Predictive value of peripheral blood biomarkers in patients with non-small-cell lung cancer responding to anti-PD-1-based treatment.

BACKGROUND: The introduction of the anti-PD-1 antibody has greatly improved the clinical outcomes of patients with non-small cell lung cancer (NSCLC). In this study, we retrospectively analyzed the efficacy of PD-1 antibody-based therapy in patients with locally advanced inoperable or metastatic NSCLC and reported an association between peripheral blood biomarkers and clinical response in these patients. METHODS: This single-center study included medical record data of patients with NSCLC treated with the PD-1 antibody as a first-line or subsequent line of treatment, either as monotherapy or in combination with chemotherapy. The patients were enrolled from 2020 to 2022. We dynamically evaluated multiple Th1 and Th2 cytokines in the blood serum and analyzed the phenotype of T cells from the peripheral blood to explore the correlation between cytokine levels, T cell phenotypes, and clinical response. RESULTS: A total of 88 patients with stage IIIA-IV NSCLC were enrolled, out of which 60 (68.18%) achieved a partial response (PR), 13 (14.77%) had stable disease (SD), and 15 (17.05%) experienced disease progression (PD). The disease control rate was 82.95%. Our results suggested a significant reduction (P = 0.002, P < 0.005) in lymphocyte absolute counts after treatment in patients with PD. Higher levels of IFN-γ (P = 0.023, P < 0.05), TNF-α (P = 0.00098, P < 0.005), IL-4 (P = 0.0031, P < 0.005), IL-5 (P = 0.0015, P < 0.005), and IL-10 (P = 0.036, P < 0.05) were detected in the peripheral blood before treatment in the PR group compared to the PD group. Moreover, patients with high levels of IL-5, IL-13, IL-4, IL-6, IFN-γ, and TNF-α (> 10 ng/mL) had superior progression-free survival compared to those with low levels (< 10 ng/mL). Furthermore, PD-1 expression on CD8+ T cells was higher in patients who showed a PR than in those who did not show a response (SD + PD; P = 0.042, P < 0.05). CONCLUSIONS: The findings of this study imply that the decrease in absolute blood lymphocyte counts after treatment is correlated with disease progression. Serum cytokine levels may predict the effectiveness and survival rates of anti-PD-1 blockade therapy in patients with NSCLC. In addition, PD-1 expression on CD8+ T cells was positively associated with better clinical response. Our findings highlight the potential of peripheral blood biomarkers to predict the effectiveness of PD-1-targeted treatments in patients with NSCLC. Larger prospective studies are warranted to further clarify the value of these biomarkers.

Membrane Trafficking-Related Genes Predict Tumor Immune Microenvironment and Prognosis in Colorectal Cancer.

Colorectal cancer (CRC) is a heterogeneous disease with varying clinical outcomes. The identification of distinct subgroups of CRC patients based on molecular profiling can aid in better understanding the disease and improving patient outcomes. This study aimed to investigate the potential of membrane trafficking-related genes (MTRGs) in sub-grouping colorectal cancer patients based on their overall survival and immune microenvironments. Consensus clustering analysis identified two distinct clusters with different expression profiles of membrane trafficking-related genes. The patients in cluster 1 had a significantly better overall survival than those in cluster 2. Furthermore, the immune microenvironments in the two clusters were also found to be significantly different, with cluster 1 having a higher immune score and more immune cells present. Functional analysis of differentially expressed genes between the two clusters revealed that MTRGs were involved in immune response and metabolic processes, and a risk signature model based on MTRGs was established to predict the prognosis of CRC patients. These findings suggest that MTRGs play a crucial role in the immune microenvironment and overall survival of CRC patients and may provide a potential target for personalized therapy.

Efficacy comparison between iliosacral screw fixation of the posterior pelvic ring fracture with the assistance of modified percutaneous three-dimensional printing guide template and conventional fluoroscopy. / æ”¹è‰¯ç»çš®ä¸‰ç»´æ‰“å°å¯¼æ¿ä¸Žä¼ ç»Ÿé€è§†è¾ åŠ©éª¶é«‚èžºé’‰å›ºå®šéª¨ç›†åŽçŽ¯éª¨æŠ˜çš„ç–—æ•ˆæ¯”è¾ƒ.

