tbuckley/cabot-search huggingface dataset:
Exploratory analysis to seek for the optimal definition of progression-free survival (PFS) in preoperative cancer therapy: Using phase III trials of Japan Clinical Oncology Group (JCOG)
Authors: K. Nakamura, T. Shibata, I. Saito, H. Fukuda
Journal: Journal of Clinical Oncology (2008)

6604 Background: PFS is often used as primary endpoint in a phase III trial comparing preoperative therapy (PO) and surgery-first therapy (SF). Because the date of surgery is systematically later in PO arm than in SF arm, the optimal definition of PFS to assure the comparability of each arm has not been established. Therefore, whether incomplete resection (IR) is defined as an event (E) of PFS is different among published trials. Thus, we estimate the differences of PFS among several typical definitions using the data of two JCOG phase III trials. Methods: The definitions of PFS are classified into 3 typical patterns: (A) IR is defined as E on the date of surgery, (B) IR or progression within 6 months after registration is defined as E at the landmark time, 6 months after registration, (C) regardless of IR, radiologically or clinically diagnosed progression is defined as E on the date of progression. Three patterns of PFS and overall survival (OS) are estimated in JCOG9907 (esophageal cancer) and JCOG0102 (cervical cancer), and hazard ratios (HR) are calculated using Cox's proportional hazard model. Hypothetical HRs of PFS are also calculated assuming larger proportion of IR in JCOG9907. Results: IRs were observed in 7.6% (25/330 pts) in JCOG9907 and 9.7% (13/134 pts) in JCOG0102. HRs of PFS in each pattern and OS are shown in the Table. The pattern of PFS showing the closest HR to that of OS is “A” in JCOG9907 and “C” in JCOG0102. Because of the small number of IR in JCOG9907, we hypothetically amplified the number of IR assuming the proportions of IR as 15%, 30%, 50%, and the maximum HR differences between three PFS resulted in 0.02, 0.06, and 0.12. Conclusions: HR of PFS differs by definition, especially if the study contains many IRs. The definition of PFS showing better surrogacy of OS is different in two studies. PFS may not be used as primary endpoint, but OS should be used in the study comparing PO and SF unless common definition of PFS is established. Three patterns of PFS and OS in the JCOG phase III trials. PFS (A): IR = event PFS (B): landmark PFS (C): IR not event OS JCOG9907 (HR) 0.795 0.798 0.808 0.687 JCOG0102 (HR) 0.884 0.895 1.031 1.330 No significant financial relationships to disclose.
<i>Toxoplasma gondii</i> TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ–mediated host defenses
Authors: Gabrielle Gay, Laurence Braun, Marie-Pierre Brenier-Pinchart, Julien Vollaire, Véronique Josserand, Rose-Laurence Bertini, Aurélie Varesano, Bastien Touquet, Pieter-Jan De Bock, Yohann Coute, Isabelle Tardieux, Alexandre Bougdour, Mohamed-Ali Hakimi
Journal: The Journal of Experimental Medicine (2016)

An early hallmark of Toxoplasma gondii infection is the rapid control of the parasite population by a potent multifaceted innate immune response that engages resident and homing immune cells along with pro- and counter-inflammatory cytokines. In this context, IFN-γ activates a variety of T. gondii–targeting activities in immune and nonimmune cells but can also contribute to host immune pathology. T. gondii has evolved mechanisms to timely counteract the host IFN-γ defenses by interfering with the transcription of IFN-γ–stimulated genes. We now have identified TgIST (T. gondii inhibitor of STAT1 transcriptional activity) as a critical molecular switch that is secreted by intracellular parasites and traffics to the host cell nucleus where it inhibits STAT1-dependent proinflammatory gene expression. We show that TgIST not only sequesters STAT1 on dedicated loci but also promotes shaping of a nonpermissive chromatin through its capacity to recruit the nucleosome remodeling deacetylase (NuRD) transcriptional repressor. We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1+ inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-γ–mediated killing. By uncovering TgIST functions, this study brings novel evidence on how T. gondii has devised a molecular weapon of choice to take control over a ubiquitous immune gene expression mechanism in metazoans, as a way to promote long-term parasitism.
Cholangiocarcinoma stem-like subset shapes tumor-initiating niche by educating associated macrophages
Authors: Chiara Raggi, Margherita Correnti, Antonio Sica, Jesper B. Andersen, Vincenzo Cardinale, Domenico Alvaro, Giovanna Chiorino, Elisa Forti, Shannon Glaser, Gianfranco Alpini, Annarita Destro, Francesca Sozio, Luca Di Tommaso, Massimo Roncalli, Jesus M. Banales, Cédric Coulouarn, Luis Bujanda, Guido Torzilli, Pietro Invernizzi
Journal: Journal of Hepatology (2016)
ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2)
Authors: Y Jiang, H-C Chen, X Su, P A Thompson, X Liu, K-A Do, W Wierda, M J Keating, W Plunkett
Journal: Blood Cancer Journal (2016)

