6-Gingerol attenuates hepatic ischemia/reperfusion injury through regulating MKP5-mediated P38/JNK pathway.

6-Gingerol, the main bioactive compound of ginger, has antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. However, it is unclear whether 6-Gingerol has protective effects against hepatic ischemia/reperfusion (I/R) injury. In this study, the mouse liver I/R injury model and the mouse AML12 cell hypoxia/reoxygenation (H/R) model were established by pretreatment with 6-Gingerol at different concentrations to explore the potential effects of 6-Gingerol. Serum transaminase levels, liver necrotic area, cell viability, inflammatory response, and cell apoptosis were used to assess the effect of 6-Gingerol on hepatic I/R or cell H/R injury. Quantitative polymerase chain reaction (qPCR) and Western blotting were used to detect the mRNA and protein expression. The results show that 6-Gingerol decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels, liver necrosis, inflammatory cytokines IL-1ß, IL-6, MCP-1, TNF-α expression, Ly6g+ inflammatory cell infiltration, protein phosphorylation of NF-κB signaling pathway, Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) positive cells, cell apoptosis rate, the protein expression of pro-apoptotic protein BAX and C-Caspase3, increased cell viability, and expression of anti-apoptotic protein BCL-2. Moreover, 6-Gingerol could increase the mRNA and protein expression of mitogen activated protein kinase phosphatase 5 (MKP5) and inhibit the activation of P38/JNK signaling pathway. In MKP5 knockout (KO) mice, the protective effect of 6-gingerol and the inhibition of P38/JNK pathway were significantly weakened. Therefore, our results suggest that 6-Gingerol exerts anti-inflammatory and anti-apoptotic effects to attenuate hepatic I/R injury by regulating the MKP5-mediated P38/JNK signaling pathway.

Phosphoglycerate mutase 5 exacerbates liver ischemia-reperfusion injury by activating mitochondrial fission.

Although the death of hepatocytes is a crucial trigger of liver ischemia-reperfusion (I/R) injury, the regulation of liver I/R-induced hepatocyte death is still poorly understood. Phosphoglycerate mutase 5 (PGAM5), a mitochondrial Serine/Threonine protein phosphatase, regulates mitochondrial dynamics and is involved in the process of both apoptosis and necrotic. However, it is still unclear what role PGAM5 plays in the death of hepatocytes induced by I/R. Using a PGAM5-silence mice model, we investigated the role of PGAM5 in liver I/R injury and its relevant molecular mechanisms. Our data showed that PGAM5 was highly expressed in mice with liver I/R injury. Silence of PGAM5 could decrease I/R-induced hepatocyte death in mice. In subcellular levels, the silence of PGAM5 could restore mitochondrial membrane potential, increase mitochondrial DNA copy number and transcription levels, inhibit ROS generation, and prevent I/R-induced opening of abnormal mPTP. As for the molecular mechanisms, we indicated that the silence of PGAM5 could inhibit Drp1(S616) phosphorylation, leading to a partial reduction of mitochondrial fission. In addition, Mdivi-1 could inhibit mitochondrial fission, decrease hepatocyte death, and attenuate liver I/R injury in mice. In conclusion, our data reveal the molecular mechanism of PGAM5 in driving hepatocyte death through activating mitochondrial fission in liver I/R injury.

Histone deacetylase 6 deficiency protects the liver against ischemia/reperfusion injury by activating PI3K/AKT/mTOR signaling.

