tbuckley/cabot-search huggingface dataset:
NCI-sponsored phase II study of [<sup>18</sup>f]fluoroestradiol (FES) as a marker of hormone sensitivity of metastatic breast cancer: Initial results.
Authors: D. A. Mankoff, H. M. Linden, J. Link, B. F. Kurland, E. K. Schubert, L. Peterson, V. K. Gadi, J. M. Specht, L. Shankar, J. F. Eary
Journal: Journal of Clinical Oncology (2011)

e11104 Background: Molecular imaging of regional ER expression in breast cancer by FES PET has been shown to indentify patients with low or absent uptake who are unlikely to respond to endocrine therapy in the salvage endocrine setting. We now report early results from a Phase II study of FES PET for patients with newly diagnosed metastatic breast cancer (MBC) conducted as part of the NCI Cancer Program Phase I/II Imaging Program and under an NCI IND. Methods: FES PET imaging was performed in 18 patients with newly diagnosed MBC arising from a documented ER+ primary tumor, prior to planned endocrine therapy. Patients also underwent FDG PET/CT to identify active areas of disease and to direct analysis of the FES PET images. Our primary endpoint for the early analysis was the fraction of patients with low or absent FES uptake, identified as one or more sites of qualitatively absent FES uptake or average FES SUV < 1.5, shown to be predictors of a lack of endocrine therapy response from prior work. We also secondarily compared FES uptake to either a metastatic lesion biopsy when obtained, clinical response to therapy in evaluable patients, or both. Results: There were no FES-related adverse events for the patients studied to date. 5/18 (28%) patients had one or more sites of qualitatively absent uptake; the same 5/18 had average SUV < 1.5. This is similar to the fraction seen in the salvage setting. Of the 5 patients with low or absent uptake, 3/5 had a metastatic biopsy that was ER-. One patient had a weakly ER+ metastatic biopsy, but had progressive disease with endocrine therapy. The other patient with a negative FES PET had a weakly ER positive biopsy but was not evaluable for clinical response; the biopsy was from the liver, a site that is not evaluable by FES PET due to normal liver metabolism. Conclusions: We conclude that early results support the potential utility of FES PET to measure regional ER expression in patients with newly diagnosed MBC and identify patients unlikely to respond to endocrine therapy.
Abstract 2679: Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma
Authors: Neel M. Fofaria, Dennie T. Frederick, Ryan J. Sullivan, Keith T. Flaherty, Sanjay K. Srivastava
Journal: Cancer Research (2015)

Abstract Melanoma harboring BRAF mutations frequently develop resistance to BRAF inhibitors, limiting the impact of treatment. The most prevalent mechanisms of acquired resistance appear to reactivate MAPK pathway. Furthermore, relatively little is known about the determinants of de novo resistance. Here, we establish such a mechanism of resistance and subsequently identified a suitable drug combination to overcome the resistance. Single treatment of BRAF mutant melanoma cell lines with vemurafenib or dabrafenib (BRAF inhibitors) alone or in combination with trametinib (MEK1/2 inhibitor) resulted in overexpression of Mcl-1. Overexpression of Mcl-1 in A375 and SK-MEL-28 by transfection completely blocked BRAF and MEK1/2 inhibitor-mediated inhibition of cell survival. Melanoma cells resistant to BRAF inhibitors showed massive expression of Mcl-1 as compared to respective sensitive cell lines. Silencing of Mcl-1 using siRNA completely sensitized resistant melanoma cells to growth suppression by BRAF inhibitors. In vivo, vemurafenib resistant A375 xenografts implanted in athymic nude mice showed substantial tumor growth inhibition when treated with a combination of vemurafenib and Mcl-1 inhibitor or siRNA. Immunohistochemistry and western blot analyses demonstrated enhanced expression of Mcl-1 and activation of ERK1/2 in vemurafenib-resistant tumors whereas level of Mcl-1 or p-ERK1/2 was diminished in the tumors of mice treated with either of the combination. Biopsied tumors from the patients treated with or resistant to BRAF inhibitors revealed overexpression of Mcl-1. These results suggest that the combination of BRAF inhibitors with Mcl-1 inhibitor may have therapeutic advantage to melanoma patients with acquired resistance to BRAF inhibitors alone or in combination with MEK1/2 inhibitors. [Supported in part by R01 grant CA129038 (to S.K.S) awarded by the National Cancer Institute]. Citation Format: Neel M. Fofaria, Dennie T. Frederick, Ryan J. Sullivan, Keith T. Flaherty, Sanjay K. Srivastava. Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma. [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 2679. doi:10.1158/1538-7445.AM2015-2679
PartitionFinder 2: New Methods for Selecting Partitioned Models of Evolution for Molecular and Morphological Phylogenetic Analyses
Authors: Robert Lanfear, Paul B. Frandsen, April M. Wright, Tereza Senfeld, Brett Calcott
Journal: Molecular Biology and Evolution (2016)