OBJECTIVES: The effect of three-dimensional (3D) printed bone-attached guide plate assisted cannulated screw fixation of pelvic fracture is reliable, but extensive soft tissue dissection is still required when installing the guide plate. This study aims to compare the efficacy of posterior pelvic ring fracture fixation with iliosacral screw insertion between the assistance of modified percutaneous patient specific 3D printed guide template and conventional fluoroscopy. METHODS: From May, 2019 and September 2021, 28 patients sustained posterior pelvic ring fractures were randomized into 2 groups: A guide template group, in which the iliosacral screw was inserted for fixation of the posterior pelvic ring fracture with the assistance of modified percutaneous patient specific 3D printed guide template, and a fluoroscopy group, in which the iliosacral screw was inserted under the guidance of conventional fluoroscopy. The operation time, fluoroscopic frequency, intraoperative blood loss, and incision length were recorded for each screw insertion. Fracture reduction was evaluated according to the Matta criteria. The screw position was evaluated according to the modified Gras classification, and the functional outcome was evaluated according to Majeed score. The parameters of both groups were compared, and statistical analysis was performed. RESULTS: All the 28 patients were followed up for 12-24 months. Of them, 15 iliosacral screws were inserted in 14 patients in the guide template group, and 14 iliosacral screws were inserted in 14 patients in the fluoroscopy group. The operation time, fluoroscopic frequency, screw deviation, incision length, and blood loss in the guide template group were 20-30(25.8±2.8) min, 9-15(12.2±1.9), 2-4(2.6±0.7) mm, 4-5(4.6±0.5) cm, and 5-10 (7.8±1.7) mL, respectively, whereas those in the fluoroscopy group were 30-60(48.1±7.5) min, 40-96(64.7±16.3), 3-6(4.2±0.9) mm, 0.8-1.2(1.0±0.1) cm, and 2-5(3.1±1.3) mL, respectively, and there were statistical significance (all P<0.001). Fracture reduction was evaluated according to the Matta criteria, and all the patients reached excellence and good (P=0.584) in the 2 groups. According to modified Gras classification, there were 12 Grade I screws, 3 Grade II screws, and 0 Grade III screws in the guide template group, and 10 Grade I screws, 3 Grade II screws, and 1 Grade III screw in the fluoroscopy group, with no statistical significance (P=0.334). The functional outcome was evaluated according to Majeed score at the last follow-up, without significant difference between the guide template group and the fluoroscopy group (P=0.908). CONCLUSIONS: Compared with the conventional fluoroscopy, it would cost less operation time, less fluoroscopic frequency and increase more accurate screw insertion to fixate the posterior pelvic ring fracture with the assistance of modified percutaneous patient specific 3D printed guide template.

Efficacy of Shuganjieyu capsule for treatment of neurologic disorders combined with depression: A meta-analysis.

Shuganjieyu capsule (SGJY) is the first Chinese herbal medicine approved for treatment of depression; however, the Shuganjieyu capsule efficacy in patients with neurologic disorders combined with depression remains to be determined. Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI) and other electronic databases were searched to obtain relevant studies through May 2019. Newcastle-Ottawa and Jadad scales are used for the quality assessed. Sensitivity analysis, subgroup analysis and meta-regression were performed to evaluate sources of heterogeneity. Sixty-seven studies were selected for further analysis. Patients who had Shuganjieyu therapy had a higher effective rate and lower Hamilton Depression Rating Scale (HAM-D) score compared to patients who had non-shuganjieyu therapy. In addition, Shuganjieyu capsule improve symptoms of patients with stroke (National Institutes of Health Stroke Scale (NIHSS) score: Weighted mean difference (WMD)= -2.64; 95% CI: -3.95 to -1.33; P<0.001), Parkinson's disease score: WMD= -2.53; 95% CI: -3.92 to -1.14; P<0.001), and sleep disorders (Pittsburgh Sleep Quality Index (PSQI) score: WMD= -4.97; 95% CI: -7.56 to -2.38; P<0.001). Our results demonstrated that there were clinical benefits for patients with neurologic disorders after Shuganjieyu capsule therapy compared with non-shuganjieyu therapy with respect to effective rate and HAM-D, NIHSS, UPDRS and PSQI scores.

Early Use of Corticosteroid May Prolong SARS-CoV-2 Shedding in Non-Intensive Care Unit Patients with COVID-19 Pneumonia: A Multicenter, Single-Blind, Randomized Control Trial.

