| 1. |
- Lang, Christian, et al.
(author)
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C-Myc protein expression indicates unfavorable clinical outcome in surgically resected small cell lung cancer
- 2024
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In: World Journal of Surgical Oncology. - 1477-7819. ; 22:1
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Journal article (peer-reviewed)abstract
- Background: By being highly involved in the tumor evolution and disease progression of small cell lung cancer (SCLC), Myc family members (C-Myc, L-Myc, and N-Myc) might represent promising targetable molecules. Our aim was to investigate the expression pattern and prognostic relevance of these oncogenic proteins in an international cohort of surgically resected SCLC tumors. Methods: Clinicopathological data and surgically resected tissue specimens from 104 SCLC patients were collected from two collaborating European institutes. Tissue sections were stained by immunohistochemistry (IHC) for all three Myc family members and the recently introduced SCLC molecular subtype-markers (ASCL1, NEUROD1, POU2F3, and YAP1). Results: IHC analysis showed C-Myc, L-Myc, and N-Myc positivity in 48%, 63%, and 9% of the specimens, respectively. N-Myc positivity significantly correlated with the POU2F3-defined molecular subtype (r = 0.6913, p = 0.0056). SCLC patients with C-Myc positive tumors exhibited significantly worse overall survival (OS) (20 vs. 44 months compared to those with C-Myc negative tumors, p = 0.0176). Ultimately, in a multivariate risk model adjusted for clinicopathological and treatment confounders, positive C-Myc expression was confirmed as an independent prognosticator of impaired OS (HR 1.811, CI 95% 1.054–3.113, p = 0.032). Conclusions: Our study provides insights into the clinical aspects of Myc family members in surgically resected SCLC tumors. Notably, besides showing that positivity of Myc family members varies across the patients, we also reveal that C-Myc protein expression independently correlates with worse survival outcomes. Further studies are warranted to investigate the role of Myc family members as potential prognostic and predictive markers in this hard-to-treat disease.
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| 2. |
- Pattaro, Cristian, et al.
(author)
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Prospective epidemiological, molecular, and genetic characterization of a novel coronavirus disease in the Val Venosta/Vinschgau : the CHRIS COVID-19 study protocol
- 2022
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In: Pathogens and Global Health. - : Taylor & Francis. - 2047-7724 .- 2047-7732. ; 116:2, s. 128-136
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Journal article (peer-reviewed)abstract
- The COVID-19 pandemic has been threatening the healthcare and socioeconomic systems of entire nations. While population-based surveys to assess the distribution of SARS-CoV-2 infection have become a priority, pre-existing longitudinal studies are ideally suited to assess the determinants of COVID-19 onset and severity.The Cooperative Health Research In South Tyrol (CHRIS) study completed the baseline recruitment of 13,393 adults from the Venosta/Vinschgau rural district in 2018, collecting extensive phenotypic and biomarker data, metabolomic data, densely imputed genotype and whole-exome sequencing data.Based on CHRIS, we designed a prospective study, called CHRIS COVID-19, aimed at: 1) estimating the incidence of SARS-CoV-2 infections; 2) screening for and investigating the determinants of incident infection among CHRIS participants and their household members; 3) monitoring the immune response of infected participants prospectively.An online screening questionnaire was sent to all CHRIS participants and their household members. A random sample of 1450 participants representative of the district population was invited to assess active (nasopharyngeal swab) or past (serum antibody test) infections. We prospectively invited for complete SARS-CoV-2 testing all questionnaire completers gauged as possible cases of past infection and their household members. In positive tested individuals, antibody response is monitored quarterly for one year. Untested and negative participants receive the screening questionnaire every four weeks until gauged as possible incident cases or till the study end.Originated from a collaboration between researchers and community stakeholders, the CHRIS COVID-19 study aims at generating knowledge about the epidemiological, molecular, and genetic characterization of COVID-19 and its long-term sequelae.
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| 3. |
- Pattaro, Cristian, et al.
