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2.
Mod Pathol ; 2020 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-32066859

RESUMEN

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.

3.
Am J Surg Pathol ; 44(2): 162-173, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31567189

RESUMEN

This study was undertaken to determine the frequency, and the clinicopathologic and genetic features, of colon cancers driven by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Of the 7008 tumors screened for NTRK expression using a pan-Trk antibody, 16 (0.23%) had Trk immunoreactivity. ArcherDx assay detected TPM3-NTRK1 (n=9), LMNA-NTRK1 (n=3), TPR-NTRK1 (n=2) and EML4-NTRK3 (n=1) fusion transcripts in 15 cases with sufficient RNA quality. Patients were predominantly women (median age: 63 y). The tumors involved the right (n=12) and left colon unequally and were either stage T3 (n=12) or T4. Local lymph node and distant metastases were seen at presentation in 6 and 1 patients, respectively. Lymphovascular invasion was present in all cases. Histologically, tumors showed moderate to poor (n=11) differentiation with a partly or entirely solid pattern (n=5) and mucinous component (n=10), including 1 case with sheets of signet ring cells. DNA mismatch repair-deficient phenotype was seen in 13 cases. Tumor-infiltrating CD4/CD8 lymphocytes were prominent in 9 cases. Programmed death-ligand 1 positive tumor-infiltrating immune cells and focal tumor cell positivity were seen in the majority of cases. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 cases. No mutations in BRAF, RAS, and PIK3CA were identified. However, other genes of the PI3K-AKT/MTOR pathway were mutated. In several cases, components of Wnt/ß-catenin (APC, AMER1, CTNNB1), p53, and TGFß (ACVR2A, TGFBR2) pathways were mutated. However, no SMAD4 mutations were found. Two tumors harbored FBXW7 tumor suppressor gene mutations. NTRK fusion tumors constitute a distinct but rare subgroup of colorectal carcinomas.

4.
J Pathol ; 250(2): 134-147, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31518438

RESUMEN

Colorectal cancer (CRC) is the fourth cause of death from cancer worldwide mainly due to the high incidence of drug-resistance. During a screen for new actionable targets in drug-resistant tumours we recently identified p65BTK - a novel oncogenic isoform of Bruton's tyrosine kinase. Studying three different cohorts of patients here we show that p65BTK expression correlates with histotype and cancer progression. Using drug-resistant TP53-null colon cancer cells as a model we demonstrated that p65BTK silencing or chemical inhibition overcame the 5-fluorouracil resistance of CRC cell lines and patient-derived organoids and significantly reduced the growth of xenografted tumours. Mechanistically, we show that blocking p65BTK in drug-resistant cells abolished a 5-FU-elicited TGFB1 protective response and triggered E2F-dependent apoptosis. Taken together, our data demonstrated that targeting p65BTK restores the apoptotic response to chemotherapy of drug-resistant CRCs and gives a proof-of-concept for suggesting the use of BTK inhibitors in combination with 5-FU as a novel therapeutic approach in CRC patients. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

5.
Cells ; 8(10)2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31581548

RESUMEN

Carboplatin/paclitaxel is the reference regimen in the treatment of advanced high-grade serous ovarian cancer (HGSOC) in neo-adjuvant chemotherapy (NACT) before interval debulking surgery (IDS). To identify new genetic markers of platinum-resistance, next-generation sequencing (NGS) analysis of 26 cancer-genes was performed on paired matched pre- and post-NACT tumor and blood samples in a patient with stage IV HGSOC treated with NACT-IDS, showing platinum-refractory/resistance and poor prognosis. Only the TP53 c.375+1G>A somatic mutation was identified in both tumor samples. This variant, associated with aberrant splicing, was in trans configuration with the 72Arg allele of the known germline polymorphism TP53 c.215C>G (p. Pro72Arg). In the post-NACT tumor sample we observed the complete expansion of the TP53 c.375+1G>A driver mutant clone with somatic loss of the treatment-sensitive 72Arg allele. NGS results were confirmed with Sanger method and immunostaining for p53, BRCA1, p16, WT1, and Ki-67 markers were evaluated. This study showed that (i) the splice mutation in TP53 was present as an early driver mutation at diagnosis; (ii) the mutational profile was shared in pre- and post-NACT tumor samples; (iii) the complete expansion of a single dominant mutant clone through loss of heterozygosity (LOH) had occurred, suggesting a possible mechanism of platinum-resistance in HGSOC under the pressure of NACT.