BACKGROUND: There is still no clinical evidence available to support or to oppose corticosteroid treatment for coronavirus disease 2019 (COVID-19) pneumonia. OBJECTIVE: To investigate the efficacy and safety of corticosteroid given to the hospitalized patients with COVID-19 pneumonia. METHODS: This was a prospective, multicenter, single-blind, randomized control trial. Adult patients with COVID-19 pneumonia who were admitted to the general ward were randomly assigned to either receive methylprednisolone or not for 7 days. The primary end point was the incidence of clinical deterioration 14 days after randomization. RESULTS: We terminated this trial early because the number of patients with COVID-19 pneumonia in all the centers decreased in late March. Finally, a total of 86 COVID-19 patients underwent randomization. There was no difference of the incidence of clinical deterioration between the methylprednisolone group and control group (4.8 vs. 4.8%, p = 1.000). The duration of throat viral RNA detectability in the methylprednisolone group was 11 days (interquartile range, 6-16 days), which was significantly longer than that in the control group (8 days [2-12 days], p = 0.030). There were no significant differences between the 2 groups in other secondary outcomes. Mass cytometry discovered CD3+ T cells, CD8+ T cells, and NK cells in the methylprednisolone group which were significantly lower than those in the control group after randomization (p < 0.05). CONCLUSIONS: From this prematurely closed trial, we found that the short-term early use of corticosteroid could suppress the immune cells, which may prolong severe acute respiratory syndrome coronavirus 2 shedding in patients with COVID-19 pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04273321.

[An experimental study on a slow-release complex with rifampicin-polylactic-co-glycolic acid-calcium phosphate cement].

OBJECTIVE: To prepare the slow-release complex with rifampicin (RFP)-polylactic-co-glycolic acid (PLGA)-calcium phosphate cement (CPC) (RFP-PLGA-CPC complex), and to study its physical and chemical properties and drug release properties in vitro.
 METHODS: The emulsification-solvent evaporation method was adopted to prepare rifampicin polylactic acid-glycolic acid (RFP-PLGA) slow-release microspheres, which were divided into 3 groups: a calcium phosphate bone cement group (CPC group), a CPC embedded with RFP group (RFP-CPC group), and a PLGA slow-release microspheres carrying RFP and the self-curing CPC group (RFP- PLGA-CPC complex group). The solidification time and porosity of materials were determined. The drug release experiments in vitro were carried out to observe the compressive strength, the change of section morphology before and after drug release. 
 RESULTS: The CPC group showed the shortest solidification time, while the RFP-PLGA-CPC complex group had the longest one. There was statistical difference in the porosity between the CPC group and the RFP-CPC group (P<0.05); Compared to the RFP-PLGA-CPC complex group, the porosity in the CPC group and the RFP-CPC group were significantly changed (both P<0.01). There was significant difference in the compressive strength between the RFP- PLGA-CPC complex group and the CPC group (P<0.01), while there was significant difference in the compressive strength between the RFP-CPC group and the CPC group (3 days: P<0.05; 30 and 60 days: P<0.01). The change of the compressive strength in the CPC was not significant in the whole process of degradation. The sizes of PLGA microspheres were uniform, with the particle size between 100-150 µm. The microspheres were spheres or spheroids, and their surface was smooth without the attached impurities. There was no significant change in the section gap in the CPC group after soaking for 3 to 60 days. The microstructure change in the RFP-CPC group was small, and the cross section was formed by small particles. The pores of section in the RFP-PLGA-CPC complex group increased obviously, and PLGA microspheres gradually disappeared until the 60th day when there were only empty cavities left. The RFP-PLGA-CPC complex group had no obvious drugs sudden release, and the cumulative drug release rate was nearly 95% in the 60 days. The linear fitting was conducted for the drug release behavior of the complex, which was in accordance with zero order kinetics equation F=0.168×t.
 CONCLUSION: The porosity of RFP-PLGA-CPC complex is significantly higher than that of CPC, and it can keep slow release of the effective anti-tuberculosis drugs and maintain a certain mechanical strength for a long time.

SLAMF8, a potential new immune checkpoint molecule, is associated with the prognosis of colorectal cancer.

Recently, immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) monoclonal antibodies (mAbs), have revolutionized the treatment of malignant tumors. Therefore, the number of studies aiming to screen and identify new immune checkpoint molecules for antitumor immunotherapy is increasing. Signaling lymphocytic activation molecule (SLAM) family members are mainly expressed by and regulate the functions of immune cells. Recent studies have shown that several SLAM family members are involved in the regulation of the tumor immune microenvironment and are promising targets for antitumor immunotherapy. Signaling lymphocytic activation molecule family member 8 (SLAMF8) is a type I cell surface glycoprotein and is encoded on chromosome 1q21. To further illustrate the clinical value of SLAMF8 in colorectal cancer (CRC), we retrospectively analyzed the relationship between SLAMF8 expression and the prognosis of CRC patients and the associations between SLAMF8 expression and the expression levels of other SLAM family members and other classic immune checkpoint molecules using The Cancer Genome Atlas (TCGA) data, RNA sequencing data, tissue immunohistochemistry staining, and systematic follow-up analysis. Here, high SLAMF8 expression was associated with poor overall survival (OS) in CRC. The mRNA expression level of SLAMF8 was positively correlated with the expression levels of multiple classic immune checkpoints and other SLAM family members. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that the pathways enriched in CRC tissues with high SLAMF8 expression were associated with the regulation of the tumor immune microenvironment.

