tbuckley/cabot-search huggingface dataset:
Application of interphase cytogenetics for the detection of t(11;14)(q13;q32) in mantle cell lymphomas
Authors: R Siebert, P Matthiesen, S Harder, Y Zhang, A Borowski, R Zühlke-Jenisch, H Plendl, S Metzke, S Joos, E Zucca, K Weber-Matthiesen, E Roggero, W Grote, B Schlegelberger
Journal: Annals of Oncology (1998)

The chromosomal translocation t(11;14)(q13;q32) is the hallmark of mantle cell lymphoma (MCL) in which it can be detected cytogenetically in about 75% of cases. The t(11;14) translocation juxtaposes the bcl-1 locus in chromosome band 11q13 next to the IgH locus in chromosome band 14q32 and, thus, leads to deregulation of the cell cycle regulatory protein cyclin D1, which is encoded by the CCND1 gene localized at the telomeric border of the bcl-1-locus. MCL has the worst prognosis of all low-grade non-Hodgkin's lymphomas (NHL). In some instances, however, histopathologic differentiation between MCL and other low-grade B-cell NHL is difficult. Therefore, detection of the t(11;14) translocation is of essential diagnostic value for the risk-adjusted management of patients with MCL. Unfortunately, chromosome analyses are frequently hampered by the low yield and quality of tumor metaphases. As the 11q13 breakpoints are scattered over a region of more than 120 kb the application of molecular genetic techniques is also limited.We established an interphase fluorescence in situ hybridization (FISH) approach for the detection of the t(11;14) translocation by use of a cosmid probe hybridizing to the IgH constant region and a YAC spanning the bcl-1 region. Cells containing a t(11;14) translocation show a colocalisation of the signals for IgH and bcl-1. Eight control samples and 15 MCL specimens were investigated.According to our control studies, samples containing more than 10% of cells with this signal constellation can be diagnosed as carrying a clonal t(11;14) translocation. All eleven MCL found to carry the t(11;14) translocation by chromosome analysis were positive in our FISH assay. Additionally, two of four MCL lacking a clonal t(11;14) translocation by chromosome analysis were shown to carry this aberration in 14% and 37% of interphase nuclei. Southern blot data indicate that our FISH assay reliably detects the t(11;14) translocation irrespective of the location of the breakpoints within the bcl-1 region.The described interphase FISH assay provides a reliable and routinely applicable tool for diagnosis of the t(11;14) translocation.
Scottish Ebola nurse is readmitted to isolation unit in London
Authors: Jacqui Wise
Journal: BMJ (2015)

Pauline Cafferkey, the Scottish nurse who contracted Ebola in Sierra Leone last December, has been readmitted to an isolation unit in London after an “unusual late complication.”

Experts have warned that the Ebola virus may persist in asymptomatic individuals and be a potential reservoir of the virus, although they added that the risk of transmission from these individuals seemed to be very low.

The virus can persist for weeks or even months in some parts of the body, such as the eye or semen, long after it has disappeared from the blood. In August the World Health Organization said that around half …
A validated gene regulatory network and GWAS identifies early regulators of T cell–associated diseases
Authors: Mika Gustafsson, Danuta R. Gawel, Lars Alfredsson, Sergio Baranzini, Janne Björkander, Robert Blomgran, Sandra Hellberg, Daniel Eklund, Jan Ernerudh, Ingrid Kockum, Aelita Konstantinell, Riita Lahesmaa, Antonio Lentini, H. Robert I. Liljenström, Lina Mattson, Andreas Matussek, Johan Mellergård, Melissa Mendez, Tomas Olsson, Miguel A. Pujana, Omid Rasool, Jordi Serra-Musach, Margaretha Stenmarker, Subhash Tripathi, Miro Viitala, Hui Wang, Huan Zhang, Colm E. Nestor, Mikael Benson
Journal: Science Translational Medicine (2015)

Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.
A Gene Encoding a DUF247 Domain Protein Cosegregates with the<i>S</i>Self-Incompatibility Locus in Perennial Ryegrass
Authors: Chloé Manzanares, Susanne Barth, Daniel Thorogood, Stephen L. Byrne, Steven Yates, Adrian Czaban, Torben Asp, Bicheng Yang, Bruno Studer
Journal: Molecular Biology and Evolution (2015)

