KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC.

Immunotherapy has become a prominent first-line cancer treatment strategy. In non-small cell lung cancer (NSCLC), the expression of PD-L1 induces an immuno-suppressive effect to protect cancer cells from immune elimination, which designates PD-L1 as an important target for immunotherapy. However, little is known about the regulation mechanism and the function of PD-L1 in lung cancer. In this study, we have discovered that KEAP1 serves as an E3 ligase to promote PD-L1 ubiquitination and degradation. We found that overexpression of KEAP1 suppressed tumor growth and promoted cytotoxic T-cell activation in vivo. These results indicate the important role of KEAP1 in anti-cancer immunity. Moreover, the combination of elevated KEAP1 expression with anti-PD-L1 immunotherapy resulted in a synergistic effect on both tumor growth and cytotoxic T-cell activation. Additionally, we found that the expressions of KEAP1 and PD-L1 were associated with NSCLC prognosis. In summary, our findings shed light on the mechanism of PD-L1 degradation and how NSCLC immune escape through KEAP1-PD-L1 signaling. Our results also suggest that KEAP1 agonist might be a potential clinical drug to boost anti-tumor immunity and improve immunotherapies in NSCLC.

Integrin signaling in cancer: bidirectional mechanisms and therapeutic opportunities.

Integrins are transmembrane receptors that possess distinct ligand-binding specificities in the extracellular domain and signaling properties in the cytoplasmic domain. While most integrins have a short cytoplasmic tail, integrin ß4 has a long cytoplasmic tail that can indirectly interact with the actin cytoskeleton. Additionally, 'inside-out' signals can induce integrins to adopt a high-affinity extended conformation for their appropriate ligands. These properties enable integrins to transmit bidirectional cellular signals, making it a critical regulator of various biological processes.Integrin expression and function are tightly linked to various aspects of tumor progression, including initiation, angiogenesis, cell motility, invasion, and metastasis. Certain integrins have been shown to drive tumorigenesis or amplify oncogenic signals by interacting with corresponding receptors, while others have marginal or even suppressive effects. Additionally, different α/ß subtypes of integrins can exhibit opposite effects. Integrin-mediated signaling pathways including Ras- and Rho-GTPase, TGFß, Hippo, Wnt, Notch, and sonic hedgehog (Shh) are involved in various stages of tumorigenesis. Therefore, understanding the complex regulatory mechanisms and molecular specificities of integrins are crucial to delaying cancer progression and suppressing tumorigenesis. Furthermore, the development of integrin-based therapeutics for cancer are of great importance.This review provides an overview of integrin-dependent bidirectional signaling mechanisms in cancer that can either support or oppose tumorigenesis by interacting with various signaling pathways. Finally, we focus on the future opportunities for emergent therapeutics based on integrin agonists. Video Abstract.

Biological function, regulatory mechanism, and clinical application of mannose in cancer.

Studies examining the regulatory roles and clinical applications of monosaccharides other than glucose in cancer have been neglected. Mannose, a common type of monosaccharide found in human body fluids and tissues, primarily functions in protein glycosylation rather than carbohydrate metabolism. Recent research has demonstrated direct anticancer effects of mannose in vitro and in vivo. Simply supplementing cell culture medium or drinking water with mannose achieved these effects. Moreover, mannose enhances the effectiveness of current cancer treatments including chemotherapy, radiotherapy, targeted therapy, and immune therapy. Besides the advancements in basic research on the anticancer effects of mannose, recent studies have reported its application as a biomarker for cancer or in the delivery of anticancer drugs using mannose-modified drug delivery systems. This review discusses the progress made in understanding the regulatory roles of mannose in cancer progression, the mechanisms underlying its anticancer effects, and its current application in cancer diagnosis and treatment.

Danhong Injection Up-regulates miR-125b in Endothelial Exosomes and Attenuates Apoptosis in Post-Infarction Myocardium.

