tbuckley/cabot-search huggingface dataset:
Discovery and characterization of INCB028060, a novel, potent and selective Met RTK inhibitor for cancer treatment
Authors: Xiangdong Liu, Holly Koblish, Qian Wang, Gengjie Yang, Leslie Hall, Xiaoming Wen, Cindy Marando, Elham Behshad, Richard Wynn, Mary Becker-Pasha, Philip Liu, Timothy Burn, Kamna Katiyar, Yanlong Li, Jason Boer, Yu Li, Sharon Diamond, Jincong Zhuo, Chunhong He, Meizhong Xu, Colin Zhang, Greg Hollis, Jordan Fridman, Kris Vaddi, Swamy Yeleswaram, Brian Metcalf, Steve Friedman, Robert Newton, Wenqing Yao, Peggy Scherle
Journal: Cancer Research (2008)

2577  The Met receptor tyrosine kinase (RTK) is the only high-affinity receptor for the hepatocyte growth factor (HGF). Met kinase activation can be achieved via HGF stimulation, Met overexpression, or a variety of activating mutations. Met activation subsequently results in pleiotropic responses that, in a cell-context dependent manner, may include cell proliferation, motility, migration, invasion, survival and angiogenesis. While these effects are important for developmental processes, when dysregulated, Met has been shown to promote tumor growth, survival and metastasis. We have identified a series of novel, potent and selective small molecule inhibitors of Met kinase activity exemplified by INCB028060. INCB028060 exhibits pM potency against Met kinase in vitro. The compound is highly specific for Met kinase with > 10,000-fold selectivity over a panel of > 50 human kinases. Using human cancer cell lines derived from tumor types where Met is frequently overexpressed, we find that INCB028060 possesses nM or sub-nM potency in blocking Met phosphorylation as well as phosphorylation of downstream effectors such as ERK, AKT, STAT3, GAB-1 and FAK. As a result, INCB028060 has demonstrated potent inhibition of Met-dependent cell migration, proliferation, and effective induction of apoptosis in tumor cells, while the compound does not inhibit the growth of tumor cells (e.g. SNU-1 gastric cancer) that do not overexpress Met. While INCB028060 does not inhibit EGFR1, EGFR3 and IGF1R directly, treatment with INCB028060 causes a dramatic reduction in phosphorylated EGFR1, EGFR3 and IGF1R in the human Met-dependent SNU5 gastric cancer and H1993 lung cancer cell lines. The data indicate that in cancer cells where the met gene is amplified, the activated Met kinase may have pleiotropic effects on multiple RTK signaling pathways and therefore could play an important role in driving tumor cell growth and survival. INCB028060 has favorable in vitro ADME characteristics and excellent in vivo PK properties. Using Met/HGF-driven xenograft mouse tumor models, we find that oral dosing of INCB028060 results in dose-dependent inhibition of tumor growth and the compound is well tolerated in mice at doses that achieve complete inhibition of tumor growth. Together, the data suggest that INCB028060 is a potent, selective and orally available Met kinase inhibitor that may have therapeutic potential.
Axillary management in early breast cancer: Surgeon attitudes in a population-based study.
Authors: Monica Morrow, Steven J. Katz, Reshma Jagsi
Journal: Journal of Clinical Oncology (2017)

