bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery and Characterization of a Novel CD4-Binding Adnectin with Potent Anti-HIV Activity
Authors: Wensel David , Sun Yongnian , Li Zhufang , Zhang Sharon , Picarillo Caryn , McDonagh Thomas , Fabrizio David , Cockett Mark , Krystal Mark , Davis Jonathan 
Published: June 2017

ABSTRACTA novel fibronectin-based protein (Adnectin) HIV-1 inhibitor was generated usingin vitroselection. This inhibitor binds to human CD4 with a high affinity (3.9 nM) and inhibits viral entry at a step after CD4 engagement and preceding membrane fusion. The progenitor sequence of this novel inhibitor was selected from a library of trillions of Adnectin variants using mRNA display and then further optimized for improved antiviral and physical properties. The final optimized inhibitor exhibited full potency against a panel of 124 envelope (gp160) proteins spanning 11 subtypes, indicating broad-spectrum activity. Resistance profiling studies showed that this inhibitor required 30 passages (151 days) in culture to acquire sufficient resistance to result in viral titer breakthrough. Resistance mapped to the loss of multiple potential N-linked glycosylation sites in gp120, suggesting that inhibition is due to steric hindrance of CD4-binding-induced conformational changes.
Capsid Assembly Modulators Have a Dual Mechanism of Action in Primary Human Hepatocytes Infected with Hepatitis B Virus
Authors: Berke Jan Martin , Dehertogh Pascale , Vergauwen Karen , Van Damme Ellen , Mostmans Wendy , Vandyck Koen , Pauwels Frederik 
Published: June 2017

ABSTRACT

Hepatitis B virus (HBV) capsid assembly is a critical step in the propagation of the virus and is mediated by the core protein. Due to its multiple functions in the viral life cycle, core became an attractive target for new antiviral therapies. Capsid assembly modulators (CAMs) accelerate the kinetics of capsid assembly and prevent encapsidation of the polymerase-pregenomic RNA (Pol-pgRNA) complex, thereby blocking viral replication. CAM JNJ-632 is a novel and potent inhibitor of HBV replication
in vitro
across genotypes A to D. It induces the formation of morphologically intact viral capsids, as demonstrated by size exclusion chromatography and electron microscopy studies. Antiviral profiling in primary human hepatocytes revealed that CAMs prevented formation of covalently closed circular DNA in a dose-dependent fashion when the compound was added together with the viral inoculum, whereas nucleos(t)ide analogues (NAs) did not. This protective effect translated into a dose-dependent reduction of intracellular HBV RNA levels as well as reduced HBe/cAg and HBsAg levels in the cell culture supernatant. The same observation was made with another CAM (BAY41-4109), suggesting that mechanistic rather than compound-specific effects play a role. Our data show that CAMs have a dual mechanism of action, inhibiting early and late steps of the viral life cycle. These effects clearly differentiate CAMs from NAs and may translate into higher functional cure rates in a clinical setting when given alone or in combination with the current standard of care.
Transcriptional Regulator TetR21 Controls the Expression of the Staphylococcus aureus LmrS Efflux Pump
Authors: Truong-Bolduc Q. C. , Wang Y. , Chen C. , Hooper D. C. 
Published: June 2017

ABSTRACT

TetR21 controls the expression of Tet38 and LmrS efflux pumps. A
tetR21
mutant, QT21, exhibited a 4-fold increase in the transcription level of
lmrS
.
Staphylococcus aureus
lmrS
overexpressor showed increases of 4-fold and 2-fold, respectively, in the MICs of chloramphenicol and erythromycin, while the MICs of
lmrS
mutant QT18 and
lmrS-tetR21
mutant QT1821 remained similar to those of parental strain RN6390. TetR21 does not bind to the promoter of
lmrS
, suggesting indirect regulation of
lmrS
.
Parasitic Protozoa and Interactions with the Host Intestinal Microbiota
Authors: Burgess Stacey L. , Gilchrist Carol A. , Lynn Tucker C. , Petri William A. 
Published: June 2017

