tbuckley/cabot-search huggingface dataset:
P125 A primary care audit on asthma patients with frequent exacerbations and the potential impact of national review of asthma deaths (NRAD) recommendations
Authors: R Chaudhuri, NC Thomson, C McCallum, H O’Pray, ST Barclay, D Murray, S MacBride-Stewart, V Sharma, M Shepherd, WT Lee
Journal: Thorax (2016)

<h3>Background</h3> One of the key recommendations of NRAD<sup>1</sup> is that patients who require 2 courses or more of oral corticosteroids (OCS) for asthma in the last 12 months should be referred to a specialist asthma service. This may put undue pressure on secondary care asthma services as the number of such patients is unknown. <h3>Aims</h3> To identify asthma patients with recurrent exacerbations who would merit referral to secondary care, and to study the biopsychosocial factors associated with frequent exacerbations. <h3>Methods</h3> Data were retrospectively collected on asthma patients aged &gt;18 years from 10 primary care practices in the North Glasgow area over a 12-month period between 2014 and 2015. All prescriptions patients received in primary care were obtained. Only patients who received asthma treatment in the last 12 months were included. Patients were identified as a ‘frequent exacerbator’ if they had received ≥2 courses of OCS for asthma, and a “short-acting beta 2-agonist (SABA) over-user” if they had required &gt;12 SABA inhalers in the last 12 months. <h3>Results</h3> Out of 2639 asthma patients studied, 7% were frequent exacerbators, 5% were SABA over-users, 1% were both. Compared with all asthma patients, frequent exacerbators were older (mean age 58 ± 16 vs 48 ± 17) and more likely to be female (68% vs 58%). They had a higher prevalence of cigarette exposure and multiple co-morbidities including COPD, gastro-oesophageal reflux, anxiety, depression, rhinitis and osteoporosis. 41% of frequent exacerbators did not have an asthma review in primary care in the last 12 months and 42% had no previous input from secondary care. The total number of patients who would merit referral to a specialist asthma service from the 10 primary care practices was 78 over a 12-month period. <h3>Conclusions</h3> Frequent exacerbators and SABA over-users account for a small proportion of asthma patients attending primary care. The number of new referrals generated by the NRAD recommendation may put additional pressure on secondary care asthma services. <h3>Funder</h3> supported by an educational grant from Novartis Pharmaceuticals. <h3>Reference</h3> Levy ML. The national review of asthma deaths: what did we learn and what needs to change? <i>Breathe (Sheff )</i> 2015;<b>11</b>(1):14–24.
Abstract PR09: The prognostic landscape of genes and infiltrating immune cells across human cancers
Authors: Andrew J. Gentles, Aaron M. Newman, Chih Long Liu, Scott V. Bratman, Weiguo Feng, Dongkyoon Kim, Viswam S. Nair, Xu Yue, Amanda Khuong, Chuong D. Hoang, Maximilian Diehn, Robert B. West, Sylvia K. Plevritis, Ash A. Alizadeh
Journal: Cancer Research (2015)