PartitionFinder 2 is a program for automatically selecting best-fit partitioning schemes and models of evolution for phylogenetic analyses. PartitionFinder 2 is substantially faster and more efficient than version 1, and incorporates many new methods and features. These include the ability to analyze morphological datasets, new methods to analyze genome-scale datasets, new output formats to facilitate interoperability with downstream software, and many new models of molecular evolution. PartitionFinder 2 is freely available under an open source license and works on Windows, OSX, and Linux operating systems. It can be downloaded from www.robertlanfear.com/partitionfinder. The source code is available at https://github.com/brettc/partitionfinder.
Contrasting Roles of Th1 and Th17 Cells in Aplastic Anaemia (AA) and Myelodysplastic Syndrome (MDS).
Authors: Shahram Y Kordasti, Sufyan M AlKhan, Ziyi Lim, Pilar Perez Abellan, Judith C W Marsh, Ghulam J Mufti
Journal: Blood (2009)
Abstract LB-284: Exome sequencing of high-risk Finnish hereditary breast and breast-ovarian cancer families
Authors: Kirsi M. Kuusisto, Tommi Rantapero, Minna Kankuri-Tammilehto, Matti Nykter, Satu-Leena Laasanen, Johanna Schleutker
Journal: Cancer Research (2015)

Background: Breast cancer has a well-established genetic component. However, genetic predisposition factors remain mostly unresolved in high-risk hereditary breast cancer families that do not carry mutations in two major susceptibility genes, BRCA1 and BRCA2. In this study, we aimed to identify rare variants contributing to disease susceptibility in the high-risk Finnish BRCA1/2-negative hereditary breast or breast-ovarian cancer families by using family-based exome sequencing approach.Methods: Germline DNA of 37 individuals from 13 high-risk hereditary breast or breast-ovarian cancer families was analyzed using targeted exome capture and massively parallel sequencing. Priority was given for rare (minor allele frequency<0.05) coding functional variants including nonsynonymous single nucleotide variants (SNVs), frameshift indels as well as stoploss/stopgain and splice-site variants. Candidate variants were selected based on the computational pathogenicity predictions by several tools and gene pathway analyses. Moreover, segregation of the variants with the disease was studied in the families. Candidate variants were confirmed by Sanger sequencing and genotyped in additional cohorts of breast cancer patients and healthy controls.Results: Altogether 21,530 rare coding functional variants (97.0% nonsynonymous SNVs, 1.6% frameshift indels, 1.4% stoploss/stopgains variants) as well as 5 splice site variants were observed in 37 individuals. Of these, 93 novel variants, that harbor genes participating in the DNA damage response pathway, were prioritized. Furthermore, only variants that were predicted to be pathogenic, were considered and they were manually studied through literature. Altogether 20 candidate variants were selected for further segregation, validation, and genotyping experiments, which are currently ongoing.Conclusions: Identified rare functional variants especially in the DNA damage response pathway genes can explain a fraction of the genetic predisposition to breast and ovarian cancer in the high-risk Finnish families.Citation Format: Kirsi M. Kuusisto, Tommi Rantapero, Minna Kankuri-Tammilehto, Matti Nykter, Satu-Leena Laasanen, Johanna Schleutker. Exome sequencing of high-risk Finnish hereditary breast and breast-ovarian cancer families. [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 LB-284. doi:10.1158/1538-7445.AM2015-LB-284
Aberrant Microtubule Organization and Wiskott-Aldrich Syndrome-like Defects in Platelets and Megakaryocytes of Profilin1-Deficient Mice
Authors: Simon Stritt, Markus Bender, Paquita Nurden, Judith van Eeuwijk, Barbara Zieger, Karim Kentouche, Harald Schulze, Henner Morbach, David Stegner, Katrin G Heinze, Sebastian Dütting, Shuchi Gupta, Walter Witke, Hervé Falet, Alain Fischer, John H. Hartwig, Bernhard Nieswandt
Journal: Blood (2014)
Research on the Mechanisms of Carcinogenesis of Ulcerative Colitis
Authors: Yan-ping Li, Tian-ming Xu, Jing-nan Li
Journal: Clinical Gastroenterology and Hepatology (2016)

