PTPLAD1 Regulates PHB-Raf Interaction to Orchestrate Epithelial-Mesenchymal and Mitofusion-Fission Transitions in Colorectal Cancer.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The poor prognosis of this malignancy is attributed mainly to the persistent activation of cancer signaling for metastasis. Here, we showed that protein tyrosine phosphatase-like A domain containing 1 (PTPLAD1) is down-regulated in highly metastatic CRC cells and negatively associated with poor survival of CRC patients. Systematic analysis reveals that epithelial-to-mesenchymal transition (EMT) and mitochondrial fusion-to-fission (MFT) transition are two critical features for CRC patients with low expression of PTPLAD1. PTPLAD1 overexpression suppresses the metastasis of CRC in vivo and in vitro by inhibiting the Raf/ERK signaling-mediated EMT and mitofission. Mechanically, PTPLAD1 binds with PHB via its middle fragment (141-178 amino acids) and induces dephosphorylation of PHB-Y259 to disrupt the interaction of PHB-Raf, resulting in the inactivation of Raf/ERK signaling. Our results unveil a novel mechanism in which Raf/ERK signaling activated in metastatic CRC induces EMT and mitochondrial fission simultaneously, which can be suppressed by PTPLAD1. This finding may provide a new paradigm for developing more effective treatment strategies for CRC.

New findings in prognostic factor assessment for adenocarcinoma of transverse colon: a comparison study between competing-risk and COX regression analysis.

Purpose: Competing-risk analysis was used to accurately assess prognostic factors for cancer-specific death in patients with adenocarcinoma of transverse colon (ATC), and the results were compared with those from a conventional Cox regression analysis. Materials and Methods: Patients diagnosed with ATC between 2000 and 2019 were selected from the Surveillance, Epidemiology, and End Results database. The crude mortality rates of patients with ATC were calculated and their differences were tested using the Gray's test, respectively. In performing multivariate analysis, the Cox regression model and the subdistribution hazard function (SD) in competing risk analysis were utilized, respectively. Results: This study included 21,477 eligible patients. The SD model indicated that age, etc. are actual independent prognostic factors. In contrast to previous recognition, the results of the Cox regression showed false-positives for sex and Carcinoembryonic antigen, and underestimated point-estimates in the stage and American Joint Committee on Cancer stage due to competing events. A detailed comparison of treatment revealed that the larger surgical scopes were prognostic risk factors compared with the smaller scope of local tumor excision, partial colectomy, or segmental resection. Patients treated with external proton beam radiotherapy had an increased risk compared with those with no radiotherapy and internal radiotherapy. Conclusions: After comparing the results of the two methods and mitigating the significant bias introduced by Cox regression, we found independent factors that really affect the prognosis of ATC. On the other hand, in terms of ATC, a larger surgical scope and external proton beam radiotherapy may not improve the long-term survival of patients. Therefore, when faced with ATC patients, these differences should be noted and treated differently from common colorectal cancer patients. Thus, clinicians are able to give more targeted treatment plans and prognostic assessments.

Age-related decline in hippocampal tyrosine phosphatase PTPRO is a mechanistic factor in chemotherapy-related cognitive impairment.

Chemotherapy-related cognitive impairment (CRCI) or "chemo brain" is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro-/- female mice with doxorubicin (DOX) because Ptpro-/- female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that SRC and EPHA4 are highly phosphorylated/activated in the hippocampi of Ptpro-/- female mice, with increased sensitivity to DOX-induced CRCI. On the other hand, restoration of PTPRO in the hippocampal CA3 region significantly ameliorate CRCI in Ptpro-/- female mice. In addition, we found that the plant alkaloid berberine (BBR) is capable of ameliorating CRCI in aged female mice by upregulating hippocampal PTPRO. Mechanistically, BBR upregulates PTPRO by downregulating miR-25-3p, which directly targeted PTPRO. These findings collectively demonstrate the protective role of hippocampal PTPRO against CRCI.

Tumor neoantigens: Novel strategies for application of cancer immunotherapy.

