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1.
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
2.
Virchows Arch ; 475(5): 665-668, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31209636

RESUMEN

We retrospectively collected a series of 82 endoscopically removed early colorectal cancers. Histological specimens were revised by two gastrointestinal pathologists, performing a re-evaluation of all risk factors for lymph node metastasis. The comparison between second opinion and first pathological report revealed that lymphovascular invasion and tumor grading showed a lower level of concordance than other parameters. Our results demonstrated that second opinion modified risk assessment in about 10% of cases. It was mainly due to a lack in reporting of some parameters at the first diagnosis and a different evaluation in second opinion for updated guidelines. Considering the subgroup of patients with modified risk assessment, clinical data revealed that tumors, re-classified as low risk, did not develop lymph node metastasis that, conversely, occurred in patients identified as high risk by second opinion. In conclusion, second opinion significantly alters risk perception of endoscopically removed early colorectal carcinomas representing a valuable tool for their appropriate clinical management.


Asunto(s)
Carcinoma/diagnóstico , Neoplasias Colorrectales/diagnóstico , Anciano , Anciano de 80 o más Años , Carcinoma/patología , Neoplasias Colorrectales/patología , Endoscopía , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Patólogos , Pronóstico , Derivación y Consulta , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo
3.
Cell Div ; 14: 2, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30976290

RESUMEN

The p27kip1 protein, mainly known as a negative regulator of cell proliferation, has also been involved in the control of other cellular processes, including the regulation of cytoskeleton dynamics. Notably, these two functions involve distinct protein domains, residing in the N- and C-terminal halves, respectively. In the last two decades, p27kip1 has been reported to interact with microtubule and acto-myosin cytoskeletons, both in direct and indirect ways, overall drawing a picture in which several factors play their role either in synergy or in contrast one with another. As a result, the role of p27kip1 in cytoskeleton dynamics has been implicated in cell migration, both in physiologic and in neoplastic contexts, modulating cytokinesis, lipid raft trafficking, and neuronal development. Recently, two distinct papers have further reported a central role for p27kip1 in the control of microtubule stability and post-translational modifications, dissecting the interaction between p27kip1 and α-tubulin-acetyl-transferase (α-TAT), an enzyme involved in the stability of microtubules, and protein-regulator of cytokinesis 1 (PRC1), a nuclear regulator of the central spindle during mitosis. In light of these recent evidences, we will comment on the role of p27kip1 on cytoskeleton regulation and its implication for cancer progression.

4.
Endosc Int Open ; 6(12): E1462-E1469, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30574536

RESUMEN

Background Implementation of colorectal cancer (CRC) screening programs increases endoscopic resection of polyps with early invasive CRC (pT1). Risk of lymph node metastasis often leads to additional surgery, but despite guidelines, correct management remains unclear. Our aim was to assess the factors affecting the decision-making process in endoscopically resected pT1-CRCs in an academic center. Methods We retrospectively reviewed patients undergoing endoscopic resection of pT1 CRC from 2006 to 2016. Clinical, endoscopic, surgical treatment, and follow-up data were collected and analyzed. Lesions were categorized according to endoscopic/histological risk-factors into low and high risk groups. Comorbidities were classified according to the Charlson comorbidity index (CCI). Surgical referral for each group was computed, and dissociation from current European CRC screening guidelines recorded. Multivariate analysis for factors affecting the post-endoscopic surgery referral was performed. Results Seventy-two patients with endoscopically resected pT1-CRC were included. Overall, 20 (27.7 %) and 52 (72.3 %) were classified as low and high risk, respectively. In the low risk group, 11 (55 %) were referred to surgery, representing over-treatment compared with current guidelines. In the high risk group, nonsurgical endoscopic surveillance was performed in 20 (38.5 %) cases, representing potential under-treatment. After a median follow-up of 30 (6 - 130) months, no patients developed tumor recurrence. At multivariate analysis, age (OR 1.21, 95 %CI 1.02 - 1.42; P  = 0.02) and CCI (OR 1.67, 95 %CI 1.12 - 3.14; P  = 0.04) were independent predictors for subsequent surgery. Conclusions A substantial rate of inappropriate post-endoscopic treatment of pT1-CRC was observed when compared with current guidelines. This was apparently related to an overestimation of patient-related factors rather than endoscopically or histologically related factors.

5.
Int J Mol Sci ; 19(9)2018 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-30149579

RESUMEN

High-grade serous epithelial ovarian cancer (HGSOC) is the fifth leading cause of cancer death in women and the first among gynecological malignancies. Despite an initial response to standard chemotherapy, most HGSOC patients relapse. To improve treatment options, we must continue investigating tumor biology. Tumor characteristics (e.g., risk factors and epidemiology) are valuable clues to accomplish this task. The two most frequent risk factors for HGSOC are the lifetime number of ovulations, which is associated with increased oxidative stress in the pelvic area caused by ovulation fluid, and a positive family history due to genetic factors. In the attempt to identify novel genetic factors (i.e., genes) associated with HGSOC, we observed that several genes in linkage with HGSOC are expressed in the ciliated cells of the fallopian tube. This finding made us hypothesize that ciliated cells, despite not being the cell of origin for HGSOC, may take part in HGSOC tumor initiation. Specifically, malfunction of the ciliary beat impairs the laminar fluid flow above the fallopian tube epithelia, thus likely reducing the clearance of oxidative stress caused by follicular fluid. Herein, we review the up-to-date findings dealing with HGSOC predisposition with the hypothesis that fallopian ciliated cells take part in HGSOC onset. Finally, we review the up-to-date literature concerning genes that are located in genomic loci associated with epithelial ovarian cancer (EOC) predisposition that are expressed by the fallopian ciliated cells.


