Publications by authors named "Annalisa Astolfi"

122 Publications

Gene Expression Landscape of SDH-Deficient Gastrointestinal Stromal Tumors.

J Clin Med 2021 Mar 4;10(5). Epub 2021 Mar 4.

Division of Oncology, IRCCS-Azienda Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy.

Background: About 20-40% of gastrointestinal stromal tumors (GISTs) lacking KIT/PDGFRA mutations show defects in succinate dehydrogenase (SDH) complex. This study uncovers the gene expression profile (GEP) of SDH-deficient GIST in order to identify new signaling pathways or molecular events actionable for a tailored therapy.

Methods: We analyzed 36 GIST tumor samples, either from formalin-fixed, paraffin-embedded by microarray or from fresh frozen tissue by RNA-seq, retrospectively collected among KIT-mutant and SDH-deficient GISTs. Pathway analysis was performed to highlight enriched and depleted transcriptional signatures. Tumor microenvironment and immune profile were also evaluated.

Results: SDH-deficient GISTs showed a distinct GEP with respect to KIT-mutant GISTs. In particular, SDH-deficient GISTs were characterized by an increased expression of neural markers and by the activation of fibroblast growth factor receptor signaling and several biological pathways related to invasion and tumor progression. Among them, hypoxia and epithelial-to-mesenchymal transition emerged as features shared with SDH-deficient pheochromocytoma/paraganglioma. In addition, the study of immune landscape revealed the depletion of tumor microenvironment and inflammation gene signatures.

Conclusions: This study provides an update of GEP in SDH-deficient GISTs, highlighting differences and similarities compared to KIT-mutant GISTs and to other neoplasm carrying the SDH loss of function. Our findings add a piece of knowledge in SDH-deficient GISTs, shedding light on their putative histology and on the dysregulated biological processes as targets of new therapeutic strategies.
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http://dx.doi.org/10.3390/jcm10051057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961685PMC
March 2021

Case Report: The Complete Remission of a Mixed Germ Cell Tumor With Somatic Type Malignancy of Sarcoma Type With a GCT-Oriented Therapy: Clinical Findings and Genomic Profiling.

Front Oncol 2021 16;11:633543. Epub 2021 Mar 16.

Department of Translational Medicine, University of Ferrara, Ferrara, Italy.

Somatic malignant transformation in a germ cell tumor (GCT) is the development of non-germ malignancies; much of available literature refers to teratoma with malignant transformation (TMT). There are various transformation histologies such as sarcoma, adenocarcinoma, primitive neuroectodermal tumors, and more rarely carcinoid tumors, hemangioendothelioma, lymphoma, or nephroblastoma. The treatments of these entities include surgery and/or chemotherapy. A standard approach in choosing chemotherapy in TMT cases has not yet been established. Many authors suggest using chemotherapeutic agents based on the transformed histology, while others recommend GCT-oriented therapy combined with surgery as the primary treatment, reserving histology-driven chemotherapies for metastatic relapse. We report the clinical findings and the genomic profile of a mixed GCT case with somatic-type malignancy of sarcoma type. We achieved a complete radiological response with GCT-oriented chemotherapy performed as salvage therapy after sarcoma-histology therapy. In addition, molecular profiles with RNA-sequencing and exome sequencing analyses of the primary tumor and the tumor with somatic-type malignancy of sarcoma type were explored.
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http://dx.doi.org/10.3389/fonc.2021.633543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008106PMC
March 2021

The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST).

Cancers (Basel) 2021 Feb 9;13(4). Epub 2021 Feb 9.

Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.

The majority of gastrointestinal stromal tumors (GIST) carry a sensitive primary KIT mutation, but approximately 5% to 10% of cases harbor activating mutations of platelet-derived growth factor receptor (PDGFRA), mainly involving the A-loop encoded by exon 18 (~5%), or more rarely the JM domain, encoded by exon 12 (~1%), or the ATP binding domain encoded by exon 14 (<1%). The most frequent mutation is the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V) in exon 18, widely recognized as D842V. This mutation, as well known, provides primary resistance to imatinib and sunitinib. Thus, until few years ago, no active drugs were available for this subtype of GIST. Conversely, recent years have witnessed the development of a new specific inhibitor-avapritinib-that has been studied in in vitro and clinical setting with promising results. In light of this primary resistance to conventional therapies, the biological background of D842V-mutant GIST has been deeply investigated to better understand what features characterize this peculiar subset of GIST, and some promising insights have emerged. Hereinafter, we present a comprehensive overview on the clinical features and the molecular background of this rare subtype of GIST.
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http://dx.doi.org/10.3390/cancers13040705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916155PMC
February 2021

Components of a Neanderthal gut microbiome recovered from fecal sediments from El Salt.

Commun Biol 2021 Feb 5;4(1):169. Epub 2021 Feb 5.

Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, Bologna, Italy.

A comprehensive view of our evolutionary history cannot ignore the ancestral features of our gut microbiota. To provide some glimpse into the past, we searched for human gut microbiome components in ancient DNA from 14 archeological sediments spanning four stratigraphic units of El Salt Middle Paleolithic site (Spain), including layers of unit X, which has yielded well-preserved Neanderthal occupation deposits dating around 50 kya. According to our findings, bacterial genera belonging to families known to be part of the modern human gut microbiome are abundantly represented only across unit X samples, showing that well-known beneficial gut commensals, such as Blautia, Dorea, Roseburia, Ruminococcus, Faecalibacterium and Bifidobacterium already populated the intestinal microbiome of Homo since as far back as the last common ancestor between humans and Neanderthals.
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http://dx.doi.org/10.1038/s42003-021-01689-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864912PMC
February 2021

Non-Coding RNAs in the Transcriptional Network That Differentiates Skeletal Muscles of Sedentary from Long-Term Endurance- and Resistance-Trained Elderly.

