Search

Micro-expression recognition based on ima- ges has made some progress, yet limitations persist. For instance, image-based recognition of micro-expressions is affected by factors such as ambient light, changes in head posture, and facial occlusion. The high temporal resolution of electroencephalogram (EEG) technology can record brain activity associated with micro-expressions and identify them objectively from a neurophysiological standpoint. Accordingly, this study introduces a novel method for recognizing micro-expressions using node efficiency features of brain networks derived from EEG signals. We designed a real-time Supervision and Emotional Expression Suppression (SEES) experimental paradigm to collect video and EEG data reflecting micro- and macro-expression states from 70 participants experiencing positive emotions. By constructing functional brain networks based on graph theory, we analyzed the network efficiencies at both macro- and micro-levels. The participants exhibited lower connection density, global efficiency, and nodal efficiency in the alpha, beta, and gamma networks during micro-expressions compared to macro-expressions. We then selected the optimal subset of nodal efficiency features using a random forest algorithm and applied them to various classifiers, including Support Vector Machine (SVM), Gradient-Boosted Decision Tree (GBDT), Logistic Regression (LR), Random Forest (RF), and eXtreme Gradient Boosting (XGBoost). These classifiers achieved promising accuracy in micro-expression recognition, with SVM exhibiting the highest accuracy of 92.6% when 15 channels were selected. This study provides a new neuroscientific indicator for recognizing micro-expressions based on EEG signals, thereby broadening the potential applications for micro-expression recognition.

Epinephrine (EP) is a very important chemical transmitter in the transmission of nerve impulses in the central nervous system of mammals. Ascorbic acid (AA) is considered to be the most important extracellular fluid antioxidant and has important antioxidant properties in the cell. In this study, a series of transition metal–polyhistidine-carboxylated multi-wall carbon nanotube nanocomposites were synthesized, and their simultaneous catalytic effects on epinephrine and ascorbic acid were investigated. The results showed that nanocomposites based on iron ions had the highest catalytic activity. The prepared biosensor expressed high selectivity toward EP and AA with LOD values of 0.1 μΜ (AA) and 0.01 μΜ (EP), and sensitivity values of 4.18 μA mM−1 with a range of 0.001–5 mM (AA), 50.98 μA mM−1 with a range of 0.2–100 μM (EP), and 265.75 μA mM−1 with a range of 0.1–1.0 mM (EP). Moreover, it showed good stability, good repeatability and high selectivity in real sample detection. This work is a reference for the design of new electrochemical enzyme-free biosensors and the detection of biomarkers.

Prostate specific antigen (PSA), as a biomarker, plays important roles in early diagnosis of male prostate diseases, especially prostate cancer. In this study, a novel electrochemical probe polymer of poly(ferriporphyrin-co-acrylamide) was synthesized, by further combined with reduced graphene oxide and gold nanoparticles, and oriented immobilization of PSA antibody, a label-free electrochemical immunosensor was obtained, and then successfully applied in the determination of PSA in 10 % non-antigen serum system. The prepared biosensor expressed high selectivity toward PSA, with a LOD of 0.001 ng mL−1, a linear range of 0.01–110 ng mL−1, and a sensitivity of 15.78 µA mL ng−1. What’s more, it showed good stability, well repeatability and high selectivity in the real PSA sample detection. This work provided certain references for the design of the new electrochemical probes and the detection of tumor markers.

Abstract This special issue explores the relationship between digital trade and security, emphasizing the geopolitical implications for the global economy in the digital age. The rapid growth of digital trade has introduced significant challenges and opportunities, necessitating robust data governance to balance national security interests with the free flow of goods, services, and data across borders. The papers explore the different models of data governance championed by the US, China, and the EU, highlighting the complexities of cross-border data flows and their impact on international relations. Through detailed analyses of various international agreements and frameworks, this special issue provides a comprehensive overview of the current landscape of digital trade and its security implications, with a particular focus on China's evolving approach to data governance and its global influence.

Abstract Through transcriptome sequencing, we previously identified a new osteosarcoma-specific, frequent fusion gene, LRP1–SNRNP25, and found that it played an important role in tumor cell invasion and migration. However, the specific mechanism remains unclear. In this article, whole-genome sequencing further confirmed that the LRP1–SNRNP25 fusion gene is formed by fusion of LRP1 exon 8 and SNRNP25 exon 2. In vitro, scratch and Transwell assays demonstrated that the migration and invasion abilities of LRP1–SNRNP25-overexpressing osteosarcoma cells were significantly increased. To explore the molecular mechanism of the LRP1–SNRNP25 fusion in affecting osteosarcoma cell migration and invasion, we evaluated the migration and invasion-related molecular signaling pathways by western blotting. Some migration- and invasion-related genes, including pJNK and MMP2, were upregulated. Coimmunoprecipitation–mass spectrometry showed that 37LRP can interact with pJNK. Western blotting confirmed that LRP1–SNRNP25 overexpression upregulates 37LRP protein expression. Immunofluorescence staining showed the intracellular colocalization of LRP1–SNRNP25 with pJNK and 37LRP proteins and that LRP1–SNRNP25 expression increased the pJNK and 37LRP levels. Coimmunoprecipitation (co-IP) confirmed that LRP1–SNRNP25 interacted with pJNK and 37LRP proteins. The pJNK inhibitor SP600125 dose-dependently decreased the pJNK/37LRP/MMP2 levels. After siRNA-mediated 37LRP knockdown, the MMP2 protein level decreased. These two experiments proved the upstream/downstream relationship among pJNK, 37LRP, and MMP2, with pJNK the farthest upstream and MMP2 the farthest downstream. These results proved that the LRP1–SNRNP25 fusion gene exerts biological effects through the pJNK/37LRP/MMP2 signaling pathway. In vivo, LRP1–SNRNP25 promoted osteosarcoma cell growth. Tumor growth was significantly inhibited after SP600125 treatment. Immunohistochemical analysis showed that the pJNK, MMP2, and Ki-67 protein levels were significantly increased in tumor tissues of LRP1–SNRNP25-overexpressing cell-injected nude mice. Furthermore, lung and liver metastasis were more prevalent in these mice. In a word, LRP1–SNRNP25 promotes invasion, migration, and metastasis via pJNK/37LRP/MMP2 pathway. LRP1–SNRNP25 is a potential therapeutic target for LRP1–SNRNP25-positive osteosarcoma.

