Deep learning for the prediction of residual tumor after radiotherapy and treatment decision-making in patients with nasopharyngeal carcinoma based on magnetic resonance imaging.

Background: Concurrent chemoradiotherapy (CCRT) and induction chemotherapy (IC) plus CCRT (IC + CCRT) are the main treatments for patients with advanced nasopharyngeal carcinoma (NPC). We aimed to develop deep learning (DL) models using magnetic resonance (MR) imaging to predict the risk of residual tumor after each of the 2 treatments and to provide a reference for patients to select the best treatment option. Methods: A retrospective study was conducted on 424 patients with locoregionally advanced NPC who underwent CCRT or IC + CCRT between June 2012 and June 2019 in the Renmin Hospital of Wuhan University. According to the evaluation of MR images taken 3 to 6 months after radiotherapy, patients were divided into 2 categories: residual tumor and non-residual tumor. Transferred U-net and Deeplabv3 neural networks were trained, and the better-performance segmentation model was used to segment the tumor area on axial T1-weighted enhanced MR images. Then, 4 pretrained neural networks for prediction of residual tumors were trained with CCRT and IC + CCRT datasets, and the performances of the models trained using each image and each patient as a unit were evaluated. Patients in the test cohort of CCRT and IC + CCRT datasets were successively classified by the trained CCRT and IC + CCRT models. Model recommendations were formed according to the classification and compared with the treatment decisions of physicians. Results: The Dice coefficient of Deeplabv3 (0.752) was higher than that of U-net (0.689). The average area under the curve (aAUC) of the 4 networks was 0.728 for the CCRT and 0.828 for the IC + CCRT models trained using a single image as a unit, whereas the aAUC for models trained using each patient as a unit was 0.928 for the CCRT and 0.915 for the IC + CCRT models, respectively. The accuracy of the model recommendation and the decision of physicians was 84.06% and 60.00%, respectively. Conclusions: The proposed method can effectively predict the residual tumor status of patients after CCRT and IC + CCRT. Recommendations based on the model prediction results can protect some patients from receiving additional IC and improve the survival rate of patients with NPC.

The safety and efficacy of immunotherapy and palliative radiotherapy in patients with metastatic non-small cell lung cancer: a systematic review and meta-analysis of 13 prospective studies.

OBJECTIVE: Whether palliative RT (pRT) can influence the prognosis of mNSCLC patients who are treated with immune checkpoint inhibitors (ICIs) is still under debate. Therefore, we performed a systematic review and meta-analysis to evaluate the efficacy and safety of pRT plus ICIs in mNSCLC patients. METHODS: PubMed, Cochrane, and Embase databases were searched, and only prospective studies and randomized controlled trials (RCTs) were included. All data were analyzed with Stata 14.0 and Review Manager Version 5.4 software. RESULTS: A total of 13 studies were included. The combined ORRs for the ICIs group, cRT plus ICIs group, and SBRT plus ICIs group were 0.22 (95% CI: 1.27, 4.04), 0.26 (95% CI: 0.04, 0.49), and 0.29 (95% CI: 0.17, 0.40), respectively. And PFS were 2.21 (95% CI: 1.71, 2.70), 4.63 (95% CI: 2.16, 7.09), and 7.38 (95% CI: 2.16, 12.60) months, respectively. OS was 5.96 (95% CI: 3.85, 8.07), 9.04 (95% CI: 6.49, 11.59), and 7.96 (95% CI: 4.02, 11.91) months for the above groups, respectively. For safety terms, patients receiving ICIs plus SBRT had an incidence of 5% (95% CI: 2%, 9%) for pneumonia. CONCLUSION: Patients with mNSCLC may benefit from the combination of ICIs and pRT therapy, but these findings need further validation.

Nomogram model for predicting esophsagogastric varices in hepatocellular carcinoma with cirrhosis.

