Risks and Clinical Predictors of Hepatocellular Carcinoma in Chinese Populations: A Real-World Study of 10,359 Patients in Six Medical Centers.

Purpose: Early detection of hepatocellular carcinoma (HCC) through surveillance could reduce this cancer-associated mortality. We aimed to develop and validate algorithms using panel serum biomarkers to identify HCC in a real-world multi-center study in China. Patients and Methods: A total of 10,359 eligible subjects, including HCCs and benign liver diseases (BLDs), were recruited from six Chinese medical centers. The three nomograms were built using logistic regression and their sensitivities and specificities were carefully assessed in training and validation cohorts. HCC patients after surgical resection were followed to determine the prognostic values of these algorithms. Prospective surveillance performance was assessed in a cohort of chronic hepatitis B patients during 144 weeks follow-up. Results: Independent risk factors such as alpha-fetoprotein (AFP), lens cuinaris agglutinin-reactive fraction of AFP (AFP-L3), des-gamma-carboxy prothrombin (DCP), albumin (ALB), and total bilirubin (TBIL) obtained from train cohort were used to construct three nomograms (LAD, C-GALAD, and TAGALAD) using logistic regression. In the training and two validation cohorts, their AUCs were all over 0.900, and the higher AUCs appeared in TAGALAD and C-GALAD. Furthermore, the three nomograms could effectively stratify HCC into two groups with different survival and recurrence outcomes in follow-up validation. Notably, TAGALAD could predict HCC up to 48 weeks (AUC: 0.984) and 24 weeks (AUC: 0.900) before clinical diagnosis. Conclusion: The proposed nomograms generated from real-world Chinese populations are effective and easy-to use for HCC surveillance, diagnosis, as well as prognostic evaluation in various clinical scenarios based on data feasibility.

Soft-tissue reconstruction with pedicled vertical rectus abdominis myocutaneous flap after total or high sacrectomy for giant sacral tumor.

BACKGROUND: The large soft-tissue defect after total or high sacrectomy for giant sacral tumor induces high incidence of wound complications. It remains a huge challenge to reconstruct the soft-tissue defect and achieve the preferred clinical outcome. METHODS: A total of 27 patients undergoing one-stage total or high sacrectomy for giant sacral tumors between 2016 and 2021 in a tertiary university hospital were retrospectively reviewed. Participants were divided into two groups. Thirteen patients underwent a pedicled vertical rectus abdominis myocutaneous (VRAM) flap reconstruction, whereas 14 patients underwent a conventional wound closure. Patient's clinical characteristics, surgical duration, postoperative complications, and outcomes were compared between the two groups. RESULTS: Patients in VRAM and non-VRAM groups were similar in baseline characteristics. The mean tumor size was 12.85 cm (range: 10-17 cm) in VRAM group and 11.79 cm (range: 10-14.5 cm) in non-VRAM group (P = 0.139). The most common giant sacral tumor is chordoma. Patients in VRAM group had a shorter length of drainage (9.85 vs 17.14 days), postoperative time in bed (5.54 vs 17.14 days), and total length of stay (19.46 vs 33.36 days) compared with patients in non-VRAM group. Patients in the VRAM group had less wound infection and debridement than patients in non-VRAM group (15.4% vs 57.1%, P < 0.001). CONCLUSIONS: This study demonstrates the advantages of pedicled VRAM flap reconstruction of large soft-tissue defects after high or total sacrectomy using the anterior-posterior approach. This choice of reconstruction is better than direct wound closure in terms of wound infection, length of drainage, and total length of stay.

Tanshinone IIA regulates CCl4 induced liver fibrosis in C57BL/6J mice via the PI3K/Akt and Nrf2/HO-1 signaling pathways.