Liver transplantation (LT) is the only effective method to treat end-stage liver disease. Hepatic ischemia-reperfusion injury (IRI) continues to limit the prognosis of patients receiving LT. Histone deacetylase 6 (HDAC6) is a unique HDAC member involved in inflammation and apoptosis. However, its role and mechanism in hepatic IRI have not yet been reported. We examined HDAC6 levels in liver tissue from LT patients, mice challenged with liver IRI, and hepatocytes subjected to hypoxia/reoxygenation (H/R). In addition, HDAC6 global-knockout (HDAC6-KO) mice, adeno-associated virus-mediated liver-specific HDAC6 overexpressing (HDAC6-LTG) mice, and their corresponding controls were used to construct hepatic IRI models. Hepatic histology, inflammatory responses, and apoptosis were detected to assess liver injury. The molecular mechanisms of HDAC6 in hepatic IRI were explored in vivo and in vitro. Moreover, the HDAC6-selective inhibitor tubastatin A was used to detect the therapeutic effect of HDAC6 on liver IRI. Together, our results showed that HDAC6 expression was significantly upregulated in liver tissue from LT patients, mice subjected to hepatic I/R surgery, and hepatocytes challenged by hypoxia/reoxygenation (H/R) treatment. Compared with control mice, HDAC6 deficiency mitigated liver IRI by inhibiting inflammatory responses and apoptosis, whereas HDAC6-LTG mice displayed the opposite phenotype. Further molecular experiments show that HDAC6 bound to and deacetylated AKT and HDAC6 deficiency improved liver IRI by activating PI3K/AKT/mTOR signaling. In conclusion, HDAC6 is a key mediator of hepatic IRI that functions to promote inflammation and apoptosis via PI3K/AKT/mTOR signaling. Targeting hepatic HDAC6 inhibition may be a promising approach to attenuate liver IRI.

Adelmidrol ameliorates liver ischemia-reperfusion injury through activating Nrf2 signaling pathway.

Liver ischemia/reperfusion (I/R) injury commonly occurs after various liver surgeries. Adelmidrol, an N- palmitoylethanolamide analog, has anti-inflammatory, anti-oxidant, and anti-injury properties. To investigate whether adelmidrol could reduce liver I/R injury, we established a mouse of liver I/R injury and an AML12 cell hypoxia-reoxygenation model to perform experiments using multiple indicators. Serum ALT and AST levels, and H&E staining were used to measure liver damage; MDA content, superoxide dismutase and glutathione activities, and dihydroethidium staining were used to measure oxidative stress; mRNA expression levels of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, MCP-1, and Ly6G staining were used to measure inflammatory response; and protein expression of Bax, Bcl-2, C-caspase3, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining were used to measure apoptosis. The experimental results showed that adelmidrol reduced liver I/R injury. In addition, adelmidrol pretreatment elevated AML12 cell activity and reduced I/R-and H/R-induced apoptosis, inflammatory injury, and oxidative stress. ML385, an inhibitor of nuclear factor erythroid2-related factor 2 (Nrf2), reverses liver I/R injury attenuated by adelmidrol. These results suggest that adelmidrol ameliorates liver I/R injury by activating the Nrf2 signaling pathway.

Mitogen activated protein kinase phosphatase 5 alleviates liver ischemia-reperfusion injury by inhibiting TAK1/JNK/p38 pathway.

Mitogen activated protein kinase phosphatase 5 (MKP5) is a member of the MKP family and has been implicated in diverse biological and pathological conditions. However, it is unknown what role MKP5 plays in liver ischemia/reperfusion (I/R) injury. In the present study, we used MKP5 global knockout (KO) and MKP5 overexpressing mice to establish a liver I/R injury model in vivo, and MKP5 knockdown or MKP5 overexpressing HepG2 cells to establish a hypoxia-reoxygenation (H/R) model in vitro. In this study we demonstrated that protein expression of MKP5 was significantly downregulated in liver tissue of mice after I/R injury, and HepG2 cells subjected to H/R injury. MKP5 KO or knockdown significantly increased liver injury, as demonstrated by elevated serum transaminases, hepatocyte necrosis, infiltrating inflammatory cells, secretion of pro-inflammatory cytokines, apoptosis, oxidative stress. Conversely, MKP5 overexpression significantly attenuated liver and cell injury. Furthermore, we showed that MKP5 exerted its protective effect by inhibiting c-Jun N-terminal kinase (JNK)/p38 activity, and its action was dependent on Transforming growth factor-ß-activated kinase 1 (TAK1) activity. According to our results, MKP5 inhibited the TAK1/JNK/p38 pathway to protect liver from I/R injury. Our study identifies a novel target for the diagnosis and treatment of liver I/R injury.

KLF6 alleviates hepatic ischemia-reperfusion injury by inhibiting autophagy.

