Publications by authors named "Stefano Landi"

172 Publications

Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2021 Sep 15. Epub 2021 Sep 15.

Division of Gastroenterology and Research Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.

Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported.

Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software.

Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk ( < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (, , and ) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance ( = 0.05/1588 = 3.1 × 10).

Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk.

Impact: This large case-control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0353DOI Listing
September 2021

Search for AL amyloidosis risk factors using Mendelian randomization.

Blood Adv 2021 07;5(13):2725-2731

Biomedical Center, Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, Czech Republic; and.

In amyloid light chain (AL) amyloidosis, amyloid fibrils derived from immunoglobulin light chain are deposited in many organs, interfering with their function. The etiology of AL amyloidosis is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited by Mendelian randomization (MR) methodology to search for factors influencing AL amyloidosis risk. We performed a 2-sample MR analyzing 72 phenotypes, proxied by 3461 genetic variants, and summary genetic data from a GWAS of 1129 AL amyloidosis cases and 7589 controls. Associations with a Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (P = 3.8 × 10-4) and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17) gene (P = 3.4 × 10-5). Two other associations with the TNFRSF (members 6 and 19L) reached a nominal significance level. The association between genetically predicted decreased fibrinogen levels may be related to roles of fibrinogen other than blood clotting. be related to its nonhemostatic role. It is plausible that a causal relationship with monocyte concentration could be explained by selection of a light chain-producing clone during progression of monoclonal gammopathy of unknown significance toward AL amyloidosis. Because TNFRSF proteins have key functions in lymphocyte biology, it is entirely plausible that they offer a potential link to AL amyloidosis pathophysiology. Our study provides insight into AL amyloidosis etiology, suggesting high circulating levels of monocytes and TNFRSF proteins as risk factors.
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http://dx.doi.org/10.1182/bloodadvances.2021004423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288669PMC
July 2021

Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma.

Carcinogenesis 2021 Aug;42(8):1037-1045

Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.
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http://dx.doi.org/10.1093/carcin/bgab057DOI Listing
August 2021

Liquid Biopsies from Pleural Effusions and Plasma from Patients with Malignant Pleural Mesothelioma: A Feasibility Study.

Cancers (Basel) 2021 May 18;13(10). Epub 2021 May 18.

Department of Biology, Genetic Unit, University of Pisa, via Derna 1, 56126 Pisa, Italy.

Background: Malignant pleural mesothelioma (MPM) is a fatal tumor with a poor prognosis. The recent developments of liquid biopsies could provide novel diagnostic and prognostic tools in oncology. However, there is limited information about the feasibility of this technique for MPMs. Here, we investigate whether cancer-specific DNA sequences can be detected in pleural fluids and plasma of MPM patients as free circulating tumor DNA (ctDNA).

Methods: We performed whole-exome sequencing on 14 tumor biopsies from 14 patients, and we analyzed 20 patient-specific somatic mutations with digital droplet PCR (ddPCR) in pleural fluids and plasma, using them as cancer-specific tumor biomarkers.

Results: Most of the selected mutations could be detected in pleural fluids (94%) and, noteworthy, in plasma (83%) with the use of ddPCR. Pleural fluids showed similar levels of somatically mutated ctDNA (median = 12.75%, average = 16.3%, standard deviation = 12.3) as those detected in solid biopsies (median = 21.95%; average = 22.21%; standard deviation = 9.57), and their paired difference was weakly statistically significant ( = 0.048). On the other hand, the paired difference between solid biopsies and ctDNA from plasma (median = 0.29%, average = 0.89%, standard deviation = 1.40) was highly statistically significant ( = 2.5 × 10), corresponding to the important drop of circulating somatically mutated DNA in the bloodstream. However, despite the tiny amount of ctDNA in plasma, varying from 5.57% down to 0.14%, the mutations were detectable at rates similar to those possible for other tumors.

Conclusions: We found robust evidence that mutated DNA is spilled from MPMs, mostly into pleural fluids, proving the concept that liquid biopsies are feasible for MPM patients.
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http://dx.doi.org/10.3390/cancers13102445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157824PMC
May 2021

Identification of Overexpressed Genes in Malignant Pleural Mesothelioma.

Int J Mol Sci 2021 Mar 8;22(5). Epub 2021 Mar 8.

Department of Biology, University of Pisa, 56126 Pisa, Italy.

