tbuckley/cabot-search huggingface dataset:
Abstract 4542: Ube2d family members, Ube2e family members and Ube2w modulate the ubiquitination and degradation of EGFR by Cbl
Authors: Ke Ma, Philip Ryan, Rachel Klevit, Stanley Lipkowitz
Journal: Cancer Research (2016)

Abstract Ubiquitin ligases (E3s) are critical component of ubiquitination. In collaboration with ubiquitin-conjugating enzymes (E2s), E3s confer specificity to the ubiquitination process and direct the conjugation of ubiquitin to one or more lysines on the target proteins. Cbl proteins are RING finger E3s that play a significant role in regulating activity of many tyrosine kinases (e.g., EGFR, MET) by ubiquitination. In our study, we used enzymatic and yeast two-hybrid assays to characterize the E2s that can interact with Cbl proteins. Using an in vitro E3 assay, we found that only the Ube2d family of E2s mediates autoubiquitination of the Cbl proteins. Subsequently, using the yeast two-hybrid system, we found that the three Ube2e family members and Ube2w interact with the RF domain of Cbl. This suggests that Ube2e and Ube2w are relevant to the ubiquitination and degradation of substrates by Cbl. Knockdown of Ube2w decreases ubiquitination of EGFR in Hela cells. In the in vitro E3 assay we found that Ube2w can monoubiquitinate Cbl and increase autoubiquitination of Cbl mediated by ube2d2. Surprisingly, we found that knockdown of Ube2e increases downregulation and ubiquitination of EGFR in HeLa cells. Mechanistically we found that three Ube2e members inhibit autoubiquitination of Cbl mediated by Ube2d2 in vitro. Further, we showed that Ube2e does not affect ubiquitin charging of Ube2d2 by the ubiquitin-activating enzyme (E1) in vitro. This suggests that Ube2e does not compete with Ube2d2 for the E1 under these conditions. Thus, our data suggest that Ube2e acts as a positive modulator of EGFR signaling by competing for Cbl with Ube2d2 and thus prevents ubiquitination and downregulation of the EGFR by Cbl in combination with Ube2d2. Together these data demonstrate that there is an E2 network which modulates the ubiquitination and downregulation of the EGFR by Cbl. Citation Format: Ke Ma, Philip Ryan, Rachel Klevit, Stanley Lipkowitz. Ube2d family members, Ube2e family members and Ube2w modulate the ubiquitination and degradation of EGFR by Cbl. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4542.
JNK Pathway Activation Modulates Acquired Resistance to EGFR/HER2–Targeted Therapies
Authors: Simin Manole, Edward J. Richards, Aaron S. Meyer
Journal: Cancer Research (2016)

Resistance limits the effectiveness of receptor tyrosine kinase (RTK)-targeted therapies. Combination therapies targeting resistance mechanisms can considerably improve response, but will require an improved understanding of when particular combinations will be effective. One common form of resistance is bypass signaling, wherein RTKs not targeted by an inhibitor can direct reactivation of pathways essential for survival. Although this mechanism of resistance is well appreciated, it is unclear which downstream signaling events are responsible. Here, we apply a combined experimental- and statistical modeling-based approach to identify a set of pathway reactivation essential for RTK-mediated bypass resistance. Differences in the downstream pathway activation provided by particular RTKs lead to qualitative differences in the capacity of each receptor to drive therapeutic resistance. We identify and validate that the JNK pathway is activated during and strongly modulates bypass resistance. These results identify effective therapeutic combinations that block bypass-mediated resistance and provide a basic understanding of this network-level change in kinase dependence that will inform the design of prognostic assays for identifying effective therapeutic combinations in individual patients. Cancer Res; 76(18); 5219-28. ©2016 AACR.
Abstract 4352: Discovery of the first cell-active inhibitors of poly(ADP Ribose) glycohydrolase through high-throughput screening and computational approaches
Authors: Bohdan Waszkowycz, Dominic James, Steven Durant, Nicola Hamilton, Cliff Jones, Stuart Jones, Allan Jordan, Alan Lau, Alison MGonagle, Mark O’Connor, Kate Smith, Alex Stowell, Julie Tucker, Ian Waddell, Donald Ogilvie
Journal: Cancer Research (2016)

