Publications by authors named "Luca Mariani"

49 Publications

EP300 selectively controls the enhancer landscape of MYCN-amplified neuroblastoma.

Cancer Discov 2021 Nov 12. Epub 2021 Nov 12.

Cancer Biology, Dana-Farber Cancer Institute

Gene expression is regulated by promoters and enhancers marked by histone H3-lysine-27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HATs), EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depend on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeted-chimaera (PROTAC) compound termed "JQAD1" that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid neuroblastoma apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Further, JQAD1 activity is critically determined by cereblon (CRBN) expression across neuroblastoma cells.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0385DOI Listing
November 2021

Coronary Plaque Rupture in Stable Coronary Artery Disease and Non-ST Segment Elevation Myocardial Infarction: An Optical Coherence Tomography Study.

J Invasive Cardiol 2021 Nov 7;33(11):E843-E850. Epub 2021 Oct 7.

Institute of Cardiology, Mazzoni Hospital, Ascoli Piceno, Italy, Via degli Iris 1, 63100 Ascoli Piceno, Italy.

Background: Plaque rupture (PR) is the main cause of coronary thrombosis in non-ST segment elevation myocardial infarction (NSTEMI), but can be found in stable coronary artery disease (CAD). Our study compared the morphology and local inflammatory activity of ruptured plaques between stable CAD and NSTEMI patients using frequency-domain optical coherence tomography (FD-OCT).

Methods: We retrospectively evaluated 70 plaques with PR at the FD-OCT (25 in stable CAD patients and 45 in NSTEMI patients). Main clinical, angiographic, and morphological features were compared.

Results: Besides an overall equivalence in clinical and angiographic features (except for more smokers among NSTEMI patients), some important FD-OCT differences in plaque morphology emerged: PR in NSTEMI was characterized by more macrophage infiltrates (78% in NSTEMI patients vs 20% in stable CAD patients; P<.001) and intraluminal thrombosis (84% in NSTEMI patients vs 48% in stable CAD patients; P<.01). Quantitative analysis showed a higher density of macrophages in NSTEMI than in stable CAD patients: median max normalized standard deviation (NSD) was 0.0934 (IQR, 0.0796-0.1022) vs 0.0689 (IQR, 0.0598-0.0787); P<.01 and mean NSD was 0.062 (IQR, 0.060-0.065) vs 0.053 (IQR, 0.051-0.060); P<.001. Other morphological features did not differ between stable CAD and NSTEMI patients. Main FD-OCT quantitative parameters like minimal lumen area and plaque length were also equivalent between the 2 groups.

Conclusions: Differences in morphological features of PR between stable CAD and NSTEMI patients suggest that local inflammation contributes to the unstable fate of the atherosclerotic plaque.
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November 2021

A TALE/HOX code unlocks WNT signalling response towards paraxial mesoderm.

Nat Commun 2021 08 26;12(1):5136. Epub 2021 Aug 26.

Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark.

One fundamental yet unresolved question in biology remains how cells interpret the same signalling cues in a context-dependent manner resulting in lineage specification. A key step for decoding signalling cues is the establishment of a permissive chromatin environment at lineage-specific genes triggering transcriptional responses to inductive signals. For instance, bipotent neuromesodermal progenitors (NMPs) are equipped with a WNT-decoding module, which relies on TCFs/LEF activity to sustain both NMP expansion and paraxial mesoderm differentiation. However, how WNT signalling activates lineage specific genes in a temporal manner remains unclear. Here, we demonstrate that paraxial mesoderm induction relies on the TALE/HOX combinatorial activity that simultaneously represses NMP genes and activates the differentiation program. We identify the BRACHYURY-TALE/HOX code that destabilizes the nucleosomes at WNT-responsive regions and establishes the permissive chromatin landscape for de novo recruitment of the WNT-effector LEF1, unlocking the WNT-mediated transcriptional program that drives NMPs towards the paraxial mesodermal fate.
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http://dx.doi.org/10.1038/s41467-021-25370-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390530PMC
August 2021

A ChIP-exo screen of 887 Protein Capture Reagents Program transcription factor antibodies in human cells.

Genome Res 2021 Sep 23;31(9):1663-1679. Epub 2021 Aug 23.

Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.