Malignant pleural mesothelioma (MPM) is a fatal tumor lacking effective therapies. The characterization of overexpressed genes could constitute a strategy for identifying drivers of tumor progression as targets for novel therapies. Thus, we performed an integrated gene-expression analysis on RNAseq data of 85 MPM patients from TCGA dataset and reference samples from the GEO. The gene list was further refined by using published studies, a functional enrichment analysis, and the correlation between expression and patients' overall survival. Three molecular signatures defined by 15 genes were detected. Seven genes were involved in cell adhesion and extracellular matrix organization, with the others in control of the mitotic cell division or apoptosis inhibition. Using Western blot analyses, we found that ADAMTS1, PODXL, CIT, KIF23, MAD2L1, TNNT1, and TRAF2 were overexpressed in a limited number of cell lines. On the other hand, interestingly, CTHRC1, E-selectin, SPARC, UHRF1, PRSS23, BAG2, and MDK were abundantly expressed in over 50% of the six MPM cell lines analyzed. Thus, these proteins are candidates as drivers for sustaining the tumorigenic process. More studies with small-molecule inhibitors or silencing RNAs are fully justified and need to be undertaken to better evaluate the cancer-driving role of the targets herewith identified.
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http://dx.doi.org/10.3390/ijms22052738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962966PMC
March 2021

Teachings After COVID-19 Outbreak From a Survey of Family Physicians.

J Am Board Fam Med 2021 Feb;34(Suppl):S222-S224

From the Interventional cardiology unit, GVM Care and Research, Maria Cecilia Hospital, Cotignola, Ravenna, Italy (MT, AC, AK); Primary Health Care Department, AUSL Romagna, Italy (IP); Dermatology unit, IRCCS di Policlinico Sant'Orsola, Via Massarenti 9, Bologna, Italy (ML); Dermatology unit, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy (ML); Primary Health Care Department, AUSL Bologna, Italy (AM); Gastroenterology and Interventional Endoscopy Unit, Local Health Authority of Bologna, Italy (SL); Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY (FT); IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (GM).

Background: Since December 2019, the dramatic escalation in coronavirus (COVID-19) cases worldwide has had a significant impact on health care systems. Family physicians (FPs) have played a critical role in the coordination of care.

Materials And Methods: In April 2020, we performed an online prospective survey to assess the impact of the pandemic on FPs' practices.

Results: Three hundred FPs were included. Mean age was 53.6 ± 13.5 years. Before the pandemic, 60.2% reported >75 outpatient visits/week, which reduced down to an average of <20/week for 79.8% of FPs; 24.2% of FPs discontinued home visits, while for 94.7% of FPs there was a >50% increase in the number of telephone consultations. Concern related to the risk of contagion was elevated (≥3/5 in 74.6%) and even higher to the risk of infecting relatives and patients (≥3/5 in 93.3%). The majority of FPs (87%) supported the role of telemedicine in the near future. Satisfaction regarding the network with hospitals/COVID-19-dedicated wards received a score ≤2/5 in 46.9% of cases.

Conclusions: The COVID-19 pandemic has had a significant impact on the working practices of FPs. A collaboration is needed with well-established networks between FPs and referral centers to provide new insights and opportunities to inform future working practices.
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http://dx.doi.org/10.3122/jabfm.2021.S1.200267DOI Listing
February 2021

Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility.

Int J Cancer 2021 06 3;148(11):2779-2788. Epub 2021 Feb 3.

Department of General Surgery, University of Heidelberg, Heidelberg, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.
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http://dx.doi.org/10.1002/ijc.33475DOI Listing
June 2021

Genetic variations in microRNA-binding sites of solute carrier transporter genes as predictors of clinical outcome in colorectal cancer.

Carcinogenesis 2021 04;42(3):378-394

Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska, Prague, Czech Republic.

One of the principal mechanisms of chemotherapy resistance in highly frequent solid tumors, such as colorectal cancer (CRC), is the decreased activity of drug transport into tumor cells due to low expression of important membrane proteins, such as solute carrier (SLC) transporters. Sequence complementarity is a major determinant for target gene recognition by microRNAs (miRNAs). Single-nucleotide polymorphisms (SNPs) in target sequences transcribed into messenger RNA may therefore alter miRNA binding to these regions by either creating a new site or destroying an existing one. miRSNPs may explain the modulation of expression levels in association with increased/decreased susceptibility to common diseases as well as in chemoresistance and the consequent inter-individual variability in drug response. In the present study, we investigated whether miRSNPs in SLC transporter genes may modulate CRC susceptibility and patient's survival. Using an in silico approach for functional predictions, we analyzed 26 miRSNPs in 9 SLC genes in a cohort of 1368 CRC cases and 698 controls from the Czech Republic. After correcting for multiple tests, we found several miRSNPs significantly associated with patient's survival. SNPs in SLCO3A1, SLC22A2 and SLC22A3 genes were defined as prognostic factors in the classification and regression tree analysis. In contrast, we did not observe any significant association between miRSNPs and CRC risk. To the best of our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to SLC transporter genes and their impact on CRC susceptibility or patient's prognosis.
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http://dx.doi.org/10.1093/carcin/bgaa136DOI Listing
April 2021

Pro64His (rs4644) Polymorphism Within Galectin-3 Is a Risk Factor of Differentiated Thyroid Carcinoma and Affects the Transcriptome of Thyrocytes Engineered via CRISPR/Cas9 System.