ABSTRACT

Parasitic protozoan infections represent a major health burden in the developing world and contribute significantly to morbidity and mortality. These infections are often associated with considerable variability in clinical presentation. An emerging body of work suggests that the intestinal microbiota may help to explain some of these differences in disease expression. The objective of this minireview is to synthesize recent progress in this rapidly advancing field. Studies of humans and animals and
in vitro
studies of the contribution of the intestinal microbiota to infectious disease are discussed. We hope to provide an understanding of the human-protozoal pathogen-microbiome interaction and to speculate on how that might be leveraged for treatment.
Metabolic heterogeneity of idiopathic pulmonary fibrosis: a metabolomic study
Authors: Zhao Yidan D , Yin Li , Archer Stephen , Lu Catherine , Zhao George , Yao Yan , Wu Licun , Hsin Michael , Waddell Thomas K , Keshavjee Shaf , Granton John , de Perrot Marc 
Published: June 2017

IntroductionIdiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown cause characterised by progressive fibrotic formation in lung tissue. We hypothesise that disrupted metabolic pathways in IPF contribute to disease pathogenesis.MethodsMetabolomics of human IPF was performed using mass spectroscopy (IPF lung=8; donor lung=8). Gene expression of key metabolic enzymes was measured using microarrays. Of the 108 metabolites whose levels were found altered, 48 were significantly increased, whereas 60 were significantly decreased in IPF samples compared with normal controls.ResultsSpecific metabolic pathways mediating the IPF remodelling were found with a downregulated sphingolipid metabolic pathway but an upregulated arginine pathway in IPF. In addition, disrupted glycolysis, mitochondrial beta-oxidation and tricarboxylic acid cycle, altered bile acid, haem and glutamate/aspartate metabolism were found in IPF samples compared with control.ConclusionsOur results show alterations in metabolic pathways for energy consumption during lung structural remodelling, which may contribute to IPF pathogenesis. We believe that this is the first report of simultaneously and systemically measuring changes of metabolites involving nine metabolic pathways in human severe IPF lungs. The measurement of the metabolites may serve in the future diagnosis and prognosis of IPF.
Combining creative writing and narrative analysis to deliver new insights into the impact of pulmonary hypertension
Authors: Goddard Julia C , Armstrong Iain J , Kiely David G , Elliot Charlie A , Charalampopoulos Athanasios , Condliffe Robin , Stone Brendan J , Sabroe Ian 
Published: June 2017

IntroductionPulmonary hypertension is life limiting. Delays in diagnosis are common, and even after treatment has been initiated, pulmonary hypertension has marked effects on many aspects of social and physical function. We believed that a new approach to examining disease impact could be achieved through a combination of narrative research and creative writing.MethodsDetailed unstructured narrative interviews with people with pulmonary hypertension were analysed thematically. Individual moments were also summarised and studied using creative writing, in which the interviewer created microstories from narrative and interview data. Stories were shared with their subjects, and with other patients, clinicians, researchers and the wider public. The study was carried out in hospital and in patients’ homes.ResultsNarrative analysis generated a rich data set which highlighted profound effects of pulmonary hypertension on identity, and demonstrated how the disease results in very marked personal change with ongoing and unpredictable requirement for adaptation. The novel methodology of microstory development proved to be an effective tool to summarise, communicate and explore the consequences of pulmonary hypertension and the clinical challenges of caring for patients with this illness.ConclusionsA holistic approach to treatment of chronic respiratory diseases such as pulmonary hypertension requires and benefits from explicit exploration of the full impacts of the illness. Narrative analysis and the novel approach of targeted microstory development can form a valuable component of the repertoire of approaches to effectively comprehend chronic disease and can also facilitate patient-focused discussion and interventions.
Breathing–swallowing discoordination is associated with frequent exacerbations of COPD
Authors: Nagami Shinsuke , Oku Yoshitaka , Yagi Naomi , Sato Susumu , Uozumi Ryuji , Morita Satoshi , Yamagata Yoshie , Kayashita Jun , Tanimura Kazuya , Sato Atsuyasu , Takahashi Ryosuke , Muro Shigeo 
Published: June 2017