Abstract Background The high mutation rate throughout the entire melanoma genome presents a major challenge in stratifying true driver events from the background mutations. Numerous recurrent non-coding alterations, such as those in enhancers, can shape tumor evolution, thereby emphasizing the importance in systematically deciphering enhancer disruptions in melanoma. Results Here, we leveraged 297 melanoma whole-genome sequencing samples to prioritize highly recurrent regions. By performing a genome-scale CRISPR interference (CRISPRi) screen on highly recurrent region-associated enhancers in melanoma cells, we identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers reveal many known and hidden mechanisms underlying melanoma growth. Utilizing extensive functional validation experiments, we demonstrate that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A, and another distal enhancer is able to sustain PTEN tumor-suppressive potential via long-range interactions. Conclusions Our study establishes a catalogue of crucial enhancers and their target genes in melanoma growth and progression, and illuminates the identification of novel mechanisms of dysregulation for melanoma driver genes and new therapeutic targeting strategies.

BackgroundSarcoma is a highly heterogeneous malignancy with a poor prognosis. Although chemotherapy and targeted therapy have improved the prognosis to some extent, the efficacy remains unsatisfactory in some patients. The efficacy and safety of immunotherapy in sarcoma need further evaluation.MethodsWe conducted a two-center study of sarcoma patients receiving PD-1 immunotherapy at Tianjin Medical University Cancer Institute and Hospital and Henan Provincial Cancer Hospital. The treatment regimens included PD-1 inhibitor monotherapy and combination therapy based on PD-1 inhibitors. The observed primary endpoints were median progression-free survival (mPFS) and median overall survival (mOS). Survival curves were compared using the Kaplan−Meier method.ResultsA total of 43 patients were included from the two centers. The median follow-up time for all patients was 13 months (range, 1-48 months). In the group of 37 patients with advanced or unresectable sarcoma, the mPFS was 6 months (95%CI: 5-12 months), and the mOS was 16 months (95%CI: 10-28 months). The ORR was 10.8% (4/37), and the DCR was 18.9% (7/37). Subgroup analysis showed no significant differences in mPFS (p=0.11) and mOS (p=0.88) between patients with PD-L1 negative/positive expression. There were also no significant differences in mPFS (p=0.13) or mOS (p=0.72) between PD-1 inhibitor monotherapy and combination therapy. Additionally, there were no significant differences in mPFS (p=0.52) or mOS (p=0.49) between osteogenic sarcoma and soft tissue sarcoma. Furthermore, the results showed no significant differences in mPFS (p=0.66) or mOS (p=0.96) between PD-1 inhibitors combined with targeted therapy and PD-1 inhibitors combined with AI chemotherapy. Among the 6 patients receiving adjuvant therapy after surgery, the mPFS was 15 months (95%CI: 6-NA months), and the mOS was not reached. In terms of safety, most adverse events were mild (grade 1-2) and manageable. The most severe grade 4 adverse events were bone marrow suppression, which occurred in 4 patients but resolved after treatment. There was also one case of a grade 4 adverse event related to hypertension.ConclusionImmunotherapy is an effective treatment modality for sarcoma with manageable safety. Further inclusion of more patients or prospective clinical trials is needed to validate these findings.

Immunotherapy is an essential therapy for individuals with advanced melanoma. However, not all patients respond to such treatment due to individual differences. We conducted a multidimensional analysis using transcriptome data from our center, as well as publicly available databases. We found that effective nivolumab treatment led to an upregulation of C2 levels, and higher levels following treatment are indicative of a good outcome. Through bioinformatics analyses and immunofluorescence, we identified a correlation between C2 and M1 macrophages. To further investigate the role of C2 in melanoma, we constructed subcutaneous tumorigenic models in C57BL/6 mice. The tumors in the C2 overexpression group exhibited significantly smaller sizes. Flow cytometric analysis of the mouse tumors demonstrated enhanced recruitment of macrophages, particularly of the M1 subtype, in the overexpression group. Moreover, single-cell RNA sequencing analysis revealed that C2-positive tumor cells exhibited enhanced communication with immune cells. We co-cultured tumor cell supernatants with macrophages in vitro and observed the induction of M1 subtype polarization. In addition, we discovered a close correlation between C2 and tertiary lymphoid structures. C2 has been demonstrated to exert a protective effect, mediated by its ability to modulate the tumor microenvironment. C2 serves as a prognostic marker for melanoma and can be employed to monitor the efficacy of immunotherapy.

