tbuckley/cabot-search huggingface dataset:
Treatment of Fabry’s Disease with the Pharmacologic Chaperone Migalastat
Authors: Dominique P. Germain, Derralynn A. Hughes, Kathleen Nicholls, Daniel G. Bichet, Roberto Giugliani, William R. Wilcox, Claudio Feliciani, Suma P. Shankar, Fatih Ezgu, Hernan Amartino, Drago Bratkovic, Ulla Feldt-Rasmussen, Khan Nedd, Usama Sharaf El Din, Charles M. Lourenco, Maryam Banikazemi, Joel Charrow, Majed Dasouki, David Finegold, Pilar Giraldo, Ozlem Goker-Alpan, Nicola Longo, C. Ronald Scott, Roser Torra, Ahmad Tuffaha, Ana Jovanovic, Stephen Waldek, Seymour Packman, Elizabeth Ludington, Christopher Viereck, John Kirk, Julie Yu, Elfrida R. Benjamin, Franklin Johnson, David J. Lockhart, Nina Skuban, Jeff Castelli, Jay Barth, Carrolee Barlow, Raphael Schiffmann
Journal: New England Journal of Medicine (2016)

Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes.The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes.The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased.Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).
Lymphomas and 3D conformal radiotherapy
Authors: P. Angelakis, J. Vrouvas, G. Kollias, C. Paraskevopoulou, A. Damatopoulou
Journal: Journal of Clinical Oncology (2005)

6708 Background: Radiotherapy has always been involved in the treatment of the lymphomas. Late toxicity, carcinogenesis in long term survivors and the advent of novel beneficial chemotherapy, resulted in general de-escalation of radiation doses. Still, higher radiation doses are necessary in at least some cases, to eradicate residual disease while at the same time there is a need to further reduce radiation doses to organs at risk. Methods: In the last three years ten patients suffering from Hodgkin’s or non Hodgkin’s lymphomas in partial or no response referred for post chemotherapy radiotherapy, were treated with 3D conformal techniques. Special CTs or PET-CTs with fiducial marks were taken, GTVs, CTVs, PTVs, organs at risk, i.e. lungs, heart, breasts, etc., were delineated, isodose curves plotted and dose volume histograms(DVHs) generated. Previous chemotherapy, degree of response, organs at risk tolerance and DVHs were in mind when prescribing radiation doses. We compared DVH in patients treated with 3D conformal, with plans and DVHs of the same patients as if they would have been treated from simulation films with extended field, mantle, or involved field techniques. Results: For the same lymphomatous burden as delineated in the PTV in the 3D conformal and in the standard X-Ray simulation techniques, DVH’s were generated for the organs at risk for 3D conformal and the standard techniques as above. In two example cases, one young male with Hodgkins disease with bulky mediastinum and infiltration of pericardium as shown in PET-CT and a similar young female with non Hodgkins with bulky mediastinum and positive cytology of pericardial infusion. Mean doses to the organs at risk were significantly reduced. The corresponding mean doses with 3D conformal, were 98% and 91% lower for the thyroid, 39% and 36% lower for the heart, 19% and 18% lower for both lungs, 44% and 72% lower for the bone marrow and 19% and 28% lower for the right and left breast. The maximum dose for the spinal cord was 28% and 50% lower with 3D conformal technique. Conclusions: In general, for the same dose to the lymphomatous burden, doses received to organs at risk with 3D conformal techniques, a universally available at present technique, were considerably lower. Detailed results will be presented. No significant financial relationships to disclose.
