitors of the EGF receptor (EGFR) in patients harboring activating EGFR mutations.

Experimental Design: We have evaluated the impact of pretreatment somatic EGFR T790M mutations, TP53 mutations, and Bcl-2 interacting mediator of cell death (BCL2L11, also known as BIM) mRNA expression in 95 patients with EGFR-mutant non–small-cell lung cancer (NSCLC) included in the EURTAC trial (trial registration: NCT00446225).

Results: T790M mutations were detected in 65.26% of patients using our highly sensitive method based on laser microdissection and peptide-nucleic acid-clamping PCR, which can detect the mutation at an allelic dilution of 1 in 5,000. Progression-free survival (PFS) to erlotinib was 9.7 months for those with T790M mutations and 15.8 months for those without, whereas among patients receiving chemotherapy, it was 6 and 5.1 months, respectively (P < 0.0001). PFS to erlotinib was 12.9 months for those with high and 7.2 months for those with low/intermediate BCL2L11 expression levels, whereas among chemotherapy-treated patients, it was 5.8 and 5.5 months, respectively (P = 0.0003). Overall survival was 28.6 months for patients with high BCL2L11 expression and 22.1 months for those with low/intermediate BCL2L11 expression (P = 0.0364). Multivariate analyses showed that erlotinib was a marker of longer PFS (HR = 0.35; P = 0.0003), whereas high BCL2L11 expression was a marker of longer PFS (HR = 0.49; P = 0.0122) and overall survival (HR = 0.53; P = 0.0323).

Conclusions: Low-level pretreatment T790M mutations can frequently be detected and can be used for customizing treatment with T790M-specific inhibitors. BCL2L11 mRNA expression is a biomarker of survival in EGFR-mutant NSCLC and can potentially be used for synthetic lethality therapies. Clin Cancer Res; 20(7); 2001–10. ©2014 AACR.
Fatostatin Displays High Antitumor Activity in Prostate Cancer by Blocking SREBP-Regulated Metabolic Pathways and Androgen Receptor Signaling
Authors: Li Xiangyan , Chen Yi-Ting , Hu Peizhen , Huang Wen-Chin
Published: February 2014

Current research links aberrant lipogenesis and cholesterogenesis with prostate cancer development and progression. Sterol regulatory element-binding proteins (SREBP; SREBP-1 and SREBP-2) are key transcription factors controlling lipogenesis and cholesterogenesis via the regulation of genes related to fatty acid and cholesterol biosynthesis. Overexpression of SREBPs has been reported to be significantly associated with aggressive pathologic features in human prostate cancer. Our previous results showed that SREBP-1 promoted prostate cancer growth and castration resistance through induction of lipogenesis and androgen receptor (AR) activity. In the present study, we evaluated the anti–prostate tumor activity of a novel SREBP inhibitor, fatostatin. We found that fatostatin suppressed cell proliferation and anchorage-independent colony formation in both androgen-responsive LNCaP and androgen-insensitive C4-2B prostate cancer cells. Fatostatin also reduced in vitro invasion and migration in both the cell lines. Further, fatostatin caused G2–M cell-cycle arrest and induced apoptosis by increasing caspase-3/7 activity and the cleavages of caspase-3 and PARP. The in vivo animal results demonstrated that fatostatin significantly inhibited subcutaneous C4-2B tumor growth and markedly decreased serum prostate-specific antigen (PSA) level compared with the control group. The in vitro and in vivo effects of fatostatin treatment were due to blockade of SREBP-regulated metabolic pathways and the AR signaling network. Our findings identify SREBP inhibition as a potential new therapeutic approach for the treatment of prostate cancer. Mol Cancer Ther; 13(4); 855–66. ©2014 AACR.
Essential Role of the Linear Ubiquitin Chain Assembly Complex in Lymphoma Revealed by Rare Germline Polymorphisms
Authors: Yang Yibin , Schmitz Roland , Mitala Joseph , Whiting Amanda , Xiao Wenming , Ceribelli Michele , Wright George W. , Zhao Hong , Yang Yandan , Xu Weihong , Rosenwald Andreas , Ott German , Gascoyne Randy D. , Connors Joseph M. , Rimsza Lisa M. , Campo Elias , Jaffe Elaine S. , Delabie Jan , Smeland Erlend B. , Braziel Rita M. , Tubbs Raymond R. , Cook James R. , Weisenburger Dennis D. , Chan Wing C. , Wiestner Adrian , Kruhlak Michael J. , Iwai Kazuhiro , Bernal Federico , Staudt Louis M.
Published: February 2014