Studying the cell composition of acral melanoma at the single-cell level could provide some clues about its poor response to immunotherapy. Here, the authors analyse acral and cutaneous melanoma patient samples using single-cell RNA-sequencing, and reveal a severe immunosuppressive state in acral melanomas

Objective: The BRAF inhibitor, vemurafenib, has been widely used in the treatment of patients with melanoma-bearing BRAFV600E mutations. While the initial response to vemurafenib is usually excellent, the majority of patients eventually develop resistance and metastatic disease. However, the underlying molecular mechanism remains elusive. The objective of this study was therefore to identify additional molecular targets responsible for vemurafenib resistance. Methods: Western blots and immunohistochemistry analyses were used to evaluate expressions of PYK2 and p-PYK2 in cultured cells and melanoma tissue microarrays. The relationships of p-PYK2 with clinicopathological parameters were statistically analyzed. Invadopodia cell invasion, and a Ca2+ assay were used to determine the effect of vemurafenib resistance-induced p-PYK2 on melanoma progression. A mouse model was used to assess the effects of PYK2 on melanoma metastasis. Results: Elevated p-PYK2 levels were detected in vemurafenib-resistant melanoma cells, and PYK2 was shown to regulate invadopodia formation in melanoma cells. Vemurafenib triggered invadopodia formation by activation of PYK2. Inhibition of PYK2 with either shRNA or the small molecule inhibitor, PF562711, dramatically reduced vemurafenib-induced invadopodia formation. Furthermore, knockdown of PYK2 significantly reduced melanoma lung metastasis in vivo. Increased expressions of p-PYK2 in melanoma patients were positively correlated with advanced stage (P = 0.002), metastasis (P < 0.001), and Clark grade (P < 0.001), and were also associated with short overall survival [hazard ratio (HR) = 3.304, P = 0.007] and progression-free survival (HR = 2.930, P = 0.001). Conclusions: PYK2 mediated vemurafenib-induced melanoma cell migration and invasion. Inhibition of PYK2 resensitized melanoma cells to vemurafenib. Phospho-PYK2 was a prognostic biomarker in melanoma patients.

PurposeTo establish and validate a machine learning based radiomics model for detection of perineural invasion (PNI) in gastric cancer (GC).MethodsThis retrospective study included a total of 955 patients with GC selected from two centers; they were separated into training (n=603), internal testing (n=259), and external testing (n=93) sets. Radiomic features were derived from three phases of contrast-enhanced computed tomography (CECT) scan images. Seven machine learning (ML) algorithms including least absolute shrinkage and selection operator (LASSO), naïve Bayes (NB), k-nearest neighbor (KNN), decision tree (DT), logistic regression (LR), random forest (RF), eXtreme gradient boosting (XGBoost) and support vector machine (SVM) were trained for development of optimal radiomics signature. A combined model was constructed by aggregating the radiomic signatures and important clinicopathological characteristics. The predictive ability of the radiomic model was then assessed with receiver operating characteristic (ROC) and calibration curve analyses in all three sets.ResultsThe PNI rates for the training, internal testing, and external testing sets were 22.1, 22.8, and 36.6%, respectively. LASSO algorithm was selected for signature establishment. The radiomics signature, consisting of 8 robust features, revealed good discrimination accuracy for the PNI in all three sets (training set: AUC = 0.86; internal testing set: AUC = 0.82; external testing set: AUC = 0.78). The risk of PNI was significantly associated with higher radiomics scores. A combined model that integrated radiomics and T stage demonstrated enhanced accuracy and excellent calibration in all three sets (training set: AUC = 0.89; internal testing set: AUC = 0.84; external testing set: AUC = 0.82).ConclusionThe suggested radiomics model exhibited satisfactory prediction performance for the PNI in GC.

Summary: Exponential accumulation of single-cell transcriptomes poses great challenge for efficient assimilation. Here, we present an approach entitled generative pretraining from transcriptomes (tGPT) for learning feature representation of transcriptomes. tGPT is conceptually simple in that it autoregressive models the ranking of a gene in the context of its preceding neighbors. We developed tGPT with 22.3 million single-cell transcriptomes and used four single-cell datasets to evalutate its performance on single-cell analysis tasks. In addition, we examine its applications on bulk tissues. The single-cell clusters and cell lineage trajectories derived from tGPT are highly aligned with known cell labels and states. The feature patterns of tumor bulk tissues learned by tGPT are associated with a wide range of genomic alteration events, prognosis, and treatment outcome of immunotherapy. tGPT represents a new analytical paradigm for integrating and deciphering massive amounts of transcriptome data and it will facilitate the interpretation and clinical translation of single-cell transcriptomes.

