tbuckley/cabot-search huggingface dataset:
Abstract 2963: Inhibition of stromal p38MAPK abrogates breast cancer metastasis
Authors: Sheila A. Stewart, Bhavna Murali, Qiaho Ren, Xinming Su, Kevin Flannagan, Xianmin Luo, Jasmine Sponagel, Yujie Fu, Elise Alspach, Kathlees Leahy, Roberta Faccio, Kathleen Weilbaecher, Joseph Monahan
Journal: Cancer Research (2017)

Abstract Bone metastasis is a devastating and fatal complication of breast cancer for which we lack effective therapies. Thus, identifying therapies that effectively limit metastases will significantly reduce comorbidities and improve long-term survival. Recently we demonstrated that the p38MAPK pathway sustains the pro-tumorigenic senescence-associated secretory phenotype (SASP) and targeting this pathway limits the tumor-promoting capabilities of senescent cells and cancer-associated fibroblasts (CAFs). Because we found that a significant percentage of p38MAPK-dependent SASP factors are expressed in the stroma associated with breast cancer lesions, we asked whether targeting p38MAPK could limit primary and metastatic breast cancer growth. While p38MAPK inhibition modestly limited primary tumor growth, we found that its inhibition significantly reduced breast cancer bone metastases by specifically targeting the stromal compartment. Further, p38MAPK inhibition was as effective as paclitaxel at limiting tumor growth in the bone but in contrast to paclitaxel, which failed to protect from cancer-induced bone loss, p38MAPK inhibition also protected against devastating bone loss. This contrasts our p38MAPK approach from zoledronic acid, which limits bone loss but fails to slow tumor growth in already engrafted tumors. Analysis of the mechanism(s) responsible for this reduced metastasis suggests that p38MAPK inhibition targets reactive and/or senescent osteoblasts within the bones of animals harboring metastatic lesions. Because we find that senescent osteoblasts are present in human bone, we postulate that they promote metastatic outgrowth and thus p38MAPK inhibition limits the pro-metastatic activities of these cells. Finally, we will present recent data from our preclinical model that demonstrates that inhibition of the p38MAPK pathway can drastically reduce metastasis from the primary site. We propose that p38MAPK is an important stromal-specific therapy for breast cancer metastasis to the bone. Citation Format: Sheila A. Stewart, Bhavna Murali, Qiaho Ren, Xinming Su, Kevin Flannagan, Xianmin Luo, Jasmine Sponagel, Yujie Fu, Elise Alspach, Kathlees Leahy, Roberta Faccio, Kathleen Weilbaecher, Joseph Monahan. Inhibition of stromal p38MAPK abrogates breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2963. doi:10.1158/1538-7445.AM2017-2963
Terminating the criminal collaboration in pancreatic cancer: Nanoparticle-based synergistic therapy for overcoming fibroblast-induced drug resistance
Authors: Liying Wang, Xiangrui Liu, Quan Zhou, Meihua Sui, Zipeng Lu, Zhuxian Zhou, Jianbin Tang, Yi Miao, Min Zheng, Weilin Wang, Youqing Shen
Journal: Biomaterials (2017)
Assessment of Burden of COPD tool: evidence not perception
Authors: Annerika H.M. Slok, Daniel Kotz, Gerard van Breukelen, Niels H. Chavannes, Maureen P.M.H. Rutten-van Mölken, Huib A.M. Kerstjens, Thys van der Molen, Guus M. Asijee, P.N. Richard Dekhuijzen, Sebastiaan Holverda, Philippe L. Salomé, Lucas M.A. Goossens, Mascha Twellaar, Johannes C.C.M. in ‘t Veen, Onno C.P. van Schayck
Journal: European Respiratory Journal (2017)

We thank Houben-Wilke et al. [1] for their comments on the Assessment of Burden of COPD (ABC) tool. They raised questions about the purpose of the ABC tool. The aims of ABC were clarified before its development, in the study protocol [2]. The ABC tool is multifaceted and was developed to measure burden of disease, facilitating shared decision making and formulation of a personal treatment plan [2–5]. All of these purposes relate to increasing self-management and stimulating behavioural change, which are, most often, important components of individual treatment plans. The goal of most treatment plans is to increase health status. Health status was therefore the primary outcome of our study [2–5]. ABC tool affects HRQoL and quality of primary/secondary COPD care but has not been tested in tertiary settings <http://ow.ly/HZYF30cmTsx>
