tbuckley/cabot-search huggingface dataset:
Abstract 1732: Effect of 19-substituted benzoquinone ansamycin Hsp90 inhibitors on Hsp90/Cdc37/co-chaperone complexes and casein kinase 2 (CK2) activity
Authors: Chuan-Hsin Chang, David Ross, David Siegel, Christopher J Moody, Russell Kitson
Journal: Cancer Research (2015)

Abstract Benzoquinone ansamycin (BQA) Hsp90 inhibitors such as 17-DMAG and 17-AAG have off target toxicities including hepatotoxicity. Mechanisms underlying the toxicity of BQAs are a function of their ability to redox cycle and/or arylate cellular nucleophiles at the unsubstituted 19-position of the molecule. Therefore, we designed 19-substituted BQAs (19BQAs) to prevent conjugation with glutathione and protein thiols as an approach to reduce the hepatotoxicity and minimize off target effects of the BQA class of Hsp90 inhibitors. Our data demonstrated that 19BQAs had reduced toxicity to liver cells relative to their parent quinones while maintaining Hsp90 inhibitory activity, validating the overall approach. 19BQAs depend on tumor cell levels of NQO1 (NAD(P)H: quinone oxidoreductase 1) for optimal activity. We examined 19-phenyl-17-DMAG as a model compound in human isogenic breast cancer cell lines MDA468 (NQO1 null) and MDA468/NQ16 (NQO1 overexpressing) and in NQO1expressing BT474 breast cancer cells. 19-phenyl-17-DMAG induced growth inhibition, apoptosis and the molecular signature of Hsp90 inhibition including decreases in Hsp90 client protein levels and compensatory induction of Hsp70. In addition, treatment of MD468/NQ16 and BT474 cell lines with 19-phenyl-17-DMAG or 17-DMAG also caused the dissociation of Hsp90 from the co-chaperone Cdc37. In these studies we also observed that treatment with19-phenyl-17-DMAG or 17-DMAG resulted in inhibition of Cdc37 phosphorylation. A major kinase responsible for phosphorylation of Cdc37 is casein kinase 2 (CK2) and inhibitors of CK2 are currently under development as anticancer drugs. CK2 activity assays, immunoprecipitation and western blot analysis demonstrated that both 19-phenyl-17-DMAG and 17-DMAG inhibited CK2 kinase activity and reduced CK2α protein subunit expression in NQO1-expressing MD468/NQ16 and BT474 breast cancer cells. Decreased phosphorylation of Cdc37 led to dissociation of the Hsp90/Cdc37/client complex and resulted in the degradation of multiple kinase clients including Raf-1, Cdk4, Akt and HER2. These data suggest that inhibition of both Hsp90 and CK2 by Hsp90 inhibitors may play a role in their antitumor effects. (Supported by CA51210). Citation Format: Chuan-Hsin Chang, David Ross, David Siegel, Christopher J Moody, Russell Kitson. Effect of 19-substituted benzoquinone ansamycin Hsp90 inhibitors on Hsp90/Cdc37/co-chaperone complexes and casein kinase 2 (CK2) activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1732. doi:10.1158/1538-7445.AM2015-1732
Enhancing the anti-tumor activity of ErbB blockade with histone deacetylase (HDAC) inhibition
Authors: P. Chinnaiyan, S. Varambally, S. A. Tomlins, S. Huang, A. M. Chinnaiyan, P. M. Harari
Journal: Journal of Clinical Oncology (2004)