Int J Mol Sci 2021 Feb 3;22(4). Epub 2021 Feb 3.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna School of Medicine, 40138 Bologna, Italy.

In a previous study, the whole transcriptome of the vastus lateralis muscle from sedentary elderly and from age-matched athletes with an exceptional record of high-intensity, life-long exercise training was compared-the two groups representing the two extremes on a physical activity scale. Exercise training enabled the skeletal muscle to counteract age-related sarcopenia by inducing a wide range of adaptations, sustained by the expression of protein-coding genes involved in energy handling, proteostasis, cytoskeletal organization, inflammation control, and cellular senescence. Building on the previous study, we examined here the network of non-coding RNAs participating in the orchestration of gene expression and identified differentially expressed micro- and long-non-coding RNAs and some of their possible targets and roles. Unsupervised hierarchical clustering analyses of all non-coding RNAs were able to discriminate between sedentary and trained individuals, regardless of the exercise typology. Validated targets of differentially expressed miRNA were grouped by KEGG analysis, which pointed to functional areas involved in cell cycle, cytoskeletal control, longevity, and many signaling pathways, including AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), which had been shown to be pivotal in the modulation of the effects of high-intensity, life-long exercise training. The analysis of differentially expressed long-non-coding RNAs identified transcriptional networks, involving lncRNAs, miRNAs and mRNAs, affecting processes in line with the beneficial role of exercise training.
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http://dx.doi.org/10.3390/ijms22041539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913629PMC
February 2021

Filaggrin Loss-of-Function Mutations Are Risk Factors for Severe Food Allergy in Children with Atopic Dermatitis.

J Clin Med 2021 Jan 11;10(2). Epub 2021 Jan 11.

Division of Pediatrics, IRCCS Azienda Ospedaliero, Universitaria di Bologna, 40138 Bologna, Italy.

Atopic dermatitis is frequently associated with the onset of other allergic conditions, such as asthma, rhino-conjunctivitis and food allergy. The etiology of atopic dermatitis is marginally understood in spite of the number of predisposing factors, above all, mutations in the gene ). In this study, the association between loss-of-function variants in the gene and other allergic manifestations, in particular food allergy, was evaluated in an Italian pediatric population affected by atopic dermatitis. The 10 more frequently mutated loci in the gene were genotyped in 238 children affected by atopic dermatitis and tested for association with clinical features of allergic disorders by a multivariate logistic regression model. R501X and 2282del4 were the only two mutations identified; 12.2% of children carry one of these variants, corresponding to an allelic frequency of 6.5%. According to multivariate statistical analysis, loss-of-function variants in the gene represent a risk factor for the onset of severe manifestations of food allergy (OR = 8.9; CI: 3.1-28.3). Peanut and hazelnut were identified as high-risk foods in patients with mutations. This study demonstrates that atopic children carrying mutations represent a high-risk population due to their predisposition to develop severe food allergy reactions, such as anaphylaxis.
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http://dx.doi.org/10.3390/jcm10020233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827548PMC
January 2021

Gene duplication, rather than epigenetic changes, drives FGF4 overexpression in KIT/PDGFRA/SDH/RAS-P WT GIST.

Sci Rep 2020 11 16;10(1):19829. Epub 2020 Nov 16.

"Giorgio Prodi" Cancer Research Center (CIRC), University of Bologna, Bologna, Italy.

Gastrointestinal stromal tumours that are wild type for KIT and PDGFRA are referred to as WT GISTs. Of these tumours, SDH-deficient (characterized by the loss of SDHB) and quadruple WT GIST (KIT/PDGFRA/SDH/RAS-P WT) subgroups were reported to display a marked overexpression of FGF4, identifying a putative common therapeutic target for the first time. In SDH-deficient GISTs, methylation of an FGF insulator region was found to be responsible for the induction of FGF4 expression. In quadruple WT, recurrent focal duplication of FGF3/FGF4 was reported; however, how it induced FGF4 expression was not investigated. To assess whether overexpression of FGF4 in quadruple WT could be driven by similar epigenetic mechanisms as in SDH-deficient GISTs, we performed global and locus-specific (on FGF4 and FGF insulator) methylation analyses. However, no epigenetic alterations were detected. Conversely, we demonstrated that in quadruple WT GISTs, FGF4 expression and the structure of the duplication were intimately connected, with the copy of FGF4 closer to the ANO1 super-enhancer being preferentially expressed. In conclusion, we demonstrated that in quadruple WT GISTs, FGF4 overexpression is not due to an epigenetic mechanism but rather to the specific genomic structure of the duplication. Even if FGF4 overexpression is driven by different molecular mechanisms, these findings support an increasing biologic relevance of the FGFR pathway in WT GISTs, both in SDH-deficient and quadruple WT GISTs, suggesting that it may be a common therapeutic target.
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http://dx.doi.org/10.1038/s41598-020-76519-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670422PMC
November 2020

Direct Antiviral Treatments for Hepatitis C Virus Have Off-Target Effects of Oncologic Relevance in Hepatocellular Carcinoma.

Cancers (Basel) 2020 Sep 19;12(9). Epub 2020 Sep 19.

Center for Applied Biomedical Research (CRBA), Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.

Background And Aims: HCV eradication by direct-acting antiviral agents (DAAs) reduces de novo hepatocellular carcinoma (HCC) incidence in cirrhosis; however, contrasting evidence about beneficial or detrimental effects still exists in patients who have already developed HCC.