Abstract Approximately 10–20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22–23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated ( ATM ), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients. SMC1 (structural maintenance of chromosomes 1) and KAP1 (KRAB-associated protein 1) were found to be unique substrates of ATM kinase by immunoblot detection following ionizing radiation. Using a pool of eight fluorescence in situ hybridization-negative CLL samples as a standard, the phosphorylation of SMC1 and KAP1 from 46 del (11q22–23) samples was analyzed using normal mixture model-based clustering. This identified 13 samples (28%) that were deficient in ATM function. Targeted sequencing of the ATM gene of these samples, with reference to genomic DNA, revealed 12 somatic mutations and 15 germline mutations in these samples. No strong correlation was observed between ATM mutation and function. Therefore, mutation status may not be taken as an indicator of ATM function. Rather, a direct assay of the kinase activity should be used in the development of therapies.
Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013
Authors: Hmwe H Kyu, Victoria F Bachman, Lily T Alexander, John Everett Mumford, Ashkan Afshin, Kara Estep, J Lennert Veerman, Kristen Delwiche, Marissa L Iannarone, Madeline L Moyer, Kelly Cercy, Theo Vos, Christopher J L Murray, Mohammad H Forouzanfar
Journal: BMJ (2016)

<b>Objective</b>&nbsp;To quantify the dose-response associations between total physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events. <b>Design</b>&nbsp;Systematic review and Bayesian dose-response meta-analysis. <b>Data sources</b>&nbsp;PubMed and Embase from 1980 to 27 February 2016, and references from relevant systematic reviews. Data from the Study on Global AGEing and Adult Health conducted in China, Ghana, India, Mexico, Russia, and South Africa from 2007 to 2010 and the US National Health and Nutrition Examination Surveys from 1999 to 2011 were used to map domain specific physical activity (reported in included studies) to total activity. <b>Eligibility criteria for selecting studies</b>&nbsp;Prospective cohort studies examining the associations between physical activity (any domain) and at least one of the five diseases studied. <b>Results</b>&nbsp;174 articles were identified: 35 for breast cancer, 19 for colon cancer, 55 for diabetes, 43 for ischemic heart disease, and 26 for ischemic stroke (some articles included multiple outcomes). Although higher levels of total physical activity were significantly associated with lower risk for all outcomes, major gains occurred at lower levels of activity (up to 3000-4000 metabolic equivalent (MET) minutes/week). For example, individuals with a total activity level of 600 MET minutes/week (the minimum recommended level) had a 2% lower risk of diabetes compared with those reporting no physical activity. An increase from 600 to 3600 MET minutes/week reduced the risk by an additional 19%. The same amount of increase yielded much smaller returns at higher levels of activity: an increase of total activity from 9000 to 12 000 MET minutes/week reduced the risk of diabetes by only 0.6%. Compared with insufficiently active individuals (total activity &lt;600 MET minutes/week), the risk reduction for those in the highly active category (≥8000 MET minutes/week) was 14% (relative risk 0.863, 95% uncertainty interval 0.829 to 0.900) for breast cancer; 21% (0.789, 0.735 to 0.850) for colon cancer; 28% (0.722, 0.678 to 0.768) for diabetes; 25% (0.754, 0.704 to 0.809) for ischemic heart disease; and 26% (0.736, 0.659 to 0.811) for ischemic stroke. <b>Conclusions</b>&nbsp;People who achieve total physical activity levels several times higher than the current recommended minimum level have a significant reduction in the risk of the five diseases studied. More studies with detailed quantification of total physical activity will help to find more precise relative risk estimates for different levels of activity.
Multiple Myeloma and Bone Marrow Microenvironment Immunohistochemical Study of the Expression of 15 Proteins Related to Myeloma Bone Disease
Authors: Patrik Flodr, Pavla Latalova, Petra Pusciznova, Tomas Pika, Jaroslav Bacovsky, Vlastimil Scudla, Jiri Minarik
Journal: Blood (2015)
Effect of GSK-3 inhibition in vitro and in vivo on antitumor effect of sorafenib in renal cell carcinoma (RCC).
Authors: H. Kawazoe, V. Bilim, K. Yuuki, S. Naito, A. Muto, Y. Tomita
Journal: Journal of Clinical Oncology (2010)