Hepatic ischemia-reperfusion (I/R) injury, a common clinical complication of liver transplantation, gravely affects patient prognosis. Krüppel-like factors (KLFs) constitute a family of C2/H2 zinc finger DNA-binding proteins. KLF6, a member of the KLF protein family, plays crucial roles in proliferation, metabolism, inflammation, and injury responses; however, its role in HIR is largely remains unknown. After I/R injury, we found that KLF6 expression in mice and hepatocytes was significantly upregulated. Mice were then subjected to I/R following injection of shKLF6- and KLF6-overexpressing adenovirus through the tail vein. KLF6 deficiency markedly exacerbated liver damage, cell apoptosis, and activation of hepatic inflammatory responses, whereas hepatic overexpression of KLF6 in mice produced the opposite results. In addition, we knocked out or overexpressed KLF6 in AML12 cells before exposing them to a hypoxia-reoxygenation challenge. KLF6 knockout decreased cell viability and increased hepatocyte inflammation, apoptosis, and ROS, whereas KLF6 overexpression had the opposite effects. Mechanistically, KLF6 inhibited the overactivation of autophagy at the initial stage, and the regulatory effect of KLF6 on I/R injury was autophagy-dependent. CHIP-qPCR and luciferase reporter gene assays confirmed that KLF6 bound to the promoter region of Beclin1 and inhibited its transcription. Additionally, KLF6 activated the mTOR/ULK1 pathway. Finally, we performed a retrospective analysis of the clinical data of liver transplantation patients and identified significant associations between KLF6 expression and liver function following liver transplantation. In conclusion, KLF6 inhibited the overactivation of autophagy via transcriptional regulation of Beclin1 and activation of the mTOR/ULK1 pathway, thereby protecting the liver from I/R injury. KLF6 is expected to serve as a biomarker for estimating the severity of I/R injury following liver transplantation.

The efficacy and safety of apatinib plus capecitabine in platinum-refractory metastatic and/or recurrent nasopharyngeal carcinoma: a prospective, phase II trial.

BACKGROUND: Previous studies have shown that monotherapy with apatinib, an oral tyrosine kinase inhibitor, has promising efficacy for treating recurrent or metastatic (RM) nasopharyngeal carcinoma (NPC) patients. In this study, we aimed to assess the efficacy and safety of apatinib combined with capecitabine as a second-line therapy or beyond for treating RM-NPC patients who failed the first-line platinum-based chemotherapy. METHODS: In this single-arm, phase II study, we enrolled RM-NPC patients who had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The sample size was determined using Simon's two-stage design. All patients were administered with apatinib 500 mg once daily and capecitabine 1000 mg/m2 twice per day on days 1-14 of each 21-day cycle. The primary endpoint was the objective response rate (ORR), and the secondary endpoints comprised disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: We enrolled 64 patients from September 2018 to August 2020. The ORR and DCR were 39.1% (95% CI, 27.1-52.1) and 85.9% (95% CI, 75.0-93.4), respectively. The median DoR was 14.4 months (95% CI, 7.8-21.0). As of April 20, 2021, the median follow-up duration was 12.0 months. The median PFS was 7.5 months (95% CI, 5.0-10.0) and the median OS was 15.7 months (95% CI, 11.3-20.1). The most common toxicities of any grade were anemia (75.0%), hand-foot syndrome (65.6%), and proteinuria (64.0%). Grade 3-4 toxicities were observed in 36 (56.3%) patients, with hypertension (14.1%), mucositis (12.4%), and fatigue (10.9%) most commonly observed. CONCLUSIONS: Apatinib plus capecitabine shows promising efficacy as a second-line treatment option in pretreated platinum-refractory RM-NPC patients. Dose selection of this combination needs further investigation considering the toxicity. TRIAL REGISTRATION: Chi-CTR1800017229.

Inhibition of macrophage migration inhibitory factor (MIF) suppresses apoptosis signal-regulating kinase 1 to protect against liver ischemia/reperfusion injury.