Chronic liver diseases caused by various factors may develop into liver fibrosis (LF). Early stage of LF could be reversible. Tanshinone IIA (Tan IIA), an extract from Salvia miltiorrhiza, has been reported to be hepatoprotective. However, the potential targets and mechanism of Tan IIA in the treatment of LF are still unclear. Our study aims at the anti-LF mechanism of Tan IIA through network pharmacological analysis combined with LF-related experiments. Serum biochemical indicators and histopathological examination showed that Tan IIA could ameliorate the process of LF in the CCl4 -induced mouse model. Western blot and immunohistochemical assays showed that Tan IIA decreased the expression of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositide 3-kinases/protein kinase B (PI3K/Akt), and nuclear factor erythroid 2-related factor/heme oxygenase-1 (Nrf2/HO-1). Compared with the model group, the Tan IIA groups increased the decreased superoxide dismutase activity and glutathione content, while decreasing the increased malondialdehyde content. These results indicate that Tan IIA may play an antioxidant role by inhibiting the expression of KRAS, PI3K/Akt, and Nrf2/HO-1 to ameliorate the progression of LF, which to some extent explains the pharmacological mechanism of Tan IIA in LF. In conclusion, our study demonstrates that Tan IIA could regulate LF via PI3K/Akt and Nrf2/HO-1 signaling pathways. It may be an effective therapeutic compound for the treatment of LF.

Single-cell profiling of the microenvironment in human bone metastatic renal cell carcinoma.

Bone metastasis is of common occurrence in renal cell carcinoma with poor prognosis, but no optimal treatment approach has been established for bone metastatic renal cell carcinoma. To explore the potential therapeutic targets for bone metastatic renal cell carcinoma, we profile single cell transcriptomes of 6 primary renal cell carcinoma and 9 bone metastatic renal cell carcinoma. We also include scRNA-seq data of early-stage renal cell carcinoma, late-stage renal cell carcinoma, normal kidneys and healthy bone marrow samples in the study to better understand the bone metastasis niche. The molecular properties and dynamic changes of major cell lineages in bone metastatic environment of renal cell carcinoma are characterized. Bone metastatic renal cell carcinoma is associated with multifaceted immune deficiency together with cancer-associated fibroblasts, specifically appearance of macrophages exhibiting malignant and pro-angiogenic features. We also reveal the dominance of immune inhibitory T cells in the bone metastatic renal cell carcinoma which can be partially restored by the treatment. Trajectory analysis showes that myeloid-derived suppressor cells are progenitors of macrophages in the bone metastatic renal cell carcinoma while monocytes are their progenitors in primary tumors and healthy bone marrows. Additionally, the infiltration of immune inhibitory CD47+ T cells is observed in bone metastatic tumors, which may be a result of reduced phagocytosis by SIRPA-expressing macrophages in the bone microenvironment. Together, our results provide a systematic view of various cell types in bone metastatic renal cell carcinoma and suggest avenues for therapeutic solutions.

Mechanistic insights into the anti-depressant effect of curcumin based on network pharmacology and experimental validation.

Curcumin (CUR) exhibits a definite curative effect in the treatment of depression. To identify potential antidepressant targets and mechanisms of action of CUR. This study used network pharmacology to explore the signaling pathways and CUR-related targets in depression. C57BL/6 J mice (male,12-14 weeks old) were randomly divided into four groups (n = 8): saline-treated (control mice), lipopolysaccharide (LPS, 2 mg/kg/day, intraperitoneally), LPS + CUR (50 mg/kg/day, intragastrically), and LPS + CUR + LY294002 (7.5 mg/kg/day, intraperitoneally). After 1 week, behavioral tests were performed. Then, neuronal damage in the prefrontal cortex of mice was evaluated by hematoxylin-eosin (HE) staining. We uncovered the main active mechanism of CUR against depression using Western blotting and enzyme-linked immunosorbent assay (ELISA). Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways showed that the most significantly enriched pathway in CUR against depression was the PI3K-Akt pathway. Moreover, 52 targets were significantly correlated with the PI3K-Akt signaling pathway and CUR-related targets. In addition, among the top 50 targets ranked by degree in the protein-protein interaction (PPI) network, there were 23 targets involved in the 52 intersection targets. Administration of LPS alone extended immobility time in the open field test (OFT) and tail suspension test (TST) and decreased sucrose consumption in the sucrose preference test (SPT). Pretreatment with CUR relieved LPS-induced changes in the behavioral tests, activity of the PI3K-Akt signaling pathway, neuronal damage in the prefrontal cortex (PFC), and inflammatory response. Moreover, inhibition of the PI3K-Akt signaling pathway by LY294002 blocked the therapeutic effects of CUR. Our study indicates that CUR may be an effective antidepressant agent in an LPS-induced mouse model, partly because of its anti-inflammatory action through the PI3K-Akt signaling pathway.

