SMO Inhibition Modulates Cellular Plasticity and Invasiveness in Colorectal Cancer

Colon Cancer (CC) is the fourth most frequently diagnosed tumor and the second leading cause of death in the USA. Abnormalities of Hedgehog pathway have been demonstrated in several types of human cancers, however the role of Hedgehog (Hh) in CC remain controversial. In this study, we analyzed the association between increased mRNA expression of GLI1 and GLI2, two Hh target genes, and CC survival and recurrence by gene expression microarray from a cohort of 382 CC patients. We found that patients with increased expression of GLI1 showed a statistically significant reduction in survival. In order to demonstrate a causal role of Hh pathway activation in the pathogenesis of CC, we treated HCT 116, SW480 and SW620 CC cells lines with GDC-0449, a pharmacological inhibitor of Smoothened (SMO). Treatment with GDC-0449 markedly reduced expression of Hh target genes GLI1, PTCH1, HIP1, MUC5AC, thus indicating that this pathway is constitutively active in CC cell lines. Moreover, GDC-0449 partially reduced cell proliferation, which was associated with upregulation of p21 and downregulation of CycD1. Finally, treatment with the same drug reduced migration and three-dimensional invasion, which were associated with downregulation of Snail1, the EMT master gene, and with induction of the epithelial markers Cytokeratin-18 and E-cadherin. These results were confirmed by SMO genetic silencing. Notably, treatment with 5E1, a Sonic Hedgehog-specific mAb, markedly reduced the expression of Hedgehog target genes, as well as inhibited cell proliferation and mediated reversion toward an epithelial phenotype. This suggests the existence of a Hedgehog autocrine signaling loop affecting cell plasticity and fostering cell proliferation andmigration/invasion in CC cell lines. These discoveries encourage future investigations to better characterize the role of Hedgehog in cellular plasticity and invasion during the different steps of CC pathogenesis.Peer reviewe

RSM approach for stochastic sensitivity analysis of the economicsustainability of a methanol production plant using renewable energy sources

This study aims at investigating the economic viability, at the pre-feasibility level, of a 5 MW electrolyserbase-methanol production plant, coupled with a PV power plant. The Authors investigated the impact ofdifferent parameters, such as the PV plant size, the electrical energy cost and the components capitalcosts on the methanol production cost and on the system economic viability. It was also analyzed theminimum recommended sale price of the methanol in order to assure an adequate time frame for thereturn of the investment, considering a different combination of the investigated parameters.An economic sensitivity analysis, based on the RSM approach, was performed in order to define themost promising economic conditions under which the plant can be considered a profitable investment interms of ARR. A guide for an economically viable plant design, allowing for the identification of the mostsuitable combination of the economic parameters, was proposed as a kind of\u201cmaps of existence\u201d. For thereference case, the Methanol Production Cost (MPC) resulted around 324V/ton and the minimummethanol sale price to achieve a PBP of 10 years. The sensitivity analysis identified the cost of electricityand the capital cost of the electrolyser as the most affecting parameters for the system economic viability.In terms of ARR, the methanol price represents the most significant factor. Considering a methanol saleprice ranging between 400 and 1200eur/ton, the ARR varied from 5% (20 year of PBP) to 20% (5years ofPBP). From the environmental point of view, it is worth underling that the methanol production planthere proposed allows to recycle about 5800 tons of CO2per year and to avoid the consumption of about5.2 MNm3of NG per year (compared to the traditional production)

A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers.

Long noncoding RNAs are emerging players in the epigenetic machinery with key roles in development and diseases. Here we uncover a complex network comprising a promoter-associated noncoding RNA (paRNA), microRNA and epigenetic regulators that controls transcription of the tumour suppressor E-cadherin in epithelial cancers. E-cadherin silencing relies on the formation of a complex between the paRNA and microRNA-guided Argonaute 1 that, together, recruit SUV39H1 and induce repressive chromatin modifications in the gene promoter. A single nucleotide polymorphism (rs16260) linked to increased cancer risk alters the secondary structure of the paRNA, with the risk allele facilitating the assembly of the microRNA-guided Argonaute 1 complex and gene silencing. Collectively, these data demonstrate the role of a paRNA in E-cadherin regulation and the impact of a noncoding genetic variant on its function. Deregulation of paRNA-based epigenetic networks may contribute to cancer and other diseases making them promising targets for drug discovery

Lightweight and Effective Convolutional Neural Networks for Vehicle Viewpoint Estimation From Monocular Images

Vehicle viewpoint estimation from monocular images is a crucial component for autonomous driving vehicles and for fleet management applications. In this paper, we make several contributions to advance the state-of-the-art on this problem. We show the effectiveness of applying a smoothing filter to the output neurons of a Convolutional Neural Network (CNN) when estimating vehicle viewpoint. We point out the overlooked fact that, under the same viewpoint, the appearance of a vehicle is strongly influenced by its position in the image plane, which renders viewpoint estimation from appearance an ill-posed problem. We show how, by inserting in the model a CoordConv layer to provide the coordinates of the vehicle, we are able to solve such ambiguity and greatly increase performance. Finally, we introduce a new data augmentation technique that improves viewpoint estimation on vehicles that are closer to the camera or partially occluded. All these improvements let a lightweight CNN reach optimal results while keeping inference time low. An extensive evaluation on a viewpoint estimation benchmark and on actual vehicle camera data shows that our method significantly outperforms the state-of-the-art in vehicle viewpoint estimation, both in terms of accuracy and memory footprint

