bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lysinibacillus fusiformis M5 Induces Increased Complexity in Bacillus subtilis 168 Colony Biofilms via Hypoxanthine
Authors: Gallegos-Monterrosa Ramses , Kankel Stefanie , Götze Sebastian , Barnett Robert , Stallforth Pierre , Kovács Ákos T. 
Published: June 2017

ABSTRACT

In recent years, biofilms have become a central subject of research in the fields of microbiology, medicine, agriculture, and systems biology, among others. The sociomicrobiology of multispecies biofilms, however, is still poorly understood. Here, we report a screening system that allowed us to identify soil bacteria which induce architectural changes in biofilm colonies when cocultured with
Bacillus subtilis
. We identified the soil bacterium
Lysinibacillus fusiformis
M5 as an inducer of wrinkle formation in
B. subtilis
colonies mediated by a diffusible signaling molecule. This compound was isolated by bioassay-guided chromatographic fractionation. The elicitor was identified to be the purine hypoxanthine using mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. We show that the induction of wrinkle formation by hypoxanthine is not dependent on signal recognition by the histidine kinases KinA, KinB, KinC, and KinD, which are generally involved in phosphorylation of the master regulator Spo0A. Likewise, we show that hypoxanthine signaling does not induce the expression of biofilm matrix-related operons
epsABCDEFGHIJKLMNO
and
tasA-sipW-tapA
. Finally, we demonstrate that the purine permease PbuO, but not PbuG, is necessary for hypoxanthine to induce an increase in wrinkle formation of
B. subtilis
biofilm colonies. Our results suggest that hypoxanthine-stimulated wrinkle development is not due to a direct induction of biofilm-related gene expression but rather is caused by the excess of hypoxanthine within
B. subtilis
cells, which may lead to cell stress and death.

IMPORTANCE
Biofilms are a bacterial lifestyle with high relevance regarding diverse human activities. Biofilms can be beneficial, for instance, in crop protection. In nature, biofilms are commonly found as multispecies communities displaying complex social behaviors and characteristics. The study of interspecies interactions will thus lead to a better understanding and use of biofilms as they occur outside laboratory conditions. Here, we present a screening method suitable for the identification of multispecies interactions and showcase
L. fusiformis
as a soil bacterium that is able to live alongside
B. subtilis
and modify the architecture of its biofilms.
Trace of nonperturbative charm content of the nucleon on Z + c-jet production
Authors: Rostami S. , Khorramian A. 
Published: June 2017

We perform a comparison of the impact of different intrinsic charm (IC) models, based on the prediction of the differential cross-sections of [Formula: see text]-boson and [Formula: see text]-jet production in [Formula: see text] collision. It is shown that regardless of choosing the model, considering nonperturbative intrinsic charm component increases the magnitude of the cross-section when the [Formula: see text] transverse momentum grows or at large rapidity [Formula: see text] of the [Formula: see text]. Moreover, to evaluate the effect of different parton distribution functions (PDFs), we also compare the results of two PDF sets in prediction of production [Formula: see text]-jet in [Formula: see text] at a center-of-mass energy of 13 TeV with taking into account the intrinsic charm contribution in the proton. It is shown that the various PDF sets give some difference in the description of the [Formula: see text]-jet cross-section.
Nature and Nurture: What Determines Tumor Metabolic Phenotypes?
Authors: Mayers Jared R. , Vander Heiden Matthew G. 
Published: June 2017