Establishment of a staging system for visceral sarcoma.

BACKGROUND: Visceral sarcoma is a rare malignancy with a poor prognosis. However, there is no recommended prognostic staging system for the malignant disease. METHOD: We analyzed the data of patients diagnosed with primary soft tissue sarcoma (STS) of the abdomen and thoracic visceral organs between 2006 and 2017 at our hospital. Prognostic factors (size, tumor grade, and lymph node metastasis) were analyzed in our cohort (n = 203) and the SEER validation cohort (n = 5826). RESULTS: Tumor size, grade, and lymph node metastasis were important prognostic factors for visceral sarcoma in both our and the SEER cohorts. Based on these prognostic factors, we established a new staging system for visceral sarcoma, by which patients could be stratified into clinically meaningful and non-overlapping stages in both our cohort and the SEER validation series. Moreover, the area under the curve (AUC) value of the staging system for 5-year survival was 0.84 (95% CI: 0.78-0.89) in our series and 0.80 (95% CI: 0.79-0.81) in SEER series, respectively. In addition, compared with the widely used FIGO staging system for female genital sarcoma, the visceral sarcoma staging system could more effectively and reliably stratify patients into four different prognostic groups. CONCLUSIONS: The visceral sarcoma staging system is applicable for STS of the abdomen and thoracic visceral organs and is better than the current FIGO staging system for female genital sarcoma and should be incorporated into the AJCC Cancer Staging Manual.

Impact of apolipoprotein A1 on tumor immune microenvironment, clinical prognosis and genomic landscape in hepatocellular carcinoma.

Background: Current knowledge on apolipoprotein A1 (APOA1) in hepatocellular carcinoma (HCC) is fragmented and even contradictory. Multi-dimensional analyses are required to comprehensively elucidate its value and underlying mechanism. Methods: We collected 49 RNA-seq datasets, 40 cell line types data and 70 scRNA pan-cancer datasets public available, including 17 HCC datasets (1754 tumor samples), and enrolled 73 pairs of HCC tissue and 516 blood samples independently from our clinics. APOA1 impacting on the HCC tumor microenvironment (TME) was analyzed using intensive data mining. Methylation sequencing, flow cytometry, quantitative PCR, western blot, immunohistochemistry and clinical chemistry assays were conducted for wet experimental investigation. Results: The APOA1 ontology fingerprint indicated that it played various crucial biological roles in HCC, primarily involved in cholesterol efflux. Consistent findings at histology, serology, and clinical follow-up revealed that high APOA1 was a good prognosis indicator of HCC. Hypermethylation in the APOA1 promoter region was found in clinical samples which is in accordance with the reduction of APOA1 in HCC. The cell cycle, DNA replication, mismatch repair pathways, and tumor cell proliferation were less observed in the HCC APOA1high subgroup. The favorable immunoregulatory abilities of APOA1 showed interesting findings: a positive correlation between APOA1 and anti-tumor immune cells (NK, CD8+ T cells) and a negative association with immune cells exerting immunosuppressive effects, including M2 macrophages. Conclusion: This is an integrative multidimensional exploration of APOA1 using bioinformatics and experiments. Both the prognostic value and anti-tumor effects based on APOA1 panoramic exploration in the HCC TME demonstrate a new potential clinical target for HCC assessment and intervention in the future.