Methods: we investigated whether sofosbuvir and daclatasvir modulate cell proliferation, invasion capability and gene expression (RNA-seq) in HCC-derived cell lines, hypothesizing possible off-target effects of these drugs. Results observed in HCC cell lines were validated in non-HCC cancer-derived cell lines and a preliminary series of human HCC tissues by qPCR and IHC.

Results: DAAs can affect HCC cell proliferation and migration capability by either increasing or reducing them, showing transcriptomic changes consistent with some unexpected drug-associated effects. Off-target gene modulation, mainly affecting ribosomal genes, mitochondrial functions and histones, points to epigenetics and proliferation as relevant events, consistent with matched phenotypic changes. A preliminary validation of in vitro findings was performed in a restricted cohort of HCC patients previously treated with DAAs, with immunohistochemical correlations suggesting DAA-treated HCCs to be more aggressive in terms of migration and epidermal-to-mesenchymal transition.

Conclusions: Our findings suggested the possible occurrence of off-target effects ultimately modulating cell proliferation and/or migration and potentially justified previous findings showing some instances of particularly aggressive HCC recurrence as well as reduced incidence of recurrence of HCC following treatment with DAAs.
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http://dx.doi.org/10.3390/cancers12092674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565876PMC
September 2020

Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile.

Cancers (Basel) 2020 Jul 31;12(8). Epub 2020 Jul 31.

"Giorgio Prodi" Cancer Research Center, University of Bologna, 40138 Bologna, Italy.

Uterine Leiomyosarcoma (uLMS) is by far the most common type of uterine sarcoma, characterized by an aggressive clinical course, a heterogeneous genetic profile and a very scarce response to cytotoxic chemotherapy. The genetic make-up of uLMS is an area of active study that could provide essential cues for the development of new therapeutic approaches. A total of 216 patients with uLMS from cBioPortal and AACR-GENIE databases were included in the study. The vast majority of patients (81%) carried at least one mutation in either , , or . The most frequently mutated gene was , with 61% of the patients harboring at least one mutation, followed by at 48%. alteration was more frequent in metastases than in primary lesions, consistent with a later acquisition during tumor progression. There was a significant trend for and mutations to occur together, while both and were mutually exclusive with respect to inactivation. Overall survival did not show significant correlation with the mutational status, even if mutation emerged as a favorable prognostic factor in the -mutant subgroup. This comprehensive analysis shows that uLMS is driven almost exclusively by the inactivation of tumor suppressor genes and suggests that future therapeutic strategies should be directed at targeting the main genetic drivers of uLMS oncogenesis.
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http://dx.doi.org/10.3390/cancers12082126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464219PMC
July 2020

Inhibition of Methyltransferase DOT1L Sensitizes to Sorafenib Treatment AML Cells Irrespective of -Rearrangements: A Novel Therapeutic Strategy for Pediatric AML.

Cancers (Basel) 2020 Jul 20;12(7). Epub 2020 Jul 20.

Pediatric Hematology-Oncology Unit, Department of Medical and Surgical Sciences DIMEC, University of Bologna, S. Orsola-Malpighi Hospital, Via Massarenti 11, 40138 Bologna, Italy.

Pediatric acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis for which there are few effective targeted approaches, despite the numerous genetic alterations, including gene rearrangements (-r). The histone methyltransferase DOT1L is involved in supporting the proliferation of -r cells, for which a target inhibitor, Pinometostat, has been evaluated in a clinical trial recruiting pediatric -r leukemic patients. However, modest clinical effects have been observed. Recent studies have reported that additional leukemia subtypes lacking -r are sensitive to DOT1L inhibition. Here, we report that targeting DOT1L with Pinometostat sensitizes pediatric AML cells to further treatment with the multi-kinase inhibitor Sorafenib, irrespectively of -r. DOT1L pharmacologic inhibition induces AML cell differentiation and modulates the expression of genes with relevant roles in cancer development. Such modifications in the transcriptional program increase the apoptosis and growth suppression of both AML cell lines and primary pediatric AML cells with diverse genotypes. Through ChIP-seq analysis, we identified the genes regulated by DOT1L irrespective of -r, including the Sorafenib target , providing mechanistic insights into the drug combination activity. Our results highlight a novel therapeutic strategy for pediatric AML patients.
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http://dx.doi.org/10.3390/cancers12071972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409321PMC
July 2020

Impact of Chemotherapy in the Adjuvant Setting of Early Stage Uterine Leiomyosarcoma: A Systematic Review and Updated Meta-Analysis.

Cancers (Basel) 2020 Jul 14;12(7). Epub 2020 Jul 14.

Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, 40128 Bologna, Italy.

Background: Although the use of adjuvant chemotherapy (AC) appears to be increasing over the past few years, several clinical trials and previous meta-analyses failed to determine whether AC could improve clinical outcomes in uterine leiomyosarcoma (uLMS). The aim of this systematic review and meta-analysis was to compare AC (with or without radiotherapy) versus observation (obs) after primary surgery in early stage uLMS.

Materials And Methods: Randomized controlled (RCTs) and non-randomized studies (NRSs) were retrieved. Outcomes of interest were as follows: distant recurrence rate, locoregional recurrence rate and overall recurrence rate. Results about distant recurrence rate, locoregional recurrence rate and overall recurrence rate were compared by calculating odds ratios (ORs) with 95% confidence intervals (CIs); ORs were combined with Mantel-Haenszel method.

Results: Nine studies were included in the analysis, involving 545 patients (AC: 252, obs: 293). Compared with obs, AC did not reduce locoregional and distant recurrence rate, with a pooled OR of 1.36 and 0.63, respectively. Similarly, administration of AC did not decrease overall recurrence rate in comparison to obs.