Neoantigen-targeted immunotherapy is a rapidly advancing field that holds great promise for treating cancer. The recognition of antigens by immune cells is a crucial step in tumor-specific killing, and neoantigens generated by mutations in cancer cells possess high immunogenicity and are selectively expressed in tumor cells, making them an attractive therapeutic target. Currently, neoantigens find utility in various domains, primarily in the realm of neoantigen vaccines such as DC vaccines, nucleic acid vaccines, and synthetic long peptide vaccines. Additionally, they hold promise in adoptive cell therapy, encompassing tumor-infiltrating cells, T cell receptors, and chimeric antigen receptors which are expressed by genetically modified T cells. In this review, we summarized recent progress in the clinical use of tumor vaccines and adoptive cell therapy targeting neoantigens, discussed the potential of neoantigen burden as an immune checkpoint in clinical settings. With the aid of state-of-the-art sequencing and bioinformatics technologies, together with significant advancements in artificial intelligence, we anticipated that neoantigens will be fully exploited for personalized tumor immunotherapy, from screening to clinical application.

Prediction of death probability in adenocarcinoma of the transverse colon: competing-risk nomograms based on 21,469 patients.

PURPOSE: Tumors in parts of the colon other than the transverse colon have been well studied, but little is known about adenocarcinoma of the transverse colon (ATC).The aim of this study was to construct nomograms using competing-risk model for accurately predicting the probability of cancer-specific and non-cancer-specific death in patients with ATC. METHODS: Data on eligible patients recorded during 2000-2019 in the Surveillance, Epidemiology, and End Results database were extracted and screened. Factors that influencing prognosis were screened for death from ATC (DATC) and death from other causes (DOC) using competing-risk analysis, including univariate and multivariate analyses based on Gray's test and the Fine-Gray model, respectively. Independent prognostic factors were identified and nomograms were constructed. For comparison, we also constructed a Cox model and an AJCC stage-only competing-risk model (AJCC model) for patients with DATC. Performance evaluations of the nomograms and comparison between the models were performed using calibration plots, Harrell's concordance index (C-index), receiver operating characteristic (ROC) curves, and the areas under the ROC curve (AUCs). The nomograms and models were validated using a validation cohort. The net reclassification index, integrated discrimination improvement, decision curves, and risk stratification were not assessed because no accepted methods were suited for competing-risk model. RESULTS: This study included 21,469 patients with ATC, and 17 and 9 independent influencing factors were identified for the construction of DATC nomograms (DATCN) and DOC nomograms (DOCN), respectively. In both the training and validation cohorts, the calibration curves indicated good agreement between the nomogram-based predictions and the actual observations in the two nomograms, respectively. The C-index of the DATCN was higher than 80% (80.3-83.3%) at 1, 3 and 5 years in both the training and validation cohorts, significantly outperforming the AJCC (76.7-78%) and Cox (75.4-79.5%) model. The C-index of the DOCN was also higher than 69% (69.0-73.6%). In terms of ROC curves at each time point, those of the DATCN were very close to the upper-left corner of the coordinate axis in both the training and validation cohorts, and their AUCs were larger than 84% (84.2-85.4%).The AUCs of the AJCC (78.4-81.1%) and Cox (79.4-81.5%) models were significantly lower (p < 0.05), and the curves were closer to the diagonal. The ROC curves of the DOCN was similar to those of the DATCN, and the AUCs were 68.5-74%. The DATCN and DOCN therefore had good consistency, accuracy, and stability, respectively. CONCLUSION: This study was the first to construct competing-risk nomograms for ATC. These nomograms have proved useful for accurately assessing patient prognoses and allowing more-individualized follow-up strategies, thereby reducing the mortality.

PTPRO suppresses lymph node metastasis of esophageal carcinoma by dephosphorylating MET.

Protein tyrosine phosphatase receptor-type O (PTPRO) is a membrane-bound tyrosine phosphatase. Notably, epigenetically silenced PTPRO due to promoter hypermethylation is frequently linked to malignancies. In this study, we used cellular and animal models, and patient samples to demonstrate that PTPRO can suppress the metastasis of esophageal squamous cell carcinoma (ESCC). Mechanistically, PTPRO can inhibit MET-mediated metastasis by dephosphorylating Y1234/1235 in the kinase activation loop of MET. Patients with PTPROlow/p-METhigh had significantly poor prognosis, suggesting that PTPROlow/p-METhigh can serve as an independent prognostic factor for patients with ESCC.

