Multi-Phase Cross-modal Learning for Noninvasive Gene Mutation Prediction in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the fourth most common cause of cancer-related death worldwide. Understanding the underlying gene mutations in HCC provides great prognostic value for treatment planning and targeted therapy. Radiogenomics has revealed an association between non-invasive imaging features and molecular genomics. However, imaging feature identification is laborious and error-prone. In this paper, we propose an end-to-end deep learning framework for mutation prediction in APOB, COL11A1 and ATRX genes using multiphasic CT scans. Considering intra-tumour heterogeneity (ITH) in HCC, multi-region sampling technology is implemented to generate the dataset for experiments. Experimental results demonstrate the effectiveness of the proposed model.Comment: Accepted version to be published in the 42nd IEEE Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBC 2020, Montreal, Canad

Global management of a common, underrated surgical task during the COVID-19 pandemic: Gallstone disease - An international survery

Background: Since the Coronavirus disease-19(COVID-19) pandemic, the healthcare systems are reallocating their medical resources, with consequent narrowed access to elective surgery for benign conditions such as gallstone disease(GD). This survey represents an overview of the current policies regarding the surgical management of patients with GD during the COVID-19 pandemic. Methods: A Web-based survey was conducted among 36 Hepato-Prancreato-Biliary surgeons from 14 Countries. Through a 17-item questionnaire, participants were asked about the local management of patients with GD since the start of the COVID-19 pandemic. Results: The majority (n = 26,72.2%) of surgeons reported an alarming decrease in the cholecystectomy rate for GD since the start of the pandemic, regardless of the Country: 19(52.7%) didn't operate any GD, 7(19.4%) reduced their surgical activity by 50–75%, 10(27.8%) by 25–50%, 1(2.8%) maintained regular activity. Currently, only patients with GD complications are operated. Thirty-two (88.9%) participants expect these changes to last for at least 3 months. In 15(41.6%) Centers, patients are currently being screened for SARS-CoV-2 infection before cholecystectomy [in 10(27.8%) Centers only in the presence of suspected infection, in 5(13.9%) routinely]. The majority of surgeons (n = 29,80.6%) have adopted a laparoscopic approach as standard surgery, 5(13.9%) perform open cholecystectomy in patients with known/suspected SARS-CoV-2 infection, and 2(5.6%) in all patients. Conclusion

A proteomic based approach for the identification of biliary markers of Cholangiocarcinoma

Cholangiocarcinoma is a cancer of the biliary epithelia with a rising incidence and a dismal prognosis. The lack of clinically useful biomarkers of the disease has led to the use of bile as a more proximal fluid in proteomic based biomarker discovery experiments. Early results have shown inherent difficulties in the acquisition, processing and reproducibility of this approach. By first establishing sample banking and developing a robust, streamlined method for processing bile for down stream proteomic investigations, we were able to perform two separate proteomic based analyses. Firstly, with the initial aim of cataloguing proteins in .bile from a patient with cholangiocarcinoma, we used a shotgun GeLC-MS/MS approach. By this method, .895 proteins were identified of which 621 had two or more significant peptides. A number of these proteins were of interest based on their known involvement in other cancers. Downstream studies on two of these molecules, Matrix Metalloproteinase-9 and Lipocalin-2, revealed up-regulation in CCA when compared to normal, benign and predisposed disease categories, suggesting they represent potential biomarkers. Secondly, we employed Difference Gel Electrophoresis (DIGE) in a comparative analysis to identify biliary markers of CCA. DIGE has greatly advanced the sensitivity and reproducibility of 2D PAGE based experiments and has, as yet, not been described in bile. Using a protocol developed in-house, we carried out a comparative analysis of bile from patients with cholangiocarcinoma and compared this between normal, benign and predisposed disease categories. By this method, 6 spots on 2D DIGE gels showed significant expression differences between disease categories with 5 showing down regulation and 1 showing upregulation in cholangiocarcinoma. This spot was identified iii as Glutathione-S-Transferase pi by MS/MS analysis and differential expression was subsequently confirmed in validation studies. The work carried out here has developed a reproducible method of processing bile for proteomic analysis and using this technique carried out two parallel proteomic based approach which has resulted in three biliary proteins that have shown promising early results. Further validation studies and newer techniques in this area are currently being undertaken.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Splice‐switch oligonucleotide‐based combinatorial platform prioritizes synthetic lethal targets CHK1 and BRD4 against MYC‐driven hepatocellular carcinoma