OBJECTIVE: To investigate the involvement of endothelial cells (ECs)-derived exosomes in the anti-apoptotic effect of Danhong Injection (DHI) and the mechanism of DHI-induced exosomal protection against postinfarction myocardial apoptosis. METHODS: A mouse permanent myocardial infarction (MI) model was established, followed by a 14-day daily treatment with DHI, DHI plus GW4869 (an exosomal inhibitor), or saline. Phosphate-buffered saline (PBS)-induced ECs-derived exosomes were isolated, analyzed by miRNA microarray and validated by droplet digital polymerase chain reaction (ddPCR). The exosomes induced by DHI (DHI-exo), PBS (PBS-exo), or DHI+GW4869 (GW-exo) were isolated and injected into the peri-infarct zone following MI. The protective effects of DHI and DHI-exo on MI hearts were measured by echocardiography, Masson's trichrome staining, and TUNEL apoptosis assay. The Western blotting and quantitative reverse transcription PCR (qRT-PCR) were used to evaluate the expression levels of miR-125b/p53-mediated pathway components, including miR-125b, p53, Bak, Bax, and caspase-3 activities. RESULTS: DHI significantly improved cardiac function and reduced infarct size in MI mice (P<0.01), which was abolished by the GW4869 intervention. DHI promoted the exosomal secretion in ECs (P<0.01). According to the results of exosomal miRNA microarray assay, 30 differentially expressed miRNAs in the DHI-exo were identified (28 up-regulated miRNAs and 2 down-regulated miRNAs). Among them, DHI significantly elevated miR-125b level in DHI-exo and DHI-treated ECs, a recognized apoptotic inhibitor impeding p53 signaling (P<0.05). Remarkably, treatment with DHI and DHI-exo attenuated apoptosis, elevated miR-125b expression level, inhibited capsase-3 activity, and down-regulated the expression levels of proapoptotic effectors (p53, Bak, and Bax) in post-MI hearts, whereas these effects were blocked by GW4869 (P<0.05 or P<0.01). CONCLUSION: DHI and DHI-induced exosomes inhibited apoptosis, promoted the miR-125b expression level, and regulated the p53 apoptotic pathway in post-infarction myocardium.

Multidirectional characterization of cellular composition and spatial architecture in human multiple primary lung cancers.

Multiple primary lung cancers (MPLCs) pose diagnostic and therapeutic challenges in clinic. Here, we orchestrated the cellular and spatial architecture of MPLCs by combining single-cell RNA-sequencing and spatial transcriptomics. Notably, we identified a previously undescribed sub-population of epithelial cells termed as CLDN2+ alveolar type II (AT2) which was specifically enriched in MPLCs. This subtype was observed to possess a relatively stationary state, play a critical role in cellular communication, aggregate spatially in tumor tissues, and dominate the malignant histopathological patterns. The CLDN2 protein expression can help distinguish MPLCs from intrapulmonary metastasis and solitary lung cancer. Moreover, a cell surface receptor-TNFRSF18/GITR was highly expressed in T cells of MPLCs, suggesting TNFRSF18 as one potential immunotherapeutic target in MPLCs. Meanwhile, high inter-lesion heterogeneity was observed in MPLCs. These findings will provide insights into diagnostic biomarkers and therapeutic targets and advance our understanding of the cellular and spatial architecture of MPLCs.

Efficacy and safety of esophagectomy via left thoracic approach versus via right thoracic approach for middle and lower thoracic esophageal cancer: a multicenter randomized clinical trial (NST1501).

