Recently, a novel classification for pulmonary adenocarcinomas (ADCs) was published, the cornerstone of which is the quantification of growth patterns. Data on reproducibility in the routine ...diagnostic setting are lacking. 100 constitutive cases of lung ADC resection specimens from our archives were classified independently by five pulmonary pathologists and two residents according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. The most frequent predominant pattern in our cohort was solid (37%), followed by acinar (35%), lepidic (20%), papillary (5%) and micropapillary (3%). κ-values for the denomination of the predominant pattern revealed substantial agreement for pulmonary pathologists (κ=0.44-0.72) and fair agreement for residents (κ=0.38-0.47). Interobserver variability was significantly higher in cases with higher slide numbers (p=0.028) and was considerably reduced after training. Intraobserver variability was low (κ=0.79-0.87). Papillary and micropapillary patterns were the most complicated patterns to evaluate, while evaluation of lepidic and solid tumour growth was straightforward. Our data imply that the novel classification of pulmonary ADC is applicable with acceptable interobserver variability if performed by specifically trained pathologists. Additional efforts are needed to harmonise the application of this novel and clinically important classification scheme of pulmonary ADC.
Relatively little is known about protective factors and the emergence and maintenance of positive outcomes in the field of adolescents with chronic conditions. Therefore, the primary aim of the study ...is to acquire a deeper understanding of the dynamic process of resilience factors, coping strategies and psychosocial adjustment of adolescents living with chronic conditions.
We plan to consecutively recruit N = 450 adolescents (12-21 years) from three German patient registries for chronic conditions (type 1 diabetes, cystic fibrosis, or juvenile idiopathic arthritis). Based on screening for anxiety and depression, adolescents are assigned to two parallel groups - "inconspicuous" (PHQ-9 and GAD-7 < 7) vs. "conspicuous" (PHQ-9 or GAD-7 ≥ 7) - participating in a prospective online survey at baseline and 12-month follow-up. At two time points (T1, T2), we assess (1) intra- and interpersonal resiliency factors, (2) coping strategies, and (3) health-related quality of life, well-being, satisfaction with life, anxiety and depression. Using a cross-lagged panel design, we will examine the bidirectional longitudinal relations between resiliency factors and coping strategies, psychological adaptation, and psychosocial adjustment. To monitor Covid-19 pandemic effects, participants are also invited to take part in an intermediate online survey.
The study will provide a deeper understanding of adaptive, potentially modifiable processes and will therefore help to develop novel, tailored interventions supporting a positive adaptation in youths with a chronic condition. These strategies should not only support those at risk but also promote the maintenance of a successful adaptation.
German Clinical Trials Register (DRKS), no. DRKS00025125 . Registered on May 17, 2021.
Background
Adult depression is a common consequence of adverse childhood experiences. There is also a higher likelihood of being affected by economic burdens after having experienced a traumatic ...event in childhood. As depression has been associated with economic burden, these long-term sequelae of childhood adversity are likely to interact.
Goals
We investigated depression and economic consequences, such as unemployment, lower level of education, lower income as long-term sequelae of adverse childhood experiences in adulthood and their interaction.
Methods
Childhood Maltreatment was measured by the German version of the Adverse Childhood Experience (ACE) questionnaire. Depression was measured by the Patient Health Questionnaire (PHQ-2). Logistic regressions were applied to investigate the risks of suffering economic burdens, with depression as a moderator.
Results
Depressive symptoms increased with the number of ACEs and were highest in those reporting four or more ACEs, especially amongst those who experienced sexual and emotional abuse, as well as neglect. Moderation analysis showed a significant effect of depression increasing almost all economic burdens. Migration background additionally increased the risk of unemployment and working in a blue-collar job. Female gender decreased the risk of unemployment and working in a blue-collar job, but increased the risk of low income and part-time employment.
Conclusion
The moderation effect of depression increased the negative impact of exposure to multiple ACEs on economic life in adulthood. Prevention of ACEs and early intervention are needed to prevent the mental health and economic consequences.