Suppressing, stimulating and/or inhibiting: The evolving management of HCC patient after liver transplantation

Liver transplantation (LT) is a curative strategy for hepatocellular carcinoma (HCC), but the risk of HCC recurrence remains a challenging problem. In patients with HCC recurrence after LT (HCC-R_LT), the locoregional and surgical approaches are complex, and the guidelines do not report evidence-based strategies for the management of immunosuppression. In recent years, immunotherapy has become an effective option for patients with advanced HCC in pre-transplant settings. However, due to the risk of potentially fatal allograft rejection, the use of immunotherapy is avoided in post-transplant settings. Combining immunosuppressants with immunotherapy in transplant patients is also challenging due to the complex tumor microenvironment and immunoreactivity. The fear of acute liver rejection and the lack of predictive factors hinder the successful clinical application of immunotherapy for post-liver transplantation HCC recurrence. This review aims to comprehensively summarize the risk of HCC-R_LT, the available evidence for the efficacy of immunotherapy in patients with HCC-R_LT, and the clinical issues regarding the innovative management of this patient population

From Listing to Recovery: A Review of Nutritional Status Assessment and Management in Liver Transplant Patients

Liver transplantation (LT) is a complex surgical procedure requiring thorough pre- and post-operative planning and care. The nutritional status of the patient before, during, and after LT is crucial to surgical success and long-term prognosis. This review aims to assess nutritional status assessment and management before, during, and after LT, with a focus on patients who have undergone bariatric surgery. We performed a comprehensive topic search on MEDLINE, Ovid, In-Process, Cochrane Library, EMBASE, and PubMed up to March 2023. It identifies key factors influencing the nutritional status of liver transplant patients, such as pre-existing malnutrition, the type and severity of liver disease, comorbidities, and immunosuppressive medications. The review highlights the importance of pre-operative nutritional assessment and intervention, close nutritional status monitoring, individualised nutrition care plans, and ongoing nutritional support and monitoring after LT. The review concludes by examining the effect of bariatric surgery on the nutritional status of liver transplant recipients. The review offers valuable insights into the challenges and opportunities for optimising nutritional status before, during, and after LT

Physical activity in liver transplant recipients: a large multicenter study

Aim Healthy lifestyle and appropriate diet are of critical importance after liver transplant (LT). We provided an analysis of the main patterns of physical activity and found factors associated with physical activity itself.Methods Clinically stable LT recipients were enrolled between June and September 2021. Patients completed a composite questionnaire about physical activity, adherence to Mediterranean Diet (MD), quality of life (QoL), and employment. Correlations were analysed using the Pearson coefficients while different subgroups were compared by t-test for independent samples or ANOVAs. Multivariable logistic regression analysis was conducted to find predictors of inactivity.Results We enrolled 511 subjects (71% males, mean age 63 +/- 10.8 years). One hundred and ninety-three patients reported high level of physical activity, 197 a minimal activity and 121 declared insufficient activity. Among these latter, 29 subjects were totally inactive. Considering the 482 LT recipients performing some kind of physical activity, almost all reported a low-quality, non-structured activity. At multivariate analysis, time from LT (odds ratio 0.94, 95% CI 0.89-0.99, p = 0.017), sedentary lifestyle (odds ratio 0.99, 95% CI 0.19-0.81, p = 0.012), low adherence to MD (odds ratio 1.22, 95% CI 1.01-1.48, p = 0.049), and low level of QoL (physical dimension) (odds ratio 1.13, 95% CI 1.08-1.17, p < 0.001), were independently associated with total inactivity.Conclusion A large portion of LT recipients report an insufficient level of physical activity or are wholly inactive. Inactivity increases with time from LT and was strongly associated with suboptimal diet and low QoL

The Neoangiogenic Transcriptomic Signature Impacts Hepatocellular Carcinoma Prognosis and Can Be Triggered by Transarterial Chemoembolization Treatment

Background/Objectives: We evaluated the relationship between the neoangiogenic transcriptomic signature (nTS) and clinical symptoms, treatment outcomes, and survival in hepatocellular carcinoma (HCC) patients. Methods: This study prospectively followed 328 patients in the derivation and 256 in the validation cohort (with a median follow-up of 31 and 22 months, respectively). The nTS was associated with disease presentation, treatments administered, and overall survival rates. Additionally, this study investigated how multiple treatments influenced changes in nTS status and alterations in microRNA expression. Results: The nTS was identified in 27.4% of patients, linked to aggressive features like multifocality and elevated alpha-fetoprotein (AFP), a pattern consistent with that of the validation cohort. Most patients in both cohorts received treatment for HCC. nTS+ patients had limited access to, and benefited less from, liver transplantation or radiofrequency ablation (RFA) compared to nTS− patients. By the end, 78.9% had died, with nTS− patients showing better median survival and response to treatments than their nTS+ counterparts, who had lower survival across all treatment types. Among those who received transarterial chemoembolization (TACE), 31.2% (21/80 patients after the initial treatment and another four following a second TACE) transitioned from an nTS− to an nTS+ status. This shift was associated with lower survival and alterations in microRNA expressions related to oncogenic pathways. Conclusions: The nTS markedly influences treatment eligibility and survival in patients with HCC. Notably, the nTS can develop after repeated TACE procedures, significantly impacting patient survival and altering oncogenic microRNA expression patterns. These findings highlight the critical role of the nTS in guiding treatment decisions and prognostication in HCC management