tbuckley/cabot-search huggingface dataset:
Abstract B07: Gain of function activities of p53R245W in a conditional knock-in mouse model
Authors: Shunbin Xiong, Yun Zhang, Guillermina Lozano
Journal: Cancer Research (2016)

Abstract Missense mutations of the p53 tumor suppressor gene are present in more than 50% of human tumors. Emerging evidence suggests that p53 missense mutations in human cancer patients are associated with the poor prognosis and drug resistance due to their gain-of-function (GOF) properties, rather than just the loss of normal p53 function. Interestingly, these missense mutations have been shown to contribute to tumor progression by different mechanisms: interactions with Smad and SREBPs, modulation of EGFR/integrin signaling, and inhibition of p63 and p73 tumor suppressors. Combined, these studies suggest that the GOF of p53 missense mutations may be dependent on cell contexts and mutation types. Of particular interest, the p53R248W mutation is one of the most frequent missense mutation among human cancer patients; yet to date a mouse model that faithfully mimics this mutation does not exist. Additionally, the majority of human cancers evolve from somatic inactivation of p53 and current mouse models do not mimic somatic mutation of p53. Thus, we generated a conditional p53WMR245/+ knock-in mouse model, which normally expresses wild type p53, but produces p53R245W by Cre-mediated deletion of wild type p53 sequences. Germ line mutation of p53R245W/+ can rescue the early embryonic lethality of Mdm2 and Mdm4 null alleles like p53 null. Preliminary analyses of p53R245W/+ cohorts indicate differences in tumor spectrum in comparison to p53+/- and p53R172H/+ mice. Somatic mutation of p53R245W has also been performed to examine germ line versus somatic differences in tumor development. This study will help us understand the in vivo contributions of different p53 missense mutations to tumorigenesis, as well as the genetic alterations that occur during tumor evolution initiated by both germ line and somatic p53 mutations. Citation Format: Shunbin Xiong, Yun Zhang, Guillermina Lozano. Gain of function activities of p53R245W in a conditional knock-in mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B07.
Women in Northern Ireland to get free abortion on NHS in England
Authors: Clare Dyer
Journal: BMJ (2017)

Women from Northern Ireland are to be given access to abortions free of charge on the NHS in England, the UK government has announced.

The climbdown came after a decision by the House of Commons speaker, John Bercow, to allow MPs to vote on an amendment to that effect to the Queen’s speech put down by the Labour MP Stella Creasy.

Several Conservatives backed the amendment, threatening the government—which has a narrow majority—with its first defeat of the new parliament.

Northern Ireland has one of the most restrictive abortion laws in Europe, …
Comprehensive genomic profiling of parathyroid carcinoma.
Authors: Hyunseok Kang, Adrian Daniel Schubert, Paul Ladenson, Douglas Wilmot Ball, Jon Chung, Alexa Betzig Schrock, Jeffrey S. Ross, Vincent A. Miller, Philip J. Stephens, Siraj Mahamed Ali
Journal: Journal of Clinical Oncology (2017)