To explore the possible signaling pathways involved in ulcerative colitis related colorectal cancer (UCRCC), we used interleukin-6(IL-6) and tumor necrosis factor alpha (TNF-α) to stimulate normal colonic epithelial cells and colon cancer cells. We observed the effects of both cytokines on β-catenin, which was the key protein in Wnt signaling pathway, so as to verify the possible mechanism of UCRCC occurrence. Normal colonic epithelial cell CCC-HIE and colon cancer cell HCT116 were chosen. Expression of β-catenin was detected by western blot and real-time PCR in both cell lines with and without stimulation of TNF-α and IL-6. To evaluate β-catenin expression in transcriptional and translational levels, we assessed β-catenin combined with nuclear TCF4 by co-immunoprecipitation, the transcriptional activity of β-catenin/TCF4 complex by dual luciferase reporter gene assay, and the activity of GSK3β by colorimetry assay. Furthermore, MAPK and PI3K signaling pathways were blocked by specific inhibitors PD98059 andLY294002respectively. Then added TNF-α and IL-6 separately to repeated experiments listed above. 1.The basic expression of β-catenin varies depending on cell lines. The expression of β-catenin is higher in cancer cells, like DLD-1, HCT116 and SW480, when compared with normal colonic epithelial cell CCC-HIE. No significant difference in the expression of β-catenin mRNA was noticed among various cell lines;2.The optimal stimulation condition for HCT116 is IL-6 50ng/ml working for 6h and TNF-α 50ng/ml working for 6h. Under optimal stimulations, β-catenin expression of HCT116 in both protein and mRNA levels were significantly elevated.3.When stimulated by IL-6 (50ng/ml, 6h) and TNF-α (50ng/ml, 6h) respectively, the upregulated β-catenin entered nucleus to form complex with TCF4. The β-catenin/TCF4 complex could specifically activate downstream gene transcription, and enhanced Wnt signaling pathway.4.The effect of IL-6 was blocked by LY294002 (30umol/L, 1h). The effect of TNF-α was blocked by LY294002 (30umol/L, 1h) and PD98059 (20umol/L, 1h), while LY294002played the main role.5.The activity of GSK3β was weakened when stimulated by IL-6 (50ng/ml, 6h) or TNF-α (50ng/ml, 6h) in HCT 116, which was partially recovered byLY294002(30umol/L, 1h) or PD98059 (20umol/L, 1h). IL-6 and TNF-α stimulated expression of β-catenin in both protein and mRNA levels, and weakened the activity of GSK3β.This process was mediated by PI3K and MAPK signaling pathways, while PI3K played the main role. When stimulated by IL-6 and TNF-α, the elevated β-catenin entered nucleus to form β-catenin/TCF4 complex, which specifically stimulated Wnt signaling pathway and led to target gene transcription. This study suggested that inflammatory cytokines and sporadic CRC activated Wnt signaling pathway through different methods, which provided new thoughts for the mechanisms of ulcerative colitis carcinogenesis.
Principles of Microbiology
Journal: JAMA (1941)

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Histopathological Findings on Liver Biopsies (bx) Do Not Correlate with Serum Markers of Fibrosis and Necro-Inflammation in Hemophiliacs (HEM) Co-Infected with Hepatitis C (HCV) and Human Immunodeficiency Virus (HIV).
Authors: Sean A. Fischer, Francis Carolyn, Kessler M. Craig
Journal: Blood (2005)
Abstract 1936: CoMEt: A statistical approach to identify combinations of mutually exclusive alterations in cancer
Authors: Hsin-Ta Wu, Mark D.M. Leiserson, Fabio Vandin, Benjamin J. Raphael
Journal: Cancer Research (2015)