Thyroid 2021 07 2;31(7):1056-1066. Epub 2021 Mar 2.

Genetic Unit, Department of Biology, University of Pisa, Pisa, Italy.

Galectin-3 () is an important glycoprotein involved in the malignant transformation of thyrocytes acting in the extracellular matrix, cytoplasm, and nucleus where it regulates TTF-1 and TCF4 transcription factors. Within gene, a common single-nucleotide polymorphism (SNP) (c.191C>A, p.Pro64His; rs4644) encoding for the variant Proline to Histidine at codon 64 has been extensively studied. However, data on rs4644 in the context of thyroid cancer are lacking. Thus, the aim of the present work was to evaluate the role of the rs4644 SNP as risk factor for differentiated thyroid cancer (DTC) and to determine the effect on the transcriptome in thyrocytes. A case/control association study in 1223 controls and 1142 unrelated consecutive DTC patients was carried out to evaluate the association between rs4644-P64H and the risk of DTC. We used the nonmalignant cell line Nthy-Ori (rs4644-C/A) and the CRISPR/Cas9 technique to generate isogenic cells carrying either the rs4644-A/A or rs4644-C/C homozygosis. Then, the transcriptome of the derivative and unmodified parental cells was analyzed by RNA-seq. Genes differentially expressed were validated by quantitative reverse transcription PCR and further tested in the parental Nthy-Ori cells after gene silencing, to investigate whether the expression of target genes was dependent on galectin-3 levels. rs4644 AA genotype was associated with a reduced risk of DTC (compared with CC, OR = 0.66; 95% confidence interval = 0.46-0.93; P = 0.02). We found that rs4644 affects galectin-3 as a transcriptional coregulator. Among 34 genes affected by rs4644, , , , and were of particular interest since their expression was rs4644-dependent (CC>AA for the first and AA>CC for the others), also in 574 thyroid tissues of Genotype-Tissue Expression (GTEx) biobank. Moreover, the expression of these genes was regulated by -silencing. Using the proximity ligation assay in Nthy-Ori cells, we found that the TTF-1 interaction was genotype dependent. Our data show that in thyroid, rs4644 is a trans-expression quantitative trait locus that can modify the transcriptional expression of downstream genes, through the modulation of TTF-1.
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http://dx.doi.org/10.1089/thy.2020.0366DOI Listing
July 2021

Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma.

Invest New Drugs 2021 06 9;39(3):644-657. Epub 2020 Dec 9.

Department of Biology, Genetic Unit, University of Pisa, 56126, Pisa, Italy.

Objectives Malignant pleural mesothelioma (MPM) is an occupational disease mainly due to asbestos exposure. Effective therapies for MPM are lacking, making this tumour type a fatal disease. Materials and Methods In order to meet this need and in view of a future "drug repositioning" approach, here we screened five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model, with a library of 1170 FDA-approved drugs. Results Among several potential compounds, we found that fludarabine (F-araA) and, to a lesser extent, risedronic acid (RIS) were cytotoxic in MPM cells, in comparison to the non-malignant Met-5A cells. In particular, F-araA reduced the proliferation and the colony formation ability of the MPM malignant cells, in comparison to the non-malignant control cells, as demonstrated by proliferation and colony formation assays, in addition to measurement of the phospho-ERK/total-ERK ratio. We have shown that the response to F-araA was not dependent upon the expression of DCK and NT5E enzymes, nor upon their functional polymorphisms (rs11544786 and rs2295890, respectively). Conclusion This drug repositioning screening approach has identified that F-araA could be therapeutically active against MPM cells, in addition to other tumour types, by inhibiting STAT1 expression and nucleic acids synthesis. Further experiments are required to fully investigate this.
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http://dx.doi.org/10.1007/s10637-020-01040-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068714PMC
June 2021

Common gene variants within 3'-untranslated regions as modulators of multiple myeloma risk and survival.

Int J Cancer 2021 04 20;148(8):1887-1894. Epub 2020 Nov 20.

Laboratory of Clinical and Transplant Immunology and Genetics, Copernicus Memorial Hospital, Lodz, Poland.