4617 Background: Sorafenib is a multikinase inhibitor which has been approved as the first-line treatment of advanced and/or metastaticrenal cell carcinoma (RCC). Sorafenib suppresses tumor growth directly by affecting tumor cells and indirectly by targeting tumor vasculature and angiogenesis. While the detailed molecular mechanisms of its action in RCC are still unclear, combining sorafenib with other signal transduction inhibitors may improve its activity and provide additional benefits to patients with RCC. Recently we showed that glycogen synthase kinase 3 (GSK-3) might be a potential new therapeutic target for RCC and targeting GSK-3 is an effective way to directly induce apoptosis in RCC, which is resistant to apoptosis-triggering treatment modalities (Br J Cancer. 101:2005-14, 2009). Methods: Here we examined effects of sorafenib on human RCC cell lines in vitro and in vivo by tumor xenograft mouse model as a single agent or in combination with a GSK-3 small molecule inhibitor AR-A014418. Protein expression and phosphorylation states were analyzed by Western blots. GSK-3 expression in cells was also confirmed by Q-RT-PCR (using TaqMan technology). Cell viability in vitro was examined by MTS assay. Morphological and biochemical features of apoptosis were detected with standard methods. Results: We detected that sorafenib induced growth inhibition of human RCC cell lines in vitro in a time (24-96 hours) and dose (2.5-10μ M) dependent manner as well as in vivo xenograft tumors in mice (30 mg/kg). Sorafenib treatment triggered apoptosis demonstrated by PARP cleavage which was more prominent with higher doses. However, in vitro sorafenib upregulated total GSK-3 expression and almost completely depleted inactive GSK3 pool as shown by diminished phosphorylation at Ser9. GSK-3 pharmacological inhibition with AR-A014418 (25 μ M, 30 mg/kg) potentiated sorafenib antitumor activity both in vitro and in vivo. Conclusions: Our results confirmed the direct antitumor effect of sorafenib in RCC andrevealed GSK-3 activation as one of potential consequence of sorafenib treatment. Targeting GSK-3 may synergize with sorafenib and this combination treatment might be a potential new approach for RCC. No significant financial relationships to disclose.
Placental transmogrification of the lung presenting as progressive symptomatic bullous emphysema
Authors: K Brüstle, S Lema, P Komminoth, W Weder, B Vrugt, W Jungraithmayr
Journal: Thorax (2016)

In 2015, a 63-year-old non-smoking male with a history of bullous emphysema, for which a wedge resection of the right lower lobe had been performed in 1972, presented with progressive dyspnoea on exertion and coughing. Pulmonary function tests demonstrated a moderate obstructive pattern with normal diffusion capacity (FEV1: 61%, FVC: 64%, TLco: 86%). CT of the thorax revealed localised bullous–cystic changes in the right lower lobe with displacement of the mediastinum to the contralateral side (figure 1). Due to the patient’s increasing respiratory distress, a right lower lobectomy was performed.



Figure 1 
CT of the thorax showing bullous–cystic changes with atelectasis of the adjacent parenchyma and displacement of the upper lobe and mediastinum.



Grossly, the specimen displayed multiple cysts with compression of the adjacent parenchyma (figure 2A). Histologically, placenta-like papillary …
Response by Di Biase et al to Letter Regarding Article, “Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial”
Authors: Luigi Di Biase, Prasant Mohanty, Sanghamitra Mohanty, Pasquale Santangeli, Chintan Trivedi, Dhanunjaya Lakkireddy, Madhu Reddy, Pierre Jais, Sakis Themistoclakis, Antonio Dello Russo, Michela Casella, Gemma Pelargonio, Maria Lucia Narducci, Robert Schweikert, Petr Neuzil, Javier Sanchez, Rodney Horton, Salwa Beheiry, Richard Hongo, Steven Hao, Antonio Rossillo, Giovanni Forleo, Claudio Tondo, J. David Burkhardt, Michel Haissaguerre, Andrea Natale
Journal: Circulation (2016)
RUNX1-ETO Expressing Hematopoietic Stem/Progenitor Cells (HSPCs) Display a Hypersensitivity To GM-CSF That Reduces Leukemogenic Potential
Authors: Stephanie Weng, Shinobu Matsuura, Miao-Chia Lo, Kentson Lam, Dan Ran, Dong-Er Zhang
Journal: Blood (2013)
Ethnic/racial barriers to cervical cancer prevention with the HPV vaccine
Authors: S. Gorin, C. Westhoff
Journal: Journal of Clinical Oncology (2009)