561 Background: The ACOSOG Z0011 trial established the safety of omitting axillary dissection (ALND) for patients with 1‒2 sentinel node (SN) metastases having breast-conserving therapy (BCT) to reduce treatment-related morbidity. Little is known about surgeon uptake of this practice. Methods: Women with stage I and II breast cancer diagnosed between 7/13‒8/15 (n=3729) reported to the Los Angeles and Georgia SEER registries were surveyed about 2 months after diagnosis. All attending surgeons identified by the patients (n=489) were sent a questionnaire and 77% (n=377) responded. Pathology reports for SN positive patients are under review. Results: Mean surgeon age was 54 years, 25% were female, and median years in practice was 21. 49% and 63% endorsed ALND for Z0011 eligible patients with 1 or 2 SN macrometastases, respectively. Surgeons were classified as low (n=92), selective (n=178), or high (n=91) users of ALND based on responses to case scenarios with SN involvement ranging from isolated tumor cells in 1 SN (12% would do ALND) to macrometastasis in 3 SNs (92% would do ALND). 93% of high-use surgeons would perform ALND for any SN macrometastasis vs 40% of selective surgeons and 1% of low-use surgeons (p&lt;.001). High-use surgeons were older, male, saw fewer breast cancer patients, and were less likely to discuss cases in tumor board (Table). High-ALND users were substantially less likely to endorse BCT margins of no ink on tumor (40%) than selective (63%) or low users (83%; p&lt;.001). Conclusions: Wide variation exists in acceptance of Z011 results with one-quarter of surgeons endorsing routine ALND. Surgeons favoring ALND also endorse wider margins for BCT, suggesting an overall more aggressive surgical approach. Lower breast volume and lack of tumor board participation identify surgeons who should be targeted for educational interventions. [Table: see text]
Peripherally inserted central catheters are associated with lower risk of bloodstream infection compared with central venous catheters in paediatric intensive care patients: a propensity-adjusted analysis
Authors: Ricardo Silveira Yamaguchi, Danilo Teixeira Noritomi, Natalia Viu Degaspare, Gabriela Ortega Cisternas Muñoz, Ana Paula Matos Porto, Silvia Figueiredo Costa, Otavio T. Ranzani
Journal: Intensive Care Medicine (2017)
Ki 67 analysis and prognostic factors in women with luminal breast cancer.
Authors: Eduardo De Figueiredo Vissotto, Alexandre Andre Balieiro Anastácio da Costa, Leonardo de Azevedo Boente, Eliza Dalsasso Ricardo, Felipe D'Almeida Costa
Journal: Journal of Clinical Oncology (2017)

e12024 Background: After screening became available for most women, breast cancer is diagnosed mainly in early stage. The decision to offer adjuvant chemotherapy to patients with luminal breast cancer is not easy and the knowledge of prognostic factors is mandatory. Ki 67 plays an important role in this context, especially in patients who do not have access to genetic signatures. Nevertheless, data available about the optimal cutoff of Ki 67 to predict luminal B subtype is still controversial. Methods: We evaluated Ki 67 and other clinical-pathological factors of women with non-metastatic hormone-positive breast cancer in a major oncologic hospital. The objective was to determine the impact of Ki 67 on the disease free survival (DFS) and the optimal cutoff. This is a retrospective cohort of patients of the AC Camargo Cancer Center between January 2007 and January 2009 selected by a random sample of convenience. Ki 67 analysis was performed through tissue-microarray (TMA). Log rank test and Cox regression were used to test the prognostic value of each variable for DFS. The optimal Ki 67 cutoff was defined plotting a curve for the hazard ratios for each Ki67 cutoff point tested and their 95% confidence intervals. Results: We evaluated 195 patients with a median follow up of 58 months. The optimal cutoff of Ki 67 was 23% for DFS (HR 3,78; CI 95% 1,3 – 10,76; p 0,012). The cutoffs of 20%, 30%, 40% and 50% were also statistically significant. The kappa concordance index between TMA and whole tissue sections was 0,567 (CI 95% 0,268-0,866; p = 0,003). Other poor prognosis factors on the surgical samples were higher histologic grade, presence of vascular-lymphatic invasion and mythotic index superior to 10 mytoses per high powerfield. On the biopsy samples, inflammatory infiltrate absent or low was found to be a poor prognostic factor Conclusions: Analysis of Ki 67 in women with non-metastatic hormone-positive breast cancer is a prognostic factor for DFS, with different cutoffs. This may suggest that Ki 67 should be considered as a continuous variable rather than a dichotomized value. Analysis of others clinical-pathological factors are still important for therapeutical decision.
Post translational changes to α-synuclein control iron and dopamine trafficking; a concept for neuron vulnerability in Parkinson’s disease
Authors: James A. Duce, Bruce X. Wong, Hannah Durham, Jean-Christophe Devedjian, David P. Smith, David Devos
Journal: Molecular Neurodegeneration (2017)

Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease.
Abstract MIP-059: MITOCHONDRIAL DYNAMICS AND DYSFUNCTION IN OVARIAN CANCER
Authors: Dong-Hui Shin, Usawadee Dier, Patrick F. Timmins, Joshua Kesterson, Rebecca Phaeton, Nadine Hempel
Journal: Clinical Cancer Research (2017)