Abstract Identifying driver mutations in cancer genomes is a significant challenge due to the mutational heterogeneity of tumors: different combinations of somatic mutations drive different tumors, even those of the same cancer type. This mutational heterogeneity arises because driver mutations target genes in signaling and regulatory pathways, each of which can be perturbed in numerous ways. We introduce CoMEt, an algorithm to identify combinations of candidate driver mutations de novo, without any prior biological knowledge (e.g. pathways or protein interactions). CoMEt searches for combinations of mutations that exhibit mutual exclusivity, a pattern expected for mutations in pathways. CoMEt uses an exact statistical test for mutual exclusivity that is less biased toward high frequency alterations than previous approaches and more sensitive in detecting combinations of lower frequency alterations. We compute the exact test using a novel tail enumeration procedure and also derive a binomial approximation. CoMEt simultaneously identifies collections of one or more combinations of mutually exclusive alterations, consistent with the observation of multiple hallmarks of cancer, and also performs simultaneous analysis of subtype-specific mutations. Finally, CoMEt uses an MCMC algorithm to sample from collections in proportion to their significance, summarizing the distribution in a marginal probability graph. We show that CoMEt outperforms other mutual exclusivity approaches on simulated and real data. We apply CoMEt to hundreds of samples from four different TCGA cancer types: gastric cancer (STAD), glioblastoma (GBM) and acute myeloid leukemia (AML), and breast cancer (BRCA). We identify multiple mutually exclusive sets within each cancer type. These include the RTK/RAS pathway in gastric cancer, the Rb and p53 signaling pathways in glioblastoma, and a collection containing multiple kinases, including FLT3, as well as the RAS genes in AML. In addition, we analyze subtype-specific mutations using CoMEt by encoding the subtype of each sample and computing exclusivity between and within subtypes. We apply this approach using four gene expression subtypes of breast cancer and identify several pathways that are enriched for mutations in specific subtypes including the PI(3)K/AKT signaling pathway in the Luminal A subtype. Many of these overlap known pathways, but others reveal novel putative cancer genes. These findings provide testable hypotheses for experimental validation. Citation Format: Hsin-Ta Wu, Mark D.M. Leiserson, Fabio Vandin, Benjamin J. Raphael. CoMEt: A statistical approach to identify combinations of mutually exclusive alterations in cancer. [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 1936. doi:10.1158/1538-7445.AM2015-1936
Phase I Trial: SABR and Ipilimumab—Letter
Authors: Susan M. Hiniker, Sunil A. Reddy, Susan M. Swetter, Susan J. Knox
Journal: Clinical Cancer Research (2017)

Tang and colleagues (September 20 issue; ref. [1][1]) report the results of a phase I clinical trial combining stereotactic ablative radiotherapy with ipilimumab in patients with metastatic solid tumors, in which 10% of patients achieved a partial response rate in lesions outside of the irradiated
158. Cryptic ATG Removal from Synthetic Introns Increase the Therapeutic Efficacy of AAV Vector Mediated Gene Transfer
Authors: Giuseppe Ronzitti, Fanny Collaud, Giulia Bortolussi, Severine Charles, Patrice Vidal, Marcelo Simon Sola, Andres Muro, Federico Mingozzi
Journal: Molecular Therapy (2016)

Inclusion of synthetic introns in adeno-associated virus (AAV) vector expression cassettes is a commonly used maneuver to drive increased transgene expression, possibly via an increased stability and/or increased nuclear translocation of mRNA. Although the positive effect of intronic sequences on transgene expression has been demonstrated in several models, less clear is whether splicing in these synthetic expression cassettes occurs with 100% efficiency and if the presence of the unspliced intron can influence the efficiency of translation of the transgene. In an effort to optimize a liver gene transfer approach to treat Crigler-Najjar (CN) syndrome, an autosomal recessive disorder caused by mutations in the UDP-glucuronosyltransferase 1 isotype A1 (UGT1A1) gene, we analyzed the sequence of a synthetic intron derived from human beta-globin intron 2 (hBB2) for motifs that may affect the transgene expression levels. This analysis revealed the presence of out of frame and in frame ATG codons before the start site of the UGT1A1 transgene. Unexpectedly, the removal of these cryptic ATGs from the intronic sequence enhanced transgene expression, which resulted in stable, long-term correction of serum bilirubin levels in animal models of CN syndrome. These results demonstrate that intron optimization increases mRNA and protein levels in vitro and enhance the efficacy of the vector in vivo. Next, we conducted a similar analysis on other intronic sequences commonly used in AAV-mediated gene transfer, showing that the removal of cryptic ATGs in the intron at the 5' of a transgene generally increases its expression. The scanning ribosome model may provide a solid explanation for our findings given that the intronic sequence is not completely removed by splicing. We thus analyzed the structure of the region at the 5' of the transgene by RT-PCR and primer elongation assay and we observed the accumulation of unspliced forms of the mRNA. We also confirmed that the presence of cryptic ATGs has a critical impact on the translation efficiency of the transgene. In conclusion, our results confirm the positive effect of an intron fused to the 5' of a transgene on its expression levels. On the other hand, our results provide evidence that the synthetic introns used in gene therapy are not spliced with 100% efficiency, thus the optimization of the sequence of the intron by removal of cryptic ATGs is important to increase the transgene expression in AAV vector-mediated gene transfer.
Liver transplantation for hepatocellular carcinoma through the lens of transplant benefit
Authors: Umberto Cillo, Alessandro Vitale, Marina Polacco, Elisa Fasolo
Journal: Hepatology (2016)