Abstract
Understanding the genetic basis of cancer has led to therapies that target driver mutations and has helped match patients with more personalized drugs. Oncogenic mutations influence tumor metabolism, but other tumor characteristics can also contribute to their metabolic phenotypes. Comparison of isogenic lung and pancreas tumor models suggests that use of some metabolic pathways is defined by lineage rather than by driver mutation. Lung tumors catabolize circulating branched chain amino acids (BCAA) to extract nitrogen for nonessential amino acid and nucleotide synthesis, whereas pancreatic cancer obtains amino acids from catabolism of extracellular protein. These differences in amino acid metabolism translate into distinct pathway dependencies, as genetic disruption of the enzymes responsible for utilization of BCAA nitrogen limits the growth of lung tumors, but not pancreatic tumors. These data argue that some cancer metabolic phenotypes are defined by cancer tissue-of-origin and environment and that these features constrain the influence of genetic mutations on metabolism. A better understanding of the factors defining tumor nutrient utilization could be exploited to help improve cancer therapy. Cancer Res; 77(12); 3131–4. ©2017 AACR.
PPARδ Reprograms Glutamine Metabolism in Sorafenib-Resistant HCC
Authors: Kim Mi-Jin , Choi Yeon-Kyung , Park Soo Young , Jang Se Young , Lee Jung Yi , Ham Hye Jin , Kim Byung-Gyu , Jeon Hui-Jeon , Kim Ji-Hyun , Kim Jung-Guk , Lee In-Kyu , Park Keun-Gyu 
Published: June 2017

Abstract
The tyrosine kinase inhibitor sorafenib is the only therapeutic agent approved for the treatment of advanced hepatocellular carcinoma (HCC), but acquired resistance to sorafenib is high. Here, we report metabolic reprogramming in sorafenib-resistant HCC and identify a regulatory molecule, peroxisome proliferator–activated receptor-δ (PPARδ), as a potential therapeutic target. Sorafenib-resistant HCC cells showed markedly higher glutamine metabolism and reductive glutamine carboxylation, which was accompanied by increased glucose-derived pentose phosphate pathway and glutamine-derived lipid biosynthetic pathways and resistance to oxidative stress. These glutamine-dependent metabolic alterations were attributed to PPARδ, which was upregulated in sorafenib-resistant HCC cells and human HCC tissues. Furthermore, PPARδ contributed to increased proliferative capacity and redox homeostasis in sorafenib-resistant HCC cells. Accordingly, inhibiting PPARδ activity reversed compensatory metabolic reprogramming in sorafenib-resistant HCC cells and sensitized them to sorafenib. Therefore, targeting compensatory metabolic reprogramming of glutamine metabolism in sorafenib-resistant HCC by inhibiting PPARδ constitutes a potential therapeutic strategy for overcoming sorafenib-resistance in HCC.
Implications: This study provides novel insight into the mechanism underlying sorafenib resistance and a potential therapeutic strategy targeting PPARδ in advanced hepatocellular carcinoma. Mol Cancer Res; 15(9); 1230–42. ©2017 AACR.
Abstract AP01: HE4 IS A BIOMARKER FOR NEWLY DIAGNOSED AND RECURRENT HIGH–GRADE SEROUS OVARIAN CANCERS WITH NORMAL CA–125 VALUES
Authors: LaVigne Katherine , Dao Fanny , Abu–Rustum Nadeem , Jelinic Petar , Ramanathan Lakshmi V. , Fleisher Martin , Levine Douglas A. 
Published: June 2017