Antibodies offer a powerful means to interrogate specific proteins in a complex milieu. However, antibody availability and reliability can be problematic, whereas epitope tagging can be impractical in many cases. To address these limitations, the Protein Capture Reagents Program (PCRP) generated over a thousand renewable monoclonal antibodies (mAbs) against human presumptive chromatin proteins. However, these reagents have not been widely field-tested. We therefore performed a screen to test their ability to enrich genomic regions via chromatin immunoprecipitation (ChIP) and a variety of orthogonal assays. Eight hundred eighty-seven unique antibodies against 681 unique human transcription factors (TFs) were assayed by ultra-high-resolution ChIP-exo/seq, generating approximately 1200 ChIP-exo data sets, primarily in a single pass in one cell type (K562). Subsets of PCRP mAbs were further tested in ChIP-seq, CUT&RUN, STORM super-resolution microscopy, immunoblots, and protein binding microarray (PBM) experiments. About 5% of the tested antibodies displayed high-confidence target (i.e., cognate antigen) enrichment across at least one assay and are strong candidates for additional validation. An additional 34% produced ChIP-exo data that were distinct from background and thus warrant further testing. The remaining 61% were not substantially different from background, and likely require consideration of a much broader survey of cell types and/or assay optimizations. We show and discuss the metrics and challenges to antibody validation in chromatin-based assays.
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http://dx.doi.org/10.1101/gr.275472.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415381PMC
September 2021

Could a 2D/3D US based model be helpful in the assessment of myometrial invasion at time of intraoperative frozen section? A pilot study.

Minerva Obstet Gynecol 2021 Jun;73(3):362-368

Department of Obstetrics and Gynecology, Mauriziano Hospital, Turin, Italy.

Background: The assessment of myometrial invasion is a pivotal step in the preoperative staging of endometrial cancer. Intraoperative frozen section (FS) represents a reliable tool in directing surgeon's choices. Preoperative transvaginal ultrasound (US) showed high accuracy in evaluating myometrial invasion. This study aimed to understand if the application of a standardized ultrasonographic protocol for the pre-operative evaluation of myometrial invasion can help pathologists in improving the accuracy of FS. Furthermore, the agreement between US and FS in the assessment of myometrial invasion was assessed.

Methods: Sixty-six patients who underwent surgery for endometrial cancer were analyzed. Preoperative 2D/3D ultrasound was performed in all the patients. Myometrial invasion was estimated by subjective assessment and objective measurement techniques. Data from US were reported to pathologists through a prefilled form with depth and site of the maximum myometrial invasion. Diagnostic performance of US and FS were compared having the definitive histological examination as the gold standard.

Results: Influenced by the information given by our 3D US-model, FS showed a 90% sensitivity and a 93% specificity, with a 93% PPV and an 89% NPV. The agreement with histology was strong (K=0.824). Myometrial invasion was missed at the level of the isthmus by FS just in one case. Subjective assessment was confirmed as the most reliable ultrasonographic technique in assessing myometrial invasion, with 90% sensitivity, 78% specificity, 80% PPV and 89% NPV. The agreement with histology was substantial (K=0.68).

Conclusions: The application of a preoperative 2D/3D US assessment would seem to help pathologists in detecting myometrial invasion in difficult areas of the uterus such as the isthmus, reducing downstaging and overtreatment.
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http://dx.doi.org/10.23736/S2724-606X.21.04777-1DOI Listing
June 2021

Estradiol/nomegestrol acetate as a first-line and rescue therapy for the treatment of ovarian and deep infiltrating endometriosis.

Gynecol Endocrinol 2021 Jul 22;37(7):646-649. Epub 2021 Mar 22.

Obstetrics and Gynecology University Department, Azienda Ospedaliera Ordine Mauriziano di Torino, Torino, Italy.

Purpose: Estradiol valerate/nomegestrol acetate (E2V/NOMAC) is a new combined oral contraceptive with a good tolerability profile and low drop-out rates, which was shown to improve menstrual-related symptoms. This study aims to evaluate its effectiveness in the control of symptoms and progression of disease in women with ovarian endomestriomas and deep infiltrating endometriosis (DIE).

Methods: This was a retrospective cohort study on 39 women with pelvic endometriosis treated with E2V/NOMAC. We assessed for each patient, at the beginning of treatment and after 6 months, the painful symptoms, through a global VAS (Visual Analogue Scale) index and the size of the greatest ovarian and/or deep infiltrating endometriotic lesions.

Results: After 6 months of treatment, a significant reduction was observed for the global VAS score for pain symptoms and for the mean size of ovarian endometriomas, whereas DIE lesions did not present significant changes in mean size.

Conclusions: E2/NOMAC was effective in reducing pain symptoms associated with pelvic endometriosis and the size of ovarian endometriomas, whereas DIE lesions remained stable. This therapy could provide good results in the control of symptoms and disease progression in women with pelvic endometriosis.
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http://dx.doi.org/10.1080/09513590.2021.1903420DOI Listing
July 2021

Sonographic features of endometriosis infiltrating the lateral parametrium.

J Gynecol Obstet Hum Reprod 2021 Sep 15;50(7):102116. Epub 2021 Mar 15.

Obstetrics and Gynecology University Department, Mauriziano Umberto I Hospital, Largo Turati 62, 10128, Torino, Italy; University of Turin, Department of Surgical Sciences, Corso Dogliotti 14, 10126, Torino, Italy. Electronic address:

Objective: Lateral parametrium endometriosis (LPE) can be associated with infiltration of ureters and hypogastric plexus, causing severe painful symptoms and functional impairment, and requiring complex and extensive surgery. The aim of this study was to evaluate the presentation of LPE lesions at transvaginal ultrasound, identifying sonographic features for disease recognition and mapping.

