Role of Human Equilibrative Nucleoside Transporter 1 (hENT1) in Intrahepatic Cholangiocarcinoma

There are few data reporting significant biological prognostic markers for iCCA affected patients. There is substantial interest in identifying and validating molecular markers to select patients with a high likelihood of benefiting from specific chemotherapy regimens. The aim of this study was to evaluate whether the intratumoral expression of hENT1, besides being a predictor of response to adjuvant Gemcitabine chemotherapy in iCCA, as we have previously demonstrated, may also represent a prognostic factor in iCCAs and may be related to the expression of tumor aggressiveness markers, Ki67 and p53. This study has permitted to evaluate the role of membrane hENT1 in iCCA cells growth. The immunohistochemistry analysis on 40 patients affected of iCCA revealed that in tumor tissues hENT1 protein could be differently expressed (negative, moderate or high) but surely, it has to be expressed on cell membrane in order to carry out its role of nucleoside transporter. Our results demonstrate a significant positive correlation between membrane hENT1 expression and ki67 score; in these terms, hENT1 would represent the intrinsic cellular key to tumor growth, being consequently related to worse prognosis. hENT1 mRNA expression and protein levels continued to be poorly understood. Various factors that influence hENT1 expression have been identified; in this study we hypothesized that hENT1 expression may be influenced from cell cycle related factors and consequently we investigated the relationship between hENT1 and mutated p53 expression in iCCA. Our finding on 40 iCCA affected patients and on cell lines suggest a significant correlation between the expression of mutated p53 and hENT1. In conclusion, membrane hENT1 seemed to characterize tumors with a high growth rate and the expression of hENT1 in iCCAs correlate with mutated p53. hENT1, besides being a predictive factor of response to adjuvant Gemcitabine, represent also a negative prognostic factor in iCCAs affected patients

Design Thinking as a Strategic Approach to E-Participation

This open access book examines how the adoption of Design Thinking (DT) can support public organisations in overcoming some of the current barriers in e-participation. Scholars have discussed the adoption of technology to strengthen public engagement through e-participation, streamline and enhance the relationship between government and society, and improve accessibility and effectiveness. However, barriers persist, necessitating further research in this area. By analysing e-participation barriers emerging from the literature and aligning them with notions in the DT literature, this book identifies five core DT practices to enhance e-participation: (i) Meaning creation and sense-making, (ii) Publics formation, (iii) Co-production, (iv) Experimentation and prototyping, and (v) Changing organisational culture. As a result, this book provides insights into enhancing tech-aided public engagement and promoting inclusivity for translating citizen input into tangible service implementations. The book triangulates qualitative analysis of relevant literature in the fields of e-participation and DT with knowledge from European projects experimenting with public participation activities implying experimentation with digital tools. This research aims to bridge the gap between theoretical frameworks and practical application, ultimately contributing to more effective e-participation and digital public services

Antitumoral Efficacy of Two Turmeric Extracts According to Different Extraction Methods in Hepatocellular Carcinoma Cell Lines

Curcuminoids, bioactive molecules contained in turmeric, have been reported to exert anticancer effects in several human cancers, including hepatocellular carcinoma (HCC). However, the extraction method can significantly affect the structural characteristics of curcuminoids and their biological properties. On this basis, in the present study we investigated the content of curcuminoids and the anticancer activity of two turmeric powders extracted according two different methodologies: solvent extraction with ethyl acetate vs an ancient Indian extraction method of boiling of rhizomes in water followed by dehydration at the sun. Results obtained showed that extraction with ethyl acetate resulted in a significant recovery of curcuminoids and anticancer activity both in terms of cell cytotoxicity and migration/invasiveness inhibition in HCC cell lines, compared to common Indian practice. Overall these findings suggest that turmeric powders could have different efficacy, depending on the extraction method. This aspect should be taken into account when choosing the best product to be employed in the prevention and treatment of human diseases, including cancer