BACKGROUND/AIMS: The prognosis for hepatocellular carcinoma (HCC) with cirrhosis is poor. The risk of death also increases in patients with esophagogastric varices (EGV). Based on routine clinical features and related noninvasive parameters, a nomogram prediction model was developed in this study to facilitate the early identification of EGV in HCC patients. METHODS: A retrospective cohort analysis of patients with HCC in the Renmin Hospital of Wuhan University from 2020 to 2021 was performed. Clinical and noninvasive parameters closely related to EGV risk were screened by univariate and multivariate logistic regression analysis and integrated into a nomogram. The nomogram was validated internally and externally by calibration, receiver operating characteristic curve and decision curve analysis (DCA). RESULTS: A total of 165 patients with HCC-related cirrhosis were recruited. In the raining cohort, multivariate logistic regression analysis identified platelet (PLT) [odds ratio (OR), 0.950; 95% confidence interval (CI), 0.925-0.977; P < 0.001], D-dimer (OR. 3.341; 95% CI, 1.751-6.376, P < 0.001), spleen diameter (SD) (OR, 2.585; 95% CI, 1.547-4.318; P < 0.001) as independent indicators for EGV. The nomogram for predicting EGV risk was well calibrated with a favorable discriminative ability and an area under curve of 0.961. In addition, the nomogram showed better net benefits in the DCA. The results were validated in the validation cohort. CONCLUSIONS: The proposed nomogram model based on three indicators (PLT, D-dimer and SD) showed an excellent predictive effect, leading to the avoidance of unnecessary esophagogastroduodenoscopy.

TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells.

OBJECTIVE: Glioblastoma is one of the most common intracranial malignant tumors with an unfavorable prognosis, and iron metabolism as well as ferroptosis are implicated in the pathogenesis of glioblastoma. The present study aims to decipher the role and mechanisms of tripartite motif-containing protein 7 (TRIM7) in ferroptosis and glioblastoma progression. METHODS: Stable TRIM7-deficient or overexpressing human glioblastoma cells were generated with lentiviral vectors, and cell survival, lipid peroxidation and iron metabolism were evaluated. Immunoprecipitation, protein degradation and ubiquitination assays were performed to demonstrate the regulation of TRIM7 on its candidate proteins. RESULTS: TRIM7 expression was elevated in human glioblastoma cells and tissues. TRIM7 silence suppressed growth and induced death, while TRIM7 overexpression facilitated growth and inhibited death of human glioblastoma cells. Meanwhile, TRIM7-silenced cells exhibited increased iron accumulation, lipid peroxidation and ferroptosis, which were significantly reduced by TRIM7 overexpression. Mechanistically, TRIM7 directly bound to and ubiquitinated nuclear receptor coactivator 4 (NCOA4) using K48-linked chains, thereby reducing NCOA4-mediated ferritinophagy and ferroptosis of human glioblastoma cells. Moreover, we found that TRIM7 deletion sensitized human glioblastoma cells to temozolomide therapy. CONCLUSION: We for the first time demonstrate that TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells, and our findings provide a novel insight into the progression and treatment for human glioblastoma.

A core-shell liquid metal-Cu nanoparticle with glutathione consumption via an in situ replacement strategy for tumor combination treatment of chemodynamic, microwave dynamic and microwave thermal therapy.

The presence of high content glutathione (GSH) provides an effective "protective shield" for tumor cells, which undoubtedly is a huge impediment to reactive oxygen species (ROS)-based treatment. Fortunately, divalent copper (Cu2+) can not only consume GSH, destroying the protection mechanism of GSH, but also can be reduced to Cu+ with excellent Fenton-like reaction activity. Hence, capitalizing on the properties of liquid metals, we introduced Cu with three different valances via an in situ replacement reaction. A stable core-shell liquid-metal based "Cu storage pool" was obtained. It can effectively deplete GSH within the cells, and simultaneously produce ·OH through a Fenton-like reaction, further improving the effect of chemodynamic therapy (CDT). Under microwave irradiation, it is also capable of producing a large amount of ROS to promote tumor treatment. In addition, the loading of ionic liquid endows LZC@IL nanoparticles with certain microwave heating performance, which is able to augment microwave thermal therapy (MWTT). With the combination of CDT, microwave dynamic therapy (MDT) and MWTT, LZC@IL has an excellent effect on tumor elimination. This work offers a new idea for the application of liquid metals and the combined treatment of tumors, which has potential application value.

7,8-Dihydroxyflavone ameliorates mitochondrial impairment and motor dysfunction in the α-synuclein 1-103 transgenic mice.