6088 Background: Parathyroid carcinoma (PC) is a rare endocrine malignancy, which can cause life-threatening hypercalcemia. Initial surgery is often noncurative, and adjunctive radiotherapy and previous chemotherapies have not been shown to be effective. Previous studies identified recurring mutations in CDC73 and PRUNE2in a limited number of patients. We queried whether comprehensive genomic profiling (CGP) would have potential to discover novel targets of therapy. Methods: DNA was extracted from 40 microns of FFPE sections from 13 consecutive cases of relapsed/metastatic PC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 672x for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Total of 13 specimens were identified from 7 male and 6 female patients. The mean age of the patients in this study was 54 years (range 38 to 76 years). All (100%) cases were Stage IV at the time of CGP. Tumor mutation burden was generally low - median mutation load per mega base was 1.8. There were 58 total GA (4.5 GA/sample) and 10 CRGA (0.8 CRGA/sample). The most frequent GA were non-CRGA mutations in TP53 (31%) and CDC73 (31%). MEN1 mutations were identified in 23% of cases. Frequent alterations in genes controlling cell cycle progression at G1 including CDKN1B, CDKN2A, CDKN2B and CDKN2C were identified (30%). The most frequent CRGA involved PTEN (23%), NF1 (23%) and KDR (15%). No alterations in BRAF or RETwere identified. A patient with KDR mutation treated with cabozantinib experienced &gt; 50% drop in PTH level and radiographic partial response in 3 months. Conclusions: CGP identified previously unreported TP53 mutations in PCs and potentially actionable genomic alterations including PTEN, NF1 and KDR. Clinical benefit and response observed in a patient treated with VEGFR targeted therapy suggest that patients with this rare tumor may be candidates for targeted therapies.
Hematological and virological features of non-Hodgkin's lymphomas associated with hepatitis C virus infection : a prospective observational study on behalf of the rete ematologica lombarda (REL)
Authors: S. Rattotti, V. Ferretti, A. Rossi, C. Rusconi, S. Fogazzi, A. Ferrario, P. Pioltelli, L. Uziel, L. Farina, M.B. Ventre, S. Rizzi, L. Morello, M. Merli, M. Balzarotti, D. Laszlo, L. Arcaini
Journal: Annals of Oncology (2011)
Quantifying asbestos in lung tissue: what debate?
Authors: Benoit Nemery, Valerie Nuyts, Kristiaan Nackaerts
Journal: European Respiratory Journal (2017)

This issue of the European Respiratory Journal contains an article entitled "The asbestos fibre burden in human lungs: new insights into the chrysotile debate" by Feder et al . [1]. Although respiratory physicians are very familiar with the devastating health effects of past asbestos exposure, many nonspecialist readers probably wonder what this "chrysotile debate" might be and how this article provides new insights into it. The debate involves the biopersistence and, hence, harmfulness of chrysotile as opposed to other types of asbestos. As is often the case with environmental issues, the implications of the debate are not just scientific. The implications of the "chrysotile debate" reach far beyond scientific circles <http://ow.ly/OUNj30bPSGU>
The CLARINET study: Assessing the effect of lanreotide autogel on tumor progression-free survival in patients with nonfunctioning gastroenteropancreatic neuroendocrine tumors.
Authors: Patrick Delavault, Martyn E Caplin, Nilani Liyange, Joelle Blumberg
Journal: Journal of Clinical Oncology (2012)

TPS4153 Background: Somatostatin analogs (SSAs) provide good symptom control in patients with neuroendrocine tumors (NETs). Clinical studies suggest SSAs also stabilize tumor growth. In a previous double-blind study (PROMID) in a mixed functioning and non-functioning gastroenteroNET population (n=85), octreotide LAR significantly increased time to tumor progression compared with placebo. The CLARINET study is being undertaken to explore the antiproliferative effects of SSAs in a more homogeneous population. Specifically, the CLARINET study is a double-blind, placebo-controlled trial assessing the effect of 120 mg of lanreotide Autogel (lanreotide Depot in the USA) on progression-free survival in patients with non-functioning gastroenteropancreatic NETs (GEP-NETs). Methods: CLARINET is a 96-week, multinational study being conducted in collaboration with UKI NETS and ENETS in patients with well or moderately differentiated non-functioning GEP-NETs and a proliferation index (Ki67) of &lt;10%. Patients are stratified by prior tumor progression status and presence/absence of previous therapies, and treated with lanreotide Autogel 120 mg or placebo. The primary endpoint is time to either disease progression (using Response Evaluation Criteria In Solid Tumors) or death. Two baseline computed tomography scans (≥12 weeks apart) are being performed, followed by additional scans at intervals up to 96 weeks. Secondary endpoints include proportion of patients alive and without tumor progression at 48 and 96 weeks, time to progression, overall survival, safety, quality of life, plasma chromogranin A levels, tumor markers, and pharmacokinetic parameters. The primary study population for the analysis will be the intention-to-treat population. Recruitment is now complete (n=204) and, thus far, the drug safety monitoring committee has identified no safety concerns. The trial is registered with ClinicalTrials.gov (NCT NCT00353496).
Predictive role of haemoglobin on disease response to neoadjuvant chemotherapy in breast cancer.
Authors: Claudia Omarini, Elena Iattoni, Maria Elisabetta Filieri, Angela Toss, Giulia Grizzi, Cinzia Del Giovane, Antonella Valentina Tamma, Stefano Cascinu, Federico Piacentini
Journal: Journal of Clinical Oncology (2016)

