Identification of Proteome-Based Immune Subtypes of Early Hepatocellular Carcinoma and Analysis of Potential Metabolic Drivers.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, ranking fourth in frequency. The relationship between metabolic reprogramming and immune infiltration has been identified as having a crucial impact on HCC progression. However, a deeper understanding of the interplay between the immune system and metabolism in the HCC microenvironment is required. In this study, we used a proteomic dataset to identify three immune subtypes (IM1-IM3) in HCC, each of which has distinctive clinical, immune, and metabolic characteristics. Among these subtypes, IM3 was found to have the poorest prognosis, with the highest levels of immune infiltration and T-cell exhaustion. Furthermore, IM3 showed elevated glycolysis and reduced bile acid metabolism, which was strongly correlated with CD8 T cell exhaustion and regulatory T cell accumulation. Our study presents the proteomic immune stratification of HCC, revealing the possible link between immune cells and reprogramming of HCC glycolysis and bile acid metabolism, which may be a viable therapeutic strategy to improve HCC immunotherapy.

CDS-DB, an omnibus for patient-derived gene expression signatures induced by cancer treatment.

Patient-derived gene expression signatures induced by cancer treatment, obtained from paired pre- and post-treatment clinical transcriptomes, can help reveal drug mechanisms of action (MOAs) in cancer patients and understand the molecular response mechanism of tumor sensitivity or resistance. Their integration and reuse may bring new insights. Paired pre- and post-treatment clinical transcriptomic data are rapidly accumulating. However, a lack of systematic collection makes data access, integration, and reuse challenging. We therefore present the Cancer Drug-induced gene expression Signature DataBase (CDS-DB). CDS-DB has collected 78 patient-derived, paired pre- and post-treatment transcriptomic source datasets with uniformly reprocessed expression profiles and manually curated metadata such as drug administration dosage, sampling time and location, and intrinsic drug response status. From these source datasets, 2012 patient-level gene perturbation signatures were obtained, covering 85 therapeutic regimens, 39 cancer subtypes and 3628 patient samples. Besides data browsing, download and search, CDS-DB also supports single signature analysis (including differential gene expression, functional enrichment, tumor microenvironment and correlation analyses), signature comparative analysis and signature connectivity analysis. This provides insights into drug MOA and its heterogeneity in patients, drug resistance mechanisms, drug repositioning and drug (combination) discovery, etc. CDS-DB is available at http://cdsdb.ncpsb.org.cn/.

BCR/ABL1ΔE7-8-9 isoform contributes to tyrosine kinase inhibitor resistance in chronic myeloid leukemia.

In chronic myeloid leukemia (CML) patients, the involvement of the BCR/ABL1 isoform in tyrosine kinase inhibitors (TKIs) resistance has attracted lots of attention. In this work, a novel isoform that encoded truncated protein due to the deletion of ABL1 exon7, 8, and 9 was reported and named BCR/ABL1ΔE7-8-9 here. This isoform was detected only in 10.2% of CML patients with inadequate responses to TKIs. BCR/ABL1Δexon7-8-9 isoform promoted S phase cell proliferation and reduced the expression of fusion gene and ABL1 phosphorylation level more slowly than that of control cells after TKIs treatment. The novel isoform has the qualities of a functional tyrosine kinase, localized in the cytoplasm, and could not be imported into the nucleus by TKIs. These results indicated that BCR/ABL1Δexon7-8-9 showed poorer sensitivity to imatinib and nilotinib than wild-type BCR/ABL1. According to molecular docking studies, nilotinib and imatinib present different binding sites and have a lower binding capacity with BCR/ABL1ΔE7-8-9 protein than the wild type. Our findings suggested that the novel isoform BCR/ABL1ΔE7-8-9 may contribute to TKIs resistance in CML due to its weakened TKIs binding ability. It enriched the mechanism of spliceosome involved in TKIs resistance. Monitoring the expression of BCR/ABL1ΔE7-8-9 helps guide the treatment of CML patients in the clinic.

Aggressive continuous passive motion exercise does not improve knee range of motion after total knee arthroplasty.