Background: Left thoracic approach (LTA) has been a favorable selection in surgical treatment for esophageal cancer (EC) patients in China before minimally invasive esophagectomy (MIE) is popular. This study aimed to demonstrate whether right thoracic approach (RTA) is superior to LTA in the surgical treatment of middle and lower thoracic esophageal squamous cell carcinoma (TESCC). Methods: Superiority clinical trial design was used for this multicenter randomized controlled two-parallel group study. Between April 2015 and December 2018, cT1b-3N0-1M0 TESCC patients from 14 centers were recruited and randomized by a central stratified block randomization program into LTA or RTA groups. All enrolled patients were followed up every three months after surgery. The software SPSS 20.0 and R 3.6.2. were used for statistical analysis. Efficacy and safety outcomes, 3-year overall survival (OS) and disease-free survival (DFS) were calculated and compared using the Kaplan-Meier method and the log-rank test. Results: A total of 861 patients without suspected upper mediastinal lymph nodes (umLN) were finally enrolled in the study after 95 ineligible patients were excluded. 833 cases (98.7%) were successfully followed up until June 1, 2020. Esophagectomies were performed via LTA in 453 cases, and via RTA in 408 cases. Compared with the LTA group, the RTA group required longer operating time (274.48±78.92 vs. 205.34±51.47 min, P<0.001); had more complications (33.8% vs. 26.3% P=0.016); harvested more lymph nodes (LNs) (23.61±10.09 vs. 21.92±10.26, P=0.015); achieved a significantly improved OS in stage IIIa patients (67.8% vs. 51.8%, P=0.022). The 3-year OS and DFS were 68.7% and 64.3% in LTA arm versus 71.3% and 63.7% in RTA arm (P=0.20; P=0.96). Conclusions: Esophagectomies via both LTA and RTA can achieve similar outcomes in middle or lower TESCC patients without suspected umLN. RTA is superior to LTA and recommended for the surgical treatment of more advanced stage TESCC due to more complete lymphadenectomy. Trial Registration: ClinicalTrials.gov NCT02448979.

[Outcome indicators in randomized controlled trials on traditional Chinese medicine intervention of sepsis-induced myocardial injury in recent five years].

This study aims to analyze the outcome indicators of randomized controlled trial(RCT) on traditional Chinese medicine(TCM) intervention of sepsis-induced myocardial injury(SIMI) in recent five years, which is expected to lay a basis for the construction of core outcome set(COS) for this disease treated by TCM. To be specific, RCT on the treatment of SIMI with TCM was retrieved from 4 Chinese databases, 3 English databases, and 2 clinical trial protocol registries. The quality of the included studies was evaluated with Cochrane risk-of-bias(ROB) tool, and the outcome indicators were analyzed. Finally, 42 RCTs were included, of which 2 were clinical trial registration schemes. The study found that 42 RCTs had a high risk of bias, and reported a total of 86 indicators in "clinical effective rate, disease severity, TCM syndrome score, inflammation, myocardium, cardiac structure and hemodynamics, electrocardiogram, immunology, metabolism and liver and kidney function, and safety". Outcome indicators on myocardium had the highest emergence frequency, followed by indicators on the cardiac structure and hemodynamics. A total of 8 RCTs reported TCM syndrome scores. Further analysis suggested the following problems in the selection of outcome indicators in the RCTs on TCM intervention of SIMI: no classification of primary and secondary indicators, disregard of endpoint indicators, irrational selection of alternative indicators, neglection of TCM characteristics, no assessment of patients' immune status, and no emphasis on economic indicators and safety indicators. Therefore, according to the recommendations of the core outcome measures in effectiveness trials(COMET) working group, a COS for TCM intervention of TCM for SIMI should be developed, so as to facilitate clinical researchers to select appropriate outcome indicators, the combination of conclusions of similar clinical studies, and the promotion of TCM interventions.

