bluuebunny/crossref_metadata_2025_split huggingface dataset:
AMPylation Is Critical for Rab1 Localization to Vacuoles Containing Legionella pneumophila
Authors: Hardiman Camille A. , Roy Craig R. 
Published: February 2014

ABSTRACT

Legionella pneumophila
is an intracellular pathogen that resides within a membrane-bound compartment that is derived from vesicles exiting the endoplasmic reticulum (ER). To create this compartment, these bacteria use a type IV secretion system to deliver effector proteins that subvert host cell functions. Several
Legionella
effector proteins modulate the function of the host protein Rab1, which is a GTPase that is recruited to the
Legionella
-containing vacuole (LCV). Here, we examined which of the Rab1-directed enzymatic activities displayed by
Legionella
effectors are important for localizing the Rab1 protein to the LCV membrane. The guanine nucleotide exchange factor (GEF) domain in the effector protein DrrA (SidM) was essential for Rab1 recruitment to the LCV and Rab1 AMPylation by the nucleotidyltransferase domain in DrrA was important for Rab1 retention.
Legionella
organisms producing mutant DrrA proteins that were severely attenuated for GEF activity
in vitro
retained the ability to localize Rab1 to the LCV. Rab1 localization to the LCV mediated by these GEF-defective mutants required AMPylation. Importantly, we found that efficient localization of Rab1 to the LCV occurred when Rab1 GEF activity and Rab1 AMPylation activity were provided by separate proteins. Rab1 phosphocholination (PCylation) by the effector protein AnkX, however, was unable to substitute for Rab1 AMPylation. Lastly, the defect in Rab1 localization to the LCV in AMPylation-deficient strains of
Legionella
was partially suppressed if the GTPase-activating protein (GAP) LepB was eliminated. Thus, our data indicate that AMPylation of Rab1 is an effective strategy to maintain this GTPase on the LCV membrane.

IMPORTANCE
Activities that enable the intracellular pathogen
Legionella pneumophila
to subvert the function of the host protein Rab1 were investigated. Our data show that a posttranslational modification called AMPylation is critical for maintaining a pool of Rab1 on the LCV membrane. AMPylation of Rab1 led to the accumulation of GTP-bound Rab1 on the LCV membrane by protecting the protein from inactivation by GAPs. Importantly, PCylation of Rab1 by the
Legionella
effector protein AnkX was neither necessary nor sufficient to maintain Rab1 on the LCV, indicating that AMPylation and PCylation represent functionally distinct activities. We conclude that modification of Rab1 by AMPylation is an effective strategy to spatially and temporally regulate the function of this GTPase on a membrane-bound organelle.
The seasonal variation of Achilles tendon ruptures in Vancouver, Canada: a retrospective study
Authors: Scott Alex , Grewal Navdeep , Guy Pierre 
Published: February 2014

ObjectiveTo examine the seasonal distribution of tendon ruptures in a large cohort of patients from Vancouver, Canada.DesignRetrospective chart review.SettingAcute Achilles tendon rupture cases that occurred from 1987 to 2010 at an academic hospital in Vancouver, Canada. Information was extracted from an orthopaedic database.ParticipantsNo direct contact was made with the participants. The following information was extracted from the OrthoTrauma database: age, sex, date of injury and season (winter, spring, summer and autumn), date of surgery if date of injury was unknown and type of injury (sport related or non-sport related/unspecified). Only acute Achilles tendon rupture cases were included; chronic cases were excluded along with those that were conservatively managed.Primary and secondary outcomesThe primary outcome was to determine the seasonal pattern of Achilles tendon rupture. Secondary outcomes, such as differences in gender and mechanism of sport (non-sport vs sport related), were also assessed.ResultsThere were 543 cases in total; 83% of the cases were men (average age 39.3) and 17% were women (average age 37.3). In total, 76% of cases were specified as sport related. The distribution of injuries varied significantly across seasons (χ2, p<0.05), with significantly more cases occurring in spring. The increase in the number of cases in spring was due to sport-related injuries, whereas non-sport-related cases were distributed evenly throughout the year.ConclusionsThe seasonality of sport-related Achilles tendon ruptures should be considered when developing preventive strategies and when timing their delivery.
Comprehensive analysis of clinico-pathological data reveals heterogeneous relations between atherosclerosis and cancer
Authors: Budczies Jan , von Winterfeld Moritz , Klauschen Frederick , Kimmritz Anna-Christin , Daniel Jan-Marcus , Warth Arne , Endris Volker , Denkert Carsten , Pfeiffer Heidi , Weichert Wilko , Dietel Manfred , Wittschieber Daniel , Stenzinger Albrecht 
Published: February 2014