Exploring the Expression and Prognosis of Mismatch Repair Proteins and PD-L1 in Colorectal Cancer in a Chinese Cohort.

Purpose: Exploring the expression and prognosis of mismatch repair proteins and PD-L1 in colorectal cancer. Patients and Methods: A total of 272 patients with surgically resected CRC were enrolled in the study from January 2018 to May 2022 at Nanjing Drum Tower Hospital (The Affiliated Hospital of Nanjing University Medical School). Surgically resected samples were collected from patients along with general, clinicopathological, and imaging data for each patient. Immunohistochemistry (IHC) was used to detect expression of MSH2, MSH6, MLH1, and PMS2 proteins in tumor tissue. X-squared (X2) testing was performed to investigate the correlation between expression of MMR proteins and PD-L1 in CRC tumor tissues and clinicopathological characteristics. Correlation analysis was also used to compare the deletion of four MMR proteins in CRC tumor tissues. A survival curve and Log rank test were used to investigate the relationship between the expression of MMR proteins and PD-L1 with regard to CRC patient prognosis and survival. Results: MMR protein expression deletion was correlated with tumor location, the degree of tissue differentiation, and TNM stage (P<0.05). PD-L1 expression was correlated with TNM stage (P<0.05). Correlation analysis of deletion of MMR protein isoform expression found that PMS2 deletion was significantly correlated with MLH1 deletion (P<0.05). Similarly, MSH2 deletion was significantly correlated with MSH6 deletion (P<0.05). PMS2 deletion was also found to be correlated with PD-L1 expression (P<0.05). Progression-free survival was found to be significantly longer in mismatch repair-proficient (pMMR) patients compared with mismatch repair-deficient (dMMR) patients. Conclusion: Deletion of MMR proteins and expression of PD-L1 are closely related to clinicopathological characteristics and overall prognosis of CRC patients. This suggests the relevance of MMR and PD-L1 as potential biomarkers for treatment of CRC patients.

Multicenter, single-arm, phase II study (CAP) of radiotherapy plus liposomal irinotecan followed by camrelizumab and anti-angiogenic treatment in advanced solid tumors.

Introduction: Combination therapeutic mode is likely to be the key to enhance the efficacy of immunotherapy in a wider range of cancer patients. Herein, we conducted an open-label, single-arm, multicenter, phase II clinical trial that enrolled patients with advanced solid tumors who had progressed after standard treatments. Methods: Radiotherapy of 24 Gy/3 fractions/3-10 days was given to the targeted lesions. Liposomal irinotecan (80mg/m2, dose could be adjusted to 60 mg/m2 for intolerable cases) was intravenously (IV) administered once within 48 hours after radiotherapy. Then, camrelizumab (200mg IV, q3w) and anti-angiogenic drugs were given regularly until disease progression. The primary endpoint was objective response rate (ORR) in the target lesions evaluated by investigators per RECIST 1.1. The secondary endpoints were disease control rate (DCR) and treatment-related adverse events (TRAEs). Results: Between November 2020 and June 2022, 60 patients were enrolled. The median follow-up was 9.0 months (95% confidence interval (CI) 5.5-12.5). Of 52 evaluable patients, the overall ORR and DCR were 34.6% and 82.7%, respectively. Fifty patients with target lesions were evaluable, the ORR and DCR of the target lesions were 35.3% and 82.4%, respectively. The median progression-free survival was 5.3 months (95% CI 3.6, 6.2), and the median overall survival was not reached. TRAEs (all grades) occurred in 55 (91.7%) patients. The most common grade 3-4 TRAEs were lymphopenia (31.7%), anemia (10.0%), and leukopenia (10.0%). Conclusion: The combination of radiotherapy, liposomal irinotecan, camrelizumab, and anti-angiogenesis therapy demonstrated promising anti-tumor activity and well tolerance in various advanced solid tumors. Clinical trial registration: https://clinicaltrials.gov/ct2/home, identifier NCT04569916.

[Study on the immunocompetence of polysaccharide extracted from root of Salvia miltiorrhiza].