PTU-131 Response to enteral nutrition predicts increased length of remission in children with Crohn's disease: Abstract PTU-131 Figure 1
Authors: A Rao, N Kamperidis, Y Koodun, S Naik, N M Croft, I R Sanderson
Journal: Gut (2012)

<h3>Introduction</h3> Exclusive enteral nutrition (EEN) is the primary therapy for children with intestinal Crohn9s disease (CD) in the UK. We hypothesised that entering remission with EEN predicted a longer duration of remission. <h3>Methods</h3> Retrospective data were obtained on children with CD from 2003 to 2006 at a tertiary paediatric gastroenterology centre. Response was determined by Physicians Global Assessment. Outcome measures investigated were: relapse rates, time to relapse, corticosteroid (CS) use and treatment escalation. Relapse was defined as worsening symptoms and/or increase in CRP with a change in medication. p Values of &lt;0.05 were considered significant. <h3>Results</h3> 75 children with CD were diagnosed between 2003 and 2006, in whom 62 had 5 year follow-up data available. 56 patients (90.3%) received EEN upon diagnosis. The others received 5-ASA [4] or antibiotics [2], and were excluded from the analysis. No patients received corticosteroids as initial treatment. The median age [range] at diagnosis was 12.87 [4.84–15.86] years. 62.5% [35] of patients had ileo-colonic disease. 94.6% [53/56] of patients tolerated EEN. 57.1% [32] of patients went into clinical remission with EEN. Corticosteroids were prescribed to those who failed to enter remission with EEN. Multivariate analysis showed no correlation between disease location (p=0.70), ethnicity (p=0.43), age (p=0.25) or CRP (p=0.73) and response to EEN. All of the patients with colonic disease relapsed over 5 years (n=7), compared to 79% [11/14] of patients with ileal disease and 77% [27/35] of patients with ileo-colonic disease (p=0.37). The patients who responded to EEN remained in remission significantly longer than the non-responders. Median time to relapse [range] over the 5 years was 17.4 [4.23–49.32] months in responders vs 9.72 [2.87–47.6] months in non-responders; p=0.041 (Abstract PTU-131 figure 1). 50% [16/32] of patients who responded to EEN had no corticosteroid use over the 5 years. There was no significant difference in those starting azathioprine between responders and non-responders (75% [23/32] vs 87.5% [21/24]; p=0.20), or in rates of infliximab (22% [7/32] vs 37.5% [9/24], p=0.24) or surgery (28% [9/32] vs 37.5% [9/24], p=0.57). <h3>Conclusion</h3> This is the first study proving that achievement of clinical remission with EEN predicts an improved outcome for paediatric patients with Crohn9s disease over the next 5 years. It is possible that this is due to improved mucosal healing in children responding to EEN. A.Rao and N.Kamperidis contributed equally and should be considered as joint first authors. <h3>Competing interests</h3> None declared.
Abstract 982: Long non-coding RNA PICSAR promotes growth of cutaneous squamous cell carcinoma by regulating ERK1/2 activity
Authors: Minna Piipponen, Liisa Nissinen, Mehdi Farshchian, Pilvi Riihilä, Atte Kivisaari, Markku Kallajoki, Juha Peltonen, Sirkku Peltonen, Veli-Matti Kähäri.
Journal: Cancer Research (2016)

Abstract Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and its incidence is increasing globally. Long non-coding RNAs (lncRNAs) are involved in various biological processes, and their role in cancer progression is emerging. The aim of this study was to find and characterize new biomarkers for evaluating the risk of progression and metastasis of cSCC and identify novel therapeutic targets for recurrent and metastatic cSCC. RNA-sequencing of cSCC cells (n = 8) and normal human epidermal keratinocytes (NHEKs, n = 4) revealed overexpression of a previously uncharacterized long intergenic non-coding RNA (lincRNA), LINC00162 in cSCC cells. Analysis of tissue sections by RNA in situ hybridization showed that LINC00162 is specifically expressed by tumor cells in cSCCs but not by keratinocytes in normal skin in vivo. The expression of LINC00162 in cSCC cells was upregulated by inhibition of the p38α and p38δ MAPKs using BIRB796 or p38α and p38δ specific siRNAs. Knockdown of LINC00162 inhibited proliferation and migration of cSCC cells, and suppressed the growth of human cSCC xenografts in vivo. Furthermore, knockdown of LINC00162 inhibited ERK1/2 activity and upregulated expression of dual specificity phosphatase DUSP6 in cSCC cells. Based on these observations, LINC00162 was named PICSAR (P38 Inhibited Cutaneous Squamous cell carcinoma Associated lincRNA). Our results provide mechanistic evidence for the role of PICSAR in promoting cSCC progression via activation of ERK1/2 signaling pathway by downregulating DUSP6 expression. These results also identify PICSAR as a novel biomarker and putative therapeutic target in cSCC. Citation Format: Minna Piipponen, Liisa Nissinen, Mehdi Farshchian, Pilvi Riihilä, Atte Kivisaari, Markku Kallajoki, Juha Peltonen, Sirkku Peltonen, Veli-Matti Kähäri. Long non-coding RNA PICSAR promotes growth of cutaneous squamous cell carcinoma by regulating ERK1/2 activity. [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 982.