1Hepatobiliary Surgery and Liver Transplant UnitPadua University HospitalPaduaItaly *ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:Umberto Cillo, M.D., F.E.B.S.Hepatobiliary Surgery and Liver Transplant Unit, Padua University Hospitalvia Giustiniani 235128 Padua, ItalyE‐mail: [email protected]Tel: +39‐049‐821‐1846 or +39‐049‐821‐2236
Reconstitution of Endothelial Progenitor Cells after Allogeneic Bone Marrow Transplantation in Children with Malignancies.
Authors: Vittorio Rosti, Margherita Massa, Elisa Bonetti, Rita Campanelli, Valentina Meli, Claudia Castelnovi, Daniela Lisini, Daria Pagliara, Tommaso Mina, Maria E. Bernardo, Daniela Montagna, Rita Maccario, Franco Locatelli
Journal: Blood (2005)
Abstract 1342: A new approach to cancer therapy based on dynamic anchor-mediated activation of tumor-specific T cells
Authors: Chih-Ping Mao, Chien-Fu Hung, TC Wu
Journal: Cancer Research (2015)

Abstract Although it has been shown that T cells can play a key role in the control of tumor progression, tumor-specific T cells almost universally suffer from a poor capacity to recognize tumor antigen due to intricate mechanisms of central and peripheral immune tolerance. It has become clear that in order for immune-based cancer therapy to be successful, the major obstacle of immune tolerance to tumor self-antigen must be overcome. Here we report a strategy to accomplish this by engineering molecular events at the interface between antigen peptide-MHC (pMHC) and TCR. In particular, our approach is based on fusion of pMHC to the protein annexin V (ANXA5), which behaves as a ‘dynamic anchor’. The dynamic anchor, in a synchronized and synergistic manner, couples the early onset of TCR signaling by cognate pMHC with a boost in pMHC-TCR affinity, with serial pMHC binding, and with extensive TCR crosslinking. In our system, the dynamic anchor is linked to pMHC and strongly attaches to the plasma membrane of cognate T cells upon (and only upon) the early onset of TCR signaling. This anchor in turn exerts a mechanical force that stabilizes interactions at the pMHC-TCR interface. Furthermore, once the dynamic anchor attaches to these T cells, it facilitates repeated, serial pMHC binding and quickly arranges into uniform 2D matrices, thereby prompting TCR crosslinking. We found that fusion of ANXA5 to pMHC augments activation of cognate T cells by several orders of magnitude (&amp;gt;1,000-fold), bypasses the need for costimulation, and breaks tolerance against a model self-antigen in vivo. Our study opens the door to a new class of vaccination that can raise a robust immune response against low affinity tumor self-antigen. Citation Format: Chih-Ping Mao, Chien-Fu Hung, TC Wu. A new approach to cancer therapy based on dynamic anchor-mediated activation of tumor-specific T cells. [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 1342. doi:10.1158/1538-7445.AM2015-1342
Alemtuzumab (ALZ) Is an Effective Treatment for Both Primary and Relapsed Severe Paraneoplastic Pemphigus (PNP) Associated to B-Cell Chronic Lymphocytic Leukemia (CLL).
Authors: Rikke Bech, Jane Baumgartner-Nielsen, N.A. Peterslund, Torben Steiniche, Karen Bang, Mette Deleuran, Francesco d’Amore
Journal: Blood (2007)