Methods: This was a retrospective case-series of women with sonographic suspect of LPE confirmed at surgical exploration. We carried out a descriptive analysis of the ultrasound patterns of presentation and compared the features of the lesions according to their location cranially or caudally to the uterine artery.

Results: Our population included 23 women, with a total of 26 parametrial lesions: all of them were hypoechoic, with absence of vascularization. Lesions lying above the uterine artery presented more frequently as ill-defined nodules (78.6 %, p < 0.01) and were associated with ipsilateral reduced or absent ovarian mobility (92.9 %, p < 0.01); the ones located below the uterine artery appeared more frequently as fan-shaped lesions with retraction of the surrounding tissues (83.3 %). Ureteral involvement was observed at surgery in 43.5 % of cases. In all patients, deep infiltrating endometriosis of the posterior compartment was observed: the utero-sacral ligaments were the most common location affected concurrently.

Conclusions: LPE may present at transvaginal sonography as hypoechoic, not vascularized lesions, most frequently with a nodular or with a fan-shaped appearance, respectively cranially or caudally to the uterine artery. Reduced ovarian sliding and ureteral involvement are commonly associated.
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http://dx.doi.org/10.1016/j.jogoh.2021.102116DOI Listing
September 2021

Appropriate use criteria for coronary angiography: a single centre experience.

Int J Cardiol Heart Vasc 2020 Dec 30;31:100677. Epub 2020 Nov 30.

Cardiology Department, Mazzoni Hospital, via degli Iris 1, 63100 Ascoli Piceno, Italy.

Background: Increasing attention is being given to the rational use of invasive procedures. In this study, we aimed to evaluate, among patients referred for coronary angiography, the appropriateness of cardiac catheterization according to the Appropriate Use Criteria (AUC) for diagnostic catheterization and to examine the relationship between the appropriateness and the presence of obstructive coronary artery disease (CAD) and revascularization.

Methods: From November 2017 to December 2018, 1188 consecutive patients referred to undergo a diagnostic catheterization were included. They were categorized as having appropriate, uncertain or inappropriate indication, using a database (Melograno System). We restricted our analysis to 9 appropriate indications including acute coronary syndromes, suspected CAD, valvular heart disease, arrhythmias and cardiomyopathy. We restricted the analysis to the subgroup of patients with suspected or known CAD and, among them, we evaluate the rate of CAD and the need for revascularization.

Results: The indications were appropriate in 1017 patients (85.6%), of uncertain appropriateness in 134 (11.3%), and inappropriate in 37 (3.1%). Restricting the analysis to the CAD subgroup, the indications were appropriate in 848 patients (83.3%), of uncertain appropriateness in 133 (13.1%) and inappropriate in 37 (3.6%). The proportion of patients with critical CAD were 75.9%, 44.3% and 29.7% in the appropriate, uncertain and inappropriate categories respectively (p < 0.001). The revascularization rate was 63.1%, 32.2% and 21.6% in the appropriate, uncertain and inappropriate categories respectively (p < 0.001).

Conclusions: Application of AUC is feasible in a community setting. Melograno system is useful to improve patient care.
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http://dx.doi.org/10.1016/j.ijcha.2020.100677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711284PMC
December 2020

Rare case of uterine cervix lymphoma with spontaneous regression: Case report.

J Obstet Gynaecol Res 2021 Feb 8;47(2):807-811. Epub 2020 Nov 8.

Department of Radiology, Azienda Ospedaliera Ordine Mauriziano di Torino, Torino, Italy.

Primary malignant lymphoma rarely occurs in the female reproductive tract, because of that they are often misdiagnosed. Lymphoma spontaneous regression is even rarer, but it is possible behavior of this disease. A case of 54-year-old female patient with a primary diffuse large B-cell lymphoma of the cervix is presented. First assumption was sarcoma or atypical adenocarcinoma; biopsies have been inconclusive and, after a partial spontaneous regression, diagnosis of lymphoma was possible only after surgery. The diagnosis was a real challenge for clinicians, radiologists and pathologists for both localization and behavior. Difficulties in diagnosis led to an over-treatment: a laparotomic bilateral hysteron salpingectomy with lymphadenectomy was performed, while chemotherapy alone would have been the right approach. Considering that prognosis and treatment of primary malignant lymphoma of the cervix are completely different than those of other malignant tumors of the uterus, this disease should be considered in the differential diagnosis.
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http://dx.doi.org/10.1111/jog.14562DOI Listing
February 2021

Unprotected left-main coronary percutaneous intervention in elderly: a retrospective analysis of practice and clinical outcome.

J Cardiovasc Med (Hagerstown) 2021 May;22(5):420-422

Interventional Cardiology Department, Mazzoni Hospital, Ascoli Piceno, Italy.

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http://dx.doi.org/10.2459/JCM.0000000000001122DOI Listing
May 2021

Endometrial thickness in the evaluation of clinical response to medical treatment for deep infiltrating endometriosis: a retrospective study.