Asunto(s)
Cistadenocarcinoma Seroso/etiología , Cistadenocarcinoma Seroso/metabolismo , Trompas Uterinas/metabolismo , Membrana Mucosa/metabolismo , Neoplasias Ováricas/etiología , Neoplasias Ováricas/metabolismo , Animales , Biomarcadores , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/etiología , Carcinoma Epitelial de Ovario/metabolismo , Cistadenocarcinoma Seroso/diagnóstico , Susceptibilidad a Enfermedades , Trompas Uterinas/patología , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Membrana Mucosa/patología , Clasificación del Tumor , Células Madre Neoplásicas/metabolismo , Oncogenes , Neoplasias Ováricas/diagnóstico
6.
Gynecol Endocrinol ; 33(3): 185-187, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28102088

RESUMEN

Most frequent causes of androgenic manifestation are Cushing's syndrome, PCO, benign and malignant androgen-secreting non adrenal tumors and iatrogenic hirsutism. Hyperplasia or neoplasms of ectopic adrenocortical gland are rare. We report a case of a 63-year old female with hirsutism and alopecia. Laboratory data highlighted increased levels of androgens. Diagnostic imaging revealed normal morphology of adrenocortical gland and ovaries. In view of the clinical picture and suspected diagnosis of extra-adrenal cause, she underwent bilateral salpingo-oophorectomy. Histologic examination showed an ectopic adrenal gland with adenoma in the ovarian and peri-ovarian tissue. At six months of follow up, the patients has no sign of hyperandrogenism. In case of hyperandrogenism in postmenopausal women and in the absence of the adrenocortical gland abnormality, ovarian origin should be considered in the differential diagnosis.


Asunto(s)
Adenoma/diagnóstico , Hiperandrogenismo/etiología , Neoplasias Ováricas/diagnóstico , Adenoma/patología , Adenoma/fisiopatología , Adenoma/cirugía , Alopecia/etiología , Alopecia/prevención & control , Diagnóstico Diferencial , Femenino , Hirsutismo/etiología , Hirsutismo/prevención & control , Humanos , Hiperandrogenismo/fisiopatología , Hiperandrogenismo/prevención & control , Persona de Mediana Edad , Neoplasias Ováricas/patología , Neoplasias Ováricas/fisiopatología , Neoplasias Ováricas/cirugía , Ovariectomía , Roma , Salpingectomía , Resultado del Tratamiento
7.
Am J Surg ; 213(4): 748-753, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27613269

RESUMEN

BACKGROUND: The aim of the present study was to evaluate the prognostic significance of perineural invasion (PNI) in locally advanced gastric cancer patients who underwent D2 gastrectomy and adjuvant chemotherapy. METHODS: The records of a series of 103 patients undergoing D2 gastrectomy with curative intent combined with adjuvant chemotherapy from January 2004 to December 2014 were retrospectively reviewed. RESULTS: PNI was positive in 47 (45.6%) specimens. The 1-, 3-, and 5-year overall survival rates were 81%, 55%, and 42%, respectively. The 1-, 3-, and 5-year disease-free survival (DFS) rates were 76%, 57%, and 49%, respectively. A multivariate analysis showed that age number of positive lymph nodes, T stage, and PNI were independently associated with overall survival. Regarding DFS, the multivariate analysis showed that only PNI was independently associated with DFS. CONCLUSIONS: PNI and T stage and positive lymph nodes are independent markers of poor prognosis in patients with gastric cancer. PNI should be incorporated in the postoperative staging system for planning follow-up after surgery and in our opinion to propose more aggressive postoperative therapies in PNI-positive patients.


Asunto(s)
Supervivencia sin Enfermedad , Invasividad Neoplásica , Perineo/patología , Neoplasias Gástricas/mortalidad , Factores de Edad , Anciano , Quimioterapia Adyuvante , Femenino , Gastrectomía , Humanos , Italia/epidemiología , Metástasis Linfática , Masculino , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia
8.
Lung Cancer ; 97: 95-8, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27237034

RESUMEN

OBJECTIVES: To investigate prevalence and age-distribution of ALK- or ROS1-translocated adenocarcinomas in patients ≤50 years of age. MATERIALS AND METHODS: Paraffin sections of pulmonary adenocarcinoma were analyzed for ALK (637 cases) and ROS1 (376 cases) translocations using FISH, and for EGFR mutations (789 cases) using mutant-specific Real-Time PCR. RESULTS: ALK or ROS1 fusions were detected in 55 of 637 cases (8.6%). When patients were stratified for age, it was found that six of six cases (100%) of lung adenocarcinoma diagnosed in patients <30 years of age were translocated for ALK (4 cases) or ROS1 (2 cases). With the increase of age, there was a gradual decrease in the percentage of positive cases. In fact, ALK-translocated or ROS1-translocated cases were 5 of 17 cases (29%) in the 31-40 years age-group, 6 of 46 cases (13%) in the 41-50 years age-group, and 38 of 568 cases (7.0%) in patients older than 50 years. The six patients <30 years of age (5F/1M), including two pediatric patients (≤18 years old), presented with stage IV disease, were never or light smoker, and had no family history of pulmonary tumours. Four of the six patients, were treated with crizotinib and had an objective response. CONCLUSIONS: Our findings provide evidence that ALK or ROS1 translocations are crucial events in tumourigenesis of pulmonary adenocarcinoma of very young patients, including pediatric patients.


Asunto(s)
Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Prevalencia , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Adolescente , Adulto , Anciano , Quinasa de Linfoma Anaplásico , Crizotinib , Receptores ErbB/genética , Femenino , Humanos , Italia/epidemiología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Pirazoles/administración & dosificación , Pirazoles/uso terapéutico , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Estudios Retrospectivos , Translocación Genética
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