Abstract Altered mitochondrial function remains a key feature of many tumor cells and drives pathways such gene expression, metabolic and stress responses, cell cycle progression and resistance to apoptosis. Many chemotherapeutics activate programmed cell death and it is thought that mitochondrial dysfunction may be one mechanism by which cancer cells evade killing by these compounds. Screening the metabolic profiles of ovarian cancer cell lines and patient ascites-derived tumor cells reveals that ovarian cancers fall into unique bioenergetic subgroups. For example, Ovarian Clear Cell Carcinomas (OCCC) display high oxygen consumption rate and glycolytic flux compared to the more common high grade serous adenocarcinoma (HGSA) subtype. In addition, we show that a portion of HGSAs have severe mitochondrial dysfunction, that is marked by a decrease in mitochondrial respiration, a lack of response to the uncoupler FCCP and a concomitant reliance on alternate metabolic pathways. Moreover, this is accompanied by enhanced chemoresistance to Cisplatin and Taxol. The cause of mitochondrial dysfunction has been attributed to a number of factors, including deregulation in mitochondrial fission/fusion dynamics. Moreover, fission is an integral component of apoptotic and authophagy pathways. Interestingly, the observed HGSA mitochondrial dysfunction correlates with aberrant fusion/fission dynamics and expression of a low molecular weight variant of the mitochondrial fission protein Drp1. The potential significance of Drp1 in ovarian cancer etiology is highlighted by TCGA data, where more than 15% of HGSA samples display significant increases in Drp1 mRNA levels, and associated amplification of the Drp1 gene DNM1L. Whether this represents the shorter, potentially dominant-negative Drp1 variant identified in our work is currently under active investigation. Our data suggest that compromised mitochondrial function and fission/fusion dynamics may be a hallmark of a previously unidentified subgroup of highly chemoresistant EOCs and that this is associated with aberrant expression of the fission protein Drp1. Studies are underway to identify the molecular identity and regulation of short Drp1, and the mechanistic links to alterations in fission, metabolic switching and chemoresistance. Citation Format: Dong-Hui Shin, Usawadee Dier, Patrick F. Timmins, Joshua Kesterson, Rebecca Phaeton and Nadine Hempel. MITOCHONDRIAL DYNAMICS AND DYSFUNCTION IN OVARIAN CANCER [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 MIP-059.
Early-onset autoimmune disease due to a heterozygous loss-of-function mutation in <i>TNFAIP3</i> (A20)
Authors: Christopher J A Duncan, Emma Dinnigan, Rachel Theobald, Angela Grainger, Andrew J Skelton, Rafiqul Hussain, Joseph D P Willet, David J Swan, Jonathan Coxhead, Matthew F Thomas, Julian Thomas, Veena Zamvar, Mary A Slatter, Andrew J Cant, Karin R Engelhardt, Sophie Hambleton
Journal: Annals of the Rheumatic Diseases (2017)

Rare Mendelian disorders increasingly contribute to our understanding of the genetic architecture of autoimmune disease and the key molecular pathways governing its pathogenesis. Early-onset autoimmune disease can arise through activating mutations in inflammatory signalling pathways or loss-of-function mutations in immunoregulatory proteins.

We investigated the molecular basis of complex autoimmunity—characterised by the onset of insulin-dependent diabetes, cytopaenias, hepatitis, enteropathy and interstitial lung disease at age 10—in a 14-year-old boy of healthy non-consanguineous British parents. Immunological analysis revealed lymphopaenia with no naive T cells and a high proportion of activated T cells (table 1). Pathogenic variants in STAT3 and FOXP3 were excluded. The clinical course was refractory to intensive immunosuppression with prednisolone, sirolimus, tacrolimus, infliximab or rituximab, necessitating haematopoietic stem cell transplantation. Twenty-one months post-transplant, he is thriving off all immunosuppressive medication with complete remission of autoimmune disease (except diabetes).

View this table:

Table 1 
Immunological and clinical parameters



Ethical approval was granted (ref: 10/H0906/22) and written informed consent provided prior to study commencement. By whole exome sequencing of peripheral blood genomic DNA (Illumina MiSeq) and downstream bioinformatic filtering (Ingenuity Variant Analysis), we identified a single biologically plausible variant—a novel de novo heterozygous 2 bp deletion in tumour necrosis factor-alpha-induced protein 3 ( TNFAIP3 , figure 1A). TNFAIP3 encodes the ubiquitin-editing enzyme A20, a negative regulator of the nuclear factor-κB (NF-κB) pathway.1 A20 removes K63-linked ubiquitin chains from key adaptor proteins, replacing them with K48-linked polyubiquitin chains, to trigger proteasomal degradation and termination of the NF-κB activation cascade.2 Polymorphisms in …
Current research priorities in perioperative intensive care medicine
Authors: Michael A. Gillies, Michael Sander, Andrew Shaw, Duminda N. Wijeysundera, John Myburgh, Cesar Aldecoa, Ib Jammer, Suzana M. Lobo, Naomi Pritchard, Michael P. W. Grocott, Marcus J. Schultz, Rupert M. Pearse
Journal: Intensive Care Medicine (2017)
Inhibition of angiogenesis by a common herb: Ocimum sactum
Authors: Pratima Nangia-Makker, Larry Tait, Victor Hogan, Avraham Raz
Journal: Cancer Research (2004)