AimsAtherosclerosis and cancer share common risk factors and involve similar molecular pathomechanisms. Most clinical and epidemiological studies show a positive correlation between atherosclerosis and smoking-related cancers and heterogeneous results for non-smoking-related cancers. However, up-to-date large-scale autopsy studies including a detailed analysis of cancer types are lacking. Therefore, we sought to investigate the relation between major cancer types and the grade of atherosclerosis in a recent well-powered autopsy cohort.MethodsIn 2101 patients, both autopsy data and clinical data including demographics, disease groups, tumour type, cause of death and grade of atherosclerosis were reviewed and statistically analysed.ResultsWe found cancer in general is associated with less atherosclerosis (OR 0.60, p<0.0001). In particular, haematological neoplasm and sarcomas were associated with much less atherosclerosis (OR=0.45, p<0.0001 and OR=0.43, p=0.087), while carcinomas were associated with moderately less atherosclerosis (OR=0.72, p=0.002). Furthermore, non-smoking-related cancers were associated with much less atherosclerosis (OR=0.41, p<0.0001), while possibly smoking-related cancer and smoking-related cancer showed no significant association. In a comprehensive analysis of 21 cancer types, biliary tract cancer, lymphomas/lymphoid leukaemias and kidney cancer were associated with much less atherosclerosis (OR=0.19, p<0.0001; OR=0.41, p<0.0001; and OR=0.48, p=0.029). In an exploratory analysis of treatment strategies, we found that tumours with a recommendation of oxazaphosphorines and pyrimidine antagonist treatment were significantly associated with less atherosclerosis (OR=0.33, p=0.0068 and OR=0.58, p=0.012).ConclusionsIn conclusion, the study showed an inverse association between cancer and atherosclerosis postmortem that depends on the cancer type and suggests a possible impact of chemotherapy regimens.
Optimized Liquid-Liquid Extractive Rerefining of Spent Lubricants
Authors: Kamal Muhammad Ashraf , Naqvi Syed Mumtaz Danish , Khan Fasihullah 
Published: February 2014

Central composite design methodology has been employed to model the sludge yield data obtained during liquid-liquid extractive rerefining of spent lubricants using an alcohol (1-butanol) and a ketone (methyl ethyl ketone) as prospective solvents. The study has resulted in two reasonably accurate multivariate process models that relate the sludge yield (R2=0.9065and 0.9072 for alcohol and ketone, resp.) to process variables (settling timet, operating temperatureT, and oil to solvent ratior). Construction of such models has allowed the maximization of the sludge yield (more than 8% and 3% in case of alcohol and ketone, resp.) so that the extraction of useable oil components from spent lubricants can economically be performed under extremely mild conditions (t = 16.7 h,T=10°C, andr=2) and fairly moderate conditions (t = 26.6 h,T=10°C, andr=5) established for the alcohol and ketone correspondingly. Based on these performance parameters alcohol appears to be superior over ketone for this extraction process. Additionally extractive treatment results in oil stocks with lesser quantity of environmentally hazardous polyaromatic hydrocarbons that are largely left in the separated sludge.
Learning Curves of Macintosh Laryngoscope in Nurse Anesthetist Trainees Using Cumulative Sum Method
Authors: Rujirojindakul Panthila , McNeil Edward , Rueangchira-urai Rongrong , Siripunt Niranuch 
Published: February 2014

Background. Tracheal intubation is a potentially life-saving procedure. This skill is taught to many anesthetic healthcare professionals, including nurse anesthetists. Our goal was to evaluate the learning ability of nurse anesthetist trainees in their performance of orotracheal intubation with the Macintosh laryngoscope.Methods. Eleven nurse anesthetist trainees were enrolled in the study during the first three months of their training. All trainees attended formal lectures and practice sessions with manikins at least one time on performing successful tracheal intubation under supervision of anesthesiology staff. Learning curves for each nurse anesthetist trainee were constructed with the standard cumulative summation (cusum) methods.Results. Tracheal intubation was attempted on 388 patients. Three hundred and six patients (78.9%) were successfully intubated on the trainees’ first attempt and 17 patients (4.4%) on the second attempt. The mean±SD number of orotracheal intubations per trainee was35.5 ± 5.1(range 30–47). Ten (90.9%) of 11 trainees crossed the 20% acceptable failure rate line. A median of 22 procedures was required to achieve an 80% orotracheal intubations success rate.Conclusion. At least 22 procedures were required to reach an 80% success rate for orotracheal intubation using Macintosh laryngoscope in nonexperienced nurse anesthetist trainees.
Vaccine-Mediated Immunotherapy Directed against a Transcription Factor Driving the Metastatic Process
Authors: Ardiani Andressa , Gameiro Sofia R. , Palena Claudia , Hamilton Duane H. , Kwilas Anna , King Thomas H. , Schlom Jeffrey , Hodge James W. 
Published: February 2014