The immense biodiversity of the Atlas Mountains in North Africa might be the result of high rates of microallopatry caused by mountain barriers surpassing 4000 meters leading to patchy habitat ...distributions. We test the influence of geographic structures on the phylogenetic patterns among Buthus scorpions using mtDNA sequences. We sampled 91 individuals of the genus Buthus from 51 locations scattered around the Atlas Mountains (Antiatlas, High Atlas, Middle Atlas and Jebel Sahro). We sequenced 452 bp of the Cytochrome Oxidase I gene which proved to be highly variable within and among Buthus species. Our phylogenetic analysis yielded 12 distinct genetic groups one of which comprised three subgroups mostly in accordance with the orographic structure of the mountain systems. Main clades overlap with each other, while subclades are distributed parapatrically. Geographic structures likely acted as long-term barriers among populations causing restriction of gene flow and allowing for strong genetic differentiation. Thus, genetic structure and geographical distribution of genetic (sub)clusters follow the classical theory of allopatric differentiation where distinct groups evolve without range overlap until reproductive isolation and ecological differentiation has built up. Philopatry and low dispersal ability of Buthus scorpions are the likely causes for the observed strong genetic differentiation at this small geographic scale.
Chromosomal instability (CIN) is an emerging hallmark of cancer and its role in therapeutic responses has been increasingly attracting the attention of the research community. To target the ...vulnerability of tumors with high CIN, it is important to identify the genes and mechanisms involved in the maintenance of CIN. In our work, we recognize the tumor suppressor gene Phosphatase and Tensin homolog (PTEN) as a potential gene causing CIN in triple-negative breast cancer (TNBC) and show that TNBC with low expression levels of PTEN can be sensitized for the treatment with poly-(ADP-ribose)-polymerase 1 (PARP1) inhibitors, independent of Breast Cancer (BRCA) mutations or a BRCA-like phenotype. In silico analysis of mRNA expression data from 200 TNBC patients revealed low expression of PTEN in tumors with a high CIN70 score. Western blot analysis of TNBC cell lines confirm lower protein expression of PTEN compared to non TNBC cell lines. Further, PTEN-deficient cell lines showed cellular sensitivity towards PARP1 inhibition treatment. DNA fiber assays and examination of chromatin bound protein fractions indicate a protective role of PTEN at stalled replication forks. In this study, we recognize PTEN as a potential CIN-causing gene in TNBC and identify its important role in the replication processes.
Chromosomal instability not only has a negative effect on survival in triple-negative breast cancer, but also on the well treatable subgroup of luminal A tumors. This suggests a general mechanism ...independent of subtypes. Increased chromosomal instability (CIN) in triple-negative breast cancer (TNBC) is attributed to a defect in the DNA repair pathway homologous recombination. Homologous recombination (HR) prevents genomic instability by repair and protection of replication. It is unclear whether genetic alterations actually lead to a repair defect or whether superior signaling pathways are of greater importance. Previous studies focused exclusively on the repair function of HR. Here, we show that the regulation of HR by the intra-S-phase damage response at the replication is of overriding importance. A damage response activated by Ataxia telangiectasia and Rad3 related-checkpoint kinase 1 (ATR-CHK1) can prevent replication stress and leads to resistance formation. CHK1 thus has a preferred role over HR in preventing replication stress in TNBC. The signaling cascade ATR-CHK1 can compensate for a double-strand break repair error and lead to resistance of HR-deficient tumors. Established methods for the identification of HR-deficient tumors for Poly(ADP-Ribose)-Polymerase 1 (PARP1) inhibitor therapies should be extended to include analysis of candidates for intra-S phase damage response.
We analyzed 121 golden jackals (
Canis aureus
) from six sample sites in Serbia with regard to genetic variability and differentiation as revealed by mitochondrial control region sequences and eight ...nuclear microsatellite loci. There was no variation at all in the mtDNA sequences, and nuclear variability was very low (average observed and expected heterozygosity of 0.29 and 0.34, respectively). This is in line with the considerable recent range expansion of this species in the Balkans and indicates a strong founder effect in the recently established Serbian population. We did not find evidence of differentiation between the northeastern jackals and those from the plain of Srem or those in between.
F
-statistics and Bayesian Structure analyses, however, were indicative of a low degree of overall differentiation in the Serbian population. A vagrant Austrian jackal that was also analyzed was genetically indistinguishable from its Serbian conspecifics.