Constitutive activation of NF-κB is a hallmark of the activated B cell–like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), owing to upstream signals from the B-cell receptor (BCR) and MYD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IκB kinase-γ, a necessary event in some pathways that engage NF-κB. Two germline polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (∼1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α-helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31–RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11–MALT1–BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL–associated Q622L polymorphism inhibited RNF31–RBCK1 binding, decreased NF-κB activation, and killed ABC DLBCL cells, credentialing this protein–protein interface as a therapeutic target.

Significance: We provide genetic, biochemical, and functional evidence that the LUBAC ubiquitin ligase is a therapeutic target in ABC DLBCL, the DLBCL subtype that is most refractory to current therapy. More generally, our findings highlight the role of rare germline-encoded protein variants in cancer pathogenesis. Cancer Discov; 4(4); 480–93. ©2014 AACR.

See related commentary by Grumati and Dikic, p. 394

This article is highlighted in the In This Issue feature, p. 377
Pretreatment Serum VEGF Is Associated with Clinical Response and Overall Survival in Advanced Melanoma Patients Treated with Ipilimumab
Authors: Yuan Jianda , Zhou Jun , Dong Zhiwan , Tandon Sapna , Kuk Deborah , Panageas Katherine S. , Wong Philip , Wu Xinqi , Naidoo Jarushka , Page David B. , Wolchok Jedd D. , Hodi F. Stephen
Published: February 2014

Ipilimumab, an antibody that blocks CTL antigen 4 (CTLA-4), improves overall survival (OS) for patients with metastatic melanoma. Given its role in angiogenesis and immune evasion, serum VEGF levels were evaluated for association with clinical benefit in ipilimumab-treated patients. Sera were collected from 176 patients treated at 3 (n = 98) or 10 mg/kg (n = 68). The VEGF levels before treatment and at induction completion (week 12) were analyzed using the Meso Scale Discovery kit. The association of the levels of VEGF with clinical responses and OS were assessed using the Fisher exact and Kaplan–Meier log-rank tests. VEGF as a continuous variable was associated with OS (P = 0.002). Using 43 pg/mL as the cutoff pretreatment VEGF value defined by maximally selected log-rank statistics, pretreatment VEGF values correlated with clinical benefit at week 24 (P = 0.019; 159 patients evaluable). Pretreatment VEGF ≥ 43 pg/mL was associated with decreased OS (median OS 6.6 vs. 12.9 months, P = 0.006; 7.4 vs. 14.3 months, P = 0.037 for 3 mg/kg; and 6.2 vs. 10.9 months, P = 0.048 for 10 mg/kg). There was no correlation between VEGF changes and clinical outcome. Serum VEGF may be a predictive biomarker for ipilimumab treatment and is worthy of prospective investigation with various forms of immunologic checkpoint blockade. Cancer Immunol Res; 2(2); 127–32. ©2014 AACR.
Sustained Complete Response to CTLA-4 Blockade in a Patient with Metastatic, Castration-Resistant Prostate Cancer
Authors: Graff Julie N. , Puri Sachin , Bifulco Carlo B. , Fox Bernard A. , Beer Tomasz M.
Published: February 2014

