Adjuvant immunotherapy in early-stage resectable non-small cell lung cancer: A new milestone.

Currently, chemotherapy is the standard adjuvant treatment for early-stage non-small cell lung cancer (NSCLC). However, adjuvant cisplatin-based chemotherapy after surgery has been shown to improve 5-year survival rates by only 4-5%. Immunotherapy using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced NSCLC, there is a growing interest in the role of immunotherapy in early-stage NSCLC. Here, we summarize the rationale for adjuvant immunotherapy, including the postoperative immunosuppressive environment and immunological effects of platinum chemotherapy. Many ongoing clinical trials and the related progress in adjuvant immunotherapy in early-stage resectable NSCLC are discussed. Furthermore, we highlight several unresolved challenges, including markers predictive of treatment benefit, the efficacy of treatment for some oncogene-addicted tumors, the optimal combination therapy, the duration of adjuvant immunotherapy, and optimal selection between neoadjuvant and adjuvant immunotherapy. Early findings in some clinical trials are promising, and updated overall survival results will be useful for validating the current role of adjuvant immunotherapy, particularly in the context of perioperative strategy.

Characterization of LTr1 derived from cruciferous vegetables as a novel anti-glioma agent via inhibiting TrkA/PI3K/AKT pathway.

Malignant glioma is the most fatal, invasive brain cancer with limited treatment options. Our previous studies show that 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr1), a major metabolite of indole-3-carbinol (I3C) derived from cruciferous vegetables, produces anti-tumour effect against various tumour cell lines. In this study we characterized LTr1 as a novel anti-glioma agent. Based on screening 134 natural compounds and comparing the candidates' efficacy and toxicity, LTr1 was selected as the lead compound. We showed that LTr1 potently inhibited the viability of human glioma cell lines (SHG-44, U87, and U251) with IC50 values of 1.97, 1.84, and 2.03 µM, respectively. Furthermore, administration of LTr1 (100,300 mg· kg-1 ·d-1, i.g. for 18 days) dose-dependently suppressed the tumour growth in a U87 xenograft nude mouse model. We demonstrated that LTr1 directly bound with TrkA to inhibit its kinase activity and the downstream PI3K/AKT pathway thus inducing significant S-phase cell cycle arrest and apoptosis in SHG-44 and U87 cells by activating the mitochondrial pathway and inducing the production of reactive oxygen species (ROS). Importantly, LTr1 could cross the blood-brain barrier to achieve the therapeutic concentration in the brain. Taken together, LTr1 is a safe and promising therapeutic agent against glioma through inhibiting TrkA/PI3K/AKT pathway.

Neuroprotective effects of a lead compound from coral via modulation of the orphan nuclear receptor Nurr1.

AIMS: To screen coral-derived compounds with neuroprotective activity and clarify the potential mechanism of lead compounds. METHODS: The lead compounds with neuroprotective effects were screened by H2 O2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP+ )-induced cell damage models in SH-SY5Y cells. CCK8 and LDH assays were used to detect cell viability. The anti-apoptosis of lead compounds was evaluated by flow cytometry. JC-1 and MitoSox assays were performed to examine the changes in mitochondrial membrane potential and mitochondrial ROS level. Survival of primary cortical and dopaminergic midbrain neurons was measured by MAP2 and TH immunoreactivities. The Caenorhabditis elegans (C. elegans) model was established to determine the effect of lead compounds on dopaminergic neurons and behavior changes. RESULTS: Three compounds (No. 63, 68, and 74), derived from marine corals, could markedly alleviate the cell damage and notably reverse the loss of worm dopaminergic neurons. Further investigation indicated that compound 63 could promote the expression of Nurr1 and inhibit neuronal apoptosis signaling pathways. CONCLUSION: Lead compounds from marine corals exerted significant neuroprotective effects， which indicated that coral might be a new and potential resource for screening and isolating novel natural compounds with neuroprotective effects. Furthermore, this study also provided a new strategy for the clinical treatment of neurodegenerative diseases such as Parkinson's disease.

CUL4B increases platinum-based drug resistance in colorectal cancer through EMT: A study in its mechanism.

Platinum-based chemotherapy drugs play a very important role in the treatment of patients with advanced colorectal cancer, but the drug resistance of platinum-based chemotherapy drugs is an important topic that puzzles us. If we can find mechanisms of resistance, it will be revolutionary for us. We analysed the differential genes, core genes and their enrichment pathways in platinum-resistant and non-resistant patients through a public database. Platinum-resistant cell lines were cultured in vitro for in vitro colony and Transwell analysis. Tumorigenesis analysis of nude mice in vivo. Verify the function of core genes. Through differential gene and enrichment analysis, we found that CUL4B was the main factor affecting platinum drug resistance and EMT. Our hypothesis was further verified by in vitro drug-resistant and wild-type cell lines and in vivo tumorigenesis analysis of nude mice. CUL4B leads to platinum drug resistance in colorectal cancer by affecting tumour EMT.

