tbuckley/cabot-search huggingface dataset:
Brief Report: Longitudinal Patterns of Response to Standard of Care Therapy for Systemic Lupus Erythematosus: Implications for Clinical Trial Design
Authors: Mimi Kim, Joan Merrill, Kenneth Kalunian, Bevra Hahn, Anita Roach, Peter Izmirly
Journal: Arthritis & Rheumatology (2016)

To evaluate longitudinal patterns of response to standard of care for systemic lupus erythematosus (SLE) in clinical trials and to identify characteristics that differentiate nonresponders from persistent responders.Data on 147 patients with moderately to severely active SLE without acute nephritis who were treated with placebo plus standard of care in two 52-week phase II/III trials were obtained from the Collective Data Analysis Initiative of the Lupus Foundation of America. Cross-sectional and longitudinal analyses of British Isles Lupus Assessment Group (BILAG)-based responses (improvement in all baseline A or B scores without new flare) were performed. Baseline characteristics that discriminated persistent responders from nonresponders were identified using logistic regression.Cross-sectional response rates decreased from 46% to 37% between 12 and 52 weeks. The overall rate of complete and sustained response, i.e., response at all visits, was only 14.3% (95% confidence interval 8.6-19.9%). Agreement between response status at 12 weeks and 36-52 weeks was low (κ = 0.15-0.29), and only 31% of initial 12-week responders maintained response at all subsequent visits. Baseline factors predictive of persistent response to standard of care included fewer organs with active disease, high C3 levels, and type of background therapy.Use of sustained rather than landmark response may reduce high placebo response rates in SLE trials that continue aggressive standard of care. Further exploration to assess the power of this end point to improve discrimination between active and placebo arms is indicated. Lack of temporal stability in response highlights a potential weakness with shorter studies. Rates of response to standard of care are affected by the severity of the disease and the aggressiveness of background immunosuppressive treatments.
M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss
Authors: Sophie J. Bradley, Julie-Myrtille Bourgognon, Helen E. Sanger, Nicholas Verity, Adrian J. Mogg, David J. White, Adrian J. Butcher, Julie A. Moreno, Colin Molloy, Timothy Macedo-Hatch, Jennifer M. Edwards, Jurgen Wess, Robert Pawlak, David J. Read, Patrick M. Sexton, Lisa M. Broad, Joern R. Steinert, Giovanna R. Mallucci, Arthur Christopoulos, Christian C. Felder, Andrew B. Tobin
Journal: Journal of Clinical Investigation (2016)

The current frontline symptomatic treatment for Alzheimer's disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR-selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.
Maintenance Lenalidomide for Adults Aged 18-65 Years with AML in First Complete Remission after Intensive Chemotherapy: A Phase Ib Dose-Escalation Study of the Australasian Leukemia and Lymphoma Group (ALLG)
Authors: Andrew Wei, Ian D Lewis, Uwe Hahn, Gavin Cull, Anoop Enjeti, Philip Campbell, Simon Z. He, Mark S Hertzberg, John F Seymour
Journal: Blood (2014)
Exposure of Cultured Human Mesenchymal Stem Cells to Chemotherapy Induces An Early and Permanent Telomere Loss: Biological and Clinical Implications
Authors: Stefano Buttiglieri, Tiziana Spatola, Marco Ruella, Alessandra Risso, Melissa Montanini, Silvia Tracchi, Lorenzo Silengo, Enrico Avvedimanto, Corrado Tarella
Journal: Blood (2010)
Baseline Body Mass Index Among Children and Adults Undergoing Allogeneic Hematopoietic Cell Transplantation: Clinical Characteristics and Outcomes
Authors: Michael Gleimer, Yumeng Li, Lawrence Chang, Sophie Paczesny, David Hanauer, David Frame, Craig A. Byersdorfer, Pavan Reddy, Thomas M. Braun, Sung Won Choi
Journal: Blood (2014)
Abstract AS15: DNA promoter hypermethylation of HIST1H2BB as a diagnostic and prognostic biomarker for ovarian cancer
Authors: Blanca L. Valle, Elisabetta Kuhn, David Sidransky, Rafael Guerrero-Preston
Journal: Clinical Cancer Research (2015)