6.
Int J Mol Sci ; 20(19)2019 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-31569791

RESUMEN

In clinical practice, patients' tissues are fixed and paraffin-embedded in order to enable histological diagnosis. Nowadays, those tissues are also used for molecular characterization. Formalin is the most used fixative worldwide, and Bouin's solution in some worldwide institutions. Among molecular targets, micro RNAs (miRNAs), the single-stranded non-coding RNAs comprised of 18 to 24 nucleotides, have been demonstrated to be resistant to fixation and paraffin-embedding processes, with consequent possible application in clinical practice. In the present study, let-7e-5p, miR-423-3p, miR-92a-1-5p, miR-30d-5p, miR-155-5p, miR-200a-3p, and miR-429 were investigated in formalin and matched Bouin's solution-fixed tissues of high grade serous ovarian cancers by means of real-time and droplet digital PCR (ddPCR). Micro RNAs were detectable and analyzable in both formalin- and Bouin's-fixed specimens, but on average, higher Ct values and lower copies/µL were found in Bouin's-fixed samples. Data from formalin-fixed samples correlated significantly for most targets with Bouin's ones, except for let-7e-5p and miR-155-5p. This study shows that miRNAs are analyzable in both formalin- and Bouin's-fixed specimens, with the possibility, after proper data normalization, to compare miRNA-based data from formalin-fixed samples to those of Bouin's-fixed ones.


Asunto(s)
MicroARNs/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Humanos , Inmunohistoquímica , MicroARNs/aislamiento & purificación , Adhesión en Parafina , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Reproducibilidad de los Resultados , Fijación del Tejido
7.
Pol J Pathol ; 70(1): 26-32, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31556548

RESUMEN

The distinction between atypical Spitz lesions, conventional melanocytic nevi including Spitz nevi, and malignant melanomas may be difficult in some cases or may even be impossible. The histological assessment of these lesions is necessary to ensure correct diagnosis and treatment. Nevertheless, pathologists may be subject to suboptimal concordance in the diagnosis of some atypical lesions. In literature, certain atypical lesions have been defined differently: the terms atypical and metastasising Spitz tumour, malignant Spitz nevus, borderline and intermediate melanocytic tumour, melanocytic tumour of uncertain malignant potential MELTUMP, and low-grade malignant melanoma have been introduced to designate this heterogeneous group of pathological entities and variants. This review focuses on some issues concerning the historical background, diagnostic state-of-the-art, evolution, and classification of these complicated lesions.


Asunto(s)
Melanoma/diagnóstico , Nevo de Células Epitelioides y Fusiformes/diagnóstico , Neoplasias Cutáneas/diagnóstico , Diagnóstico Diferencial , Humanos , Melanoma/patología , Nevo de Células Epitelioides y Fusiformes/patología , Neoplasias Cutáneas/patología
8.
Front Oncol ; 9: 513, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31263680

RESUMEN

Probe based confocal laser endomicroscopy (pCLE) is an advanced technique which provides imaging of gastrointestinal mucosa at subcellular resolution and, importantly, a valid tool for the evaluation of microvasculature during endoscopic examination. In order to assess intratumoral vascularization and the efficiency of blood flow in locally advanced gastric cancer, we examined 57 patients through pCLE imaging. The vascular alterations in gastric cancer were mainly characterized by leakage and by the presence of tortuous and large size vessels. Defects in blood flow were detected very rarely. No association between the angiogenic score and the gastric tumor site or histological type was observed. Interestingly, no correlation was also found with the tumor grading indicating that the vascular angiogenic anomalies in gastric cancer represent an early pathological event to be observed and detected. The majority of patients displayed unchanged vascular alterations following neoadjuvant chemotherapy and this positively correlated with stable or progressive disease, suggesting that an unaltered angiogenic score could per se be indicative of poor therapeutic efficacy. Different vascular parameters were evaluated by immunofluorescence using bioptic samples and the vessel density did not correlate with clinical staging, site or histologic type. Interestingly, only CD105, Multimerin-2 and GLUT1 were able to discriminate normal from tumoral gastric mucosa. Taken together, these findings indicate that functional and structural angiogenic parameters characteristic of tumor blood network were fully detectable by pCLE. Moreover, the evaluation of tumor vasculature by real-time assessment may provide useful information to achieve tailored therapeutic interventions for gastric cancer patients.