Traditional Chinese medicine injections with activating blood circulation, equivalent effect of anticoagulation or antiplatelet, for acute myocardial infarction: A protocol for the systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: In spite of a growing number in the use of percutaneous coronary intervention (PCI) in China, the mortality of acute myocardial infarction (AMI) has not decreased. Traditional Chinese medicine injections for Activating Blood Circulation (TCMi-ABC), equivalent effect of anticoagulation or antiplatelet, are widely used in China; however, the improvement of fatality towards AMI is unclear. Therefore, we intend to conduct a systematic review and meta-analysis to evaluate the efficacy and safety of TCMi-ABC in treatment with AMI. METHODS: Based on the "National Medical Products Administration of China," TCMi-ABC with AMI treatment indication will be selected, including Danhong injection, Sodium Tanshinone IIA Sulfonate injection, Danshen Chuanxiongqin injection, and Puerarin injection. Randomized controlled studies will be searched from as follows: PubMed, Embase, the CENTRAL in Cochrane Library, Chinese Biomedical Literature Database (SinoMed), China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wanfang Data Knowledge Service Platform. Two researchers will work independently on literature selection, data extraction, and quality assessment. The outcomes focus on the effects of TCMi-ABC on fatality of patients with AMI in hospitalization and in the long term, the incidence of malignant arrhythmia, left ventricular ejection fraction, and adverse events. RevMan 5.4.1 software was used for mate analysis. RESULTS: This study will conduct a comprehensive literature search and provide a systematic synthesis of current published data to explore the efficacy and safety of TCMi-ABC for AMI. CONCLUSION: This study will provide high-quality evidence for treatment of AMI with TCMi-ABC in terms of efficacy and safety, which may help clinicians make a better complementary treatment schedule of patients with AMI.

A randomized, placebo-controlled, double-blind trial to evaluate efficacy and safety of Shen-Yuan-Dan capsules, a traditional Chinese medicine, for treatment of peri-procedure myocardial injury following percutaneous coronary intervention.

BACKGROUND: Peri-procedural myocardial injury (PMI) is a common complication of percutaneous coronary intervention (PCI), which cannot be entirely avoided using available treatments. The findings of earlier research have shown that Shen-Yuan-Dan (SYD) capsules, a traditional Chinese medicine, can potentially alleviating PMI. This study aimed to confirm further this hypothesis in a rigorous, well-designed randomized controlled study. METHODS: Our clinical trial was randomized, double-blinded, and placebo-controlled. A total of 181 patients with unstable angina (UA) undergoing elective PCI were randomized to pretreatment with SYD or a placebo under the basis of conventional treatment; 87 patients were pretreated with SYD (4 capsules, 3 times a day, with a further 4 capsules 2 h before PCI) 3 days before the procedure, and 94 patients were given a placebo. No patients received reloading statins before PCI, and SYD or placebo was maintained for 1 month after PCI. The primary endpoint was the incidence of PMI. The secondary endpoint was calculating the incidence rate of all 30-day major adverse cardiovascular events (all-cause mortality, non-fatal myocardial infarction, unplanned revascularization). The safety outcomes, including abnormalities in electrocardiogram and serum biochemical examinations caused by drug use, were also tested. RESULTS: The levels of creatine kinase-myocardial band (CK-MB) in both the SYD and placebo groups were increased at 4 h and 24 h after PCI compared with before the procedure (P < 0.05). The incidence rate of PMI in the SYD group (10.3 %) was lower than that in the placebo group (34 %) (absolute difference, 23.7 % [95 % CI, 11.7-34.8 %], P < 0.01). After taking SYD, the relative risk reduction (RRR) and absolute risk reduction (ARR) were 69.7 % and 24.3 %, respectively; further, number needed to treat (NNT) was 4.2. The 30-day major adverse cardiovascular event (MACE) rate was not statistically different between the SYD and placebo groups (6.9 % vs. 9.6 %, P = 0.352). There were no abnormal situations during the trial. CONCLUSION: These findings showed that pretreatment with SYD could safely reduce the incidence rate of PMI in patients with UA undergoing elective PCI. Further study on the effects of SYD and how it can improve adverse cardiovascular events outcomes is needed.

Clinical Characteristics and Risk Factors of Periprocedural Myocardial Injury in Patients with Elective PCI in a TCM Hospital.