Abstract Deregulation of MYC is among the most frequent oncogenic drivers in hepatocellular carcinoma (HCC). Unfortunately, the clinical success of MYC‐targeted therapies is limited. Synthetic lethality offers an alternative therapeutic strategy by leveraging on vulnerabilities in tumors with MYC deregulation. While several synthetic lethal targets of MYC have been identified in HCC, the need to prioritize targets with the greatest therapeutic potential has been unmet. Here, we demonstrate that by pairing splice‐switch oligonucleotide (SSO) technologies with our phenotypic‐analytical hybrid multidrug interrogation platform, quadratic phenotypic optimization platform (QPOP), we can disrupt the functional expression of these targets in specific combinatorial tests to rapidly determine target–target interactions and rank synthetic lethality targets. Our SSO‐QPOP analyses revealed that simultaneous attenuation of CHK1 and BRD4 function is an effective combination specific in MYC‐deregulated HCC, successfully suppressing HCC progression in vitro. Pharmacological inhibitors of CHK1 and BRD4 further demonstrated its translational value by exhibiting synergistic interactions in patient‐derived xenograft organoid models of HCC harboring high levels of MYC deregulation. Collectively, our work demonstrates the capacity of SSO‐QPOP as a target prioritization tool in the drug development pipeline, as well as the therapeutic potential of CHK1 and BRD4 in MYC‐driven HCC

Targeted inhibition of purine metabolism is effective in suppressing hepatocellular carcinoma progression

Tumor-specific metabolic rewiring, acquired to confer a proliferative and survival advantage over nontransformed cells, represents a renewed focus in cancer therapy development. Hepatocellular carcinoma (HCC), a malignancy that has hitherto been resistant to compounds targeting oncogenic signaling pathways, represents a candidate cancer to investigate the efficacy of selectively antagonizing such adaptive metabolic reprogramming. To this end, we sought to characterize metabolic changes in HCC necessary for tumorigenesis. We analyzed gene expression profiles in three independent large-scale patient cohorts who had HCC. We identified a commonly deregulated purine metabolic signature in tumors with the extent of purine biosynthetic enzyme up-regulation correlated with tumor grade and a predictor of clinical outcome. The functional significance of enhanced purine metabolism as a hallmark in human HCC was then validated using a combination of HCC cell lines, patient-derived xenograft (PDX) organoids, and mouse models. Targeted ablation of purine biosynthesis by knockdown of the rate-limiting enzyme inosine-5'-monophosphate dehydrogenase (IMPDH) or using the drug mycophenolate mofetil (MMF) reduced HCC proliferation in vitro and decreased the tumor burden in vivo. In comparing the sensitivities of PDX tumor organoids to MMF therapy, we found that HCC tumors defined by high levels of IMPDH and guanosine nucleosides were most susceptible to treatment. Mechanistically, a phosphoinositide 3-kinase (PI3K)-E2F transcription factor 1 (E2F1) axis coordinated purine biosynthetic enzyme expression, deregulation of which altered the activity of mitogen-activated protein kinase/RAS signaling. Simultaneously abolishing PI3K signaling and IMPDH activity with clinically approved inhibitors resulted in greatest efficacy in reducing tumor growth in a PDX mouse model. Conclusion: Enhanced purine metabolic activity regulated by PI3K pathway-dependent activation of E2F1 promotes HCC carcinogenesis, suggesting the potential for targeting purine metabolic reprogramming as a precision therapeutic strategy for patients with HCC.Accepted versio

Global management of a common, underrated surgical task during the COVID-19 pandemic: Gallstone disease - An international survery

Background: Since the Coronavirus disease-19(COVID-19) pandemic, the healthcare systems are reallocating their medical resources, with consequent narrowed access to elective surgery for benign conditions such as gallstone disease(GD). This survey represents an overview of the current policies regarding the surgical management of patients with GD during the COVID-19 pandemic. Methods: A Web-based survey was conducted among 36 Hepato-Prancreato-Biliary surgeons from 14 Countries. Through a 17-item questionnaire, participants were asked about the local management of patients with GD since the start of the COVID-19 pandemic. Results: The majority (n = 26,72.2%) of surgeons reported an alarming decrease in the cholecystectomy rate for GD since the start of the pandemic, regardless of the Country: 19(52.7%) didn't operate any GD, 7(19.4%) reduced their surgical activity by 50-75%, 10(27.8%) by 25-50%, 1(2.8%) maintained regular activity. Currently, only patients with GD complications are operated. Thirty-two (88.9%) participants expect these changes to last for at least 3 months.In 15(41.6%) Centers, patients are currently being screened for SARS-CoV-2 infection before cholecystectomy [in 10(27.8%) Centers only in the presence of suspected infection, in 5(13.9%) routinely]. The majority of surgeons (n = 29,80.6%) have adopted a laparoscopic approach as standard surgery, 5(13.9%) perform open cholecystectomy in patients with known/suspected SARS-CoV-2 infection, and 2(5.6%) in all patients. Conclusion: In the ongoing COVID-19 emergency, the surgical treatment of GD is postponed, resulting in a huge number of untreated patients who could develop severe morbidity. Updated guidelines and dedicated pathways for patients with benign disease awaiting elective surgery are mandatory to prevent further aggravation of the overloaded healthcare systems. Keywords: COVID-19 pandemic; Cholecystectomy; Elective surgery; Gallstone disease; SARS-CoV-