We evaluated the association between germline genetic variants located within the 3'-untranlsated region (polymorphic 3'UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3'-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis.
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http://dx.doi.org/10.1002/ijc.33377DOI Listing
April 2021

Variation rs2235503 C > A Within the Promoter of Affects Transcriptional Rate of Mesothelin and Plasmatic Levels of the Soluble Mesothelin-Related Peptide.

Front Genet 2020 18;11:975. Epub 2020 Aug 18.

Department of Biology, University of Pisa, Pisa, Italy.

Soluble mesothelin-related peptide (SMRP) is a promising biomarker for malignant pleural mesothelioma (MPM), but several confounding factors can reduce SMRP-based test's accuracy. The identification of these confounders could improve the diagnostic performance of SMRP. In this study, we evaluated the sequence of 1,000 base pairs encompassing the minimal promoter region of the gene to identify expression quantitative trait loci (eQTL) that can affect SMRP. We assessed the association between four promoter variants and SMRP levels in a cohort of 72 MPM and 677 non-MPM subjects, and we carried out assays to investigate their functional role. Our results show that rs2235503 is an eQTL for associated with increased levels of SMRP in non-MPM subjects. Furthermore, we show that this polymorphic site affects the accuracy of SMRP, highlighting the importance of evaluating the individual's genetic background and giving novel insights to refine SMRP specificity as a diagnostic biomarker.
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http://dx.doi.org/10.3389/fgene.2020.00975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461867PMC
August 2020

Tissue expression of lactate transporters (MCT1 and MCT4) and prognosis of malignant pleural mesothelioma (brief report).

J Transl Med 2020 09 4;18(1):341. Epub 2020 Sep 4.

Department of Biology, University of Pisa, Pisa, Toscana, Italy.

Background: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm of the pleura, mainly related to asbestos exposure. As in other solid tumors, malignant cells exhibit high glucose uptake and glycolytic rates with increased lactic acid efflux into the interstitial space. Lactate transport into and out of cells, crucial to maintaining intracellular pH homeostasis and glycolysis, is carried out by monocarboxylate transporters (MCTs) and the chaperone basigin (CD147). We set out to examine the clinical significance of basigin, MCT1 and MCT4 in the context of MPM and to evaluate their expression in relation to the evolution of the disease.

Methods: We used immunohistochemistry to measure the expression of basigin, MCT1 and MCT4 in a cohort of 135 individuals with MPM compared to a series of 15 non-MPM pleura specimens. Moreover, by Kaplan-Meier and Cox analyses we evaluated whether an expression over the average of these markers could be associated with the patients' overall survival (OS).

Results: We detected positive staining of basigin, MCT1, and MCT4 in most MPM specimens. In particular, MCT4 was always positive in malignant tissues but undetectable in the 4 normal pleural specimens incorporated within the tissue microarray. This was confirmed in the additional series of 15 normal pleural samples. Moreover, MCT4 expression was significantly associated with reduced OS.

Conclusion: In this study, the tissue expression of basigin did not prove to be exploitable as a diagnostic or prognostic marker for MPM patients. The expression of MCT1 was not informative either, being tightly correlated with that of basigin. However, the expression of MCT4 showed promise as a diagnostic/therapeutic and prognostic biomarker.
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http://dx.doi.org/10.1186/s12967-020-02487-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650278PMC
September 2020

Germline genetic variability in pancreatic cancer risk and prognosis.

Semin Cancer Biol 2020 Aug 18. Epub 2020 Aug 18.

Department of Biology, University of Pisa, Pisa, Italy.

Pancreatic cancer (PC), particularly its most common form, pancreatic ductal adenocarcinoma (PDAC), is relatively rare but highly lethal. Knowledge about PC risk factors could in the long term contribute to early diagnosis and mortality reduction. We review the current status of research on germline genetic factors for PC risk. Genome-wide association studies (GWAS) successfully identified common loci convincingly associated with PC risk, an endeavor that is still ongoing. The function of only a handful of risk loci has being thoroughly characterized so far. Secondary analyses of existing GWAS data are being used to discover novel loci. GWAS data have also been used to study additional risk factors with a Mendelian randomization approach. Polygenic/multifactorial risk scores show much larger risks than individual variants, but their use for risk stratification in the population is not warranted yet. At the other end of the spectrum of inherited PC risk factors, rare high-penetrance variants co-segregating with the disease have been observed in familial cancer syndromes that include PC, or in families with multiple recurrence of PC alone. Rare variants predicted to have a deleterious effect on function are studied also with a case-control approach, by resequencing candidate genes or whole-exomes/whole-genomes. Telomere length and mitochondrial DNA copy number are useful additional DNA-based markers of PC susceptibility. The role of common variants in prognosis of PC patients has also been explored, albeit with more limited success than risk. Finally, genetics of pancreatic neuroendocrine tumors (PNET), a rarer and heterogeneous form of PC, is still understudied.
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http://dx.doi.org/10.1016/j.semcancer.2020.08.003DOI Listing
August 2020

and as Possible Drivers for Malignant Pleural Mesothelioma.