4109  Ocimum sanctum (OS), also known as holy basil, or tulsi, has been used in European and Asian countries, mainly India, as a medicinal herb since ancient times. Experimental evidence has shown it to possess chemopreventive, radiation protecting, and free radical scavenging properties. We prepared crude aqueous extract from the leaves of OS and performed in vitro and in vivo studies. Our results show that OS extracts inhibited breast cancer cell (MDA-MB-435) migration towards Matrigel significantly at 0.1 and 0.2% concentrations (w/v). Similarly, it inhibited the migration of human umbilical vein endothelial cells (HUVEC) towards galectin-3 at a concentration of 0.2% (w/v). However, no significant inhibition in migration was observed at the same concentration towards Matrigel and fibronectin indicating the specificity of inhibition. OS extract also inhibited the induction of cycloxygenase COX-2 in MDA-MB-231 breast cancer cells treated with tetradecanoyl phorbol acetate (TPA). In vitro capillary tube formation in the 3 dimensional cultures of HUVEC on Matrigel was inhibited by the leaf extracts at 0.02, 0.05 and 0.1% concentrations (w/v). Matrigel plug assay using MDA-MB-231 cells in the presence or absence of 0.01 and 0.1% OS leaf extracts showed a significant reduction in the number of blood vessels and COX-2 expression. Our results suggest that OS leaf extract can be used as an anti-tumorigenic and anti-angiogenic agent in breast cancer models.
Tissue Engineering: Engineered 3D Cardiac Fibrotic Tissue to Study Fibrotic Remodeling (Adv. Healthcare Mater. 11/2017)
Authors: Amir Hossein Sadeghi, Su Ryon Shin, Janine C. Deddens, Giuseppe Fratta, Serena Mandla, Iman K. Yazdi, Gyan Prakash, Silvia Antona, Danilo Demarchi, Marc P. Buijsrogge, Joost P. G. Sluijter, Jesper Hjortnaes, Ali Khademhosseini
Journal: Advanced Healthcare Materials (2017)

Ali Khademhosseini and co-workers describe an engineered 3D fibrotic heart tissue, which is created by fabricating physiologically relevant cardiac tissues with native-like mechanical properties in article number 1601434. Upon exogenous stimulation with profibrotic transforming growth factor beta-1, these tissues reveal fibrogenic changes, such as collagen production, myofibroblast activation, and electrophysiological disturbances.
Upsurge of infections caused by Salmonella Concord among Ethiopian adoptees in Denmark, 2009
Authors: R Sjøgren Hendriksen, C Kjelsø, M Torpdahl, S Ethelberg, K Mølbak, F  M Aarestrup
Journal: Eurosurveillance (2010)

Multidrug-resistant (MDR) Salmonella Concord has been associated with adoptees from Ethiopia. In 2009, Denmark saw an increase in MDR S. Concord infections among Ethiopian adoptees.
Mitochondrial Dynamics Mediated by Mitofusin 1 Is Required for POMC Neuron Glucose-Sensing and Insulin Release Control
Authors: Sara Ramírez, Alicia G. Gómez-Valadés, Marc Schneeberger, Luis Varela, Roberta Haddad-Tóvolli, Jordi Altirriba, Eduard Noguera, Anne Drougard, Álvaro Flores-Martínez, Mónica Imbernón, Iñigo Chivite, Macarena Pozo, Andrés Vidal-Itriago, Ainhoa Garcia, Sara Cervantes, Rosa Gasa, Ruben Nogueiras, Pau Gama-Pérez, Pablo M. Garcia-Roves, David A. Cano, Claude Knauf, Joan-Marc Servitja, Tamas L. Horvath, Ramon Gomis, Antonio Zorzano, Marc Claret
Journal: Cell Metabolism (2017)
Abstract NTOC-109: MULTI–FUNCTIONAL RNA NANOPARTICLES FOR TARGETED DELIVERY OF THERAPEUTIC DRUGS FOR OVARIAN CANCER
Authors: Varatharasa Thiviyanathan, Xin Li, Fengmei Pi, Hui Zhang, Hongyu Wang, Farzin Haque, David Gorenstein, Peixuan Guo
Journal: Clinical Cancer Research (2017)

