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Purpose:Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma (ICC). However, little is known about the intertumor heterogeneity (ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making.Experimental Design:We obtained 66 tumor samples from 16 patients with multifocal ICC and characterized the tumor and immune heterogeneity using whole-exome sequencing, bulk and single-cell RNA sequencing, methylation microarray, and multiplex immunostaining. Patients were divided into high- or low-ITH groups according to the median ITH index. Two independent cohorts were used to validate findings. Responses to anti-PD-1 therapy were assessed.Results:Multifocal ICC presented considerable intertumor genomic, transcriptional, and epigenomic heterogeneity within a patient in high ITH group. The immune profile among multiple tumors within a patient was relatively less heterogeneous in high- or low-ITH group, and consistent responses of multiple tumors to anti-PD-1 immunotherapy were observed. Unsupervised clustering of immune markers identified one low and one high immune subtype, with higher immune cell infiltration, closer tumor–immune cell interactions, and upregulated IFN-signature expression in high-immune subtype. Determining expression levels of CD8B and ICOS facilitated this immune classification and prediction of patient prognosis. Finally, promoter DNA methylation contributed to different immune profiles of two subtypes by regulating immune-gene expression.Conclusions:There is comprehensive heterogeneity in the genome, transcriptome, and epigenome of multifocal ICC. On the basis of the less heterogeneous immune profile of ICC, we suggest an immune classification that stratifies patients' prognosis and may support personalized immunotherapy.

Supplementary Data from Multiomic Analysis Reveals Comprehensive Tumor Heterogeneity and Distinct Immune Subtypes in Multifocal Intrahepatic Cholangiocarcinoma

Ultraviolet B (UVB) is one of the most dangerous insults for skin, which can cause skin sunburn, pigment disease, photoaging, and photocarcinogenesis. This study aimed to identify pathogenic genes related to ferroptosis in the skin of humans after UVB radiation.The gene expression profiles (GSE41078, GSE54413) were downloaded from the Gene Expression Omnibus (GEO) database, and the ferroptosis-related genes (FRGs) were downloaded from the Genecards database. To identify the differentially expressed genes (DEGs) and obtain differentially expressed FRGs by intersecting DEGs with FRGs. To identify the functional annotation and potential pathways by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Differentially expressed FRGs-associated protein-protein interaction network (PPI) was performed by STRING database and Cytoscape software.A total of 628 co-expressed DEGs of the two profiles (GSE41078 and GSE54413) were identified, including 371 upregulated and 257 downregulated DEGs. A total of 32 differentially expressed FRGs were identified. The results of GO analyses showed that, in the biological processes, UVB had a great influence on the response to oxidative stress; in the molecular functions, UVB had a great influence on antioxidant activity; in the cellular components, UVB had a great influence on endocytic vesicle lumen. The key pathways of differentially expressed FRGs were identified by KEGG analyses. The most significant 12 central node genes were identified by PPI network.We identified differentially expressed FRGs candidate genes and pathways in UVB-induced skin photodamage, which could contribute to the development of new therapeutic targets for skin photodamage.

SummaryRevealing differential tumor immune microenvironment (TIME) characteristics between true versus de novo hepatocellular carcinoma (HCC) recurrence could help optimal development and use of immunotherapies. Here, we studied the TIME of recurrent HBV-related HCCs by 5’and VDJ single-cell and bulk RNA-sequencing, flow cytometry, and multiplexed immunofluorescence. Analyses of mutational profiles, evolutionary trajectories, and clonal architecture using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The TIME of truly recurrent HCCs was characterized by an increased abundance in KLRB1+CD8+ T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+ T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed an upregulated GDF15 expression level on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited anti-tumor immunity in the TIME of truly recurrent lesions. In contrast, we found that myeloid cells’ crosstalk with T cells mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCC. In conclusion, our results support genomic diagnosis and immune profiling for guiding immunotherapy implementation based on the type of HCC recurrence and TIME.HighlightsTruly recurrent lesions are seeded before primary tumor diagnosis, and that de novo cancer can occur earlier than the clinically used 2-year limit.ScRNA-seq unravels distinct immune ecosystems in true versus de novo HCC recurrences, highlighting the need for different immunotherapy strategies for two types of HCC recurrence.CD8+ T cells in de novo recurrence displayed cytotoxic and exhausted phenotypes while those in truly recurrent lesions showed a memory phenotype with weak cytotoxicity.HCC cells expressing the inhibitory molecule GDF15 were in the proximity of DCs only in truly recurrent lesions.High GDF15 expression level was associated with truly recurrent HCC and worse prognosis.Graphical abstract