Nocturnal Oximetry–based Evaluation of Habitually Snoring Children
Authors: Roberto Hornero, Leila Kheirandish-Gozal, Gonzalo C. Gutiérrez-Tobal, Mona F. Philby, María Luz Alonso-Álvarez, Daniel Álvarez, Ehab A. Dayyat, Zhifei Xu, Yu-Shu Huang, Maximiliano Tamae Kakazu, Albert M. Li, Annelies Van Eyck, Pablo E. Brockmann, Zarmina Ehsan, Narong Simakajornboon, Athanasios G. Kaditis, Fernando Vaquerizo-Villar, Andrea Crespo Sedano, Oscar Sans Capdevila, Magnus von Lukowicz, Joaquín Terán-Santos, Félix Del Campo, Christian F. Poets, Rosario Ferreira, Katalina Bertran, Yamei Zhang, John Schuen, Stijn Verhulst, David Gozal
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: The vast majority of children around the world undergoing adenotonsillectomy for obstructive sleep apnea–hypopnea syndrome (OSA) are not objectively diagnosed by nocturnal polysomnography because of access availability and cost issues. Automated analysis of nocturnal oximetry (nSpO2), which is readily and globally available, could potentially provide a reliable and convenient diagnostic approach for pediatric OSA.Methods: Deidentified nSpO2 recordings from a total of 4,191 children originating from 13 pediatric sleep laboratories around the world were prospectively evaluated after developing and validating an automated neural network algorithm using an initial set of single-channel nSpO2 recordings from 589 patients referred for suspected OSA.Measurements and Main Results: The automatically estimated apnea–hypopnea index (AHI) showed high agreement with AHI from conventional polysomnography (intraclass correlation coefficient, 0.785) when tested in 3,602 additional subjects. Further assessment on the widely used AHI cutoff points of 1, 5, and 10 events/h revealed an incremental diagnostic ability (75.2, 81.7, and 90.2% accuracy; 0.788, 0.854, and 0.913 area under the receiver operating characteristic curve, respectively).Conclusions: Neural network–based automated analyses of nSpO2 recordings provide accurate identification of OSA severity among habitually snoring children with a high pretest probability of OSA. Thus, nocturnal oximetry may enable a simple and effective diagnostic alternative to nocturnal polysomnography, leading to more timely interventions and potentially improved outcomes.
The Sustained Effects of a Dual GIP/GLP-1 Receptor Agonist, NNC0090-2746, in Patients with Type 2 Diabetes
Authors: Juan Pablo Frias, Edward J. Bastyr, Louis Vignati, Matthias H. Tschöp, Christophe Schmitt, Klara Owen, Rune Haubo Christensen, Richard D. DiMarchi
Journal: Cell Metabolism (2017)
Abstract LB-031: Deciphering distinct roles of RASA2 in melanomagenesis
Authors: Rand Arafeh, Nouar Qutob, Rafi Rafi Emmanuel, Jason Madore, Abdel Elkahloun, James S. James S. Wilmott, Jared J. Gartner, Antonella Di Pizio, Ron Rotkopf, Ken Dutton-Regester, Victoria Hill, Antonia Pritchard, Jimmy C. Lin, Steven A Rosenberg, Javed Khan, Shifra Ben-Dor, Masha Y. Masha Y. Niv, Igor Ulitsky, Graham J Mann, Richard A. Scolyer, Nicholas K. Hayward, Yardena Samuels
Journal: Cancer Research (2017)

Abstract Melanoma is the deadliest form of human skin cancer. The incidence of melanoma continues to rise. Recent advances in knowledge of melanoma genetics, genomics and biology has led to an optimistic view of the therapeutic outlook for melanoma patients. We analyzed sequence data from &amp;gt;500 melanoma genomes/exomes to identify novel tumor suppressor genes in melanoma. RASA2 was identified as the most highly somatically mutated novel tumor suppressor gene. RASA2 was mutated in 5% of melanomas and deleted in an additional 16.4% of cases. RASA2 is a GTPase Activating Protein (GAP) that regulates RAS; which is one of the most highly mutated oncogenes in melanoma but drugs targeting RAS have as yet shown poor efficacy. The role of RASA2 has not been investigated in melanoma. NF1, which encodes another RAS- specific GAP, was found to be frequently mutated in melanoma. Interestingly, mutations in RASA2 and NF1 co-occur in the same patients with high frequency. We plan to elucidate the roles of RASA2 in melanomagenesis and to understand why RASA2 and