E3 ligase MG53 suppresses tumor growth by degrading cyclin D1.

Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors. Here we show that in colorectal and gastric cancer patients, MG53 is downregulated in more than 80% of tumors compared to the normal gastrointestinal tissues from the same patient, and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival. Mechanistically, MG53 catalyzes the K48-linked ubiquitination and subsequent degradation of cyclin D1. Thus, increased expression of MG53 leads to cell cycle arrest at G1, and thereby markedly suppresses cancer cell proliferation in vitro as well as tumor growth in mice with xenograft tumors or AOM/DSS induced-colorectal cancer. Consistently, MG53 deficiency results in accumulation of cyclin D1 protein and accelerates cancer cell growth both in culture and in animal models. These findings define MG53 as a tumor suppressor via facilitating cyclin D1 degradation, highlighting the therapeutic potential of targeting MG53 in treating cancers with dysregulated cyclin D1 turnover.

Metabolomics and network analysis uncovered profound inflammation-associated alterations in hepatitis B virus-related cirrhosis patients with early hepatocellular carcinoma.

Patients with hepatitis B virus (HBV)-related liver cirrhosis (LC) are at high risk for hepatocellular carcinoma (HCC). Limitations in the early detection of HCC give rise to poor survival in this high-risk population. Here, we performed comprehensive metabolomics on health individuals and HBV-related LC patients with and without early HCC. Compared to non-HCC patients (N = 108) and health controls (N = 80), we found that patients with early HCC (N = 224) exhibited a specific plasma metabolome map dominated by lipid alterations, including lysophosphatidylcholines, lysophosphatidic acids and bile acids. Pathway and function network analyses indicated that these metabolite alterations were closely associated with inflammation responses. Using multivariate regression and machine learning approaches, we identified a five-metabolite combination that showed significant performances in differentiating early-HCC from non-HCC than α-fetoprotein (area under the curve values, 0.981 versus 0.613). At metabolomic levels, this work provides additional insights of metabolic dysfunction related to HCC progressions and demonstrates the plasma metabolites might be measured to identify early HCC in patients with HBV-related LC.

Modification and application of "zero-line" incision design in total endoscopic gasless unilateral axillary approach thyroidectomy: A preliminary report.

Introduction: Gasless unilateral trans-axillary approach (GUA) thyroidectomy has witnessed rapid development in technologies and applications. However, the existence of surgical retractors and limited space would increase the difficulty of guaranteeing the visual field and disturb safe surgical manipulation. We aimed to develop a novel zero-line method for incision design to access optimal surgical manipulation and outcomes. Methods: A total of 217 patients with thyroid cancer who underwent GUA were enrolled in the study. Patients were randomly classified into two groups (classical incision and zero-line incision), and their operative data were collected and reviewed. Results: 216 enrolled patients underwent and completed GUA; among them, 111 patients were classified into the classical group, and 105 patients were classified into the zero-line group, respectively. Demographic data, including age, gender, and the primary tumor side, were similar between the two groups. The duration of surgery in the classical group was longer (2.66 ± 0.68 h) than in the zero-line group (1.40 ± 0.47 h) (p < 0.001). The counts of central compartment lymph node dissection were higher in the zero-line group (5.03 ± 3.02 nodes) than that in the classical group (3.05 ± 2.68 nodes) (p < 0.001). The score of postoperative neck pain was lower in the zero-line group (1.0 ± 0.36) than that in the classical group (3.3 ± 0.54) (p < 0.05). The difference in cosmetic achievement was not statistically significant (p > 0.05). Conclusion: The "zero-line" method for GUA surgery incision design was simple but effective for GUA surgery manipulation and worth promoting.

Boris knockout eliminates AOM/DSS-induced in situ colorectal cancer by suppressing DNA damage repair and inflammation.