Abstract Targeted delivery of therapeutic drugs and imaging agents remains a promising option in the treatment and diagnosis of ovarian cancer. We have developed a new class of affinity ligands that specifically recognize the ovarian cancer cells. We are using these ligands as homing devices to deliver the therapeutic drugs to ovarian cancer cells using multifunctional nanoparticles made up of RNA molecules. The affinity ligands, called Aptamers, are short, chemically modified DNA oligonucleotides and are emerging as attractive alternatives for monoclonal antibodies. Using cell-SELEX methods, we screened a large combinatorial library and have isolated two DNA thioaptamers that specifically bind human ovarian cancer cells. These thioaptamers, named ENDO 28 and ENDO 31, showed specific binding and tissue penetration towards human ovarian cancer vasculature tissue. Using mass-spectroscopy based proteomics, we have identified Annexin A2, a membrane protein upregulated in various tumor types, as the protein target for ENDO28 and ENDO31. We have assembled RNA nanoparticles using the pRNA-three way junction (3WJ) platform and conjugated the ENDO28 thioaptamer as the targeting ligand. This multifunctional RNA nanoparticle (ENDO28-RNA NP) is used to carry Doxorubicin to specifically to ovarian cancer cells. Our results showed the ENDO28 containing RNA nanoparticles delivered the Doxorubicin to the Annexin A2(+)ve ovarian cancer cells, while the control nanoparticles failed to deliver. We further tested the specificity of ENDO28-RNA NP, by using Annexin A2 (-ve) cell lines (HEK293T). Our results showed that the ENDO28 containing RNA NPs do not deliver Doxorubicin to HEK293T cells, further supporting that ENDO28 can be used for targeted delivery therapeutic drugs to ovarian cancer cells, while sparing the normal cells. Our ultimate goal is the development of patient-optimized aptamer-nanoparticle delivery systems for chemotherapy and molecular diagnostics imaging. Citation Format: Varatharasa Thiviyanathan,, Xin Li, Fengmei Pi, Hui Zhang, Hongyu Wang, Farzin Haque, David Gorenstein and Peixuan Guo. MULTI–FUNCTIONAL RNA NANOPARTICLES FOR TARGETED DELIVERY OF THERAPEUTIC DRUGS FOR OVARIAN CANCER [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 NTOC-109.
Negative predictive value of ipsilateral axillary ultrasound in the pre-operative assessment of invasive breast cancer.
Authors: Bita Ameri, Riti Kanesa-Thasan, Maysa M. Abu-Khalaf, Adam C. Berger, Tara Eisenberg, Melissa A. Lazar, Alexander Sevrukov, Theodore N. Tsangaris, Nylah Wasti, Annina Wilkes, Alliric Isaac Willis, Lisa Zorn, Elizabeth Hsu
Journal: Journal of Clinical Oncology (2017)

e12080 Objective: To determine if a negative preoperative axillary ultrasound predicts a negative sentinel lymph node biopsy at surgery. Background: Axillary lymph node involvement is an important prognostic indicator in patients with breast cancer. Sentinel lymph node biopsy (SLNB) is currently the gold standard for determining the presence or absence of axillary metastases. Pre-operative axillary ultrasound is often used to evaluate axillary lymph node status prior to surgery and SLNB. Although there are no established guidelines on when preoperative axillary ultrasound is performed, at our institution we evaluate the axilla when invasive breast cancer is suspected. This study evaluated the negative predictive value (NPV) of axillary ultrasound compared to the pathology results of SLNB. Methods: In this single-center IRB-approved retrospective study, 3 years of breast imaging data (2014-2016) were reviewed. 137 patients had pathology verified invasive breast cancer with negative preoperative axillary ultrasound and subsequent SLNB. All patients had clinically negative axillae. Based upon the pathology results of SLNB, the negative predictive value of preoperative axillary ultrasound was calculated. Negative axillary ultrasound is defined as the absence of morphologically abnormal lymph nodes on imaging. A lymph node is considered morphologically normal when there is preserved fatty hilum and a uniform cortex measuring 3 mm or less. Results: Out of 137 patients with invasive breast cancer who had negative preoperative axillary ultrasound, 122 had negative SLNB results and 15 had positive SLNB results. Preoperative axillary ultrasound demonstrated a NPV of 89.1% for the detection of axillary metastatic disease at the time of SLNB. Conclusions: Negative axillary ultrasound excluded axillary metastatic disease in 89.1% of patients. This data suggests that negative axillary ultrasound may have a role in the setting of failed SLNB (no lymph nodes found at the time of surgery) in deciding whether to pursue axillary dissection.