Objective: To investigate the clinical characteristics of patients with unstable angina (UA) who received elective percutaneous coronary intervention (PCI) in a traditional Chinese medicine (TCM) hospital and to analyze the related risk factors of periprocedural myocardial injury (PMI). Methods: On the basis of cross-sectional investigation, the case-control method was adopted. We retrospectively collected clinical data of patients with UA who successfully received elective PCI in Beijing Hospital of TCM from February 2017 to February 2019. Based on the occurrence of PMI, the case-control was formed. The influence of related factors on PMI occurrence was analyzed using the logistic multiple regression equation based on the parameters between the comparison groups. Results: 1. Incidence of PMI and related clinical features: Of the 265 UA patients, the incidence of PMI was 26.4%, nearly one quarter (23.4%) had old myocardial infarction, nearly half (45.3%) had previously received coronary intervention. The prevalence of patients with previous hypertension (75.8%), type 2 diabetes (57%), and high-low-density lipoprotein cholesterolemia (69.3%) exceeded 50%, more than 50% of the patients have triple-vessel disease (50.2%). 2. Features of TCM syndrome elements: The main TCM syndromes of the investigated patients are blood stasis syndrome (81.1%) and Qi deficiency syndrome (77.3%), the others include Phlegm turbidity syndrome (53.2%), Yang deficiency syndrome (50.9%), Yin deficiency syndrome (50.1%), Qi stagnation syndrome (30.1%), and coagulated cold syndrome (17.1%). 3. Factors of PMI occurrence: According to the occurrence of PMI, 265 patients were divided into PMI group (n = 70) and non-PMI group (n = 195). The comparison between groups shows that the preoperative SYNTAX score, the number of stents, and the total length of stents of the patients in the PMI group were higher than those in the non-PMI group (P < 0.05); the patients in the PMI group treated by Shen-Yuan-Dan (SYD), a Chinese medicine prescription with Qi-supplementing and blood stasis-purging, were significantly lower than those in the non-PMI group (P < 0.05). Brought these four factors (preoperative SYNTAX score, number of stents implanted, total length of implanted stents, and treated by SYD) into the binary logistic regression equation, those who were only treated by SYD have statistical significance in the equation as a protective factor (OR 0.327, 95% CI 0.117-0.916, P=0.033). Conclusion: Patients with UA who received elective PCI in TCM institutions may have clinical characteristics including multiple accompanying diseases and high stenosis coronary artery, in which the incidence of poor blood glucose control and high rate of three-vessel coronary disease are particularly significant. The TCM syndromes are mainly Qi deficiency and blood stasis syndromes. The decrease of PMI may be attributed to the application of SYD in the real world. This trial is registered at ChiCTR2100043465.

Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial.

Platinum-based chemotherapy is the standard first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). In this phase 3 study (ClinicalTrial.gov: NCT03829969), 514 patients with treatment-naïve advanced ESCC were randomized (1:1) to receive toripalimab or placebo in combination with paclitaxel plus cisplatin (TP) every 3 weeks for up to 6 cycles, followed by toripalimab or placebo maintenance. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS is observed for the toripalimab arm over the placebo arm (hazard ratio [HR] = 0.58; 95% CI, 0.46-0.74; p < 0.0001). The prespecified interim analysis of overall survival (OS) also reveals a significant OS improvement for patients treated with toripalimab plus TP over placebo plus TP (HR = 0.58; 95% CI, 0.43-0.78; p = 0.0004). The incidences of grade ≥3 treatment-emergent adverse events are similar between the two arms. Toripalimab plus TP significantly improves PFS and OS in patients with treatment-naïve, advanced ESCC, with a manageable safety profile.

Effects of Danhong Injection () on Peri-Procedural Myocardial Injury and Microcirculatory Resistance in Patients with Unstable Angina Undergoing Elective Percutaneous Coronary Intervention: A Pilot Randomized Study.

