Descriptions of somatic cell divisions were made as early as the eighteenth and nineteenth centuries with varying degrees of accuracy. In this paper, we would like to present a forgotten Polish ...scientist Waclaw Mayzel (1847–1916), who described somatic mitosis in the corneal epithelium of the frog in 1875 almost simultaneously with the recognized discoveries of animal mitosis by Otto Bütschli and plant mitosis by Eduard Strasburger.
Albert de la Chapelle—pro memoriam Limon, Janusz; Mrózek, Krzysztof
Journal of applied genetics,
09/2021, Volume:
62, Issue:
3
Journal Article
Peer reviewed
In this brief article, we celebrate the life and numerous scientific achievements of Dr. Albert de la Chapelle, a pioneer in the fields of human genetics and cytogenetics.
Although the mutational status in gastrointestinal stromal tumors (GIST) can predict the response to treatment with tyrosine kinase inhibitors, the role of tumor genotype as a prognostic factor ...remains controversial. The ConticaGIST study sought to determine the pathologic and molecular factors associated with disease-free survival (DFS) in patients with operable, imatinib-naive GIST.
Clinicopathologic and molecular data from 1,056 patients with localized GIST who underwent surgery with curative intention (R0/R1) and were registered in the European ConticaGIST database were prospectively obtained and reviewed. Risk of tumor recurrence was stratified using the modified NIH criteria. The median follow-up was 52 months.
On testing for potential prognostic parameters, the following were associated with inferior DFS on multivariable Cox model analysis: primary nongastric site, size >10 cm, mitotic index >10 mitoses per 50 high power field, and the KIT exon 9 duplication hazard ratio (HR), 1.47; 95% confidence interval (CI), 0.9-2.5; P = 0.037 and KIT exon 11 deletions involving codons 557 and/or 558 KITdel-inc557/558; HR, 1.45; 95% CI, 1.0-2.2; P = 0.004. Conversely, PDGFRA exon 18 mutations were indicators of better prognosis HR, 0.23; 95% CI, 0.1-0.6; P = 0.002. KITdel-inc557/558 were an adverse indicator only in GIST localized in the stomach (P < 0.001) but not in tumors with nongastric origin. In gastric GIST, all other mutations presented remarkably superior 5-year DFS.
In conclusion, tumor genotype is an independent molecular prognostic variable associated with gastric GIST and should be used for optimizing tailored adjuvant imatinib treatment.
Abstract Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by the extension of the CAG repeats in exon 1 of the HTT gene and is transmitted in a dominant manner. The present ...study aimed to assess whether patients’ sex, in the context of mutated and normal allele length, contributes to age on onset (AO) of HD. The study population comprised a large cohort of 3723 HD patients from the European Huntington’s Disease Network’s REGISTRY database collected at 160 sites across 17 European countries and in one location outside Europe. The data were analyzed using regression models and factorial analysis of variance (ANOVA) considering both mutated allele length and sex as predictors of patients’ AO. AO, as described by the rater’s estimate, was found to be later in affected women than in men across the whole population. This difference was most pronounced in a subgroup of 1273 patients with relatively short variants of the mutated allele (40–45 CAG repeats) and normal alleles in a higher half of length distribution—namely, more than 17 CAG repeats; however, it was also observed in each group. Our results presented in this observational study point to sex-related differences in AO, most pronounced in the presence of the short mutated and long normal allele, which may add to understanding the dynamics of AO in Huntington’s Disease. Trial registration : ClinicalTrials.gov identifier NCT01590589.
Folate and homocysteine are involved in DNA synthesis and methylation processes, which are deregulated during carcinogenesis.
The aim of this study was to assess the relationship between ...folate/homocysteine concentrations, the functional polymorphisms of folate/homocysteine genes and lung cancer risk among cigarette smokers.
The study included 132 lung cancer patients and 396 controls from northern Poland, matched by sex, age and smoking status. The median cigarette pack-years of smoking among both cases and controls was 30.0. Serum, red blood cell (RBC) folates and serum homocysteine concentrations were measured. The genotypes in selected polymorphic sites of the MTHFR, CBS, SHMT1, MTHFD1, MTRR, MTR, TYMS DHFR, TCN2, and SLC19A1 genes were determined. All study participants underwent scanning with low-dose computed tomography.
Serum folate concentrations above the median (> 17.5 nmol/l among the healthy controls) were associated with an increased lung cancer risk (odds ratio OR, 1.54, 95% confidence intervals CI, 1.04-2.29, P = 0.031). An analogous trend was observed when the population was analysed after subdivision according to RBC folate concentrations, that is, above a value of 506.5 nmol/l (OR, 1.53; 95% CI, 0.95-2.47; P = 0.084). Additionally, in a subset of women, an increased risk of lung cancer development was associated with the SLC19A1 c.80AA genotype (c.80AA versus GG OR, 3.14; 95% CI, 1.32-7.46; P = P = 0.010).
These results suggest that, in the population consisting of heavy smokers, high folate levels add to the cancerogenic effect of smoking.
