The nuclear-cytoplasmic trafficking of a chromatin-modifyng and remodelling protein (KMT2C), in osteosarcoma

Osteosarcoma is the most common paediatric primary non-hematopoietic bone tumor; the survival is related to the response to chemotherapy and development of metastases. KMT2C is a chromatin-modifying and remodelling protein and its expression has never been studied in osteosarcoma. The aim of this study was to understand the role of KMT2C in the osteosarcoma carcinogenesis and metastatic progression to identify a new molecular target and to provide new therapeutic approach. We performed the immunohistochemical and gene expression analysis of KMT2C in 32 samples of patients with diagnosis of osteosarcoma with known clinicpathological data and we analysed the expression of genes involved in the metastatic pathway in four osteosarcoma cell lines by blocking the KMT2C expression using siRNA. We found a nuclear-cytoplamic trafficking of KMT2C and the cytoplasmic localization was higher than the nuclear localization (p < 0.0001). Moreover, the percentage of cells with cytoplasmic positivity increased from low grade primary tissue to metastatic tissues. The cytoplasmic localization of KMT2C could lead to a change in its function supporting osteosarcoma carcinogenesis and progression. Our hypothesis is that KMT2C could affect the enhancer activity of genes influencing the invasive properties and metastatic potential of osteosarcoma

Increased plasma proneurotensin levels identify NAFLD in adults with and without type 2 diabetes

Context Neurotensin (NT), an intestinal peptide released by fat ingestion, promotes lipid absorption; higher circulating NT levels are associated with type 2 diabetes (T2D), obesity, and cardiovascular disease. Whether NT is related to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has not been fully investigated. Objective To study the relationship between plasma proneurotensin 1 to 117 (pro-NT), a stable fragment of the NT precursor hormone, and the presence/severity of NAFLD/NASH and to unravel correlates of increased pro-NT levels. Design/Setting/Participants For this cross-sectional study, 60 obese individuals undergoing bariatric surgery for clinical purposes were recruited. The association between pro-NT and NAFLD was further investigated in 260 consecutive subjects referred to our outpatient clinics for metabolic evaluations, including liver ultrasonography. The study population underwent complete metabolic characterization; in the obese cohort, liver biopsies were performed during surgery. Main Outcome Measures Plasma pro-NT levels in relation to NAFLD/NASH. Results Obese subjects with biopsy-proven NAFLD (53%) had significantly higher plasma pro-NT than those without NAFLD (183.6 ± 81.4 vs 86.7 ± 56.8 pmol/L, P &lt; 0.001). Greater pro-NT correlated with NAFLD presence (P &lt; 0.001) and severity (P &lt; 0.001), age, female sex, insulin resistance, and T2D. Higher pro-NT predicted NAFLD with an area under receiver operating characteristic curve of 0.836 [95% confidence interval (CI), 0.73 to 0.94; P &lt; 0.001]. Belonging to the highest pro-NT quartile correlated with increased NAFLD risk (odds ratio, 2.62; 95% CI, 1.08 to 6.40) after adjustment for confounders. The association between higher pro-NT and NAFLD was confirmed in the second cohort independently from confounders. Conclusions Increased plasma pro-NT levels identify the presence/severity of NAFLD; in dysmetabolic individuals, NT may specifically promote hepatic fat accumulation through mechanisms likely related to increased insulin resistance. © 2018 Endocrine Society

Evaluation of the management of Hr-HPV+/PapTest- women. Results at 1-year recall

With cervical cancer screening the choice of 1-year as a period of follow-up in positive high-risk HPV women without cytological lesions is still under discussion. We evaluated the management of these women and the role of HPV genotyping test. We did a cervical cancer screening study of women aged 35-64 with primary high-risk HPV test. Women positive for high-risk HPV with negative cytology were followed-up after 1 year. In this study we selected women with high-risk HPV+/PapTest- resulted high-risk HPV+ at recall and performed the PapTest and HPV genotyping test. The detection rate of squamous high grade (CIN2+) relative to the total screened cohort was 2.1‰, and it was 0.2‰ at the 1-year recall. The colposcopy performed in women referred at the 1-year recall accounted for 48.8% of the total (baseline + 1-year recall), and 84.3% of these women had no cytological lesions. The most frequent hr-HPV genotype detected was HPV16 and 66.7% of co-infections were due to HPV16 and HPV18. 54.5% of women presented a persistent infection at 1-year recall with the same HPV subtype, 50% of persistent infections was due to HPV16 and 16.7% of these were determined to be CIN2+ histological lesions. Our data show that it may be useful to extend the period of follow-up for women hr-HPV+/PapTest- so as to reduce the number of unnecessary colposcopies due to the transitory infections and that the genotyping test could help to identify the persistent infections in which HPV16 is involved

Management of women aged 25-34 with diagnosis of ASCUS in the screening center of Latina.