Int J Mol Sci 2020 Jul 9;21(14). Epub 2020 Jul 9.

Department of Biology, Genetic Unit, University of Pisa, 56126 Pisa, Italy.

For malignant pleural mesothelioma (MPM) novel therapeutic strategies are urgently needed. In a previous study, we identified 51 putative cancer genes over-expressed in MPM tissues and cell lines. Here, we deepened the study on nine of them (, , , , (), , , , and ) to ascertain whether they are truly mesothelial cancer driver genes (CDGs) or genes overexpressed in an adaptive response to the tumoral progression ("passenger genes"). Through a fast siRNA-based screening, we evaluated the consequences of gene depletion on migration, proliferation, colony formation capabilities, and caspase activities of four MPM (Mero-14, Mero-25, IST-Mes2, and NCI-H28) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model. The depletion of and significantly reduced cell proliferation and colony formation and increased caspase activity. In particular, the findings for RAN resemble those observed for other types of cancer. Thus, we evaluated the in vitro effects of importazole (IPZ), a small molecule inhibitor of the interaction between RAN and importin-β. We showed that IPZ could have effects similar to those observed following gene silencing. We also found that primary cell lines from one out of three MPM patients were sensitive to IPZ. As and deserve further investigation with additional in vitro and in vivo studies, they emerged as promising CDGs, suggesting that their upregulation could play a role in mesothelial tumorigenesis and aggressiveness. Furthermore, present data propose the molecular pathways dependent on RAN as a putative pharmacological target for MPM patients in the view of a future personalized medicine.
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http://dx.doi.org/10.3390/ijms21144856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402288PMC
July 2020

Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction.

J Med Genet 2021 06 26;58(6):369-377. Epub 2020 Jun 26.

Cancer Center Amsterdam, Amsterdam, The Netherlands.

Background: Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection.

Objective: We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score.

Methods: We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes.

Results: The scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10, highest vs lowest quintile of the weighted multifactorial score).

Conclusion: We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.
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http://dx.doi.org/10.1136/jmedgenet-2020-106961DOI Listing
June 2021

The role of regional health systems on the waiting time inequalities in health care services: Evidences from Italy.

Health Serv Manage Res 2021 08 31;34(3):136-147. Epub 2020 May 31.

Department of Economics, University of Genoa Faculty of Economics, Genova, Italy.

Inequalities in effective access to healthcare are present among countries and within the same country. Despite in Italy exist the principle of equity in access to health system, there are evidence of different access rates in the form of unequal waiting time within the country. Waiting times are an instruments to ration healthcare services dealing with resource scarsity. Theoretically, it is a fair tool because waiting times should depend only on health needs and not on the ability to pay. However, a growing literature has pointed out that belonging to a particular socioeconomic status leads to waiting times inequalities for healthcare services. Many countries have socioeconomic disparities among regions, and healthcare organizations need to take into account these differences. The increasing power of Regional Health Authorities in decentralized health systems, as in the case of Italy, has generated different organizational ways to provide health care, possibly leading to different access rates in the form of unequal waiting time within the country. This paper aims to understand if the administrative area (Regional Health Authorities) in charge of health services affects waiting times lowering or strengthening health care access inequalities. Using a series of logistic regression models, this work suggests the presence of two vectors: socioeconomic inequalities and regional inequalities. Health organizations need to implement different kinds of answers for each vectors of inequalities.
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http://dx.doi.org/10.1177/0951484820928302DOI Listing
August 2021

Redesign of a GI endoscopy unit during the COVID-19 emergency: A practical model.

Dig Liver Dis 2020 10 16;52(10):1178-1187. Epub 2020 May 16.

Humanitas Clinical and Research Center, Digestive Endoscopy Unit, Division of Gastroenterology, Rozzano (Milan).

The pandemic diffusion of the SARS-CoV-2 infection throughout the world required measures to prevent and strategies to control the infection, as well as the reallocation of the hospital structures in order to take care of an increased number of infected patients. Endoscopy Units should be able to perform endoscopic procedures on COVID-19 infected as well as on noninfected patients. The aim of this manuscript is to propose a model for a fast reorganization of the endoscopy department environment in order to safely perform endoscopic procedures in this Pandemic COVID-19 scenario, according to the current advices given by the Scientific Societies.
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http://dx.doi.org/10.1016/j.dld.2020.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229969PMC
October 2020

Genome-wide association study identifies an early onset pancreatic cancer risk locus.