Abstract Background: Until recently, epithelial ovarian cancers were thought to arise from the ovarian surface epithelial cells. However, recent studies suggest that the majority of high grade serous carcinomas (HGSCs) arise from lesions in the fallopian tubes. DNA promoter hypermethylation of certain genes is often an early event in tumorigenesis, and it can be detected in blood and other bodily fluids, making it a feasible biomarker strategy for early detection of tumors. Purpose of study: Therefore, we sought to determine the methylation profile of HGSCs as compared to fallopian tube epithelium. Using the Infinium HumanMethylation 450 Array, that permits to quantitatively assess over 450,000 methylation sites, within and outside of CpG islands and more than 20,000 genes per sample, at single-nucleotide resolution, we have obtained the genome-wide methylation profile of HGSC and fallopian tubal epithelium. We conducted a pilot study by comparing the global methylation in 12 HGSC tissue samples to 15 fallopian tube epithelium samples. In addition, we compared the methylation profile among long-term survivors (more than 5 years) and short-term survivors (2-3 years) of HGSCs. Results: Our results identified the HIST1H2BB promoter as the most differentially methylated region when comparing HGSC with normal fallopian tube samples. Furthermore, we also found that HIST1H2BB is differentially methylated in HGSC patients with long-term survival when compared to patients with short-term survival. Conclusions: Taken together, these results support the potential of HIST1H2BB promoter hypermethylation as a diagnostic and prognostic biomarker. Our findings could lead to the development of a biomarker for the diagnosis and/or prognosis of ovarian cancer and could contribute to the current understanding of the mechanisms of progression in ovarian cancer. Citation Format: Blanca L. Valle, Elisabetta Kuhn, David Sidransky, Rafael Guerrero-Preston. DNA promoter hypermethylation of HIST1H2BB as a diagnostic and prognostic biomarker for ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS15.
Determinants of Persisting Thrombocytopenia In Patients with Type 1 Gaucher Disease Treated with Alglucerase/Imiglucerase for 4–5 Years
Authors: Maria D. Cappellini, Nadia Belmatoug, Alex Cole, Stephan vom Dahl, Patrick Deegan, Jack Goldblatt, Barry E. Rosenbloom, Anna Tylki-Szymañska, Neal J. Weinreb, Ari Zimran, Carla Hollak
Journal: Blood (2010)
480. In Vivo Gene Targeting for HIV Immunoprophylaxis using Promoterless AAV Without Nucleases
Authors: Adi Barzel, Sangeetha Satheesan, Huang Yong, Chen Y. Jenny, Rossi John, Kay A. Mark
Journal: Molecular Therapy (2015)

Expression of broadly neutralizing antibodies (bNAbs) from AAV can provide protection against infections by different pathogens, including: HIV, Influenza and Plasmodium falciparum. Wide use of such vectored immunoprophylaxis will depend on the safety profile and on the duration of the immune effect. Alarmingly, AAV injection in neonatal mice has been associated with subsequent development of hepatocellular carcinoma (HCC) and adenoma (HCA) in a manner that is strictly dependent on the vector borne promoter. In addition, when the antibody is expressed from an AAV episome, the duration of prophylaxis might be limited by vector dilution when transfected cells divide. Alternatively, nucleases can be used to promote stable transgene expression, but these may be associated with adverse effects such as immunogenicity and genotoxicity. Recently, we have shown that AAV could be used for promoterless gene targeting without nucleases for stable expression of coagulation factor IX in the context of hemophilia treatment (Barzel et al. Nature 2015). Here, we apply a similar methodology to target the integration of a gene coding for a bNAb against HIV to be driven upon integration by the strong Albumin promoter in the liver. Tail vein injection of our vector, coding for the VRC01 anti HIV bNAb, at 1E12 vector genomes per mouse into adult B6 mice leads to high (250 ng/ml) and stable levels of the bNAb in the plasma of the mice. We further show that the bNAb from the plasma is highly effective in binding the HIV envelope glycoprotein: gp120. In order to assess the potential of our approach in HIV prophylaxis and cure we have transplanted neonatal NOD/SCID/gc null (NSG) mice with human CD34+ HSC cells (1E6 cells/pup). Mice that are effectively reconstituted with human immune cells will be challenged with HIV (100-200ng p24 units) either prior to injection with our bNAb coding AAV (to assess therapeutic potential) or following such an injection (to assess prophylactic potential). For HIV and other infections where conventional vaccination is challenging, stable immunoprophylaxis using a promoterless AAV coding for a bNAb may constitute a safe and efficient alternative.
CEBPA Germline Mutation Screening in Cytogenetically Normal Acute Myeloid Leukemia with Somatically Acquired CEBPA Mutations.
Authors: Andrea Corbacioglu, Stefan Fröhling, Corinna Mendla, Karina Eiwen, Marianne Habdank, Hartmut Döhner, Richard F. Schlenk, Konstanze Döhner
Journal: Blood (2007)
Abstract 2158: PDK1-dependent activation of RSK is an absolute requirement for PI3K oncogenic activity in the thyroid gland
Authors: Arturo Orlacchio, Antonio Di Cristofano
Journal: Cancer Research (2015)