The Brother of Regulator of Imprinted Sites (BORIS, gene symbol CTCFL) has previously been shown to promote colorectal cancer cell proliferation, inhibit cancer cell apoptosis, and resist chemotherapy. However, it is unknown whether Boris plays a role in the progression of in situ colorectal cancer. Here Boris knockout (KO) mice were constructed. The function loss of the cloned Boris mutation that was retained in KO mice was verified by testing its activities in colorectal cell lines compared with the Boris wild-type gene. Boris knockout reduced the incidence and severity of azoxymethane/dextran sulfate-sodium (AOM/DSS)-induced colon cancer. The importance of Boris is emphasized in the progression of in situ colorectal cancer. Boris knockout significantly promoted the phosphorylation of γH2AX and the DNA damage in colorectal cancer tissues and suppressed Wnt and MAPK pathways that are responsible for the callback of DNA damage repair. This indicates the strong inhibition of colorectal cancer in Boris KO mice. By considering that the DSS-promoted inflammation contributes to tumorigenesis, Boris KO mice were also studied in DSS-induced colitis. Our data showed that Boris knockout alleviated DSS-induced colitis and that Boris knockdown inhibited the NF-κB signaling pathway in RAW264.7 cells. Therefore Boris knockout eliminates colorectal cancer generation by inhibiting DNA damage repair in cancer cells and relieving inflammation in macrophages. Our findings demonstrate the importance of Boris in the development of in situ colorectal cancer and provide evidence for the feasibility of colorectal cancer therapy on Boris.

Metabolic signatures in pericardial fluid and serum are associated with new-onset atrial fibrillation after isolated coronary artery bypass grafting.

Postoperative atrial fibrillation (POAF) is a common complication of coronary artery bypass grafting (CABG) procedures. However, the molecular mechanism of POAF remains poorly understood, hence the absence of effective prevention strategies. Here we used targeted metabolomics on pericardial fluid and serum samples from CABG patients to investigate POAF-associated metabolic alterations and related risk prediction of new-onset AF. Nine differential metabolites in various metabolic pathways were found in both pericardial fluid and serum samples from patients with POAF and without POAF. By using machine learning algorithms and regression models, a 4-metabolite (aceglutamide, ornithine, methionine, and arginine) risk prediction model was constructed and showed accurate performance in predicting POAF in both discovery and validation sets. This work extends the metabolic insights of the cardiac microenvironment and blood in patients with POAF and paves the way for the use of targeted metabolomics for predicting POAF in patients with CABG surgery.

Modified Iliac Screw in Lumbopelvic Fixation After Sacral Tumor Resection: A Single-Center Case Series.

BACKGROUND: Traditional iliac screw, S2-alar iliac screw, and modified iliac screw are the 3 common techniques for lumbopelvic fixation. The application of the modified iliac technique in sacral spinal tumors has been rarely reported. OBJECTIVE: To report the feasibility and safety of modified iliac screws after sacral tumor resection and their preliminary clinical outcomes. METHODS: Twenty-seven patients who underwent sacral tumor resection with modified iliac screw fixation between August 2017 and August 2021 at our center were clinically and radiographically evaluated. RESULTS: A total of 59 iliac screws were inserted by freehand according to the anatomic landmarks. The mean operation time was 207 minutes (range, 140-435 minutes). The average estimated blood loss was 1396 mL (300-4200 mL). Computed tomography scans showed that 2 (3.4%) screws penetrated the iliac cortex, indicating a 96.6% implantation accuracy rate. There were no iatrogenic neurovascular or visceral structure complications observed. The mean minimal distances from the screw head to the skin were 24.9 and 25.8 mm on the left and right sides, respectively. The mean minimal distances from the screw head to the horizontal level of the posterior superior iliac spine were 7.9 and 8.3 mm on the left and right sides, respectively. Two patients (7.4%) underwent reoperation for wound infection. At the latest follow-up, no patient had complications of screw head prominence, pseudarthrosis, or instrument failure. CONCLUSION: The modified iliac screw is characterized by its minimal invasiveness and simplicity of placement. It is an ideal alternative for lumbopelvic fixation after sacral tumor resection.