3029 Background: Molecular inhibition of the ErbB signaling pathway is under active investigation as a promising anti-cancer treatment strategy. Pre-clinical studies suggest that enhanced anti-tumor activity may be achieved by maximizing ErbB signaling inhibition. Using high throughput screening with cDNA microarrays, we identified HDAC inhibitors as having strong potential to enhance the effects of anti-ErbB agents. Methods: Microarray: Total RNA was isolated from cells after 12 and 24 hours exposure to HDAC inhibitor SAHA (suberoylanilide hydroxamic acid). cDNA probes were prepared from experimental and appropriate reference RNA samples, labeled, and hybridized to 20K human cDNA. Data was validated using quantitative real time RT-PCR. Cell Proliferation: Exponentially growing cells were incubated in medium containing vehicle control, CI-1033 (pan-ErbB tyrosine kinase inhibitor), SAHA, or both drugs in combination for 72 hours. Cells were then stained with 0.5% crystal violet and cell viability was determined using relative absorbance. Apoptosis: Caspase activity was analyzed by fluorescence spectroscopy using a fluorescein labeled pan-caspase inhibitor. Results: Array studies using SAHA in prostate and breast cancer cell lines show decreased transcript expression (> 50%) of EGFR and ErbB2. Findings from the array data were validated using real time RT-PCR and western blot analysis. Enhanced proliferative inhibition was seen in prostate (DU145, PC3), breast (SKBr3, MCF7), and head and neck tumor cells (UM-SCC6) when SAHA was combined with CI-1033. Combining HDAC inhibition with EGFR blockade demonstrated strong abrogation of EGFR and AKT signaling following EGF stimulation, as well as a supra-additive increase in caspase activity (p<0.05). Conclusions: These results suggest that used cooperatively, anti-ErbB agents and HDAC inhibitors may offer a unique and potentially potent strategy of dual targeted therapy. Based on emerging preclinical data, we are currently designing Phase I clinical trials which combine HDAC inhibitors with ErbB blockade. No significant financial relationships to disclose.
Pentraxin-3: An Easily Measurable Soluble Factor to Improve Post-Transplant Graft Versus Host Disease Monitoring and Management.
Authors: Erica Dander, Ivan Cuccovillo, Paola Vinci, Sonia Bonanomi, Lucia Di Maio, Giovanna Lucchini, Maddalena Migliavacca, Paolo Perseghin, Attilio Rovelli, Adriana Balduzzi, Alberto Mantovani, Barbara Bottazzi, Andrea Biondi, Giovanna D'Amico
Journal: Blood (2009)
478. Highly Efficient Targeted Gene Addition in CD34+ Hematopoietic Stem/Progenitor Cells by Combining ZFN mRNA and AAV6 Donor Delivery
Authors: Jianbin Wang, Colin M. Exline, Josh DeClercq, Patrick Li, Philip D. Gregory, Paula M. Cannon, Michael C. Holmes
Journal: Molecular Therapy (2015)

Zinc-finger nucleases (ZFNs) drive highly efficient genome editing by generating a site-specific DNA double-strand break (DSB) at a predetermined site in the genome. Subsequent repair of this break via the non-homologous end-joining (NHEJ) or homology-directed repair (HDR) pathways results in targeted gene disruption or gene correction/addition, respectively. Hematopoietic stem/progenitor cells (HSPC) are an important clinical target for gene therapy. These cells can be readily harvested from the subject, engineered using viral vectors, and re-introduced back into the patient where they give rise to all of the mature cells of the blood and immune system. Thus the ability to edit the genome of HSPCs could provide a corrective therapy for a number of monogenic diseases. However, achieving high levels of editing by HDR may be significantly more challenging than gene knockout by NHEJ. Here we report that the combination of delivering the ZFNs as mRNA and corrective donor DNA via a rAAV6 vector can induce highly efficient targeted gene addition in CD34+ HSPCs. Using CCR5-specific ZFNs and donor DNA templates as a model system we show that targeted addition of a novel restriction fragment length polymorphism (RFLP) was consistently achieved at >15%, while insertion of an eGFP expression cassette was achieved at >10% of the CCR5 loci in mobilized CD34+ cells. Furthermore, targeting the AAVS1 "safe harbor" locus with a pair of AAVS1-specific ZFNs (mRNA) and a RFLP donor (rAAV6) resulted in >30% of AAVS1 alleles specifically being edited to include the RFLP, suggesting this genome editing approach to achieve highly efficient targeted gene addition in CD34+ cells can be applied to different genetic loci. Edited HSPC undergo normal hematopoiesis in both in vitro differentiation assays and during engraftment of NSG mice. Using fetal liver derived cells, editing of primitive and more committed CD34+ HSPC subsets was observed at similar levels in HSPC CFU cultures, and by analysis of sorted populations of treated HSPC, including LT-HSC, and through the secondary transplantation of NSG mice. The use of ZFNs in combination with rAAV6 delivery of the donor DNA provides a significant advance in genome editing that has great potential for targeted correction of human disease-causing mutations and permanent transgene addition in human CD34+ HSPC.
Comprehensive Metaproteomic Analyses of Urine in the Presence and Absence of Neutrophil-Associated Inflammation in the Urinary Tract
Authors: Yanbao Yu, Patricia Sikorski, Madeline Smith, Cynthia Bowman-Gholston, Nicolas Cacciabeve, Karen E. Nelson, Rembert Pieper
Journal: Theranostics (2016)