IntroductionImpaired coordination between breathing and swallowing (breathing–swallowing discoordination) may be a significant risk factor for the exacerbation of chronic obstructive pulmonary disease (COPD). We examined breathing–swallowing discoordination in patients with COPD using a non-invasive and quantitative technique and determined its association with COPD exacerbation.MethodsWe recruited 65 stable outpatients with COPD who were enrolled in our prospective observational cohort study and did not manifest an apparent swallowing disorder. COPD exacerbation was monitored for 1 year before and 1 year after recruitment. Swallowing during inspiration (the I-SW pattern) and swallowing immediately followed by inspiration (the SW-I pattern) were identified.ResultsThe mean frequency of the I-SW and/or SW-I patterns (I-SW/SW-I rate) was 21.5%±25.5%. During the 2-year observation period, 48 exacerbation incidents (25 patients) were identified. The I-SW/SW-I rate was significantly associated with the frequency of exacerbation. During the year following recruitment, patients with a higher I-SW/SW-I frequency using thicker test foods exhibited a significantly higher probability of future exacerbations (p=0.002, log-rank test).ConclusionsBreathing–swallowing discoordination is strongly associated with frequent exacerbations of COPD. Strategies that identify and improve breathing–swallowing coordination may be a new therapeutic treatment for patients with COPD.
FOXM1 in Cancer: Interactions and Vulnerabilities
Authors: Gartel Andrei L. 
Published: June 2017

Abstract
FOXM1 is a transcription factor of the Forkhead family that is required for cell proliferation of normal cells. However, FOXM1 is repeatedly overexpressed in a variety of human cancers, and it has been implicated in all major hallmarks of cancer delineated by Hanahan and Weinberg. It has been postulated that the oncogenic potential of FOXM1 is determined by its capacity to transactivate target genes that are implicated in different phases of cancer development. However, FOXM1 may also play an oncogenic role by interacting with other proteins, such as β-catenin or SMAD3 to induce oncogenic WNT and TGFβ signaling pathways, respectively. In this review, I will discuss the protein–protein interactions of FOXM1 that are critical for cancer development and may represent novel targets for anticancer drugs. Cancer Res; 77(12); 3135–9. ©2017 AACR.
Human Subjects Protection and Cancer Surveillance Research: Revised Regulations, Expanded Opportunities
Authors: McLaughlin Robert H. , Gomez Scarlett Lin , Deapen Dennis , Induni Marta 
Published: June 2017

Abstract
On January 19, 2017, the United States federal government issued revisions to the Common Rule under which scientists who receive federal funding conduct research involving human subjects. The revised Common Rule expressly addresses public health surveillance in relation to scientific research and the protection of human subjects, and its impacts are anticipated to contribute to the efficiency of activities, including cancer registration and surveillance, and research that uses cancer registry data. Cancer Res; 77(12); 3140–3. ©2017 AACR.
The Landscape of Isoform Switches in Human Cancers
Authors: Vitting-Seerup Kristoffer , Sandelin Albin 
Published: June 2017

Abstract
Alternative usage of transcript isoforms from the same gene has been hypothesized as an important feature in cancers. However, differential usage of gene transcripts between conditions (isoform switching) has not been comprehensively characterized in and across cancer types. To this end, we developed methods for identification and visualization of isoform switches with predicted functional consequences. Using these methods, we characterized isoform switching in RNA-seq data from &gt;5,500 cancer patients covering 12 solid cancer types. Isoform switches with potential functional consequences were common, affecting approximately 19% of multiple transcript genes. Among these, isoform switches leading to loss of DNA sequence encoding protein domains were more frequent than expected, particularly in pancancer switches. We identified several isoform switches as powerful biomarkers: 31 switches were highly predictive of patient survival independent of cancer types. Our data constitute an important resource for cancer researchers, available through interactive web tools. Moreover, our methods, available as an R package, enable systematic analysis of isoform switches from other RNA-seq datasets.
Implications: This study indicates that isoform switches with predicted functional consequences are common and important in dysfunctional cells, which in turn means that gene expression should be analyzed at the isoform level.
Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/9/1206/F1.large.jpg. Mol Cancer Res; 15(9); 1206–20. ©2017 AACR.
IKKβ-Mediated Resistance to Skin Cancer Development Is Ink4a/Arf-Dependent
Authors: Page Angustias , Bravo Ana , Suarez-Cabrera Cristian , Alameda Josefa P. , Casanova M. Llanos , Lorz Corina , Segrelles Carmen , Segovia José C. , Paramio Jesús M. , Navarro Manuel , Ramirez Angel 
Published: June 2017