(author)
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The Cooperative Health Research in South Tyrol (CHRIS) study : rationale, objectives, and preliminary results
- 2015
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In: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 13
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Journal article (peer-reviewed)abstract
- The Cooperative Health Research In South Tyrol (CHRIS) study is a population-based study with a longitudinal lookout to investigate the genetic and molecular basis of age-related common chronic conditions and their interaction with life style and environment in the general population. All adults of the middle and upper Vinschgau/Val Venosta are invited, while 10,000 participants are anticipated by mid-2017. Family participation is encouraged for complete pedigree reconstruction and disease inheritance mapping. After a pilot study on the compliance with a paperless assessment mode, computer-assisted interviews have been implemented to screen for conditions of the cardiovascular, endocrine, metabolic, genitourinary, nervous, behavioral, and cognitive system. Fat intake, cardiac health, and tremor are assessed instrumentally. Nutrient intake, physical activity, and life-course smoking are measured semi-quantitatively. Participants are phenotyped for 73 blood and urine parameters and 60 aliquots per participant are biobanked (cryo-preserved urine, DNA, and whole and fractionated blood). Through liquid-chromatography mass-spectrometry analysis, metabolite profiling of the mitochondrial function is assessed. Samples are genotyped on 1 million variants with the Illumina HumanOmniExpressExome array and the first data release including 4570 fully phenotyped and genotyped samples is now available for analysis. Participants' follow-up is foreseen 6 years after the first visit. The target population is characterized by long-term social stability and homogeneous environment which should both favor the identification of enriched genetic variants. The CHRIS cohort is a valuable resource to assess the contribution of genomics, metabolomics, and environmental factors to human health and disease. It is awaited that this will result in the identification of novel molecular targets for disease prevention and treatment.
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| 4. |
- Prasuhn, Jannik, et al.
(author)
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Task matters-challenging the motor system allows distinguishing unaffected Parkin mutation carriers from mutation-free controls
- 2021
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In: Parkinsonism & Related Disorders. - : Elsevier. - 1353-8020 .- 1873-5126. ; 86, s. 101-104
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Journal article (peer-reviewed)abstract
- Background: Heterozygous carriers of Parkin mutations are suggested to be at risk of developing Parkinson's disease, while biallelic variants are associated with typical autosomal recessive early-onset PD. Investigating unaffected heterozygous mutation carriers holds the potential of a deeper understanding of monogenic PD and has implications for PD in general, in particular regarding the prodromal phase.Objectives: To discriminate healthy Parkin mutation carriers from healthy non-mutation carriers using a multimodal approach.Methods: Twenty-seven healthy heterozygous Parkin mutation carriers (13 female. age: 48 +/- 13 years) and 24 healthy non-mutation carriers (14 female. age: 48 +/- 15 years) from the CHRIS study (Cooperative Health Research in South Tyrol) were recalled based on their genetic profile and underwent a blinded assessment of motor and non-motor PD symptoms, transcranial sonography and sensor-based posturography and gait analyses under different conditions with increasing difficulty. For the latter, gradient-boosted trees were used to discriminate between carriers and non-carriers. The classification accuracy and the area under the curve of the receiver-operator characteristics curve were calculated.Results: We observed no differences concerning motor or non-motor symptoms and substantia nigra hyperechogenicity. The best gradient-boosted trees-based model on posturography measurements (tandem feet, eyes closed, firm surface), however, showed a classification accuracy of up to 86%. The best-performing gradientboosted trees-based model for gait analyses showed a balanced accuracy of up to 87% (dual-tasking).Conclusions: Sensor-based quantification of movements allows to discriminate unaffected heterozygous mutation carriers from mutation-free controls. Thereby, it is crucial to challenge the motor system with more difficult tasks to unmask subtle motor alterations.
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| 5. |
- Velicky, Philipp, et al.
(author)
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Genome amplification and cellular senescence are hallmarks of human placenta development
- 2018
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In: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 14:10
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Journal article (peer-reviewed)abstract
- Genome amplification and cellular senescence are commonly associated with pathological processes. While physiological roles for polyploidization and senescence have been described in mouse development, controversy exists over their significance in humans. Here, we describe tetraploidization and senescence as phenomena of normal human placenta development. During pregnancy, placental extravillous trophoblasts (EVTs) invade the pregnant endometrium, termed decidua, to establish an adapted microenvironment required for the developing embryo. This process is critically dependent on continuous cell proliferation and differentiation, which is thought to follow the classical model of cell cycle arrest prior to terminal differentiation. Strikingly, flow cytometry and DNAseq revealed that EVT formation is accompanied with a genome-wide polyploidization, independent of mitotic cycles. DNA replication in these cells was analysed by a fluorescent cell-cycle indicator reporter system, cell cycle marker expression and EdU incorporation. Upon invasion into the decidua, EVTs widely lose their replicative potential and enter a senescent state characterized by high senescence-associated (SA) beta-galactosidase activity, induction of a SA secretory phenotype as well as typical metabolic alterations. Furthermore, we show that the shift from endocycle-dependent genome amplification to growth arrest is disturbed in androgenic complete hydatidiform moles (CHM), a hyperplastic pregnancy disorder associated with increased risk of developing choriocarinoma. Senescence is decreased in CHM-EVTs, accompanied by exacerbated endoreduplication and hyperploidy. We propose induction of cellular senescence as a ploidy-limiting mechanism during normal human placentation and unravel a link between excessive polyploidization and reduced senescence in CHM.
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