Abstract Aberrant activation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway plays a key role in thyroid tumorigenesis, particularly in follicular thyroid cancer (FTC) and anaplastic thyroid cancer (ATC). Accordingly, conditional deletion of Pten in the mouse thyroid epithelium induces constitutive activation of the PI3K/AKT pathway, and causes thyroid hyperplasia at birth that progresses to invasive and metastatic follicular carcinoma. This phenotype is dramatically accelerated by simultaneous deletion of Trp53, leading to the development of ATC, or activation of Kras, leading to poorly differentiated carcinomas. The PDK1 kinase plays a central role in the PI3K signaling cascade, acting as a master regulator of PI3K downstream effectors belonging to the AGC kinases family, such as AKT and S6K1. Additional AGC kinases are controlled by PDK1 independent of PI3K activity. PDK1 possesses a substrate docking site, the “PIF pocket”, required for the phosphorylation of most AGC kinases (including S6K, PKC, SGK, and RSK) but not of AKT. The L155E PDK1 mutant disrupts the PIF pocket and impairs AGC kinase activation, without any effect on AKT activation. Thanks to this differential mechanism of substrate activation, we are defining the relative contribution of AKT and other PDK1 targets to the neoplastic transformation process in Pten-/- thyrocytes. Surprisingly, in vivo disruption of the PIF-pocket completely abrogates neoplastic transformation of Pten-/- thyroids, even in the face of AKT constitutive activation. This finding supports the hypothesis that the linear PI3K-AKT pathway is not sufficient to drive thyroid transformation and that concomitant activation of additional PDK1-dependent pathways is absolutely required. We now show that RSK family members (RSK1-3) are essential components of this PDK1-dependent accessory pathway. Remarkably, RSK3 levels in the thyroid are increased in the absence of Pten, and RSK activity in thyroid cells is abrogated when PDK1 PIF-pocket is mutated. Genetic and pharmacological inhibition of RSK drastically impairs [Pten,Trp53]-/- ATC cell proliferation both in vitro and in vivo, in syngeneic allograft models. Taken together, our data identify a new signaling cascade that is essential for neoplastic transformation of thyroid epithelial cells, and thus a new critical candidate for drug development. Citation Format: Arturo Orlacchio, Antonio Di Cristofano. PDK1-dependent activation of RSK is an absolute requirement for PI3K oncogenic activity in the thyroid gland. [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 2158. doi:10.1158/1538-7445.AM2015-2158
337. CRISPR/Cas9 Mediated Highly Efficient Genome Engineering in Mouse Embryos
Authors: Khurshida Begum, Bert W. O'Malley, Francesco J. DeMayo, Paul Overbeek
Journal: Molecular Therapy (2015)