Background: Hepatic ischemia-reperfusion (I/R) injury is a major complication leading to surgical failures in liver resection, transplantation, and hemorrhagic shock. The role of cytokine macrophage migration inhibitory factor (MIF) in hepatic I/R injury is unclear. Methods: We examined changes of MIF expression in mice after hepatic I/R surgery and hepatocytes challenged with hypoxia-reoxygenation (H/R) insult. Subsequently, MIF global knock-out mice and mice with adeno-associated-virus (AAV)-delivered MIF overexpression were subjected to hepatic I/R injury. Hepatic histology, the inflammatory response, apoptosis and oxidative stress were monitored to assess liver damage. The molecular mechanisms of MIF function were explored in vivo and in vitro. Results: MIF was significantly upregulated in the serum whereas decreased in liver tissues of mice after hepatic I/R injury. MIF knock-out effectively attenuated I/R -induced liver inflammation, apoptosis and oxidative stress in vivo and in vitro, whereas MIF overexpression significantly aggravated liver injury. Via RNA-seq analysis, we found a significant decreased trend of MAPK pathway in MIF knock-out mice subjected hepatic I/R surgery. Using the apoptosis signal-regulating kinase 1 (ASK1) inhibitor NQDI-1 we determined that, mechanistically, the protective effect of MIF deficiency on hepatic I/R injury was dependent on the suppressing of the ASK1-JNK/P38 signaling pathway. Moreover, we found MIF inhibitor ISO-1 alleviate hepatic I/R injury in mice. Conclusion: Our results confirm that MIF deficiency suppresses the ASK1-JNK/P38 pathway and protects the liver from I/R -induced injury. Our findings suggest MIF as a novel biomarker and therapeutic target for the diagnosis and treatment of hepatic I/R injury.

Common genetic driver mutation in NSCLC and their association with thromboembolic events: A retrospective study.

This retrospective study aimed to estimate the incidence, risk factors of thromboembolism events (TEs) in non-small cell lung cancer patients harboring common gene mutation, and evaluate a genetic link between oncogenes and the risk of TEs in Asian patients with NSCLC. METHODS: Univariate and multivariate Cox's proportional hazards regression models were used to identify the strongest predictors of TE development and evaluate the risk of TE in patients with different gene statuses of NSCLC patients. RESULTS: In univariate and multivariate COX analysis, patient with squamous cell carcinoma (HR 3.01, 95% CI: [1.06,8.56]; p = 0.039), multi-site metastases (HR: 2.72; 95% CI: [1.08,6.92]; p = 0.032) or high white blood cell (WBC) (HR 3.24, 95% CI: [1.46,7.22]; p = 0.004), less hemoglobin (HGB) (HR 4.89, 95% CI: [1.90,12.64]; p = 0.001), are at higher risk of thrombosis. At the molecular level, ROS and ALK rearrangement is highly associated with TE development, with HR of 4.04 (95%CI: [1.54,10.58]; p = 0.005) and HR of 3.57 (95% CI: [1.01,12.66]; p = 0.049) in univariate analysis, and even higher in multivariate analysis. EGFR mutations seem to be a protective factor against TE in univariate analyses (HR:0.28, 95%CI [0.12,0.65], p = 0.003) but are not statistically significant in the multivariate model. No correlation between KRAS mutations and TE events in both models. Besides, a numerically higher cumulative incidence of thrombosis event was observed in patients who used TKI (HR 1.473; 95% CI: [0.682, 3.181]; p = 0.32). CONCLUSION: Our study demonstrated that driver gene mutation may increase the risk of thrombosis in non-small cell lung cancer patients. The presence of ALK/ROS rearrangements in our study is associated with an approximately threefold to fourfold increase in thrombosis risk in NSCLC patients. For advanced-stage patients who used TKI, an increased incidence of thrombosis risk and shorter follow-up were observed.

Title: Multi-Omics and Immune Landscape of Proliferative LncRNA Signatures: Implications for Risk Stratification and Immunotherapy in Hepatocellular Carcinoma.