While the life expectancy of the population has increased, Alzheimer's disease (AD) has emerged as one of the greatest health problems of old age. AD is characterized by neuronal loss and cognitive ...decline. In the AD brain, there is a decrease in levels of acetylcholinesterase (AChE) and an increase in the levels of the related enzyme butyrylcholinesterase (BChE), that accumulate in plaques and tangles. Apolipoprotein E (ApoE) is a major cholesterol carrier and plays an important role in maintaining lipid homeostasis. APOE-ε4 constitutes the most important known genetic risk factor for late-onset AD. It has been proposed that the BCHE-K allele (Ala539Thr) acts in synergy with the APOE-ε4 allele to promote risk for AD. However, there is insufficient evidence to support a correlation. Most studies focused only on the coding regions of the genes. In this study, we analyzed sequence regions beyond the BCHE coding sequence. We found synergy between APOE-ε4 and SNPs localized in 5'UTR (rs1126680) and in intron 2 (rs55781031) of the BCHE-K allele (rs1803274) in 18% of patients with late-onset AD (n = 55). The results show that the coexistence of the APOE-ε4 allele and 3 SNPs in the BCHE gene is associated with a highly elevated risk of late-onset AD. SNP (rs1126680) in 5'UTR of the BCHE gene is located 32 nucleotides upstream of the 28 amino acid signal peptide. Mass spectrometry analysis of the BChE protein produced by SNP (rs1126680) showed that the mutation caused an in frame N-terminal extension of 41 amino acids of the BChE signal peptide. The resultant variant with a 69 amino acid signal peptide, designated N-BChE, may play a role in development of AD.
Background The specificity of brush cytology for detection of malignant pancreatobiliary strictures is high, but its sensitivity is moderate. Fluorescence in situ hybridization (FISH) can be used to ...detect chromosomal aneuploidy in biliary brushing specimens, and, according to some reports, it may improve the sensitivity of routine cytology. Objective To assess the role of routine cytology and FISH in detection of malignant pancreatobiliary strictures. Design Prospective study performed between September 2008 and August 2010. Setting University hospital. Patients This study involved 81 patients with bile duct or pancreatic duct strictures. Intervention Brush cytology obtained during ERCP from pancreatic duct or bile duct strictures and analysis of smears by routine cytology and FISH. Main Outcome Measurements Sensitivity, specificity, and positive and negative predictive values of routine cytology and FISH calculated with a 95% confidence interval. Results The sensitivity of routine cytology was 35.19%, and specificity was 100%. When atypia was identified as positive, the resultant sensitivity was 53.7%, and specificity was 100%. Sensitivity of FISH was 51.85%, and specificity was 88.89%. When either routine cytology was positive or atypia was observed or when the FISH result was positive, sensitivity was the highest (72.22%), and it was statistically significant in comparison with both routine cytology with atypia ( P < .036) and FISH ( P < .023), but specificity was lower than that of routine cytology (88.89% vs 100%). Limitations Use of a DNA probe set that was designed for detection of urothelial carcinoma. Limited number of patients. Conclusion FISH improved the sensitivity of routine cytology. Pancreatic duct brushings were a reliable material for detection of chromosomal abnormalities by FISH. The best diagnostic result was achieved by combining routine cytology with FISH.
Gastrointestinal stromal tumors (GIST) mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM) or sunitinib (SU). Arterial ...hypertension (AH) is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+) GIST patients after IM failure.
We identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2nd line treatment). Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs) of VEGFA and VEGFR2 genes.
One year progression-free survival (PFS; calculated from the start of SU) rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM) was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks) in 55 patients with AH vs. 22% (median 17 weeks) in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively) than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively). We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism (OR: 10.0 p = 0.041 and OR: 10.5; p = 0.015, respectively).
We confirmed that many advanced GIST patients benefit from SU therapy with OS > 1.5 year. Primary tumor KIT/PDGFRA genotype and SU-induced AH, as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS.
The introduction of adjuvant imatinib in gastrointestinal stromal tumors (GISTs) raised debate over the accuracy of National Institutes of Health risk criteria and the significance of other ...prognostic factors in GIST.
Tumor aggressiveness and other clinicopathological factors influencing disease-free survival (DFS) were assessed in 335 patients with primary resectable CD117-immunopositive GISTs (median follow-up, 31 months after primary tumor resection) from a prospectively collected tumor registry.
Overall median DFS was 37 months, and estimated 5-year DFS was 37.8 %. In univariate analysis, high or intermediate risk group (P < .000001), mitotic index >5/50 high-power field (P < .00001), primary tumor size >5 cm (P < .00001), nongastric primary location (P = .0001), male sex (P = .01), R1 resection/tumor rupture (P = .0003), and epithelioid cell or mixed cell pathological subtype (P = .05) negatively affected DFS. In multivariate analysis, statistically significant factors negatively influencing DFS for model 1 were mitotic index >5/50 high-power field (P = .004), primary tumor size >5 cm (P = .001), male sex (P = .003), R1 resection/tumor rupture (P = .04), and nongastric primary tumor location (P = .02), and for model 2 were high/intermediate risk primary tumor (P < .0001 and P = .008, respectively), male sex (P = .007), resection R1/tumor rupture (P = .01), and nongastric primary tumor location (P = .02). Five-year DFS for high, intermediate, and low/very low risk group was 20%, 54%, and 96%, respectively.
The risk criteria for assessing the natural course of primary GISTs were validated, but additional independent prognostic factors-primary tumor location and sex--were also identified.
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