Adjuvant treatment in biliary tract cancer

Biliary tract cancers (BTCs) are a heterogeneous group of malignancies with a dismal prognosis. Despite radical surgery, the five-year overall survival (OS) does not exceed 40% in the best series. Adjuvant treatments are widely used even though they have mainly been investigated in small retrospective series until recently. Available data suggest that chemotherapy with 5-fluorouracil (and relative prodrugs) or gemcitabine can reduce the risk of relapse and potentially improve patients\u2019 long-term outcome. The role of adjuvant radiotherapy seems to be confined to patients with positive surgical margins. In addition, patients with highrisk factors for relapse (nodal involvement and non-radical resection) benefit most from chemotherapy. Recent results from large randomized trials have clarified the benefit of adjuvant treatments and probably defined a new standard of care

Asbestos exposure as an additional risk factor for small duct intrahepatic cholangiocarcinoma: a pilot study

: Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy, recently classified in small duct and large duct morphological subtypes. Growing evidence suggests asbestos as a putative risk factor for iCCA, albeit no correlation between asbestos and iCCA morphology has been investigated so far. The aim of the present study was to assess the relationship between asbestos exposure and iCCA morphological subtype. Forty patients with surgically removed iCCA were prospectively enrolled: asbestos exposure was assessed according to the Italian National Mesothelioma Register questionnaire. From the surgical iCCA specimens the main histopathological variables were collected, including the small duct (sd-iCCA, 32 patients) and large duct subtypes (ld-iCCA, 8 patients). Five sd-iCCA cases had a definite/probable occupational exposure to asbestos, while no cases of ld-iCCA were classified as being occupationally exposed (definite/probable). Other kind of asbestos exposure (i.e. possible occupational, familial, environmental) were recorded in 16 sd-iCCA and 3 ld-iCCA. Cases with unlikely exposure to asbestos were 11 sd-iCCA (35.5%) and 5 ld-iCCA (62.5%). In conclusion, these findings seem to indicate that sd-iCCA might be more frequently associated to asbestos exposure rather than ld-iCCA, suggesting that asbestos fibres might represent a parenchymal, rather than a ductal risk factor for iCCA. This pilot study must be confirmed by further case-control studies or large independent cohorts

A gene and protein expression study on four porcine genes related to intramuscular fat deposition

Intramuscular fat (IMF) content has a prominent role in meat quality, affecting sensory attributes such as flavour and texture. In the present research, we studied in samples of porcine Semimembranosus muscle four genes related to lipid metabolism and whose gene expressions have been associated to IMF deposition: FASN, SCD, LIPE and LPL. We analysed both mRNA and protein expressions in two groups of Italian Large White pigs divergent for Semimembranosus IMF deposition, with the aim of comparing the levels of four genes and enzymes between the two groups and identifying possible coexpression links. The obtained results suggest a prominent role of LIPE enzyme in IMF hydrolysis, as the samples with low IMF deposition show a significantly higher amount of this lipase. Finally, a poorly known correlation was found between LIPE and FASN enzymes only in female individuals. These results provide new information for the understanding of IMF deposition

PARP Inhibitors in Biliary Tract Cancer: A New Kid on the Block?

Poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) represent an effective therapeutic strategy for cancer patients harboring germline and somatic aberrations in DNA damage repair (DDR) genes. BRCA1/2 mutations occur at 1–7% across biliary tract cancers (BTCs), but a broader spectrum of DDR gene alterations is reported in 28.9–63.5% of newly diagnosed BTC patients. The open question is whether alterations in genes that are well established to have a role in DDR could be considered as emerging predictive biomarkers of response to platinum compounds and PARPi. Currently, data regarding PARPi in BTC patients harboring BRCA and DDR mutations are sparse and anecdotal; nevertheless, a variety of clinical trials are testing PARPi as monotherapy or in combination with other anticancer agents. In this review, we provide a comprehensive overview regarding the genetic landscape of DDR pathway deficiency, state of the art and future therapeutic implications of PARPi in BTC, looking at combination strategies with immune-checkpoint inhibitors and other anticancer agents in order to improve survival and quality of life in BTC patients

Plasma membrane localization of human equilibrative nucleoside transporter 1 (hENT-1) to predict better outcome of adjuvant gemcitabine in cholangiocarcinoma (CC) patients.