9.
Onco Targets Ther ; 12: 4577-4583, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31354291

RESUMEN

The potential role of the probe-based confocal laser endomicroscopy (pCLE) has been analyzed in different pathologic conditions of the gastrointestinal tract. Here, we analyzed a case of extrapulmonary high grade neuroendocrine rectal carcinoma (HGNEC) using, for the first time, the pCLE system. A 72-year old man was diagnosed with an 8 cm diameter rectal HGNEC by standard colonoscopy integrated with the pCLE system. The diagnosis of neuroendocrine carcinoma was confirmed by immunohistochemical analyses. By using the pCLE system, we well defined and resolved vascular structures and mucosal architecture. An altered mucosal pattern and vascular defects, peculiar for HGNEC, were observed at high magnification, allowing the identification of a pattern which was quite different from that observed in poorly differentiated adenocarcinomas (PDA) where tissues appear darker, very irregular, even if glandular structures can still be recognized. This underlines the usefulness of pCLE in discriminating HGNECs from PDAs. In conclusion, pCLE could represent a valid and helpful method for in vivo HGNEC diagnosis, allowing prompt and careful management of the patient.

10.
EBioMedicine ; 46: 79-93, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31303496

RESUMEN

BACKGROUND: Metastatic colorectal cancer (CRC) remains a deadly disease. Identifying locally advanced CRC patients with high risk of developing metastasis and improving outcome of metastatic CRC patients require discovering master regulators of metastasis. In this context, the non-coding part of the human genome is still largely unexplored. METHODS: To interrogate the non-coding part of the human genome and disclose regulators of CRC metastasis, we combined a transposon-based forward genetic screen with a novel in vitro assay, which forces cells to grow deprived of cell-substrate and cell-cell contacts (i.e. forced single cell suspension assay - fSCS). FINDINGS: We proved that fSCS selects CRC cells with mesenchymal and pro-metastatic traits. Moreover, we found that the transposon insertions conferred CRC cells resistance to fSCS and thus metastatic advantage. Among the retrieved transposon insertions, we demonstrated that the one located in the 3'UTR of BTBD7 disrupts miR-23b::BTBD7 interaction and contributes to pro-metastatic traits. In addition, miR-23b and BTBD7 correlate with CRC metastasis both in preclinical experiments and in clinical samples. INTERPRETATION: fSCS is a simple and scalable in vitro assay to investigate pro-metastatic traits and transposon-based genetic screens can interrogate the non-coding part of the human genome (e.g. miRNA::target interactions). Finally, both Btbd7 and miR-23b represent promising prognostic biomarkers and therapeutic targets in CRC. FUND: This work was supported by Marie Curie Actions (CIG n. 303877) and Friuli Venezia Giulia region (Grant Agreement n°245574), Italian Association for Cancer Research (AIRC, MFAG n°13589), Italian Ministry of Health (GR-2010-2319387 and PE-2016-02361040) and 5x1000 to CRO Aviano.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Interferencia de ARN , Comunicación Celular , Línea Celular Tumoral , Proliferación Celular , Transición Epitelial-Mesenquimal/genética , Matriz Extracelular/metabolismo , Pruebas Genéticas , Humanos , Metástasis de la Neoplasia , Estadificación de Neoplasias
11.
Cancers (Basel) ; 11(6)2019 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-31238520