Adjuvant Chemotherapy in Node-Negative Advanced Gastric Cancer Patients.

Currently, there is still controversy on postoperative adjuvant chemotherapy for node-negative advanced gastric cancer. Herein, we sought to evaluate the role of postoperative adjuvant chemotherapy in these patients. We retrospectively analyzed the clinical and pathological characteristics of 363 node-negative advanced gastric cancer patients in our hospital from 1996 to 2007 who underwent gastrectomy and D2 lymphadenectomy. We compared the survival rate of the surgery-only group with that of the adjuvant chemotherapy treatment group. The 5-year survival rates of patients in the surgery-only group and the chemotherapy treatment group were 70.7% and 73.8%, respectively. There was no significant difference in the survival rate between patients receiving postoperative chemotherapy and patients not receiving chemotherapy (P=0.328). However, postoperative chemotherapy treatment significantly increased the survival rate of pT4aN0M0 patients (P=0.020), although it did not exert a direct effect on the survival rate in pT2N0M0 and pT3N0M0 patients (P=0.990 and P=0.895). We also summarized and analyzed the side effects and safety of postoperative adjuvant chemotherapy. The rate of chemotherapy-related adverse events was 79.9%. Although 61 (36.1%) patients had to adjust their chemotherapy dose, no patient died from side effects. In conclusion, postoperative chemotherapy treatment is safe but did not show a direct impact on the survival rate of the node-negative advanced gastric cancer patients. However, pT4aN0M0 patients can benefit from postoperative adjuvant chemotherapy after undergoing D2 radical resections.

[Effects of oxymatrine and vincristine on drug resistance in HCT-8/VCR cells and its mechanism].

OBJECTIVE: To study the effects of oxymatrine and vincristine on resistance in HCT-8/VCR cells and its mechanism. METHODS: HCT-8 / VCR cells were cultured in vitro and were divided into blank control group, oxymatrine group, vincristine group, oxymatrine and vincristine combined group, each group had 6 complexes. The drug resistance of HCT-8/VCR cells was investigated by CCK-8 when treated with vincristine alone or in combination with oxymatrine. The autophagy was determined by monodansylcadaverine (MDC) staining. The level of IL-6 was detected by ELISA. The expressions of autophagy-related gene P62, LC3-Ⅱ / LC3-Ⅰ, Beclin-1 protein and TLR4 were detected by Western blot assay. RESULTS: Oxymatrine combined with vincristine could reduce the drug resistance of HCT-8 / VCR cells by the reversal multiple of 3.23. Compared with the blank control group, the content of autophagosome and the content of IL-6 in the oxymatrine group and the combination group were also decreased significantly (P＜0.01). The content of autophagosome in the vincristine group was increased and the content of IL-6 was also significantly increased (P＜0.01). Compared with the oxymatrine group, the combination group had higher autophagosome content, while IL-6 content was decreased (P＜0.01); Western blot experiments showed that compared with the blank control group, the expression of P62 in the oxymatrine group was decreased (P＜0.05), while the expressions of LC3-Ⅱ / LC3-Ⅰ, Beclin-1 and TLR4 were all increased (P＜0.05). The expression of P62 in the vincristine group and the combined group was increased (P＜0.05), and the expressions of LC3-Ⅱ / LC3-Ⅰ, Beclin-1, and TLR4 were all decreased (P＜0.05). Compared with the vincristine group, the expression of P62 was increased in the combination group (P＜0.05), and the expressions of LC3-Ⅱ / LC3-Ⅰ, Beclin-1, and TLR4 were all decreased (P＜0.05). CONCLUSION: Oxymatrine combined with vincristine can reduce the drug resistance of HCT-8/VCR cells, which may be related to the regulation of autophagy activity and TLR4 signal activation.

Adaptation of Defensive Strategies by the Pea Aphid Mediates Predation Risk from the Predatory Lady Beetle.