OBJECTIVE: To evaluate the effect of Danhong Injection (, DH) on the index of microcirculatory resistance (IMR) and myocardial injury in patients with unstable angina undergoing elective percutaneous coronary intervention (PCI). METHODS: Seventy-eight patients with unstable angina were randomly divided into DH group (39 cases) and the control group (39 cases) during elective PCI. Randomization was performed using a random-number table. The DH group received DH at a dosage of 40 mL (mixed with 250 mL saline, covered by a light-proof bag, intravenous drip) during PCI and daily for 7 consecutive days, while the control group only received the same dosage of saline. Both groups received standardized treatment. The IMR and fractional flow reserve (FFR) were measured at maximal hyperemia before and after PCI. Myocardial markers, including myoglobin, creatine kinase (CK), creatine kinase MB (CK-MB), and coronary troponin T (cTnT) values were measured at baseline and 24 h after PCI. RESULTS: Among the 78 patients enrolled, the baseline and procedural characteristics were similar between the two groups. There was no significant difference in pre-PCI myocardial markers and coronary physiological indexes between the two groups. However, post-PCI CK and CK-MB levels in the DH group were significantly lower than those in the control group (111.97 ± 80.97 vs. 165.47 ± 102.99, P=0.013; 13.08 ± 6.90 vs. 19.75 ± 15.49, P=0.016). Post-PCI myoglobin and cTNT-positive tend to be lower in the DH group than in the control group but did not reach statistical significance (88.07 ± 52.36 vs. 108.13 ± 90.94, P=0.52; 2.56% vs.7.69%, P=0.065). Compared with the control group, the post-IMR levels of the DH group tended to decrease, but there was no statistical difference (20.73 ± 13.15 vs. 26.37 ± 12.31, P=0.05). There were no statistical differences in post-FFR in both groups. The peri-procedural myocardial injury of the DH group was significantly lower than that of the control group (2.56% vs. 15.38%, P=0.025). During the 30-d follow-up period, no major adverse cardiovascular events occurred in either group. CONCLUSION: This study demonstrated benefit of DH in reducing myocardial injury and potential preserving microvascular function in patients with unstable angina undergoing elective PCI.

Identification and Characterization of Robust Hepatocellular Carcinoma Prognostic Subtypes Based on an Integrative Metabolite-Protein Interaction Network.

Metabolite-protein interactions (MPIs) play key roles in cancer metabolism. However, our current knowledge about MPIs in cancers remains limited due to the complexity of cancer cells. Herein, the authors construct an integrative MPI network and propose a MPI network based hepatocellular carcinoma (HCC) subtyping and mechanism exploration workflow. Based on the expressions of hub proteins on the MPI network, two prognosis-distinctive HCC subtypes are identified. Meanwhile, multiple interdependent features of the poor prognostic subtype are observed, including hypoxia, DNA hypermethylation of metabolic pathways, fatty acid accumulation, immune pathway up-regulation, and exhausted T-cell infiltration. Notably, the immune pathway up-regulation is probably induced by accumulated unsaturated fatty acids which are predicted to interact with multiple immune regulators like SRC and TGFB1. Moreover, based on tumor microenvironment compositions, the poor prognostic subtype is further divided into two sub-populations showing remarkable differences in metabolism. The subtyping shows a strong consistency across multiple HCC cohorts including early-stage HCC. Overall, the authors redefine robust HCC prognosis subtypes and identify potential MPIs linking metabolism to immune regulations, thus promoting understanding and clinical applications about HCC metabolism heterogeneity.

AQP3-mediated H2 O2 uptake inhibits LUAD autophagy by inactivating PTEN.

It is widely accepted that redox reprogramming participates in malignant transformation of lung adenocarcinoma (LUAD). However, the source of excessive reactive oxygen species (ROS) and the downstream signaling regulatory mechanism are complicated and unintelligible. In the current study, we newly identified the aquaporin 3 (AQP3) as a LUAD oncogenic factor with capacity to transport exogenous hydrogen peroxide (H2 O2 ) and increase intracellular ROS levels. Subsequently, we demonstrated that AQP3 was necessary for the facilitated diffusion of exogenous H2 O2 in LUAD cells and that the AQP3-dependent transport of H2 O2 accelerated cell growth and inhibited rapamycin-induced autophagy. Mechanistically, AQP3-mediated H2 O2 uptake increased intracellular ROS levels to inactivate PTEN and activate the AKT/mTOR pathway to subsequently inhibit autophagy and promote proliferation in LUAD cells. Finally, we suggested that AQP3 depletion retarded subcutaneous tumorigenesis in vivo and simultaneously decreased ROS levels and promoted autophagy. These findings underscore the importance of AQP3-induced oxidative stress in malignant transformation and suggest a therapeutic target for LUAD.