NF1 mutations co-occur despite the fact that both proteins are RasGAPs. Ras includes three isoforms: NRas, KRas and HRas. Our preliminary data show that RASA2 is more specific to NRAS and that NF1 is more specific to KRAS and HRAS. This finding highlights the existence of a paradigm of cooperativity in which combined loss of multiple negative regulators (RASA2 and NF1) of the RAS pathway is required for melanoma development. Therefore, this type of enhancement of RAS signaling is possibly selected for in some melanomas. We will apply a proteomic screen using BioID to identify RASA2 and NF1 binding partners to provide insights into the functional effects and consequences of alterations in RASA2 and NF1. We expect that these studies will not only identify the cellular components that contribute to the Ras signaling pathway but will also identify potential novel therapeutic targets. Citation Format: Rand Arafeh, Nouar Qutob, Rafi Rafi Emmanuel, Jason Madore, Abdel Elkahloun, James S. James S. Wilmott, Jared J. Gartner, Antonella Di Pizio, Ron Rotkopf, Ken Dutton-Regester, Victoria Hill, Antonia Pritchard, Jimmy C. Lin, Steven A Rosenberg, Javed Khan, Shifra Ben-Dor, Masha Y. Masha Y. Niv, Igor Ulitsky, Graham J Mann, Richard A. Scolyer, Nicholas K. Hayward, Yardena Samuels. Deciphering distinct roles of RASA2 in melanomagenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-031. doi:10.1158/1538-7445.AM2017-LB-031
Thermo-sensitive hydrogel of pectin/chitosan containing gold nanoparticles for biological applications
Authors: Fábio Tentor, Danielle Lazarin-Bidóia, Letícia C. Bonkovoski, Johny P. Monteiro, Elton G. Bonafé, Celso V. Nakamura, Sandro A.S. Venter, Adley F. Rubira, Edvani C. Muniz, Alessandro F. Martins
Journal: Journal of Controlled Release (2017)
Abstract 16915: Later Onset of Pyrexia Associated With Better Outcomes in Post-arrest Patients Treated With Targeted Temperature Management
Authors: Anne V Grossestreuer, Benjamin S Abella, Michael W Donnino, Douglas J Wiebe, David F Gaieski
Journal: Circulation (2016)

Introduction:  Post-arrest pyrexia has been associated with worse outcomes in recent studies. While targeted temperature management (TTM) serves as prophylaxis against pyrexia during active temperature management, it is unknown how the timing of post-TTM pyrexia relates to outcomes. In patients who had a post-arrest temperature ≥38°C, we sought to evaluate the association between timing of pyrexic temperatures post-arrest and after the initiation of TTM and neurologic outcomes at hospital discharge.   Hypothesis:  We hypothesized that later timing of pyrexia would be associated with worse outcomes.   Methods:  We identified cardiac arrest patients who returned to normothermia following TTM with serial temperatures recorded during 144 hours post-arrest from a US multicenter registry. Our dependent variable was neurologic outcome (Cerebral Performance Category (CPC) score dichotomized into “good” (1-2) and “poor” (3-5)); secondary outcome was survival to hospital discharge. Time to pyrexia onset was defined as the first time there was a recorded temperature ≥38°C after the patient had completed TTM maintenance and returned to a temperature ≥36.5°C.   Results:  Of 502 TTM-treated patients at 14 hospitals between 2005-2015 who had serial temperatures recorded, 466 patients had information on the time between collapse and post-normothermia temperatures; 195 (42%) had a pyrexic temperature. Of the initial 502 patients, 434 patients had data on the time between induction of TTM and post-normothermia temperatures; 201 (46%) had a pyrexic temperature. Mean age in the whole cohort was 59±16 years, 59% were male, and 39% had an initial shockable rhythm. 44% survived to hospital discharge; 34% had a CPC 1-2 at discharge. In adjusted analyses, delayed onset of fever was associated with improved neurologic (OR from induction: 1.1, 95% CI 1.0-1.2, p   Conclusions:  Later onset of pyrexia following TTM is associated with better survival and neurologic outcomes. Whether active maintenance of normothermia would prevent early pyrexia and improve outcomes requires further investigation.
Retrospective analysis of the role of CA 15-3 as a biomarker for breast cancer relapse.