CRISPR/Cas9 is an RNA-based adaptive immune system used by bacteria and archaea to cleave foreign nucleic acids (e.g. bacteriophage DNA). This system has been adapted as a tool to edit mammalian genes with high efficiency and specificity. Here, we describe our use of the CRISPR/Cas9 system to achieve targeted gene knock outs and targeted gene repair in one cell stage mouse embryos. We have efficiently mutated tyrosinase (a coat color gene), p53 (a tumor suppressor gene), and Cacna1a (a voltage-gated ion channel gene) in mouse embryos by injection of Cas9 mRNA plus either a single or paired guide RNAs (sgRNAs). Single sgRNAs typically induced deletions of 1 bp to several hundred bp at their target site whereas paired sgRNAs generated localized deletions at high efficiency. For gene repair, we used 700 bp to 2 kb donor DNAs and a single sgRNA to promote gene correction by homology-mediated repair. Our experimental data revealed 8 to 18% efficiency of gene correction. When we used two sgRNAs to target a single exon, all of the newborn mice from one experiment showed targeted therapy for an inherited genetic disorder, albinism. No one has previously published a protocol that has achieved gene repair with this level of effectiveness. Our results confirm that the CRISPR/Cas9 system can be used for efficient gene targeting and gene repair in vivo.
Abstract 36: Cross-talk of the cytokine pathways in cancer progression
Authors: Andrei V. Bakin, Michelle Limoge, Amy Beattie
Journal: Cancer Research (2015)

Abstract Anti-inflammatory TGFβ and pro-inflammatory TNFα/IL1β cytokines are among the major cytokines in tumor microenvironment that drive cancer progression and metastasis. Published studies implicate TGFβ-activated protein kinase TAK1 as an important mediator in cytokine-driven tumor invasion and metastasis. TAK1 is an ubiquitin-dependent protein kinase that can activate NFκB and MAPK signaling cascades. This study addressed several foremost questions such as a) what signaling cascade is activated by the cytokine crosstalk and what are major transducers and effectors of this crosstalk; b) whether a crosstalk is associated with a specific genetics or cell type, for example a specific molecular subtype of breast cancer. Molecular profiling study identified a TAK1-dependent molecular signature and revealed a close association of the TAK1 molecular signature with triple-negative breast cancers. The cytokines synergistically stimulated expression of a set of pro-invasive and pro-metastatic molecules including matrix metalloproteinase 9 (MMP9). shRNA screening study identified specific molecular transducers of TAK1 that mediate MMP9 expression and cell motility. In particular, our study found an essential role of RELA but not NFKB2 in regulation of MMP9. Addressing a signaling crosstalk, we found that TGFβ and TNFα robustly activated a significant level of canonical signaling via SMADs and RELA/NFkB, respectively, but neither of these cytokines cross-talked to stimulate canonical transducers for a respective cytokine. Instead, TGFβ and TNFα synergized in activation of MAPK signaling and up-regulation of specific transcription targets of the cytokine pathways. In summary, anti-inflammatory TGFβ and pro-inflammatory TNFα cytokines synergize in stimulation of tumor invasion and metastatic potential by cooperating in TAK1-mediated regulation of MAPK signaling and expression of target genes. A TAK1 molecular signature is associated with triple-negative breast cancers. Citation Format: Andrei V. Bakin, Michelle Limoge, Amy Beattie. Cross-talk of the cytokine pathways in cancer progression. [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 36. doi:10.1158/1538-7445.AM2015-36
CYP1A1*2A polymorphism as a prognostic factor for the advanced lung cancer patients treated with EGFR-TKI and its correlation with EGFR mutation.
Authors: Q. Nie, S. An, X. Yang, W. Zhong, R. Liao, J. Yang, X. Zhang, Z. Chen, J. Su, Z. Xie, Y. Huang, Y. L. Wu
Journal: Journal of Clinical Oncology (2011)