The roles of PM2.5-induced mitochondrial damage and oxidative stress on mast cell degranulation were examined in vitro. Mast cells were treated with suspensions of PM2.5 in Dulbecco’s modified Eagl...

Background The reverse shoulder arthroplasty (RSA) may be a promising alternative for proximal humerus tumours because of good postoperative shoulder function. However, the conventional reverse shoulder prosthesis can not meet individual needs and RSA has been associated with a relatively high complication rate. Therefore, implant design and surgical reconstruction technique warrant further study. Methods Between September 2015 and May 2018, 7 patients were treated via RSA after en-bloc resection of the proximal humerus tumours. A 3D-printed guiding baseplate was used to assist the implant of the 3D-printed glenoid prosthesis; a personalized humerus prosthesis was used to reconstruct the proximal humerus. The functional outcomes were assessed by range of motion (ROM) of the shoulder joint, Musculoskeletal Tumour Society (MSTS) functional score, and Toronto Extremity Salvage Score (TESS). We also analyzed tumour recurrence, metastases, and complications associated with the reconstruction procedure. Results All patients were observed for 14 to 36 months, with an average of 23.6 months. At the final follow-up, the mean MSTS score was 85.7% (range, 73.3-93.3%), and the mean TESS score was 90.0% (range, 84.1-95.9%). No instability, infection, scapular notching, loosening or fracture were observed in this series. One patient with GCT suffered from pulmonary metastasis, while one with osteosarcoma died because of pulmonary metastasis. Conclusion The 3D-printed guiding baseplate facilitated the accurate implantation of the glenoid prosthesis. The RSA based on a 3D-printed glenoid prosthesis and a personalized custom-made humerus prosthesis significantly improved the shoulder function and decreased the complication rate. Further studies of a larger scale with longer follow-up are required to validate this technology.

BackgroundMounting studies reveal the relationship between inflammatory markers and post-therapy prognosis. Yet, the role of the systemic inflammatory indices in preoperative microvascular invasion (MVI) prediction for hepatocellular carcinoma (HCC) remains unclear.Patients and MethodsIn this study, data of 1,058 cases of patients with HCC treated in the First Affiliated Hospital of Sun Yat-sen University from February 2002 to May 2018 were collected. Inflammatory factors related to MVI diagnosis in patients with HCC were selected by least absolute shrinkage and selection operator (LASSO) regression analysis and were integrated into an “Inflammatory Score.” A prognostic nomogram model was established by combining the inflammatory score and other independent factors determined by multivariate logistic regression analysis. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to evaluate the predictive efficacy of the model.ResultsSixteen inflammatory factors, including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, etc., were selected by LASSO regression analysis to establish an inflammatory score. Multivariate logistic regression analysis showed that inflammatory score (OR = 2.14, 95% CI: 1.63–2.88, p < 0.001), alpha fetoprotein (OR = 2.02, 95% CI: 1.46–2.82, p < 0.001), and tumor size (OR = 2.37, 95% CI: 1.70–3.30, p < 0.001) were independent factors for MVI. These three factors were then used to establish a nomogram for MVI prediction. The AUC for the training and validation group was 0.72 (95% CI: 0.68–0.76) and 0.72 (95% CI: 0.66–0.78), respectively.ConclusionThese findings indicated that the model drawn in this study has a high predictive value which is capable to assist the diagnosis of MVI in patients with HCC.