The grass family (Poaceae), the fourth largest family of flowering plants, encompasses the most economically important cereal, forage, and energy crops, and exhibits a unique gametophytic self-incompatibility (SI) mechanism that is controlled by at least two multiallelic and independent loci, S and Z. Despite intense research efforts over the last six decades, the genes underlying S and Z remain uncharacterized. Here, we report a fine-mapping approach to identify the male component of the S-locus in perennial ryegrass (Lolium perenne L.) and provide multiple evidence that a domain of unknown function 247 (DUF247) gene is involved in its determination. Using a total of 10,177 individuals from seven different mapping populations segregating for S, we narrowed the S-locus to a genomic region containing eight genes, the closest recombinant marker mapping at a distance of 0.016 cM. Of the eight genes cosegregating with the S-locus, a highly polymorphic gene encoding for a protein containing a DUF247 was fully predictive of known S-locus genotypes at the amino acid level in the seven mapping populations. Strikingly, this gene showed a frameshift mutation in self-compatible darnel (Lolium temulentum L.), whereas all of the self-incompatible species of the Festuca–Lolium complex were predicted to encode functional proteins. Our results represent a major step forward toward understanding the gametophytic SI system in one of the most important plant families and will enable the identification of additional components interacting with the S-locus.
Discovery of oncoproteins as cancer biomarkers and molecular targets for antibody-based immunotherapy.
Authors: Y. Daigo, A. Takano, Y. Nakamura
Journal: Journal of Clinical Oncology (2011)

10568 Background: Identification of cancer-specific oncoproteins is an effective approach to develop new diagnostics and therapeutics. Methods: We have established a strategy as follows to identify new oncoproteins; i) To identify genes overexpressed in 120 clinical lung cancers using the cDNA microarray representing 27,648 genes, ii) To verify the candidate genes for their low expression in 23 normal tissues by northern-blotting, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering 279 non-small cell lung cancers (NSCLCs), iv) To verify whether they are essential for the invasion of cancer cells by Matrigel invasion assays, and v) To measure their serum protein levels by ELISA using two independent sets of patients’ s samples. Results: We identified 30 oncoproteins and selected a secreted protein, Dickkopf-1 (DKK1). A high level of DKK1 expression was associated with poor prognosis for patients with non-small cell lung cancer (NSCLC; P=0.0039, N=279), and multivariate analysis confirmed its independent prognostic value. We established an ELISA to measure serum levels of DKK1 and found that serum DKK1 levels were significantly higher in serologic samples from 1252 patients with various cancers than in 207 healthy controls. The proportions of the serum DKK1-positive cases was 70% for NSCLC, 69.4% for SCLC, 63% for esophageal cancer, 50.8% for pancreatic cancer, 38.6% for gastric cancer, 53% for hepatocellular carcinoma, 29.9% for bile duct cancer, 65.1% for breast cancer, and 59.3% for cervical cancer, while only 10 (4.8%) of 207 healthy volunteers were falsely diagnosed, which was superior to conventional tumor markers such as carcinoembryonic antigen. The diagnostic value of serum DKK1 was validated in additional sets of samples. In addition, exogenous expression of DKK1 increased the invasive activity of mammalian cells. Anti-DKK1 antibody inhibited the invasive activity and the growth of cancer cells in vitro and in vivo without any obvious toxicity. Conclusions: DKK1 is a potential target for the development of a highly sensitive biomarker as well as new drugs such as nucleic acid drugs, therapeutic antibodies, and cancer vaccines.
Prediction of response to FOLFOX in metastatic colorectal cancer by mtTFA
Authors: Y. Yoshida, J. Hasegawa, R. Nezu, Y. Kim, M. Hirota, K. Yoshikawa, H. Ohashi, K. Kawano, H. Izumi, K. Kohno
Journal: Journal of Clinical Oncology (2008)