OBJECTIVE: To study the immune activity of polysaccharide extracted from root of Salvia miltiorrhiza. METHODS: Investigated the effects of polysaccharide extracted from root of Salvia miltiorrhiza on lymphocyte proliferation response of mouse induced by LPS (the lipopolysaccharide LPS), phagocytosis of the peritoneal macrophage of mice to chick erythrocytes and the mouse models of delayed type hypersensitivity (DTH) response induced by DNFB. RESULTS: Lymphocyte proliferation and phagocytosis of the peritoneal macrophage of mice could be promoted by the polysaccharide, which could inhibit ear edema and capillary permeability increase induced by DNFB and enlarged the thymus and splenic index in mice. The expression of iNOS, IFN-alpha and IL-1beta was inhibited significantly in the treatment group. CONCLUSION: The polysaccharide extracted from Salvia miltiorrhiza can improve immune function.

Transcriptome Profiling to the Effects of Drought Stress on Different Propagation Modes of Tea Plant (Camellia sinensis).

Tea plant (Camellia sinensis) is an important economic beverage crop. Drought stress seriously affects the growth and development of tea plant and the accumulation of metabolites, as well as the production, processing, yield and quality of tea. Therefore, it is necessary to understand the reaction mechanism of tea plant under drought conditions and find efficient control methods. Based on transcriptome sequencing technology, this study studied the difference of metabolic level between sexual and asexual tea plants under drought stress. In this study, there were multiple levels of up-regulation and down-regulation of differential genes related to cell composition, molecular function and biological processes. Transcriptomic data show that the metabolism of tea plants with different propagation modes of QC and ZZ is different under drought conditions. In the expression difference statistics, it can be seen that the differential genes of QC are significantly more than ZZ; GO enrichment analysis also found that although differential genes in biological process are mainly enriched in the three pathways of metabolic, single organism process and cellular process, cellular component is mainly enriched in cell, cell part, membrane, and molecular function, and binding, catalytic activity, and transporter activity; the enrichment order of differential genes in these pathways is different in QC and ZZ. This difference is caused by the way of reproduction. The further study of these differential genes will lay a foundation for the cultivation methods and biotechnology breeding to improve the quality of tea.

Berberine induces non-small cell lung cancer apoptosis via the activation of the ROS/ASK1/JNK pathway.

Background: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Berberine (BBR), an isoquinoline alkaloid, is commonly used in traditional Chinese medicine. Previous studies have shown that BBR has a potential anti-tumor effect. However, the mechanisms of BBR on mitochondrial function in anti-lung cancer remain unknown. The aim of this study was to explore mitochondrial function in anti-tumor mechanisms of BBR in NSCLC. Methods: The NSCLCs were cultured and treated with various doses (40, 80, 120 µg/mL) of BBR for 24 and 48 h. Cell viability was evaluated using Cell Counting Kit-8 (CCK-8). Cell apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. Relative protein expression was examined by western blot and immunohistochemical (IHC) analysis. Results: BBR potently suppressed NSCLC cells growth by inducing apoptosis in a dose-and time-dependent manner. BBR induced apoptosis in NSCLC cells as evidenced by caspase-3 cleavage, cytochrome c release, and mitochondrial membrane depolarization. BBR-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of c-jun-NH2-kinase (JNK) and the JNK inhibitor (SP600125) significantly suppressed BBR-induced apoptosis, N-acetyl cysteine (NAC), a ROS scavenger, was sufficient to both suppress apoptosis signal-regulating kinase 1 (ASK1) and JNK activation and disrupt apoptotic induction. Conclusions: The results suggest that BBR induces apoptosis of NSCLC cells via ROS-mediated ASK1/JNK activation and the mitochondrial pathway.

Novel Fluorescent Probe Based on Rare-Earth Doped Upconversion Nanomaterials and Its Applications in Early Cancer Detection.

In this paper, a novel rare-earth-doped upconverted nanomaterial NaYF4:Yb,Tm fluorescent probe is reported, which can detect cancer-related specific miRNAs in low abundance. The detection is based on an upconversion of nanomaterials NaYF4:Yb,Tm, with emissions at 345, 362, 450, 477, 646, and 802 nm, upon excitation at 980 nm. The optimal Yb3+:Tm3+ doping ratio is 40:1, in which the NaYF4:Yb,Tm nanomaterials have the strongest fluorescence. The NaYF4:Yb, Tm nanoparticles were coated with carboxylation or carboxylated protein, in order to improve their water solubility and biocompatibility. The two commonly expressed proteins, miRNA-155 and miRNA-150, were detected by the designed fluorescent probe. The results showed that the probes can distinguish miRNA-155 well from partial and complete base mismatch miRNA-155, and can effectively distinguish miRNA-155 and miRNA-150. The preliminary results indicate that these upconverted nanomaterials have good potential for protein detection in disease diagnosis, including early cancer detection.