Parkinson's disease (PD) is the most common motor-associated neurodegenerative disease. Although the pathogenesis of PD is still wrapped in the mist, accumulating evidence indicates that mitochondrial dysfunction contributes to the onset and progression of PD. We previously reported that the lysosomal protease asparagine endopeptidase (AEP) cleaves α-synuclein in the brains of PD patients. The major product, α-synuclein 1-103, significantly promotes PD-like histological changes and motor dysfunction. However, the underlying molecular mechanisms remain unknown. Here we show that α-synuclein 1-103 fragment interacts with mitochondria and induces morphological and functional abnormalities of mitochondria. Furthermore, we investigated the protective effects of 7,8-dihydroxyflavone (7,8-DHF) on mitochondrial dysfunction induced by α-synuclein 1-103 fragment. We found that 7,8-DHF ameliorated α-synuclein 1-103-induced mitochondrial impairment and motor dysfunction. These results indicate that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating PD.

Tumor-derived biomimetic nanozyme with immune evasion ability for synergistically enhanced low dose radiotherapy.

High doses of radiation can cause serious side effects and efficient radiosensitizers are urgently needed. To overcome this problem, we developed a biomimetic nanozyme system (CF) by coating pyrite (FeS2) into tumor-derived exosomes for enhanced low-dose radiotherapy (RT). CF system give FeS2 with immune escape and homologous targeting abilities. After administration, CF with both glutathione oxidase (GSH-OXD) and peroxidase (POD) activities can significantly lower the content of GSH in tumor tissues and catalyze intracellular hydrogen peroxide (H2O2) to produce a large amount of ·OH for intracellular redox homeostasis disruption and mitochondria destruction, thus reducing RT resistance. Experiments in vivo and in vitro showed that combining CF with RT (2 Gy) can provide a substantial suppression of tumor proliferation. This is the first attempt to use exosomes bionic FeS2 nanozyme for realizing low-dose RT, which broaden the prospects of nanozymes.

HMGB1 Promotes Resistance to Doxorubicin in Human Hepatocellular Carcinoma Cells by Inducing Autophagy via the AMPK/mTOR Signaling Pathway.

Chemoresistance remains as a major hindrance in the treatment of hepatocellular carcinoma (HCC). High mobility group box protein 1 (HMGB1) enhances autophagic flux and protects tumor cells from apoptosis, which results in acquired drug resistance. However, the exact mechanisms underlying HMGB1-modulated autophagy in HCC chemoresistance remain to be defined. In the present study, we found that administration of doxorubicin (DOX) significantly promoted HMGB1 expression and induced HMGB1 cytoplasmic translocation in human HCC cell lines BEL7402 and SMMC7721, which enhanced autophagy that contributes to protecting HCC cells from apoptosis and increasing drug resistance. Moreover, we observed HMGB1 translocation and elevation of autophagy in DOX-resistant BEL7402 and SMMC7721 cells. Additionally, inhibition of HMGB1 and autophagy increased the sensitivities of BEL-7402 and SMMC-7721 cells to DOX and re-sensitized their DOX-resistant cells. Subsequently, we confirmed with HMGB1 regulated autophagy by activating the 5' adenosine monophosphate-activated protein kinase (AMPK)/mTOR pathway. In summary, our results indicate that HMGB1 promotes acquired DOX resistance in DOX-treated BEL7402 and SMMC7721 cells by enhancing autophagy through the AMPK/mTOR signaling pathway. These findings provide the proof-of-concept that HMGB1 inhibitors might be an important targeted treatment strategy for HCC.

A Preliminary Study of the Complement Component 1q Levels in Predicting the Efficacy of Combined Immunotherapy in Patients with Lung Cancer.