USP12 promotes nonsmall cell lung cancer progression through deubiquitinating and stabilizing RRM2.

RRM2 is the catalytic subunit of ribonucleotide reductase (RNR), which catalyzes de novo synthesis of deoxyribonucleotide triphosphates (dNTPs) and plays critical roles in cancer cell proliferation. RRM2 protein level is controlled by ubiquitination mediated protein degradation system; however, its deubiquitinase has not been identified yet. Here we showed that ubiquitin-specific peptidase 12 (USP12) directly interacts with and deubiquitinates RRM2 in non-small cell lung cancer (NSCLC) cells. Knockdown of USP12 causes DNA replication stress and retards tumor growth in vivo and in vitro. Meanwhile, USP12 protein levels were positively correlated to RRM2 protein levels in human NSCLC tissues. In addition, high expression of USP12 was associated with poor prognosis in NSCLC patients. Therefore, our study reveals that USP12 is a RRM2 regulator and targeting USP12 could be considered as a potential therapeutical strategy for NSCLC treatment.

CYP1B1 inhibits ferroptosis and induces anti-PD-1 resistance by degrading ACSL4 in colorectal cancer.

Immune checkpoint blockade (ICB) is a promising treatment strategy for colorectal cancer (CRC) patients. However, most CRC patients do not response well to ICB therapy. Increasing evidence indicates that ferroptosis plays a critical role in immunotherapy. ICB efficacy may be enhanced by inducing tumor ferroptosis. Cytochrome P450 1B1 (CYP1B1) is a metabolic enzyme that participates in arachidonic acid metabolism. However, the role of CYP1B1 in ferroptosis remains unclear. In this study, we demonstrated that CYP1B1 derived 20-HETE activated the protein kinase C pathway to increase FBXO10 expression, which in turn promoted the ubiquitination and degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4), ultimately inducing tumor cells resistance to ferroptosis. Furthermore, inhibiting CYP1B1 sensitized tumor cells to anti-PD-1 antibody in a mouce model. In addition, CYP1B1 expression was negatively correlated with ACSL4 expression, and high expression indicates poor prognosis in CRC. Taken together, our work identified CYP1B1 as a potential biomarker for enhancing anti-PD-1 therapy in CRC.

Targeting LAYN inhibits colorectal cancer metastasis and tumor-associated macrophage infiltration induced by hyaluronan oligosaccharides.

The accumulation of hyaluronan oligosaccharides (oHA) in colorectal cancer (CRC) is closely related to tumor metastasis, but the underlying mechanism remains unclear. In this study, we first described that LAYN, a novel HA receptor, was upregulated in CRC tissue. Aberrant LAYN expression correlated with CRC metastasis and poor prognosis and positively correlated with tumor-associated macrophage (TAM) infiltration and M2 macrophage polarization in the tumor environment. Both in vitro and in vivo studies demonstrated that LAYN is activated by oHA and subsequently induces CRC metastasis and macrophage infiltration. Mechanistic studies demonstrated that oHA activates LAYN by binding to the 60-68th amino acid region of the extracellular segment. oHA-induced LAYN activation promoted metastasis and CCL20 secretion through the NF-kB pathway in CRC cells. Furthermore, targeting LAYN using a blocking antibody prevented oHA-mediated tumor metastasis, TAM infiltration and M2 polarization. This study revealed the LAYN activation mechanism and identified a potential target for the treatment of CRC tumor exhibiting high oHA levels.

High endothelial venules proportion in tertiary lymphoid structure is a prognostic marker and correlated with anti-tumor immune microenvironment in colorectal cancer.