Abstract
IKKβ (encoded by IKBKB) is a protein kinase that regulates the activity of numerous proteins important in several signaling pathways, such as the NF-κB pathway. IKKβ exerts a protumorigenic role in several animal models of lung, hepatic, intestinal, and oral cancer. In addition, genomic and proteomic studies of human tumors also indicate that IKBKB gene is amplified or overexpressed in multiple tumor types. Here, the relevance of IKKβ in skin cancer was determined by performing carcinogenesis studies in animal models overexpressing IKKβ in the basal skin layer. IKKβ overexpression resulted in a striking resistance to skin cancer development and an increased expression of several tumor suppressor proteins, such as p53, p16, and p19. Mechanistically, this skin tumor–protective role of IKKβ is independent of p53, but dependent on the activity of the Ink4a/Arf locus. Interestingly, in the absence of p16 and p19, IKKβ-increased expression favors the appearance of cutaneous spindle cell–like squamous cell carcinomas, which are highly aggressive tumors. These results reveal that IKKβ activity prevents skin tumor development, and shed light on the complex nature of IKKβ effects on cancer progression, as IKKβ can both promote and prevent carcinogenesis depending on the cell type or molecular context.
Implications: The ability of IKKβ to promote or prevent carcinogenesis suggests the need for further evaluation when targeting this protein. Mol Cancer Res; 15(9); 1255–64. ©2017 AACR.
Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex
Authors: Han Xiaoqing , Ranganathan Prathibha , Tzimas Christos , Weaver Kelly L. , Jin Ke , Astudillo Luisana , Zhou Wen , Zhu Xiaoxia , Li Bin , Robbins David J. , Capobianco Anthony J. 
Published: June 2017

Abstract
It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml, and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner. Furthermore, results indicate that Notch recruits Polycomb Repressor Complex 2 (PRC2) and Lysine Demethylase 1 (KDM1A/LSD1) to these promoters, which leads to changes in the epigenetic landscape and repression of transcription. The demethylase activity of LSD1 is a prerequisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex was identified containing LSD1, PRC2, and the Notch ternary complex. These findings demonstrate a novel function of Notch and provide further insight into the mechanisms of Notch-mediated tumorigenesis.
Implications: This study provides rationale for the targeting of epigenetic enzymes to inhibit Notch activity or use in combinatorial therapy to provide a more profound therapeutic response. Mol Cancer Res; 15(9); 1173–83. ©2017 AACR.
Abstract AP06: SUBCLINICAL SIGNIFICANCE OF CIRCULATING TUMOR CELLS IN EPITHELIAL OVARIAN CANCER AS AN EARLY INDICATEOR OF RECURRENCE
Authors: Ruiz Carmen , Zheng Serena , Duggan Bridgette , Hicks James , Kuhn Peter 
Published: June 2017