AbstractNumerous reports have now demonstrated that the epithelial-to-mesenchymal transition (EMT) process is involved in solid tumor progression, metastasis, and drug resistance. Several transcription factors have been implicated as drivers of EMT and metastatic progression, including Twist. Overexpression of Twist has been shown to be associated with poor prognosis and drug resistance for many carcinomas and other tumor types. The role of Twist in experimental cancer metastases has been principally studied in the 4T1 mammary tumor model, where silencing of Twist in vitro has been shown to greatly reduce in vivo metastatic spread. Transcription factors such as Twist are generally believed to be “undruggable” because of their nuclear location and lack of a specific groove for tight binding of a small molecule inhibitor. An alternative approach to drug therapy targeting transcription factors driving the metastatic process is T-cell–mediated immunotherapy. A therapeutic vaccine platform that has been previously characterized consists of heat-killed recombinant Saccharomyces cerevisiae (yeast) capable of expressing tumor-associated antigen protein. We report here the construction and characterization of a recombinant yeast expressing the entire Twist protein, which is capable of inducing both CD8+ and CD4+ Twist-specific T-cell responses in vivo. Vaccination of mice reduced the size of primary transplanted 4T1 tumors and had an even greater antitumor effect on lung metastases of the same mice, which was dependent on Twist-specific CD8+ T cells. These studies provide the rationale for vaccine-induced T-cell–mediated therapy of transcription factors involved in driving the metastatic process. Cancer Res; 74(7); 1945–57. ©2014 AACR.
Curative Properties of Noninternalizing Antibody–Drug Conjugates Based on Maytansinoids
Authors: Perrino Elena , Steiner Martina , Krall Nikolaus , Bernardes Gonçalo J.L. , Pretto Francesca , Casi Giulio , Neri Dario 
Published: February 2014

Abstract
It is generally thought that the anticancer efficacy of antibody–drug conjugates (ADC) relies on their internalization by cancer cells. However, recent work on an ADC that targets fibronectin in the tumor microenvironment suggests this may not be necessary. The alternatively spliced extra domains A and B (EDA and EDB) of fibronectin offer appealing targets for ADC development, because the antigen is strongly expressed in many solid human tumors and nearly undetectable in normal tissues except for the female reproductive system. In this study, we describe the properties of a set of ADCs based on an antibody targeting the alternatively spliced EDA of fibronectin coupled to one of a set of potent cytotoxic drugs (DM1 or one of two duocarmycin derivatives). The DM1 conjugate SIP(F8)-SS-DM1 mediated potent antitumor activity in mice bearing DM1-sensitive F9 tumors but not DM1-insensitive CT26 tumors. Quantitative biodistribution studies and microscopic analyses confirmed a preferential accumulation of SIP(F8)-SS-DM1 in the subendothelial extracellular matrix of tumors, similar to the pattern observed for unmodified antibody. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative and compatible with pharmaceutical development. Our findings offer a preclinical proof-of-concept for curative ADC targeting the tumor microenvironment that do not rely upon antigen internalization. Cancer Res; 74(9); 2569–78. ©2014 AACR.
Tumor-Infiltrating Myeloid Cells Activate Dll4/Notch/TGF-β Signaling to Drive Malignant Progression
Authors: Ohnuki Hidetaka , Jiang Kan , Wang Dunrui , Salvucci Ombretta , Kwak Hyeongil , Sánchez-Martín David , Maric Dragan , Tosato Giovanna 
Published: February 2014

