Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

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低氧运动干预肥胖模型大鼠下丘脑Nesfatin-1和Ghrelin水平

文题释义：Ghrelin：是一种含有28个氨基酸残基的短肽，于1999年被发现，主要由胃底分泌，在下丘脑中也有表达，其可促进摄食、减少能量消耗和增加体质量，是目前发现的唯一促食欲激素。 Nesfatin-1：是一种由82个氨基酸组成的神经肽，于2006年被发现，具有减少摄食、调节能量平衡和减轻体质量的作用。 背景：均衡饮食和科学运动是公认的安全、有效且经济的体质量管理干预方式，但运动本身有时却提升了减肥者食欲，如果将低氧环境刺激和有氧运动干预结合，可能会收到最好的减质量效果。下丘脑作为机体调控摄食和能量平衡的中枢，其调控因子与肥胖症发病机制之间的关系备受关注。 目的：观察低氧或/和运动后肥胖大鼠下丘脑nesfatin-1和ghrelin水平变化，探讨低氧或/和运动影响机体摄食和体质量的神经内分泌机制。 方法：60只营养性肥胖SD大鼠均分为常氧安静组、常氧运动组、16.3%低氧安静组、16.3%低氧运动组、13.3%低氧安静组和13.3%低氧运动组，进行8周的低氧或/和运动干预。低氧环境采用低氧发生器分别营造体积分数为16.3%氧气和13.3%氧气环境，低氧干预组大鼠每天12 h在低氧环境中生活和运动；运动干预采用跑台运动方案(跑速20 m/min、坡度0°)，持续时间40 min，5 d/周。记录干预期大鼠体质量、摄食量，计算干预前后Lee’s指数，用ELISA试剂盒检测干预后大鼠下丘脑nesfatin-1和ghrelin水平。 结果与结论：①干预后大鼠体质量与Lee’s指数：单纯低氧环境刺激对大鼠体质量、Lee’s指数的影响没有单纯有氧运动刺激明显，而当低氧和运动结合时，其效果优于单一刺激；②干预期间大鼠日均摄食量：常氧安静组保持平稳，其余各组均减少，尤以16.3%低氧运动组、13.3%低氧运动组明显；③下丘脑nesfatin-1和ghrelin水平：低氧结合运动可影响大鼠下丘脑nesfatin-1水平，其中13.3%低氧运动组的nesfatin-1水平最高；单纯的运动或低氧均可影响大鼠下丘脑ghrelin水平，而单一运动刺激效果强于单一低氧刺激，当二者结合时降低效果更明显；④双因素方差分析：体质量和ghrelin水平受运动的影响，体质量、Lee’s指数和摄食量受氧气体积分数的影响，体质量、nesfatin-1和ghrelin水平受运动×氧气体积分数的影响；⑤结果表明，8周低氧运动可能通过影响肥胖大鼠下丘脑nesfatin-1与ghrelin水平来减少大鼠的摄食量，抑制其体质量增长，降低其Lee’s指数，但具体机制需待进一步研究。 ORCID: 0000-0002-1519-7825(范锦勤) 中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程     

Bioinformatic analysis of cytokine expression in the proximal and distal nerve stumps after peripheral nerve injury

In our previous study, we investigated the dynamic expression of cytokines in the distal nerve stumps after peripheral nerve injury using microarray analysis, which can characterize the dynamic expression of proteins. In the present study, we used a rat model of right sciatic nerve transection to examine changes in the expression of cytokines at 1, 7, 14 and 28 days after injury using protein microarray analysis. Interleukins were increased in the distal nerve stumps at 1–14 days post nerve transection. However, growth factors and growth factor-related proteins were mainly upregulated in the proximal nerve stumps. The P-values of the inflammatory response, apoptotic response and cell-cell adhesion in the distal stumps were higher than those in the proximal nerve stumps, but the opposite was observed for angiogenesis. The number of cytokines related to axons in the distal stumps was greater than that in the proximal stumps, while the percentage of cytokines related to axons in the distal stumps was lower than that in the proximal nerve stumps. Visualization of the results revealed the specific expression patterns and differences in cytokines in and between the proximal and distal nerve stumps. Our findings offer potential therapeutic targets and should help advance the development of clinical treatments for peripheral nerve injury. Approval for animal use in this study was obtained from the Animal Ethics Committee of the Chinese PLA General Hospital on September 7, 2016(approval No. 2016-x9-07).     

Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response

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ADORA1 Inhibition Promotes Tumor Immune Evasion by Regulating the ATF3-PD-L1 Axis

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Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia

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Induced and natural regulatory T cells in human cancer

Introduction: Evidence suggests that FOXP3⁺CD25^highCD4⁺ regulatory T cells (Treg) which accumulate in cancer may have beneficial or unfavorable effects on prognosis. The presence in tumor-associated inflammatory infiltrates of two subsets of Treg with distinct phenotypic and functional profiles might explain these conflicting observations.

Areas covered: Human inducible (i) Treg arising by tumor-driven conversion of conventional CD4⁺ T cells are highly suppressive, therapy-resistant Treg which down-regulate anti-tumor immune responses, promoting tumor growth. Natural (n) Treg, normally responsible for maintaining peripheral tolerance, control cancer-associated inflammation, which favors tumor progression. This division of labor between nTreg and iTreg is not absolute, and overlap may be common. Nevertheless, iTreg play a critical and major role in cancer and cancer therapy. The tumor microenvironment determines the type, frequency and suppression levels of accumulating Treg.