Abstract
PURPOSE: CA125 is widely used for the diagnosis and monitoring of women with epithelial ovarian cancer. However, CA125 will not be elevated in ~20% of patients. Human epididymis protein 4 (HE4) was approved by the FDA in 2008 to monitor ovarian cancer. The objective of this study was to evaluate whether HE4 would serve as a useful biomarker in patients with a normal CA125 at either the time of diagnosis or at the time of recurrence.
METHODS: Twenty–one patients with high–grade serous ovarian cancer and CA125 values &lt;50U/ml at the time of diagnosis were identified from a bank of serum specimens collected between 2006–2012. Twenty patients with high–grade serous ovarian cancer and CA125 values &gt;1000U/ml served as positive controls and 11 patients without disease served as negative controls. Fourteen patients with an elevated CA125 at diagnosis (&gt;50 U/ml) and a normal CA125 at the time of recurrence were also identified. HE4 was measured using the Abbott Architect i2000 assay and validation was performed using the Fujirebio HE4 ELISA assay. Normal age–based HE4 values were obtained from the published literature (Urban N, et al.; PMID: 22962406). Data was compared between groups using standard two–sided statistical tests.
RESULTS: At the time of diagnosis, the mean HE4 was 1082±437.9 in the positive control patients with elevated CA125, the mean HE4 was 50.96±11.43 in the patients without disease, and 214.4±236.9 in patients with a normal CA–125 (P = &lt;.0001 compared to normal controls; Student's t–test). At the time of recurrence, the mean HE4 was 102.7±83.29 in patients with normal CA125 levels. For 12 of 14 (86%) patients, the HE4 value was greater than the expected normal age–based reference.
CONCLUSIONS: These preliminary data suggest that HE4 values are elevated in newly diagnosed ovarian cancer patients with a normal CA125 value. HE4 also appears to be a potentially useful biomarker for detecting recurrent disease in patients with an elevated CA125 at the time of diagnosis who have a normal CA125 level at the time of recurrence.
Citation Format: Katherine LaVigne, MD, Fanny Dao, MS, Nadeem Abu–Rustum, MD, Petar Jelinic, PhD, Lakshmi V. Ramanathan, PhD, Martin Fleisher, PhD, Douglas A. Levine, MD. HE4 IS A BIOMARKER FOR NEWLY DIAGNOSED AND RECURRENT HIGH–GRADE SEROUS OVARIAN CANCERS WITH NORMAL CA–125 VALUES [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 AP01.
Abstract AP07: USE OF COMMON MEDICATIONS AND SURVIVAL AFTER OVARIAN CANCER DIAGNOSIS
Authors: Merritt Melissa A. , Rice Megan S. , Tworoger Shelley S. , Poole Elizabeth M. 
Published: June 2017

Abstract
BACKGROUND: Ovarian cancer is the 5th deadliest cancer among US women. Although clinical characteristics (e.g., disease stage and histology) and treatment (e.g., optimal debulking) predict outcomes, little is known about whether modifiable factors contribute to prognosis. Inflammation and chronic stress have both been implicated in ovarian cancer progression. Therefore, we evaluated whether use of analgesics (aspirin; other non–steroidal anti–inflammatory drugs [NSAIDs], or acetaminophen) or beta–blockers (a common medication for hypertension that targets stress signaling pathways) is associated with ovarian cancer prognosis.
METHODS: The Nurses' Health Study is a prospective study of 121,700 US nurses who have completed biennial questionnaires on lifestyle, medications, and disease diagnosis since 1976. Regular aspirin use (&gt; 2 times/week over the prior year) was queried on every questionnaire since 1980; regular use of other NSAIDs or acetaminophen was queried since 1990; and use of beta–blockers was queried since 1988. We used Cox proportional hazards regression to calculate relative risks (RRs) and 95% confidence intervals (CI), adjusting for tumor and personal characteristics. Women diagnosed with stage IV ovarian cancer were excluded from the analysis.
RESULTS: Available case numbers ranged from 427–779, depending on the medication. Women who regularly used aspirin after diagnosis had a 45% lower risk of dying due to ovarian cancer (RR: 0.55; 95% CI: 0.35–0.86). Post–diagnosis use of other NSAIDs was associated with a suggestive decreased risk of ovarian cancer death (RR: 0.89; 95% CI: 0.60–1.32). There was no association of pre–diagnosis use of any of the analgesic medications with prognosis, nor was there an association of post–diagnosis acetaminophen use with survival. Similarly, there was no association with either pre–diagnosis (RR: 0.92; 95% CI: 0.69–1.23) or post–diagnosis (RR: 0.93; 95% CI: 0.62–1.40) use of beta blockers.
CONCLUSIONS: In this study of analgesic and beta blocker use among ovarian cancer patients, regular use of aspirin after diagnosis appeared to improve survival. Power was limited for some analysis, particularly current use of non–aspirin NSAIDS as there were relatively few current users available for analysis (114 women were current users; 49 of whom died of ovarian cancer during follow–up). Overall, our results suggest that reducing inflammation after diagnosis may be beneficial for improving survival. Future analyses will consider other hypertension medications and well as other modifiable lifestyle factors.
Citation Format: Melissa A. Merritt, Megan S. Rice, Shelley S. Tworoger, Elizabeth M. Poole. USE OF COMMON MEDICATIONS AND SURVIVAL AFTER OVARIAN CANCER DIAGNOSIS [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 AP07.
Abstract AP09: GENOMIC ALTERATIONS IN ENDOMETRIOSIS
Authors: Anglesio Michael S. , Nazeran Tayyebeh M. , Horlings Hugo M. , Lac Vivian , Lum Amy , Senz Janine , Ho Julie , Wang Amy , Wong Fontayne , Allaire Catherine , Williams Christina , Gilks C. Blake , Yong Paul J. , Huntsman David G. 
Published: June 2017