We present the case of a man with metastatic, castration-resistant prostate cancer, who had a complete prostate-specific antigen (PSA) response after 2½ doses of ipilimumab. His treatment course was complicated by diarrhea and autoimmune hepatitis, both of which resolved within 4 months. Sera and biopsy specimens were accessed, and sera from pretreatment and day 113 were analyzed. Augmented antibody responses were detected against 11 potential tumor antigens, with responses ranging from 5- to 20-fold in day 113 sera compared with baseline. Genes that were targets of a strong antibody response (arbitrarily set at 10-fold or greater increase) were analyzed by real-time PCR for expression in the tumor biopsy cDNA. Of the top 5 genes, only 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) could be identified in the amplified tumor biopsy cDNA. Using an antibody to HIBCH, immunohistochemical analysis documented strong expression of the protein. Together, these data suggest that an augmented antibody response to HIBCH, an antigen that was expressed by the patient's prostate cancer, could have contributed to the clinical response. After 16 months of PSA stability, he discontinued his androgen-suppression therapy. With the return of his testosterone, his PSA increased slightly, likely originating from his intact prostate. He has been disease free for the past 6 years without any additional therapy. Cancer Immunol Res; 2(5); 399–403. ©2014 AACR.
The Influence of Erythropoietin (EPO T→G) and α-Actinin-3 (ACTN3 R577X) Polymorphisms on Runners' Responses to the Dietary Ingestion of Antioxidant Supplementation Based on Pequi Oil (Caryocar brasiliense Camb.): A Before-After Study
Authors: Ribeiro Ieler Ferreira , Miranda-Vilela Ana Luisa , Klautau-Guimarães Maria de Nazaré , Grisolia Cesar Koppe
Published: February 2014

Background/Aims: As diet can affect an individual's genes and these can affect response to supplementation, we aimed to investigate the influence of erythropoietin (EPO T→G) and α-actinin-3 (ACTN3 R577X) polymorphisms on plasma lipid peroxidation, hemogram and biochemical dosages of creatine kinase, aspartate aminotransferase, alanine aminotransferase and C-reactive protein (including high-sensitivity C-reactive protein) of runners (n = 123) before and after 14 days of 400 mg pequi oil supplementation, a natural carotenoid-rich oil, after races under closely comparable conditions. Methods/Results: Blood samples were taken immediately after racing to perform the tests. Before pequi oil supplementation, EPO polymorphism influenced erythrogram and plateletgram results, suggesting an aerobic advantage for the TG genotype and a disadvantage for the GG genotype as regards possible microvascular complications, while no association was found for ACTN3 polymorphism with endurance performance. Both polymorphisms influenced the runners' response to pequi oil: significant responses were observed for the EPO TT genotype in erythrocyte, hematocrit, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration values, and for the TT and TG genotypes in red blood cell distribution width values. Significant differences were also observed in the plateletgram for the TT and TG genotypes. ACTN3 mainly influenced aspartate aminotransferase and creatine kinase values: heterozygotes had a significant reduction in aspartate aminotransferase values and homozygous individuals (XX) in creatine kinase values after pequi oil supplementation. Conclusion: These results emphasize the importance of studying nutrigenomic effects on athletes' performance.
Suppression of Spontaneous Ca Elevations Prevents Atrial Fibrillation in Calsequestrin 2-Null Hearts
Authors: Faggioni Michela , Savio-Galimberti Eleonora , Venkataraman Raghav , Hwang Hyun Seok , Kannankeril Prince J. , Darbar Dawood , Knollmann Björn C.
Published: February 2014

Background—

Atrial fibrillation (AF) risk has been associated with leaky ryanodine receptor 2 (RyR2) Ca release channels. Patients with mutations in RyR2 or in the sarcoplasmic reticulum Ca-binding protein calsequestrin 2 (Casq2) display an increased risk for AF. Here, we examine the underlying mechanisms of AF associated with loss of Casq2 and test mechanism-based drug therapy.

Methods and Results—

Compared with wild-type Casq2
+/+
mice, atrial burst pacing consistently induced atrial flutter or AF in Casq2
−/−
mice and in isolated Casq2
−/−
hearts. Atrial optical voltage maps obtained from isolated hearts revealed multiple independent activation sites arising predominantly from the pulmonary vein region. Ca and voltage mapping demonstrated diastolic subthreshold spontaneous Ca elevations (SCaEs) and delayed afterdepolarizations whenever the pacing train failed to induce AF. The dual RyR2 and Na channel inhibitor R-propafenone (3 μmol/L) significantly reduced frequency and amplitude of SCaEs and delayed afterdepolarizations in atrial myocytes and intact atria and prevented induction of AF. In contrast, the S-enantiomer of propafenone, an equipotent Na channel blocker but much weaker RyR2 inhibitor, did not reduce SCaEs and delayed afterdepolarizations and failed to prevent AF.