e12542 Background: Tumour hypoxia has been shown to play an important role in the outcome of cancer patients. Data on the predictive role of haemoglobin (Hb) on disease response to primary therapies in breast cancer (BC) are lacking. The purpose of this study is to evaluate the influence of Hb level throughout treatment course in predicting the response to neoadjuvant chemotherapy. Methods: 252 patients diagnosed with stage I-III BC treated with anthracycline-taxane based primary chemotherapy were evaluated. Patient and tumor characteristics and treatment information were collected. Standard biological parameters (Ki67, nuclear grade, hormone receptors and HER2 status) were correlated with pathologic complete response (pCR). We focused on Hb (baseline and after therapy levels, drop in Hb throughout treatment) and its correlation to pCR rate. The Hb cut-off to discriminate anaemic vs non-anaemic patients was set at 12,0 g/dl. Results: Globally, pCR was achieved in 58 patients (23%), mainly in case of younger age ( < 50 years = 29%, ≥ 50 years = 17%; p = 0.01), high nuclear grade (Grade1-2 = 0%, grade 3 = 27%; p < 0.0001), high ki67 ( > 20% = 26%, < 20% = 12%; p = 0.02) and hormone receptor negative status (Luminal B/HER2 negative = 9%, Luminal B/HER2 positive = 32%, HER2 enriched = 46%, triple negative = 37%; p < 0.0001). Median baseline Hb was 13,3 g/dl while median Hb level after chemotherapy was 11.6 g/dl: pCR was not influenced by Hb level before and after primary chemotherapy. No difference in Hb levels were observed stratifying patients according to nuclear grade, tumour stage and cancer subtypes. Anaemia due to chemotherapy was reported in 56% of patients. The decrease in Hb levels from baseline was greater in patients with lower response rate. On univariate analysis, a decrease in Hb ≥ 2 g/dl was associated with a significantly lower rate of pCR (15% vs 43%; p = 0.047). This correlation was even more evident in the subgroup of anaemic patients (17% vs 32%; p = 0.037). Conclusions: A decrease in Hb ≥ 2 g/dl during neoadjuvant chemotherapy may negatively affect the rate of pCR in BC patients, thus suggesting that anaemia should be avoided in order to obtain the best response to primary treatments.
Comprehensive genomic profiling to identify tumor mutational burden (TMB) as an independent predictor of response to immunotherapy in diverse cancers.
Authors: Aaron Goodman, Shumei Kato, Lyudmila Bazhenova, Sandip Pravin Patel, Garrett Michael Frampton, Vincent A. Miller, Phil Stephens, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2017)

e14508 Background: Immunotherapy induces durable responses in a subset of patients with cancer. High TMB may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. Methods: We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free and overall survival (PFS, OS). Results: Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥ 20 mutations/mb) vs. low to intermediate TMB was 22/38 (58%) vs. 23/113 (20%) (P = 0.0001); median PFS, 12.8 vs. 3.3 months (P = &lt;0.0001); median OS, not reached vs. 16.3 months (P = 0.0036) (Table). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders vs. non-responders treated with anti-PD-1/PD-L1 monotherapy was 18.0 vs. 5.0 mutations/mb (P &lt; 0.0001). Comparable data was observed when patients with melanoma (N = 52) and NSCLC (N = 36) were excluded (N = 63 patients; 19 tumor types). Interestingly, anti-CTLA4/anti-PD-1 combinations vs. anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%) (P = 0.004) and PFS (P = 0.024). Conclusions: Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. [Table: see text]
Kindlin-2 Regulates the Growth of Breast Cancer Tumors by Activating CSF-1–Mediated Macrophage Infiltration
Authors: Khalid Sossey-Alaoui, Elzbieta Pluskota, Katarzyna Bialkowska, Dorota Szpak, Yvonne Parker, Chevaun D. Morrison, Daniel J. Lindner, William P. Schiemann, Edward F. Plow
Journal: Cancer Research (2017)