RESUMEN

BACKGROUND: Bruton's tyrosine kinase (BTK) is involved in the immune response and its deficiency impairs B cell maturation. We evaluated the expression of a novel BTK isoform, p65BTK, in colorectal cancer (CRC), to identify its impact on survival. MATERIALS AND METHODS: This retrospective study evaluated 87 consecutive stage III CRC patients treated at the National Cancer Institute of Aviano (1999-2017). Multiple specimens were collected and analyzed for staining intensity and percentage of tumor cells positive for p65BTK. Prognostic impact was tested by univariate Cox regression analysis. RESULTS: After a median follow-up of 82.59 months, median disease-free survival (DFS) and overall survival (OS) were 11.67 months and 31.33 months, respectively. Interestingly, 10% of patients did not express p65BTK. For the immunohistochemistry IHC intensity 1, the best cutoff point was 1% of p65BTK positivity; for IHC intensity 2, it was 50%; and for IHC intensity 3, it was 80%. Through univariate analysis, patients with highly expressed p65BTK (IHC intensity 3 and ≥80%) were shown to have the worst prognosis in terms of DFS (HR: 6.23; p = 0.005; 95% C.I. 1.75-22.79) and OS (HR: 2.54; p = 0.025; 95% C.I. 1.12-5.76). CONCLUSIONS: p65BTK is frequently expressed in CRC and, if highly expressed, is an unfavourable prognostic factor. However, further confirmation is needed and its potential targeting needs to be studied.

12.
Cells ; 8(6)2019 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-31197119

RESUMEN

Next-generation sequencing (NGS) technology has advanced knowledge of the genomic landscape of ovarian cancer, leading to an innovative molecular classification of the disease. However, patient survival and response to platinum-based treatments are still not predictable based on the tumor genetic profile. This retrospective study characterized the repertoire of somatic mutations in advanced ovarian cancer to identify tumor genetic markers predictive of platinum chemo-resistance and prognosis. Using targeted NGS, 79 primary advanced (III-IV stage, tumor grade G2-3) ovarian cancer tumors, including 64 high-grade serous ovarian cancers (HGSOCs), were screened with a 26 cancer-genes panel. Patients, enrolled between 1995 and 2011, underwent primary debulking surgery (PDS) with optimal residual disease (RD < 1 cm) and platinum-based chemotherapy as first-line treatment. We found a heterogeneous mutational landscape in some uncommon ovarian histotypes and in HGSOC tumor samples with relevance in predicting platinum sensitivity. In particular, we identified a poor prognostic signature in patients with HGSOC harboring concurrent mutations in two driver actionable genes of the panel. The tumor heterogeneity described, sheds light on the translational potential of targeted NGS approach for the identification of subgroups of patients with distinct therapeutic vulnerabilities, that are modulated by the specific mutational profile expressed by the ovarian tumor.


Asunto(s)
Heterogeneidad Genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Femenino , Humanos , Persona de Mediana Edad , Tasa de Mutación , Estadificación de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genética
13.
Pathogens ; 8(2)2019 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-31109082

RESUMEN

Helicobacter pylori (H. pylori) represents an independent risk factor for Gastric Cancer (GC). First Degree Relatives (FDR) of GC subjects and Autoimmune Gastritis (AG) patients are both at increased risk for GC. H. pylori genetic heterogeneity within the gastric niche of FDR and AG individuals has been little explored. To understand whether they exploit an increased H. pylori stability and virulence, 14 AG, 25 FDR, 39 GC and 13 dyspeptic patients (D) were investigated by a cultural PCR-based approach characterizing single colonies-forming-units. We chose three loci within the Cytotoxin-associated gene-A Pathogenicity Island (CagPAI) (cagA,cagE,virB11), vacA, homA and homB as markers of virulence with reported association to GC. Inflammatory/precancerous lesions were staged according to Sydney System. When compared to D, FDR, similarly to GC patients, were associated to higher atrophy (OR = 6.29; 95% CI:1.23-31.96 in FDR; OR = 7.50; 95% CI:1.67-33.72 in GC) and a lower frequency of mixed infections (OR = 0.16; 95% CI:0.03-0.81 in FDR; OR = 0.10; 95% CI:0.02-0.48 in GC). FDR presented also an increased neutrophil infiltration (OR = 7.19; 95% CI:1.16-44.65). Both FDR and GC carried a higher proportion of CagPAI+vacAs1i1mx+homB+ profiles (OR = 2.71; 95% CI: 1.66-4.41 and OR = 3.43; 95% CI: 2.16-5.44, respectively). Conversely, AG patients presented a lower frequency of subtypes carrying a stable CagPAI and vacAs1i1mx. These results underline different H. pylori plasticity in FDR and AG individuals, and thus, a different host-bacterium interaction capacity that should be considered in the context of eradication therapies.