YB1 regulates miR-205/200b-ZEB1 axis by inhibiting microRNA maturation in hepatocellular carcinoma.

BACKGROUND: Y-box binding protein 1 (YB1 or YBX1) plays a critical role in tumorigenesis and cancer progression. However, whether YB1 affects malignant transformation by modulating non-coding RNAs remains largely unknown. This study aimed to investigate the relationship between YB1 and microRNAs and reveal the underlying mechanism by which YB1 impacts on tumor malignancy via miRNAs-mediated regulatory network. METHODS: The biological functions of YB1 in hepatocellular carcinoma (HCC) cells were investigated by cell proliferation, wound healing, and transwell invasion assays. The miRNAs dysregulated by YB1 were screened by microarray analysis in HCC cell lines. The regulation of YB1 on miR-205 and miR-200b was determined by quantitative real-time PCR, dual-luciferase reporter assay, RNA immunoprecipitation, and pull-down assay. The relationships of YB1, DGCR8, Dicer, TUT4, and TUT1 were identified by pull-down and coimmunoprecipitation experiments. The cellular co-localization of YB1, DGCR8, and Dicer were detected by immunofluorescent staining. The in vivo effect of YB1 on tumor metastasis was determined by injecting MHCC97H cells transduced with YB1 shRNA or shControl via the tail vein in nude BALB/c mice. The expression levels of epithelial to mesenchymal transition markers were detected by immunoblotting and immunohistochemistry assays. RESULTS: YB1 promoted HCC cell migration and tumor metastasis by regulating miR-205/200b-ZEB1 axis partially in a Snail-independent manner. YB1 suppressed miR-205 and miR-200b maturation by interacting with the microprocessors DGCR8 and Dicer as well as TUT4 and TUT1 via the conserved cold shock domain. Subsequently, the downregulation of miR-205 and miR-200b enhanced ZEB1 expression, thus leading to increased cell migration and invasion. Furthermore, statistical analyses on gene expression data from HCC and normal liver tissues showed that YB1 expression was positively associated with ZEB1 expression and remarkably correlated with clinical prognosis. CONCLUSION: This study reveals a previously undescribed mechanism by which YB1 promotes cancer progression by regulating the miR-205/200b-ZEB1 axis in HCC cells. Furthermore, these results highlight that YB1 may play biological functions via miRNAs-mediated gene regulation, and it can serve as a potential therapeutic target in human cancers.

The double-edged roles of ROS in cancer prevention and therapy.

Reactive oxygen species (ROS) serve as cell signaling molecules generated in oxidative metabolism and are associated with a number of human diseases. The reprogramming of redox metabolism induces abnormal accumulation of ROS in cancer cells. It has been widely accepted that ROS play opposite roles in tumor growth, metastasis and apoptosis according to their different distributions, concentrations and durations in specific subcellular structures. These double-edged roles in cancer progression include the ROS-dependent malignant transformation and the oxidative stress-induced cell death. In this review, we summarize the notable literatures on ROS generation and scavenging, and discuss the related signal transduction networks and corresponding anticancer therapies. There is no doubt that an improved understanding of the sophisticated mechanism of redox biology is imperative to conquer cancer.

Clinical recommendations for perioperative immunotherapy-induced adverse events in patients with non-small cell lung cancer.

Perioperative adjuvant treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). In particular, the success of immune checkpoint inhibitors, such as antibodies against PD-1 and PD-L1, in patients with lung cancer has increased our expectations for the success of these therapeutics as neoadjuvant immunotherapy. Neoadjuvant therapy is widely used in patients with resectable stage IIIA NSCLC and can reduce primary tumor and lymph node stage, improve the complete resection rate, and eliminate microsatellite foci; however, complete pathological response is rare. Moreover, because the clinical benefit of neoadjuvant therapy is not obvious and may complicate surgery, it has not yet entered the mainstream of clinical treatment. Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancellation of surgery, additional illness, and even death, and have therefore attracted much attention. In this article, we draw on several sources of information, including (i) guidelines on adverse reactions related to immune checkpoint inhibitors, (ii) published data from large-scale clinical studies in thoracic surgery, and (iii) practical experience and published cases, to provide clinical recommendations on adverse events in NSCLC patients induced by perioperative immunotherapy.