OBJECTIVE: To evaluate the value of serum complement component 1q (C1q) levels in predicting the efficacy of combined immunotherapy in patients with lung cancer. METHODS: A total of 42 patients with lung cancer who received combined immunotherapy in the cancer center of Renmin Hospital of Wuhan University were included in this study. The clinical data of serum C1q and lactate dehydrogenase (LDH) levels before and three weeks after immunotherapy were collected. RESULTS: Response evaluation showed that the number of patients with complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) was 0 (0%), 26 (61.9%), 14 (33.3%), and 2 (4.8%), respectively. The CR/PR group (patients with CR or PR) showed higher pC1q (C1q level before immunotherapy) and iC1q (C1q level 3 weeks after immunotherapy) than the SD/PD group (patients with SD or PD). The LDH reduction (96.2%) and C1q increment (84.6%) in the CR/PR group 3 weeks after immunotherapy were higher than those of the SD/PD group, and the differences were statistically significant. Logistic regression analysis indicated that pC1q, iC1q, and LDH level trends 3 weeks after the treatment were significantly correlated to the efficacy of combined immunotherapy with odds ratios of 8.185, 5.500, and 0.031, respectively. CONCLUSION: High C1q levels before immunotherapy and increased C1q levels and decreased LDH levels 3 weeks afterward suggest good therapeutic effects of combined immunotherapy in patients with lung cancer. Serum C1q levels have certain clinical significance in predicting the efficacy of combined immunotherapy.

Potential predictors for survival in hepatocellular carcinoma patients treated with immune checkpoint inhibitors: A meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICI) are increasingly used in hepatocellular carcinoma (HCC) trials. However, the correlations between early endpoints, such as progression free survival (PFS), objective response rate (ORR), and disease control rate (DCR), and overall survival (OS) are unclear. In this study, the correlations between OS and other early endpoints were evaluated in HCC patients who received ICI. METHODS: Pubmed and Embase were searched to October 2020. Clinical studies evaluating efficacy and outcomes of HCC patients treated with ICI were included. ORR, DCR, PFS and OS were extracted from individual studies. The Spearman's rank correlation coefficient and linear regression model were used to assess the correlation. RESULTS: 74 studies involving 9001 HCC cases were included. For HCC patients treated with ICI, the pooled ORR and DCR were 16% (95% CI: 14-18%) and 52% (95% CI: 47-57%), and the median PFS and OS were 3.75 (95% CI: 2.88-4.90) months, and 13.20 (95% CI: 11.88-14.82) months, retrospectively. The correlation between ORR, DCR, PFS and OS were 0.35 (R2 = 0.21, p < 0.05), 0.43 (R2 = 0.18, p < 0.05), and 0.50 (R2 = 0.33, p < 0.05), respectively. Further, the association between PFS and OS of the combination strategy showed a better correlation (rs = 0.79, R2 = 0.75, p < 0.05). CONCLUSION: These results suggest that PFS could be potential surrogates for OS, especially PFS for patients who treated with ICI combination regimen.

Inhibition of miR-128-3p Attenuated Doxorubicin-Triggered Acute Cardiac Injury in Mice by the Regulation of PPAR-γ.

BACKGROUND: The clinical usefulness of doxorubicin (DOX), an anthracycline with antitumor activity, is limited by its cardiotoxicity. Oxidative stress and myocardial apoptosis were closely associated with DOX-induced cardiac dysfunction. It has been reported that microRNA-128-3p (miR-128-3p) was involved into the regulation of redox balance. However, the role of miR-128-3p in DOX-related cardiac injury remains not yet understood. The aim of this study was to investigate the biological effect of miR-128-3p in DOX-induced cardiotoxicity. METHODS: To induce DOX-related acute cardiac injury, mice were subjected to a single injection of DOX. Inhibition of myocardial miR-128-3p was achieved by an adeno-associated virus (AAV9) system carrying a miR-128-3p sponge. RESULTS: The data in our study indicated that miR-128-3p was upregulated in DOX-treated hearts and cardiomyocytes. Inhibition of miR-128-3p attenuated DOX-related cardiac injury and improved cardiac function in mice. Moreover, miR-128-3p inhibition could suppress myocardial inflammatory response, oxidative damage, and cell apoptotic death in DOX-treated mice. Further analysis showed that miR-128-3p could directly target peroxisome proliferator-activated receptor γ (PPAR-γ) and decrease PPAR-γ expression. Moreover, the protective effects provided by miR-128-3p inhibition were abolished by a PPAR-γ antagonist in vivo and in vitro. CONCLUSIONS: miR-128-3p inhibition attenuated DOX-related acute cardiac injury via the regulation of PPAR-γ in mice.