Abstract
BACKGROUND: Endometriosis affects ~10% of reproductive–aged women and is characterized by extra–uterine biphasic growth of uterine endometrial epithelium and stroma. Endometriosis is widely considered to be a hormonally–dependent inflammatory condition and is classified into three anatomically defined types: deep infiltrating endometriosis that locally invades pelvic organs; ovarian endometriotic cysts, and superficial peritoneal endometriosis. A clonal “precursor–cancer” link to co–occurring clear cell and endometrioid ovarian cancers has been established and somatic mutations occur in these cancer–associated endometriotic cysts, including distant benign–appearing lesions. The spectrum of genetic alteration in non–cancer associated endometriosis is not known.
METHODS: We screened a pilot series of 10 deep–infiltrating [pelvic] endometriosis lesions, without co–occurrence or history of cancer, for somatic alterations using laser captured endometrial stroma and epithelium. Two overlapping amplicon panels and digital PCR were used to validate mutations.
RESULTS: In four of ten cases we validated the presence of activating codon 12 KRAS mutations. Mutations were restricted to the epithelium and no evidence of any alterations was found in the stromal fraction.
CONCLUSIONS: We provide incontrovertible evidence of activating KRAS mutations in 40% of deep infiltrating endometriosis. This frequency of KRAS mutations is substantially higher than what has been observed in clear cell (CCOC) or endometrioid (ENOC) ovarian cancers and the occurrence of non–ovarian primary CCOC/ENOC is largely anecdotal. Our evidence suggests that these mutations represent core features of endometriosis itself, rather than a risk of malignant transformation. Overall we propose this as an opportunity to fundamentally shift the study of endometriosis to a spectrum of neoplasms. This may lead to the generation of a molecularly informed classification system and ultimately to improved prognostication and treatment.
Citation Format: Michael S. Anglesio, Tayyebeh M. Nazeran, Hugo M. Horlings, Vivian Lac, Amy Lum, Janine Senz, Julie Ho, Amy Wang, Fontayne Wong, Catherine Allaire, Christina Williams, C. Blake Gilks, Paul J. Yong, and David G. Huntsman. GENOMIC ALTERATIONS IN ENDOMETRIOSIS [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 AP09.
Abstract AP15: MODULATION OF OXIDATIVE STRESS AND SUBSEQUENT INDUCTION OF APOPTOSIS AND ENDOPLASMIC RETICULUM STRESS ALLOWS CITRAL TO DECREASE CANCER CELL PROLIFERATION
Authors: Kapur Arvinder , Felder Mildred , Fass Lucas , Kaur Justanjot , Czarnecki Austin , Rathi Kavya , Zeng San , Osowski Kathryn Kalady , Howell Colin , Xiong May P. , Whelan Rebecca J. , Patankar Manish S. 
Published: June 2017