Background: Long noncoding RNAs (lncRNAs) are significantly implicated in tumor proliferation. Nevertheless, proliferation-derived lncRNAs and their latent clinical significance remain largely unrevealed in hepatocellular carcinoma (HCC). Methods: This research enrolled 658 HCC patients from five independent cohorts. We retrieved 50 Hallmark gene sets from the MSigDB portal. Consensus clustering was applied to identify heterogeneous proliferative subtypes, and the nearest template prediction (NTP) was utilized to validate the subtypes. We introduced an integrative framework (termed "ProLnc") to identify proliferation-derived lncRNAs. Moreover, a proliferation-related signature was developed and verified in four independent cohorts. Results: In 50 Hallmarks, seven proliferation pathways were significantly upregulated and correlated with a worse prognosis. Subsequently, we deciphered two heterogeneous proliferative subtypes in TCGA-LIHC. Subtype 2 displayed enhanced proliferative activities and a worse prognosis, whereas subtype 1 was associated with hyperproliferative HCC and a favorable prognosis. The NTP further verified the robustness and reproducibility of two subtypes in four cohorts derived from different platforms. Combining the differentially expressed lncRNAs from two subtypes with proliferative lncRNA modulators from our ProLnc pipeline, we determined 230 proliferation-associated lncRNAs. Based on the bootstrapping channel and the verification of multiple cohorts, we further identified ten lncRNAs that stably correlated with prognosis. Subsequently, we developed and validated a proliferative lncRNA signature (ProLncS) that could independently and accurately assess the overall survival (OS) and relapse-free survival (RFS) of HCC patients in the four cohorts. Patients with high ProLncS score displayed significantly genomic alterations (e.g., TP53 mutation, 8p23-8p24 copy number variation) and higher abundances of immune cells and immune checkpoint molecules, which suggested immunotherapy was more suitable for patients with high ProLncS score. Conclusion: Our work provided new insights into the heterogeneity of tumor proliferation, and ProLncS could be a prospective tool for tailoring the clinical decision and management of HCC.

Chemiresistive gas sensors based on electrospun semiconductor metal oxides: A review.

Semiconductor metal oxide (SMO) gas sensors have attracted considerable attention for detecting environmental pollution, as well as the accidental leakage of flammable, explosive, and toxic gases. SMOs are known to exhibit high sensitivity, fast response time, and excellent selectivity towards various types of gases. Many new strategies have been implemented to improve these characteristics. Among the materials produced by these methods, nanomaterials (NMs) synthesized by electrospinning have unprecedented advantages, including catalyst introduction, morphological control, thermodynamic stability, unique physicochemical properties, composition adjustment, and rapid adsorption-desorption rates of the NMs, and are appealing for the designing highly sensitive and selective gas sensors. This review highlights the latest findings on the design and fabrication of electrospun gas sensors for detecting various gases including hydrogen (H2), methane (CH4), nitrogen monoxide (NO), hydrogen sulfide (H2S), ammonia (NH3), ethanol (C2H5OH), acetone (CH3COCH3), formaldehyde (HCHO) and toluene (C6H5CH3). Studies have indicated that NMs with different shapes (e.g., nanotubes, nanowires, nanoflowers, nanosheets, nanorods, nanofilms, and nanofibers) and compositions (single-phase SMOs, modified SMOs, nanocomposites of SMOs, and SMOs combined with carbon nanomaterials) display high response values, long-term stability, low humidity dependence, fast response/recovery times, and low detection limits for gases. Finally, conclusions and future perspectives for gas sensors based on the electrospinning technique are discussed.

Smartphone-Based Platforms for Clinical Detections in Lung-Cancer-Related Exhaled Breath Biomarkers: A Review.

Lung cancer has been studied for decades because of its high morbidity and high mortality. Traditional methods involving bronchoscopy and needle biopsy are invasive and expensive, which makes patients suffer more risks and costs. Various noninvasive lung cancer markers, such as medical imaging indices, volatile organic compounds (VOCs), and exhaled breath condensates (EBCs), have been discovered for application in screening, diagnosis, and prognosis. However, the detection of markers still relies on bulky and professional instruments, which are limited to training personnel or laboratories. This seriously hinders population screening for early diagnosis of lung cancer. Advanced smartphones integrated with powerful applications can provide easy operation and real-time monitoring for healthcare, which demonstrates tremendous application scenarios in the biomedical analysis region from medical institutions or laboratories to personalized medicine. In this review, we propose an overview of lung-cancer-related noninvasive markers from exhaled breath, focusing on the novel development of smartphone-based platforms for the detection of these biomarkers. Lastly, we discuss the current limitations and potential solutions.

Artificial Intelligent Olfactory System for the Diagnosis of Parkinson's Disease.