Authors: Marwan Elahi Shaikh, Samantha Hall, Sijin Wen, Hui Liu, Abdul Miah, Mohamad Adham Salkeni
Journal: Journal of Clinical Oncology (2017)

e23051 Background: The latest ASCO guidelines regarding tumor markers in breast cancer do not recommend routine monitoring of serum CA 15-3 (CA) levels alone as a marker for relapse. They do, however, acknowledge their use in conjunction with a patient’s history, physical exam, and diagnostic imaging. The study objective is to evaluate CA as a marker for relapse and determine its continued use in our patient population. Methods: We performed a retrospective analysis on female stage I-III breast cancer patients with an elevated CA marker treated in our cancer center between 2009-2014. Patients with metachronous or synchronous malignancies were excluded. Patients were categorized into three groups: Group 1 (elevated CA at relapse), Group 2 (normal CA at relapse, with elevation post-relapse), Group 3 (elevated CA without relapse). Categorical variables were collected to fulfill our objectives and the Fisher’s exact test was used to assess the correlation between them. The incidence rate and its 95% confidence interval were estimated based on the binomial distribution. Results: Out of 340 initially screened patients, 92 met our inclusion criteria: Group 1 (n = 25), Group 2 (n = 23), Group 3 (n = 44). The PPV for an elevated CA as a marker for relapse was 36% (95% CI: 26-48%). On routine surveillance, patients with elevated CA levels were more likely to have relapse if they presented with nausea (p = 0.02), myalgia (p = 0.003), or axial bone pain (p = 0.04). At relapse, an elevated CA was associated with fatigue (p = 0.02), myalgia (p = 0.01), liver metastases (p = 0.01), axial bone metastases (p = 0.005), and peripheral bone metastases (p = 0.0002). In patients with an elevated CA, a BMI &lt; 25 had a higher incidence of relapse in comparison to those with a BMI ≥ 25 (p = 0.01). Conclusions: Our study suggests that a patient’s history, physical, and symptom-dictated imaging should be the main way to screen for relapse in stage I-III breast cancer. Based on the higher incidence of relapse in patients with both an elevated CA and symptoms of nausea, myalgia, or axial bone pain, we conclude that serum CA levels may be used as an adjunctive test in symptomatic patients. Our data also suggests that elevated CA levels may be less useful in detecting relapse in patients with BMI ≥ 25.
Abstract 4641: Wild type APC is an independent marker of poor prognosis in late stage colorectal cancer
Authors: Abdul K. Siraj, Rong Bu, Shaham Beg, Tariq Masoodi, Khawla S. Al-Kuraya
Journal: Cancer Research (2017)

Abstract Background: Colorectal cancer (CRC) is one of the commonest cancer worldwide and ranks as the most common cancer in males and the third most common among females in Saudi Arabia. Wnt pathway alteration is well known in colorectal cancer. In this study we aimed to comprehensively study Wnt pathway alterations in a large cohort of Middle Eastern colorectal patients and to know its role in this unique ethnic group. Methods: 426 CRC cases were analyzed for APC, AXIN2 and CTNNB1 somatic mutations by targeted capture sequencing and protein expression status by immunohistochemistry in tissue microarray format. Results were analyzed for association with any clinicopathological parameters and for prognostic significance. Results: The incidence of APC, AXIN2 and CTNNB1 mutations in our patient cohort were 58.2%, 4.2% and 3.8% respectively. APC mutation was associated with grade 2 tumors (p=0.0494) and male sex (p=0.0349). AXIN2 mutation were associated with grade 3 tumors (p=0.0231), MSI-high tumors (p&amp;lt;0.0001) and AXIN2 protein expression loss (p=0.0056). CTNNB1 mutations were associated with MSI-high tumors (p=0.0076). AXIN2 and CTNNB1 mutation were significantly associated with each other (p=0.0263). Wild type APC was associated with poor overall survival and was an independent marker of poor prognosis in late stage CRC (p=0.0200). Conclusion: We reported the incidence of Wnt pathway alterations in this unique ethnic group on which such data is lacking. APC mutation plays major and other genes minor role in Wnt pathway activation. Incidence of APC mutation in this group is comparatively high compared to reported incidence worldwide. Wild type APC independently predicts poor prognosis in Middle Eastern late stage colorectal patients. Citation Format: Abdul K. Siraj, Rong Bu, Shaham Beg, Tariq Masoodi, Khawla S. Al-Kuraya. Wild type APC is an independent marker of poor prognosis in late stage colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4641. doi:10.1158/1538-7445.AM2017-4641