1546 Background: High risk types of the human papilloma virus (HPV) are necessary though not sufficient causes of the vast majority of cervical cancers. Black women have the highest prevalence of HPV (20.6%, 95% CI, 19.8–21.5%), followed by Latinas (14.1%, 95% CI, 13.9, 14.4%). Black women have the highest rates of mortality from cervical cancer, followed by Latinas. Recent population-based data reveal low uptake of the HPV vaccine (∼25%), particularly among Black women and Latinas. Objectives: The aim of this systematic review is to describe the supports and barriers to HPV vaccine inoculation among Black and Hispanic U.S. women. Methods: We conducted a systematic literature review of studies with more than one observation point or a comparison group that were published over the past 10 years, using a standardized extraction protocol. Inter-rater reliability rates were high (&gt; 0.98). Of 64 English-language articles from peer-reviewed journals, we selected 16 for review. Results: We found barriers at the policy, provider, and patient levels. Barriers at the policy level include access to health care, cost, insurance coverage, vaccine availability, limited knowledge of the HPV vaccine, and media coverage that stigmatizes inoculation. At the provider level, knowledge about HPV incidence and transmission as well as physician recommendation are important factors that influence parental and patient acceptability of the HPV vaccine. Providers report difficulty in discussing STIs with parents, preadolescents, and adolescents. Providers are hesitant to store a vaccine that will be less widely used. Office-based procedures present structural impediments to dissemination of the vaccine. At the patient level, barriers include limited awareness of the vaccine, socioeconomic status, perception of risk based on sexual history, fear of vaccine safety, socio-cultural, economic, and religious factors. Conclusions: Policy, provider, and patient-focused intervention approaches to increasing dissemination of the HPV vaccine are proposed to increase uptake among Black women and Latinas. No significant financial relationships to disclose.
The Role Of Deregulated HMGA2 Expression With Promoter Methylation Of p16 In Myeloproliferative Neoplasms
Authors: Kayo Shirado Harada, Kazuhiko Ikeda, Kazuei Ogawa, Hideyoshi Noji, Hideo Kimura, Tatsuyuki Kai, Soji Morishita, Norio Komatsu, Yasuchika Takeishi
Journal: Blood (2013)
749. Escape from Tumor Dormancy Following Gene- or Viro-Therapies Is Mediated by Acquisition of a Phenotype in Which Innate Immune Surveillance Actively Drives Tumor Cell Recurrence
Authors: Tim Kottke, Diana Rommelfanger, Kevin G. Shim, Jose Pulido, Jill Thompson, Karishma Rajani, Oleg Bobr, Peter Selby, Elizabeth Ilett, Alan Melcher, Richard Vile
Journal: Molecular Therapy (2016)

When established (~0.3-0.5cm) primary murine B16 tumors are treated with either cytotoxic gene therapy (HSVtk/GCV), oncolytic virotherapy (intra-tumoral reovirus) or adoptive T cell therapy, a proportion of mice will become apparently tumor free. However, if the animals are observed for prolonged periods of time (>60-100 days), the majority of mice will develop aggressively growing recurrent tumors. Excision of the site of tumor injection during the period of tumor dormancy (no palpable tumor) indicated that residual tumor cells are readily detectable in most mice by histology. Unexpectedly, it was extremely difficult to re-grow the tumor cells from these specks of minimal residual disease in vitro. However, by screening multiple cytokines for their ability to support re-growth of recurrent B16 cells, we identified TNF-α as a major growth factor for recurrent cells. Conversely, treatment of primary B16 populations with TNF-α led to highly significant reductions in tumor cell viability. Similarly, depletion of NK cells, or antibody blockade of TNF-α, from C57Bl/6 mice led to significantly increased tumorigencity of primary B16 tumors. In contrast, depletion of NK cells allowed for decreased tumorigenicity of TNF-α stimulated recurrent B16 cells recovered from mice in a state of minimal residual disease. These data suggest that tumor recurrence may be mediated by a distinct phenotypic switch in vivo. Thus, initially, primary tumor cells are highly sensitive to innate immune cell surveillance through NK cells and TNF-α. However, escape from dormancy in vivo is associated with acquisition of a phenotype in which such TNF-α-mediated immune surveillance actively drives tumor growth. TNF-α growth promoted recurrent cells also expressed high levels of PD-L1 compared to primary tumor cells, suggesting that this may be a further mechanism by which recurrences could emerge in vivo, even in the presence of anti tumor T cell responses. Consistent with this hypothesis, recurrence was significantly inhibited in vivo following gene, viro- or adoptive T cell therapies, by treatment with TNF-α blockade or systemic checkpoint inhibitor therapy.
Novel Ciliate Genetic Code Variants Including the Reassignment of All Three Stop Codons to Sense Codons in<i>Condylostoma magnum</i>
Authors: Stephen M. Heaphy, Marco Mariotti, Vadim N. Gladyshev, John F. Atkins, Pavel V. Baranov
Journal: Molecular Biology and Evolution (2016)