Conclusion: According to our results, AC (with or without radiotherapy) did not decrease recurrence rate in early stage uLMS; thus, the role of AC in this setting remains unclear.
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http://dx.doi.org/10.3390/cancers12071899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409135PMC
July 2020

Gene Expression Profiling of PDGFRA Mutant GIST Reveals Immune Signatures as a Specific Fingerprint of D842V Exon 18 Mutation.

Front Immunol 2020 2;11:851. Epub 2020 Jun 2.

Medical Oncology Unit, S.Orsola-Malpighi University Hospital, Bologna, Italy.

Platelet Derived Growth Factor Receptor Alpha (PDGFRA) mutations occur in only about 5-7% of gastrointestinal stromal tumors (GIST), notably with alterations on exons 12/14/18. The most frequent PDGFRA mutation is the exon 18 D842V, which is correlated to specific clinico-pathological features, such as primary imatinib resistance and higher indolence. Here, we present a gene expression profile (GEP) comparison of D842V vs. PDGFRA with mutations other than D842V (non-D842V). GEP was followed by bioinformatic analysis aimed at evaluating differential expression, tumor microenvironment composition and pathway enrichment. We found a large set of oncogenes, transcription factors and nuclear receptors downregulated in the D842V mutant. Conversely, D842V showed a significant enrichment of immune- and interferon- related gene signatures. Differences in tumor microenvironment composition were also highlighted, including a higher abundance of CD8+ T-cells and an overexpression of the T cell-inflamed signature in the D842V mutant subgroup, which is predictive of immunotherapy response. PDGFRA D842V vs. non-D842V GIST display a different expression profile, with a prominent immunological signature, that could represent a proof of principle for testing immunotherapeutic strategies in this drug-orphan subset of GIST.
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http://dx.doi.org/10.3389/fimmu.2020.00851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326057PMC
March 2021

Skeletal Muscle Gene Expression in Long-Term Endurance and Resistance Trained Elderly.

Int J Mol Sci 2020 Jun 2;21(11). Epub 2020 Jun 2.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna School of Medicine, 40138 Bologna, Italy.

Physical exercise is deemed the most efficient way of counteracting the age-related decline of skeletal muscle. Here we report a transcriptional study by next-generation sequencing of vastus lateralis biopsies from elderly with a life-long high-level training practice ( = 9) and from age-matched sedentary subjects ( = 5). Unsupervised mixture distribution analysis was able to correctly categorize trained and untrained subjects, whereas it failed to discriminate between individuals who underwent a prevalent endurance ( = 5) or a prevalent resistance ( = 4) training, thus showing that the training mode was not relevant for sarcopenia prevention. KEGG analysis of transcripts showed that physical exercise affected a high number of metabolic and signaling pathways, in particular those related to energy handling and mitochondrial biogenesis, where AMPK and AKT-mTOR signaling pathways are both active and balance each other, concurring to the establishment of an insulin-sensitive phenotype and to the maintenance of a functional muscle mass. Other pathways affected by exercise training increased the efficiency of the proteostatic mechanisms, consolidated the cytoskeletal organization, lowered the inflammation level, and contrasted cellular senescence. This study on extraordinary individuals who trained at high level for at least thirty years suggests that aging processes and exercise training travel the same paths in the opposite direction.
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http://dx.doi.org/10.3390/ijms21113988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312229PMC
June 2020

Genetic aberrations and molecular biology of cardiac sarcoma.

Ther Adv Med Oncol 2020 18;12:1758835920918492. Epub 2020 May 18.

Department of Specialized, Experimental and Diagnostic Medicine, Medical Oncology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti, 9, Bologna, Bologna 40138, Italy.

Cardiac tumors are rare and complex entities. Early assessment and differentiation between non-neoplastic and neoplastic masses, be they benign or malignant, is essential for guiding diagnosis, determining prognosis, and planning therapy. Cardiac sarcomas represent the most frequent primary malignant histotype. They could have manifold presentations so that the diagnosis is often belated. Moreover, considering their rarity and the limitation due to the cardiac location itself, the optimal multimodal management of patients affected by primary cardiac sarcomas still remains highly difficult and outcome dismal. Therefore, there is an urgent need to improve these results mainly focusing on more adequate tools for prompt diagnosis and exploring new and more effective therapies. Knowledge about the molecular landscape and pathogenesis of cardiac sarcoma is even more limited due to the rarity of this disease. In this sense, the molecular characterization of heart tumors could unfold potentially novel, druggable targets. In this review, we focused on genetic aberrations and molecular biology of cardiac sarcomas, collecting the scarce information available and resuming all the molecular findings discovered in each tumor subtype, with the aim to get further insights on mechanisms involved in tumor growth and to possibly highlight specific molecular profiles that can be used as diagnostic tests and unveil new clinically actionable targets in this tricky and challenging disease.
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http://dx.doi.org/10.1177/1758835920918492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238448PMC
May 2020

The Emerging Role of the FGF/FGFR Pathway in Gastrointestinal Stromal Tumor.

Int J Mol Sci 2020 May 7;21(9). Epub 2020 May 7.

Medical Oncology Unit, S.Orsola-Malpighi University Hospital, 40138 Bologna, Italy.