Amphiphysin I cleavage by asparagine endopeptidase leads to tau hyperphosphorylation and synaptic dysfunction.

Neurofibrillary tangles composed of hyperphosphorylated tau and synaptic dysfunction are characteristics of Alzheimer's disease (AD). However, the underlying molecular mechanisms remain poorly understood. Here, we identified Amphiphysin I mediates both tau phosphorylation and synaptic dysfunction in AD. Amphiphysin I is cleaved by a cysteine proteinase asparagine endopeptidase (AEP) at N278 in the brains of AD patients. The amount of AEP-generated N-terminal fragment of Amphiphysin I (1-278) is increased with aging. Amphiphysin I (1-278) inhibits clathrin-mediated endocytosis and induces synaptic dysfunction. Furthermore, Amphiphysin I (1-278) binds p35 and promotes its transition to p25, thus activates CDK5 and enhances tau hyperphosphorylation. Overexpression of Amphiphysin I (1-278) in the hippocampus of Tau P301S mice induces synaptic dysfunction, tau hyperphosphorylation, and cognitive deficits. However, overexpression of the N278A mutant Amphiphysin I, which resists the AEP-mediated cleavage, alleviates the pathological and behavioral defects. These findings suggest a mechanism of tau hyperphosphorylation and synaptic dysfunction in AD.

Protective Effects of Oroxylin A against Doxorubicin-Induced Cardiotoxicity via the Activation of Sirt1 in Mice.

Doxorubicin- (DOX-) related cardiac injury impairs the life quality of patients with cancer. This largely limited the clinical use of DOX. It is of great significance to find a novel strategy to reduce DOX-related cardiac injury. Oroxylin A (OA) has been identified to exert beneficial effects against inflammatory diseases and cancers. Here, we investigated whether OA could attenuate DOX-induced acute cardiotoxicity in mice. A single dose of DOX was used to induce acute cardiac injury in mice. To explore the protective effects, OA was administered to mice for ten days beginning from five days before DOX injection. The data in our study indicated that OA inhibited DOX-induced heart weight loss, reduction in cardiac function, and the elevation in myocardial injury markers. DOX injection resulted in increased oxidative damage, inflammation accumulation, and myocardial apoptosis in vivo and in vitro, and these pathological alterations were alleviated by treatment of OA. OA activated the sirtuin 1 (Sirt1) signaling pathway via the cAMP/protein kinase A, and its protective effects were blocked by Sirt1 deficiency. OA treatment did not affect the tumor-killing action of DOX in tumor-bearing mice. In conclusion, OA protected against DOX-related acute cardiac injury via the regulation of Sirt1.

MicroRNA-223-3p Protect Against Radiation-Induced Cardiac Toxicity by Alleviating Myocardial Oxidative Stress and Programmed Cell Death via Targeting the AMPK Pathway.

Objectives: Radiotherapy improves the survival rate of cancer patients, yet it also involves some inevitable complications. Radiation-induced heart disease (RIHD) is one of the most serious complications, especially the radiotherapy of thoracic tumors, which is characterized by cardiac oxidative stress disorder and programmed cell death. At present, there is no effective treatment strategy for RIHD; in addition, it cannot be reversed when it progresses. This study aims to explore the role and potential mechanism of microRNA-223-3p (miR-223-3p) in RIHD. Methods: Mice were injected with miR-223-3p mimic, inhibitor, or their respective controls in the tail vein and received a single dose of 20 Gy whole-heart irradiation (WHI) for 16 weeks after 3 days to construct a RIHD mouse model. To inhibit adenosine monophosphate activated protein kinase (AMPK) or phosphodiesterase 4D (PDE4D), compound C (CompC) and AAV9-shPDE4D were used. Results: WHI treatment significantly inhibited the expression of miR-223-3p in the hearts; furthermore, the levels of miR-223-3p decreased in a radiation time-dependent manner. miR-223-3p mimic significantly relieved, while miR-223-3p inhibitor aggravated apoptosis, oxidative damage, and cardiac dysfunction in RIHD mice. In addition, we found that miR-223-3p mimic improves WHI-induced myocardial injury by activating AMPK and that the inhibition of AMPK by CompC completely blocks these protective effects of miR-223-3p mimic. Further studies found that miR-223-3p lowers the protein levels of PDE4D and inhibiting PDE4D by AAV9-shPDE4D blocks the WHI-induced myocardial injury mediated by miR-223-3p inhibitor. Conclusion: miR-223-3p ameliorates WHI-induced RIHD through anti-oxidant and anti-programmed cell death mechanisms via activating AMPK by PDE4D regulation. miR-223-3p mimic exhibits potential value in the treatment of RIHD.

Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Pathologically, PD is characterized by the formation of Lewy bodies (LBs) in the brain, which mainly comprises phosphorylated and aggregated α-synuclein (α-syn). The aberrant aggregation of α-syn is believed to play a key role in the pathogenesis of PD. While α-syn expression can be reduced by antisense oligonucleotides (ASOs), the challenge to deliver ASOs safely and effectively into the neurons remains unresolved. Here, we developed a safe and highly effective ASO delivery method by using exosomes. We first identified the ASO sequence that selectively reduced α-syn expression: ASO4. Exosome-mediated delivery of ASO4 (exo-ASO4) showed high cellular uptake and low toxicity in primary neuronal cultures. Exo-ASO4 also significantly attenuated α-syn aggregation induced by pre-formed α-syn fibrils in vitro. Exo-ASO4 intracerebroventricular injection into the brains of α-syn A53T mice, a transgenic model of PD, significantly decreased the expression of α-syn and attenuated its aggregation. Furthermore, exo-ASO4 ameliorated the degeneration of dopaminergic neurons in these mice. Finally, the α-syn A53T mice showed significantly improved locomotor functions after exo-ASO4 injection. Overall, this study demonstrates that exosome-mediated ASO4 delivery may be an effective treatment option for PD.

Cofilin 1 promotes the aggregation and cell-to-cell transmission of α-synuclein in Parkinson's disease.

The histopathological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is the major component. Converging evidence supports the prion-like transmission of α-synuclein aggregates in the onset and progression of PD. Intracellular α-synuclein aggregates into pathological fibrils, which can be transferred from aggregate-producing cells to aggregate-free cells, triggering neuronal injury and the progression of pathology. However, the specific mechanisms mediating the aggregation and transmission of pathological α-synuclein remain unknown. Here we show that cofilin 1 binds to α-synuclein and promotes its aggregation. The mixed fibrils consist of cofilin 1 and α-synuclein are more compact and more potent than pure α-synuclein fibrils in seeding α-synuclein aggregation. Cofilin 1 also facilitates the uptake of α-synuclein fibrils and finally induces neuronal dysfunction. Together, these observations indicate that cofilin 1 acts as a crucial mediator in the aggregation and propagation of pathological α-synuclein, contributing to the pathogenesis of PD.

Immune checkpoint modulators in cancer immunotherapy: Recent advances and combination rationales.

As a new hallmark of cancer, immune surveillance evading plays a critical role in carcinogenesis. Through modulating the immune checkpoints, immune cells in tumor microenvironment can be harnessed to battle cancer cells. In recent years, the administration of anti-CTLA or/and anti-PD-1/L1 antibody has exhibited unexpected antitumor effect in multiple types of cancer, motivating the researchers to find more potential immune checkpoints as clinical targets. A wealth of clinical trials have been done to evaluate the safety and efficacy of monotherapy or combination therapy with immune checkpoint modulators. However, there still exist problems such as low response rate and adverse events in the clinical, which in turn leads us to the basic study. The better understanding of the crosstalk between the immune cells and the cancer cells within the microenvironment may inspire us new ideas for cancer treatment. In this review, we mainly summarize the recent advances in application of immune checkpoint modulators and the combination rationales, and discuss the problems existing in the precision therapy with immune checkpoint modulators.

Hepatitis B virus X protein-induced SH2 domain-containing 5 (SH2D5) expression promotes hepatoma cell growth via an SH2D5-transketolase interaction.