Objective: Sarcomas are a group of rare malignancies with various subtypes. Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies, including anti-programmed death-1 (PD-1)-based therapies. Methods: We retrospectively analyzed clinical data of 24 metastatic sarcoma patients from June 15, 2016 to December 30, 2019. These patients mainly received angiogenesis inhibitors combined with anti-PD-1 therapy after they became resistant to traditional treatments. Furthermore, 8 patients underwent panel DNA and whole transcript sequencing. Results: Six patients received 2 cycles of anti-PD-1 therapy and were included in the safety evaluation only group. The median follow-up time was 5.77 months. The median progression-free survival was 7.59 months, the overall response rate was 16.7% and the disease control rate was 55.6%. Based on whole exome and transcript sequencing data, there was no association between TMB, TNB, MSI, HLA-LOH, and PD-L1 expressions and sarcoma types with clinical responses. Immunotherapy efficacy and bioinformatics analyses indicated higher intratumoral heterogeneity (ITH) in progressive disease (PD) patients and lower ITH in partial response (PR) and stable disease patients. A higher percentage of immune cell infiltration, especially monocytes, was observed in PR patients. Active stromal gene expression was increased in PD patients but decreased in PR patients. Enrichment analysis revealed that an increased TGF-β signaling pathway was reversely correlated with anti-PD-1 efficacy, while a decreased inflammatory response signaling pathway was positively correlated with anti-PD-1 efficacy. Conclusions: Our study showed PD-1 inhibitors combined with anti-angiogenesis agents were effective and well-tolerated. ITH, monocyte ratio, stroma subtypes, and the status of immune-associated signaling pathways may be related with anti-PD-1 based therapy.

Chimeric antigen receptor T-cell (CAR-T) therapy has been approved for relapsed/refractory B-cell lymphomas and greatly improves disease outcomes. The impressive success has inspired the application of this approach to other types of tumors. The relapsed/refractory T-cell malignancies are characteristic of high heterogeneity and poor prognoses. The efficacy of current treatments for this group of diseases is limited. CAR-T therapy is a promising solution to ameliorate the current therapeutic situation. One of the major challenges is that normal T-cells typically share mutual antigens with malignant cells, which causes fratricide and serious T-cell aplasia. Moreover, T-cells collected for CAR transduction could be contaminated by malignant T-cells. The selection of suitable target antigens is of vital importance to mitigate fratricide and T-cell aplasia. Using nanobody-derived or naturally selected CAR-T is the latest method to overcome fratricide. Allogeneic CAR-T products and CAR-NK-cells are expected to avoid tumor contamination. Herein, we review the advances in promising target antigens, the current results of CAR-T therapy clinical trials in T-cell malignancies, the obstacles of CAR-T therapy in T-cell malignancies, and the solutions to these issues.

BackgroundVisceral sarcomas are a rare form of soft tissue sarcoma. This study aimed to evaluate the survival and prognostic factors and effective treatments for visceral sarcomas.MethodsAll patients with visceral sarcoma referred to our center between January 2010 and December 2021 were retrospectively analyzed. The Kaplan-Meier method and a log-rank test were used for survival analysis.ResultsA total of 53 patients with visceral sarcoma were analyzed in this study with the median age at diagnosis of 57 (range, 24-77) years. Among them, 37 (69.8%) and 16 (30.2%) patients had localized and metastatic diseases at the initial presentation, respectively, and 44 patients underwent surgical resection. The median follow-up, event-free survival (EFS) and overall survival (OS) were 63.0 (range, 2-130), 42.0 months (95% confidence interval [CI] 10.879-73.121) and 45.0 months (95% CI 9.938-80.062), respectively. The 5-year EFS and OS rates were 44% and 46%, respectively. Univariate analysis of prognostic indicators illustrated that metastasis at presentation, surgery, surgical margin and the types of surgery were significantly associated with OS and EFS. In this study, combined chemotherapy or radiotherapy had no effects on EFS and OS.ConclusionPrimary visceral sarcoma is an uncommon and aggressive malignant tumor with a higher rate of local recurrence. In the largest cohort of visceral sarcomas in China to date, we identified metastases at presentation, surgery, surgical margin, and the types of surgery as independent predictors of survival. The combination of chemotherapy and radiotherapy did not affect survival.

BackgroundTumorigenesis and progression are intimately associated with inflammation. However, the inflammatory landscape in soft tissue sarcoma (STS) and its clinical consequences are yet unknown, and more investigation is needed.MethodsRNA-seq expression data for STS and corresponding normal tissues were downloaded from The Cancer Genome Atlas database and the Genotype-Tissue Expression Portal. Differential and prognostic analyses were performed based on known inflammatory response genes from Gene Set Enrichment Analysis (GSEA). We utilized LASSO-Cox analysis to determine hub genes and built an inflammatory score (INFscore) and risk stratification model. Furthermore, a nomogram, including the risk stratification model, was established to predict the prognosis. We further elucidated the characteristics among different risk STS patients by GSEA, gene set variation analysis, and detailed immune infiltration analysis. Finally, the INFscore and risk stratification model in predicting prognosis and depicting immune microenvironment status were verified by pan-cancer analysis.ResultsFive hub genes (HAS2, IL1R1, NMI, SERPINE1, and TACR1) were identified and were used to develop the INFscore. The risk stratification model distinguished the immune microenvironment status and evaluated the efficacy of immunotherapy and chemotherapy in STS. The novel nomogram had good efficacy in predicting the prognosis of STS patients. Finally, a pan-cancer investigation verified the association of INFscore with prognosis and immunity.ConclusionsAccording to the present study, the risk stratification model can be used to evaluate STS prognosis, tumor microenvironment status, immunotherapy, and chemotherapy efficacy. The novel nomogram has an excellent predictive value. Thus, the INFscore and risk stratification model has potential value in assessing the prognosis and immune status of multiple malignancies.