Background: Currently, Parkinson's disease (PD) diagnosis is mainly based on medical history and physical examination, and there is no objective and consistent basis. By the time of diagnosis, the disease would have progressed to the middle and late stages. Pilot studies have shown that a unique smell was present in the skin sebum of PD patients. This increases the possibility of a noninvasive diagnosis of PD using an odor profile. Methods: Fast gas chromatography (GC) combined with a surface acoustic wave sensor with embedded machine learning (ML) algorithms was proposed to establish an artificial intelligent olfactory (AIO) system for the diagnosis of Parkinson's through smell. Sebum samples of 43 PD patients and 44 healthy controls (HCs) from Fourth Affiliated Hospital of Zhejiang University School of Medicine, China, were smelled by the AIO system. Univariate and multivariate methods were used to identify the significant volatile organic compound (VOC) features in the chromatograms. ML algorithms, including support vector machine, random forest (RF), k nearest neighbor (KNN), AdaBoost (AB), and Naive Bayes (NB), were used to distinguish PD patients from HC based on the VOC peaks in the chromatograms of sebum samples. Results: VOC peaks with average retention times of 5.7, 6.0, and 10.6 s, respectively, corresponding to octanal, hexyl acetate, and perillic aldehyde, were significantly different in PD and HC. The accuracy of the classification based on the significant features was 70.8%. Based on the odor profile, the classification had the highest accuracy and F1 of the five models with 0.855 from NB and 0.846 from AB, respectively, in the process of model establishing. The highest specificity and sensitivity of the five classifiers were 91.6% from NB and 91.7% from RF and KNN, respectively, in the evaluating set. Conclusions: The proposed AIO system can be used to diagnose PD through the odor profile of sebum. Using the AIO system is helpful for the screening and diagnosis of PD and is conducive to further tracking and frequent monitoring of the PD treatment process.

Veratric acid alleviates liver ischemia/reperfusion injury by activating the Nrf2 signaling pathway.

Oxidative stress following liver ischemia/reperfusion (I/R) is an important pathological mechanism responsible for liver injury. Veratric acid (VA) is a phenolic benzoic acid that has been reported to have antioxidant properties. However, whether VA has protective effects against liver I/R injury remains unclear. In the present study, a mouse liver I/R injury model was established. VA was administered intragastrically for one week before liver I/R. Biochemical indicators, histological analysis, cell apoptosis, oxidative stress, and pathway proteins were tested to evaluate the protective effects of VA on liver I/R injury. Furthermore, a mouse AML12 hepatocyte hypoxia/reoxygenation (H/R) model was used to explore the underlying mechanism. VA alleviated liver I/R injury, as manifested by decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver necrotic area, oxidative stress, and hepatocyte apoptosis. VA pretreatment increased the expression of Nrf2 and its downstream antioxidant proteins heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase 1 (NQO-1). In addition, VA pretreatment increased AML12 cell activity and decreased oxidative stress; it also decreased the apoptosis induced by H/R. Moreover, the protective effect of VA on hepatocytes was related to the activation of the Nrf2 signaling pathway, and to increases in the Nrf2, HO-1, and NQO-1 protein expression. The inhibition of Nrf2 with ML385 offseted VA-mediated protection in AML12 cells. In conclusion, these results suggest that VA protects the liver from oxidative stress and apoptosis induced by liver I/R injury by activating the Nrf2 signaling pathway.

High expression of DHX9 promotes the growth and metastasis of hepatocellular carcinoma.

BACKGROUND: DHX9, an NTP-dependent RNA helicase, is closely associated with the proliferation and metastasis of some tumor cells and the prognosis of patients, but its role in hepatocellular carcinoma (HCC) is not well-known. This study was performed to explore the expression and role of DHX9 in HCC. METHODS: The expression of DHX9 in HCC tissues and cell lines was detected by TCGA database, qPCR, western blotting, and immunohistochemistry. The relationship between the DHX9 expression level and the prognosis of patients with HCC was accessed. Then, the function of DHX9 knockdown in HCC cells was examined by CCK-8, scratch, Transwell, and apoptosis assays. Epithelial-mesenchymal transition (EMT) was detected by western blotting. RESULTS: DHX9 was highly expressed in HCC tissues by analyzing both TCGA database and clinical samples. High DHX9 expression level was associated with TNM stage, vascular invasion and metastasis of HCC patients, and was an independent adverse prognostic factor. DHX9 knockdown significantly inhibited cell proliferation, migration, invasion and EMT and increased cell apoptosis in HCC cells. CONCLUSION: Our findings suggest that DHX9 participates in the progression of HCC as an oncogene and may be a potential target for the clinical diagnosis and therapy of HCC.