Abstract Molecular profiles of tumors and tumor-associated cells hold great promise as biomarkers of clinical outcomes. However, existing datasets are fragmented and difficult to analyze systematically. We present a pan-cancer resource and comprehensive meta-analysis of expression signatures from ~18,000 human tumors with overall survival outcomes across 39 malignancies. While a third of prognostic genes were cancer-specific, a FOXM1 regulatory network is a major predictor of adverse outcomes, while favorably prognostic genes largely reflect tumor-associated leukocytes. Using a novel computational approach, we enumerated leukocyte subsets in bulk tumor transcriptomes, revealing complex novel malignancy-specific associations between 22 distinct leukocytes and cancer survival. Tumor-associated neutrophil-like polymorphonuclear cell and plasmacytic cells emerged as significant but opposite predictors of survival for diverse solid tumors, including breast and lung adenocarcinomas. Our results introduce new analytical tools for delineating prognostic genes and leukocytes within and across cancers, and shed light on the impact of tumour heterogeneity on cancer outcomes, with applications for discovering novel biomarkers and therapeutic targets Citation Format: Andrew J. Gentles, Aaron M. Newman, Chih Long Liu, Scott V. Bratman, Weiguo Feng, Dongkyoon Kim, Viswam S. Nair, Xu Yue, Amanda Khuong, Chuong D. Hoang, Maximilian Diehn, Robert B. West, Sylvia K. Plevritis, Ash A. Alizadeh. The prognostic landscape of genes and infiltrating immune cells across human cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr PR09.
Strategies to improve survival of patients with intrahepatic cholangiocarcinoma undergoing liver transplantation
Authors: Rahul Gupta, Jyoti Gupta
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We read with interest the work by Sapisochin et al.1 on the role of liver transplantation (LT) in the treatment of very early intrahepatic cholangiocarcinoma (iCCA). This study demonstrated that very early iCCA had better survival rates than advanced iCCA and that patients with very early iCCA and cirrhosis may be considered for LT. The authors reported that the most frequent site of recurrence was extrahepatic (16 of 19 patients [84.2%]). This finding suggests that there is need to combine systemic therapies to LT to improve survival apart from appropriate patient selection. Another observation that supports the use of other therapies along with LT was better 1‐, 3‐, and 5‐year actuarial survival in a nonincidental advanced iCCA group compared with an incidental advanced iCCA group with a lower tumor recurrence rate (54.2% versus 62.5%; P = 0.7), though this finding was not statistically significant because of the small sample size. We believe that preoperative treatment may be responsible for this difference, because 69.2% of the patients in the nonincidental group received preoperative tumor therapy. Hong et al.,2 in their study of 37 cases of iCCA, concluded that addition of neoadjuvant and adjuvant therapies with LT for advanced iCCA significantly reduced tumor recurrence rate. An important aspect of systemic therapy apart from chemotherapy is antiviral treatment. The incidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in the study patients was 47.9%. Studies in patients with HBV‐ or HCV‐related hepatocellular carcinoma have shown better survival and lower recurrence in those receiving antiviral therapy after curative treatment.3 It would be interesting to know how many patients in each group (very early versus advanced) received antiviral therapy and whether it had any impact on the outcomes. Finally, we are interested to know why diagnosed cases of iCCA who underwent LT were not included in this study along with misdiagnosed cases, as that would have increased the patient population and allowed better comparison with incidental cases.
Abstract 3659: Target validation and structural optimization of selective small molecule survivin inhibitors as potential anti-cancer agents
Authors: Jin Wang, Min Xiao, Duane D. Miller, Wei Li
Journal: Cancer Research (2015)

Abstract The anti-apoptotic protein survivin is highly expressed in most human cancer cells, but has very low expression in normal differentiated cells. Thus survivin is widely considered as an attractive cancer drug target. Herein we report the in vitro and in vivo study on a series of novel survivin inhibitors modified from our recently identified hit compound UC-112. NCI 60-cell line screening assay showed that three new analogs with oxyquinoline scaffold had GI50 values within the nanomolar range (513 nM, 646 nM and 891 nM). These new compounds can overcome the P-gp mediated multidrug-resistance in cancer cell lines. Western blot analyses demonstrated the high selectivity for survivin inhibition among other members in the inhibitor of apoptosis protein family. Mechanistic studies such as isothermal calorimetry measurements, survivin protein pull-down assay and fluorescence polarization assay confirm that these novel compounds indeed target survivin and inhibit its function. The most active compound showed excellent aqueous solubility of 148.7 μM (PBS pH7.4), reasonable metabolic stability (half-life) of 51 minutes as tested in human liver microsomes, and no significant inhibitions to major CYP enzymes except one of CYPs. Rat pharmacokinetic studies indicated good pharmacokinetic profiles for this novel scaffold. When tested in an A375 human melanoma xenograft model, this compound effectively suppressed tumor growth and strongly induced cancer cell apoptosis in tumor tissues. Overall, our study has demonstrated that these cell-permeable small molecular survivin inhibitors possessing a novel scaffold could be developed as potent anti-tumor therapeutic agents. Citation Format: Jin Wang, Min Xiao, Duane D. Miller, Wei Li. Target validation and structural optimization of selective small molecule survivin inhibitors as potential anti-cancer agents. [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 3659. doi:10.1158/1538-7445.AM2015-3659
Molecular profiling of melanoma tumor biopsies to identify a response signature to the multi-RTK inhibitor, E7080.
Authors: J. J. Nemunaitis, D. S. Hong, R. Kurzrock, N. N. Senzer, N. C. Twine, T. Kadowaki, M. Ren, Y. Funahashi, J. P. O'Brien, J. S. Simon, A. Eisen
Journal: Journal of Clinical Oncology (2011)

