TP53 is not a prognostic markerâ clinical consequences of a generally disregarded fact

Technological progress within the last 15â 20 years has significantly increased our knowledge about the molecular basis of cancer development, tumor progression, and treatment response. As a consequence, a vast number of biomarkers have been proposed, but only a small fraction of them have found their way into clinical use. The aim of this paper is to describe the specific demands a clinically relevant biomarker should meet and how biomarkers can be tested stepwise. We name this procedure the â tripleâ R principleâ : robustness, reproducibility, and relevance. The usefulness of this principle is illustrated with the marker TP53. Since it is mutated in a broad spectrum of cancer entities, TP53 can be considered a very promising marker. Thus, TP53 has been studied in detail but there is still no explicit consensus about its clinical value. By considering our own experience and reviewing the literature, we demonstrate that a major problem of current biomarker research is disregard of whether the biomarker is prognostic or predictive. As an example, it is demonstrated that TP53 is not a prognostic marker, but rather a purely predictive marker, and that disregard of this fact has made this otherwise strong biomarker appear as not being clinically useful so far.Many biomarkers have been proposed for cancer, but only a small fraction of them are clinically useful. This paper describes the specific demands a clinically relevant biomarker should meet and how biomarkers can be tested stepwise. This is illustrated with the marker TP53, which has been studied in detail but for which there is still no explicit consensus about its clinical value.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146810/1/nyas13947.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146810/2/nyas13947_am.pd

A comprehensive candidate gene approach identifies genetic variation associated with osteosarcoma

<p>Abstract</p> <p>Background</p> <p>Osteosarcoma (OS) is a bone malignancy which occurs primarily in adolescents. Since it occurs during a period of rapid growth, genes important in bone formation and growth are plausible modifiers of risk. Genes involved in DNA repair and ribosomal function may contribute to OS pathogenesis, because they maintain the integrity of critical cellular processes. We evaluated these hypotheses in an OS association study of genes from growth/hormone, bone formation, DNA repair, and ribosomal pathways.</p> <p>Methods</p> <p>We evaluated 4836 tag-SNPs across 255 candidate genes in 96 OS cases and 1426 controls. Logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI).</p> <p>Results</p> <p>Twelve SNPs in growth or DNA repair genes were significantly associated with OS after Bonferroni correction. Four SNPs in the DNA repair gene <it>FANCM </it>(ORs 1.9-2.0, <it>P </it>= 0.003-0.004) and 2 SNPs downstream of the growth hormone gene <it>GH1 </it>(OR 1.6, <it>P </it>= 0.002; OR 0.5, <it>P </it>= 0.0009) were significantly associated with OS. One SNP in the region of each of the following genes was significant: <it>MDM2</it>, <it>MPG</it>, <it>FGF2</it>, <it>FGFR3</it>, <it>GNRH2</it>, and <it>IGF1</it>.</p> <p>Conclusions</p> <p>Our results suggest that several SNPs in biologically plausible pathways are associated with OS. Larger studies are required to confirm our findings.</p

Borderline work : does it have any impact on motivation? A study amongst white-collar workers

I takt med den tekniska utvecklingen och den nuvarande pandemin förändras också de traditionella arbetsförhållandena till mer flexibla förhållanden. De gränser som tidigare fanns mellan privatliv och arbetsliv suddas ut och arbetet kräver ett större ansvar från arbetstagarna. Syftet med studien är att undersöka om flexibelt arbete har något samband med individers motivation. De flexibla arbetsförhållanden som undersöks i den här studien innefattar flextid, distansarbete, egen planering av arbetstid samt att vara kontaktbar utanför ordinarie arbetstid. Dessa förhållanden, tillsammans med motivation, mäts för att undersöka om flexibelt arbete har något  samband med individers motivation. Det undersöktes även om det fanns några skillnader kopplat till kön och ålder. Motivationsteorierna som studien utgår från är tvåfaktorteorin, Self-determination theory (SDT) och de yttre och inre faktorer som påverkar individens beteenden. Data samlades in i form av en webenkät som distribuerades till olika chefer och som i sin tur skickade vidare till sina medarbetare via gruppmejl och på internportal till deltagarna. Antalet deltagare som svarade på enkäten var n = 104. I studien besvarades tre frågeställningar och de analyser som genomfördes var; regressionsanalyser, korrelationsanalyser och t-tester. Analyserna visade att det fanns ett samband mellan flexibelt arbete och inre motivation men inget samband mellan flexibelt arbete och yttre motivation. Det fanns även skillnader gällande kön och yttre motivation men inte för inre motivation. Några skillnader gällande ålder kunde inte tydas för inre eller yttre motivation. Studiens resultat var i linje med tidigare forskning