Abstract Interplay between tumor cells and host cells in the tumor microenvironment dictates the development of all cancers. In breast cancer, malignant cells educate host macrophages to adopt a protumorigenic phenotype. In this study, we show how the integrin-regulatory protein kindlin-2 (FERMT2) promotes metastatic progression of breast cancer through the recruitment and subversion of host macrophages. Kindlin-2 expression was elevated in breast cancer biopsy tissues where its levels correlated with reduced patient survival. On the basis of these observations, we used CRISPR/Cas9 technology to ablate Kindlin-2 expression in human MDA-MB-231 and murine 4T1 breast cancer cells. Kindlin-2 deficiency inhibited invasive and migratory properties in vitro without affecting proliferation rates. However, in vivo tumor outgrowth was inhibited by &amp;gt;80% in a manner associated with reduced macrophage infiltration and secretion of the macrophage attractant and growth factor colony-stimulating factor-1 (CSF-1). The observed loss of CSF-1 appeared to be caused by a more proximal deficiency in TGFβ-dependent signaling in Kindlin-2–deficient cells. Collectively, our results illuminate a Kindlin-2/TGFβ/CSF-1 signaling axis employed by breast cancer cells to capture host macrophage functions that drive tumor progression. Cancer Res; 77(18); 5129–41. ©2017 AACR.
Extracellular Vesicle Biology in the Pathogenesis of Lung Disease
Authors: Serge P. Nana-Sinkam, Mario Acunzo, Carlo M. Croce, Kai Wang
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Abstract As our understanding of diseases of the lung continues to evolve, we recognize that the mechanisms that drive cell/environment communication leading to disease development and progression are complex. In 2008, investigators first identified intact cell free microRNAs in circulation with some localized within lipid-encapsulated microvesicles termed extracellular vesicles (EVs). Prior to and following this discovery, investigators have determined that EVs may drive biological processes fundamental to human disease and homeostasis. The cargo in EVs which includes, proteins, miRNAs and mRNAs is protected from degradation, often reflects the pathogenesis of the cell of origin and may serve as a conduit for communication between cells subsequently reprogramming recipient cell function. Furthermore, EVs have been detected in bodily fluids including blood urine, sputum and bronchoalveolar lavage. The release and shuttling of EVs between cells following both environmental exposure and during disease development and progression has added a new layer of complexity to cell-cell communication in lung disease. While the majority of studies implicating EVs in human biology have been conducted in cancer, we have witnessed an emergence of EV based studies in other physiopathological conditions. EV mediated transfer of genetic content may link environmental stressors to the lung immune response through intercellular communication within the lung and development of disease. This perspective will focus on the growing field of EV biology in human lung diseases and its application to both the development and progression of lung disease and in biomarker discovery.
Effect of hyperbaric oxygen treatment on chemotherapy sensitivity in acute myeloid leukemia.
Authors: Tara L. Lin, Abigale Berry, Amanda L. Wise, Hemantkumar Chavan, Partha Kasturi, Joseph Fontes, Brea Lipe, Omar Salah Aljitawi
Journal: Journal of Clinical Oncology (2016)