Int J Cancer 2020 10 1;147(8):2065-2074. Epub 2020 May 1.

Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.

Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore, we performed a genome-wide association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset ≤60 years, of whom 198 with age of onset ≤50, and 3227 controls from PanScan I-II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P < 1 × 10 ). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset ≤60 years, of whom 265 with age of onset ≤50, and 4142 controls from the PANDoRA consortium while in the in silico data, we observed no statistically significant association. However, the resulting meta-analysis supported the association (P = 1.15 × 10 ). In conclusion, we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature.
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http://dx.doi.org/10.1002/ijc.33004DOI Listing
October 2020

Polymorphisms Within the Proto-Oncogene and Risk of Sporadic Medullary Thyroid Carcinoma.

Thyroid 2020 11 5;30(11):1579-1588. Epub 2020 May 5.

Endocrine Unit, Department of Clinical and Experimental Medicine, University Hospital of Cisanello, Pisa, Italy.

Sporadic medullary thyroid carcinoma (sMTC) is an uncommon neoplasia arising from the calcitonin-producing parafollicular cells of the thyroid. Previous studies evaluated whether single nucleotide polymorphisms (SNPs) within (a pivotal proto-oncogene for this disease) are associated with the risk for developing sMTC, but the results are inconclusive. In this work, we evaluated the association of -SNPs c.74-126G>T (rs2565206), p.Gly691Ser (rs1799939, G>A), p.Leu769 = (rs1800861, G>T), p.Ser836 = (rs1800862, C>T), and p.Ser904 = (rs1800863, C>G) (listed in the order of their chromosomal location) with sMTC. This is one of the largest casecontrol association studies carried out on sMTC, including 585 sMTC cases (negative for germline mutations within ), 1529 patients affected by sporadic nonmedullary thyroid carcinoma (sNMTC), and 989 healthy controls, from central and southern Italy and collected in the period 2000-2017. sNMTC patients showed similar genotype and allele frequencies compared with healthy controls. On the other hand, among sMTC patients, the T-allele of p.Leu769 = was less frequent (OR = 0.70 [CI 0.58-0.84],  = 1.9 × 10) and rare homozygotes TT showed an OR = 0.32 ([CI 0.17-0.60],  = 2.3 × 10). Moreover, a statistically significant excess of the haplotype 2 (characterized by the alleles T-G-G-C-C of the listed SNPs) was observed ( = 3.9 × 10). The SNPs were not associated with the expression of mRNA, that is, they did not exert an effect in as quantitative trait locus (cis-eQTL). However, a strong eQTL association was found for p.Leu769 = and the neighboring gene ( = 9.3 × 10; effect-size = -0.65), whose function in cancer is unknown. This study shows that specific haplotypes, in particular haplotype 2 and the T-allele of p.Leu769 = , are associated with a reduced risk of sMTC in Italians.
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http://dx.doi.org/10.1089/thy.2019.0352DOI Listing
November 2020

What is Best Testing Ground for Clinical Evaluation of Single-use Duodenoscopes?

Clin Gastroenterol Hepatol 2020 07 14;18(8):1899-1900. Epub 2020 Feb 14.

Gastroenterology and Interventional Endoscopy Unit, Local Health Authority of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1016/j.cgh.2020.02.018DOI Listing
July 2020

Correction to: Psychiatric disorders and SLC6A4 gene variants: possible effects on alcohol dependence and alzheimer's disease.

Mol Biol Rep 2020 03;47(3):2415

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123, Bologna, Italy.

The following authors have double affiliations: Stefania Boccia, Marco Di Nicola and they should read.
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http://dx.doi.org/10.1007/s11033-020-05260-6DOI Listing
March 2020

Genetic variants associated with psychotic symptoms across psychiatric disorders.

Neurosci Lett 2020 02 13;720:134754. Epub 2020 Jan 13.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Italy. Electronic address:

Background: Recent evidence suggests that psychiatric symptoms share a common genetic liability across diagnostic categories. The present study investigated the effects of variants within previously identified relevant genes on specific symptom clusters, independently from the diagnosis.

Methods: 1550 subjects affected by Schizophrenia (SCZ), Major Depressive Disorder or Bipolar Disorder were included. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depression Rating Scale (HDRS). Principal component analysis and a further clinical refinement were used to define symptom clusters. Clusters scores were tested for association with 46 genetic variants within nine genes previously linked to one or more major psychiatric disorders by large genome wide association studies (ANK3, CACNA1C, CACNB2, FKBP5, FZD3, GRM7, ITIH3, SYNE1, TCF4). Exploratory analyses were performed in each disorder separately to further elucidate the SNPs effects.