15079 Background: We previously reported that mitochondrial transcription factor A (mtTFA) preferentially recognizes cisplatin- damaged DNA via physical interaction with p53 and is upregulated by the treatment with cisplatin and 5-FU (Yoshida et al, Cancer Res. 2003). The aim of this study was to evaluate whether expression of mtTFA and/or p53 predicts clinical outcome in patients with metastatic colorectal cancer treated with modified FOLFOX6 (mFOLFOX6). Methods: From January 2006 to May 2007, 33 patients who had metastatic lesions from colorectal cancer treated with mFOLFOX6 at the Osaka Rosai Hospital were included in this study. They consisted of 18 women (54.5%) and 15 men (45.5%), with a median age of 64 years (29–84). Patients were treated with oxaliplatin 85mg/m2 plus leucovorin 200mg/m2 as a 2-h infusion at day 1, followed by 5-FU bolus 400mg/m2 and 46-h continuous infusion of 2400 mg/m2. Treatment was repeated in 2-week intervals for at least 5 cycles. The expressions of mtTFA and p53 of resected primary tumors were examined by immunohistochemistry. Results: Among 33 patients, 13 patients (CR 1, PR 12) achieved a confirmed response to therapy. The positive rates was 42.4% (14/33; CR 1, PR 1, SD/PD 12) for mtTFA and 57.6% (19/33; CR 1, PR 6, SD/PD 12) for p53, respectively. Strong expression of mtTFA was detected in 2 of 13 CR/PR (15.4%) and in 12 of 20 SD/PD (60%), indicating that the expression of mtTFA was significant negative correlation with respond to chemotherapy (P=0.011). On the other hand, there were no significant differences between response to chemotherapy and p53 expression pattern (P=0.727). Conclusions: Immunohistochemical studies for mtTFA may be useful in prediction of response to mFOLFOX6. No significant financial relationships to disclose.
Randomized phase II trial of neoadjuvant vs. adjuvant docetaxel plus cisplatin in patients with locally advanced gastric carcinoma: An interim analysis
Authors: J. Chun, S. Park, H. Kim, Y. Kim, K. Ryu, J. Lee, J. Lee, C. Kim, J. Lee, J. Bae
Journal: Journal of Clinical Oncology (2006)

4030 Background: The perioperative treatment strategy for locally advanced gastric cancer (LAGC) has not been clearly established. We conducted a randomized phase II study of neoadjuvant vs. adjuvant docetaxel/cisplatin (DC) chemotherapy in LAGC. Methods: LAGC was radiographically defined by CT and PET. Pts were randomized to receive neoadjuvant or adjuvant DC (docetaxel 36 mg/m 2 + cisplatin 40 mg/m 2 on D1, D8, q 3 wks X 3 cycles) according Japanese staging system (IIIa, IIIb, IV M-, and IV with a single M+ node). Results: All planned 88 pts in 44 per each arm were enrolled between Jan 2003 and Nov 2005. One pt was not eligible. The median age was 57 yrs vs. 58 yrs, PS 1 90.7% vs. 84.1%, and stage III/IV 72.1%/27.9% vs. 70.5%/29.5% in the neoadjuvant and adjuvant arm, respectively. Clinical response rate of 42 evaluable pts in neoadjuvant arm according to WHO criteria was 64.3% (95% CI 49.8–78.8%) with CR 2.4%, PR 61.9%, SD 31.0%, and PD 4.7%. There was no treatment related death. Comparison of G3/4 adverse events in neoadjuvant vs. adjuvant arm were; leukopenia 14.0% vs. 32.4% (p=0.04), neutropenia 37.2% vs. 62.2% (p=0.02), febrile neutropenia 0% vs. 2.7%, diarrhea 2.3% vs. 10.8%, stomatitis 2.3% vs. 8.1% (p=NS). There were no difference in the postoperative morbidity and the duration of hospital stay between both arms, but surgery was delayed in one pt who developed tuberculosis during neoadjuvant chemotherapy. Downstaging of the T stage could be obtained in 6 (14.3%) among 42 evaluable pts in neoadjuvant arm, according to EUS. Conclusions: Both neoadjuvant and adjuvant DC chemotherapy were relatively well tolerated in LAGC, with the lower incidence of G3/4 toxicities in neoadjuvant arm. Neoadjuvant DC showed a high response rate and a modest downstaging effect. (Supported by National Cancer Center Grant; Docetaxel was provided by Sanofi Aventis Korea) [Table: see text] No significant financial relationships to disclose.
A phase I/II study of CR011-vcMMAE, an antibody toxin conjugate drug, in patients with unresectable stage III/IV melanoma
Authors: P. Hwu, M. Sznol, H. Kluger, L. Rink, K. B. Kim, N. E. Papadopoulos, D. Sanders, P. Boasberg, C. E. Ooi, O. Hamid
Journal: Journal of Clinical Oncology (2008)