Gastrointestinal stromal tumors (GIST) are rare neoplasms of mesenchymal origin arising in the gastrointestinal tract. The vast majority are characterized by mutually exclusive activating mutations in KIT or Platelet-derived growth factor alpha (PDGFRA) receptors, or less frequently by succinate dehydrogenase complex (SDH) or NF1 inactivation, with very rare cases harboring mutant BRAF or RAS alleles. Approximately 5% of GISTs lack any of such mutations and are called wild-type (WT) GISTs. Recently, deregulated Fibroblast Growth Factor (FGF)/FGF-receptor (FGFR) signaling emerged as a relevant pathway driving oncogenic activity in different molecular subgroups of GISTs. This review summarizes all the current evidences supporting the key role of the FGF/FGFR pathway activation in GISTs, whereby either activating mutations, oncogenic gene fusions, or autocrine/paracrine signaling have been detected in WT, SDH-, or KIT-mutant GISTs.
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http://dx.doi.org/10.3390/ijms21093313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246647PMC
May 2020

Targeted Deep Sequencing Uncovers Cryptic KIT Mutations in KIT/PDGFRA/SDH/RAS-P Wild-Type GIST.

Front Oncol 2020 22;10:504. Epub 2020 Apr 22.

"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.

Gastrointestinal stromal tumors (GIST) are known to carry oncogenic KIT or PDGFRA mutations, or less commonly SDH or NF1 gene inactivation, with very rare cases harboring mutant BRAF or RAS alleles. Approximately 10% of GISTs are devoid of any of such mutations and are characterized by very limited therapeutic opportunities and poor response to standard treatments. Twenty-six sporadic KIT/PDGFRA/SDH/RAS-pathway wild type GIST were profiled for the molecular status of genes frequently altered in GIST by a targeted next generation sequencing (NGS) approach. Molecular findings were validated by alternative amplicon-based targeted sequencing, immunohistochemistry, gene expression profiling and Sanger sequencing. Three patients harboring NF1 inactivating mutations were identified and excluded from further analysis. Intriguingly, five patients carried cryptic KIT alterations, mainly represented by low-allele-fraction mutations (12-16% allele ratio). These mutations were confirmed by another targeted NGS approaches and supported by CD117 immuno-staining, gene expression profiling, Sanger sequencing, with peak signals at the level of background noise, and by the patients' clinical course assessment. This study indicates that ~20% patients diagnosed with a KIT/PDGFRA/SDH/RAS-pathway wild-type GIST are carriers of pathogenic KIT mutations, thus expected to be eligible for and responsive to the various therapeutic lines of TK-inhibitors in use for KIT/PDGFRA-mutant GIST. The centralization for a second level molecular analysis of GIST samples diagnosed as wild-type for KIT and PDGFRA is once again strongly recommended.
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http://dx.doi.org/10.3389/fonc.2020.00504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188756PMC
April 2020

Shotgun Metagenomics of Gut Microbiota in Humans with up to Extreme Longevity and the Increasing Role of Xenobiotic Degradation.

mSystems 2020 Mar 24;5(2). Epub 2020 Mar 24.

Unit of Microbial Ecology of Health, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

The gut microbiome of long-lived people display an increasing abundance of subdominant species, as well as a rearrangement in health-associated bacteria, but less is known about microbiome functions. In order to disentangle the contribution of the gut microbiome to the complex trait of human longevity, we here describe the metagenomic change of the human gut microbiome along with aging in subjects with up to extreme longevity, including centenarians (aged 99 to 104 years) and semisupercentenarians (aged 105 to 109 years), i.e., demographically very uncommon subjects who reach the extreme limit of the human life span. According to our findings, the gut microbiome of centenarians and semisupercentenarians is more suited for xenobiotic degradation and shows a rearrangement in metabolic pathways related to carbohydrate, amino acid, and lipid metabolism. Collectively, our data go beyond the relationship between intestinal bacteria and physiological changes that occur with aging by detailing the shifts in the potential metagenomic functions of the gut microbiome of centenarians and semisupercentenarians as a response to progressive dietary and lifestyle modifications. The study of longevity may help us understand how human beings can delay or survive the most frequent age-related diseases and morbidities. In this scenario, the gut microbiome has been proposed as one of the variables to monitor and possibly support healthy aging. Indeed, the disruption of host-gut microbiome homeostasis has been associated with inflammation and intestinal permeability as well as a general decline in bone and cognitive health. Here, we performed a metagenomic assessment of fecal samples from semisupercentenarians, i.e., 105 to 109 years old, in comparison to young adults, the elderly, and centenarians, shedding light on the longest compositional and functional trajectory of the human gut microbiome with aging. In addition to providing a fine taxonomic resolution down to the species level, our study emphasizes the progressive age-related increase in degradation pathways of pervasive xenobiotics in Western societies, possibly as a result of a supportive process within the molecular continuum characterizing aging.
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http://dx.doi.org/10.1128/mSystems.00124-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093822PMC
March 2020

Paratesticular Mesenchymal Malignancies: A Single-Center Case Series, Clinical Management, and Review of Literature.

Integr Cancer Ther 2020 Jan-Dec;19:1534735419900554

Sant'Orsola-Malpighi Hospital, Bologna, Italy.

Primary soft tissue sarcomas arising from the male urinary and genital tract are rare tumors, only accounting for 1% to 2% of all malignancies of the genitourinary tract. Clinical management of advanced disease is lacking in standardized recommendations due to the rarity of the disease. To date, complete and extensive surgery represents the only curative and standardized approach for localized disease, while the impact of retroperitoneal lymphadenectomy and adjuvant treatments on clinical outcomes are still unclear. Similarly, a standardized systemic treatment for advanced metastatic disease is still missing. Four out of 274 patients have been identified in our sarcoma population. The mean age was 54 years (range = 45-73). The histotypes showed liposarcoma in 2 cases and leiomyosarcoma in the remaining 2 cases. In all 4 cases, the disease was localized at presentation, patients underwent complete surgery, and no adjuvant treatments were done. Three cases presented a recurrence of disease at a mean follow-up of 86 months (range = 60-106 months), more than 7 years. Two cases were treated with a second surgery and chemotherapy and 1 case only with chemotherapy. Sharing data about clinical management of paratesticular mesenchymal tumors is a key issue due to the rarity of this tumor's subtype. In this article, we report the clinical history of 4 patients affected by paratesticular mesenchymal tumor. In particular, main issues of interest are the decision of postoperative treatment and systemic treatment at time of disease recurrence.
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http://dx.doi.org/10.1177/1534735419900554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050957PMC
March 2020

Effect of Lactobacillus acidophilus D2/CSL (CECT 4529) supplementation in drinking water on chicken crop and caeca microbiome.