Inflammation in the urinary tract results in a urinary proteome characterized by a high dynamic range of protein concentrations and high variability in protein content. This proteome encompasses plasma proteins not resorbed by renal tubular uptake, renal secretion products, proteins of immune cells and erythrocytes derived from trans-urothelial migration and vascular leakage, respectively, and exfoliating urothelial and squamous epithelial cells. We examined how such proteins partition into soluble urine (SU) and urinary pellet (UP) fractions by analyzing 33 urine specimens 12 of which were associated with a urinary tract infection (UTI). Using mass spectrometry-based metaproteomic approaches, we identified 5,327 non-redundant human proteins, 2,638 and 4,379 of which were associated with SU and UP fractions, respectively, and 1,206 non-redundant protein orthology groups derived from pathogenic and commensal organisms of the urogenital tract. Differences between the SU and UP proteomes were influenced by local inflammation, supported by respective comparisons with 12 healthy control urine proteomes. Clustering analyses showed that SU and UP fractions had proteomic signatures discerning UTIs, vascular injury, and epithelial cell exfoliation from the control group to varying degrees. Cases of UTI revealed clusters of proteins produced by activated neutrophils. Network analysis supported the central role of neutrophil effector proteins in the defense against invading pathogens associated with subsequent coagulation and wound repair processes. Our study expands the existing knowledge of the urinary proteome under perturbed conditions, and should be useful as reference dataset in the search of biomarkers.
Lymphocyte Recovery At Day 28 Post-Transplant Is Predictive Of Relapse In Patients With Acute Myeloid Leukemia Transplanted With Peripheral Blood Stem Cell Grafts
Authors: Fotios V. Michelis, Hans A. Messner, Jieun Uhm, Vikas Gupta, John Kuruvilla, Jeffrey H. Lipton, Dennis Dong Hwan Kim
Journal: Blood (2013)
Hepatostat: Liver regeneration and normal liver tissue maintenance
Authors: George K. Michalopoulos
Journal: Hepatology (2016)

In contrast to all other organs, liver‐to‐body‐weight ratio needs to be maintained always at 100% of what is required for body homeostasis. Adjustment of liver size to 100% of what is required for homeostasis has been called “hepatostat.” Removal of a portion of any other organ is followed with local regeneration of a limited degree, but it never attempts to reach 100% of the original size. The complex mechanisms involved in this uniquely hepatic process encompass a variety of regenerative pathways that are specific to different types of injury. The most studied form of liver regeneration (LR) is that occurring after loss of hepatocytes in a single acute injury, such as rodent LR after two‐thirds partial hepatectomy or administration of damaging chemicals (CCl 4 , acetaminophen, etc.). Alternative regenerative pathways become activated when normal regeneration is thwarted and trigger the appearance of “progenitor” cells. Chronic loss of hepatocytes is associated with regenerative efforts characterized by continual hepatocyte proliferation and often has adverse consequences (development of cirrhosis or liver cancer). Even though a very few hepatocytes proliferate at any given time in normal liver, the mechanisms involved in the maintenance of liver weight by this slow process in the absence of liver injury are not as well understood. (H epatology 2017;65:1384‐1392)
Identification of New Genomic Lesions in Childhood ALL without Known Genetic Aberrations: A Microarray Study of Gene Expression and Genotype Data.
Authors: Silvia Bungaro, Marta Campo Dell’Orto, Dario Basso, Tatiana A. Gorletta, Manoj Raghavan, Anna Leszl, Bryan D. Young, Giuseppe Basso, Gertruy te Kronnie, Silvio Bicciato, Andrea Biondi, Giovanni Cazzaniga
Journal: Blood (2006)
Concurrent, cisplatin-based chemotherapy with accelerated radiotherapy for advanced head and neck cancer patients
Authors: K. A. Skladowski, T. Rutkowski, A. Wygoda, M. Golen, B. Pilecki, W. Przeorek, B. Lukaszczyk-Widel
Journal: Journal of Clinical Oncology (2008)