Arch Gynecol Obstet 2021 01 14;303(1):161-168. Epub 2020 Sep 14.

Department of Surgical Sciences, University of Turin, Corso Dogliotti 14, 10126, Torino, Italy.

Purpose: Deep infiltrating endometriosis (DIE) is associated with severe pelvic pain and functional impairment of bowel, urinary, and sexual functions. Though hormone therapy with progestins, either as single agents or combined with estrogens, is effective in managing symptoms, some patients may experience a suboptimal response. Endometrial thickness assessed by transvaginal ultrasound examination, reflecting the overall estrogen stimulation, may correlate with the clinical response to hormonal treatments.

Methods: A retrospective study was carried out on 61 women with DIE affecting the bowel or the recto-vaginal septum, undergoing hormone treatment. The symptoms of patients were evaluated at the baseline and after 12 months of therapy, calculating a global Visual Analogue Scale score (gVAS) encompassing dysmenorrhea, dyspareunia, chronic pelvic pain, dyschezia, abdominal pain and dysuria. Patients were divided into two subgroups using, as a calculated cut-off value, the mean endometrial thickness in our population at 12 months. The change in gVAS score during the 12 months of treatment was then compared between the two groups.

Results: Women with a thinner endometrium (< 3.3 mm) showed a better response to treatment in terms of symptoms control as compared to patients with a thicker endometrium (mean gVAS score reduction 9.2 ± 1.3 vs. 5.2 ± 1.3, p = 0.036). The correlation between endometrial thickness and symptomatic response was also confirmed (p = 0.041) on multivariate linear regression analysis including as covariates age, size of lesions of DIE, presence of uterine adenomyosis, ovarian endometriosis and type of medical treatment.

Conclusion: Endometrial thickness on ultrasound transvaginal examination is correlated with better response rates to hormone therapy in terms of symptoms control. A thinner endometrium, probably resulting from a more efficient suppression of estrogen stimulation, is associated with improved symptoms. These results may aid clinicians in monitoring and tailoring hormonal treatments during follow-up of women with symptomatic DIE.
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http://dx.doi.org/10.1007/s00404-020-05794-xDOI Listing
January 2021

A rare case of ovarian adenomyoma mimicking primary invasive ovarian cancer with a contralateral serous borderline ovarian tumor: A case report and review of the literature.

Heliyon 2020 Jul 24;6(7):e04406. Epub 2020 Jul 24.

Academic Department of Gynecology and Obstetrics, University of Turin, Mauriziano Hospital, Turin, Italy.

Extrauterine adenomyoma is a rare type of benign tumor, characterized by nodular aggregate of smooth muscle, endometrial glands and endometrial stroma, arising outside the uterus. In this study we describe a case of primary ovarian adenomyoma associated with endometriotic cysts with contralateral serous borderline tumor in a 40-year-old woman and we highlight how preoperative exams could lead to the suspicious of invasive cancer. We provide a review of the literature, analyzing all cases of extrauterine adenomyoma published so far, classifying them on the basis of pathogenetic theories proposed, localization of the lesion, imaging modalities and treatment adopted.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385463PMC
July 2020

LIN28B regulates transcription and potentiates MYCN-induced neuroblastoma through binding to ZNF143 at target gene promotors.

Proc Natl Acad Sci U S A 2020 07 29;117(28):16516-16526. Epub 2020 Jun 29.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215;

LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis, at least, in part, through inhibition of microRNA biogenesis. Here, we report that overexpression of either wild-type (WT) LIN28B or a LIN28B mutant that is unable to inhibit processing increases the penetrance of MYCN-induced neuroblastoma, potentiates the invasion and migration of transformed sympathetic neuroblasts, and drives distant metastases in vivo. Genome-wide chromatin immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) and coimmunoprecipitation experiments show that LIN28B binds active gene promoters in neuroblastoma cells through protein-protein interaction with the sequence-specific zinc-finger transcription factor ZNF143 and activates the expression of downstream targets, including transcription factors forming the adrenergic core regulatory circuitry that controls the malignant cell state in neuroblastoma as well as and that are involved in neuronal cell adhesion and migration. These findings reveal an unexpected -independent function of LIN28B in transcriptional regulation during neuroblastoma pathogenesis.
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http://dx.doi.org/10.1073/pnas.1922692117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368283PMC
July 2020

Predictors of response after a second attempt of pharmacological labor induction: a retrospective study.

Arch Gynecol Obstet 2020 07 22;302(1):117-125. Epub 2020 May 22.

Obstetrics and Gynaecology Unit, Mauriziano Umberto I Hospital, Largo Turati 62, 10128, Turin, Italy.

Purpose: The aim of our study was to assess the outcomes of a prolonged induction carried out with a second sequential cycle of pharmacological stimulation after unsatisfactory response to a first attempt, and to highlight variables correlated with higher response rates.