We analysed 229 Eurasian otters from eastern and north‐western Germany, Denmark and southern Sweden based on sequences of the mtDNA control region and genotypes at 12 polymorphic nuclear ...microsatellite loci. The main focus of the study lay on the north‐west German otters from Schleswig‐Holstein, which represent a newly established and expanding population recolonizing a formerly inhabited region, thereby closing the distributional gap between the large eastern population and the long‐isolated and genetically depleted Danish population. As found before in this species, mtDNA variability was very low but we identified a hitherto unknown haplotype in Sweden. Expected heterozygosities were between 0.46 and 0.69 and thus within the range known from the literature. There were only weak signs of a founder effect in the Schleswig‐Holstein otters with respect to allelic diversity (but not heterozygosity). Nevertheless, there was a statistically significant bottleneck signal based on deviations from mutation‐drift equilibrium in Schleswig‐Holstein. All statistical approaches (amovas, factorial correspondence analysis, assignment tests and Bayesian structure analysis) unequivocally showed that north‐western Germany has so far been predominantly recolonized by otters of east German origin, but we also found evidence of admixture through immigration from Denmark. Both the Danish and the north‐west German otter population will benefit from further exchange in the wake of the ongoing range expansion.
Zusammenfassung
Insgesamt 229 Fischotter aus dem Osten und Nordwesten Deutschlands sowie aus Dänemark und Südschweden wurden auf der Basis von Sequenzen der mitochondrialen Kontrollregion und Genotypen an 12 polymorphen nukleären Mikrosatellitenloci populationsgenetisch untersucht. Hauptaugenmerk lag auf dem Bestand in Schleswig‐Holstein, der in jüngster Zeit neu etabliert wurde und sich weiterhin ausbreitet. Damit schließt dieser die Verbreitungslücke zwischen der großen Population im Osten und den lange isolierten und genetisch verarmten Ottern in Dänemark. Im Einklang mit früheren Studien war die Variabilität des mitochondrialen Markers sehr gering; es wurde jedoch ein bisher unbekannter Haplotyp in Schweden nachgewiesen. Die erwartete Heterozygotie lag mit Werten zwischen 0.46 und 0.69 im für Fischotter üblichen Bereich. Es gab schwache Anzeichen eines Gründereffektes für Schleswig‐Holstein in Bezug auf Alleldiversität, nicht jedoch Heterozygotie. Dennoch war ein Bottleneck‐Test basierend auf Abweichungen vom Mutationsdrift‐Gleichgewicht für Schleswig‐Holstein statistisch signifikant. Alle statistischen Verfahren (amovas, FCA, Assignment‐Tests und Bayesianische Structure‐Analyse) zeigten, dass Nordwestdeutschland bisher überwiegend vom Osten her wiederbesiedelt wird, doch wurden auch genetische Spuren einer Immigration aus Dänemark gefunden. Sowohl die dänische als auch die nordwestdeutsche Fischotterpopulation werden von einem weiteren genetischen Austausch im Zuge der gegenwärtigen Ausbreitung profitieren.
Abstract Background Replication-dependent radiosensitization of tumors ranks among the most promising tools for future improvements in tumor therapy. However, cell cycle checkpoint signaling during S ...phase is a key for maintaining genomic stability after ionizing irradiation allowing DNA damage repair by stabilizing replication forks, inhibiting new origin firing and recruiting DNA repair proteins. As the impact of the different types of DNA damage induced by ionizing radiation on replication fork functionality has not been investigated, this study was performed in tumor cells treated with various agents that induce specific DNA lesions. Methods U2OS cells were exposed to methyl methanesulfonate (MMS) to induce base damage, low or high concentrations of hydrogen peroxide for the induction of SSBs, Topotecan to induce DSBs at replication, Mitomycin C (MMC) to induce interstrand cross-links or ionizing irradiation to analyze all damages. Chk1 phosphorylation, origin firing and replication fork progression, and cell cycle distribution were analyzed. Results In our system, the extent of Chk1 phosphorylation was dependent on the type of damage induced and prolonged Chk1 phosphorylation correlated with the inhibition of replication initiation. Ionizing radiation, high concentrations of hydrogen peroxide, and Topotecan affected replication elongation much more strongly that the other agents. Almost all agents induced a slight increase in the S phase population but subsequent G2 arrest was only observed in response to those agents that strongly inhibited replication elongation and caused prolonged Chk1 phosphorylation. Conclusions Our data suggest that to improve radiotherapy, radiosensitivity in S phase could be increased by combining irradiation with agents that induce secondary DSB or inhibit checkpoint signaling, such as inhibitors of PARP or Chk1.
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