14.
Cancers (Basel) ; 11(5)2019 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-31083432

RESUMEN

Autoimmune atrophic gastritis (AAG) is associated with an increased risk of certain types of gastric cancer (GC). Helicobacter pylori (H. pylori) infection may have a role in the induction and/or maintenance of AAG and GC. Toll-like receptors (TLR) are essential for H. pylori recognition and subsequent innate and adaptive immunity responses. This study therefore aimed to characterize TLR polymorphisms, and features of bacterial flagellin A in samples from patients with AAG (n = 67), GC (n = 114) and healthy donors (HD; n = 97). TLR5 rs5744174 C/C genotype was associated with GC, lower IgG anti H. pylori response and a higher H. pylori flagellin A abundance and motility. In a subset of patients with AAG, H. pylori strains showed a reduction of the flagellin A abundance and a moderate motility compared with strains from GC patients, a prerequisite for active colonization of the deeper layers of the mucosa, host immune response and inflammation. TLR9 rs5743836 T allele showed an association with serum gastrin G17. In conclusion, our study suggests that alterations of flaA protein, moderate motility in H. pylori and two polymorphisms in TLR5 and TLR9 may favor the onset of AAG and GC, at least in a subset of patients. These findings corroborate the function of pathogen-host cell interactions and responses, likely influencing the pathogenetic process.

15.
ACS Med Chem Lett ; 10(4): 475-480, 2019 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-30996782

RESUMEN

STARD3 is a cellular protein that represents an attractive target for cancer therapy, being overexpressed in breast cancer and implied in the development of colorectal, gastric, and prostate cancers. Unfortunately, no STARD3 inhibitor has been identified yet. In this work, an in silico strategy was applied to predict a reliable binding mode of cholesterol into STARD3 and to develop a pharmacophore-based virtual screening protocol that allowed the identification of the first STARD3 inhibitor ever reported. The identified compound VS1 binds STARD3 with micromolar affinity (IC50 = 35 µM) and shows antiproliferative activity in breast (MCF7 and MDA- MB-231) and colon (HCT-116) cancer cell lines in the same concentration range (IC50 = 49.7-105.5 µM). Although VS1 has a moderate potency, we demonstrated that it specifically targets STARD3 in the cells and induces its degradation. Overall, the results confirm the reliability of the computational strategies herein applied and the identification of the first hit compound for the development of novel potent STARD3 inhibitors.

16.
ACS Med Chem Lett ; 10(4): 517-521, 2019 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-30996789

RESUMEN

One of the most promising applications of DNA origami is its use as an excellent evolution of nanostructured intelligent systems for drug delivery, but short in vivo lifetime and immune-activation are still major challenges to overcome. On the contrary, stealth liposomes have long-circulation time and are well tolerated by the immune system. To overcome DNA origami limitations, we have designed and synthesized a compact short tube DNA origami (STDO) of approximately 30 nm in length and 10 nm in width. These STDO are highly stable ≥48 h in physiological conditions without any postsynthetic modifications. The compact size of STDO precisely fits inside a stealthy liposome of about 150 nm and could efficiently remotely load doxorubicin in liposomes (LSTDO) without a pH driven gradient. We demonstrated that this innovative drug delivery system (DDS) has an optimal tumoral release and high biocompatible profiles opening up new horizons to encapsulate many other hydrophobic drugs.