BackgroundThe rarity and complexity of soft tissue sarcoma (STS) make it a challenge to determine the incidence, survival, and metastasis rates. In addition, the clinicopathological risk factors for lymph node metastasis have rarely been reported.MethodsData on patients diagnosed with STS in the SEER database from 2000 to 2018 were extracted by SEER*Stat 8.3.9.1, and the incidence trend was calculated by Joinpoint 4.9 software. The KM method was used to calculate the survival curve, and the log-rank method was used to compare differences in the survival curves. The clinicopathological risk factors for lymph node metastasis were screened by logistic regression.ResultsAmong the 35987 patients, 4299 patients (11.9%) had distant metastasis. The overall lymph node metastasis rate was 6.02%, which included patients suffering from both lymph node and distant metastasis. Considering that some lymph node metastases might be accompanying events of distant metastasis, the rate of only lymph node metastasis in STS patients decreased to 3.42% after excluding patients with distant metastasis. Patients with only lymph node metastases (N1/2M0) had a significantly worse prognosis than those without metastases (N0M0) but a better prognosis than those with only distant metastases (N0M1) (p

Abstract Background Whether non‐sentinel lymph node (SLN)‐positive melanoma patients can benefit from completion lymph node dissection (CLND) is still unclear. The current study was performed to identify the prognostic role of non‐SLN status in SLN‐positive melanoma and to investigate the predictive factors of non‐SLN metastasis in acral and cutaneous melanoma patients. Methods The records of 328 SLN‐positive melanoma patients who underwent radical surgery at four cancer centers from September 2009 to August 2017 were reviewed. Clinicopathological data including age, gender, Clark level, Breslow index, ulceration, the number of positive SLNs, non‐SLN status, and adjuvant therapy were included for survival analyses. Patients were followed up until death or June 30, 2019. Multivariable logistic regression modeling was performed to identify factors associated with non‐SLN positivity. Log‐rank analysis and Cox regression analysis were used to identify the prognostic factors for disease‐free survival (DFS) and overall survival (OS). Results Among all enrolled patients, 220 (67.1%) had acral melanoma and 108 (32.9%) had cutaneous melanoma. The 5‐year DFS and OS rate of the entire cohort was 31.5% and 54.1%, respectively. More than 1 positive SLNs were found in 123 (37.5%) patients. Positive non‐SLNs were found in 99 (30.2%) patients. Patients with positive non‐SLNs had significantly worse DFS and OS (log‐rank P

PurposeOur previously study showed that recombinant human endostatin (Endostar) combined with chemotherapy had significant activity to increase the mPFS in patients with advanced sarcomas with tolerable side effects. However, the small cohort size and short follow-up time made it difficult to screen sensitive sarcoma subtypes and determine whether there is an overall survival benefit. With the largest sarcoma cohort to our knowledge, we try to confirm the efficacy and safety of chemotherapy combined with Endostar in stage IV sarcomas, with the specific purpose of finding out the sensitive sarcoma types for this combined treatment.MethodsAfter the exclusion of ineligible patients, 156 patients with stage IV bone and soft tissue sarcomas were included in this study according to the inclusion criteria.ResultsBy the end of follow-up, the ORR was 10.7% (9/84) vs 1.4% (1/72) (p=0.041), the DCR was 26.2% (22/84) vs 5.6% (4/72) (p=0.001) in the combined group and chemotherapy group, respectively. The mPFS of combined group was significantly longer than the chemotherapy group (10.42 vs 6.87 months, p=0.003). The mOS were 26.84 months and 23.56 months, without significant difference (p= 0.481). In osteogenic sarcoma, there was no statistically significant difference in the mPFS between the two groups (p=0.59), while in the soft tissue sarcoma, the mPFS in the combined group was significantly higher than that of the chemotherapy group (11.27 vs 8.05 months, p=0.004). Specifically, undifferentiated polymorphic sarcoma (UPS) was the possible sarcoma subtypes that benefited from the combined therapy. For the 38 UPS patients (28 patients in the combined group and 10 patients in the chemotherapy group), the mPFS in the combined group was up to 14.88 months, while it was only 7.1 months in the chemotherapy group, with a significant difference (p=0.006). The most common adverse events in the combined group were myelosuppression, gastrointestinal reactions and abnormal liver function, without significant difference in two groups.ConclusionChemotherapy plus Endostar could prolong mPFS and improve ORR and DCR in patients with stage IV soft tissue sarcoma, suggesting that the combined therapy could improve the patient prognosis in soft tissue sarcomas, especially the UPS patients.

Abstract The mitogen‐activated protein kinase (MAPK) signaling pathway plays a significant role in mediating cellular physiological activities, such as proliferation, differentiation, apoptosis, and senescence. This signaling pathway is composed of several major proto‐oncogenes of RAS/RAF/MEK/ERK, among which the BRAF proto‐oncogene, as one of the three members of the RAF family, has a higher mutation rate than ARAF and CRAF and has attracted extensive attention. Regarding the BRAF mutation, approximately 95% of BRAF mutations belong to the BRAF V600E mutation, which can enhance the expression of the MAPK signaling pathway and is thus related to the occurrence and development of various malignant tumors and has been successfully identified as a therapeutic target. Moreover, drug resistance to BRAF inhibitor treatment also appears to be an important issue. Considering the successful use of BRAF inhibitors in melanoma, we provide a brief overview of the BRAF mutations, including their basic structures and activation mechanisms, and the new classification method for BRAF mutations. Most importantly, we summarize the results of BRAF inhibitor treatment in different sarcomas. To overcome drug resistance to BRAF inhibitor treatment, we also outline the different mechanisms of drug resistance to BRAF inhibitor treatment and introduce the combination strategy of BRAF inhibitors with other targeted therapies.

