Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease

Lung cancer diagnostics have progressed greatly in the previous decade. Development of molecular testing to identify an increasing number of potentially clinically actionable genetic variants, using smaller samples obtained via minimally invasive techniques, is a huge challenge. Tumour heterogeneity and cancer evolution in response to therapy means that repeat biopsies or circulating biomarkers are likely to be increasingly useful to adapt treatment as resistance develops. We highlight some of the current challenges faced in clinical practice for molecular testing of EGFR, ALK, and new biomarkers such as PDL1. Implementation of next generation sequencing platforms for molecular diagnostics in non-small-cell lung cancer is increasingly common, allowing testing of multiple genetic variants from a single sample. The use of next generation sequencing to recruit for molecularly stratified clinical trials is discussed in the context of the UK Stratified Medicine Programme and The UK National Lung Matrix Trial

Toward a New Approach to Evaluating Significance in Recent-Past Preservation Planning with a Case Study of 1960s Properties in Philadelphia County

In evaluating a stock of recent-past buildings, it is important to stay alert to the ways in which recent-past heritage is more difficult to assess, and what we might be prone to do to make it easier to assess. It is not enough to involve numerous people in the process and to articulate our method of analysis. We as preservation professionals must also consciously strive to avoid cognitive shortcuts. We must set evaluative standards and choose priorities, without simply dismissing a great portion of the built environment as “crap” or accepting self-evidence as a measure of significance. Complexity should not be a cause for despair. We must lead the public in a more self-reflexive view of built heritage, without getting stuck in never-ending philosophizing and debating. The field would benefit from a more systematic, methodical approach to championing pluralism in heritage and recognizing the polysemy in cultural objects, which nonetheless helps to uncover priorities of highest significance. In sum, prior to, and in addition to, preservation advocacy efforts to publicize and popularize buildings of the recent-past, preservation planning efforts must establish better methods for identifying resources and assessing their significance. In light of the issues and caveats just introduced, this study asks: what is an optimal inventory method for a municipal/county-level commission or nonprofit organization to identify priorities for preservation planning for the recent-past

Detection and Molecular Diversity of Cryptosporidium spp. and Giardia duodenalis in the Endangered Iberian Lynx (Lynx pardinus), Spain

Cryptosporidium spp. and Giardia duodenalis are the main non-viral causes of diarrhoea in humans and domestic animals globally. Comparatively, much less information is currently available in free-ranging carnivore species in general and in the endangered Iberian lynx (Lynx pardinus) in particular. Cryptosporidium spp. and G. duodenalis were investigated with molecular (PCR and Sanger sequencing) methods in individual faecal DNA samples of free-ranging and captive Iberian lynxes from the main population nuclei in Spain. Overall, Cryptosporidium spp. and G. duodenalis were detected in 2.4% (6/251) and 27.9% (70/251) of the animals examined, respectively. Positive animals to at least one of them were detected in each of the analysed population nuclei. The analysis of partial ssu rRNA gene sequences revealed the presence of rodent-adapted C. alticolis (n = 1) and C. occultus (n = 1), leporid-adapted C. cuniculus (n = 2), and zoonotic C. parvum (n = 2) within Cryptosporidium, and zoonotic assemblages A (n = 5) and B (n = 3) within G. duodenalis. Subgenotyping analyses allowed for the identification of genotype VaA19 in C. cuniculus (gp60 locus) and sub-assemblages AI and BIII/BIV in G. duodenalis (gdh, bg, and tpi loci). This study represents the first molecular description of Cryptosporidium spp. and G. duodenalis in the Iberian lynx in Spain. The presence of rodent/leporid-adapted Cryptosporidium species in the surveyed animals suggests spurious infections associated to the Iberian lynx's diet. The Iberian lynx seems a suitable host for zoonotic genetic variants of Cryptosporidium (C. parvum) and G. duodenalis (assemblages A and B), although the potential risk of human transmission is regarded as limited due to light parasite burdens and suspected low excretion of infective (oo)cysts to the environment by infected animals. More research should be conducted to ascertain the true impact of these protozoan parasites in the health status of the endangered Iberian lynx.This article is based upon work from project LIFE 19NAT/ES001055 LYNXCONNECT ‘Creating a genetically and demographically functional Iberian Lynx (Lynx pardinus) metapopulation (2020–2025)’ supported by the European Commission. J.C.-G. was supported by the Centre for Biomedical Research Network (CB21/13/00083), Health Institute Carlos III, Ministry of Science and Innovation and European Union-Next Generation EU. S.C.-S. was supported by an FPU grant (FPU19/06026) funded by the Spanish Ministry of Universities. D.J.-M. holds a PhD contract granted by Own Research Plan of the University of Córdoba. D.G.-B. is the recipient of a Sara Borrell research contract (CD19CIII/00011) funded by the Spanish Ministry of Science, Innovation and Universities. A.D. is the recipient of a PFIS contract (FI20CIII/00002) funded by the Spanish Ministry of Science, Innovation and Universities. We thank all the veterinarians and animal keepers of ex situ and in situ conservation programs involved in the sampling as well as all the members of the CAD centre for their assistance in the collection of samples and epidemiological information. We also gratefully acknowledge Junta de Andalucía and Junta de Comunidades de Castilla-La Mancha.S