BACKGROUND: High endothelial venules (HEV) and tertiary lymphoid structures (TLS) are associated with clinical outcomes of patients with colorectal cancer (CRC). However, because HEV are components of TLS, there have been few studies of the role of the HEV proportion in TLS (HEV/TLS). This study investigated the role of the HEV/TLS and its relationship with the tumor immune microenvironment in CRC. METHODS: A retrospective analysis of 203 cases of tissue pathologically diagnosed as CRC after general surgery was performed at the First Affiliated Hospital of Jinan University from January 2014 to July 2017. Paraffin sections were obtained from the paracancerous intestinal mucosal tissues. The area of HEV and TLS and immune cells were detected by immunohistochemistry. We further divided the positive HEV expression group into the high HEV/TLS group and the low HEV/TLS group by the average area of HEV/TLS. After grouping, the data were also analyzed using the chi-square test, Kaplan-Meier method, and univariate and multivariate Cox proportional risk regression analyses. A correlation analysis of the HEV/TLS and immune cells as well as angiogenesis was performed. RESULTS: Patients with a high HEV/TLS in CRC tissue were associated with longer OS, DFS and lower TNM stage. Meanwhile, CRC tissue with a high HEV/TLS showed a greater ability to recruit the CD3+ T cells, CD8+ T cells and M1 macrophages and correlated with less angiogenesis. Conclusively, high HEV/TLS links to the favorable prognosis of CRC patients and correlated with anti-tumor immune microenvironment, which can be a potential biomarker for prognosis of CRC patients. CONCLUSION: A high HEV/TLS is associated with a favorable prognosis for CRC and is correlated with the anti-tumor immune microenvironment. Therefore, it is a potential biomarker of the CRC prognosis.KEY MESSAGESHigh HEV/TLS is associated with a favorable prognosis for CRC.High HEV/TLS correlated with the anti-tumor immune microenvironment of CRC and can serve as a novel prognostic biomarker.

Efficacy and Safety of Hyaluronic Acid Intra-articular Injection after Arthroscopic Knee Surgery: A Systematic Review and Meta-analysis.

OBJECTIVE: Hyaluronic acid (HA) intra-articular injection after arthroscopic knee surgery has been widely applied but its efficacy and safety remain controversial. The aim of this systematic review is to analyze the efficacy and safety of HA intra-articular injection after arthroscopic knee surgery, and to compare the efficacy of HA with different molecular weights. METHODS: We conducted a systematic literature search in PubMed, Embase, Google scholar and the Cochrane library from inception to 16 September 2022 for English-written articles, in order to identify randomized controlled trials that evaluated the clinical efficacy and/or safety of HA intra-articular injection after arthroscopic knee surgery. Then we meta-analyzed the outcomes of patients given intra-articular HA injections postoperatively and control patients. We also evaluated the influence of HA with different molecular weights. In every calculation, sensitive analysis was performed. The visual analogue scale (VAS) for pain, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and adverse events were selected as the primary outcome measurements, while Lysholm, International Knee Documentation Committee (IKDC) and Tegner score were selected as the secondary outcome measurements. Publication bias of every outcome was evaluated using egger test. RESULTS: Fifteen studies involving 951 knees were included and 12 of them were used to performed the meta-analysis. The results showed no significant difference between the HA group and control group according to VAS, whether assessed at less (P = 0.90) or more than 6 months (P = 0.55). Besides, there were no statistical differences between the HA group and control group according to subgroup analysis (Ps = 0.77, 0.91 and 0.81 in anterior cruciate ligament reconstruction, meniscectomy and overall groups, respectively). Compared to control group, the overall effect of WOMAC score showed no significant differences (P = 0.25), nor did in two subgroups (P = 0.37 and P = 0.22). Outcomes measured by Lysholm (P = 0.13), IKDC (P = 0.86) and Tegner (P = 0.42) scores showed no significant differences, either. The analysis of the risk of adverse events indicated no increase in HA groups (P = 0.06). We found no significant differences between high- and low-molecular-weight HA at 6 (P = 0.96) or 12 months (P = 0.93) postoperatively. Two studies failed to pass the sensitive analysis and the reasons were discussed detailly and acceptable publication bias was observed. CONCLUSIONS: Although HA injection after arthroscopic knee surgery is safe, the available evidence does not support its efficacy in pain relief and functional recovery. Therefore, the application of HA injection after arthroscopic knee surgery is not recommended.