Abstract
BACKGROUND: After diagnosis of cancer and subsequent treatment, a fraction of epithelial ovarian cancer (EOC) patients relapse with distant metastatic disease. While the fraction of the treated population that will relapse is predictable, there is not yet a way to determine the specific cases that will become metastatic. This transition between localized and disseminated cancer is clinically identified by the appearance of the patient's original cancer in a new anatomic location by various imaging methodologies or the increase of surrogate serum biomarkers. The actual biologic transition point, however, clearly occurs at some point prior to the time when metastasis becomes clinically evident. This becomes relevant during periods when disease is not clinically evident, where more sensitive identification methods of relapsing cancer may offer opportunities for therapy before tumor burden rises to an incurable level.
PURPOSE: With the observation that circulating tumor cells (CTCs) are found in cancer patients with no clinical evidence of disseminated disease prior to clinically evident relapse, we sought to investigate whether the presence of CTCs in the circulatory compartment could possibly indicate tumor dissemination at its earliest time point and whether that could be leveraged to develop predictive models and markers that identify patients prior to clinical evidence of recurrent disease.
METHODS: Peripheral blood samples collected after chemotherapy from 18 patients diagnosed with serous EOC were evaluated using the High Definition– Single Cell Assay (HD–SCA) for HD–CTCs enumeration, cytomorphological analysis and DNA copy number variation (CNV) profiling.
RESULTS: HD–CTCs (≥1 CTC/mL) were detected in 9 (50%) of these patients, 3 of whom relapsed. Despite the genomic heterogeneity of the CTCs analyzed, single cell CNV profiles from one of these recurrent patients showed clonal cyclin E1 amplification on chromosome 19 and ARID1A tumor suppressor gene deletion on chromosome 1, genomic alterations consistent with EOC.
CONCLUSION: The data suggests malignancy of multiple, single CTCs in recurrent patients, and further analysis of CTCs from non–recurrent patients could provide the means to determine the subclinical significance of CTCs in ovarian cancer. Earlier diagnosis of relapse, and subsequent personalized treatment, could eventually lead to more favorable prognoses in EOC patients.
Citation Format: Carmen Ruiz, Serena Zheng, Bridgette Duggan, James Hicks and Peter Kuhn. SUBCLINICAL SIGNIFICANCE OF CIRCULATING TUMOR CELLS IN EPITHELIAL OVARIAN CANCER AS AN EARLY INDICATEOR OF RECURRENCE [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP06.
Abstract AP10: A NOVEL PAN–ALDH1A INHIBITOR INDUCES NECROPTOSIS IN OVARIAN CANCER STEM–LIKE CELLS AND SYNERGIZES WITH CHEMOTHERAPY TO IMPROVE OUTCOMES
Authors: Chefetz Ilana , Hong Linda , Yang Kun , Huddle Brandt , Landen Charles , Hurley Thomas , Larsen Scott D. , Buckanovich Ronald J. 
Published: June 2017

Abstract
BACKGROUND: We recently demonstrated that Aldehyde dehydrogenase (ALDH) activity and the stem cell marker CD133 can be used to define an ovarian cancer cell differentiation hierarchy. We demonstrated that even small increases in multipotent ALDHbrightCD133+ cancer stem–like cells (CSC) significantly increase chemotherapy resistance and tumor initiation capacity. ALDH1A family members (ALDH1A1, 1A2, and 1A3) have been implicated as the primary enzymes identifying CSC and have been strongly linked with chemotherapy resistance. Given the expression of ALDH1A family members in CSC and their role in chemotherapy resistance we hypothesized they could be important therapeutic targets.
METHODS AND RESULTS: We developed a panel of novel ALDH inhibitors (ALDHi). We identified a DEAB analog 673540 (673A) which inhibits all three ALDH1A1 enzymes (IC50 ~220nM). Pan–ALDH1A inhibition, induced necroptotic cell death specifically in ALDHbright and CD133+ ovarian CSC. 673A induced necroptosis was driven by the induction of the mitochondrial uncoupling proteins, UCP1 and UCP3, and reduction in OXPHOS capacity. Necroptosis was caspase and RIP1 independent, but is associated with MLKL translocation to membrane, and DRP1 activation and translocation to mitochondria. 673A therapy was highly synergistic with chemotherapy, reducing tumor initiation capacity, and resulting in a 60% tumor cure rate in multiple tumor models in–vivo.
CONCLUSIONS: ALDHi are highly active in experimental models of ovarian cancer. As ALDHi induce metabolic necroptosis, ALDHi are active in apoptosis resistant ovarian cancer cell lines. These studies support the development of ALDHi as novel therapeutics for ovarian cancer.
Citation Format: Ilana Chefetz, Linda Hong, Kun Yang, Brandt Huddle, Charles Landen, Thomas Hurley, Scott D. Larsen, and Ronald J. Buckanovich. A NOVEL PAN–ALDH1A INHIBITOR INDUCES NECROPTOSIS IN OVARIAN CANCER STEM–LIKE CELLS AND SYNERGIZES WITH CHEMOTHERAPY TO IMPROVE OUTCOMES [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP10.