Hyperprogression under immunotherapy: a new form of immunotherapy response?-a narrative literature review.

OBJECTIVE: Update the last known review, and summarize the definitions, diagnostic criteria, reported risk factors, possible mechanisms and potential biomarkers of hyperprogressive disease (HPD) under immunotherapy. BACKGROUND: Immunotherapy is a relatively new systemic therapy adding a new method of treatment of especially advanced cancer patients. In a variety of immunotherapies, however, an unexpected acceleration of tumor growth, known as HPD, is observed in approximately 30% of patients after immune checkpoint inhibitor (ICI) treatment. HPD has a deleterious survival effect on patients and represents an urgent issue for both clinicians and patients. Existing literature has reviewed and summarized the definition, diagnostic criteria, reported risk factors and possible mechanisms of hyperprogression. However, with the gradual deepening of the exploration of HPD, researchers have made significant breakthroughs in elucidating the mechanism and mechanism of HPD and exploring biomarkers. METHODS: The search was conducted on Google Scholar and PubMed in January and May of 2021. We searched among English papers with no limitation on the publication year. We have included retrospective studies, case reports and basic researches related to HPD in the collection, we also referred to some review articles on HPD in recent years. A qualitative-interpretive approach was used for data extraction. CONCLUSIONS: HPD is considered to be an acceleration of tumor growth after ICI treatment that is not only due to immune infiltration but also due to real disease progression, with an incidence of about 4-30% in all retrospective published studies to date. Currently, the most widely used criteria of HPD contain Response Evaluation Criteria in Solid Tumors (RECIST) and tumor growth rate (TGR) or tumor growth kinetics. The common risk factors and underlying mechanisms of HPD have not yet been fully elucidated. However, based on the poor prognosis of HPD, there have been many advances in the exploration of biomarkers in recent years, like the prediction of HPD, such as LDH levels of peripheral blood, liquid biopsy, and radiomics, etc.

miR­140­5p alleviates mouse liver ischemia/reperfusion injury by targeting CAPN1.

Ischemia/reperfusion (I/R)­induced liver injury remains a primary concern in liver transplantation and hepatectomy. Previous studies have indicated that microRNAs (miRs) are involved in multiple pathophysiological processes, including liver I/R. miR­140­5p reportedly inhibits inflammatory responses and apoptosis in several diseases; however, the role of miR­140­5p in liver I/R remains unknown. The present study aimed to investigate the potential role and mechanism of miR­140­5p on liver I/R injury. Mouse liver I/R and mouse AML12 cell hypoxia/reoxygenation (H/R) models were established. miR­140­5p mimics, inhibitor or agonists were used to overexpress or inhibit miR­140­5p in vitro and in vivo. Reverse transcription­quantitative polymerase chain reaction was used to detect miR­140­5p expression. Liver and cell injury were evaluated using several biochemical assays. The association between miR­140­5p and calpain­1 (CAPN1) was confirmed using a dual­luciferase reporter assay. The results revealed that miR­140­5p expression was decreased in the mouse model of liver I/R injury and AML12 cells subjected to H/R, while overexpressed miR­140­5p reduced liver injury in vivo and cell injury in vitro. In addition, CAPN1 was determined to be a target of miR­140­5p; overexpressed CAPN1 abrogated the effect of miR­140­5p on H/R­induced cell injury. The present study indicated that miR­140­5p protected against liver I/R by targeting CAPN1, which may provide a novel therapeutic target for liver I/R injury.

Real time detection of 3-nitrotyrosine using smartphone-based electrochemiluminescence.