Methods: A retrospective study was carried out on 157 women who underwent a two-step labor induction by vaginal prostaglandins followed by a second cycle of prostaglandins or intravenous oxytocin. Outcomes assessed were mode of delivery and maternal and neonatal morbidity. Main variables of pregnancy and delivery were collected to identify factors predicting the mode of delivery.

Results: Among 157 patients, 63 (40.1%) achieved a vaginal delivery, whereas 94 (59.9%) underwent Cesarean section, 9 women (5.7%) had postpartum hemorrhage; in 2 cases (1.3%), an Apgar score < 7 at 5 min from birth was reported. Higher risk of Cesarean section was observed with advanced maternal age (OR 1.13 for additional year, CI 1.04-1.22) and nulliparity (OR 8.84, CI 2.69-29.06), whereas the response rates were better in carriers of group B streptococcus colonization (OR 0.38, CI 0.17-0.84) and in women with favorable cervical status after the first stimulation (OR 0.81 for additional point of Bishop score, CI 0.70-0.94).

Conclusion: Labor induction with two cycles of pharmacological stimulation is a procedure with fairly good success rates and a low risk of maternal and neonatal complications. Factors predicting its success encompass younger age, parity, a positive recto-vaginal swab for group B streptococcus and a favorable cervix following the first cycle of stimulation.
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http://dx.doi.org/10.1007/s00404-020-05578-3DOI Listing
July 2020

MEDEA: analysis of transcription factor binding motifs in accessible chromatin.

Genome Res 2020 05 18;30(5):736-748. Epub 2020 May 18.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Deciphering the interplay between chromatin accessibility and transcription factor (TF) binding is fundamental to understanding transcriptional regulation, control of cellular states, and the establishment of new phenotypes. Recent genome-wide chromatin accessibility profiling studies have provided catalogs of putative open regions, where TFs can recognize their motifs and regulate gene expression programs. Here, we present motif enrichment in differential elements of accessibility (MEDEA), a computational tool that analyzes high-throughput chromatin accessibility genomic data to identify cell-type-specific accessible regions and lineage-specific motifs associated with TF binding therein. To benchmark MEDEA, we used a panel of reference cell lines profiled by ENCODE and curated by the ENCODE Project Consortium for the ENCODE-DREAM Challenge. By comparing results with RNA-seq data, ChIP-seq peaks, and DNase-seq footprints, we show that MEDEA improves the detection of motifs associated with known lineage specifiers. We then applied MEDEA to 610 ENCODE DNase-seq data sets, where it revealed significant motifs even when absolute enrichment was low and where it identified novel regulators, such as NRF1 in kidney development. Finally, we show that MEDEA performs well on both bulk and single-cell ATAC-seq data. MEDEA is publicly available as part of our Glossary-GENRE suite for motif enrichment analysis.
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http://dx.doi.org/10.1101/gr.260877.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263192PMC
May 2020

Metastatic Bilateral Strumal Carcinoid: A Case Report and Review of the Literature.

Anticancer Res 2019 Sep;39(9):5053-5056

Academic Department of Gynecology and Obstetrics, University of Turin, Mauriziano Hospital, Turin, Italy.

Primary ovarian carcinoids are very rare tumors that belong to the germ cell family of ovarian malignancies. They account for less than 1% of all carcinoid tumors and for less than 0.1% of all ovarian neoplasms. Recurrences are even rarer, with only few cases reported in the literature. Strumal carcinoid has recently been recognized as an extremely rare distinct entity. We report on a patient with bilateral mature cystic teratoma with millimetric foci of ovarian strumal carcinoid who developed lymph node para aortic metastasis after 30 years from primary diagnosis. Our case is thus far the second report of a metastatic strumal carcinoid and the first one in which strumal carcinoid occurred bilaterally and was also metastatic.
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http://dx.doi.org/10.21873/anticanres.13697DOI Listing
September 2019

Coronary epicardic vasospasm in patient treated with desatinib for lymphoblastic leukaemia: the other side of the medal.

Eur Heart J 2019 04;40(15):1235

Interventional Cardiology Department, Mazzoni Hospital, Via degli Iris 1, Ascoli Piceno, Italy.

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http://dx.doi.org/10.1093/eurheartj/ehz054DOI Listing
April 2019

A patient with multiple Swiss cheese aspect coronary lesions: optical coherence tomography to guide coronary angioplasty.

Future Cardiol 2018 09 20;14(5):375-380. Epub 2018 Sep 20.

Cardiology Department, Mazzoni Hospital, Ascoli Piceno, Italy.

Although spontaneous recanalization of coronary thrombi has been reported pathologically, it is rarely recognized in clinical practice. We presented a rare case of recanalized thrombi of the right coronary artery and distal left anterior descending artery in a patient with an anterior ST segment elevation myocardial infarction treated with primary percutaneous intervention of the proximal left anterior descending artery. Optical coherence tomography aspect of right coronary artery was consistent with a 'Swiss cheese' appearance that represented recanalization of organized thrombi. Optical coherence tomography has been essential to discriminate the underlying mechanism and may provide useful information for an appropriate treatment approach.
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http://dx.doi.org/10.2217/fca-2018-0035DOI Listing
September 2018

Intracoronary imaging to guide percutaneous coronary intervention: Clinical implications.