Conclusions—

Loss of Casq2 increases risk of AF by promoting regional SCaEs and delayed afterdepolarizations in atrial tissue, which can be prevented by RyR2 inhibition with R-propafenone. Targeting AF caused by leaky RyR2 Ca channels with R-propafenone may be a more mechanism-based approach to treating this common arrhythmia.
National Assessment of Warfarin Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation
Authors: Dlott Jeffrey S. , George Roberta A. , Huang Xiaohua , Odeh Mouneer , Kaufman Harvey W. , Ansell Jack , Hylek Elaine M.
Published: February 2014

Background—

Anticoagulation control with warfarin, as assessed by the international normalized ratio (INR), is challenging. Time in the therapeutic range has been inversely correlated with major hemorrhage, thrombosis, and mortality. Quest Diagnostics offers standardized INR laboratory testing services to approximately half of US physician practices. To inform national stroke prevention strategies, we evaluated anticoagulation control in office-based community practices.

Methods and Results—

We selected individuals with ≥2 months of INR data, INR results of >1.2, and an ICD-9 diagnosis code of atrial fibrillation. Frequency of INR testing and time in the therapeutic range were analyzed by age, sex, length of testing period, number of referred patients per provider, and median household income (based on home ZIP code). We identified 138 319 individuals referred by 37 939 physicians, yielding a total of 2 683 674 INR results. Patients had a mean age of 74 years; 81% were ≥65 years of age, and 55% were ≥75 years of age. The mean time in the therapeutic range was 53.7% overall and improved with time on treatment, increasing from 47.6% for patients with <6 months of testing to 57.5% for those with ≥6 months of testing (
P
<0.0001). The number of patients tested per physician practice was positively associated with time in the therapeutic range. Younger age, female sex, and lower income were also independently associated with poorer anticoagulant control.

Conclusion—

This study demonstrates widespread suboptimal anticoagulation control, suggesting an urgent need to improve oral anticoagulation care for most patient segments in the United States.
Statistical Thermodynamics Concepts and Mathematical Tools for a Multi-Agent Ecosystem
Authors: Segovia Javier
Published: February 2014

Finding the distribution of systems over their possible states is a mathematical problem. One possible solution is the method of the most probable distribution developed by Boltzmann. This method has been instrumental in developing statistical mechanics and explaining the origin of many thermodynamics concepts, like entropy or temperature, but is also applicable in many other fields like ecology or economics. Artificial ecosystems have many features in common with ecological or economic systems, but surprisingly the method does not appear to have been very successful in this field of application. The hypothesis of this article is that this failure is due to the incorrect interpretation of the method's concepts and mathematical tools. We propose to review and reinterpret the method so that it can be correctly applied and all its potential exploited in order to study and characterize the global behavior of an artificial multi-agent ecosystem.
Three new species of Stelis (Orchidaceae; Pleurothallidinae) from Mexico
Authors: Solano GOMEZ Rodolfo
Published: February 2014

Three new species in the genus Stelis (Orchidaceae) are here described and illustrated for the first time: two have been previously mentioned and are published formally here. For each taxon, information is provided about its distribution, habitat, phenology, traits that distinguish it from similar species, and conservation status. A line drawing, photo, and map for the known localities of the three species are provided.
A systematic classification of Ephedraceae: living and fossil
Authors: Yang Yong
Published: February 2014

A number of Ephedroid macrofossils have been described from the Early Cretaceous in the last decade, indicating huge diversity of early Ephedraceae. However, relationships among these fossils and modern Ephedra remain ambiguous. This study proposes a new systematic classification of the family at the generic level based on the reduction and sterilization evolutionary hypothesis of female reproductive organs. Two subfamilies and two tribes are described as new to science. In this new classification, the family Ephedraceae consists of two subfamilies: Siphonospermoideae Y. Yang subfam. nov. and Ephedroideae Y. Yang subfam. nov., and the latter subfamily is divided again into two tribes: Liaoxieae Y. Yang trib. nov. and Ephedreae Y. Yang trib. nov. Ten genera are included in the new classification, and two genera are listed as doubtful due to their taxonomic characters being insufficient to place them in Ephedraceae.
An annotated and revised checklist of pleurostome ciliates (Protista: Ciliophora: Litostomatea) from Slovakia, Central Europe
Authors: VĎAČNÝ PETER , RAJTER ĽUBOMÍR
Published: February 2014