mRNA translation in many ciliates utilizes variant genetic codes where stop codons are reassigned to specify amino acids. To characterize the repertoire of ciliate genetic codes, we analyzed ciliate transcriptomes from marine environments. Using codon substitution frequencies in ciliate protein-coding genes and their orthologs, we inferred the genetic codes of 24 ciliate species. Nine did not match genetic code tables currently assigned by NCBI. Surprisingly, we identified a novel genetic code where all three standard stop codons (TAA, TAG, and TGA) specify amino acids in Condylostoma magnum. We provide evidence suggesting that the functions of these codons in C. magnum depend on their location within mRNA. They are decoded as amino acids at internal positions, but specify translation termination when in close proximity to an mRNA 3′ end. The frequency of stop codons in protein coding sequences of closely related Climacostomum virens suggests that it may represent a transitory state.
Inactivation of Cancer Mutations Utilizing CRISPR/Cas9
Authors: Christina Gebler, Tim Lohoff, Maciej Paszkowski-Rogacz, Jovan Mircetic, Debojyoti Chakraborty, Aylin Camgoz, Martin V Hamann, Mirko Theis, Christian Thiede, Frank Buchholz
Journal: JNCI Journal of the National Cancer Institute (2016)

Although whole-genome sequencing has uncovered a large number of mutations that drive tumorigenesis, functional ratification for most mutations remains sparse. Here, we present an approach to test functional relevance of tumor mutations employing CRISPR/Cas9. Combining comprehensive sgRNA design and an efficient reporter assay to nominate efficient and selective sgRNAs, we establish a pipeline to dissect roles of cancer mutations with potential applicability to personalized medicine and future therapeutic use.
Impact of RECIST 1.1 modifications on clinical trial eligibility.
Authors: T. Urban, C. A. Sadow, J. M. Cleary, G. J. Harris, A. D. Van Den Abbeele
Journal: Journal of Clinical Oncology (2011)

e16555 Background: New RECIST 1.1 criteria include more stringent size criteria for lymph node assessment in metastatic disease requiring a short axis measurement of 15 mm for measurable nodes. This change may increase specificity for malignant nodal involvement, at the risk of excluding patients (pts) with lymphadenopathy as the only site of metastatic spread. The aim of our study was to determine how many pts enrolled in RECIST 1.0 trials would not meet eligibility criteria when the new RECIST 1.1 lymph node criteria are applied. Methods: Data from 3,470 pts enrolled in 149 trials using RECIST 1.0 for assessment were retrospectively reviewed. Pts with measurable extranodal disease were excluded, as their eligibility would not change. Pts with lymphadenopathy as the only site of metastatic disease were assessed to determine eligibility by RECIST 1.1. Clinical, pathologic, or radiographic information was used to determine whether excluded nodes were malignant. The percent of pts with malignant nodes that would have been excluded by RECIST 1.1 was calculated with 95% confidence intervals (CI). Results: Of 3,470 pts, 449 (13%) had abnormal nodes as the only site of measurable disease. Using RECIST 1.1, 201 of 449 (45%) pts were ineligible. Of these, 80% (161/201) had malignant or highly suspicious lymphadenopathy according to: 1) lymph node biopsy (n=42); 2) fluctuation of tumor markers correlating with nodal size (n=13); follow-up imaging showing progression +/- new sites of disease (n=40); 4) follow-up imaging showing response with non-target regression (n=9); 5) correlative FDG-PET imaging showing significant FDG uptake (n=14); 6) node in a site typical of spread from the primary malignancy (n=43). Of pts with node-only metastatic disease (n=449), 409 had malignant lymphadenopathy according to our defined criteria: 161 pts had nodes with short axis < 15 mm and 248 pts had nodes ≥ 15 mm, meeting RECIST 1.1 size criteria. Therefore, 39% of pts (161/409, CI: 35%, 44%) with node-only disease would have been ineligible for RECIST 1.1 trials. Conclusions: The impact of lymph node size modification in RECIST 1.1 may be substantial on pt accrual for clinical trials using RECIST 1.1; investigators need to be aware of the impact node criteria changes may have on pt enrollment.