PLoS One 2020 24;15(1):e0228338. Epub 2020 Jan 24.

Department of Agricultural and Food Sciences, Alma Mater Studiorum - University of Bologna, Ozzano dell'Emilia, Bologna, Italy.

In this study we gained insights into the effects of the supplementation with Lactobacillus acidophilus D2/CSL (CECT 4529) in the chicken drinking water on crop and caeca microbiomes. The probiotic was supplemented at the concentrations of 0.2 g Lactobacillus acidophilus/day/bird and 0.02 g Lactobacillus acidophilus/day/bird and its effect on the crop and caeca microbiomes was assessed at 14 and 35 days of rearing. The results showed that mean relative abundance of Lactobacillus acidophilus in the caeca did not show significative differences in the treated and control birds, although Lactobacillus acidophilus as well as Faecalibacterium prausnitzii, Lactobacillus crispatus and Lactobacillus reuteri significantly increased over time. Moreover, the treatment with the high dose of probiotic significantly increased the abundance of Clostridium asparagiforme, Clostridium hathewayi and Clostridium saccharolyticum producing butyrate and other organic acids supporting the chicken health. Finally, at 35 days, the Cell division protein FtsH (EC 3.4.24.-) and the Site-specific recombinase genes were significantly increased in the caeca of birds treated with the high dose of probiotic in comparison to the control group. The results of this study showed that Lactobacillus acidophilus D2/CSL (CECT 4529) supplementation in the drinking water at the concentrations of 0.2 and 0.02 g Lactobacillus acidophilus/day/bird improved beneficial microbes and functional genes in broiler crops and caeca. Nevertheless, the main site of action of the probiotic is the crop, at least in the early stage of the chicken life. Indeed, at 14 days Lactobacillus acidophilus was significantly higher in the crops of chickens treated with the high dose of LA in comparison to the control (14.094 vs 1.741%, p = 0.036).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228338PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980619PMC
April 2020

Genetics and treatment of gastrointestinal stromal tumors with immune checkpoint inhibitors: what do we know?

Pharmacogenomics 2020 03 24;21(4):231-234. Epub 2020 Jan 24.

"Giorgio Prodi" Cancer Research Center (CIRC), University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.2217/pgs-2019-0173DOI Listing
March 2020

Successful multidisciplinary clinical approach and molecular characterization by whole transcriptome sequencing of a cardiac myxofibrosarcoma: A case report.

World J Clin Cases 2019 Oct;7(19):3018-3026

Department of Specialized, Experimental and Diagnostic Medicine, Medical Oncology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy.

Background: Cardiac tumors are rare and complex entities. Surgery represents the cornerstone of therapy, while the role of adjuvant treatment remains unclear and, in case of relapse or metastatic disease, the prognosis is very poor. Lack of prospective, randomized clinical trials hinders the generation of high level evidence for the optimal diagnostic workup and multimodal treatment of cardiac sarcomas. Herein, we describe the multidisciplinary clinical management and molecular characterization of a rare case of cardiac myxofibrosarcoma in an elderly woman.

Case Summary: A 73-year-old woman presented signs and symptoms of acute left-sided heart failure. Imaging examination revealed a large, left atrial mass. With suspicion of a myxoma, she underwent surgery, and symptoms were promptly relieved. Histology showed a cardiac myxofibrosarcoma, a rare histotype of cardiac sarcoma. Eight months later, disease unfortunately relapsed, and after a multidisciplinary discussion, a chemotherapy with doxorubicin and then gemcitabine was started, achieving partial radiologic and complete metabolic response, which was maintained up to 2 years and is still present. This report is focused on the entire clinical path of our patient from diagnosis to follow-up, through surgery and strategies adopted at relapse. Moreover, due to their rarity, very little is known about the molecular landscape of myxofibrosarcomas. Thus, we also performed and described preliminary genome analysis of the tumor tissue to get further insight on mechanisms involved in tumor growth, and to possibly unveil new clinically actionable targets.

Conclusion: We report a case of cardiac myxofibrosarcoma that achieved a very good prognosis due to an integrated surgical, cardiac and oncologic treatment strategy.
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http://dx.doi.org/10.12998/wjcc.v7.i19.3018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795718PMC
October 2019

Immune microenvironment profiling of gastrointestinal stromal tumors (GIST) shows gene expression patterns associated to immune checkpoint inhibitors response.

Oncoimmunology 2019;8(9):e1617588. Epub 2019 Jun 4.

"Giorgio Prodi" Cancer Research Center (CIRC), University of Bologna, Bologna, Italy.