17019 Background As the altered fractionation has become a standard radiation treatment (RT) for moderately advanced head and neck cancer (H&NC) patients, we decided to make use the accelerated fractionation with systemic cisplatin-based therapy for highly advanced lesions. Methods Fifty eight patients with H&NC in clinical stage IV treated between 1999 and 2003 were prospectively evaluated. Treatment assumed the administration of 3 courses of cisplatin (100mg/m2) and vinorelbin, and continuously fractionated irradiation (7 fractions per week) to the total dose of 68Gy in 40 fractions. Results One patient death could be related to the treatment. Planned RT dose has been realized in 56 patients (96%) but in 11 patients total dose was escalated within the range 70–78Gy because of residual lesion investigated at the end of treatment. Between 15th and 48th day of combined treatment all patients developed confluent mucositis, which lasted about 60 days (median value). All required anti-inflammatory and analgesic treatment including corticosteroids and opioids respectively. Tube feeding was realized in 15% of pts. During the first year of the study all 16 consecutive patients have been developing grade 3–4 neutropenia and 31% of them grade 3–4 anaemia. This was the reason to give only 2 courses of chemotherapy for 12 of them (75%) and to modify the schedule with drug-dose reduction: by 25% the dose of cisplatin and by 33% the dose of vinorelbin. Generally all patients received at least 2 courses of chemotherapy and 44of them (76%) realized full prescribed chemotherapy regimen (in 28 pts chemotherapy was widened up to 4 courses). Median follow-up is 35 months. Three-year loco-regional control and disease free survival rates are respectively 60% and 50%. During follow-up 15 patients died - 12 of them from cancer disease, in 9 patients salvage surgery was performed: 6 lymph node resections and 3 resections of residual tumour. Organ preservation has been noted at 65% of patients. Conclusions Concomitant chemo-radiotherapy in patients with advanced, fairly unresectable head and neck tumours produces very promising early results. After chemotherapy dose reduction the treatment is feasible in clinical practice and bow us towards a multicenter phase III study. No significant financial relationships to disclose.
Abstract 4173: Endoglin regulation of Smad2/3 function mediates beclin1 expression and endothelial autophagy during angiogenesis
Authors: Nam Y. Lee, Christopher Pan, Sanjay Kumar
Journal: Cancer Research (2015)

Abstract Autophagy is the targeted degradation of proteins and organelles critical for homeostasis and cell survival. Transforming growth factor beta (TGF-beta) is known to differentially regulate autophagy under distinct physiological conditions by inducing inhibitory, stimulatory, or a combination of these opposing signaling pathways. Importantly, how TGF-beta signaling controls autophagic responses in the endothelial cell (EC) system during angiogenesis remains unknown. Here we identified endoglin, an EC-specific TGF-beta co-receptor essential for angiogenesis, as a key determinant of autophagy. We found that Smad2/3 are major transcriptional regulators of basal autophagy that specifically target beclin1 (BECN1) gene expression. Selectively blocking ALK5 activation or silencing endogenous Smad2/3 markedly increased BECN1 expression whereas altering ALK1/Smad1/5/8 signaling had no effect. Endoglin potentiates basal autophagy by suppressing ALK5/Smad2/3 activation. Notably, increased beclin1 levels upon Smad2/3 knockdown directly correlated with enhanced autophagy during angiogenesis. Taken together, these results establish endoglin as a critical mediator of autophagy and demonstrate a new cellular mechanism by which Smad2/3 inhibits angiogenesis. Citation Format: Nam Y. Lee, Christopher Pan, Sanjay Kumar. Endoglin regulation of Smad2/3 function mediates beclin1 expression and endothelial autophagy during angiogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4173. doi:10.1158/1538-7445.AM2015-4173
Why Oxygen Is Not Necessary for All STEMIs
Authors: Nick Fitterman
Journal: JAMA Internal Medicine (2016)