Int J Cardiol 2019 Jan 6;274:394-401. Epub 2018 Sep 6.

Section of Interventional Cardiology, MedStar Cardiovascular Research Network, MedStar Washington Hospital Center, United States of America.

Background: Over the last decade, the intra-coronary imaging (ICI) has emerged to guide percutaneous coronary intervention (PCI), thus overcoming the limitations of "luminology" offered by angiography.

Methods: In this review, we aim at purely focusing on the clinical implications of the employment of ICI in the routine practice, thus providing suggestions for future applications. In particular, we will describe the principal contributions and implications of ICI in the following different clinical settings: 1) assessment of clinical and imaging outcomes of PCI; 2) guiding PCI before and after stent implantation; 3) identification of mechanisms of stent failure.

Results: Several studies showed the capability of ICI in assessing the clinical and imaging outcomes of PCI. In particular, they have compared the ICI-guided PCI with the angiography-guided procedures, emphasizing the advantages of using imaging. Indeed, ICI can characterize the coronary plaque, provide a precise estimation of the coronary stenosis, select the appropriate method of intervention, and optimize stent deployment and lesion coverage. Finally, ICI has been shown to be useful to point out the mechanisms of stent failure.

Conclusions: ICI can facilitate decision-making in patients with unclear angiographic findings, guide-selected interventions and optimize the final PCI results in complex lesions or. in high-risk patients. Finally, by the identification of specific mechanisms of stent failure, the ICI can allow to adopt a tailored therapy for the singles cases.
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http://dx.doi.org/10.1016/j.ijcard.2018.09.017DOI Listing
January 2019

Identification of Human Lineage-Specific Transcriptional Coregulators Enabled by a Glossary of Binding Modules and Tunable Genomic Backgrounds.

Cell Syst 2017 09;5(3):187-201.e7

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard-MIT Division of Health Sciences and Technology (HST), Harvard Medical School, Boston, MA 02115, USA; Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Transcription factors (TFs) control cellular processes by binding specific DNA motifs to modulate gene expression. Motif enrichment analysis of regulatory regions can identify direct and indirect TF binding sites. Here, we created a glossary of 108 non-redundant TF-8mer "modules" of shared specificity for 671 metazoan TFs from publicly available and new universal protein binding microarray data. Analysis of 239 ENCODE TF chromatin immunoprecipitation sequencing datasets and associated RNA sequencing profiles suggest the 8mer modules are more precise than position weight matrices in identifying indirect binding motifs and their associated tethering TFs. We also developed GENRE (genomically equivalent negative regions), a tunable tool for construction of matched genomic background sequences for analysis of regulatory regions. GENRE outperformed four state-of-the-art approaches to background sequence construction. We used our TF-8mer glossary and GENRE in the analysis of the indirect binding motifs for the co-occurrence of tethering factors, suggesting novel TF-TF interactions. We anticipate that these tools will aid in elucidating tissue-specific gene-regulatory programs.
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http://dx.doi.org/10.1016/j.cels.2017.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657590PMC
September 2017

Frequency-domain optical coherence tomography plaque morphology in stable coronary artery disease: sex differences.

Coron Artery Dis 2017 Sep;28(6):472-477

Department of Cardiology, Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy.

Background: The cause for discrepancy in the clinical presentation and outcome of coronary artery disease (CAD) between men and women is not established. Different prevalences of risk factors or specific sex-related atherosclerotic aspects have been advocated as possible explanations. We investigated coronary plaque morphology looking at possible differences in plaque vulnerability between men and women with stable CAD.

Patients And Methods: We retrospectively collected and analyzed clinical data and coronary plaque morphology by frequency-domain optical coherence tomography in men and women with stable CAD.

Results: A total of 181 (139 were in men and 42 in women) plaques from 138 patients were analyzed. The mean age was similar between men and women. Besides an overall absence of significant differences in the vast majority of risk factors and comorbidities, men had a higher prevalence of active smoking (19 vs. 2%, P=0.006), previous myocardial infarction (17 vs. 2%, P=0.01), and previous percutaneous coronary interventions (42 vs. 17%, P=0.003). Frequency-domain optical coherence tomography in women showed significantly more plaque-vulnerability features as testified by higher percent of lipid-rich plaques (55 vs. 36%, P=0.03), macrophages (21 vs. 5%, P=0.003), and microvessels (24 vs. 8%, P=0.01). Multivariate analysis showed that female sex was associated independently with lipid-rich plaques (P=0.034) and macrophages (P=0.001). In the analysis restricted to the more severe lesions that were revascularized, women continued to be characterized by more adverse morphological features, such as macrophages (30 vs. 7%, P=0.004) and lipid-rich plaques (63 vs. 39%, P=0.045).