Abstract 3817: Recombinant stapled proteins for the treatment of chronic myeloid leukemia
Authors: Benjamin J. Bruno, Sean P. Cornillie, Thomas E. Cheatham, Daniel H. Chou, Carol S. Lim
Journal: Cancer Research (2016)

Abstract The oncoprotein Bcr-Abl is the cause of chronic myeloid leukemia (CML). Current therapies target the tyrosine kinase domain of Bcr-Abl, but due to their non-curative nature, resistance to these drugs is common. Therefore, new treatments are needed for those patients refractive to available therapies. Bcr-Abl homo-oligomerization via its N-terminal coiled coil (CC) domain is required for tyrosine kinase activity. Our previous work has shown that it is possible to inhibit Bcr-Abl activity by targeting the CC domain with a peptidomemetic known as CCmut, delivered as a protein using a cell-penetrating peptide (CPP-CCmut). CPP-CCmut selectively enters leukemic cells and inhibits Bcr-Abl, as seen by Western blot, 7AAD, Annexin V, cell proliferation, and colony forming assays. This leukemia cell-permeable CPP-CCmut protein domain is our lead compound for CML therapy, but to be translatable to the clinic it must be modified to improve proteolytic stability. For this reason, we created stapled versions of this CPP-CCmut. Stapled peptides are resistant to proteolysis, and are emerging as a viable strategy for disrupting protein-protein interactions in diseases including HIV and cancer. Until recently, peptide stapling required incorporation of unnatural amino acids; therefore these peptides were created via solid-state synthesis. However, the synthesis of the 81 amino acid CPP-CCmut is no trivial matter. The ability to staple a longer sequence such as our protein domain is now possible using thiol-ene coupling. This exciting new chemistry allows for the stapling of recombinant proteins at substituted cysteine residues (instead of stapling substituted unnatural amino acids incorporated into synthetically made peptides). Thiol-ene coupling is used here to staple recombinant CPP-CCmut, and provides a path for translation of our lead compound to the clinic. Molecular modeling has identified optimal locations for staples on CPP-CCmut, which include 29/36, 36/43, 50/57, 57/64, as well as double staples 29/36-50/57 and 36/43-50/57. These staple locations still allow for dimerization of CPP-CCmut with Bcr-Abl, as indicated by free energy calculations and helicity. The staple locations have also been optimized for maximal coverage from proteolytic degradation. This work acts as a proof-of-concept that proteins (not just peptides) can be stapled, thus greatly expanding the variety and complexity of stapled proteins for use in the exciting field of targeting protein-protein interfaces to treat disease. Citation Format: Benjamin J. Bruno, Sean P. Cornillie, Thomas E. Cheatham, Daniel H. Chou, Carol S. Lim. Recombinant stapled proteins for the treatment of chronic myeloid leukemia. [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 3817.