Targeting ARF1-IQGAP1 interaction to suppress colorectal cancer metastasis and vemurafenib resistance.

INTRODUCTION: Acquired resistance to BRAF inhibitor vemurafenib is frequently observed in metastatic colorectal cancer (CRC), and it is a thorny issue that results in treatment failure. As adaptive responses for vemurafenib treatment, a series of cellular bypasses are response for the adaptive feedback reactivation of ERK signaling, which warrant further investigation. OBJECTIVES: We identified ARF1 (ADP-ribosylation factor 1) as a novel regulator of both vemurafenib resistance and cancer metastasis, its molecular mechanism and potential inhibitor were investigated in this study. METHODS: DIA-based quantitative proteomics and RNA-seq were performed to systematic analyze the profiling of vemurafenib-resistant RKO cells (RKO-VR) and highly invasive RKO cells (RKO-I8), respectively. Co­immunoprecipitation assay was performed to detect the interaction of ARF1 and IQGAP1 (IQ-domain GTPase activating protein 1). An ELISA-based drug screen system on FDA-approved drug library was established to screen the compounds against the interaction of ARF1-IQGAP1.The biological functions of ARF1 and LY2835219 were determined by transwell, western blotting, Annexin V-FITC/PI staining and in vivo experimental metastasis assays. RESULTS: We found that ARF1 strongly interacted with IQGAP1 to activate ERK signaling in VR and I8 CRC cells. Deletion of IQGAP1 or inactivation of ARF1 (ARF-T48S) restored the invasive ability induced by ARF1. As ARF1-IQGAP1 interaction is essential for ERK activation, we screened LY2835219 as novel inhibitor of ARF1-IQGAP1 interaction, which inactivated ERK signaling and suppressed CRC metastasis and vemurafenib-resistance in vitro and in vivo with no observed side effect. Furthermore, LY2835219 in combined treatment with vemurafenib exerted significantly inhibitory effect on ARF1-mediated cancer metastasis than used independently. CONCLUSION: This study uncovers that ARF1-IQGAP1 interaction-mediated ERK signaling reactivation is critical for vemurafenib resistance and cancer metastasis, and that LY2835219 is a promising therapeutic agent for CRC both as a single agent and in combination with vemurafenib.

A five-protein prognostic signature with GBP2 functioning in immune cell infiltration of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is of poor clinical outcomes, and currently lacks reliable prognostic biomarkers. By analyzing the datasets of the Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we established a five-protein prognostic signature containing GBP2, HLA-DRA, ISG15, ISG20 and ITGAX. Our data indicate that this signature was closely correlated with advanced stage, higher pathological grade, and unfavorable survivals in patients with ccRCC. We further functionally characterized GBP2. Overexpression of GBP2 enhanced the phosphorylation of STAT2 and STAT3 to trigger JAK-STAT signaling and promote cell migration and invasion in ccRCC. Treatment of Ruxolitinib, a specific inhibitor of JAK/STAT, attenuated the GBP2-mediated phenotypes. Patients with high GBP2 expression were accompanied with more infiltration of immune cells positively stained with CD3, CD8, CD68, and immune checkpoint markers PD-1 and CTLA4, which was validated by Opal multiplex immunohistochemistry in ccRCC tissues. More CD8 + T cells and CD68 + macrophages were observed in patients expressing high GBP2. Taken together, a five-protein prognostic signature was constructed in our study. GBP2 has an oncogenic role via modulating JAK-STAT signaling and tumor immune infiltration, and thus may serve as a potential therapeutic target in ccRCC.

PADI1 and Its Co-Expressed Gene Signature Unveil Colorectal Cancer Prognosis and Immunotherapy Efficacy.