Abstract DNA repair is a critical process for the survival and normal proliferation of healthy cells. However, given the enhanced levels of cellular stress and genomic instability, these repair processes are even more critical to the survival of malignant cells, where rates of DNA damage are considerably increased. Given this, inhibitors of DNA damage repair have seen a resurgence of interest in recent years in an effort to exploit tumour cell vulnerabilities. One such example of this approach has resulted in the recent approval of the PARP inhibitor olaparib (Lynparza™) for women with advanced ovarian cancer associated with defective BRCA genes. Olaparib acts against the poly(ADP-ribose)polymerase (PARP) enzymes, more recently re-defined as the ARTD (Diphtheria toxin-like human ADP-ribosyltransferase) enzyme class. Whilst PARP is widely known to play critical and well-understood roles in DNA repair, poly(ADP ribose) glycohydrolase (PARG) is less well known but equally essential for effective DNA repair, degrading PAR chains and facilitating effective DNA repair. However, its inhibition may offer several key advantages over PARP inhibition. Most critically, whilst there are 18 isoforms, there exists only a single PARG protein, offering a specific point of therapeutic intervention. However, due to the open nature of the PARG binding cleft and the nature of the binding site, this protein has been considered to be difficult to inhibit with small, drug-like small molecules, particularly in the cellular context. This poster will describe our efforts to overcome these challenges against this challenging target and report our early successes achieved through innovative computational chemistry strategies. These efforts have delivered several credible, drug-like startpoints for further medicinal chemistry optimisation. Citation Format: Bohdan Waszkowycz, Dominic James, Steven Durant, Nicola Hamilton, Cliff Jones, Stuart Jones, Allan Jordan, Alan Lau, Alison MGonagle, Mark O’Connor, Kate Smith, Alex Stowell, Julie Tucker, Ian Waddell, Donald Ogilvie. Discovery of the first cell-active inhibitors of poly(ADP Ribose) glycohydrolase through high-throughput screening and computational approaches. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4352.
PTH-046 Enteric nervous system stem cell-containing neurospheres: all that glitters is not gold?
Authors: E Binder, M Cananzi, A J Burns, N Thapar
Journal: Gut (2010)

<h3>Introduction</h3> Enteric nervous system (ENS) stem cells provide potential therapeutic tools for hitherto incurable gut neuropathies. Recent progress confirms they can be generated from human gut in cell aggregates or neurospheres (NS), but numerous challenges remain. Although previous studies have suggested that NS are a source of putative stem cells, can be successfully propagated and expanded in culture, and transplanted, few have assessed their purity and implications for clinical use. The aim of this study was to characterise the cellular content of NS generated and propagated in culture and identify putative cellular markers for better selective isolation or enrichment of ENS stem cells for therapy. <h3>Methods</h3> Transgenic Wnt1-Cre/Floxed-YFP mice (express yellow fluorescent protein (YFP) in all Neural Crest (NC)-derived and ENS cells) were used. FACS-selection of YFP-positive cells from dissociated gut was used to isolate NC-derived cells to generate NS, which were then compared to those from YFP-negative (non-NC) or unsorted (mixed – akin to current protocols for human ENS stem cells) gut cells. Using immunostaining and clonogenic studies putative markers were then quantitatively assessed across all cultures for their ability to enrich for ENS stem cells, and studies applied to human tissue. <h3>Result</h3> All cell fractions (unsorted (US), sorted YFP-positive (SoP) and sorted YFP-negative (SoN)) contained cells capable of generating NS. US NS showed partial YFP fluorescence unlike those from SoP (pure YFP) and SoN (no YFP). SoP NS appeared perfectly spherical unlike the others which were irregular and formed faster. NS characterisation showed that US NS contained both NC cells (YFP positive+any of-Tuj1, GFAP, p75, Sox10) and significant numbers of non-NC cells (positive for any of SMA, c-kit, cytokeratin). SoP NS contained NC cells only and SoN NS non-NC cells only. Both the precursor marker Nestin and proliferation marker PH3 were positive in both NC and non-NC cells although PH3 showed higher expression in non-NC cells. NS from all sources could be propagated and expanded in culture over multiple passages, but this did not alter the mixed (NC/non-NC) cellular content of US NS. The low affinity neurotrophin receptor p75 could be used to FACS-sort YFP-positive cells from dissociated gut (mixed NC/non-NC), and was also expressed in NS generated from human gut. <h3>Conclusion</h3> Current protocols to generate ENS stem cell-containing NS for transplantation need refinement to reduce contamination with proliferating non-NC cells, which may carry safety implications if inadvertently transplanted in conditions of specific neuronal loss (eg, Hirschsprung9s disease). Putative markers (eg, p75) may enable selective isolation or enrichment of ENS stem cells for clinical use.
A case report of cardiac intimal sarcoma treated with pazopanib and dexamethasone (DEX)
Authors: Takanori Yamaguchi, Mikiya Ishihara, Satoshi Tamaru, Komei Nishimura, Hiroyasu Oda, Yumiko Sugawara, Yoshiki Yamashita, Toshiro Mizuno, Naoyuki Katayama
Journal: Annals of Oncology (2015)
Severe glucose-6-phosphate dehydrogenase deficiency leads to susceptibility to infection and absent NETosis
Authors: Ulrich Siler, Susana Romao, Emilio Tejera, Oleksandr Pastukhov, Elena Kuzmenko, Rocio G. Valencia, Virginia Meda Spaccamela, Bernd H. Belohradsky, Oliver Speer, Markus Schmugge, Elisabeth Kohne, Manfred Hoenig, Joachim Freihorst, Ansgar S. Schulz, Janine Reichenbach
Journal: Journal of Allergy and Clinical Immunology (2016)
“Prediabetes”: Are There Problems With This Label? No, We Need Heightened Awareness of This Condition!
Authors: William T. Cefalu
Journal: Diabetes Care (2016)