Abstract
Myeloid cells that orchestrate malignant progression in the tumor microenvironment offer targets for a generalized strategy to attack solid tumors. Through an analysis of tumor microenvironments, we explored an experimental model of lung cancer that uncovered a network of Dll4/Notch/TGF-β1 signals that links myeloid cells to cancer progression. Myeloid cells attracted to the tumor microenvironment by the tumor-derived cytokines CCL2 and M-CSF expressed increased levels of the Notch ligand Dll4, thereby activating Notch signaling in the tumor cells and amplifying tumor-intrinsic Notch activation. Heightened Dll4/Notch signaling in tumor cells magnified TGF-β–induced pSMAD2/3 signaling and was required to sustain TGF-β–induced tumor cell growth. Conversely, Notch blockade reduced TGF-β signaling and limited lung carcinoma tumor progression. Corroborating these findings, by interrogating RNAseq results from tumor and adjacent normal tissue in clinical specimens of human head and neck squamous carcinoma, we found evidence that TGF-β/Notch crosstalk contributed to progression. In summary, the myeloid cell-carcinoma signaling network we describe uncovers novel mechanistic links between the tumor microenvironment and tumor growth, highlighting new opportunities to target tumors where this network is active. Cancer Res; 74(7); 2038–49. ©2014 AACR.
Phase I Trial of a Bivalent Gangliosides Vaccine in Combination with β-Glucan for High-Risk Neuroblastoma in Second or Later Remission
Authors: Kushner Brian H. , Cheung Irene Y. , Modak Shakeel , Kramer Kim , Ragupathi Govind , Cheung Nai-Kong V. 
Published: February 2014

AbstractPurpose: To report on a phase I trial designed to find the maximally tolerated dose in children of the immunologic adjuvant OPT-821 in a vaccine containing neuroblastoma-associated antigens (GD2 and GD3; Clinicaltrials.gov NCT00911560). Secondary objectives were to obtain preliminary data on immune response and activity against minimal residual disease (MRD). Treatment also included the immunostimulant β-glucan.Experimental Design: Patients with neuroblastoma in ≥2nd complete/very good partial remission received vaccine subcutaneously (weeks 1–2–3–8–20–32–52). Vaccine contained 30 μg each of GD2 and GD3 stabilized as lactones and conjugated to the immunologic carrier protein keyhole limpet hemocyanin; and OPT-821, which was dose escalated as 50, 75, 100, and 150 μg/m2 per injection. Oral β-glucan (40 mg/kg/day, 14 days on/14 days off) started week 6.Results: The study was completed with 15 patients because there was no dose-limiting toxicity at 150 μg/m2 of OPT-821 (the dosing used in adults). Thirteen of fifteen patients received the entire protocol treatment, including 12 who remain relapse-free at 24+ to 39+ (median 32+) months and 1 who relapsed (single node) at 21 months. Relapse-free survival was 80% ± 10% at 24 months. Vaccine and β-glucan were well tolerated. Twelve of fifteen patients had antibody responses against GD2 and/or GD3. Disappearance of MRD was documented in 6 of 10 patients assessable for response.Conclusions: This immunotherapy program lacks major toxicity and is transportable to any outpatient clinic. Patient outcome is encouraging but the efficacy is uncertain because of the complexity and heterogeneity of prior therapies. A larger phase II trial is underway. Clin Cancer Res; 20(5); 1375–82. ©2014 AACR.
Beneficial Effects of RAF Inhibitor in Mutant BRAF Splice Variant–Expressing Melanoma
Authors: Hartsough Edward J. , Basile Kevin J. , Aplin Andrew E. 
Published: February 2014

AbstractResistance to RAF inhibitors such as vemurafenib and dabrafenib is a major clinical problem in the treatment of melanoma. Patients with mutant BRAF melanoma that progress on RAF inhibitors have limited treatment options, and drug removal from resistant tumors may elicit multiple effects. A frequent mechanism of resistance to RAF inhibitors is caused by expression of mutant BRAF splice variants. RAF inhibitor–resistant cell lines, generated in vivo, were tested as to whether or not mutant BRAF splice variants confer a fitness advantage in the presence of RAF inhibitor. Critically, cells expressing distinct mutant BRAF splice variants grow more efficiently in vitro and in vivo in the presence of the vemurafenib analog, PLX4720, compared with in the absence of inhibitor. PLX4720-treated BRAF splice variant–expressing cells exhibited levels of phospho-extracellular signal–regulated kinase (ERK)1/2 comparable to untreated parental cells. In addition, a reduction in phospho-ERK1/2 levels following treatment with the MEK inhibitor, trametinib (GSK1120212) phenocopied the fitness benefit provided by PLX4720. These data indicate that mutant BRAF splice variant–expressing melanoma cells are benefited by defined concentrations of RAF inhibitors.Implications: This study provides evidence that RAF inhibitor–resistant melanoma cells benefit from continued therapy. Mol Cancer Res; 12(5); 795–802. ©2014 AACR.
Pubertal Bisphenol A Exposure Alters Murine Mammary Stem Cell Function Leading to Early Neoplasia in Regenerated Glands
Authors: Wang Danhan , Gao Hui , Bandyopadhyay Abhik , Wu Anqi , Yeh I-Tien , Chen Yidong , Zou Yi , Huang Changjiang , Walter Christi A. , Dong Qiaoxiang , Sun Lu-Zhe 
Published: February 2014