The exploration of quantum dot-molecular beacon based MoS2 fluorescence probing for myeloma-related Mirnas detection.

Highly sensitive and reliable detection of multiple myeloma remains a major challenge in liquid biopsy. Herein, for the first time, quantum dot-molecular beacon (QD-MB) functionalized MoS2 (QD-MB @MoS2) fluorescent probes were designed for the dual detection of multiple myeloma (MM)-related miRNA-155 and miRNA-150. The results indicate that the two probes can effectively detect miRNA-155 and miRNA-150 simultaneously with satisfactory recovery rates, and the limit of detections (LODs) of miRNA-155 and miRNA-150 in human serum are low to 7.19 fM and 5.84 fM, respectively. These results indicate that our method is the most sensitive detection so far reported and that the designed fluorescent probes with signal amplification strategies can achieve highly sensitive detection of MM-related miRNAs for MM diagnosis.

QiShenYiQi Pill Ameliorates Cardiac Fibrosis After Pressure Overload-Induced Cardiac Hypertrophy by Regulating FHL2 and the Macrophage RP S19/TGF-ß1 Signaling Pathway.

Purpose: Heart failure (HF) is a leading cause of morbidity and mortality worldwide, and it is characterized by cardiac hypertrophy and fibrosis. However, effective treatments are not available to block cardiac fibrosis after cardiac hypertrophy. The QiShenYiQi pill (QSYQ) is an effective treatment for chronic HF. However, the underlying mechanism remains unclear. Methods: In the present study, a pressure overload-induced cardiac hypertrophy model was established in rats by inducing ascending aortic stenosis for 4 weeks. QSYQ was administered for 6 weeks, and its effects on cardiac fibrosis, myocardial apoptosis, RP S19 release, macrophage polarization, TGF-ß1 production, and TGF-ß1/Smad signaling were analyzed. In vitro studies using H9C2, Raw264.7, and RDF cell models were performed to confirm the in vivo study findings and evaluate the contribution to the observed effects of the main ingredients of QSYQ, namely, astragaloside IV, notoginsenoside R1, 3,4-dihydroxyl-phenyl lactic acid, and Dalbergia odorifera T. C. Chen oil. The role of four-and-a-half LIM domains protein 2 (FHL2) in cardiac fibrosis and QSYQ's effects were assessed by small interfering RNAs (siRNAs). Results: QSYQ ameliorated cardiac fibrosis after pressure overload-induced cardiac hypertrophy and attenuated cardiomyocyte apoptosis, low FHL2 expression, and TGF-ß1 release by the injured myocardium. QSYQ also inhibited the following: release of RP S19 from the injured myocardium, activation of C5a receptors in monocytes, polarization of macrophages, and release of TGF-ß1. Moreover, QSYQ downregulated TGF-ßR-II expression induced by TGF-ß1 in fibroblasts and inhibited Smad protein activation and collagen release and deposition. Conclusion: The results showed that QSYQ inhibited myocardial fibrosis after pressure overload, which was mediated by RP S19-TGF-ß1 signaling and decreased FHL2, thus providing support for QSYQ as a promising therapy for blocking myocardial fibrosis.

Ameliorative effect and mechanism of Si-Ni-San on chronic stress-induced diarrhea-irritable bowel syndrome in rats.