ST6GAL1 inhibits metastasis of hepatocellular carcinoma via modulating sialylation of MCAM on cell surface.

The poor prognosis of hepatocellular carcinoma (HCC) is mainly because of its high rate of metastasis. Thus, elucidation of the molecular mechanisms underlying HCC metastasis is of great significance. Glycosylation is an important post-translational modification that is closely associated with tumor progression. Altered glycosylation including the altered sialylation resulting from aberrant expression of ß-galactoside α2,6 sialyltransferase 1 (ST6GAL1) has long been considered as an important feature of cancer cells. However, there is limited information on the roles of ST6GAL1 and α2,6 sialylation in HCC metastasis. Here, we found that ST6GAL1 and α2,6 sialylation were negatively correlated with the metastatic potentials of HCC cells. Moreover, ST6GAL1 overexpression inhibited migration and invasion of HCC cells in vitro and suppressed HCC metastasis in vivo. Using a metabolic labeling-based glycoproteomic strategy, we identified a list of sialylated proteins that may be regulated by ST6GAL1. In particular, an increase in α2,6 sialylation of melanoma cell adhesion molecule (MCAM) inhibited its interaction with galectin-3 and decreased its expression on cell surface. In vitro and in vivo analysis showed that ST6GAL1 exerted its function in HCC metastasis by regulating MCAM expression. Finally, we found the relative intensity of sialylated MCAM was negatively correlated with tumor malignancy in HCC patients. Taken together, these results demonstrate that ST6GAL1 may be an HCC metastasis suppressor by affecting sialylation of MCAM on cell surface, which provides a novel insight into the roles of ST6GAL1 in HCC progression and supports the functional complexity of ST6GAL1 in a cancer type- and tissue type-specific manner.

The preoperative value of fine-needle aspiration in adult soft tissue lesions: An analysis of 514 cases at Shanghai Cancer Center.

BACKGROUND: Fine-needle aspiration (FNA) cytology is a rapid, inexpensive, and uncomplicated method. However, its role in the assessment of soft tissue lesions (STL) remains controversial, and its ability to guide surgical treatment remains unclear. This study investigated the positive predictive value (PPV) of FNA for detecting malignancy and its guiding role in the surgical treatment of STL. METHODS: We retrospectively reviewed 514 patients with STL who underwent preoperative FNA and surgical resection between March 2015 and August 2021. Imaging assessments confirmed that radical surgery was possible. The FNA results were compared with the final postoperative histopathology. RESULTS: Of the 514 patients with STL, 496 (mean age, 48.9 years; range, 21-91 years) were eligible for analysis, the male to female ratio was 111:100. According to the 496 FNA results, 90 (18.2%) were positive for malignancy, 84 (16.9%) were suspicious for malignancy, 80 (16.1%) were spindle cell present, and 242 (48.8%) were negative for malignant cells. Compared with postoperative histopathology, FNA correctly detected all 90 malignant lesions and 203 of the 242 benign lesions. A total of 39 false-negative results were obtained. FNA showed an accuracy of 88.3%, sensitivity of 69.8%, specificity of 100%, negative predictive value (NPV) of 83.9%, and PPV of 100%. In the other seven validation cohorts (n = 1157), FNA had a consistently high PPV, with values all more than 93%. CONCLUSION: Our results demonstrate that FNA has a high PPV for detecting malignancy. For patients with resectable lesions and malignant FNA, the core needle biopsy (CNB) step can be omitted with multidisciplinary evaluation, and subsequent radical surgery can be performed.

Customized Multilevel 3D Printing Implant for Reconstructing Spine Tumor: A Retrospective Case Series Study in a Single Center.