The category of "prediabetes" defined by the American Diabetes Association comprises a range of intermediate hyperglycemia based on fasting or 2-h postload glucose or on HbA1c Over the recent past, the "cut points" identifying this stage have changed, i.e., a lower fasting glucose level is used. On one hand, it can be argued that the change to a lower cut point identifies a group of individuals still at higher risk and provides heightened awareness for a condition associated with higher risk for cardiovascular disease. In addition, identification of individuals at this stage may represent a chance of earlier intervention in the disease. However, the argument against this definition of prediabetes is that it disguises the differences in the three subcategories and creates problems in interpreting observations on interventions and outcomes. In addition, it can be argued that the enormous numbers of people identified with the criteria far exceeds the capacity of health care systems to respond through individual care, particularly without evidence that interventions benefit any category other than impaired glucose tolerance. Thus, there does not appear to be consensus on the definition using the cut points identified. Controversy also remains as to whether there are glycemic metrics beyond HbA1c that can be used in addition to HbA1c to help assess risk of an individual developing diabetes complications. Given the current controversy, a Point-Counterpoint debate on this issue is provided herein. In the preceding point narrative, Dr. Yudkin provides his argument that there are significant problems with this label. In the counterpoint narrative below, Dr. Cefalu argues that the cut points are appropriate and do provide useful and important information in trying to reduce the future burden of diabetes.-William T. CefaluEditor in Chief, Diabetes Care.
Reply
Authors: Wonhyo Seo, Eunjung Jo, Won‐Il Jeong
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. Author names in bold designate shared co‐first authorship. We appreciate Dr. Lu and colleagues for the great interest in our article.1 They raise important points regarding the source of interleukin (IL)‐17A in liver fibrosis as well as the expression of Toll‐like receptor 3 (TLR3) and its role in hepatic stellate cells (HSCs) that deserve further investigation. Although Lu et al. quoted that "several immune cells produce IL‐17A in response to diverse liver injuries," our study focused to identify the initial source and producing mechanism of IL‐17A at the early stage of liver injury, rather than at the chronic stage. Therefore, we have validated that the major source of IL‐17A is γδ T cells in acute liver injury, in which HSCs stimulate robust IL‐17A production in γδ T cells by exosome‐mediated the TLR3 signaling pathway. In terms of IL‐17A expression, studies from Kisseleva's and our group reported that both quiescent and activated HSCs express IL‐17A, but its expression is not up‐regulated in vitro with or without stimulation of IL‐17A.1 Interestingly, our study showed that exosome‐ or poly I:C‐mediated TLR3 activation in quiescent HSCs produces a small amount of IL‐17A and increases chemokine (C‐C motif) ligand 20 expression. Subsequently, it recruits and amplifies IL‐17A production of γδ T cells by up‐regulating expression of retinoic acid receptor‐related orphan receptor gamma t (RORγt). However, quiescent HSCs without TLR3 and conditioned media of IL‐17A‐depleted quiescent HSCs do not enhance IL‐17A production of γδ T cells. In contrast, activated HSCs cannot produce IL‐17A, even though more expression of TLR3 is detected than quiescent HSCs. Quiescent HSCs can express TLR3, and its activation may contribute to protection against infection and alcoholic liver injury by producing several cytokines.3 In natural killer (NK) cells, poly I:C‐mediated TLR3 activation attenuates liver fibrosis by killing HSCs.5 In our study, there are no evidences of exosome‐mediated NK cell activation and protective roles of TLR3 in HSCs.1 Based on these findings, TLR3 may play diverse roles in different liver disease or depending on specific cell types. However, unanswered questions should be addressed in the future investigation.
Peptides from NM23B - A Transcription Factor with NDP Kinase Activity - Are Expressed on the Surface of Leukemic Cells and Are Recognized by T-Lymphocytes.
Authors: Sabine Tschiedel, Annette Reinhardt, Peter Ruschpler, T. Woelfel, C. Woelfel, Niederwieser Dietger, Gentilini Chiara
Journal: Blood (2005)
The feasibility and safety of extracorporeal carbon dioxide removal to avoid intubation in patients with COPD unresponsive to noninvasive ventilation for acute hypercapnic respiratory failure (ECLAIR study): multicentre case–control study
Authors: Stephan Braune, Annekatrin Sieweke, Franz Brettner, Thomas Staudinger, Michael Joannidis, Serge Verbrugge, Daniel Frings, Axel Nierhaus, Karl Wegscheider, Stefan Kluge
Journal: Intensive Care Medicine (2016)
Endoscopic ultrasound-guided gastrojejunostomy with a Nagi stent for relief of jejunal loop obstruction following hepaticojejunostomy
Authors: Sudipta Chowdhury, Reuben Kurien, A. Bharath, Amit Dutta, Deepu David, C. Bharath, Anjilivelil Joseph
Journal: Endoscopy (2016)