Objective: To analyze the efficacy and safety of apatinib in the treatment of stage IV osteogenic sarcoma after chemotherapy failure through a single-arm, prospective, and open clinical phase II study. Methods: Information on 34 patients with stage IV osteogenic sarcoma treated with apatinib after failure of chemotherapy in Tianjin Medical University Cancer Institute and Hospital between September 2015 and December 2019 was collected and analyzed. The participants included 23 males and 11 females, with an average age of 35.24 years (11–73 years). The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), PFS rate (PFR), and overall survival (OS) were evaluated. The treatment-related adverse events (AEs) and safety of apatinib were also evaluated. Results: Of the 34 patients, 33 were able to be evaluated for efficacy. One patient received apatinib treatment for less than one cycle; therefore, only safety analysis was performed. The 12-week clinical evaluation showed that 2 patients had a partial response (PR), 24 patients had stable disease (SD), and 7 patients had progressive disease (PD). The ORR, DCR, and PFR at 12 weeks were 6.06% (2/33), 78.79% (26/33), and 82%, respectively. By the end of the follow-up, 6 patients had SD (18.18%, 6/33), 27 patients had PD (81.82%, 27/33), and 15 patients died because of disease progression (45.45%, 15/33). The ORR was 0 (0/33), the DCR was 18.18% (6/33), and the median PFS (mPFS) was 7.89 months (95% CI: 4.56–11.21). The median OS (mOS) was 17.61 months (95% CI: 10.85–24.37). The most common treatment-related AEs were hand-foot syndrome (35.29%, 12/34), proteinuria (32.35%, 11/34), and hypertension (32.35%, 11/34). Conclusions: Apatinib is effective and well tolerated in stage IV osteogenic sarcoma patients after chemotherapy failure.

Summary: We developed Miscell, a self-supervised learning approach with deep neural network as latent feature encoder for mining information from single-cell transcriptomes. We demonstrated the capability of Miscell with canonical single-cell analysis tasks including delineation of single-cell clusters and identification of cluster-specific marker genes. We evaluated Miscell along with three state-of-the-art methods on three heterogeneous datasets. Miscell achieved at least comparable or better performance than the other methods by significant margin on a variety of clustering metrics such as adjusted rand index, normalized mutual information, and V-measure score. Miscell can identify cell-type specific markers by quantifying the influence of genes on cell clusters via deep learning approach.

Background: When patients with desmoid tumors (DTs) present uncontrolled clinical symptoms, surgery is an effective treatment, but the high postoperative recurrence rate is a major problem. The significance of adjuvant radiotherapy has been debated for many years, and the significance of aggressive surgery has not been reported.Methods: Medical records for DT patients were collected. KM analysis and the Mann–Whitney U-test were performed to evaluate the role of radiotherapy and aggressive surgery in the entire cohort and different subgroups.Results: Of 385 DT patients, 267 patients with R0 resection were included in the final analysis. A total of 53 patients (19.85%) experienced recurrence. Although radiotherapy showed no significant effect on recurrence-free survival (RFS) or time to recurrence (TTR) in the entire cohort, radiotherapy delayed recurrence in the age ≤ 30 years old subgroup (TTR = 35 months with surgery plus radiotherapy, TTR = 11 months with surgery alone; p = 0.014) and the tumor diameter >5 cm subgroup (TTR = 26 months with surgery plus radiotherapy, TTR = 11 months with surgery alone; p = 0.02) among patients with a single tumor. Aggressive surgery improved RFS in the tumor diameter >5 cm subgroup (p = 0.049) but not the entire cohort.Conclusions: Although radiotherapy cannot improve RFS, it can delay recurrence in the age ≤ 30 years old subgroup and the tumor diameter >5 cm subgroup among patients with a single tumor. For patients with large invasive tumors and multiple involved sites, aggressive surgery could be selected to achieve complete tumor resection to improve RFS.