Src Inhibits the Hippo Tumor Suppressor Pathway through Tyrosine Phosphorylation of Lats1
Authors: Yuan Si, Xinyan Ji, Xiaolei Cao, Xiaoming Dai, Lingyi Xu, Hongxia Zhao, Xiaocan Guo, Huan Yan, Haitao Zhang, Chu Zhu, Qi Zhou, Mei Tang, Zongping Xia, Li Li, Yu-Sheng Cong, Sheng Ye, Tingbo Liang, Xin-Hua Feng, Bin Zhao
Journal: Cancer Research (2017)

Abstract The Hippo pathway regulates cell proliferation, apoptosis, and stem cell self-renewal, and its inactivation in animal models causes organ enlargement followed by tumorigenesis. Hippo pathway deregulation occurs in many human cancers, but the underlying mechanisms are not fully understood. Here, we report tyrosine phosphorylation of the Hippo pathway tumor suppressor LATS1 as a mechanism underlying its regulation by cell adhesion. A tyrosine kinase library screen identified Src as the kinase to directly phosphorylate LATS1 on multiple residues, causing attenuated Mob kinase activator binding and structural alteration of the substrate-binding pocket in the kinase domain. Cell matrix adhesion activated the Hippo pathway effector transcription coactivator YAP partially through Src-mediated phosphorylation and inhibition of LATS1. Aberrant Src activation abolished the tumor suppressor activity of LATS1 and induced tumorigenesis in a YAP-dependent manner. Protein levels of Src in human breast cancer tissues correlated with accumulation of active YAP dephosphorylated on the LATS1 target site. These findings reveal tyrosine phosphorylation of LATS1 by Src as a novel mechanism of Hippo pathway regulation by cell adhesion and suggest Src activation as an underlying reason for YAP deregulation in tumorigenesis. Cancer Res; 77(18); 4868–80. ©2017 AACR.
Abstract 2579: Identifying pathways that regulate the turnover of gain-of-function p53 mutant proteins in ovarian cancer cells
Authors: Achuth Padmanabhan, Nicholes Candelaria, Kwong-Kwok Wong, Bryan C. Nikolai, David Lonard, Bert W. O'Malley, JoAnne S. Richards
Journal: Cancer Research (2017)

Abstract Ovarian cancer is the fifth leading cause for cancer-associated deaths among women in the US. High-grade serous ovarian carcinoma is the most common histological subtype and is characterized by frequent (&amp;gt;90%) mutations in the TP53 (p53) gene. Gain-of-function (GOF) p53 mutant proteins form highly stable aggregates that accumulate in ovarian cancer cells and have been shown to have oncogenic activity. Increasing evidence indicates the stabilization of GOF p53 mutants to be important for tumor progression and drug resistance. Therefore, selective degradation of the GOF p53 mutant proteins is a highly attractive therapeutic strategy to specifically target ovarian cancer cells. We identified that a small molecule named MCB-613, originally discovered as a stimulator of steroid receptor coactivator-3 (SRC-3), causes rapid degradation of the usually stable p53R175H conformational mutant aggregates leading to catastrophic cell death in human ovarian cancer cell lines. Our results indicate this effect is independent of SRC-3 mediated gene expression, but rather by post-translational modification of p53 mutant protein. Upon MCB-613 treatment, the p53R175H mutant is rapidly exported from the nucleus, ubiquitinated and degraded through a lysosomal pathway. Interestingly, in contrast to its effect on the p53R175H mutant, MCB-613 causes a slight stabilization of wild type (WT) p53 but had less of an effect on the turnover of other frequently observed p53 mutants (R248Q and R273H) in human ovarian cancer cell lines. MCB-613 also causes a rapid decrease in MDM2 protein but not mRNA. Further, the effect of MCB-613 on p53R175H is phenocopied by multiple deubiquitinase (DUB) inhibitors, confirming the role of ubiquitination in the selective turnover of p53R175H mutant aggregates. Taken together, these results show that different pathways regulate the turnover of WT p53 and the specific GOF p53 mutant proteins. We are currently investigating the precise mechanism by which MCB-613 and the different DUB inhibitors induce selective turnover of p53R175H mutant protein. We anticipate the proposed work to significantly advance our understanding of pathways important in ovarian cancer progression and pave way for the development of new targeted therapies for ovarian cancer patients with specific p53 mutations. This work is funded by NIH-CA-181808, NIH-HD-07857 and NIH-HD-076596. Citation Format: Achuth Padmanabhan, Nicholes Candelaria, Kwong-Kwok Wong, Bryan C. Nikolai, David Lonard, Bert W. O'Malley, JoAnne S. Richards. Identifying pathways that regulate the turnover of gain-of-function p53 mutant proteins in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2579. doi:10.1158/1538-7445.AM2017-2579