Expert opinion: In cancer, a selective removal or silencing of iTreg and not of nTreg should be a therapeutic goal. However, the implementation of this challenging strategy requires further studies of cellular and molecular crosstalk among immune cells in the tumor microenvironment.     

Interventional effect of laser acupoint radiation on the expression of Nissl body and brain-derived neurotrophic factor in newborn rat models with ischemic/hypoxic cerebral injury

BACKGROUND: Some researches report that He-Ne laser can activate function of erythrocytes and increase content of blood and oxygen via bio-stimulating effect; therefore, it suspects that laser radiation at Baihui and Dazhui can partially increase blood circulation for oxygen-supplying content of brain and improve functional status of neurons. OBJECTIVE: To verify the effects of laser radiation at Baihui and Dazhui on the expression of Nissl body of brain tissue neurons and brain-derived neurotrophic factor (BDNF) in newborn rats with ischemic/hypoxic cerebral injury. DESIGN: Randomized controlled animal study. SETTING: Department of Neurological Histochemistry, Xianning University. MATERIALS: Forty Wistar rats of 7–8 days old, weighing 15–20 g and of both genders, were selected from Wuhan Experimental Animal Center. All the rats were randomly divided into sham operation group (n =8), model group (n =16) and radiation group (n =16). The experimental animals were disposed according to ethical criteria. BDNF kit was provided by Wuhan Boster Bioengineering Co., Ltd. METHODS: The experiment was carried out in the Department of Neurological Histochemistry, Xianning University from April 2005 to October 2006. Rats in the radiation group and model group were performed with ligation of left common carotid artery, recovered at room temperature for 1–6 days, maintained in self-made hypoxic cabin under normal pressure and injected mixture gas (0.05 volume fraction of O2 and 0.92 volume fraction of N2) for 2 hours. In addition, rats in the sham operation group were treated with separation of left common carotid artery but not ligation and hypoxia. Rats in the model group were not given any treatment; while, rats in the radiation group were exposed with He-Ne laser of 63.28 nm in the wave length at Baihui and Dazhui acupoints on the second day after ischemia-hypoxia. The radiation was given for 10 minutes per day and once a day. Ten days were regarded as a course and the rats were exposed for 2 courses in total. At 20 days after routine breeding, left hemisphere tissues of rats in the three groups were collected for staining of Nissl body and immunohistochemistry of BDNF. MAIN OUTCOME MEASURES: Nissl body staining in left hemisphere tissue and expression of immune positive cells of BDNF. RESULTS: All 40 rats were involved in the final analysis. ① Nissl body staining: Neuronal cytoplasm of brain tissue was full of blue granule Nissl bodies in the sham operation group; while, Nissl body in neuronal cytoplasm in the model group was stained slightly and had a certain degree of degeneration; meanwhile, there were a lot of blank area in ischemic region. Nissl body in neuron cytoplasm was gradually recovered in the radiation group and relieved as compared with that in the model group. ② Positive cells of BDNF: Number of immune positive cells of BDNF which were ligated in lateral cerebral hemisphere of rats in the model group was higher than that in the sham operation group (P < 0.05); while, BDNF expression in the radiation group was increased as compared with that in the model group (P < 0.05). CONCLUSION: After laser acupoint radiation, Nissl body is increased and BDNF expression is also increased. This suggests that laser acupoint radiation has neuroprotective effect on brain tissue after ischemia-hypoxia injury.     

Prognostic significance of carbonic anhydrase IX expression by cancer‐associated fibroblasts in lung adenocarcinoma

BACKGROUND:

Cancer tissue is comprised of cancer cells and several types of stromal cells, including cancer‐associated fibroblasts (CAFs). Carbonic anhydrase (CA) IX has been used as an endogenous hypoxia marker, and although its expression by cancer cells has been reported to be associated with a poor outcome in a board range of tumors, to the authors' knowledge, the biologic significance of its expression by CAFs remains unclear.

METHODS:

The authors investigated CA IX expression by CAFs and cancer cells immunohistochemically in 158 consecutive resected cases of lung adenocarcinoma.

RESULTS:

CA IX was expressed by CAFs in 39 (24.7%) of the 158 cases and by cancer cells in 40 (25.3%) cases. CA IX expression by CAFs was found to be significantly correlated with conventional prognostic factors, including pathologic tumor classification and lymph node involvement. A univariate analysis and the log‐rank test demonstrated a significant association between CA IX expression by CAFs (P = .006 and P = .0052, respectively) and by cancer cells (P = .020 and P = .0179, respectively) with lower survival rate. A multivariate analysis of these 2 factors indicated a statistically significant association between CA IX expression by CAFs and a lower survival rate (hazards ratio [HR], 1.797; P = .032), but not between expression by cancer cells and lower survival rate (HR, 1.561; P = .102).

CONCLUSIONS:

The findings of the current study indicate that CA IX expression by CAFs was a better predictor of outcome than CA IX expression by cancer cells and provides new insights into the biologic significance of CAFs in the hypoxic microenvironment of the lung adenocarcinoma. Cancer 2009. © 2009 American Cancer Society.