AbstractPerinatal exposure to bisphenol A (BPA) has been shown to cause aberrant mammary gland morphogenesis and mammary neoplastic transformation. Yet, the underlying mechanism is poorly understood. We tested the hypothesis that mammary glands exposed to BPA during a susceptible window may lead to its susceptibility to tumorigenesis through a stem cell–mediated mechanism. We exposed 21-day-old Balb/c mice to BPA by gavage (25 μg/kg/d) during puberty for 3 weeks, and a subset of animals were further challenged with one oral dose (30 mg/kg) of 7,12-dimethylbenz(a)anthracene (DMBA) at 2 months of age. Primary mammary cells were isolated at 6 weeks, and 2 and 4 months of age for murine mammary stem cell (MaSC) quantification and function analysis. Pubertal exposure to the low-dose BPA increased lateral branches and hyperplasia in adult mammary glands and caused an acute increase of MaSC in 6-week-old glands and a delayed increase of luminal progenitors in 4-month-old adult gland. Most importantly, pubertal BPA exposure altered the function of MaSC from different age groups, causing early neoplastic lesions in their regenerated glands similar to those induced by DMBA exposure, which indicates that MaSCs are susceptible to BPA-induced transformation. Deep sequencing analysis on MaSC-enriched mammospheres identified a set of aberrantly expressed genes associated with early neoplastic lesions in patients with human breast cancer. Thus, our study for the first time shows that pubertal BPA exposure altered MaSC gene expression and function such that they induced early neoplastic transformation. Cancer Prev Res; 7(4); 445–55. ©2014 AACR.
Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment
Authors: Yue Wen , Yang Chung S. , DiPaola Robert S. , Tan Xiang-Lin 
Published: February 2014

Abstract
Pancreatic cancer, as the fourth leading cause of cancer-related deaths, carries a poor prognosis with a median survival of 6 months and a dismal 5-year survival rate of 3% to 5%. These statistics highlight an urgent need for novel chemopreventive and therapeutic strategies for this malignancy. Metformin and aspirin have been explored as two emerging cancer chemoprevention agents for different types of cancers, including pancreatic cancer. Here, we review the effects of both metformin and aspirin on pancreatic tumorigenesis and their potential actions in pancreatic cancer. Special attention is paid to their effects on the important signaling pathways of pancreatic cancer development as well as possible mechanisms for synergy between these two agents. For metformin, the most important mechanism may involve the inhibition of mTOR signaling via AMP-activated protein kinase (AMPK)-dependent and -independent pathways. For aspirin, the major mechanism is the anti-inflammatory action through the inhibition of COX-1/COX-2 and modulation of the NFκB or STAT3 pathway. In addition, aspirin may activate AMPK, and both agents may affect Notch, Wnt/β-catenin, and other signaling pathways. The combination of metformin and aspirin will provide additive and possibly synergistic effects for the prevention and treatment of pancreatic cancer. Cancer Prev Res; 7(4); 388–97. ©2014 AACR.
Reversal of NK-Cell Exhaustion in Advanced Melanoma by Tim-3 Blockade
Authors: da Silva Ines Pires , Gallois Anne , Jimenez-Baranda Sonia , Khan Shaukat , Anderson Ana C. , Kuchroo Vijay K. , Osman Iman , Bhardwaj Nina 
Published: February 2014

AbstractThe immunoregulatory protein T-cell immunoglobulin- and mucin-domain–containing molecule-3 (Tim-3) mediates T-cell exhaustion and contributes to the suppression of immune responses in both viral infections and tumors. Tim-3 blockade reverses the exhausted phenotype of CD4+ and CD8+ T cells in several chronic diseases, including melanoma. Interestingly, natural killer (NK) cells constitutively express Tim-3; however, the role of Tim-3 in modulating the function of these innate effector cells remains unclear, particularly in human diseases. In this study, we compared the function of Tim-3 in NK cells from healthy donors and patients with metastatic melanoma. NK cells from the latter were functionally impaired/exhausted, and Tim-3 blockade reversed this exhausted phenotype. Moreover, Tim-3 expression levels were correlated with the stage of the disease and poor prognostic factors. These data indicate that Tim-3 can function as an NK-cell exhaustion marker in advanced melanoma and support the development of Tim-3–targeted therapies to restore antitumor immunity. Cancer Immunol Res; 2(5); 410–22. ©2014 AACR.