8595 Background: E7080 is an oral TKI targeting VEGFR1-3, FGFR1-4, PDGFRβ, RET and KIT, which affects tumor cell proliferation and tumor vascularization in laboratory models. Tumor response (RECIST) and prolonged disease stabilization (> 6 months) were observed in melanoma patients treated in phase I. The present study sought to identify predictive genomic/proteomic signatures. Methods: 25 patients with metastatic melanoma received E7080 10mg twice daily continuously. Biopsy of accessible lesions was performed pre-treatment D1 and on D22 post-treatment. The patient responses were: 2 PR, 14 SD > 3 months, 1 SD > 2 months and 5 PD (3 patients non evaluable). Tumor biopsies (D1 and D22) were frozen and preserved for sectioning. Melanoma cells and tumor infiltrating vasculature (IHC CD31+) were separately collected by laser capture micro-dissection for profiling from ~ 5,000 cells on Affymetrix U133+2 microarrays and from ~30,000 cells via a gel electrophoretic-tryptic digest-LC/MS/ MS method. Results: From 25 patient samples, 22 D1 samples yielded quality melanoma mRNA samples for hybridization and analyses used data from ~24,000 RMA-normalized probes. The genomic data was analyzed using Student's T-test based on clinical benefit (=PR or SD ≥ 6 months); regression analysis for the continuous measure of tumor shrinkage and by Cox proportional regression based on PFS. The analysis identified genes encoding elements of the target RTK signaling pathways. At the intersection of the regression analyses was a set of 46 genes correlating with the observed clinical response. Conclusions: A small set of genes in melanoma cells may potentially be used to predict clinical response in melanoma patients to E7080. The list will be refined based on on-going proteomic analysis of melanoma cells, gene expression data from the tumor vasculature and genotyping for melanoma-associated mutations from these same tumors. These will be tested for their predictive value in an ongoing Ph2 trial.
Hematopoietic stem cell reserve and aging in patients undergoing autologous transplant
Authors: A. Arora, J. G. Sharp, J. C. Lynch, K. Petersen, V. Whalen, M. A. Kessinger
Journal: Journal of Clinical Oncology (2004)

6653 Background: Literature regarding the association of aging and stem cell numbers is conflicting. No compelling evidence exists that hematopoietic stem cell numbers decline with age. Early progenitor cells represent only a fraction of total CD34 cells. The ratio of CFU-GM/CD34 provides an estimate of the proportion of primitive hematopoietic stem cells in the stem cell compartment. The hypothesis is that primitive stem cell numbers decrease with age. The present study attempted to determine if a decline in stem cell reserve occurs with age in patients undergoing autologous hematopoietic stem cell transplant for various malignancies. Methods: Four hundred and thirty six patients who underwent autologous peripheral blood stem cell transplant from 10/97 to 12/02 were included in this retrospective analysis. Patient characteristics included: age, gender, race/ethnicity, ABO blood group, weight, height, body surface area; disease and treatment characteristics included: diagnosis at the time of transplant, bone marrow involvement by the tumor, number of chemotherapy regimens and h/o prior radiation; collection characteristics included: number of mononuclear cells/kg (MNC), CFU-GM/kg (Colony Forming Unit- Granulocyte Monocyte), CD34+ cells/kg and the ratio of CFU-GM/CD34. Results: The multivariate analysis demonstrated that MNC doses were associated with a significantly higher CFU-GM/CD34 ratio (p<0.0001) presumably reflecting the need to collect a greater number of MNC to reach a target CD34 cell dose for transplant in patients with lower stem cells reserves. However, no significant decrease in the ratio of CFU-GM/CD34 ratio was found with age and, in fact, patients aged 60 or more had a significantly lower ratio (p=0.01) as compared to the younger patients, indicating no general compromise in the stem cell reserve of this selected group of patients with aging. CONCLUSION: Older patients who were candidates for transplantation showed no significant decline in their stem cell reserve with aging. Individual susceptibilities and co-morbid conditions, rather than a general decline in stem cells may result in increased chemo-toxicity with aging. No significant financial relationships to disclose.
Time to response (TTR) and early tumor shrinkage (ETS) in recurrent glioblastoma patients treated with bevacizumab: an exploratory analysis of the prospective randomized AVAREG (ML25739) phase II study
Authors: E. Franceschi, G. Finocchiaro, V. Zagonel, M. Reni, A. Fabi, C. Caserta, M. Clavarezza, E. Maiello, G. Carteni, G. Rosti, R. Agati, A. Tosoni, E. Proietti, A. Paccapelo, A.A. Brandes
Journal: Annals of Oncology (2015)
Abstract 1741: GRP78 / BiP / HSPA5 expression and those of other chaperone proteins is rapidly degraded by OSU-03012 and Viagra exposure: Implications for anti-cancer and anti-pathogen therapies
Authors: Laurence A. Booth, Jane L. Roberts, Paul Dent
Journal: Cancer Research (2015)