Conclusion: Women with stable CAD may be characterized by plaques that have increased prevalence of vulnerability compared with men. These findings support the hypothesis of sex-specific differences in the development of atherosclerosis.
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http://dx.doi.org/10.1097/MCA.0000000000000522DOI Listing
September 2017

JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling.

Development 2017 03 26;144(5):856-865. Epub 2017 Jan 26.

Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Copenhagen, Denmark

Components of the KDM7 family of histone demethylases are implicated in neuronal development and one member, PHF8, is often found to be mutated in cases of X-linked mental retardation. However, how PHF8 regulates neurodevelopmental processes and contributes to the disease is still largely unknown. Here, we show that the catalytic activity of a PHF8 homolog in , JMJD-1.2, is required non-cell-autonomously for proper axon guidance. Loss of JMJD-1.2 dysregulates transcription of the Hedgehog-related genes and , the overexpression of which is sufficient to induce the axonal defects. Deficiency of either or , or reduced expression of homologs of genes promoting Hedgehog signaling, restores correct axon guidance in mutants. Genetic and overexpression data indicate that Hedgehog-related genes act on axon guidance through actin remodelers. Thus, our study highlights a novel function of in axon guidance that might be relevant for the onset of X-linked mental retardation and provides compelling evidence of a conserved function of the Hedgehog pathway in axon migration.
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http://dx.doi.org/10.1242/dev.142695DOI Listing
March 2017

Reciprocal insulation analysis of Hi-C data shows that TADs represent a functionally but not structurally privileged scale in the hierarchical folding of chromosomes.

Genome Res 2017 03 5;27(3):479-490. Epub 2017 Jan 5.

Friedrich Miescher Institute for Biomedical Research, Basel, CH-4058, Switzerland.

Understanding how regulatory sequences interact in the context of chromosomal architecture is a central challenge in biology. Chromosome conformation capture revealed that mammalian chromosomes possess a rich hierarchy of structural layers, from multi-megabase compartments to sub-megabase topologically associating domains (TADs) and sub-TAD contact domains. TADs appear to act as regulatory microenvironments by constraining and segregating regulatory interactions across discrete chromosomal regions. However, it is unclear whether other (or all) folding layers share similar properties, or rather TADs constitute a privileged folding scale with maximal impact on the organization of regulatory interactions. Here, we present a novel algorithm named CaTCH that identifies hierarchical trees of chromosomal domains in Hi-C maps, stratified through their reciprocal physical insulation, which is a single and biologically relevant parameter. By applying CaTCH to published Hi-C data sets, we show that previously reported folding layers appear at different insulation levels. We demonstrate that although no structurally privileged folding level exists, TADs emerge as a functionally privileged scale defined by maximal boundary enrichment in CTCF and maximal cell-type conservation. By measuring transcriptional output in embryonic stem cells and neural precursor cells, we show that the likelihood that genes in a domain are coregulated during differentiation is also maximized at the scale of TADs. Finally, we observe that regulatory sequences occur at genomic locations corresponding to optimized mutual interactions at the same scale. Our analysis suggests that the architectural functionality of TADs arises from the interplay between their ability to partition interactions and the specific genomic position of regulatory sequences.
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http://dx.doi.org/10.1101/gr.212803.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340975PMC
March 2017

Impaired removal of H3K4 methylation affects cell fate determination and gene transcription.

Development 2016 10 30;143(20):3751-3762. Epub 2016 Aug 30.

Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen DK-2200, Denmark

Methylation of histone 3 lysine 4 (H3K4) is largely associated with promoters and enhancers of actively transcribed genes and is finely regulated during development by the action of histone methyltransferases and demethylases. H3K4me3 demethylases of the KDM5 family have been previously implicated in development, but how the regulation of H3K4me3 level controls developmental processes is not fully established. Here, we show that the H3K4 demethylase RBR-2, the unique member of the KDM5 family in C. elegans, acts cell-autonomously and in a catalytic-dependent manner to control vulva precursor cells fate acquisition, by promoting the LIN-12/Notch pathway. Using genome-wide approaches, we show that RBR-2 reduces the H3K4me3 level at transcription start sites (TSSs) and in regions upstream of the TSSs, and acts both as a transcription repressor and activator. Analysis of the lin-11 genetic locus, a direct RBR-2 target gene required for vulva precursor cell fate acquisition, shows that RBR-2 controls the epigenetic signature of the lin-11 vulva-specific enhancer and lin-11 expression, providing in vivo evidence that RBR-2 can positively regulate transcription and cell fate acquisition by controlling enhancer activity.
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http://dx.doi.org/10.1242/dev.139139DOI Listing
October 2016

Sonographic Pitfall in Endometriotic Ovarian Cysts: A Rare Case of a Spontaneous Sigmoid Colonic Perforation in a Nonpregnant Woman.