Background: Chronic stress-induced diarrhea is a common clinical condition, characterized by an abnormal bowel movement and loose stools, which lacks effective treatment in the clinic. Si-Ni-San (SNS) is a compound traditional Chinese medicine extensively used in China for stress-related diarrhea. However, the mechanism is unclear. Methods: Male Wistar rats (200 ± 20 g) were placed in a restraint cylinder and fixed horizontally for 3 h once daily for 21 consecutive days to establish a chronic restraint stress (CRS) rat model. SNS (0.6944 g/kg or 1.3888 g/kg) was given by gavage 1 h before the restraint once daily for 21 consecutive days. We examined the fecal score, dopamine ß hydroxylase (DßH), and c-fos expression in locus coeruleus, norepinephrine (NE) content in ileum and plasma, expression of α1 adrenergic receptors, MLCK, MLC, and p-MLC in the colon and mesenteric arteries, contraction of isolated mesenteric arteries, The expression of subunit δ of ATP synthase (ATP5D) in intestinal tissues, ATP, ADP, and AMP content in the ileum and colon, occludin expression between ileum epithelial cells, the number of enterochromaffin cells (ECs) and mast cells (MCs) in the ileum, and 5-hydroxytryptamine (5-HT) content in the ileum and plasma. Results: After SNS treatment, the fecal score was improved. The increased expression of DßH and c-fos in locus coeruleus was inhibited. SNS suppressed the increased NE content in the ileum and plasma, down-regulated α1 adrenergic receptors in mesenteric arteries and MLCK, MLC, p-MLC in the colon and mesenteric arteries, and inhibited the contraction of mesenteric arteries. SNS also increased the ATP content in the ileum and colon, inhibited low expression of ATP5D in intestinal tissues, inhibited the decrease of ATP/ADP in the ileum and ATP/AMP in the colon, and up-regulated the occludin expression between ileum epithelial cells. In addition, SNS inhibited the increase of ECs and MCs in the ileum and the increase of 5-HT content in the ileum and plasma. Conclusion: This study demonstrated that SNS could improve CRS-induced abnormal feces in rats. This effect was related to the inhibition of CRS-induced increased expression of DßH and c-fos in the locus coeruleus, NE content in the ileum and plasma, and the contraction of isolated mesenteric arteries; inhibition of energy metabolism abnormality and decreased occludin expression; inhibition of increased ECs and MCs in the ileum, and 5-HT content in the ileum and plasma.

Highly Sensitive Detection of miRNA-155 Using Molecular Beacon-Functionalized Monolayer MoS2 Nanosheet Probes with Duplex-Specific Nuclease-Mediated Signal Amplification.

MicroRNA-155 (miRNA-155) as a characteristic myeloma-associated biomarker exhibits significant potential application in the diagnosis of multiple myeloma (MM). In this paper, a novel type of molecular beacon (MB)-functionalized monolayer MoS2 nanosheet probe was proposed as fluorescent probe for high-sensitive assays of miRNA-155that uses a duplexspecificnuclease (DSN) enzyme to amplify the fluorescence signal. The preparation and detection conditions of the fluorescent probes were optimized in some aspects, such as the concentration of MoS2 (0.80 µM) and DSN (0.2 U), and the incubation time of DSN (30 min). The probesexhibited a sensitive fluorescence response to miRNA-155 and the fluorescence signal of the assay was significantly amplified by the cleavage of DSN. The relationship between F/F0 and logC miRNA follows a linear calibration curve, and the limit of detection (LOD) of miRNA-155 in 10% human serum is calculated to be 10.96 fM based on this relationship. The good performance and fluorescence amplification effect of the fluorescent probe were confirmed by studying the recovery of miRNA-155 in 10% human serum, which was ranged from 98.32% to 106.3% with a relative standard deviation of less than 4.14%. Besides, the high expression of miRNA-155 in clinic blood of MM patients was sensitively distinguished from healthy peoples by using the proposed probes. The proposed novel fluorescent probe based on the DSN can be used to detect miRNA-155 in human serum and provide a potential, convenient and reliable tool for diagnosis of MM.

α-Lipoic Acid Targeting PDK1/NRF2 Axis Contributes to the Apoptosis Effect of Lung Cancer Cells.

As an antioxidant, α-lipoic acid (LA) has attracted much attention to cancer research. However, the exact mechanism of LA in cancer progression control and prevention remains to be unclear. In this study, we demonstrated that α-lipoic acid has inhibitory effects on the proliferation, migration, and proapoptotic effects of non-small-cell lung cancer (NSCLC) cell lines A549 and PC9. LA-induced NSCLC cell apoptosis was mediated by elevated mitochondrial reactive oxygen species (ROS). Further study confirmed that it is by downregulating the expression of PDK1 (the PDH kinase), resulted in less phospho-PDH phenotype which could interact with Keap1, the negative controller of NRF2, directly leading to NRF2 decrease. Thus, by downregulating the NRF2 antioxidant system, LA plays a role in promoting apoptosis through the ROS signaling pathway. Moreover, LA could enhance other PDK inhibitors with the proapoptosis effect. In summary, our study shows that LA promotes apoptosis and exerts its antitumor activity against lung cancer by regulating mitochondrial energy metabolism enzyme-related antioxidative stress system. Administration of LA to the tumor-bearing animal model further supported the antitumor effect of LA. These findings provided new ideas for the clinical application of LA in the field of cancer therapy.

SLAMF8 expression predicts the efficacy of anti-PD1 immunotherapy in gastrointestinal cancers.