Results: five PANSS clusters (Negative; Impulsiveness; Cognitive; Psychotic; Depressive) and four HDRS clusters (Core Depressive; Somatic; Psychotic-like; Insomnia) were identified. CACNA1C rs11615998 was associated with HDRS Psychotic cluster in the whole sample. In the SCZ sample, CACNA1C rs11062296 was associated with PANSS Impulsiveness cluster and CACNA1C rs2238062 was associated with PANSS negative cluster.

Discussion: CACNA1C rs11615998 was associated with psychotic symptoms (C-allele carriers have decreased psychotic-risk) independently from the diagnosis, in line with the evidence of a cross disorder effect of many risk variants. This gene was previously associated with SCZ and cross-disorder liability to psychiatric disorders. Our findings confirmed that deep phenotyping is pivotal to clarify the role of genetic variants on symptoms patterns.
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http://dx.doi.org/10.1016/j.neulet.2020.134754DOI Listing
February 2020

Locked posterior fracture-dislocation of the shoulder.

Acta Biomed 2019 12 5;90(12-S):139-146. Epub 2019 Dec 5.

U.O. ortopedia e traumatologia, ospedale M. Bufalini, Cesena (FC), Italy.

Background And Aim Of The Work: To describe a valid option for the treatment of locked posterior fracture-dislocation of the shoulder (LPFDS) and to compare it to the literature about this topic.

Methods: We present a small case series (3 patients), with a medium follow up at 4 years and 5 months. We accurately describe our surgical strategies, underlining the choice of approach, reduction and fixation.

Results: The three patients showed excellent functional and radiological results at the follow up examinations, with a full range of shoulder movements and complete regain of pre-trauma activities. A lateral approach (standard or minimally invasive), a reduction technique with a Shantz pin in the head and in the humeral shaft, and fixation with a locking plate were used in the three patients.

Conclusion: LPFDS is a challenging lesion, hard to recognize and to treat. Our suggested method of treatment is highly reproducible and has revealed itself to be very effective in achieving good results.
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http://dx.doi.org/10.23750/abm.v90i12-S.8972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233701PMC
December 2019

Non-compensatory aggregation method to measure social and material deprivation in an urban area: relationship with premature mortality.

Eur J Health Econ 2020 Apr 6;21(3):381-396. Epub 2019 Dec 6.

Department of Management, Ca' Foscari University of Venice, Venice, Italy.

Health inequalities exist between nations, regions, and even smaller units. In societies where social and economic structures change rapidly and continuously, analysis of health socioeconomic determinants plays a fundamental role to provide proper policy answers. This study aims to measure accurately two different conceptions of deprivation by developing two different indexes using non-compensatory among sub-indicators aggregation methods. The proposed indicators are compared with premature mortality to verify deprivation's effect on health status. The results show that materially deprived areas are not necessarily socially deprived and vice versa. Material deprivation has a positive statistical co-graduation with premature mortality, while social deprivation has no association with premature mortality.
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http://dx.doi.org/10.1007/s10198-019-01139-xDOI Listing
April 2020

Use, effectiveness and tolerability of budesonide-MMX in ulcerative colitis: A real-life experience.

United European Gastroenterol J 2019 11 17;7(9):1164-1170. Epub 2019 Jul 17.

Gastroenterology Unit, University of Milan, Milan, Italy.

Background: Budesonide-MMX has an established role in the management of relapsing mild-to-moderate ulcerative colitis. Data regarding effectiveness and tolerability in real-life clinical practice are limited.

Aim: The aim of this study was to assess the use of budesonide-MMX in ulcerative colitis, as well as short-term effectiveness and tolerability in real-life practice.

Methods: We conducted a retrospective study of adult patients with mild-to-moderate ulcerative colitis treated with budesonide-MMX at four tertiary inflammatory bowel disease centres in Italy from June 2016 to February 2018. Demographic and clinical features of patients, the use of budesonide-MMX, disease course and concomitant therapy were recorded. The primary outcome assessed was clinical remission at 2 months.

Results: A total of 82 patients with active mild-to-moderate ulcerative colitis were included in the study with a mean age of 45.9 years and a median partial Mayo Score of 4 (interquartile range 3-5). A total of 41 patients were male. Overall, 36 had extensive colitis, 38 left-sided colitis and eight proctitis. Treatments at the time of inclusion included 10 patients receiving biologic therapy, seven azathioprine and 54 mesalazine or salazopyrin. The main reasons for the addition of budesonide-MMX were clinical relapse (47.5%) or inadequate response to current therapy (39.0%). In total, 50% of patients achieved clinical remission, whereas 9.8% had clinical improvement. No response was noted in 40.2% of subjects. Using multivariate binary logistic regression, a moderate degree of activity was the main independent predictor of non-response. Eight significant adverse effects were reported in six patients with three discontinuing treatment.