Background: The role of adjuvant chemotherapy in CC is controversial and, to date, no standard treatment has been established in this setting. Some institutions offer gemcitabine (GEM) as adjuvant strategy to radically resected CC patients. The efficient uptake of this drug into cells requires the expression and plasma membrane localization of hENT-1. A recent study showed that a high hENT-1 expression closely associated with better survivals in macroscopically (R0 + R1) resected CC patients treated with adjuvant GEM plus S-1. In the present study, we analyzed the relationship between hENT-1 expression/localization and disease free survival (DFS) in CC patients undergone surgery and treated with adjuvant GEM. Methods: A total of 71 CC patients (44 intra-hepatic and 27 extra-hepatic) operated between 2002 and 2011 (46 R0 and 25 R1) and treated with adjuvant GEM (1000 mg/m2, 1-8-15/21 days planned for 6 months) in our institution were enrolled and retrospectively analyzed for hENT-1 expression/localization by immunohistochemistry. Main outcome measure was DFS. Hazard ratios (HR) of relapse and associated 95% confidence intervals (95% CIs) were obtained from proportional hazards regression models stratified on quintiles of propensity score (estimated from baseline covariates). Results: 26/71 patients (36.6%) showed a high hENT-1 plasma membrane expression. During a median follow-up of 18.1 months (IQR 9.1\u201336.2) 49 relapses were observed. Patients with a high expression of hENT-1 showed a reduced risk of relapse (HR 0.50, 95%CI 0.26\u20130.99, p=0.047). Noteworthy, the effect of hENT-1 appeared to increase across tertiles of duration of gemcitabine-based adjuvant chemotherapy (lower tertile, 102 days: HR 0.87, 95%CI 0.30\u20132.53; middle tertile, 103\u2013170 days: HR 0.68, 95%CI 0.22\u20132.06; higher tertile, 171 days: 0.20, 95%CI 0.04\u20130.94). Conclusions: High plasma membrane hENT-1 expression was associated with a longer DFS among CC patients. The interaction between hENT-1 expression and duration of chemotherapy deserves further investigations, as it could be useful to tailor optimal GEM-based adjuvant chemotherapies

Activated FGFR2 signalling as a biomarker for selection of intrahepatic cholangiocarcinoma patients candidate to FGFR targeted therapies

Abstract FGFR inhibitors have been developed to inhibit FGFR activation and signal transduction; notwithstanding, currently the selection of intrahepatic cholangiocarcinoma (iCCA) patients for these drugs only relies on the detection of FGFR2 genetic alterations (GAs) in tumor tissues or circulating tumor DNAs, without concomitant assessment of FGFR2 signalling status. Accordingly, we performed multi-omic analyses of FGFR2 genes and FGFR2 signalling molecules in the tissue samples from 36 iCCA naïve patients. Gain-of-function FGFR2 GAs were detected in 7 patients, including missense mutations (n = 3; p.F276C, p.C382R and p.Y375C), translocations (n = 1) and copy number gain (n = 4; CNV ≥ 4). In contrast, among 29 patients with wild-type FGFR2, 4 cases showed activation of FGFR2 signalling, as they expressed the FGFR2 ligand FGF10 and phosphorylated FGFR2/FRS2α proteins; the remaining 25 cases resulted negative for activated FGFR2 signalling, as they lacked FGFR2 (n = 8) or phosphorylated FRS2α (n = 17) expression. Overall, we found that activation of FGFR2 signalling occurs not only in iCCA naïve patients with FGFR2 GAs, but also in a subgroup carrying wild-type FGFR2. This last finding entails that also this setting of patients could benefit from FGFR targeted therapies, widening indication of these drugs for iCCA patients beyond current approval. Future clinical studies are therefore encouraged to confirm this hypothesis

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