Peptidyl arginine deiminase 1 (PADI1) catalyzes protein citrullination and has a role in regulating immune responses. The tumor immune microenvironment has been reported to be important in colorectal cancer (CRC), which was correlated with the ability of CRC patients to benefit from immunotherapy. However, there is a lack of molecular markers for matching CRC immunotherapy. Previously, single-gene risk models have only considered the effect of individual genes on intrinsic tumor properties, ignoring the role of genes and their co-expressed genes as a whole. In this study, we analyzed the differential expression of PADI1 in colorectal cancer (CRC). We found that PADI1 was highly expressed in CRC. Subgroup survival analysis revealed a prognostic survival difference for PADI1 in CRC patients aged less than 65 years, male, T stage, N0, M0, and stage I-II (p < 0.05). In addition, we analyzed the functions and signaling pathways associated with PADI1 in CRC and found that it was highly enriched in several immune-related functions and pathways. Then, a set of PADI1 co-expressed genes (PCGs) risk-prognosis scores was developed with PADI1 as the core, which could accurately predict the prognosis of CRC (p < 0.05). PCGs risk score can be an independent prognostic factor for CRC. A new set of Norman plot models were developed for clinical characteristics with age, sex, and TNM stage, which can accurately predict CRC 1, 3, and 5 years survival, and calibration curves and decision curve analysis (DCA) validated the accuracy of the models. The risk score assessed the immune microenvironment of CRC and found that the immune score was higher in the low-risk group, and CD4+ T cells, helper T cells, and eosinophils were more infiltrated in the low-risk group (p < 0.05). Immunotherapy efficacy was better in the low-risk group (p < 0.05). The underlying mechanism may be that the high-risk group of PCGs was enriched in some pathways that promote immune escape and immune dysfunction. In conclusion, PCGs may better predict CRC prognosis and immunotherapeutic response.

Endostatin induces normalization of blood vessels in colorectal cancer and promotes infiltration of CD8+ T cells to improve anti-PD-L1 immunotherapy.

Introduction: The purpose of this study was to evaluate recombinant human endostatin (rHE)-induced normalization of the tumor vasculature in colorectal cancer (CRC) and to evaluate the therapeutic effects of combined treatment with rHE and a programmed death ligand-1 (PD-L1) inhibitor. Methods: A mouse subcutaneous tumorigenesis model was established to evaluate the antitumor effects of endostatin combined with a PD-L1 inhibitor on CRC. Intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DW MRI) was used to evaluate changes in the intratumor microcirculation in response to combined treatment with endostatin and a PD-L1 inhibitor. The infiltration density and function of CD8+ T cells in tumors were evaluated using flow cytometry. Finally, clinical specimens were used to evaluate the expression area of tumor vascular pericytes and CD8+ T cells in tumor tissues. Results: The antitumor effects of endostatin combined with a PD-L1 inhibitor were significantly greater than those of endostatin or a PD-L1 inhibitor alone. On the ninth day of intervention, the endostatin group showed significantly higher pseudo diffusion parameter (D*) and microvascular volume fraction (F) values in tumors than those in the control group or PD-L1 group. After 27 days of intervention, the endostatin groups showed significantly lower levels of vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-ß than those in the control group. Treatment of CD8+ T cells with endostatin for 24 h did not alter the expression levels of markers of reduced T-cell activity. However, endostatin reversed the VEGF-mediated inhibition of the secretion of interferon (IFN)-γ from T cells. The results in CRC clinical samples showed that treatment with endostatin induced significantly higher infiltration of CD8+ T cells compared with treatment that did not include endostatin. Furthermore, the expression area of pericytes was significantly positively related to the infiltration density of CD8+ T cells and overall survival time. Conclusion: Endostatin improved the antitumor effects of PD-L1 inhibitors on CRC, significantly increased the activity of CD8+ T cells, and synergistically improved the tumor treatment effect of the two inhibitors.

Case report: The MSI-L/p-MMR metastatic rectal cancer patient who failed systemic therapy responds to anti-PD-1 immunotherapy after stereotactic body radiation-therapy.