Conclusion: In real-life clinical practice, budesonide-MMX is commonly used in combination with other therapies, both for acute disease flares and for partial response to therapy.
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http://dx.doi.org/10.1177/2050640619864257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826517PMC
November 2019

DNA polymerases in the risk and prognosis of colorectal and pancreatic cancers.

Mutagenesis 2019 12;34(5-6):363-374

Department of Biology, University of Pisa, Pisa, Italy.

Human cancers arise from the alteration of genes involved in important pathways that mainly affect cell growth and proliferation. DNA replication and DNA damages recognition and repair are among these pathways and DNA polymerases that take part in these processes are frequently involved in cancer onset and progression. For example, damaging alterations within the proofreading domain of replicative polymerases, often reported in patients affected by colorectal cancer (CRC), are considered risk factors and drivers of carcinogenesis as they can lead to the accumulation of several mutations throughout the genome. Thus, replicative polymerases can be involved in cancer when losses of their physiological functions occur. On the contrary, reparative polymerases are often involved in cancer precisely because of their physiological role. In fact, their ability to repair and bypass DNA damages, which confers genome stability, can also counteract the effect of most anticancer drugs. In addition, the altered expression can characterise some type of cancers, which exacerbates this aspect. For example, all of the DNA polymerases involved a damage bypass mechanism, known as translesion synthesis, with the only exception of polymerase theta, are downregulated in CRC. Conversely, in pancreatic ductal adenocarcinoma (PDAC), most of these polymerase result upregulated. This suggests that different types of cancer can rely on different reparative polymerases to acquire drug resistance. Here we will examine all of the aspects that link DNA polymerases with CRC and PDAC.
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http://dx.doi.org/10.1093/mutage/gez031DOI Listing
December 2019

Psychiatric disorders and SLC6A4 gene variants: possible effects on alcohol dependence and alzheimer's disease.

Mol Biol Rep 2020 Jan 8;47(1):191-200. Epub 2019 Oct 8.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123, Bologna, Italy.

Serotoninergic system is one of the most important neurotransmission systems investigated in the field of psychiatry. Extensive evidence reveals how alterations of this system, and especially of the SLC6A4 gene, may be associated with psychiatric disorders. In this study we aimed to evaluate the pleiotropic nature of SLC6A4 alterations and their association with the overall risk of brain diseases rather than disorder-specific. SLC6A4 variants, namely 5HTTLPR, STin2, rs2066713, rs25531, rs4251417, rs6354 and rs7224199 were investigated in 4 independent cohorts of subjects with specific psychiatric disorders, including Alcohol dependence disorder (ALC), Alzheimer disease (ALZ), Schizophrenia (SCZ) and Bipolar disorder (BPD). Other variables (biochemical parameters and Psychiatric scales scores) were also tested for association. SLC6A4 polymorphisms are not associated with the risk of developing major psychiatric disorders (SCZ and BPD); however some signals were detected in ALC (HTTLPR p = 9.25 × 10, p = 7.24 × 10; rs2066713 p = 6.35 × 10; rs25531 p = 2.95 × 10; rs4251417 p = 2.46 × 10), and ALZ (rs6354 p = 1.22 × 10; rs7224199 p = 1.00 × 10, p = 2.65 × 10) cohorts. Some associations were also observed on exploratory analyses. Our findings did not reveal any major influence on SCZ and BPD development; On the other hand, some alteration of the SLC6A4 sequence were associated with an increased risk of ALC and ALZ disorders, suggesting common pathways. The results of this study should be carefully interpreted since it suffers of some inherent limitations (e.g. cohort size, slight ethnic heterogeneity). Further analyses may provide better detail on the molecular processes behind SLC6A4 alterations.
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http://dx.doi.org/10.1007/s11033-019-05119-5DOI Listing
January 2020

Socioeconomic Status and Waiting Times for Health Services: Current Evidences and Next Area of Research.

Health Serv Insights 2019 2;12:1178632919871295. Epub 2019 Sep 2.

Department of Economics and Business Studies, University of Genoa, Genoa, Italy.

Waiting times are an issue in many countries, excessive waiting for treatments may deteriorate patient's health status and reduce treatment effectiveness potentially, becoming a barrier in the access to health care services. Waiting time to be equitable should be related only to the health need, people with the same health need have to wait the same time, without any difference due to socioeconomic status. In the commentary, the results of the extensive literature review and policy implications are discussed.
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http://dx.doi.org/10.1177/1178632919871295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724484PMC
September 2019
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