OBJECTIVE: To investigate the clinical efficacy and safety of 3D printed artificial vertebral body for patients who underwent multilevel total en bloc spondylectomy (TES) and analyze whether it could reduce the incidence of implant subsidence. METHODS: This is a retrospective study. From January 2017 to May 2018, eight consecutive cases with spine tumor undergoing multilevel TES were analyzed. All patients underwent X-ray and CT examinations to evaluate the stability of internal fixation during the postoperative follow-up. Demographic, surgical details, clinical data, and perioperative complications was collected. Visual analog scale, Frankel score, and spinal instability neoplastic score (SINS) classification were also recorded. RESULTS: There were six cases of primary spinal tumor and two cases of metastatic spinal tumor. All patients achieved remarkable pain relief and improvement in neurological function. Five patients underwent operation through the posterior approach, one patient underwent operation through the anterior approach and the remaining two patients through a combined anterior and posterior approach. At the last follow-up period, X-rays showed that the 3D printed artificial vertebral body of all cases matched well, and the fixation was reliable. Hardware failure such as loosening, sinking, breaking, and displacement wasn't observed during the follow-up period. CONCLUSION: 3D printed customized artificial vertebral body can provide satisfying good clinical and radiological outcomes for patients who have undergone multilevel TES.

Sparse logistic regression revealed the associations between HBV PreS quasispecies and hepatocellular carcinoma.

BACKGROUND: Chronic infection with hepatitis B virus (HBV) has been proved highly associated with the development of hepatocellular carcinoma (HCC). AIMS: The purpose of the study is to investigate the association between HBV preS region quasispecies and HCC development, as well as to develop HCC diagnosis model using HBV preS region quasispecies. METHODS: A total of 104 chronic hepatitis B (CHB) patients and 117 HBV-related HCC patients were enrolled. HBV preS region was sequenced using next generation sequencing (NGS) and the nucleotide entropy was calculated for quasispecies evaluation. Sparse logistic regression (SLR) was used to predict HCC development and prediction performances were evaluated using receiver operating characteristic curves. RESULTS: Entropy of HBV preS1, preS2 regions and several nucleotide points showed significant divergence between CHB and HCC patients. Using SLR, the classification of HCC/CHB groups achieved a mean area under the receiver operating characteristic curve (AUC) of 0.883 in the training data and 0.795 in the test data. The prediction model was also validated by a completely independent dataset from Hong Kong. The 10 selected nucleotide positions showed significantly different entropy between CHB and HCC patients. The HBV quasispecies also classified three clinical parameters, including HBeAg, HBVDNA, and Alkaline phosphatase (ALP) with the AUC value greater than 0.6 in the test data. CONCLUSIONS: Using NGS and SLR, the association between HBV preS region nucleotide entropy and HCC development was validated in our study and this could promote the understanding of HCC progression mechanism.

Deep learning for predicting immunotherapeutic efficacy in advanced non-small cell lung cancer patients: a retrospective study combining progression-free survival risk and overall survival risk.

Background: Radiomics based on computed tomography (CT) images is potential in promoting individualized treatment of non-small cell lung cancer (NSCLC), however, its role in immunotherapy needs further exploration. The aim of this study was to develop a CT-based radiomics score to predict the efficacy of immune checkpoint inhibitor (ICI) monotherapy in patients with advanced NSCLC. Methods: Two hundred and thirty-six ICI-treated patients were retrospectively included and divided into a training cohort (n=188) and testing cohort (n=48) at a ratio of 8 to 2. The efficacy outcomes of ICI were evaluated based on overall survival (OS) and progression-free survival (PFS). We designed a survival network and combined it with a Cox regression model to obtain patients' OS risk score (OSRS) and PFS risk score (PFSRS). Results: Based on OSRS and PFSRS, patients were divided into high- and low-risk groups in the training cohort and the test cohort with distinctly different [training cohort, log-rank P<0.001, hazard ratio (HR): 4.14; test cohort, log-rank P=0.014, HR: 4.54] and PFS (training cohort, log-rank P<0.001, HR: 4.52; test cohort, log-rank P<0.001, HR: 6.64). Further joint evaluation of OSRS and PFSRS showed that both were significant in the Cox regression model (P<0.001), and multi-overall survival risk score (MOSRS) displayed more outstanding stratification capabilities than OSRS in both the training (P<0.001) and test cohorts (P=0.002). None of the clinical characteristics were significant in the Cox regression model, and the score that predicted the best immune response was not as good as the risk score from follow-up information in the performance of prognostic stratification. Conclusions: We developed a CT imaging-based score with the potential to become an independent prognostic factor to screen patients who would benefit from ICI treatment, which suggested that CT radiomics could be applied for individualized immunotherapy of NSCLC. Our findings should be further validated by future larger multicenter study.