Background: Traditionally, patients with microsatellite stability (MSS)/microsatellite instability-Low (MSI-L)/proficient mismatch repair (p-MMR) metastatic colorectal cancer (mCRC) have had poor benefit from immunotherapy. Therefore, how to enhance the response of immunotherapy is still a challenge for MSS/MSI-L/p-MMR CRC patient. Case presentation: We report a special case of a rectal cancer patient with programmed death-ligand 1 (PD-L1) negative expression, MSI-L/p-MMR, tumor mutational burden-low (TMB-L) and liver metastases, who partial response (PR) to immunotherapy after systemic therapy failure including chemotherapy, anti-angiogenesis therapy and stereotactic body radiation-therapy (SBRT). The computed tomography (CT) results showed that among three liver metastases had been reduction or disappearance after Tislelizumab treatment for three times. Besides, the carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) decrease and maintained at a low level for 3 months. The progression-free survival (PFS) of patient has exceeded 3 months. Conclusions: This case indicates that the patient with MSI-L/p-MMR mCRC can respond to anti-PD-1 immunotherapy after systemic therapy. And the SBRT (targeting liver metastases) may a method for increase-sensitivity of immunotherapy in CRC patients with MSI-L/p-MMR.

Neoantigen-based cancer vaccination using chimeric RNA-loaded dendritic cell-derived extracellular vesicles.

Cancer vaccines critically rely on the availability of targetable immunogenic cancer-specific neoepitopes. However, mutation-based immunogenic neoantigens are rare or even non-existent in subgroups of cancer types. To address this issue, we exploited a cancer-specific aberrant transcription-induced chimeric RNA, designated A-Pas chiRNA, as a possible source of clinically relevant and targetable neoantigens. A-Pas chiRNA encodes a recently discovered cancer-specific chimeric protein that comprises full-length astrotactin-2 (ASTN2) C-terminally fused in-frame to the antisense sequence of the 18th intron of pregnancy-associated plasma protein-A (PAPPA). We used extracellular vesicles (EVs) from A-Pas chiRNA-transfected dendritic cells (DCs) to produce the cell-free anticancer vaccine DEXA-P . Treatment of immunocompetent cancer-bearing mice with DEXA-P inhibited tumour growth and prolonged animal survival. In summary, we demonstrate for the first time that cancer-specific transcription-induced chimeric RNAs can be exploited to produce a cell-free cancer vaccine that induces potent CD8+ T cell-mediated anticancer immunity. Our novel approach may be particularly useful for developing cancer vaccines to treat malignancies with low mutational burden or without mutation-based antigens. Moreover, this cell-free anticancer vaccine approach may offer several practical advantages over cell-based vaccines, such as ease of scalability and genetic modifiability as well as enhanced shelf life.

Tyrosine Phosphatase PTPRO Deficiency in ERBB2-Positive Breast Cancer Contributes to Poor Prognosis and Lapatinib Resistance.

Despite the initial benefit from treating ERBB2-positive breast cancer with tyrosine kinase inhibitor lapatinib, resistance develops inevitably. Since the expression of protein tyrosine phosphatase receptor-type O (PTPRO), a member of the R3 subfamily of receptor protein tyrosine phosphatases (PTPs), is inversely correlated with the aggressiveness of multiple malignancies, we decided to explore the correlation between PTPRO and lapatinib resistance in ERBB2-positive breast cancer. Results of immunohistochemical (IHC) staining and the correlation analysis between the expression levels of PTPRO and the clinicopathological parameters indicate that PTPRO is downregulated in cancer tissues as compared with normal tissues and negatively associated with differentiation, tumor size, tumor depth, as well as the expression of ERBB2 and Ki67. Results from Kaplan-Meier analyses indicate that lower expression of PTPRO is correlated with shorter relapse-free survival for patients with ERBB2-positive breast cancer, and multivariable Cox regression analysis found that PTPRO can potentially serve as an independent prognostic indicator for ERBB2-positive breast cancer. Results from both human breast cancer cells with PTPRO knockdown or overexpression and mouse embryonic fibroblasts (MEFs) which derived from Ptpro +/+ and Ptpro -/- mice with then stably transfected plasmid FUGW-Erbb2 consistently demonstrated the essentiality of PTPRO in the lapatinib-mediated anticancer process. Our findings suggest that PTPRO is not only able to serve as an independent prognostic indicator, but upregulating PTPRO can also reverse the lapatinib resistance of ERBB2-positive breast cancer.

Multiple accounting and driving factors of water resources use: A case study of Shanghai.