Few studies were conducted investigating the immunological profiles in gastrointestinal stromal tumors (GIST). Adaptive and innate immune cells are present in the tumor microenvironment, indicating GIST as inflamed tumors. In addition, murine models suggested a potential interaction between immune components and imatinib. In this retrospective study, the GIST immunological profile was investigated through analysis and immunohistochemistry (IHC), exploring the basis for immunotherapy approaches. Gene expression profiles (GEP) from 31 KIT/PDGFRA-mutant GIST were analyzed to evaluate the tumor microenvironment and immunotherapy predictive signatures such as the expanded IFN-γ-induced immune signature (EIIS) and the T-cell-inflamed signature (TIS). GEP and IHC supported the presence of immune infiltrate in GIST, with dominance of CD4+ and CD8+ T cells and M2 macrophages showing a remarkable similarity with melanoma microenvironment. The EIIS genes were expressed in most of GIST samples and positively correlated with PD-L1 abundance ( < .0001). Co-expression was also found between PD-L1 and CD8A ( < .0001) or CD8B ( = .0003). Moreover, the median TIS score for GIST was between the 65th and 70th percentile of the Cancer Genome Atlas dataset, in the same range of tumors responding to anti-PD-1/PD-L1. Analysis of the Gene Expression Omnibus database GIST samples pre- and post-treatment confirmed that imatinib downregulates PD-L1 and IRF1 expression through the inhibition of KIT and PDGFRA, thus contributing to counteract the suppressed adaptive immune response against GIST. The presence of a rich immune infiltrate in GIST along with the presence of TIS and EIIS suggests that GIST may benefit from immunotherapy along with tyrosine kinase inhibitors.
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http://dx.doi.org/10.1080/2162402X.2019.1617588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685519PMC
February 2021

Comparative Assessment of Antitumor Effects and Autophagy Induction as a Resistance Mechanism by Cytotoxics and EZH2 Inhibition in INI1-Negative Epithelioid Sarcoma Patient-Derived Xenograft.

Cancers (Basel) 2019 Jul 19;11(7). Epub 2019 Jul 19.

Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, Italy.

Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline- and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin-ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin-ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.
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http://dx.doi.org/10.3390/cancers11071015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678245PMC
July 2019

Mechanisms of resistance to a PI3K inhibitor in gastrointestinal stromal tumors: an approach to identify novel druggable targets.

Cancer Manag Res 2019 5;11:6229-6244. Epub 2019 Jul 5.

Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

Gastrointestinal stromal tumors (GISTs) represent a worldwide paradigm of target therapy. The introduction of tyrosine kinase inhibitors has deeply changed the prognosis of GIST patients, however, the majority of them acquire secondary mutations and progress. Unfortunately, besides tyrosine-kinase inhibitors, no other therapeutic options are available. Therefore, it is mandatory to identify novel molecules and/or strategies to overcome the inevitable resistance. In this context, after promising preclinical data on the novel PI3K inhibitor BYL719, the NCT01735968 trial in GIST patients who had previously failed treatment with imatinib and sunitinib started. BYL719 has attracted our attention, and we comprehensively characterized genomic and transcriptomic changes taking place during resistance. For this purpose, we generated two in vitro GIST models of acquired resistance to BYL719 and performed an omic-based analysis by integrating RNA-sequencing, miRNA, and methylation profiles in sensitive and resistant cells. We identified novel epigenomic mechanisms of pharmacological resistance in GISTs suggesting the existence of pathways involved in drug resistance and alternatively acquired mutations. Therefore, epigenomics should be taken into account as an alternative adaptive mechanism. Despite the fact that currently we do not have patients in treatment with BYL719 to verify this hypothesis, the most intriguing result is the involvement of H19 and PSTA1 in GIST resistance, which might represent druggable targets.
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http://dx.doi.org/10.2147/CMAR.S189661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615718PMC
July 2019

Exosomes from CD99-deprived Ewing sarcoma cells reverse tumor malignancy by inhibiting cell migration and promoting neural differentiation.

Cell Death Dis 2019 06 17;10(7):471. Epub 2019 Jun 17.

Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano 1/10, 40136, Bologna, Italy.

Ewing sarcoma (EWS) is an aggressive mesenchymal tumor with unmet clinical need and significant social impacts on children, adolescents, and young adults. CD99, a hallmark surface molecule of EWS, participates in crucial biological processes including cell migration, differentiation, and death. EWS cells can release CD99 through exosomes (EXOs), specialized extracellular vesicles with major cell communication roles. Here we show that, as a consequence of CD99 silencing, EWS cells deliver exosomes with oncosuppressive functions that significantly reduce tumor aggressiveness. These CD99-lacking microvesicles modulate gene expression of the EWS-recipient cells, reduce proliferation and migration, in turn inducing a more-differentiated less-malignant phenotype. The most relevant effects were detected on the activator protein-1 signaling pathway whose regulation was found to be dependent on the specific cargo loaded in vesicles after CD99 shutdown. Investigation of the miRNA content of CD99-deprived EXOs identified miR-199a-3p as a key driver able to reverse EWS malignancy in experimental models as well as in clinical specimens. All together, our data provide evidence that the abrogation of CD99 in EWS tumor cells leads to produce and release EXOs capable to transfer their antineoplastic effects into the nearby tumor cells, suggesting a novel atypical role for these microvesicles in reversion of malignancy rather than in priming the soil for progression and metastatic seeding. This conceptually innovative approach might offer a new therapeutic opportunity to treat a tumor still refractory to most treatments.
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http://dx.doi.org/10.1038/s41419-019-1675-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572819PMC
June 2019

BCOR involvement in cancer.

Epigenomics 2019 05 31;11(7):835-855. Epub 2019 May 31.

