Late-onset benefit in progressive advanced hepatocellular carcinoma with continued sorafenib therapy: a case report

<p>Abstract</p> <p>Introduction</p> <p>In the past, no effective systemic therapy has existed for patients with advanced hepatocellular carcinoma. Sorafenib, an oral multikinase inhibitor, has recently been shown to improve overall survival in patients with advanced hepatocellular carcinoma in two randomized, double-blinded, placebo-controlled trials. This drug has been approved as the first-line therapy for advanced hepatocellular carcinoma patients. We report an intriguing case of advanced hepatocellular carcinoma in which the patient achieved late- onset partial response by prolonged administration of sorafenib in spite of progressive disease.</p> <p>Case presentation</p> <p>A 54-year-old Japanese man was treated with sorafenib for multiple lung metastases after surgical resection for advanced hepatocellular carcinoma accompanied by vascular invasion of the left branch of the portal vein. Although the effective diagnosis was progressive disease, almost all sites began to reduce or disappear eight months after the diagnosis of progressive disease. A dramatic reduction in alpha-fetoprotein and des-gamma-carboxy prothrombin levels was observed. The patient finally achieved partial response and his status remains unchanged.</p> <p>Conclusions</p> <p>If tolerated, prolonged sorafenib treatment may be beneficial.</p

Fragment Molecular Orbital Based Interaction Analyses on Complexes Between RBD Variants and ACE2

The spike protein plays an important role in the infection of SARS-CoV-2 to human cells, and the binding affinity of receptor binding domain (RBD) to angiotensin-converting enzyme 2 (ACE2) is of special interest. In this report, we present a series of interaction analyses for the RBD - ACE2 complex (PDB ID: 6M0J) and mutated complexes of UK (B.1.1.7 lineage), South Africa (B1.351) and Brazil (B1.1.248) types, based on the fragment molecular orbital (FMO) calculations. The effects of mutations are investigated in terms of inter-fragment interaction energies (IFIEs), indicating the higher affinities of RBD variants with ACE2

Failure Factors to Reach the Blind End Using a Short-Type Single-Balloon Enteroscope for ERCP with Roux-en-Y Reconstruction: A Multicenter Retrospective Study

Background. Failure factors in reaching the blind end (papillae of Vater, bilioenteric anastomosis) during short-type single-balloon enteroscope-assisted endoscopic retrograde cholangiopancreatography (sSBE-assisted ERCP) in patients with Roux-en-Y (R-Y) reconstruction remain to be evaluated. Aims. We investigated the failure factors in such patients. Methods. We retrospectively studied 253 initial sessions of sSBE-assisted ERCP at three endoscopy centers from April 2008 through September 2017, examining failure factors and complications associated with scope insertion in patients with R-Y reconstruction. Results. R-Y reconstruction was performed in 157 patients (with gastrectomy: 122 patients; without gastrectomy plus bilioenteric anastomosis: 35 patients). R-Y without gastrectomy (p=0.001; odds ratio (OR), 5.73; 95% confidence interval (CI), 2.07 to 16.01) and the presence of peritoneal dissemination (p=0.021; OR, 4.71; 95% CI, 1.27 to 17.54) were significant failure factors. Insufficient sSBE length was the cause of failure in 17 (11%) of the 157 patients, and 13 (76%) of the 17 patients were with R-Y without gastrectomy. In cases of insufficient short-type length, using a long-type SBE significantly increased the success rate (p=0.002). Gastrointestinal stenosis was a significant failure factor (p=0.011) in patients with peritoneal dissemination. Perforation occurred in 2 patients who responded to conservative treatment. Conclusions. Failure factors during sSBE-assisted ERCP were R-Y without gastrectomy and the presence of peritoneal dissemination

Prediction of Binding Pose and Affinity of SARS-CoV-2 Main Protease and Repositioned Drugs by Combining Docking, Molecular Dynamics, and Fragment Molecular Orbital Calculations

COVID-19 remains a global pandemic, necessitating the urgent development of more effective therapeutics. By combining molecular docking, molecular dynamics (MD), and fragment molecular orbital (FMO) calculations, the binding structure and properties with Mpro were predicted for Nelfinavir (NLF), which was identified as a candidate compound through drug repositioning targeting the Main Protease (Mpro) produced by the causative virus, SARS-CoV-2. For the four docking poses selected by scoring using FMO energy, 100 structures each from the MD trajectory were sampled, and FMO calculations were performed and ranked based on binding energy. Besides the interaction between NLF and each Mpro residue, the desolvation effect of the pocket affected the ranking order. Furthermore, we identified several residues important in ligand recognition, including Glu47, Asp48, Glu166, Asp187, and Gln189, all of which interacted strongly with NLF. Asn142 was mentioned as a residue with hydrogen bonds or CH/π interaction with NLF; however, it was considered a transient interacting residue because of its unstable structure. Moreover, the tert-butyl group of NLF had no interaction with Mpro. Identifying weak interactions provides candidates for substituting ligand functional groups and important suggestions for drug discovery using drug repositioning. Our approach provides a new guideline for structure-based drug design starting from a candidate compound whose complex crystal structure has not been obtained