Abstract Background Epidermal growth factor receptor (EGFR) and epidermal growth factor receptor pathway substrate 8 (Eps8) have been widely reported to be expressed in various tumors. Eps8 is an important active kinase substrate of EGFR that directly binds to the juxtamembrane (JXM) domain of EGFR to form an EGFR/Eps8 complex. The EGFR/Eps8 complex is involved in regulating cancer progression and might be an ideal target for antitumor therapy. This study focused on the screening of small-molecule inhibitors that target the EGFR/Eps8 complex in breast cancer and non-small cell lung cancer (NSCLC). Methods In silico virtual screening was used to identify small-molecule EGFR/Eps8 complex inhibitors. These compounds were screened for the inhibition of A549 and BT549 cell viability. The direct interaction between EGFR and Eps8 was measured using coimmunoprecipitation (CoIP) and JXM domain replacement assays. The antitumor effects of the inhibitors were analyzed in cancer cells and xenograft models. An acute toxicity study of EE02 was performed in a mouse model. In addition, the effect of the EE02 inhibitor on the protein expression of elements downstream of the EGFR/Eps8 complex was determined by western blotting and protein chip assays. Results In this study of nearly 390,000 compounds screened by virtual database screening, the top 29 compounds were identified as candidate small-molecule EGFR/Eps8 complex inhibitors and evaluated by using cell-based assays. The compound EE02 was identified as the best match to our selection criteria. Further investigation demonstrated that EE02 directly bound to the JXM domain of EGFR and disrupted EGFR/Eps8 complex formation. EE02 selectively suppressed growth and induced apoptosis in EGFR-positive and Eps8-positive breast cancer and NSCLC cells. More importantly, the PI3K/Akt/mTOR and MAPK/Erk pathways downstream of the EGFR/Eps8 complex were suppressed by EE02. In addition, the suppressive effect of EE02 on tumor growth in vivo was comparable to that of erlotinib at the same dose. Conclusions We identified EE02 as an EGFR/Eps8 complex inhibitor that demonstrated promising antitumor effects in breast cancer and NSCLC. Our data suggest that the EGFR/Eps8 complex offers a novel cancer drug target.

Cancer: Starving sarcomas into submission A drug that inhibits blood vessel growth offers a potentially promising treatment for a class of tumors with a poor prognosis. Sarcomas form in bone and connective tissue, and patients with advanced disease have a five-year survival rate of less than 10%. Researchers led by Jilong Yang of the Tainjin Medical University Cancer Institute & Hospital in China tested apatanib, a drug that starves tumors by preventing blood vessel development, in late-stage sarcoma patients. Strikingly, 15% of the patients experienced tumor reduction after treatment, and more than half overall achieved at least partial disease control. Adverse events were generally mild, but Yang and colleagues observed that patients who experienced certain side-effects achieved a greater survival benefit from treatment. These results support further investigation of this drug, and offer hints of possible biomarkers to predict response.

BackgroundSurgery is an important treatment option for desmoid tumor (DT) patients, but how to decrease and predict the high recurrence rate remains a major challenge.MethodsDesmoid tumor patients diagnosed and treated at Tianjin Cancer Institute & Hospital were included, and a web-based nomogram was constructed by screening the recurrence-related risk factors using Cox regression analysis. External validation was conducted with data from the Fudan University Shanghai Cancer Center.ResultsA total of 385 patients were identified. Finally, after excluding patients without surgery, patients who were lost to follow-up, and patients without complete resection, a total of 267 patients were included in the nomogram construction. Among these patients, 53 experienced recurrence, with a recurrence rate of 19.85%. The 3-year and 5-year recurrence-free survival (RFS) rates were 82.5% and 78%, respectively. Age, tumor diameter, admission status, location, and tumor number were correlated with recurrence in univariate Cox analysis. In multivariate Cox analysis, only age, tumor diameter and tumor number were independent risk factors for recurrence and were then used to construct a web-based nomogram to predict recurrence. The concordance index (C-index) of the nomogram was 0.718, and the areas under the curves (AUCs) of the 3-year and 5-year receiver operating characteristic (ROC) curves were 0.751 and 0.761, respectively. In the external validation set, the C-index was 0.706, and the AUCs of the 3-year and 5-year ROC curves are 0.788 and 0.794, respectively.ConclusionsAge, tumor diameter, and tumor number were independent predictors of recurrence for DTs, and a web-based nomogram containing these three predictors could accurately predict RFS (https://stepforward.shinyapps.io/Desmoidtumor/).

BackgroundThe administration of second- or third-generation anti-CD19 chimeric antigen receptor (CAR) T cells has remarkably improved the survival of patients with relapsed or refractory B cell malignancies. However, there are limited clinical results from fourth-generation CAR-T cell therapy, and the factors affecting response rate and survival have not been fully determined.MethodsLymphoma patients with progression or relapse after intensive treatments, including hematopoietic stem cell transplantation, and life expectancy >2 months were enrolled in the study. Peripheral lymphocytes were collected through apheresis, and magnetically selected T cells were lentivirally transduced with a 4th-generation CAR featuring an anti-CD19 CAR and the iCasp9 suicide switch (4SCAR19). The patients received 4SCAR19 T cell infusion after approximately seven days of expansion and a conditioning regimen comprising cyclophosphamide/fludarabine. The efficacy, safety, and risk factors were evaluated.ResultsA total of 21 patients with relapsed/refractory B cell non-Hodgkin lymphoma were enrolled and received 4SCAR19 T cell infusions at a median dose of 8.9×105 CAR-T cells/kg. The overall response rate was 67% [95% confidence interval (CI), 43 to 85], with 43% of patients achieving a complete response and 24% having a partial response. The overall and complete response rates were 58 and 33% in the diffuse large B-cell lymphoma (DLBCL) group and 78 and 56% in the non-DLBCL group, respectively. The median overall survival was 23.8 months (95% CI, not reached), with a median follow-up of 13.7 months. Factors affecting overall survival were International Prognostic Index (IPI), disease type, and remission status after CAR-T cell treatment. The most common adverse events of grade 3 or 4 during treatment were neutropenia (76%), leukopenia (71%), and thrombocytopenia (29%). The incidence of cytokine release syndrome (CRS) was 14%, and all cases were grade 1. One patient developed grade 3 neurotoxicity. No deaths were attributed to infusion of 4SCAR19 T cells, CRS, or neurotoxicity.ConclusionsIn this study, patients with relapsed or refractory B cell non-Hodgkin’s lymphoma who received 4SCAR19 T cell therapy had durable responses and few of adverse events. The IPI model is suitable for evaluating the prognosis of patients receiving CAR-T cell therapy.Trial registrationChinese Clinical Trial Registry (http://www.chictr.org.cn): ChiCTR-OOC-16007779.