J Ultrasound Med 2016 Nov;35(11):2522-2523

Academic Department of Gynecologic Oncology, Mauritian Hospital Umberto I, Torino, Italy.

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http://dx.doi.org/10.7863/ultra.16.01096DOI Listing
November 2016

Effect on Clinical Restenosis of an Ultra-Thin-Strut Bare Metal Cobalt-Chromium Stent Versus a Thin-Strut Stainless Steel Stent.

J Interv Cardiol 2016 Jun 31;29(3):300-10. Epub 2016 May 31.

Department of Cardiology, Mazzoni Hospital, Ascoli Piceno, Italy.

Objectives: To prospectively compare the impact of ultrathin-strut cobalt-chromium (Cro-Co) bare metal stent (BMS) versus thin-strut stainless steel (SS) BMS on clinically driven target lesion revascularization (TLR).

Background: Stent characteristics are an important determinant of restenosis. Thinner strut Cro-Co BMS is associated with a reduction of neointimal formation compared to SS BMS. The advantages of Cro-Co BMS in a real-world population is not clear.

Methods: Patients undergoing percutaneous coronary intervention (PCI) with BMS for any reason were enrolled. Patient with multi-vessel PCI, multi-lesions PCI, PCI of unprotected left main and coronary grafts were not excluded. They were divided in two groups according to stent type: Cro-Co or SS group. The primary endpoint was clinically driven TLR at follow-up.

Results: A total of 383 patients were enrolled: 222 in SS and 161 in Cro-Co group. During the follow-up, Cro-Co patients had a significantly lower occurrence of TLR compared to SS patients (1.9% vs 8.6%, P = 0.006). There were no significant differences for the composite endpoint of death, myocardial infarct, and stroke (4.9% in Cro-Co group vs 9.5% in SS group, P = 0.119). At multivariate analysis, the variables that were predictors of TLR were: use of SS stent (OR 4.43, P = 0.019) and diabetes (OR 2.84, P = 0.025).

Conclusions: Ultra-thin strut Cro-Co BMS is associated with a significant reduction of clinically driven TLR in all comers population with any type of coronary disease complexity. (J Interven Cardiol 2016;29:300-310).
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http://dx.doi.org/10.1111/joic.12300DOI Listing
June 2016

Survey of variation in human transcription factors reveals prevalent DNA binding changes.

Science 2016 Mar 24;351(6280):1450-1454. Epub 2016 Mar 24.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences of human transcription factors (TFs), but the consequences of such variation remain largely unexplored. We developed a computational, structure-based approach to evaluate TF variants for their impact on DNA binding activity and used universal protein-binding microarrays to assay sequence-specific DNA binding activity across 41 reference and 117 variant alleles found in individuals of diverse ancestries and families with Mendelian diseases. We found 77 variants in 28 genes that affect DNA binding affinity or specificity and identified thousands of rare alleles likely to alter the DNA binding activity of human sequence-specific TFs. Our results suggest that most individuals have unique repertoires of TF DNA binding activities, which may contribute to phenotypic variation.
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http://dx.doi.org/10.1126/science.aad2257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825693PMC
March 2016

A real world single centre experience using the STENTYS self-expanding coronary stent.

Int J Cardiol 2016 Apr 3;209:57-9. Epub 2016 Feb 3.

Cardiology Department, Mazzoni Hospital, Via degli Iris n. 1, Ascoli Piceno 63100, Italy.

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http://dx.doi.org/10.1016/j.ijcard.2016.02.010DOI Listing
April 2016

The H3K4me3/2 histone demethylase RBR-2 controls axon guidance by repressing the actin-remodeling gene wsp-1.

Development 2016 Mar 25;143(5):851-63. Epub 2016 Jan 25.

Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark Centre for Epigenetics, University of Copenhagen, 2200 Copenhagen, Denmark

The dynamic regulation of histone modifications is important for modulating transcriptional programs during development. Aberrant H3K4 methylation is associated with neurological disorders, but how the levels and the recognition of this modification affect specific neuronal processes is unclear. Here, we show that RBR-2, the sole homolog of the KDM5 family of H3K4me3/2 demethylases in Caenorhabditis elegans, ensures correct axon guidance by controlling the expression of the actin regulator wsp-1. Loss of rbr-2 results in increased levels of H3K4me3 at the transcriptional start site of wsp-1, with concomitant higher wsp-1 expression responsible for defective axon guidance. In agreement, overexpression of WSP-1 mimics rbr-2 loss, and its depletion restores normal axon guidance in rbr-2 mutants. NURF-1, an H3K4me3-binding protein and member of the chromatin-remodeling complex NURF, is required for promoting aberrant wsp-1 transcription in rbr-2 mutants and its ablation restores wild-type expression of wsp-1 and axon guidance. Thus, our results establish a precise role for epigenetic regulation in neuronal development by demonstrating a functional link between RBR-2 activity, H3K4me3 levels, the NURF complex and the expression of WSP-1.
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http://dx.doi.org/10.1242/dev.132985DOI Listing
March 2016
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