e18518 Background: Insights into the biology of chemotherapy resistance may suggest novel strategies to treat Acute Myeloid Leukemia (AML). We examined the role of hyperbaric oxygen (HBO) in AML sensitivity to chemotherapy, oxygen consumption, reactive oxygen species (ROS) generation, glycolytic pathway activation and gene expression. Methods: Human AML cell lines HL-60 and MV-411 were treated with cytarabine followed by HBO (100% oxygen at 2.5 atmosphere absolutes for 2 hours in an in vitro HBO chamber) or normobaric culture conditions. At 24 hours, cells were analyzed for proliferation, apoptosis and oxygen consumption. Studies of HBO- treated cells without chemotherapy included CellROX Oxidative Stress assay and real-time PCR with primer sets specific for human hexokinase2 and phosphofructokinase to examine HBO effects on glycolysis. Gene expression profiling by the Human Transcriptome Array 2.0 (Affymetrix) examined differences in gene expression following HBO in HL-60 cells and AML patient samples. Results: Leukemia cells treated with HBO and cytarabine demonstrated reduced proliferation and increased late apoptosis confirming increased sensitivity to cytarabine. Treatment with HBO plus cytarabine resulted in increased oxygen consumption measured by the seahorse assay at 24 hours post-HBO in MV-411 cells compared to cytarabine alone. Significant increases in ROS levels were observed at 24 hours post-HBO for both cell lines when compared to non-treated cells. Glycolysis pathway components human hexokinase 2 and phosphofructokinase were upregulated in HL60 and MV411 cells treated with HBO compared to controls. Gene expression profiling showed that approximately 200 genes in coding regions were upregulated in HBO-treated HL-60 cells; specific piRNA clusters were downregulated in both AML cell line HL60 and an AML bone marrow sample when treated with HBO. Conclusions: HBO treatment significantly increases the sensitivity to cytarabine in AML cell lines in vitro, an effect associated with increased late apoptosis and changes in cellular respiration. Increased ROS, upregulation of glycolysis-related enzymes and changes in gene expression profiling provide insight into potential mechanisms of HBO in AML.
Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome
Authors: William D. Foulkes, Junne Kamihara, D. Gareth R. Evans, Laurence Brugières, Franck Bourdeaut, Jan J. Molenaar, Michael F. Walsh, Garrett M. Brodeur, Lisa Diller
Journal: Clinical Cancer Research (2017)

Gorlin syndrome and rhabdoid tumor predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumors. Individuals with Gorlin syndrome can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life. Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (PTCH1) and Suppressor of fused (SUFU)SUFU mutation carriers appear to have an especially high risk of early-onset medulloblastoma. Surveillance MRI in the first years of life in SUFU mutation carriers is, therefore, recommended. Given the risk of basal cell carcinomas, regular dermatologic examinations and sun protection are also recommended. Rhabdoid tumors (RT) are tumors initially defined by the descriptive "rhabdoid" term, implying a phenotypic similarity with rhabdomyoblasts at the microscopic level. RTs usually present before the age of 3 and can arise within the cranium as atypical teratoid/rhabdoid tumors or extracranially, especially in the kidney, as malignant rhabdoid tumors. However, RTs of both types share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4, each of which encodes a chromatin remodeling family member. SMARCA4 mutations are particularly associated with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The outcome following a diagnosis of any of these tumors is often poor, and the value of surveillance is unknown. International efforts to determine surveillance protocols are underway, and preliminary recommendations are made for carriers of SMARCB1 and SMARCA4 mutations. Clin Cancer Res; 23(12); e62-e67. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
NCCN Guidelines Insights: Antiemesis, Version 2.2017
Authors: Michael J. Berger, David S. Ettinger, Jonathan Aston, Sally Barbour, Jason Bergsbaken, Philip J. Bierman, Debra Brandt, Dawn E. Dolan, Georgiana Ellis, Eun Jeong Kim, Steve Kirkegaard, Dwight D. Kloth, Ruth Lagman, Dean Lim, Charles Loprinzi, Cynthia X. Ma, Victoria Maurer, Laura Boehnke Michaud, Lisle M. Nabell, Kim Noonan, Eric Roeland, Hope S. Rugo, Lee S. Schwartzberg, Bridget Scullion, John Timoney, Barbara Todaro, Susan G. Urba, Dorothy A. Shead, Miranda Hughes
Journal: Journal of the National Comprehensive Cancer Network (2017)

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis address all aspects of management for chemotherapy-induced nausea and vomiting. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Antiemesis, specifically those regarding carboplatin, granisetron, and olanzapine.