Effect of Danhong Injection () on Improving Coronary Microcirculation Injury after Percutaneous Coronary Intervention.

OBJECTIVE: To explore the effectiveness of Danhong Injection () on improving microcirculatory injury after percutaneous coronary intervention (PCI) in patients with coronary heart disease (CHD). METHODS: A randomized controlled trial was conducted and 90 patients were enrolled. A random sequence was generated using statistical analysis software. Patients with microcirculatory injuries after PCI were randomly divided into 3 groups for treatment (30 subjects in each group): Danhong Injection group: after PCI, Danghong Injections were given with intravenous administration with 40 mL twice a day for a week; statins intensive group: after PCI, atorvastatin calcium tablets were given oral medication with 80 mg once, and then atorvastatin 40 mg daily for 1 week; the control group: after PCI, atorvastatin calcium tablets were given oral medication with 10-20 mg daily for 1 week. The index of microcirculation resistance (IMR) was used to assess microcirculatory injury during PCI. The IMR of the target vessel was reexamined after 1 week of drug treatment. RESULTS: After one week's drug treatment, IMR was significantly decreased in both statins intensive group and Danhong Injection group compared with the control group (P<0.01), but no difference was found between statins intensive group and Danhong injection group (14.03 ± 2.54 vs. 16.03 ± 5.72 U, P=0.080). CONCLUSIONS: The efficacy of Danhong Injection is non-inferior to statin. Early use of Danhong Injection after PCI can effectively improve coronary microcirculation injury after PCI.

Acute Myocardial Infarction in Chinese Medicine Hospitals in China from 2006 to 2013: An Analysis of 2311 Patients from Hospital Data.

OBJECTIVE: To assess the trends in characteristics, treatments, and outcomes of acute myocardial infarction (AMI) patients in tertiary Chinese medicine (CM) hospitals in China between 2006 and 2013. METHODS: This retrospective study was based on two nationwide epidemiological surveys of AMI in tertiary CM hospitals during 2 years (2006 and 2013). Patients admitted to the hospital for AMI were enrolled. Hospital records were used as the data source. Case data were derived regarding baseline characteristics, treatments, and outcomes of patients to assess changes from 2006 to 2013. Logistic regression was used to analyze the relationship between prognosis, general influencing factors of disease, and various treatment measures. RESULTS: Totally 26 tertiary CM hospitals in 2006 and 29 tertiary CM hospitals in 2013 (18 were repetitive) were surveyed. A total of 2,311 patients with AMI were enrolled (1,094 cases in 2006 and 1,217 cases in 2013). From 2006 to 2013, the mean age did not significantly change, but the proportion of patients younger than 65 years increased. The prevalence of risk factors such as hypertension, diabetes, and hyperlipidemia also increased. Significant increases were observed in primary percutaneous coronary intervention [20.48% (2006) vs. 24.90% (2013)] and revascularization [36.11% (2006) vs. 52.42% (2013)]. In-hospital mortality decreased from 11.15% in 2006 to 10.60% in 2013. A mortality logistic regression analysis identified reperfusion therapy [odds ratio (OR), 0.222; 95% confidence interval (CI), 0.106-0.464], Chinese patent medicines (OR, 0.394; 95% CI, 0.213-0.727), and CM decoctions (OR, 0.196; 95% CI, 0.109-0.353) as protective factors. CONCLUSION: Reperfusion and revascularization capabilities of tertiary CM hospitals have improved significantly, but in-hospital mortality has not significantly decreased. Efforts are needed to improve medical awareness of AMI and expand the use of CM to reduce in-hospital mortality in China.