Sequence variation in mature microRNA-608 and benefit from neo-adjuvant treatment in locally advanced rectal cancer patients

Single nucleotide polymorphisms (SNPs) in microRNA genes have been associated with colorectal cancer (CRC) risk, survival and response to treatment. Conflicting results are available on the association between rs4919510, a SNP in mature miR-608 and clinical outcome in CRC. Here, we analyzed the association between rs4919510 and benefit from perioperative treatment in a randomised phase II trial of neoadjuvant Capecitabine and Oxaliplatin (CAPOX) followed by chemo-radiotherapy, surgery and adjuvant CAPOX ± Cetuximab in high-risk locally advanced rectal cancer (LARC). A total of 155/164 (94.5%) patients were assessable. 95 (61.3%) were homozygous for CC, 55 (35.5%) heterozygous (CG) and 5 (3.2%) homozygous for GG. Median follow-up was 64.9 months. In the CAPOX arm the 5-year progression-free survival (PFS) and overall survival (OS) rates were 54.6% and 60.7% for CC and 82.0% and 82.1% for CG/GG, respectively (HR PFS 0.13, 95% CI: 0.12-0.83, P = 0.02; HR OS 0.38, 95% CI: 0.14-1.01, P = 0.05). In the CAPOX-C arm PFS and OS were 73.2 and 82.2%, respectively for CC carriers and 64.6 and 73.1% for CG/GG carriers (HR PFS 1.38, 95% CI: 0.61-3.13, P = 0.44; HR OS 1.34, 95% CI: 0.52-3.48, P = 0.55). An interaction was found between study treatment and rs4919510 genotype for both PFS (P = 0.02) and OS (P = 0.07). This is the first study investigating rs4919510 in LARC. The CC genotype appeared to be associated with worse prognosis compared to the CG/GG genotype in patients treated with chemotherapy and chemo-radiotherapy alone. Addition of Cetuximab to chemotherapy and chemo-radiotherapy in CC carriers appeared to improve clinical outcome

Genetics and prognostication in splenic marginal zone lymphoma: revelations from deep sequencing

PURPOSE: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies.EXPERIMENTAL DESIGN: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted re-sequencing and explored potential clinical implications in a multinational cohort of 175 SMZL patients.RESULTS: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%) and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time-to-first-treatment (0.12 vs. 1.11 yrs; P=0.01). In multivariate analysis mutations in NOTCH2 (HR 2.12, 95%CI 1.02-4.4, P=0.044) and 100% germline IGHV gene identity (HR 2.19, 95%CI 1.05-4.55, P=0.036) were independent markers of short time-to-first-treatment, while TP53 mutations were an independent marker of short overall survival (HR 2.36, 95% CI 1.08-5.2, P=0.03).CONCLUSIONS: We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively.<br/