e13098 Background: Now EGFR mutation had confirmed as a predictor for NSCLC patients treated with EGFR-TKI. Our study aimed to detect the correlation among EGFR mutations and polymorophisms of EGFR and CYP1A1 genes and their associations with clinical outcome of NSCLC patients treated with EGFR-TKI. Methods: We evaluated the EGFR mutations, the genotypes for Intron1 (CA) n repeat, R497K genetic polymorphisms in EGFR gene and *2A (3801T>C), *2C (2455A>G) single nucleotide polymorphisms (SNPs) in CYP1A1 gene by PCR-RFLP, DNA sequence methods in 70 Chinese patients with NSCLC. Genetic polymorphisms were correlated to EGFR mutations. As to subgroup of 36 patients who accepted the EGFR-TKI , the associations among the EGFR mutations, the genomic polymorphisms of EGFR and CYP1A1 and clinical outcome of the EGFR-TKI were analyzed. Results: The EGFR Intron1 (CA) n and CYP1A1*2A, *2C polymorphisms were correlated with EGFR mutations (P=0.006, P=0.001, and P=0.008, respectively) and all the three polymorphisms were also associated with EGFR 19 exon delection (P=0.007, P=0.033, and P=0.006, respectively); whereas the multivariate analysis demonstrated that only CYP1A1*2A polymorphism was associated with EGFR mutations (P=0.002). For 36 patients treated with EGFR-TKI, the EGFR mutation and CYP1A1*2A polymorphism showed correlation with clinical response of EGFR-TKI(P=0.000, P=0.007); and patients’ overall survival(P=0.032, P=0.000); However, the multivariate analysis confirmed that the EGFR mutation is the most effective predictive factor (P=0.044 ), and the Cox regression analysis showed that CYP1A1*2A polymorphism is independent prognostic factor for patients treated with EGFR-TKI (P=0.003). Conclusions: The study demonstrate that the EGFR Intron1 (CA)n repeat polymorphism and the CYP1A1*2A , *2C polymorphisms are correlated with EGFR somatic mutations; for NSCLC patients with -TKI therapy, the EGFR mutation is still the most effective predictor for clinical response of EGFR-TKI, whereas the CYP1A1*2A polymorphism is a independent prognostic factor. The results of this study need large size numbers to confirm.
Platelet-Derived Factors Allow Human Mesenchymal Stem Cells to Spontaneously Undergo Endochondral Bone Differentiation and Provide Bone Marrow Support in a Xenogenic In Vivo Model
Authors: Nathalie Etchart, Andreas Reinisch, Anna Ortner, Margareta Frühwirth, Rokhsareh Rohban, Claudia Url, Katharina Schallmoser, Christine Beham-Schmid, Dirk Strunk
Journal: Blood (2011)
Drug-sensitiveFGFR3 mutations in lung adenocarcinoma
Authors: P. Chandrani, K. Prabhash, R. Prasad, V. Sethunath, M. Ranjan, P. Iyer, J. Aich, H. Dhamne, D.N. Iyer, P. Upadhyay, B. Mohanty, P. Chandna, R. Kumar, A. Joshi, V. Noronha, V. Patil, A. Ramaswamy, A. Karpe, R. Thorat, P. Chaudhari, A. Ingle, A. Choughule, A. Dutt
Journal: Annals of Oncology (2016)

Lung cancer is the leading cause of cancer-related deaths across the world. In this study, we present therapeutically relevant genetic alterations in lung adenocarcinoma of Indian origin.Forty-five primary lung adenocarcinoma tumors were sequenced for 676 amplicons using RainDance cancer panel at an average coverage of 1500 × (reads per million mapped reads). To validate the findings, 49 mutations across 23 genes were genotyped in an additional set of 363 primary lung adenocarcinoma tumors using mass spectrometry. NIH/3T3 cells over expressing mutant and wild-type FGFR3 constructs were characterized for anchorage independent growth, constitutive activation, tumor formation and sensitivity to FGFR inhibitors using in vitro and xenograft mouse models.We present the first spectrum of actionable alterations in lung adenocarcinoma tumors of Indian origin, and shows that mutations of FGFR3 are present in 20 of 363 (5.5%) patients. These FGFR3 mutations are constitutively active and oncogenic when ectopically expressed in NIH/3T3 cells and using a xenograft model in NOD/SCID mice. Inhibition of FGFR3 kinase activity inhibits transformation of NIH/3T3 overexpressing FGFR3 constructs and growth of tumors driven by FGFR3 in the xenograft models. The reduction in tumor size in the mouse is paralleled by a reduction in the amounts of phospho-ERK, validating the in vitro findings. Interestingly, the FGFR3 mutations are significantly higher in a proportion of younger patients and show a trend toward better overall survival, compared with patients lacking actionable alterations or those harboring KRAS mutations.We present the first actionable mutation spectrum in Indian lung cancer genome. These findings implicate FGFR3 as a novel therapeutic in lung adenocarcinoma.