Abstract We examined the interaction between the non-coxib OSU-03012 with phosphodiesterase 5 (PDE5) inhibitors to determine the role of the chaperone GRP78/BiP/HSPA5 in the response of cells. Sildenafil (Viagra) interacted in a greater than additive fashion with OSU-03012 to kill tumor cells including stem-like and anoikis resistant cells. Treatment of cells with OSU-03012/sildenafil: abolished the expression of growth factor receptors and plasma membrane drug efflux pumps; and caused a more rapid degradation of GRP78 and of other important chaperone proteins e.g. HSP27, HSP40, HSP60, HSP70 and HSP90. Decreased expression of receptors and pumps was dependent upon enhanced PERK-eIF2 signaling and blocked by GRP78 over-expression. The combination of OSU-03012/sildenafil synergized with sorafenib to kill tumor cells. GRP78 is also a protein required for human virus reproduction. Pre-treatment of mammalian cells with OSU-03012/sildenafil reduced expression of the coxsakie and adenovirus receptor in parallel with also reducing the ability of a serotype 5 adenovirus or coxsakie virus B4 to infect and to reproduce. Similar data were obtained using Cytomegalovirus and Influenza viruses. OSU-03012/sildenafil decreased the expression of: NPC1 and TIM1; LAMP1; and NTCP1, receptors for Ebola / Hepatitis A, Lassa fever, and Hepatitis B viruses, respectively. Bacteria express a GRP78 homologue and phosphodiesterases, and treatment of multi-antibiotic resistant E. coli and N. gonorrhoeae with OSU-03012/PDE5 inhibitor combinations was bactericidal and restored antibiotic sensitivity. Thus modulation of GRP78 function may be of therapeutic use in multiple human pathologies. Citation Format: Laurence A. Booth, Jane L. Roberts, Paul Dent. GRP78 / BiP / HSPA5 expression and those of other chaperone proteins is rapidly degraded by OSU-03012 and Viagra exposure: Implications for anti-cancer and anti-pathogen therapies. [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 1741. doi:10.1158/1538-7445.AM2015-1741
A QTc study of cabazitaxel in patients with advanced solid tumors.
Authors: James Lloyd Wade, Shaker R. Dakhil, Ari David Baron, Sylvie Rottey, Frederick E. Millard, Gedske Daugaard, Jean-Pascal H. Machiels, William A. Conkright, Sunil Sharma, Patricia M.M.B. Soetekouw, Jeffrey Yachnin, Lisa Sengeløv, Peter van Veldhuizen, Sanjiv S. Agarwala, TX Quyen Nguyen, Mustapha Chadjaa, Pierre Maison-Blanche
Journal: Journal of Clinical Oncology (2012)

e15115 Background: Cabazitaxel (Cbz) improves overall survival in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure, compared with mitoxantrone (HR 0.70; 95% CI 0.59–0.83; p&lt;0.0001). Following Cbz approval for the treatment of mCRPC, this study was undertaken to evaluate any effect of Cbz on the QTc interval. Methods: This prospective, multinational, open-label study (NCT01087021) enrolled pts with advanced solid tumors (without other therapeutic options). Cbz 25 mg/m² IV was administered on Day 1 Q3W. QTc and other ECG intervals were assessed on Day 1 of Cycle 1. Triplicate ECGs were obtained from 12-lead Holter recordings and concomitant serial blood samples were collected for pharmacokinetic (PK) analysis. The primary endpoint was change from baseline in the corrected QTc interval (according to the Fridericia formula [QTcF]). Results: A total of 96 pts were enrolled; 32 pts under the original protocol (6-h Holter) and 64 pts following protocol amendment 1, which extended ECG and PK monitoring (24-h Holter). Median age was 63 yrs (69.8% male), 30.5% and 57.9% of pts were ECOG PS 0 and 1 respectively; 33 pts (34.4%) had prostate cancer. Screening ECG was abnormal but not clinically significant in 39.6% of pts. The majority (n=65) of pts received ≥ 3 treatment cycles; safety and ECG parameters were evaluated in 95 and 94 pts, respectively. In the 24-h Holter group (n=63), the maximum least squares (LS) mean change from baseline in QTcF was 4.8 msec (90% CI 2.1–7.5), returning to baseline by 24 h. Similar results were observed in the overall population (n=94). At C max , Cbz concentration had no effect on QTcF change from baseline; the mean (CV%) C max (n=91) and AUC (n=92) were 276 ng/ml (63%) and 1245 ng.h/ml (82%). The LS mean change from baseline in heart rate increased up to 24 h but remained &lt; 10 beats per minute. The most common grade 3/4 AEs were neutropenia (27.4%), febrile neutropenia (12.6%), fatigue (12.6%) and dehydration (5.3%). No grade 3/4 cardiac AEs were reported. Of the 6 deaths reported, 1 (infection) was study drug related. Conclusions: Cbz had no significant effect on QTc interval in pts with advanced tumors. The Cbz safety profile is consistent with previous findings and with other taxane-based therapies.
Misfolding cationic trypsinogen variant p.L104P causes hereditary pancreatitis
Authors: Balázs Csaba Németh, Árpád V Patai, Miklós Sahin-Tóth, Péter Hegyi
Journal: Gut (2016)