Hepatitis B virus X protein (HBx) critically contributes to the development of hepatocellular carcinoma (HCC). However, the mechanisms by which HBx promotes HCC remain unclear. In the present study, using a combination of gene expression profiling and immunohistochemistry, we found higher levels of SH2 domain-containing 5 (SH2D5) in liver tissue from HBV-associated HCC (HBV-HCC) patients than in adjacent nontumor tissues. Moreover, HBV infection elevated SH2D5 levels, and we observed that HBx plays an important role in SH2D5 induction. We also found that HBx triggers SH2D5 expression through the NF-κB and c-Jun kinase pathways. Employing SH2D5 overexpression or knockdown, we further demonstrate that SH2D5 promotes HCC cell proliferation both in vitro and in vivo While investigating the mechanism of SH2D5-mediated stimulation of HCC cell proliferation, we noted that HBV induces SH2D5 binding to transketolase (TKT), a pentose phosphate pathway enzyme, thereby promoting an interaction between and signal transducer and activator of transcription 3 (STAT3). Furthermore, HBx stimulated STAT3 phosphorylation at Tyr-705 and promoted the activity and downstream signaling pathway of STAT3 via the SH2D5-TKT interaction. Taken together, our results suggest that SH2D5 is an HBV-induced protein capable of binding to TKT, leading to induction of HCC cell proliferation.

Bevacizumab improves survival in metastatic colorectal cancer patients with primary tumor resection: A meta-analysis.

It is not well determined whether primary tumor resection is associated with better outcomes in metastatic colorectal cancer (mCRC) patients treated with bevacizumab. In this meta-analysis, we aimed to assess the prognostic role of primary tumor resection in mCRC treated with bevacizumab. Electronic databases including the Cochrane library, Embase, and Pubmed were searched until April 2018. Clinical studies assessing the influence of primary tumor resection on the efficacy of bevacizumab in patients with mCRC were identified. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). Seven studies including 2760 mCRC patients were finally included. The results of the meta-analysis were in favor of bevacizumab to patients with resected primary tumor in terms of OS (HR = 0.50, 95%CI: 0.39-0.64; p < 0.01), and PFS (HR = 0.65, 95%CI: 0.51-0.81; p < 0.01). Administration of bevacizumab in mCRC patients with resected primary tumor had a better OS (HR = 0.65, 95%CI: 0.56-0.74; p < 0.01), when compared to chemotherapy(CT). Adding bevacizumab to mCRC patients without resection of primary tumor also had a better OS (HR = 0.78, 95%CI: 0.65-0.94; p < 0.01) and PFS (HR = 0.71, 95%CI: 0.57-0.88; p < 0.01) compared to chemotherapy alone. In conclusion, mCRC patients with resected primary tumor have better survival than those without surgery of primary tumor when treated with bevacizumab. Primary tumor resection status should be taken into consideration when using bevacizumab in mCRC.

Global microarray profiling identified hsa_circ_0064428 as a potential immune-associated prognosis biomarker for hepatocellular carcinoma.

BACKGROUND: Increasing evidence has shown that circular RNAs (circRNAs) are involved tumourigenesis and metastasis of hepatocellular carcinoma (HCC); however, progression about its function in HCC is relatively slow. Here, we aimed to investigate whether plasma circRNAs could reflect the tumour-infiltrating lymphocytes (TILs) in HCC tumour tissues and serve as prognosis biomarker for HCC. METHODS: Tissue samples of patients with HCC were subjected to immunohistochemistry staining against CD8 to examine the TILs. Then, we investigated the expression profile of circRNAs by microarray between plasma of patients with HCC with high TILs and low TILs, and the differentially expressed circRNAs were validated with qRT-PCR. Statistical analysis was performed with SPSS software and GraphPad Prism. RESULTS: We have demonstrated that patients with HCC with high TILs exhibit a significant better overall survival, suggesting clinical outcome could be predicted by TILs. Global circRNA microarray between plasma of patients with HCC with high TILs and low TILs successfully identified six differentially expressed novel circRNAs. Among them, the expression of hsa_circ_0064428 was significantly reduced in patients with HCC with high TILs but increased in patients with low TILs. Moreover, hsa_circ_0064428 was negatively correlated with patient's survival, tumour size and metastasis. CONCLUSION: These findings together imply that hsa_circ_0064428 could be considered as a potential HCC prognosis biomarker. Future in-depth research is required to further illustrate the involvement of hsa_circ_0064428 in HCC tumourigenesis and metastasis.