Previous research papers on urban water resources accounting were confined to the perspectives of production and consumption, ignoring the perspective of income. This paper proposes a systems framework to analyze the income, production, and consumption-based water uses and underlying driving forces of a city based on the methods of multi-scale input-output analysis and structural decomposition analysis. A case study is performed for Shanghai as a megacity. The results show that the income, production and consumption-based water uses of Shanghai had decreased from 5.70 billion m3, 10.85 billion m3 and 28.45 billion m3 in 2007 to 2.80 billion m3, 6.20 billion m3 and 24.10 billion m3 in 2017, respectively. Domestic imported primary inputs had emerged as an important virtual water supplier of Shanghai and its share of total supply-side water use had increased from 23.92% in 2007 to 42.95% in 2017. Meanwhile, about 46% and 40% of Shanghai's total consumption-based water use had been imported from other Chinese regions and foreign countries in 2017, respectively. It is revealed that trade played an important role in relieving water use pressure in Shanghai. The factors that had increased the uses of water resources in Shanghai include population, per capita value-added, per capita output, final consumption structure, and per capita final consumption. The factors that had reduced the water uses in Shanghai include technology, value added mix, output structure, value added structure, domestic import, commodity mix, and foreign import. It is suggested that in addition to curbing urban water use from the production side, more targeted water-saving measures should be devised from the supply (e.g., restricting loan to heavy water-consuming enterprises) and consumption sides (e.g., encouraging residents to buy low-water products).

Thrombospondin-2 holds prognostic value and is associated with metastasis and the mismatch repair process in gastric cancer.

BACKGROUND: This study aims to investigate thrombospondin 2 (TSP2) expression levels in gastric cancer (GC) and determine the relationship between TSP2 and clinical characteristics and prognosis. METHODS: The online database Gene Expression Profile Interactive Analysis (GEPIA) was used to analyse TSP2 mRNA expression levels in GC. The Kaplan-Meier plotter prognostic analysis tool was used to evaluate the influence of TSP2 expression on clinical prognosis in GC patients. TSP2 expression levels were analysed in paraffin-embedded GC samples and adjacent normal tissues by immunohistochemistry. The relationship between the clinicopathological characteristics and prognosis of GC patients was assessed. Transwell experiments were used to evaluate the effect of TSP2 on HGC27 and AGS cell invasion and migration. The EdU experiment was used to detect the effect of transfection of TSP2 on cell proliferation, and the flow cytometry experiment was used to detect the effect of TSP2 on cell apoptosis and the cell growth cycle. Western blotting (Wb) technology was used to detect MMP, E-cadherin, N-cadherin, Vimentin, Snail, AKT, PI3K, and VEGF protein expression in HGC27 cells. RESULTS: Compared with normal tissues, TSP2 mRNA expression in GC was significantly upregulated and was closely related to the clinical stage of GC. High TSP2 expression significantly affected the OS, FP and PPS of patients with GC. Among these patients, TSP2 expression levels did not affect the prognosis of patients with GC in the N0 subgroup but significantly affected the prognosis of patients with GC in the N (1 + 2 + 3) subgroup. TSP2 protein expression levels were significantly higher in GC tissue compared with normal tissues (P < 0.01). The overall survival (OS) and relapse-free survival (RFS) of patients with high TSP2 expression were lower than those of patients with low TSP2 expression. Cells transfected with the TSP2-silencing sequence exhibited increased apoptosis and inhibition of proliferation, migration and invasion. AKT and PI3K expression in cells was significantly downregulated (P < 0.01). AKT, PI3K and VEGF expression in cells transfected with the TSP2 silencing sequence was significantly reduced. Proliferation, migration, invasion ability, and TSP2 expression levels significantly correlated with mismatch repair genes, such as PMS2, MSH6, MSH2, and MLH1 (P < 0.05). CONCLUSION: TSP2 expression is significantly increased in GC. TSP2 expression is closely related to metastasis and the mismatch repair process in GC patients and affects GC patient prognosis. The mechanism may involve regulating gastric cancer cell proliferation and migration by modulating the VEGF/PI3K/AKT signalling pathway. TSP2 is a potential marker and therapeutic target for the prognosis of GC patients.