Data presented in this article are supplementary materials to the research article entitled “IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway in malignant melanoma”. Data for melanoma patients who did not receive anti-PD-1 treatment were obtained from Tianjin Medical University Cancer Institute & Hospital from February 1981 to May 2013. Kaplan–Meier was used for survival analysis. RNA sequencing data from 28 melanoma patients receiving anti-PD-1 therapy were download from GEO database (GSE78220). Cluster analysis of RNA expression was performed using R (package pheatmap). The difference of PD-L1 expression was analysed by the Boxplot (R ggplot2 package). Differences between each group were analyzed by Fisher exact test. Information of 13 melanoma patients who had failed prior chemotherapy and treated in the Tianjin Medical University Cancer Institute & Hospital between July 2015 and December 2018 was collected. The response was captured by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1).

Background: There is no standard treatment for stage IV soft tissue sarcoma (STS) after the failure of Adriamycin-based chemotherapy. This phase II study (NCT03121846) assessed the efficacy and safety of apatinib (YN968D1), a new tyrosine kinase inhibitor that targets VEGFR-2, for patients with stage IV STS after chemotherapy failure. Methods: Forty-two subjects with stage IV STSs who had failed chemotherapy and who received Apatinib were recruited between September 2015 and February 2018. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the PFS rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Treatment-related adverse effects (AEs) were evaluated. Results: Forty-two subjects were evaluated for AEs and 38 subjects were evaluated for efficacy. At 12 weeks, the PFR, ORR, and DCR were 70%, 26.32% (10/38), and 86.84% (33/38), respectively. Regarding overall responses, the ORR and DCR were 23.68% (9/38) and 57.89% (22/38), respectively. The median PFS was 7.87 months, and the median overall survival (OS) was 17.55 months. The most common AEs included hypertension (n = 18, 42.86%), hand-foot-skin reaction (n = 15, 35.71%), apositia (n = 13, 30.95%), and proteinuria (n = 11, 26.19%). No subjects had grade 4 AEs and 11 subjects (26.19%) experienced grade 3 AEs, mainly hypertension, hand-foot-skin reaction, proteinuria, apositia, fatigue, pain, and dysgeusia. Notably, the subjects who experienced hypertension, hand-foot-skin reaction, or proteinuria had significantly longer OS than those without these AEs (P = 0.0003). Conclusion: With the largest Chinese STS cohort to date, we report that apatinib show good efficacy in advanced STS subjects with significant higher ORR and some adverse events may predict prognosis.

Abstract Histone acetylation and deacetylation are important epigenetic mechanisms that regulate gene expression and transcription. Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family that not only participates in histone acetylation and deacetylation but also targets several nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 (HSP90), to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. Furthermore, HDAC6 also upregulates several critical factors in the immune system, such as program death receptor-1 (PD-1) and program death receptor ligand-1 (PD-L1) receptor, which are the main targets for cancer immunotherapy. Several selective HDAC6 inhibitors are currently in clinical trials for cancer treatment and bring hope for patients with malignant tumors. A fuller understanding of HDAC6 as a critical regulator of many cellular pathways will help further the development of targeted anti-HDAC6 therapies. Here, we review the unique features of HDAC6 and its role in cancer, which make HDAC6 an appealing drug target.

Abstract Low-density lipoprotein receptor-related protein 1 (LRP1, also known as CD91), a multifunctional endocytic and cell signaling receptor, is widely expressed on the surface of multiple cell types such as hepatocytes, fibroblasts, neurons, astrocytes, macrophages, smooth muscle cells, and malignant cells. Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression. For example, LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase (MMP)-2 and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor, the serine/threonine protein kinase signaling pathway, and the expression of Caspase-3. LRP1-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion. In addition, LRP1 has been shown to be down-regulated by microRNA-205 and methylation of LRP1 CpG islands. Furthermore, a novel fusion gene, LRP1-SNRNP25, promotes osteosarcoma cell invasion and migration. Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.

Polyimide (PI) is a kind of polymer material with properties of high heat-resistance and good mechanical strength. As a special engineering material, it has been widely used in the fields of aviation, nanotechnology, etc. PI has been regarded as one of the most promising engineering plastics in the future. Therefore, further research must be made on its mechanical properties and machinability of the PI, especially in ultra-precision machining. In this paper, both of the mechanical properties and machinability have been studied respectively. Through the nanoindentation experiment, the nanoindentation hardness and elastic modulus of PI are analyzed. Also, the single point diamond turning (SPDT) experiment is conducted to show that the form accuracy and surface roughness of PI surface can reach a submicron degree in peak-to-valley (PV) and a nanometer scale in surface roughness (Ra) respectively. The results demonstrate that the PI possesses good mechanical properties and machinability.