Condyloma acuminatum (CA) of the anal canal is difficult to treat and subject to relapse.. We investigated the effects of aminolevulinic acid-based photodynamic therapy (ALA-PDT) combined with oral acitretin during therapy of refractory CA in the anal canal. We also conducted a clinical retrospective study for the treatment of intra-anal CA.A total of 101 patients diagnosed with intra-anal CA were enrolled. All patients underwent liquid nitrogen cryotherapy as a basic treatment until visible wart clearance. Patients were divided into two groups depending on the treatment modality after cryotherapy. ALA-PDT group with 51 patients was given ALA-PDT treatment, and ALA-PDT plus acitretin group with 50 patients was given ALA-PDT treatment combined with oral acitretin. The cure rate, recurrence rate, and adverse reactions of the two groups were analyzed and recorded.The cure rate in the ALA-PDT plus acitretin group was 94% (47/50), which was significantly higher than 80.4% (41/51) in ALA-PDT group. The recurrence rate in the ALA-PDT plus acitretin group was 6% (3/50), which was lower than 19.6% (10/51) in ALA-PDT group (P0.05).ALA-PDT combined with oral acitretin is effective and safe in the treatment of refractory CA in anal canal, and with further study may become an option for these patients.

Purpose: Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma (ICC). However, little is known about the intertumor heterogeneity (ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making. Experimental Design: We obtained 66 tumor samples from 16 patients with multifocal ICC and characterized the tumor and immune heterogeneity using whole-exome sequencing, bulk and single-cell RNA sequencing, methylation microarray, and multiplex immunostaining. Patients were divided into high- or low-ITH groups according to the median ITH index. Two independent cohorts were used to validate findings. Responses to anti-PD-1 therapy were assessed. Results: Multifocal ICC presented considerable intertumor genomic, transcriptional, and epigenomic heterogeneity within a patient in high ITH group. The immune profile among multiple tumors within a patient was relatively less heterogeneous in high- or low-ITH group, and consistent responses of multiple tumors to anti-PD-1 immunotherapy were observed. Unsupervised clustering of immune markers identified one low and one high immune subtype, with higher immune cell infiltration, closer tumor–immune cell interactions, and upregulated IFN-signature expression in high-immune subtype. Determining expression levels of CD8B and ICOS facilitated this immune classification and prediction of patient prognosis. Finally, promoter DNA methylation contributed to different immune profiles of two subtypes by regulating immune-gene expression. Conclusions: There is comprehensive heterogeneity in the genome, transcriptome, and epigenome of multifocal ICC. On the basis of the less heterogeneous immune profile of ICC, we suggest an immune classification that stratifies patients' prognosis and may support personalized immunotherapy.

INTRODUCTION The use of Acuseal arteriovenous graft (AAVG) is spreading in end-stage renal disease (ESRD) patients for its advantages in early cannulation. However, comparison of clinical outcomes between AAVGs and standard arteriovenous grafts (SAVGs) is limited. In this study, we compared the performance of AAVGs and SAVGs. METHODS Consecutive ESRD patients underwent prosthetic vascular access between October 2017 and May 2019 at a single center were identified. Patients were divided into AAVG group and SAVG group. Patients' demographics, perioperative characteristics, and clinical outcomes were collected. Primary, primary assisted, and secondary patency rates were compared using Kaplan-Meier analyses. Postsurgery complications were compared using chi-square test or the Fisher's exact test. FINDINGS A total of 304 arteriovenous grafts (AVGs) were implanted in 145 males and 159 females (mean age, 60.1 years; range, 20-91 years), comprising 143 AAVGs and 161 SAVGs. Median time to first cannulation was 3 days (interquartile range [IQR], 1-15 days) in the AAVG group and 30 days (IQR, 20-52 days) in the SAVG group (P