Within a species, individual animals adopt various defensive strategies to resist natural enemies, but the defensive strategies that are adopted in response to variations in predation risk are poorly understood. Here, we assessed consecutive foraging processes on cohorts of two biotypes (green and red) of the pea aphid, Acyrthosiphon pisum, by the predatory lady beetle Propylea japonica, to investigate the adaptive mechanism underlying the defensive strategy. We observed the behavioral responses of individuals (continue feeding or escape, i.e., walk away or drop off from initial feeding site), simultaneously quantified the amount of alarm pheromone, (E)-ß-farnesene (EßF) released from cohorts using gas chromatography-mass spectrometry (GC-MS), and recorded the foraging times of predators in intervals. The results indicated that: (1) the anti-predator responses differed markedly between biotypes and among the stages of the consecutive foraging processes. (2) Few green cohorts tended to release EßF during the first foraging; those that did released only a low dose that did not increase the number of escapes. However, the amount of EßF rose rapidly following the second foraging process, which caused an intense escape response. In contrast, more red cohorts released greater amounts of EßF, which caused more individuals to escape from their innate feeding sites during the first foraging. During the second foraging, more red individuals tended to escape without releasing EßF in greater quantities. (3) The foraging time was effectively shortened in each biotype cohort that adopted diverse defensive strategies. This study of the defensive strategies of the pea aphid may contribute to understanding the intraspecific differences in aphid defense mechanisms.

Inhibitory effects of emodin, baicalin, schizandrin and berberine on hefA gene: treatment of Helicobacter pylori-induced multidrug resistance.

AIM: To investigate the inhibitory effects of emodin, baicalin, etc. on the hefA gene of multidrug resistance (MDR) in Helicobacter pylori (H. pylori). METHODS: The double dilution method was used to screen MDR H. pylori strains and determine the minimum inhibitory concentrations (MICs) of emodin, baicalin, schizandrin, berberine, clarithromycin, metronidazole, tetracycline, amoxicillin and levofloxacin against H. pylori strains. After the screened MDR stains were treated with emodin, baicalin, schizandrin or berberine at a 1/2 MIC concentration for 48 h, changes in MICs of amoxicillin, tetracycline, levofloxacin, metronidazole and clarithromycin were determined. MDR strains with reduced MICs of amoxicillin were selected to detect the hefA mRNA expression by real-time quantitative PCR. RESULTS: A total of four MDR H. pylori strains were screened. Treatment with emodin, baicalin, schizandrin and berberine significantly decreased the MICs of amoxicillin and tetracycline against some strains, decreased by 1 to 2 times, but did not significantly change the MICs of clarithromycin, levofloxacin, and metronidazole against MDR strains. In the majority of strains with reduced MICs of amoxicillin, hefA mRNA expression was decreased; one-way ANOVA (SPSS 12.0) used for comparative analysis, P < 0.05. CONCLUSION: Emodin, baicalin, schizandrin and berberine significantly decreased the MICs of amoxicillin and tetracycline against some H. pylori strains, possibly by mechanisms associated with decreasing hefA mRNA expression.

[Study on ultrasonic extraction and macroporous resin purification techniques of total flavones from Sedum lineare].

OBJECTIVE: To optimize the ultrasonic extraction condition and purification process of total flavonoids in Sedum lineare by macroporous resin. METHODS: Optimum ultrasonic extraction conditions (ethanol concentration, solid/liquid, ultrasonic time, working temperature) were obtained through orthogonal design. The adsorption ratio and eluting ratio of total flavones were selected as indexes. RESULTS: The optimum ultrasonic extraction condition was 80% ethanol, solid/liquid 1:40, ultrasonic 20 min at 30 degrees C. The adsorbed AB-8 macroporous resin column was eluted by 80% ethanol at the eluting velocity of 2 mL/min, the eluting ratio and purity of total flavones was 94.72% and 43.51%, respectively. CONCLUSION: The method is simple and low cost.

Effect of needle damage on the release rate of Masson pine (Pinus massoniana) volatiles.

The effect of needle damage on the release rate of Masson pine (Pinus massoniana Lamb.) volatiles was examined. Needles were continuously damaged by mechanical damage (MDP) or by feeding of pine caterpillar (Dendrolimus punctatus) larvae (LFP); undamaged pine was used as a control (UDP). Volatiles were collected before damage, and at 16, 24, 40, 48, 64, 72, 88 and 96 h post-damage, and analyzed. The analyses revealed that 19 compounds identified as constitutive volatiles from UDP were terpenes and green leaf odors. The release rate of volatiles from MDP or LFP was higher than that from UDP. At 96 h post-damage, emission from MDP or LFP returned to the same level as that of UDP. Some volatiles, including sabinene, ocimene, limonene-1,2-epoxide, linalool, linalool acetate, germacrene D: -4-ol, farnesol, and (E)-4,8-dimethyl-1,3,7-nonatriene were induced by mechanical damage and/or larval attack. Furthermore, the release rate of linalool acetate, farnesol, or (E)-4,8-dimethyl-1,3,7-nonatriene from LFP was higher than that from MDP. Based on an exact estimation of the proportion of damaged pine needles, a significant linear correlation between the release rate of total volatiles identified and the proportion of damaged needles was found in the case of LFP but not MDP.