A 27-year-old man with unresectable periampullary neoplasm underwent a Roux-en-Y hepaticojejunostomy with gastrojejunostomy 1 year previously. He presented with a 1-month history of progressive yellowish discoloration of his eyes, abdominal pain and distension, and intermittent high fever with chills and rigors. On admission his results showed a bilirubin of 9 mg/dL, alkaline phosphatase of 1467 IU/mL, and total white blood cell (WBC) count of 28 700/mm3. A blood culture grew Escherichia coli. A contrast-enhanced computed tomography (CT) scan of the abdomen showed a grossly dilated loop of jejunum with distal obstruction, in communication with a patent hepaticojejunostomy anastomosis ([Fig. 1]).
The Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Nephrotic Syndrome-Associated Hypercholesterolemia
Authors: Mary E. Haas, Amy E. Levenson, Xiaowei Sun, Wan-Hui Liao, Joseph M. Rutkowski, Sarah D. de Ferranti, Valerie A. Schumacher, Philipp E. Scherer, David J. Salant, Sudha B. Biddinger
Journal: Circulation (2016)

Background: In nephrotic syndrome, damage to the podocytes of the kidney produces severe hypercholesterolemia for which novel treatments are urgently needed. PCSK9 (proprotein convertase subtilisin/kexin type 9) has emerged as an important regulator of plasma cholesterol levels and therapeutic target. Here, we tested the role of PCSK9 in mediating the hypercholesterolemia of nephrotic syndrome. Methods: PCSK9 and plasma lipids were studied in nephrotic syndrome patients before and after remission of disease, mice with genetic ablation of the podocyte (Podocyte Apoptosis Through Targeted Activation of Caspase-8, Pod-ATTAC mice) and mice treated with nephrotoxic serum (NTS), which triggers immune-mediated podocyte damage. In addition, mice with hepatic deletion of Pcsk9 were treated with NTS to determine the contribution of PCSK9 to the dyslipidemia of nephrotic syndrome. Results: Patients with nephrotic syndrome showed a decrease in plasma cholesterol and plasma PCSK9 on remission of their disease ( P &lt;0.05, n=47–50). Conversely, Pod-ATTAC mice and NTS-treated mice showed hypercholesterolemia and a 7- to 24-fold induction in plasma PCSK9. The induction of plasma PCSK9 appeared to be attributable to increased secretion of PCSK9 from the hepatocyte coupled with decreased clearance. Interestingly, knockout of Pcsk9 ameliorated the effects of NTS on plasma lipids. Thus, in the presence of NTS, mice lacking hepatic Pcsk9 showed a 40% to 50% decrease in plasma cholesterol and triglycerides. Moreover, the ability of NTS treatment to increase the percentage of low-density lipoprotein–associated cholesterol (from 9% in vehicle-treated Flox mice to 47% after NTS treatment), was lost in mice with hepatic deletion of Pcsk9 (5% in both the presence and absence of NTS). Conclusions: Podocyte damage triggers marked inductions in plasma PCSK9, and knockout of Pcsk9 ameliorates dyslipidemia in a mouse model of nephrotic syndrome. These data suggest that PCSK9 inhibitors may be beneficial in patients with nephrotic syndrome–associated hypercholesterolemia.
Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery
Authors: Eric M Scott, Anason Halees, Yuval Itan, Emily G Spencer, Yupeng He, Mostafa Abdellateef Azab, Stacey B Gabriel, Aziz Belkadi, Bertrand Boisson, Laurent Abel, Andrew G Clark, Fowzan S Alkuraya, Jean-Laurent Casanova, Joseph G Gleeson
Journal: Nature Genetics (2016)
Autologous Stem Cell Transplantation For Adult Burkitt Lymphoma In The Rituximab Era: A Retrospective Study Of The Lymphoma Working Party (LWP) Of The European Group For Blood and Marrow Transplantation (EBMT)
Authors: Ariane Boumendil, Herve Finel, Anna Sureda, Harry C. Schouten, Mohamad Mohty, Guustaaf van Imhoff, Wilfried Schroyens, Jurgen Finke, Nicolaas Pm Schaap, Ignazio Majolino, Mario Bargetzi, Enrico Maria Pogliani, Boris Afanasyev, Peter Dreger, Mahmoud D. Aljurf
Journal: Blood (2013)
Abstract 5013: A meta-analysis of MSI frequency and race in colorectal cancer
Authors: Hassan Ashktorab, Sadhna Ahuja, Lakshmi Kannan, Xavier Llor, Nathan Ellis, Rosa M. Xicola, Adeyinka O. Laiyemo, John M. Carethers, Hassan Brim, Mehdi Nouraie
Journal: Cancer Research (2016)