Pleurostomatids are predatory ciliates, living especially in the periphyton and benthos of various freshwater and marine habitats. In the present work, we provide an annotated and revised checklist of this ciliate group from the territory of Slovakia. Altogether 29 pleurostome species belonging to five genera have been reported there: Acineria incurvata, Ac. punctata, Ac. uncinata, Amphileptus claparedii, Am. falcatus, Am. fusiformis, Am. parafusidens, Am. pleurosigma, Am. procerus, Am. punctatus, A. rotundus, Litonotus alpestris, Li. anguilla, Li. carinatus, Li. crystallinus, Li. cygnus, Li. fasciola, Li. fusidens, Li. hirundo, Li. lamella, Li. minisculus, Li. muscorum, Li. obtusus, Li. triqueter, Li. varsaviensis, Loxophyllum helus, Lo. meleagris, Lo. rostratum, and Siroloxophyllum utriculariae. We have catalogued these records providing the following data for each species: (1) author(s) and date of publication; (2) name(s) of the species as appeared in the publication(s) followed by chronologically listed references including relevant page(s) in literature; (3) nomenclatural and taxonomic notes if needed; (4) main morphological characters; (5) morphological data on Slovak populations if available; and (6) all faunistic records.
Review: Britain’s day-flying Moths by David Newland, Robert Still and Andy Smith
Authors: HOARE ROBERT
Published: February 2014

This very attractive field guide belongs to a series that is winning widespread and justified praise for layout, design and overall quality. It covers the 133 ‘macro-moths’ that fly, or are readily disturbed, by day in the British Isles. It also includes a small selection (22 species) of the numerous day-flying ‘micro-moths’. First impressions are excellent: as with others in the series, the book is beautifully designed for field use, compact, and comes with a transparent plastic cover to protect it from the elements. Other welcome ‘field’ features are the life-size photographs of selected species inside the back cover, together with a ruler along the edge of that page. The main species accounts that make up the bulk of the book devote a page to each species and are illustrated by photographs of live moths in their natural habitats. The photographs are almost universally of very fine quality.
New Oriental tribe Iscini, new non-dilatognathan species of Notophlebia Peters & Edmunds 1970 and independent origin of Dilatognathus-type mouth apparatus in Atalophlebiinae (Ephemeroptera: Leptophlebiidae)
Authors: KLUGE NIKITA J.
Published: February 2014

A new tribe, Iscini tr. n., comprising the Oriental genera Isca Gillies 1951 and Notophlebia Peters & Edmunds 1970, is established. A new species, Notophlebia ganeshi sp. n., is described based on male and female imagos reared from larvae. The new species markedly differs from N. jobi Sivaramakrishnan & Peters 1984 by its non-specialized larval mouth apparatus. The larva of N. jobi has a highly specialized mouth apparatus of the «Dilatognathus-type»; this type of mouth apparatus has evolved independently in several non-related leptophlebiid taxa.
Potamalpheops tyrymembe sp. n.: the first southwestern Atlantic species of the shrimp genus Potamalpheops Powell, 1979 (Caridea: Alpheidae)
Authors: SOLEDADE GUIDOMAR O. , SANTOS PATRICIA S. , ALMEIDA ALEXANDRE O.
Published: February 2014

A new species of the alpheid shrimp genus Potamalpheops Powell, 1979, P. tyrymembe sp. n., is described based on several specimens collected from burrows of the ucidid crab Ucides cordatus (Linnaeus, 1763) and other, unknown burrowing decapods, on a mangrove flat between the Baiano and Serra rivers, Povoado de Tremembé, Maraú, state of Bahia, Brazil (14º08’51.9”S, 39º05’04.4”W). The new species belongs to the P. monodi (Sollaud, 1932) species group, based on the presence of two pairs of spiniform setae on the distal margin of the telson and non-enlarged male chelipeds. It is characterized by a short rostrum and absence of setae on the pterygostomial angle of the carapace.