Abstract
The monoterpenoid, citral, when delivered through PEG-b-PCL nanoparticles inhibits in vivo growth of 4T1 breast tumors. Here, we show that citral inhibits proliferation of multiple human cancer cell lines. In p53 expressing ECC-1 and OVCAR-3 but not in p53-deficient SKOV-3 cells, citral induces G1/S cell cycle arrest and apoptosis as determined by Annexin V staining and increased cleaved caspase3 and Bax and decreased Bcl-2. In SKOV-3 cells, citral induces the ER stress markers CHOP, GADD45, EDEM, ATF4, Hsp90, ATG5, and phospho-eIF2α. The molecular chaperone 4-phenylbutyric acid attenuates citral activity in SKOV-3 but not in ECC-1 and OVCAR-3 cells. In p53-expressing cells, citral increases phosphorylation of serine-15 of p53. Activation of p53 increases Bax, PUMA, and NOXA expression. Inhibition of p53 by pifithrin-α, attenuates citral-mediated apoptosis. Citral increases intracellular oxygen radicals and this leads to activation of p53. Inhibition of gluthatione synthesis by L-buthionine sulfoxamine increased potency of citral. Pretreatment with N-acetylcysteine decreases phosphorylation of p53 in citral-treated ECC-1 and OVCAR-3. These results define a p53-dependent, and in the absence of p53, ER stress-dependent mode of action of citral. This study indicates that citral in PEG-b-PCL nanoparticle formulation should be considered for treatment of breast and other tumors.
Citation Format: Arvinder Kapur, Mildred Felder, Lucas Fass, Justanjot Kaur, Austin Czarnecki, Kavya Rathi, San Zeng, Kathryn Kalady Osowski, Colin Howell, May P. Xiong, Rebecca J. Whelan, Manish S. Patankar. MODULATION OF OXIDATIVE STRESS AND SUBSEQUENT INDUCTION OF APOPTOSIS AND ENDOPLASMIC RETICULUM STRESS ALLOWS CITRAL TO DECREASE CANCER CELL PROLIFERATION [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 AP15.
Abstract AP25: INHIBITION OF HDAC ACTIVITY SELECTIVELY INHIBITS ARID1A–MUTATED OVARIAN CLEAR CELL CARCINOMA THROUGH A NOVEL P53 REGULATORY MECHANISM
Authors: Bitler Benjamin G. , Park Pyoung Hwa , Hai Yang , Aird Katherine M. , Wang Yemin , Huntsman David G. , Cho Kathleen R. , Christianson David W. , Zhang Rugang 
Published: June 2017