Background Microvascular invasion (MVI) remains a risk factor for tumor recurrence and metastasis in hepatocellular carcinoma (HCC). No effective and well-recognized method can detect MVI before surgery. Inflammatory markers reflect the immune environment and have been proven to be related to prognosis as well as the presence of MVI in HCC. We aimed to establish an MVI predictive model based on inflammatory markers. Methods Data of 1058 cases of HCC patients treated in the First Affiliated Hospital of Sun Yat-sen University from November 2003 to December 2015 were collected. In a ratio of 7 : 3, patients were divided into the training group (740 cases) and the validating group (318 cases). Inflammatory factors related to MVI diagnosis in HCC patients were selected by LASSO regression analysis, and were then integrated into an ‘Inflammatory Score’. A prognostic Nomogram model was established by combining the Inflammatory Score and the independent factors determined by multivariate logistic regression analysis. The consistency index (C-index) and the area under the curve (AUC) were used to evaluate the predictive efficacy of the model. Results A total of 1058 HCC patients were included in this retrospective study, 430 of whom (40.6%) were diagnosed with MVI. Sixteen inflammatory factors, including neutrophil, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, etc., were selected by LASSO regression analysis to establish an Inflammatory Score. Multivariate logistic regression analysis showed that Inflammatory Score (OR = 2.186, 97.5% CI: 1.656–2.950), age (OR = 0.987, 97.5% CI: 0.973–1.000), alpha fetoprotein (OR = 1.923, 97.5% CI: 1.380–2.690), tumor size (OR = 2.308, 97.5% CI: 1.656–3.220) were independent factors in the diagnosis of MVI in HCC patients. These four factors were then used to establish a Nomogram for MVI prediction. The C-index of the Nomogram prediction model was 0.72. The AUC for the training and validating group were 0.720 and 0.721, respectively. Conclusions The Nomogram prediction model drawn in this study has a high prognostic value, which is capable of improving the diagnosis efficiency of MVI in HCC patients.

Increasing evidence suggests that an exogenous electromagnetic field might be involved in many biologic processes which are of great importance for therapeutic interventions. Pulsed electromagnetic fields (PEMFs) are known to be a noninvasive, safe and effective therapy agent without apparent side effects. Numerous studies have shown that PEMFs possess the potential to become a stand-alone or adjunctive treatment modality for treating musculoskeletal disorders. However, several issues remain unresolved. Prior to their widely clinical application, further researches from well-designed, high-quality studies are still required to standardize the treatment parameters and derive the optimal protocol for health-care decision making. In this review, we aim to provide current evidence on the mechanism of action, clinical applications, and controversies of PEMFs in musculoskeletal disorders.

Condyloma acuminatum is a sexually transmitted disease caused by human papillomavirus infection, which mostly occurs in the external genitalia, vulva, perianal, and the Intraurethral condyloma acuminatum is relatively rare. Treatment of urethral warts present a challenge especially if the proximal urethra is involved. Here, we report a case of intractable urethral condyloma acuminatum involving the urethral meatus and mid penile urethra with scar. This case suggested that local Photodynamic therapy in condyloma of the whole anterior urethra appears to be not only safe and effective, but also might be able to improve existing scars.

Background Increasing evidence indicates the important value of the neutrophil-to-lymphocyte ratio (NLR) in various cancers. In this meta-analysis, we will explore the potential role of pretreatment NLR in patients with bone sarcomas. Methods A systematic literature search of the PubMed, Embase and Web of Science databases for relevant articles was performed with the deadline of December 29, 2019. The hazard ratio (HR) and its 95% confidence interval (CI) were calculated to evaluate the association between NLR and overall survival (OS) in patients with bone sarcomas. Results A total of 1131 patients in 6 studies were included in this meta-analysis. The pooled HR of 2.26 (95%CI: 1.83-2.69, p

Deep non-negative matrix factorization (DNMF) is a promising method for non-negativity multi-layer feature extraction. Most of DNMF algorithms are repeatedly to run single-layer NMF to build the hierarchical structure. They have to eliminate the accumulated error via fine-tuning strategy, which is, however, too time-consuming. To deal with the drawbacks of existing DNMF algorithms, this paper proposes a novel deep auto-encoder using back-propagation neural network (BPNN). It can automatically yield a deep non-negative matrix factorization, called BPNN based DNMF (BP-DNMF). The proposed BP-DNMF algorithm is empirically shown to be convergent. Compared with some state of the art DNMF algorithms, experimental results demonstrate that our approach achieves superior clustering performance and has high computing efficiency as well.