Selective MEK Inhibition with AZD-6244 (selumetinib) in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A University of Chicago Phase II Consortium Trial
Authors: Natalie Galanina, Sonali M. Smith, Chuanhong Liao, Adam M. Petrich, Bernadette Libao, Ron Gartenhaus, Jason R Westin, Kenneth S. Cohen, James Knost, Walter Stadler, Austin Doyle, Theodore Karrison, Leo I. Gordon, Andrew M Evens
Journal: Blood (2015)
A Novel Ring-Substituted Diindolylmethane 1,1-bis [3′-(5-methoxyindolyl)]-1-(p-t-butylphenyl) Methane Abrogates ERK Activation and Induces Apoptosis in Acute Myeloid Leukemia (AML).
Authors: Rooha Contractor, Ismael J. Samudio, Zeev Estrov, David Harris, James A. McCubrey, Stephen H. Safe, Michael Andreeff, Marina Konopleva
Journal: Blood (2004)
Infusion of “off-the-shelf” Third Party Ex Vivo Expanded Cord Blood Progenitor Cells As Supportive Care Following Clofarabine with High Dose Cytarabine and Granulocyte Colony-Stimulating Factor Priming for the Treatment of AML,
Authors: Colleen Delaney, Pamela S Becker, Filippo Milano, Ian Nicoud, Shelly Heimfeld, Ivy Riffkin, Adrienne Papermaster, Frederick R. Appelbaum, Irwin D. Bernstein, Elihu H. Estey
Journal: Blood (2011)
Abstract 664: Insulin receptor signaling contributes to mammary tumorigenesis in mice
Authors: Yekaterina Poloz, Samar Mouaaz, Sonya Lam, Vuk Stambolic
Journal: Cancer Research (2016)

Abstract A recent convergence of clinical and epidemiological evidence suggests that hyperinsulinemia associated with obesity and type 2 diabetes leads to higher incidence and poor outcome of breast cancer (BC). To probe the role of insulin signaling in BC, we created the MMTV-driven polyoma middle T BC model mice with an inducible mammary epithelium-specific deletion of the insulin receptor (INSR). Deletion of INSR in the mammary gland considerably reduced the mammary tumour burden in the INSR knockout mice as compared to the INSR wildtype controls, without affecting the tumour onset. The average weight of individual tumours was similar across the genotypes, suggesting that deletion of INSR affected the tumour initiation potential of the epithelial cells rather than tumour growth. Deletion of INSR also affected the metastasis of mammary tumours to the lung, with the INSR knockout mice presenting with half the number of metastases compared to the INSR wildtype controls. Our ongoing efforts are focused on mapping the signaling events downstream of the INSR that govern tumour initiation and metastasis in our mice, as well as modeling the impact of obesity on tumors in this model system, with the ultimate goal of identifying the role of INSR signaling in BC development and progression. Citation Format: Yekaterina Poloz, Samar Mouaaz, Sonya Lam, Vuk Stambolic. Insulin receptor signaling contributes to mammary tumorigenesis in mice. [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 664.