OBJECTIVES: Epstein-Barr virus (EBV) infection is associated with a better response to anti-PD1 immunotherapy. We hypothesised that genetic alterations induced by EBV infection are responsible for the activation of key immune responses and hence are predictive of anti-PD1 efficacy. METHODS: With transcriptome data of gastric cancer (GC), we explored differentially expressed genes (DEGs) specific for EBV infection and performed coexpression network analysis using the DEGs to identify the consistent coexpression genes (CCGs) between EBV-positive and EBV-negative GC tissues. We selected the tag genes of the CCGs and validated them using RNA sequencing and immunohistochemistry. We established murine models and collected tissues from clinical patients to test the value of SLAMF8 in predicting anti-PD1 treatment. The location and expression of SLAMF8 were characterised by multiplex immunofluorescence and quantitative PCR. Moreover, exogenous overexpression and RNA-sequencing analysis were used to test the potential function of SLAMF8. RESULTS: We identified 290 CCGs and validated the tag gene SLAMF8 in transcriptome data of gastrointestinal cancer (GI). We observed that the T-cell activation pathway was significantly enriched in high-expression SLAMF8 GI cancers. Higher SLAMF8 expression was positively associated with CD8 expression and a better response to anti-PD1 treatment. We further observed dynamically increased expression of SLAMF8 in murine models relatively sensitive to anti-PD1 treatment. SLAMF8 was mainly expressed on the surface of macrophages. Exogenous overexpression of SLAMF8 in macrophages resulted in enrichment of positive regulation of multiple immune-related pathways. CONCLUSION: Higher SLAMF8 expression may predict better anti-PD1 immunotherapy efficacy in GI cancer.

[Influences of peroxisome proliferator-activated receptor gamma 2 genetic polymorphism on the effects of dietary intervention to the blood lipids abnormalities].

OBJECTIVE: To find out the effects of peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) genetic polymorphism and nutrition intervention to blood lipid abnormal population. METHODS: 412 hyperlipemia residents of Han group were screened from 3 main districts in Nanjing by multistage stratified cluster random sampling, and separated into nutritional intervention and control group by simple random method. The intervention group (221 individuals) were provided with coarse good grain and health education while only health education was provided for the control group (191 individuals). Medical examinations (including body mass index (BMI), waist-to-hip ratio (WHR); total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and fasting blood glucose (FBG)) were taken every 6 months between March 2007 and March 2008, and PPARgamma2 genetic polymorphism was also detected later. RESULTS: After intervention, TC levels of intervention group and control group were (4.90 +/- 0.86) and (5.16 +/- 0.94) mmol/L respectively; TG levels were (1.68 +/- 0.97) and (2.29 +/- 1.10) mmol/L respectively; HDL-C levels were (1.35 +/- 0.36) and (1.16 +/- 0.33) mmol/L respectively, all of the differences were significant in statistics (t values were -2.95, -6.01, 5.55 respectively, P < 0.01). The levels of BMI ((24.81 +/- 3.21) kg/m(2)), WHR (0.88 +/- 0.07), FBG ((5.40 +/- 1.17) mmol/L), TC ((4.92 +/- 0.87) mmol/L) and TG ((1.68 +/- 1.01) mmol/L) decreased significantly (t values were 19.06, 16.43, 1.98, 8.86, -14.32 respectively, P < 0.01) compared to the levels before intervention (BMI (25.39 +/- 3.30) kg/m(2), WHR (0.92 +/- 0.07), FBG (6.07 +/- 2.17) mmol/L, TC (5.28 +/- 0.94) mmol/L and TG (2.70 +/- 1.86) mmol/L), while HDL-C (1.37 +/- 0.36) mmol/L increased significantly compared to the level before intervention (1.13 +/- 0.42) mmol/L (t = -7.68, P < 0.01) in the individuals with Pro/Pro of intervention group. WHR (0.90 +/- 0.06) and TG ((1.71 +/- 0.59) mmol/L) decreased significantly compared to the levels before intervention (WHR (0.95 +/- 0.06) and TG (2.58 +/- 1.12) mmol/L) (t values were -3.53 and -8.05 respectively, P < 0.01) in the ones with Pro/Ala. Moreover, susceptibility of change for BMI in Pro/Pro genotype carriers ((-1.21 +/- 1.02) kg/m(2)) was significantly greater than that in Pro/Ala genotype carriers ((-0.58 +/- 1.85) kg/m(2), t = -6.29, P < 0.01). CONCLUSION: Several indices of individuals with Pro/Pro improved obviously after nutrition intervention, which showed that effects of intervention to these people were better than those with Pro/Ala and Ala/Ala.