AIMS AND OBJECTIVES: The aim of this study was to evaluate the effects of continuous passive motion on the range of motion, postoperative pain and life quality of patients undergoing total knee arthroplasty within six months after the operation. BACKGROUND: Total knee arthroplasty reduces pain and improves range of motion of the osteoarthritic knee joint. Continuous passive motion increases postoperative movement, but there is some controversy regarding whether aggressive continuous passive motion can improve range of motion or life quality, and whether it induces more pain. DESIGN: A prospective controlled study was conducted in a medical centre in Taiwan from January to December 2006. METHODS: One hundred and seven patients were recruited. The patients underwent the basic rehabilitation protocols (the control group) or the basic rehabilitation protocols and additional daily use of continuous passive motion for more than six hours per day (the experimental group). The range of motion, modified Short Form-36 (SF-36) and semi-quantitative visual analogue scale were recorded. Results. Range of motion increased from 109° preoperatively to 125° at six months postoperatively in the treatment group and from 111° preoperatively to 125° at six months postoperatively in the control group. Visual analogue scale decreased from 7·78 preoperatively to 0·37 at six months postoperatively in the treatment group and from 7·92 preoperatively to 0·21 at six months postoperatively in the control group. The SF-36 improved from 3·76 preoperatively to 1·77 at six months postoperatively in the treatment group and from 3·68 preoperatively to 1·83 at six months postoperatively in the control group. There was no significant difference in range of motion, visual analogue scale and SF-36 between groups at each visit. CONCLUSION: With the advances in total knee arthroplasty surgical technique, aggressive continuous passive motion does not provide obvious benefits. RELEVANCE TO CLINICAL PRACTICE: Total knee arthroplasty can alleviate pain and improve range of motion, but aggressive continuous passive motion does not provide additional benefits.

CPDR: An R Package of Recommending Personalized Drugs for Cancer Patients by Reversing the Individual's Disease-Related Signature.

Due to cancer heterogeneity, only some patients can benefit from drug therapy. The personalized drug usage is important for improving the treatment response rate of cancer patients. The value of the transcriptome of patients has been recently demonstrated in guiding personalized drug use, and the Connectivity Map (CMAP) is a reliable computational approach for drug recommendation. However, there is still no personalized drug recommendation tool based on transcriptomic profiles of patients and CMAP. To fill this gap, here, we proposed such a feasible workflow and a user-friendly R package-Cancer-Personalized Drug Recommendation (CPDR). CPDR has three features. 1) It identifies the individual disease signature by using the patient subgroup with transcriptomic profiles similar to those of the input patient. 2) Transcriptomic profile purification is supported for the subgroup with high infiltration of non-cancerous cells. 3) It supports in silico drug efficacy assessment using drug sensitivity data on cancer cell lines. We demonstrated the workflow of CPDR with the aid of a colorectal cancer dataset from GEO and performed the in silico validation of drug efficacy. We further assessed the performance of CPDR by a pancreatic cancer dataset with clinical response to gemcitabine. The results showed that CPDR can recommend promising therapeutic agents for the individual patient. The CPDR R package is available at https://github.com/AllenSpike/CPDR.

Percutaneous antegrade screwing for anterior column fracture of acetabulum with fluoroscopic-based computerized navigation.

INTRODUCTION: Open reduction and internal fixation has been the gold standard for displaced fracture involving weightbearing dome and fractures with intra-articular fragments. However, extensile exposure can lead to complications. Fracture with minimal displacement can be fixed by a minimally invasive method. Percutaneous screwing for an anterior column fracture of acetabulum under conventional 2D fluoroscopy is a demanding technique. With fluoroscopic-based computerized navigation, we can determine the position of a screw real time intra-operatively with less exposure to radiation. We proposed that a fluoroscopy-based computerized navigational system would simplify operation procedures. The purpose of this study is to test the application of the fluoroscopy-based computerized navigational system for anterior column fracture of acetabulum. MATERIALS AND METHODS: A prospective cohort study was conducted. Three patients with mildly displaced or non-displaced anterior column fracture of acetabulum were treated with a retrograde lag screw under a fluoroscopy-based computer navigation system. There were two males and one female with a mean age of 39 years and all patients were followed up for more than 1 year. Patients were allowed to perform joint movement exercises and to walk with partial weightbearing on the first day post-operatively. RESULTS: The mean operation time was 40 min (range 30-45 min) from the use of fluoroscopy to wound closure and the mean total fluoroscopy time was 38 s (range 35-45 s). Total blood loss was less than 10 ml. The patients were pain free 1 week after the operation and had good functional recovery thereafter. No complication was noted postoperatively. CONCLUSION: Though the indication for this procedure is limited, we think that there should be potential to apply the screw with less radiation by fluoroscopic-based computerized navigation. Once anatomic reduction can be achieved by the close method in the anterior column fracture of the acetabulum, percutaneous screw fixation under fluoroscopic-based computerized navigation could be a reliable method; however; validating the position of the guide pin and screw by fluoroscopy is suggested.