Abstract
PURPOSE OF THE STUDY: ARID1A is mutated ~50% and 30% of clear cell (OCCC) and endometrioid (OEC) ovarian cancers, respectively. Over 90% of the ARID1A mutations observed in ovarian cancer are frame-shift or nonsense mutations that result in loss of ARID1A protein expression. In several cancers including OCCC, ARID1A and p53 mutations are often mutually exclusive. OCCC carries a worse prognosis compared to the other histosubtypes of ovarian cancer. Thus, there is an urgent clinical need for improved therapeutic strategies.
EXPERIMENTAL PROCEDURE: To investigate the role of specific HDACs in the context of ARID1A expression, we examined the effect of knocking down HDACs in an isogenic OCCC cell line with and without ARID1A expression. Utilizing a panel of ARID1A-mutated and wildtype OCCC cell lines, we evaluated the effect of HDAC knockdown and inhibition through a variety of 2D and 3D assays. We also examined the consequence of HDAC inhibition on tumor growth, survival, and dissemination in an in vivo mouse model of ovarian cancer.
SUMMARY OF THE DATA: We have discovered that ARID1A is involved in the repression of HDACs, and ARID1A-inactivation promotes aberrant transcriptional regulation of HDACs. Importantly, we uncovered a novel HDAC-dependent regulatory mechanism of p53. Several HDAC inhibitors are currently in clinical trials. We found HDAC inhibitors were more selective in ARID1A-mutated OCCC cell lines compared to ARID1A-wildtype cells. We observed that HDAC inhibition led to a significant increase in apoptosis in ARID1A-mutated cells. In an orthotopic intra-bursal xenograft model using ARID1A wildtype and deficient cells, the HDAC inhibitor suppressed primary tumor growth and inhibited tumor cell dissemination only in the ARID1A-mutated tumors. Significantly, HDAC inhibition significantly improved the survival of mice bearing ARID1A-mutated tumors.
CONCLUSIONS: These findings imply that HDAC inhibition represents a novel therapeutic strategy for ARID1A-deficient cancers. This study further elucidates the observed mutual exclusivity of ARID1A and p53. Importantly, we have uncovered a novel regulatory mechanism of p53 mediated through ARID1A and HDACs. Clinically, this study describes a precision medicine approach to the treatment of ARID1A-mutated OCCC.
Citation Format: Benjamin G. Bitler, Pyoung Hwa Park, Yang Hai, Katherine M. Aird, Yemin Wang, David G. Huntsman, Kathleen R. Cho, David W. Christianson, Rugang Zhang. INHIBITION OF HDAC ACTIVITY SELECTIVELY INHIBITS ARID1A–MUTATED OVARIAN CLEAR CELL CARCINOMA THROUGH A NOVEL P53 REGULATORY MECHANISM [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 AP25.
Abstract AP29: BRCA1 RING DOMAIN–DEFICIENT PROTEINS PROMOTE PARP INHIBITOR AND PLATINUM RESISTANCE
Authors: Wang Yifan , Krais John J. , Bernhardy Andrea J. , Nicolas Emmanuelle , Cai Kathy Q. , Harrell Maria I. , Kim Hyoung H. , George Erin , Swisher Elizabeth M. , Simpkins Fiona , Johnson Neil 
Published: June 2017

Abstract
Although cancers harboring BRCA1 mutations initially respond well to platinum and poly(ADP-ribose)-polymerase inhibitor (PARPi) therapy, resistance invariably arises and is a major clinical problem. The BRCA1185delAG allele is a common inherited mutation located close to the protein translation start site, thought to produce a short peptide devoid of function. In this study, we utilized the SUM1315MO2 cancer cell line that harbors a hemizygous BRCA1185delAG mutation to study PARPi and platinum resistance. SUM1315MO2 cells were initially PARPi and cisplatin sensitive but readily acquired resistance. PARPi and cisplatin resistant clones did not harbor secondary reversion mutations. Rather, increased expression of a RING domain-deficient BRCA1 protein (Rdd-BRCA1) was required for resistance. Translation initiation occurred downstream of the frameshift mutation, likely at the BRCA1-Met-297 codon. In contrast to full-length BRCA1, Rdd-BRCA1 did not require BARD1 interaction for stability. Functionally, Rdd-BRCA1 formed irradiation-induced foci and supported RAD51 foci-formation. Ectopic overexpression of Rdd-BRCA1 promoted partial PARPi and cisplatin resistance in vitro and in vivo. Furthermore, Rdd-BRCA1 protein expression was detectable in recurrent carcinomas from germline BRCA1185delAG mutation carriers. Taken together, these results indicate that RING-deficient BRCA1 proteins are hypomorphic, and when expressed at high enough levels are capable of contributing to PARPi and platinum resistance.
Citation Format: Yifan Wang, John J. Krais, Andrea J. Bernhardy, Emmanuelle Nicolas, Kathy Q. Cai, Maria I. Harrell, Hyoung H. Kim, Erin George, Elizabeth M. Swisher, Fiona Simpkins and Neil Johnson. BRCA1 RING DOMAIN–DEFICIENT PROTEINS PROMOTE PARP INHIBITOR AND PLATINUM RESISTANCE [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 AP29.