We read the recent publication of Schnúr et al. [1] with great interest, in which the authors proposed that a subset of human cationic trypsinogen (PRSS1) variants cause chronic pancreatitis by inducing misfolding and endoplasmic reticulum (ER) stress rather than increased intra-pancreatic trypsin activity.PRSS1 variants that promote premature trypsinogen activation are the strongest known risk factors for chronic pancreatitis; often associated with autosomal dominant hereditary pancreatitis.ER-stress causing PRSS1 variants, on the other hand, have been mostly found in sporadic disease with no family history suggesting these variants might confer lower risk.To refute this notion, here we report a hereditary pancreatitis family of Hungarian origin carrying the heterozygous c.311T>C (p.L104P) PRSS1 variant which was recently demonstrated to induce misfolding and ER stress.[2]The index patient, his mother and first cousin developed recurrent acute or chronic pancreatitis in this family (Figure 1).Sanger sequencing was carried out on genomic DNA of all 12 live family members after informed consent was obtained.All exons of the PRSS1, SPINK1, CTRC and CPA1 genes and exons 4, 10 and 11 of the CFTR gene were sequenced in all affected subjects.In all unaffected family members PRSS1 exon 3 was sequenced.In the unaffected children of the index patient's cousin CTRC exons 2 and 3 were also analyzed.All three affected members were heterozygous for the p.L104P PRSS1 variant.Interestingly, both children of the index
Abstract 741: Anti-tumor activity and acquired resistance mechanism of dovitinib in RET-rearranged lung adenocarcinoma
Authors: Chan Woo Kang, Kang Won Jang, Byoung Chul Cho
Journal: Cancer Research (2015)

Abstract Background: RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib, a potent inhibitor of FGFR, VEGFR, and PDGFR, on RET-rearranged LADC is not known. This aims of the study are to explore anti-tumor effects and mechanism of acquired resistance of dovitinib in RET-rearranged LADC. Results: Dovitinib potently induced cell cycle arrest in G1 phase and dose-dependent suppression of phosphorylation of RET and ERK in LC-2/ad LADC cells harboring CCDC6-RET rearrangement. Selective inhibition of dovitinib on autophosphorylation of RET kinases was confirmed in HEK293 cells expressing KIF5B-RET or CCDC6-RET. In Human RTK array, dovitinib did not show significant inhibition of phosphorylation on FGFR or VEGFR in LC-2/ad cells. Dovitinib exhibited growth inhibition of LC-2/ad cells more efficiently than vandetanib, sunitinib, and sorafenib, which was confirmed in vivo xenograft models. To identify the acquired resistance mechanism, we established resistant cells to dovitinib (LC-2/ad DR) from LC-2/ad cell line. Knockdown of RET or dovitinib did not inhibit RET-induced ERK phosphorylation in LC-2/ad DR cells. Using microarray and immunoblotting, we confirmed aberrant focal adhesion kinase signaling, including c-Src. Dasatinib, a Src inhibitor, suppressed ERK phosphorylation and growth of LC-2/ad DR cells. Conclusion: Dovitinib can be a potential therapeutic option for RET-rearranged LADC. Acquired resistance to dovitinib can be overcome by targeting SRC. Citation Format: Chan Woo Kang, Kang Won Jang, Byoung Chul Cho. Anti-tumor activity and acquired resistance mechanism of dovitinib in RET-rearranged lung adenocarcinoma. [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 741. doi:10.1158/1538-7445.AM2015-741
Dic(17;18)(p11.2;p11.2) Is a Recurring Abnormality in Chronic Lymphocytic Leukemia Associated with Aggressive Disease.
Authors: Jennifer A Woyach, John C. Byrd, John Zhao, Andrew McFaddin, Amy S Ruppert, Thomas S Lin, Leslie Andritsos, Kristie A Blum, Joseph M Flynn, Jeffrey Alan Jones, Nyla A. Heerema
Journal: Blood (2009)