Antibody responses to galectin-8, TARP and TRAP1 in prostate cancer patients treated with a GM-CSF-secreting cellular immunotherapy

A critical factor in clinical development of cancer immunotherapies is the identification of tumor-associated antigens that may be related to immunotherapy potency. In this study, protein microarrays containing >8,000 human proteins were screened with serum from prostate cancer patients (N = 13) before and after treatment with a granulocyte–macrophage colony-stimulating factor (GM-CSF)-secreting whole cell immunotherapy. Thirty-three proteins were identified that displayed significantly elevated (P ≤ 0.05) signals in post-treatment samples, including three proteins that have previously been associated with prostate carcinogenesis, galectin-8, T-cell alternative reading frame protein (TARP) and TNF-receptor-associated protein 1 (TRAP1). Expanded analysis of antibody induction in metastatic, castration-resistant prostate cancer (mCRPC) patients (N = 92) from two phase 1/2 trials of prostate cancer immunotherapy, G-9803 and G-0010, indicated a significant (P = 0.03) association of TARP antibody induction and median survival time (MST). Antibody induction to TARP was also significantly correlated (P = 0.036) with an increase in prostate-specific antigen doubling time (PSADT) in patients with a biochemical (PSA) recurrence following prostatectomy or radiation therapy (N = 19) from in a previous phase 1/2 trial of prostate cancer immunotherapy, G-9802. RNA and protein encoding TARP and TRAP1 was up-regulated in prostate cancer tissue compared to matched normal controls. These preliminary findings suggest that antibody induction to TARP may represent a possible biomarker for treatment response to GM-CSF secreting cellular immunotherapy in prostate cancer patients and demonstrates the utility of using protein microarrays for the high-throughput screening of patient-derived antibody responses.     

The Tumor Suppressor pVHL Down-regulates Never-in-Mitosis A-related Kinase 8 via Hypoxia-inducible Factors to Maintain Cilia in Human Renal Cancer Cells

NEK8 (never in mitosis gene A (NIMA)-related kinase 8) is involved in cytoskeleton, cilia, and DNA damage response/repair. Abnormal expression and/or dysfunction of NEK8 are related to cancer development and progression. However, the mechanisms that regulate NEK8 are not well declared. We demonstrated here that pVHL may be involved in regulating NEK8. We found that CAK-I cells with wild-type vhl expressed a lower level of NEK8 than the cells loss of vhl, such as 786-O, 769-P, and A-498 cells. Moreover, pVHL overexpression down-regulated the NEK8 protein in 786-O cells, whereas pVHL knockdown up-regulated NEK8 in CAK-I cells. In addition, we found that the positive hypoxia response elements (HREs) are located in the promoter of the nek8 sequence and hypoxia could induce nek8 expression in different cell types. Consistent with this, down-regulation of hypoxia-inducible factors α (HIF-1α or HIF-2α) by isoform-specific siRNA reduced the ability of hypoxia inducing nek8 expression. In vivo, NEK8 and HIF-1α expression were increased in kidneys of rats subjected to an experimental hypoxia model of ischemia and reperfusion. Furthermore, NEK8 siRNA transfection significantly blocked pVHL-knockdown-induced cilia disassembling, through impairing the pVHL-knockdown-up-regulated NEK8 expression. These results support that nek8 may be a novel hypoxia-inducible gene. In conclusion, our findings show that nek8 may be a new HIF target gene and pVHL can down-regulate NEK8 via HIFs to maintain the primary cilia structure in human renal cancer cells.     

Interaction between the Effects of Inside and Outside Na and K on Bullfrog Skin Potential

The composition of the solution bathing one border of the isolated frog skin affects the response of the potential across the skin to changes in the composition of the solution bathing the opposite border. Increasing the K concentration of the inside (corium) bathing solution decreased the sensitivity of the potential to a change in outside Na concentration. Decreasing the outside Na concentration decreased the sensitivity of the potential to a change in inside K concentration. Increasing the total ionic strength of the outside bathing solution or of both bathing solutions decreased the sensitivity of the potential to a change in outside Na concentration.     

下丘脑外侧区注射TRH对大鼠胃酸分泌的影响

本文采用连续收集胃腔灌流法,观察下丘脑外侧区(LHA)注射促甲状腺激素释放激素(TRH)对大鼠胃酸分泌的影响,并分析TRH在LHA促进胃酸分泌的作用机制。结果表明:(1)LHA注射TRH(1μg)明显地刺激胃酸分泌;(2)预先向LHA注射酚妥拉明(10μg)、美多心安(5μg)及胃泌素抗体1μl(1:640)并不影响TRH的泌酸作用,如预先向LHA注射阿托品(5μg)则可消除TRH的泌酸效应;(3)垂体摘除及肾上腺切除均不影响TRH的泌酸作用;(4)隔下迷走神经切断后,LHA注入TRH的泌酸效应仍然出现,但持续时间显著缩短;腹腔交感神经节摘除后,TRH仍能促进胃酸分泌,但分泌量少而平稳。以上结果提示:LHA是TRH中枢泌酸效应的有关结构之一,其中枢机制是通过胆碱能M受体中介的,腹腔交感神经节和膈下迷走神经是TRH泌酸效应的传出途径。前者引起的泌酸反应出现较早且引起泌酸高峰,但持续时间短;后者则引起低平的持续分泌。     

低通气量呼吸对犬左空心肌收缩性的影响

大量的研究表明,急性呼吸衰竭时多伴有心血管功能的损害,但有关急性呼吸衰竭对于左室心肌收缩性的影响所知甚少。本文对开胸麻醉犬在低通气引起呼吸衰竭时,左室心肌收缩性的变化进行了观测和分析。结果表明,在实验组(n=9)低通气呼吸(通气量小于160ml/min/kg,PaO_2小于60mmHg)时,心率(HR)、主动脉平均压(MOP)、左室收缩峰压(LV-SP)、左室内压最大上升速率(dP/dt_(max))、节段心肌发展张力(DT)及其最大发展速率(dT/dt_(max))均显著降低,心肌开始收缩至dp/dt_(max)的时间(t-dp/dt_(max))和至dT/dt_(max)的时间(t-dT/dt_(max))则显著增加,与低通气呼吸前比较均有统计学差异。而在对照组(n=5)保持正常通气(通气量大于450ml/min/kg,PaO_2大于70mmHg),观察45min,未见上述指标有明显改变。本研究表明,急性呼吸衰竭时左室心肌收缩性严重受损。     

江苏泗洪下草湾中中新世脊椎动物群——6.鸟纲

本文记述了近年来在江苏泗洪下草湾组中补采到的6种鸟类,其中包括天岗琵鹭 Platalea tiangangensis sp. nov.和松林庄古石鸡 Palaeoalectoris songlinensis gen. et sp. nov.,前者系琵鹭属迄今最早的记录,后者为雉科鹑族目前已知最早的成员.     

四川盐源盆地哺乳类化石及其意义

本文简述盐源盆地上新世和更新世晚期两个不同时代的哺乳动物化石十余种,据之修正了该盆地晚新生代沉积的时代和对比关系.