Combining scales to assess suicide risk

Authors posting Accepted Author Manuscript online should later add a citation for the Published Journal Article indicating that the Article was subsequently published, and may mention the journal title provided they add the following text at the beginning of the document: “NOTICE: this is the author’s version of a work that was accepted for publication in Journal of Cardiovascular Echography. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Psychiatric Research, [VOL#, ISSUE#, (DATE)] DOI#”A major interest in the assessment of suicide risk is to develop an accurate instrument, which could be easily adopted by clinicians. This article aims at identifying the most discriminative items from a collection of scales usually employed in the assessment of suicidal behavior. Methods: The answers to the Barrat Impulsiveness Scale, International Personality Disorder Evaluation Screening Questionnaire, BrowneGoodwin Lifetime History of Aggression, and Holmes & Rahe Social Readjustment Rating Scale provided by a group of 687 subjects (249 suicide attempters, 81 non-suicidal psychiatric inpatients, and 357 healthy controls) were used by the Lars-en algorithm to select the most discriminative items. Results: We achieved an average accuracy of 86.4%, a specificity of 89.6%, and a sensitivity of 80.8% in classifying suicide attempters using 27 out of the 154 items from the original scales. Conclusions: The 27 items reported here should be considered a preliminary step in the development of a new scale evaluating suicidal risk in settings where time is scarce.This article was supported by the National Alliance for Research on Schizophrenia and Affective Disorders (NARSAD), Fondo de Investigacion Sanitaria (FIS) PI060092, Fondo de Investigacion Sanitaria FIS RD06/0011/0016, ETES (PI07/90207), the Conchita Rabago Foundation, and the Spanish Ministry of Health, Instituto de Salud Carlos III, CIBERSAM (Intramural 521 Project, P91B; SCO/3410/2004)

Guidance Statement On BRCA1/2 Tumor Testing in Ovarian Cancer Patients

International audienceThe approval, in 2015, of the first poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib, Lynparza) for platinum-sensitive relapsed high-grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast or ovarian cancer. Furthermore, testing of tumor samples to identify the estimated 3%-9% of patients with somatic BRCA1/2 mutations who, in addition to germline carriers, could benefit from PARPi therapy is also now being considered. This new testing paradigm poses some challenges, in particular the technical and analytical difficulties of analyzing chemically challenged DNA derived from formalin-fixed, paraffin-embedded specimens. The current manuscript reviews some of these challenges and technical recommendations to consider when undertaking BRCA1/2 testing in tumor tissue samples to detect both germline and somatic BRCA1/2 mutations. Also provided are considerations for incorporating genetic analysis of ovarian tumor samples into the patient pathway and ethical requirements

Моделирование пуска синхронных высоковольтных двигателей прямым включением в сеть с помощью пакета MATLAB SIMULINK

Материалы IX Междунар. межвуз. науч.-техн. конф. студентов, магистрантов и аспирантов,Гомель, 28–29 апр. 2009 г

GRB 130831a: Rise and demise of a magnetar at z = 0.5

Open Access.--14th Marcel Grossman Meeting On Recent Developments in Theoretical and Experimental General Relativity, Astrophysics and Relativistic Field Theories; University of Rome "La Sapienza"Rome; Italy; 12 July 2015 through 18 July 2015; Code 142474.-- http://www.icra.it/mg/mg14/Gamma-ray bursts (GRBs) are the brightest explosions in the universe, yet the properties of their energy sources are far from understood. Very important clues, however, can be deduced by studying the afterglows of these events. We present observations of GRB 130831A and its afterglow obtained with Swift, Chandra, and multiple ground-based observatories. This burst shows an uncommon drop in the X-ray light curve at about 100 ks after the trigger, with a decay slope of α 7. The standard Forward Shock (FS) model offers no explanation for such a behaviour. Instead, a model in which a newly born magnetar outflow powers the early X-ray emission is found to be viable. After the drop, the X-ray afterglow resumes its decay with a slope typical of FS emission. The optical emission, on the other hand, displays no clear break across the X-ray drop and its decay is consistent with that of the late X-rays. Using both the X-ray and optical data, we show that the FS model can explain the emission after 100 ks. We model our data to infer the kinetic energy of the ejecta and thus estimate the efficiency of a magnetar “central engine” of a GRB. Furthermore, we break down the energy budget of this GRB into prompt emission, late internal dissipation, kinetic energy of the relativistic ejecta, and compare it with the energy of the accompanying supernova, SN 2013fu. Copyright © 2018 by the Editors.All rights reserved.Peer reviewe

A Search for Jet Handedness in Hadronic Z0Z^0 Decays

We have searched for signatures of polarization in hadronic jets from $Z^0 \to q \bar{q}$ decays using the ``jet handedness'' method. The polar angle asymmetry induced by the high SLC electron-beam polarization was used to separate quark jets from antiquark jets, expected to be left- and right-polarized, respectively. We find no evidence for jet handedness in our global sample or in a sample of light quark jets and we set upper limits at the 95% C.L. of 0.063 and 0.099 respectively on the magnitude of the analyzing power of the method proposed by Efremov {\it et al.}Comment: Revtex, 8 pages, 2 figure