Pediatric Oncology & Hematology Unit 'Lalla Seràgnoli', S Orsola-Malpighi Hospital, 40138 Bologna, Italy.

 is a gene that encodes for an epigenetic regulator involved in the specification of cell differentiation and body structure development and takes part in the noncanonical polycomb repressive complex 1. This review provides a comprehensive summary of BCOR's involvement in oncology, illustrating that various aberrations, such as the internal tandem duplications of the PCGF Ub-like fold discriminator domain and different gene fusions (mainly ), represent driver elements of various sarcomas such as clear cell sarcoma of the kidney, primitive mesenchymal myxoid tumor of infancy, small round blue cell sarcoma, endometrial stromal sarcoma and histologically heterogeneous CNS neoplasms group with similar genomic methylation patterns known as CNS-HGNET-BCOR. Furthermore, other alterations (often loss of function mutations) recur in a large variety of mesenchymal, epithelial, neural and hematological tumors, suggesting a central role in cancer evolution.
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http://dx.doi.org/10.2217/epi-2018-0195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595546PMC
May 2019

NR4A3 fusion proteins trigger an axon guidance switch that marks the difference between EWSR1 and TAF15 translocated extraskeletal myxoid chondrosarcomas.

J Pathol 2019 09 14;249(1):90-101. Epub 2019 May 14.

Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma histotype with uncertain differentiation. EMC is hallmarked by the rearrangement of the NR4A3 gene, which in most cases fuses with EWSR1 or TAF15. TAF15-translocated EMC seem to feature a more aggressive course compared to EWSR1-positive EMCs, but whether the type of NR4A3 chimera impinges upon EMC biology is still largely undefined. To gain insights on this issue, a series of EMC samples (7 EWSR1-NR4A3 and 5 TAF15-NR4A3) were transcriptionally profiled. Our study unveiled that the two EMC variants display a distinct transcriptional profile and that the axon guidance pathway is a major discriminant. In particular, class 4-6 semaphorins and axonal guidance cues endowed with pro-tumorigenic activity were more expressed in TAF15-NR4A3 tumors; vice versa, class 3 semaphorins, considered to convey growth inhibitory signals, were more abundant in EWSR1-NR4A3 EMC. Intriguingly, the dichotomy in axon guidance signaling observed in the two tumor variants was recapitulated in in vitro cell models engineered to ectopically express EWSR1-NR4A3 or TAF15-NR4A3. Moreover, TAF15-NR4A3 cells displayed a more pronounced tumorigenic potential, as assessed by anchorage-independent growth. Overall, our results indicate that the type of NR4A3 chimera dictates an axon guidance switch and impacts on tumor cell biology. These findings may provide a framework for interpretation of the different clinical-pathological features of the two EMC variants and lay down the bases for the development of novel patient stratification criteria and therapeutic approaches. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766969PMC
September 2019

Effect of a low protein diet on chicken ceca microbiome and productive performances.

Poult Sci 2019 Sep;98(9):3963-3976

Department of Agricultural and Food Sciences, University of Bologna, 40126, Bologna, Italy.

The aim of this study was to investigate the impact of supplementation of a low protein diet on ceca microbiome and productive performances of broiler chickens. A total of 1,170 one-day-old male chicks (Ross 308) were divided in 2 diet groups and reared in the same conditions up to 42 D. Birds belonging to the control group were fed a basal diet. Birds belonging to the low protein group the basal diet with a reduced level of crude protein (-7%). Cecum contents from randomly selected birds were collected at 14 and 42 D within each diet group, submitted to DNA extraction and then tested by shotgun metagenomic sequencing. Abundances of species belonging to Actinobacteria and Proteobacteria were mainly affected by the diet as well as interaction between diet and time, while species belonging to Firmicutes and Cyanobacteria changed mainly according to the age of the birds. At family level, Lactobacillaceae significantly decreased in the low protein group up to 14 D. However, at the end of the rearing period the same family was significantly higher in the low protein group. The most abundant functional genes, represented by cystine desulfurase, alpha-galactosidase, and serine hydroxymethyltransferase, displayed comparable abundances in both diet groups, although significative differences were identified for less abundant functional genes at both sampling times. Birds fed control and low protein diets showed similar productive performances. However, in the finisher phase, feed conversion rate was significantly better in chickens fed the low protein diet. Overall, this study showed that a reduced intake of crude protein in broilers increases the abundance of Lactobacillaceae in the ceca over time and this seems to be linked to a better feed conversion rate between 36 and 42 D. A reduced intake of crude protein in chicken production can help to improve exploitation of edible resources, while reducing the emission of nitrogen pollutants in the environment.
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http://dx.doi.org/10.3382/ps/pez132DOI Listing
September 2019

Gain of FGF4 is a frequent event in KIT/PDGFRA/SDH/RAS-P WT GIST.

Genes Chromosomes Cancer 2019 09 16;58(9):636-642. Epub 2019 Apr 16.

Department of Specialized, Experimental and Diagnostic Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Gastrointestinal stromal tumors (GIST) lacking mutations in KIT/PDGFRA or RAS pathways and retaining an intact SDH complex are usually referred to as KIT/PDGFRA/SDH/RAS-P WT GIST or more simply quadruple WT GIST (~5% of all GIST). Despite efforts made, no recurrent genetic event in quadruple WT GIST has been identified so far. To further investigate this disease, we performed high throughput copy number analysis on quadruple WT GIST specimens identifying a recurrent focal gain in band 11q13.3 (involving FGF3/FGF4) in 6/8 cases. This event was not found in the other molecular GIST subgroups. FGF3/FGF4 duplication was associated with high expression of FGF4, both at mRNA and protein level, a growth factor normally not expressed in adult tissues or in KIT/PDGFRA-mutated GIST. FGFR1 was found to be the predominant FGF receptor expressed and phosphorylation of AKT was detected, suggesting that a FGF4-FGFR1 autocrine loop could stimulate downstream signaling in quadruple WT GIST. Together with the recent reports of quadruple WT cases carrying FGFR1 activating alterations, these findings strengthen the hypothesis of a potential involvement of FGFR pathway deregulation in quadruple WT GIST, which may represent a rationale for novel therapeutic approaches.
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http://dx.doi.org/10.1002/gcc.22753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619263PMC
September 2019