17.
Mol Genet Genomic Med ; 7(5): e587, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30916491

RESUMEN

BACKGROUND: Inherited epimutations of Mismatch Repair (MMR) genes are responsible for Lynch Syndrome (LS) in a small, but well defined, subset of patients. Methylation of the MSH2 promoter consequent to the deletion of the upstream EPCAM gene is found in about 1%-3% of the LS patients and represents a classical secondary, constitutional and tissue-specific epimutation. Several different EPCAM deletions have been reported worldwide, for the most part representing private variants caused by an Alu-mediated recombination. METHODS: 712 patients with suspected LS were tested for MMR mutation in our Institute. EPCAM deletions were detected by multiplex ligation-dependent probe amplification (MLPA) and then defined by Long-Range polymerase chain reaction (PCR)/Sanger sequencing. A comprehensive molecular characterization of colorectal cancer (CRC) tissues was carried out by immunohistochemistry of MMR proteins, Microsatellite Instability (MSI) assay, methylation specific MLPA and transcript analyses. In addition, somatic deletions and/or variants were investigated by MLPA and next generation sequencing (NGS). RESULTS: An EPCAM deletion was found in five unrelated probands in Italy: variants c.556-490_*8438del and c.858+1193_*5826del are novel; c.859-1430_*2033del and c.859-670_*530del were previously reported. All probands were affected by CRC at young age; tumors showed MSI and abnormal MSH2/MSH6 proteins expression. MSH2 promoter methylation, as well as aberrant in-frame or out-of-frame EPCAM/MSH2 fusion transcripts, were detected in CRCs and normal mucosae. CONCLUSION: An EPCAM deletion was the causative variant in about 2% of our institutional series of 224 LS patients, consistent with previously estimated frequencies. Early age and multiple CRCs was the main clinical feature of this subset of patients.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Molécula de Adhesión Celular Epitelial/genética , Eliminación de Gen , Frecuencia de los Genes , Adulto , Metilación de ADN , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Fenotipo
18.
Arch Pathol Lab Med ; 143(8): 1006-1011, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30779593

RESUMEN

CONTEXT.­: A significant negative trend in length of cone excision has been observed in recent years, leading to a higher percentage of positive endocervical excision margin and close (<1 mm) negative endocervical margin cases. OBJECTIVE.­: To evaluate the rate of disease persistence and recurrence after cervical excision for cervical intraepithelial neoplasia in relation to a close (<1 mm), negative, or positive endocervical margin. DESIGN.­: We retrospectively analyzed a cohort of patients with cervical intraepithelial neoplasia having a carbon dioxide laser cervical excision performed by the same operator. We evaluated the rate of positive follow-up in relation to the status of endocervical margin. RESULTS.­: We found a higher percentage of positivity at follow-up and recurrence rate between 13 and 24 months in patients with positive margin than for patients with negative or close endocervical margin (P = .005 and P = .006, respectively), with no difference between negative and close margin (7.0% versus 8.3%, P = .89, and 1.2% versus 0%, P = .83, respectively). CONCLUSIONS.­: Women with close and negative endocervical margin presented similar risk of positivity at long-term follow-up, disease persistence, and recurrence between 13 and 24 months, so the histopathologic report of a free endocervical margin less than 1 mm should not categorize the patient as being at increased risk of treatment failure. Therefore, the only information that the pathologist should report is the state of the margin (positive or negative), regardless of the negative endocervical margin length.

19.
J Cell Physiol ; 2019 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-30697729

RESUMEN

Peptidyl-prolyl cis-trans isomerase, NIMA-interacting 1 (PIN1) is a peptidyl-prolyl isomerase that binds phospho-Ser/Thr-Pro motifs in proteins and catalyzes the cis-trans isomerization of proline peptide bonds. PIN1 is overexpressed in several cancers including high-grade serous ovarian cancer. Since few therapies are effective against this cancer, PIN1 could be a therapeutic target but effective PIN1 inhibitors are lacking. To identify molecules with in vivo inhibitory effects on PIN1, we used consensus docking to model existing PIN1-ligand X-ray structures and to screen a chemical database for candidate inhibitors. Ten molecules were selected and tested in cellular assays, leading to the identification of VS10 that bound and inhibited PIN1. VS10 treatment reduced the viability of ovarian cancer cell lines by inducing proteasomal PIN1 degradation, without effects on PIN1 transcription, and also reduced the levels of downstream targets ß-catenin, cyclin D1, and pSer473-Akt. VS10 is a selective PIN1 inhibitor that may offer new opportunities for treating PIN1-overexpressing tumors.

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