Abstract 2149: The anti-EGFR antibody mixture Sym004 overcomes acquired resistance to cetuximab in colorectal cancer
Authors: Francisco J. Sanchez-Martin, Alba Dalmases, Beatriz Bellosillo, Guillem Argiles, Mariona Gelabert, Israel Cañadas, Joana Vidal, Giulia Siravegna, Sabrina Arena, Klaus Koefoed, Laura Visa, Oriol Arpí, Ivan D. Horak, Mar Iglesias, Christopher Stroh, Michael Kragh, Ana Rovira, Joan Albanell, Alberto Bardelli, Josep Tabernero, Clara Montagut
Journal: Cancer Research (2016)

Abstract The anti-EGFR monoclonal antibodies (MoAbs) cetuximab and panitumumab are used to treat ‘RAS’ wild type metastatic colorectal cancer (MCRC), providing significant clinical benefit in patients. However, all patients ultimately develop disease progression, driven by acquisition of mutations in downstream effectors and in the extracellular domain (ECD) of EGFR, in approximately 25% of the cases. Sym004 is a novel 1:1 mixture of two non-overlapping anti-EGFR MoAbs that has recently shown promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent cetuximab resistance driven by EGFR ECD mutations. Functional studies were performed to assess drug-receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of cetuximab, panitumumab and Sym004. Cell viability and molecular effects of the drugs were assayed in cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to cetuximab that harbored an EGFR mutation in the post-cetuximab tumor sample. Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to cetuximab harboring EGFR ECD mutations maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As a proof of principle, a patient with a tumor harboring an EGFR mutation (G465R) following cetuximab therapy benefited from Sym004 therapy. These data suggest that Sym004 is an active drug in MCRC resistant to cetuximab/panitumumab mediated by EGFR mutations. Overall, EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials. Citation Format: Francisco J. Sanchez-Martin, Alba Dalmases, Beatriz Bellosillo, Guillem Argiles, Mariona Gelabert, Israel Cañadas, Joana Vidal, Giulia Siravegna, Sabrina Arena, Klaus Koefoed, Laura Visa, Oriol Arpí, Ivan D. Horak, Mar Iglesias, Christopher Stroh, Michael Kragh, Ana Rovira, Joan Albanell, Alberto Bardelli, Josep Tabernero, Clara Montagut. The anti-EGFR antibody mixture Sym004 overcomes acquired resistance to cetuximab 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 2149.
Overall survival in patients with lung cancer using a web-application-guided follow-up compared to standard modalities: Results of phase III randomized trial.
Authors: Fabrice Denis, Claire Lethrosne, Nicolas Pourel, Olivier Molinier, Yoann Pointreau, Julien Domont, Hugues Pierre Bourgeois, Helene Senellart, Pierre Tremolieres, Thibaut Lizee, Jaafar Bennouna, Thierry Urban, Claude El Kouri, Alexandre Charron, Anne-Lise Septans, Magali Balavoine, Cyrielle Rolley, Sebastien Landry, Philippe Solal-Celigny, Christophe Letellier
Journal: Journal of Clinical Oncology (2016)

LBA9006 Background: We developed a web-application for an early detection of symptomatic relapse, complications and early supportive care in high-risk lung cancer patients between visits. A dynamical analysis of the weekly self-reported symptoms automatically triggered physician visit. Methods: We performed a national multi-institutional phase 3 prospective randomized study to compare web-application follow-up (experimental arm) for which patient’s self-scored symptoms that were weekly sent (between planned visits) to the oncologist and a clinical routine assessment with a CT-scan (every 3-6 months or at investigator’s discretion - standard arm). High risk lung cancer patients without progression and with a 0-2 performance status (PS) after an initial treatment were included. Maintenance chemotherapy or TKI therapy were allowed. In the experimental arm, an email alert was sent to the oncologist when some predefined clinical criteria were fulfilled: an imaging was then quickly prescribed. Early supportive cares were provided if adequate. The primary endpoint was to detect an improvement of 12% in 9 months survival in favor of the experimental arm (α = 5%, β = 20%, unilateral test). The boundary for declaring superiority with respect to overall survival at the pre-planned interim analysis was a p-value of less than 0.006. The PS at relapse, the quality of life (QOL) and cost-effectiveness were also investigated. Results: 121 patients were included in the intent-to-test survival analysis (90% were stage III/IV, median age: 65 y): 60 (61) in the experimental (standard) arms with equivalent baseline characteristics. Median follow-up was 9 months. Median overall survival in months was 19 (11.8), p=0.0014 (n = 121; HR = 0.33; 95 % CI, 0.16-0.67) and the PS at the first relapse was 0-1 for 81.5% (35.3%) of the patients (p&lt;0.001) in the experimental (standard) arm. Conclusions: This trial shows a significant survival improvement using Web-application-guided follow-up that allowed better PS at relapse, earlier supportive care and reduction of routine imaging. QOL and cost analysis results will be presented during the meeting. Clinical trial information: NCT02361099.