In cervical cancer screening program of Latina (Italy) the hr-HPV as primary test is performed only on women aged 35-64 while women aged 25-34 are invited to perform PapTest. The aim of this study was to evaluate the impact of the application of the PapTest in women aged 25-34 and to evaluate the management of ASCUS. Women aged 25-34 were invited to perform PapTest according to the Italian guidelines; women with diagnosis of LSIL+ were referred to colposcopy while women with diagnosis of ASCUS were referred to hr-HPV test and only women resulted positive were referred to colposcopy. The 4.0% of women resulted positive to PapTest and the referral rate to colposcopy was 3.5%. The PPV value for CIN2+ at colposcopy was 7.2% and the Detection Rate (DR) for CIN2+ was 2.40‰. The ASCUS category was diagnosed in 41.8% of women resulted positive to PapTest and between them the 70.6% resulted positive to the hr-HPV test. The referral rate to colposcopy of women resulted positive to hr-HPV test was 1.1%. The PPV for CIN2+ at colposcopy and the DR of CIN2+ was 8.4% and 0.96‰ respectively. Between women with diagnosis of ASCUS, only 6 women showed a CIN2+ lesion (4 CIN2 and 2 CIN3). The present study showed that this algorithm, applied to women aged 25-34, obtained a good performance in term of test specificity (98%) and confirm that the application of hr-HPV test in the management of ASCUS leads to a decreased of inappropriate colposcopy due to transitory infection in young women

Neurotensin is a lipid-induced gastrointestinal peptide associated with visceral adipose tissue inflammation in obesity

Neurotensin (NT) is a 13-amino acid peptide localized in the neuroendocrine cells of the small intestine, which promotes fat absorption and fatty acids translocation in response to lipid ingestion. NT-knock-out mice fed with a high-fat diet are protected from obesity, fatty liver, and the development of insulin-resistance. In humans, higher plasma levels of pro-NT, which is the stable circulating precursor of NT, predict obesity, type 2 diabetes (T2D), and cardiovascular disease. In obesity, the presence of visceral adipose tissue (VAT) inflammation leads to unfavorable metabolic outcomes and is associated with the development of T2D and non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the relationship between plasma pro-NT levels and the presence of VAT inflammation in biopsies from 40 morbidly obese subjects undergoing bariatric surgery. We demonstrated that higher proNT levels are significantly associated with greater macrophages infiltration, HIF-1&alpha;, WISP-1, and UNC5B expression in VAT (all p < 0.01) due to the diagnosis of T2D and NAFLD. The overall results show that, in obesity, pro-NT is a biomarker of VAT inflammation and insulin-resistance. Additionally, NT may be involved in the development of dysmetabolic conditions likely mediated by increased gut fat absorption and the presence of a proinflammatory milieu in the adipose tissue

Polypoid lesions of the gallbladder in a consecutive series of 2631 patients. A single-center experience