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Proteomic Analysis of Acute Promyelocytic Leukemia Reveals That PML-RARalpha Induces Cell Cycle Progression and Mitotic Exit by Increased Expression and Decreased Ser63 Phosphorylation of OP18.
Authors: A. PeerZada, M. Geletu, J. Pullikan, V. Reddy, W. Hiddemann, G. Behre
Journal: Blood (2004)
Correlation between treatment with aromatase inhibitors and carotid intima-media thickness, carotid stenosis and abdominal aortic diameter. A prospective cohort study
Authors: E. Blondeaux, M. Lambertini, D. Musio, S. Vecchio, F. Poggio, V. Gazzola, D. Palmieri, P. Bruzzi, G. Rossi, S. Pastorino, M.C. Perfumo, P. Pronzato, D. Palombo, C. Bighin, L. Del Mastro
Journal: Annals of Oncology (2015)
Abstract B31: The MUC4 oncomucin mediates resistance of human pancreatic cancer cells to FOLFIRINOX drugs
Authors: Nicolas Skrypek, Nihad Boukrout, Fatima Lahdaoui, Céline Schulz, Romain Vasseur, Belinda Duchêne, Isabelle Van Seuningen, Nicolas Jonckheere
Journal: Cancer Research (2016)

Abstract Introduction: Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in western countries with an extremely poor prognosis because of a lack of efficient therapeutic tools. Gemcitabine, a fluorinated analog of deoxycytidine, is the main chemotherapy in PDAC, but survival remains poor. FOLFIRINOX, a more aggressive protocol combining 5-fluorouracil (5-FU), irinotecan/SN-38, oxaliplatin and leucovorin, emerged as a new option in patients with metastatic pancreatic cancer. MUC4 is a membrane-bound oncomucin involved in pancreatic cancer (PC) pathogenesis and chemoresistance to gemcitabine. MUC4 is not expressed in healthy pancreas whereas its expression increases constantly during carcinogenetic progression. In this work, we aimed to decipher the involvement of MUC4 and associated cellular mechanisms in chemoresistance to FOLFIRINOX drugs. Material and Methods: MUC4 expression was knocked down (KD) by stable ShRNA in CAPAN-1/-2 PC cells. IC50 and cell viability to FOLFIRINOX drugs were determined by tetrazolium salt (MTT) assays. Expression of genes involved in drug metabolism was assessed by quantitative RT-PCR (qRT-PCR) and Western blot. MiRnomes of Mock and MUC4-KD cells were determined using miRNA array (8x15K Agilent). Results: MUC4 depletion in PC cells leads to an increase of sensitivity to 5-FU and to an increased resistance to oxaliplatin. Combined treatments of 5-FU and oxaliplatin (FOX) lead to an intermediate survival rate suggesting additional effects. This altered chemosensitivity is associated with an altered expression of drug transporters/channels and drug metabolism actors. Notably, an increase of CTR1 and ATP7B transporters and DPYD enzyme was observed in MUC4-KD cells. Furthermore, we have observed downregulation of miR-96-5p, miR-132-3p and miR-210 suggesting a possible link between MUC4 expression, drug resistance and regulation by miRNAs. The involvement of these molecules is currently validated by transient RNA interference and miRNA transfections. Conclusion: this work led to the identification of proteins and miRNAs specifically involved in priming PC chemoresistance. These factors may represent critical therapeutic targets and also robust prognostic/predictive markers, and thus provide better healthcare and management of PC patients. Citation Format: Nicolas Skrypek, Nihad Boukrout, Fatima Lahdaoui, Céline Schulz, Romain Vasseur, Belinda Duchêne, Isabelle Van Seuningen, Nicolas Jonckheere.{Authors}. The MUC4 oncomucin mediates resistance of human pancreatic cancer cells to FOLFIRINOX drugs. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B31.