As an oxidase stress biomarker, 3-nitrotyrosine is closely associated with many cardiovascular diseases. Thus, early diagnosis and real time detection of 3-nitrotyrosine at bedside are highly important. Herein, we developed a handheld electrochemiluminescence (ECL) analysis device, which integrates printed circuit board (PCB) for electrical stimulation and smartphone for optical signals readout. Fast and accurate determination of 3-nitrotyrosine was achieved with Antibody/Ru(dcpy)32+@AuNPs/MoS2 modified Au electrode (Ab/Ru@AuNPs/MoS2) for ECL analysis. The linear range of 3-nitrotyrosine detection was from 10-8 mol/L to 10-6 mol/L with a detection limit of 8.4 × 10-9 mol/L. In addition, an Android application was developed to realize real time analysis of ECL emissions and results readout for detection. To confirm the usage of the device, spiked serum with different concentrations was tested and the results indicated the practical reliability and stability of this device. The operating procedure for ECL analysis in this device is extremely easy and electrical stimulation was adjustable from 0 V to 5 V for general ECL systems. Thus, we believe this handheld device for ECL analysis has extensive prospects for application in Point-of-care testing and health caring.

Contribution of microalgae to carbon sequestration in a natural karst wetland aquatic ecosystem: An in-situ mesocosm study.

Carbonate rock weathering coupled with aquatic photosynthesis in karst areas is an important part in the formation of terrestrial carbon sinks. The capacity of photosynthetic carbon sequestration by aquatic microalgae and carbonic anhydrase (CA) is integral in the estimation of carbon sink potential of karst aquatic ecosystems. To date, carbon sequestration by aquatic microalgae in karst areas has been investigated in laboratory experiments. In the present work, the capacity of carbon sequestration by microalgae and CA under natural karst aquatic conditions and the main environmental factors were investigated in field in-situ mesocosms. The Sizhitan Pond of the Huixian karst wetland in Guilin City, Guangxi Province, China, was selected as a typical karst natural water body for this study. The capacity of photosynthetic carbon sequestration varied with microalgal community composition. The microalgal communities with active extracellular CA showed high capacity of carbon sequestration. The average conversion of inorganic carbon to relatively stable organic carbon by microalgae in the Huixian karst wetland aquatic ecosystem was estimated as 4207.5 t C/a. Approximately 28.7% of the bicarbonate fed by the karst underground river was fixed into organic carbon by microalgal photosynthesis. The major environmental factors affecting the capacity of carbon sequestration by microalgae in the karst wetland aquatic ecosystem were the water CA activity, illumination, temperature, total phosphorus and total nitrogen. This study is the first to address the contribution of aquatic microalgae and CA to carbon sequestration under natural karst aquatic conditions. The findings contribute to establishing groundwork for substantiating the carbon sink potential in global karst ecosystems.

Hdc-expressing myeloid-derived suppressor cells promote basal-like transition and metastasis of breast cancer.

Metastases are the greatest contributors to death from breast cancer. Here, we identified a distinct subpopulation of luminal breast cancer characterized by cytokeratin 14 (CK14) expression in secondary colonies rather than primary tumors. This entity possessed a poorer prognosis compared to their CK14- counterparts. Immunohistochemical analysis showed that myeloid-derived suppressor cells (MDSCs) were recruited into the tumor microenvironment and exhibited a close spatial relationship with CK14+ cancer cells. We demonstrated that histidine decarboxylase (Hdc) is capable of labeling myeloid-biased hematopoietic stem cell/progenitor cell (HSC/HSPC) and immature myeloid cells infiltrating in tumor tissues. FACS data obtained from Hdc-CreERT2; eGFP; MMTV-PyVT female mice revealed an increased percentage of Hdc+ PMN-MDSCs in metastatic masses. Hdc+ PMN-MDSCs expressed high levels of canonical Wnts, including Wnt2, Wnt4, Wnt5a, and Wnt7b, to aberrantly activate Wnt/ß-catenin signaling in CK14+ malignant cells. ß-catenin translocated from the membrane into the cytoplasm and nucleus. Targeted ablation of Hdc+ PMN-MDSCs-derived Wnts through porcupineflox/flox and iDTR transgenic models hampered the metastatic cascade, making Hdc+ immature myeloid cells an attractive candidate for tailed immunotherapies.