Genetic studies discover novel coding and non-coding mutations in patients with Wilson's disease in China.

OBJECTIVES: Wilson disease (WD) is a rare autosomal recessive genetic disorder associated with various mutations in the ATP7B gene and leads to significant disability or death if untreated. Early diagnosis and proper therapy usually predict a good prognosis, especially in pre-symptomatic WD. Genetic testing provides an accurate and effective diagnostic method for the early diagnosis of WD. METHODS: We recruited 18 clinically diagnosed WD patients from 16 unrelated families and two independent individuals. The next-generation sequencing of the ATP7B gene was performed. The 293T cell lines were divided into wild-type (WT) ATP7B and mutated ATP7B groups. Cell proliferation was determined by Cell Counting Kit-8 (CCK-8) assay and apoptosis was detected by Annexin V/propidium iodide (PI) assays. RESULTS: Pedigree analysis showed that compound heterozygous variants (17/18, 94.44%) were present in the majority of WD patients. A total of 33 ATP7B gene variants were identified, including three variants with uncertain significance (VUS) [two splice mutations (c.51+2T>G, c.1543+40G>A) and one frameshift mutation (c.3532_3535del)]. The CCK-8 and apoptosis assays demonstrated that the VUS of ATP7B could significantly affect the transportation of copper. CONCLUSIONS: The study revealed genetic defects of 16 Chinese families and two independent individuals with WD, which enriched the mutation spectrum of the ATP7B gene worldwide and provided valuable information for studying the mutation types of ATP7B in the Chinese populations. Genetic testing in WD patients is necessary to shorten the time to initiate therapy, reduce damage to the liver and improve the prognosis.

In Silico Analysis of the Correlation of KIF2C with Prognosis and Immune Infiltration in Glioma.

Glioblastoma (GBM) is one of the most commonly pivotal malignant caners. Numerous reports have revealed the crucial roles of immune infiltration in the initiation and progression of GBM. In this study, we first identified differentially expressed genes (DEGs) in the progression of GBM using CGGA databases. Totally, 156 upregulated DEGs and 251 downregulated DEGs were revealed. By constructing a protein-protein interaction network, KIF2C was identified as a hub gene in GBM. Further analysis revealed an evidently positive association existing in KIF2C expression and the advanced stages of gliomas. Higher expression of KIF2C was in WHO grade IV samples relative to that in grade III and grade II samples. In addition, our results showed that KIF2C was higher in IDH1 wild-type samples than IDH1 mutant glioma samples, in 1p/19q noncodel samples than 1p/19q code glioma samples, and in recurrent samples than primary glioma samples. Moreover, our results showed that higher expression of KIF2C correlated with shorter survival time in both primary and recurrent gliomas and could act as a potential biomarker for the prognosis of GBM. Further analysis demonstrated that higher expression of KIF2C was related to higher levels of endothelial cell, T cell CD8+ naïve, common lymphoid progenitor, T cell CD4+ Th2, T cell CD4+ Th2, macrophage, macrophage M1, T cell CD4+ memory, and T cell CD4+ effector memory, but was related to lower levels of NK cell, B cell plasma, T cell CD4+ Th1, T cell regulatory (Tregs), neutrophil, and T cell NK. We thought this study could provide potential biomarkers for the prediction of prognosis and immune infiltration of gliomas.