9029 Background: Glycoprotein NMB (GPNMB) is highly expressed in melanoma. CR011-vcMMAE is comprised of a human monoclonal antibody against the extracellular domain of GPNMB conjugated to the microtubule toxin monomethyl auristatin E (MMAE). CR011- vcMMAE has potent anti-tumor activity in vitro (IC50 1.25–5 μg/ml) and in animal models. A first-in-man phase 1 trial was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of CR011-vcMMAE administered intravenously every 3 weeks. Methods: Eligible patients (pts) had unresectable stage III/IV melanoma and ≤ 1 prior cytotoxic therapy. CR011-vcMMAE doses were escalated in successive cohorts of 3–6 pts by 100% until the first drug-related grade 2 adverse event (AE), then by 40%. Results: 28 pts (median age 64.5 years, range 47–81 years) were treated in 9 cohorts (0.03 - 2.63 mg/kg) for a median of 4 cycles (range 2–14 cycles). The most frequent AEs of any grade were pain (45%), diarrhea (40%), fatigue (35%), nausea (35%), and rash/erythema (32%). Doses ≥ 1.34 mg/kg (n=10) were associated with a higher incidence of rash (n=6) and grade 3/4 neutropenia (n=5). At 2.63 mg/kg 3/3 pts developed grade 2–3 rash ± desquamation, considered a dose-limiting toxicity in one pt. PK analysis showed dose-dependent exposure of total antibody and terminal half-life of 43 hours at 2.63 mg/kg. Maximum free levels of MMAE were ∼ 1.3% of maximum levels of total antibody. In 27 pts with post-baseline scans, 1 had a partial response (PR) and 14 (52%) had stable disease (SD) at first evaluation (8 pts with SD ≥ 11 weeks and median duration 15 weeks, range 11–41 weeks). Of the 9 assessable pts at doses ≥ 1.34 mg/kg, there was 1 PR and 7 (78%) SD at first evaluation, including one pt with reduction in liver and splenic metastases. Three of these 9 pts continue treatment on study. Conclusions: The MTD for CR011-vcMMAE is ≤ 2.63 mg/kg every 3 weeks. Dose-dependent anti-tumor activity was observed. A Phase II expansion is planned at the MTD. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration CuraGen Corporation Curagen
Cyclin D1 repression as a marker of erlotinib response in aerodigestive tract cancers
Authors: W. J. Petty, K. H. Dragnev, V. A. Memoli, T. H. Davis, W. C. Nugent, I. R. Williams, K. K. Iwata, M. Hamilton, J. R. Rigas, E. Dmitrovsky
Journal: Journal of Clinical Oncology (2004)

3093 Background: Erlotinib (OSI-774, Tarceva™) is an epidermal growth factor receptor (HER1) tyrosine kinase inhibitor (TKI) with clinical activity in lung cancer. Mechanisms engaged during clinical response to erlotinib need to be determined. Methods: Using cultured human bronchial epithelial cells, in vitro effects of erlotinib were investigated. Cells were treated with erlotinib and effects on HER1 and cell cycle regulatory proteins were determined by immunoblot analyses. To evaluate further molecular changes in patient tumor specimens, a phase II pharmacokinetic and pharmacodynamic trial was performed in patients with aerodigestive tract cancers, who were candidates for serial tumor sampling. Five patients were enrolled and 4 patients were evaluable (3 NSCLC, 1 laryngeal SCC). Each received erlotinib at an oral dose of 150mg daily. Detailed plasma pharmacokinetics were performed on days 1 and 8. Tissue and plasma concentrations were determined at the second tissue sampling on day 9. Changes in the described markers were assessed immunohistochemically by comparing pre- and post-treatment biopsies. Results: In vitro studies revealed that erlotinib caused a dose-dependent increase in total HER1 and p27 and a prominent decrease in cyclin D1 expression. In the clinical trial, no treatment related deaths or serious adverse events were observed. Of 4 evaluable patients, 3 had symptomatic benefit and 2 of those 3 had pathologic evidence of activity (necrosis). Pre- and post-treatment tumor specimens revealed that cyclin D1 and Ki-67 decreased in the 2 patients with both clinical and pathologic responses while the remaining 2 patients, one of whom had symptomatic benefit, had no change in cyclin D1 or Ki-67 expression. Assessment of pharmacokinetics revealed that the 24 hour AUC increased by day 8 with a median accumulation index of 1.62. Tissue pharmacokinetics revealed appreciable tissue penetration with a median tissue:plasma ratio of 0.434. Conclusions: Erlotinib was well tolerated in this trial with appreciable tissue penetration in aerodigestive tract tumors. This study strongly suggests cyclin D1 as a potential surrogate marker of erlotinib response in vivo. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI Pharmaceuticals OSI Pharmaceuticals OSI Pharmaceuticals Abbott; Amgen; Aventis; Bristol-Myers Squibb; Genentech; GlaxoSmithKline; Ligand; Merck; Ortho Biotech; OSI; Pfizer; Roche
Prediction of responsiveness to adjuvant anthracyclines in high-risk breast cancer patients
Authors: N. Brünner, B. Ejlertsen, M. Jensen, K. V. Nielsen, E. Balslev, B. B. Rasmussen, G. L. Willemoe, P. B. Hertel, A. Knoop, H. Mouridsen
Journal: Journal of Clinical Oncology (2009)