Abstract BACKGROUND: African Americans(AA) are at a higher risk of colorectal cancer (CRC) and some studies report a higher frequency of microsatellite instability (MSI) in their tumors while others report lower frequency compared to Caucasians. AIM: To determine and evaluate the association of race and clinical factors with MSI rate through meta- analysis. METHODS: Twenty-two studies out of 15105 (1997-2015) were evaluated after a search in different literature databases, using keywords “colorectal cancer, microsatellite instability”. We used random effect meta-analysis to calculate the MSI frequency in all studies as well as in African American and Caucasian samples. Meta-regression analysis was used to assess the univariate effect of race, gender, age, tumor location and stage on MSI rate. RESULTS: The overall MSI frequency among CRCs was 17% (95%CI: 15%-19%, I2 = 91%). The MSI rate among racial groups were 12%, 12% and 14% in AAs, Hispanics and Caucasians respectively and was not significantly different. Sub-group analysis of studies with racial information indicates MSI OR (95% CI) of 0.78 (0.58-1.06) for AAs compared to Caucasians. CONCLUSION: CRCs demonstrate an MSI frequency of 17%. MSI frequency differences between AAs and Caucasians were not pronounced, suggesting other factors contribute to the racial disparity. There is a large variation in MSI rate between different studies. Methodology approaches and biological sources of this variation should be investigated. Citation Format: Hassan Ashktorab, Sadhna Ahuja, Lakshmi Kannan, Xavier Llor, Nathan Ellis, Rosa M. Xicola, Adeyinka O. Laiyemo, John M. Carethers, Hassan Brim, Mehdi Nouraie. A meta-analysis of MSI frequency and race in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5013.
Abstract 1326: 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoside a novel c-Myc inhibitor induces GNMT expression and apoptosis in hepatocellular carcinoma
Authors: Rajni Kant, Chia Hung Yen, Chung Kuang Lu, Chien Yi Tung, Yi-Ming Chen
Journal: Cancer Research (2016)

Abstract 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoside (PGG) possesses potent anticancer activities. We identified PGG as GNMT inducer by using GNMT based drug screening platform. In this study we aimed to find the mechanism of action of PGG in hepatocellular carcinoma (HCC). We used microarray analysis to identify the differently expressed genes induced by PGG. Microarray experiment showed that c-Myc was involved in all detected pathways in enrichment analysis. PGG suppressed c-Myc mRNA and protein expression in Huh7 and Hep G2 cells. Knocked-down of c-Myc resulted in significant induction of GNMT promoter activity and endogenous GNMT mRNA expression. Furthermore, overexpression of c-Myc significantly inhibited GNMT promoter activity and endogenous GNMT protein expression. Moreover, PGG not only inhibited c-Myc mRNA expression but also induced degradation of c-Myc protein in Huh7 cells. Finally we found that PGG induces apoptosis in Huh7 cells. Taken together, PGG is a novel c-Myc inhibitor and induces GNMT through c- Myc modulation in HCC. Our results also suggest that PGG may potentially be a good drug candidate for HCC and c-Myc overexpressing cancers. Citation Format: Rajni Kant, Chia Hung Yen, Chung Kuang Lu, Chien Yi Tung, Yi-Ming Chen. 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranoside a novel c-Myc inhibitor induces GNMT expression and apoptosis in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1326.