Flykt från känslor : en intervjustudie om åtta kvinnors väg in i tungt narkotikamissbruk

Sammanfattning Syftet med vår uppsats var att studera kvinnors upplevelser av vägen in i ett tungt narkotikamissbruk och beroende. Vi ville därigenom öka förståelsen och förklara deras upplevelser ur aspekterna uppväxtår och tonår. Vi har valt att utgå från den grundade teorin då vi genomfört vår studie. Vi har genomfört en intervjuundersökning med åtta kvinnor, där vi sökte närma oss kvinnornas berättelser så förutsättningslöst som möjligt. Detta för att låta kvinnornas upplevelser stå i centrum. Genom tre separata urval och analyser framkom kärnan till kvinnornas missbrukssituation; Flykten från känslor. Intervjuresultatet påvisar att mönster av uppväxtproblematik hos respondenterna, med likartade uppväxtvillkor vilka bland annat utgörs av våld och missbruk i hemmet. Kärnkategorin synliggjorde den process som leder kvinnorna in i ett tungt missbruk via Uppväxtförhållanden, Utanförskap, Förlust, Svek samt Ensamhet. För att fördjupa förståelsen har vi relaterat vårt empiriska resultat till Stämplingsteorier enligt Becker och Goldberg, Stigma enligt Goffman samt Socialt arv enligt Jonsson. Resultatet av vår studie visar att grunden, kärnkategorin, utgörs av en flykt från känslor och att detta är vinsten av missbruket. Nyckelord: Kvinnor, tungt narkotikamissbruk, Stämplingsteori, Stigma, Socialt arv, Grundad Teor

TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients

We investigated the hypothesis that the varying treatment efficacy of adjuvant 5-fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status. ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol. Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344–3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic. The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect

Strategy for prevention of cancers of the esophagus

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the animal reflux-inflammation models for Barrett's esophagus and esophageal adenocarcinoma; genomic/epigenomic analyses; eflornithine-based combinations; the molecular derangements that promote neoplastic transformation; the role of COX-2 inhibitors, proton pump inhibitors, and phase II trials in Barrett's adenocarcinoma; statins in chemoprevention and treatment of esophageal cancer; and biomarkers as potential targets in Barrett's adenocarcinoma

Pancho trial (p53-adapted neoadjuvant chemotherapy for resectable esophageal cancer) completedmutation rate of the marker higher than expected

Background In operable esophageal cancer patients, neoadjuvant therapy benefits only those who respond to the treatment. The Pancho trial represents the first prospective randomized trial evaluating the relevance of the mark53 status for predicting the effect of two different neoadjuvant chemotherapies. Method Biomarker analysis was conducted using the mark53 analysis. Calculation of patient number needed was based on a 60% rate of marker positivity, deduced from the results of a phase II pilot study. Results From 20072012, the Pancho trial recruited 235 patients with operable esophageal cancer in Austria. A total of 181 patients were eligible and could be subjected to mark53 analysis and randomization. After randomizing 74 patients, the overall TP53 mutation rate was 79%. However, due to the high prevalence of marker positivity, the number of projected patients was increased to 181 patients in order to ensure a sufficient number of marker-negative patients. After completion of the trial, the overall TP53 mutation rate was 77.9%. Conclusion Due to high medical need, the recruitment for the academic trial was excellent. Mark53 analysis clearly detected more mutations in the TP53 gene as compared to the cancer-specific p53 literature. Final analysis examining the interaction between the mark53 status and the effect of chemotherapies applied in the Pancho trial is now awaited.(VLID)359159