INTRODUZIONE: La diagnosi ultrasonografica (US) delle lesioni polipoidi della colecisti (PLG) è difficile per la bassa sensibilità (SE) della metodica. Non sono stati ancora completamenti definiti i criteri di selezione dei pazienti con PLG da indirizzare al trattamento chirurgico o al follow-up. L’indagine istopatologica (EI) rappresenta il gold standard per la diagnosi di polipi non-neoplastici (colesterolotici, infiammatori, fibroepiteliali, adenomiomatosici), di polipi neoplastici (carcinomi, carcinoidi), di lesioni precancerose non polipoidi (displasia dibasso ed alto grado, metaplasia intestinale di tipo muciparo, metaplasia gastrica di tipo pilorico) e di irregolarità nodulari parietali della colecistite xanto-granulomatosa. Gli scopi dello studio sono stati quelli di valutare in un campione di pazienti sottoposti a colecistectomia, la prevalenza dei polipi non neoplastici e neoplastici e la sensibilità dell’US tradizionale trans-addominale rispetto all’EI nell’identificazione delle PLG. MATERIALI E METODI: Studio osservazionale retrospettivo, condotto su un campione di 2631 pazienti, sottoposti a colecistectomia laparoscopica e open, in elezione e in urgenza, identificati mediante il codice ICD-9-CM 51.2, nel periodo Aprile 2005 - Marzo 2018, presso l’ospedale universitario “A. Fiorini” di Terracina - Polo Pontino, “Sapienza” Università di Roma. Tutti i pazienti erano stati sottoposti a US. RISULTATI: Il campione esaminato era costituito da 1175(44.6%) M, età media 56 anni, range 25-95 anni, 1456(55.4%) F, età media 46anni, range 17-90 anni. La diagnosi US di PLG veniva posta in 38/2631(1.4%) pazienti. All’esame istologico i polipi erano identificati in 68/2631(2.6%) pazienti, associati a litiasi biliare in 28/2631 (1.1%) casi. Dal confronto US e EI la diagnosi ecografica risultava gravata da falsi positivi (FP) (8/38; 21%) e falsi negativi (FN) (38/2631; 1.45%), con SE 44% (95% c.i.:32.2-55.7). L’incidenza istologica di PLG neoplastiche è stata dello 0.38% (10/2631), 3M e 7F, età media 64 anni, (range 49-80 anni). In 3 casi le neoplasie erano state identificate all’US (3/10; 30 % VP); nei restanti 7 casi costituivano reperto istologico incidentale (7/10; 70 % FN), di cui 5 con diametro &gt;1cm nel contesto di un quadro clinico di colecistite acuta litiasica e 2 con diametro &lt;1cm in un quadro di litiasi non complicata. DISCUSSIONE: L’US tradizionale trans-addominale sottostimava l’incidenza delle PLG rispetto all’EI (p=0.021) e i FP per PLG isolate sono stati causa di errata indicazione al trattamento chirurgico. Il confronto fra diagnosi US ed EI conferma la bassa SE della metodica ecografica nell’identificazione delle PLG, sia in presenza che in assenza di litiasi biliare. Il sesso femminile si è dimostrato specifico fattore di rischio per PLG benigne e maligne e lesioni mucosali non polipoidi (p=0.041). Nel nostro studio, probabilmente, le cause della mancata identificazione US delle irregolarità parietali maligne erano l’oscuramento della lesione dall’esordio clinico della neoplasia in colecistite acuta litiasica (in 5 pazienti) e le dimensioni &lt;1cm in presenza di litiasi non complicata (in 2 pazienti). La dimensione della lesione parietale &lt;0.5cm non escludeva la loro natura neoplastica. Attualmente la prevenzione e la diagnosi di GBC è basata sul precoce riscontro e trattamento delle lesioni polipoidi potenzialmente evolutive nell’arco di circa 15 anni. CONCLUSIONI: Probabilmente la colecistectomia precoce in tutti i pz con PLG di diametro &lt;1cm, isolate o associate a calcoli, sintomatici e asintomatici, può contribuire alla riduzione dell’incidenza del GBC.BACKGROUND: Challenges in the diagnosis of polypoid gallbladder lesion (PLG) is due to the low sensibility (SE) of ultrasound scan (US), and the selection criteria of patients with PLG to be addressed to surgical treatment or followup are not yet fully defined. MATERIALS AND METHODS: Retrospective observational study was conducted on 2631 patients, 1175(44.6%) M, mean age 56 years, 1456(55.4%) F, mean age 46 years, who underwent laparoscopic and open cholecystectomy. RESULTS: The US diagnosis for PLG was placed in 38/2631(1.4%) patients. On histological examination (HE) the polyps were identified in 68/2631(2.6%) patients and it was associated with biliary lithiasis in 28/2631 (1.1%) cases. From the US and HE comparison, the ultrasound diagnosis was burdened by false positives (8/38; 21%) and false negatives (38/2631;1.45%), with SE 44% (95% c.i.:32.2-55.7). The histological incidence of gall bladder cancer (GBC) was 0.38%(10/2631). DISCUSSION: US survey underestimated the incidence of PLG compared to the histological finding (p=0.021). Female gender has been shown to be a specific risk factor for benign and malignant PLG and non-polypoid mucosal lesions (p=0.041). The parietal lesion size &lt;0.5cm does not exclude the neoplastic nature. Currently the prevention and diagnosis of GBC is based on the early detection and treatment of potentially evolutionary polypoid lesions over a period of about 15 years. CONCLUSIONS: It is probably that early cholecystectomy in all the patients with PLG of diameter &lt;1cm, isolated or associated with lithiasis, symptomatic and asymptomatic, can contribute to the reduction of the incidence of GBC