597 Background: HER-2, TOP2A, and TIMP-1 have shown predictive properties regarding benefit from anthracyclines in patients with breast cancer. In the present study, TIMP-1 IHC was integrated with TOP2A FISH and HER-2 status in two separate profiles. Methods: The DBCG 89-D trial randomized 980 high-risk Danish breast cancer patients to nine series of CMF or CEF. CEF was superior to CMF in terms of DFS and OS (Ejlertsen et al, EJC 2007). HER-2 status and TOP2A copy number changes were determined as described previously (Knoop et al, J Clin Oncol. 2005). TMA s were constructed and analyzed centrally for TIMP-1 expression by IHC (± tumor cell immunoreactivity). TIMP-1 was combined with HER-2 into a joint HT marker (HT-non-responsive (HT-NR): HER-2 normal and TIMP-1 positive or HT-responsive (HT-R): HER-2 positive and/or TIMP-1 negative) and with TOP2A into a joint 2T marker (2T-NR: TOP2A normal and TIMP-1 positive or 2T-R: TOP2A abnormal and/or TIMP-1 negative). Relationships between IDFS, OS and the HT/2Tprofiles were analyzed using multivariate regression analysis. Results: Among patients with a HT-R profile CEF was superior to CMF in terms of both invasive disease-free survival (IDFS) (HR 0.62; 95% CI 0.45–0.86; p = 0.004) and overall survival (OS) (HR 0.63; 95% CI, 0.45–0.87; p = 0.005). In patients with a HT-NR profile, no significant differences between CEF and CMF were demonstrated for IDFS or OS. A significant HT profile (HT-R or HT-NR) versus treatment (CEF or CMF) interaction was detected by the Wald-test for both IDFS (p = 0.036) and OS (p = 0.047). An even more pronounced separation was observed regarding the 2T profile, and in patients with a 2T-R profile treatment with CEF was superior to CMF in terms of IDFS (HR 0.48; 95% CI 0.34–0.69; p &lt; 0.001) and OS (HR 0.54; 95% CI, 0.38–0.77; p &lt; 0.001). No significant difference was observed in patients with a 2T-NR profile. A highly significant 2T profile versus treatment interaction was detected for IDFS (p &lt; 0.001) and OS (p = 0.004). Conclusions: Profiles created by joining TIMP-1 with either HER-2 status or TOP2A gene status seems advantageous compared to the use of a single marker. [Table: see text]
Quantitative Imaging in Cancer Clinical Trials
Authors: Thomas E. Yankeelov, David A. Mankoff, Lawrence H. Schwartz, Frank S. Lieberman, John M. Buatti, James M. Mountz, Bradley J. Erickson, Fiona M.M. Fennessy, Wei Huang, Jayashree Kalpathy-Cramer, Richard L. Wahl, Hannah M. Linden, Paul E. Kinahan, Binsheng Zhao, Nola M. Hylton, Robert J. Gillies, Laurence Clarke, Robert Nordstrom, Daniel L. Rubin
Journal: Clinical Cancer Research (2016)

Abstract As anticancer therapies designed to target specific molecular pathways have been developed, it has become critical to develop methods to assess the response induced by such agents. Although traditional, anatomic CT, and MRI examinations are useful in many settings, increasing evidence suggests that these methods cannot answer the fundamental biologic and physiologic questions essential for assessment and, eventually, prediction of treatment response in the clinical trial setting, especially in the critical period soon after treatment is initiated. To optimally apply advances in quantitative imaging methods to trials of targeted cancer therapy, new infrastructure improvements are needed that incorporate these emerging techniques into the settings where they are most likely to have impact. In this review, we first elucidate the needs for therapeutic response assessment in the era of molecularly targeted therapy and describe how quantitative imaging can most effectively provide scientifically and clinically relevant data. We then describe the tools and methods required to apply quantitative imaging and provide concrete examples of work making these advances practically available for routine application in clinical trials. We conclude by proposing strategies to surmount barriers to wider incorporation of these quantitative imaging methods into clinical trials and, eventually, clinical practice. Our goal is to encourage and guide the oncology community to deploy standardized quantitative imaging techniques in clinical trials to further personalize care for cancer patients and to provide a more efficient path for the development of improved targeted therapies. Clin Cancer Res; 22(2); 284–90. ©2016 AACR.