BACKGROUND & AIMS: :An immediately inducible gene by gonadotropin was isolated from rat ovaries primed with pregnant mare serum gonadotropin (PMSG) by using a subtraction cloning procedure. Homology analysis revealed that the gene is a rat homologue of scavenger receptor class B-I, which was recently identified as a specific receptor for high density lipoprotein (HDL). The structure of rat SRBI was determined by nucleotide sequence analysis of full-length cDNAs for SRBI. Northern blot analysis revealed that rat SRBI mRNA levels were rapidly and strongly increased within 3 h by the injection of PMSG. In situ hybridization study revealed that SRBI mRNA was strongly induced in theca interna cells of immature rat ovary stimulated with 30 IU of PMSG for 6 h. SRBI mRNA expression was also observed in corpora lutea of the adult rat ovary. These findings indicate that expression of SRBI mRNA is restricted to and induced in the ovarian steroidogenic cell types where cholesterol is used as a substrate for synthesis of steroid hormones. Our data strongly suggest that SRBI may play a significant role in the ovarian steroidogenesis by mediating selective uptake of cholesterol from HDL to ovarian theca interna cells or to corpus luteum.

背景与目标： : 使用减法克隆程序从用妊娠母马血清促性腺激素 (PMSG) 引发的大鼠卵巢中分离出促性腺激素立即诱导的基因。同源性分析表明，该基因是清道夫受体B-I类的大鼠同源物，最近被鉴定为高密度脂蛋白 (HDL) 的特异性受体。通过SRBI全长cdna的核苷酸序列分析确定大鼠SRBI的结构。Northern印迹分析显示，通过注射PMSG，大鼠SRBI mRNA水平在3小时内迅速且强烈地增加。原位杂交研究表明，用30 IU的PMSG刺激6 h，在未成熟大鼠卵巢的卵泡膜细胞中强烈诱导SRBI mRNA。在成年大鼠卵巢的黄体中也观察到了SRBI mRNA的表达。这些发现表明，SRBI mRNA的表达仅限于并在其中胆固醇用作合成类固醇激素的底物的卵巢类固醇生成细胞类型中诱导。我们的数据强烈表明，SRBI可能通过介导胆固醇从HDL到卵巢卵泡膜细胞或黄体的选择性摄取而在卵巢类固醇生成中起重要作用。

BACKGROUND & AIMS: :Phosphorus MRS was evaluated as a monitor of tumour therapeutic response to the herpes simplex virus thymidine kinase suicide gene therapy paradigm. In vivo 31P spectra were obtained from subcutaneous rat C6 gliomas constitutively expressing the HSVtk gene post treatment with ganciclovir (GCV, 15 mg/kg i.p., twice-daily). Significant regression (p < 0.1) of tumour volume was observed 10 days after beginning GCV administration. However, no changes in tumour pH or energy metabolites from pre-treatment values were observed. High-resolution 31P spectra of tumour extracts revealed a statistically significant reduction in the phosphocholine to phosphoethanolamine ratio six days post-GCV administration. These results indicate that the HSVtk/GCV-induced killing of tumours is not associated with corresponding changes in 31P MRS-observable energy metabolites and pH. The observed reduction in the PE/PC ratio may provide a non-invasive in vivo indicator of therapeutic efficacy.

背景与目标： : 磷MRS被评估为对单纯疱疹病毒胸苷激酶自杀基因治疗范例的肿瘤治疗反应的监测仪。体内31p光谱是从用更昔洛韦治疗后组成性表达HSVtk基因的皮下大鼠C6神经胶质瘤获得的 (GCV，15 mg/kg i.P.，每天两次)。在开始GCV给药10天后观察到肿瘤体积的显著回归 (p <0.1)。然而，未观察到肿瘤pH或能量代谢物与治疗前值的变化。肿瘤提取物的高分辨率31p光谱显示，GCV给药六天后，磷酸胆碱与磷酸乙醇胺的比率在统计学上显着降低。这些结果表明，HSVtk/GCV诱导的肿瘤杀伤与31P MRS可观察到的能量代谢产物和pH的相应变化无关。观察到的PE/PC比率的降低可能提供治疗功效的非侵入性体内指标。

BACKGROUND & AIMS: :In this study, the contribution of the CD5+ B cell to the preferential expression of VH 7183 and Q52 observed early in development was determined. CD5+ and CD5- B cells from BALB/c mice were isolated by fluorescence-activated cell sorter and the expression of particular VH gene families was determined directly by in situ hybridization. The results indicate that CD5+ B cells obtained from both adult and neonatal animals express Q52 at increased levels compared with CD5- B cells. Preferential expression of VH 7183 was observed only in the neonatal CD5- B cell subset. Thus, the increased expression of VH 7183 early in development is caused by the CD5- subset whereas increased Q52 expression is caused by the CD5+ subset. These results indicate that the fetal/neonatal conventional B cell is distinct from conventional adult B cells in terms of Ig gene repertoire expression.

背景与目标： : 在这项研究中，确定了CD5 b细胞对发育早期观察到的VH 7183和Q52的优先表达的贡献。通过荧光激活细胞分选仪分离BALB/c小鼠的CD5和CD5-b细胞，并通过原位杂交直接确定特定VH基因家族的表达。结果表明，与CD5-b细胞相比，从成年动物和新生动物获得的CD5 b细胞表达Q52的水平更高。仅在新生儿cd5-b细胞亚群中观察到VH 7183的优先表达。因此，VH 7183在发育早期的表达增加是由CD5-子集引起的，而Q52表达增加是由CD5 + 子集引起的。这些结果表明，就Ig基因库表达而言，胎儿/新生儿常规b细胞与常规成人b细胞不同。

BACKGROUND & AIMS: :The utility of the Aspergillus fumigatus cellobiohydrolase cbhB promoter for controlled gene expression has been investigated. cbhB message was present at high levels in the presence of carboxymethylcellulose and undetected in the presence of glucose. A reporter construct using the cbhB promoter showed similar behaviour and gave lower message levels than the Aspergillus nidulans alcA promoter under repressing conditions. An RNAi construct driven by the cbhB promoter was used to down-regulate the alb1 gene; transformants showed low alb1 message levels and a loss-of-function phenotype with carboxymethylcellulose, while both wild-type message levels and phenotype were seen with glucose. The cbhB promoter is therefore tightly controlled and can be exploited for the study of A. fumigatus.

背景与目标： : 研究了烟曲霉纤维二糖水解酶cbhB启动子在控制基因表达中的效用。cbhB信息在羧甲基纤维素存在下以高水平存在，而在葡萄糖存在下未检测到。在抑制条件下，使用cbhB启动子的报告构建体表现出相似的行为，并且给出的信息水平低于构巢曲霉alcA启动子。由cbhB启动子驱动的RNAi构建体用于下调alb1基因; 转化子显示出较低的alb1信息水平和羧甲基纤维素的功能丧失表型，而葡萄糖则观察到野生型信息水平和表型。因此，cbhB启动子受到严格控制，可用于烟曲霉的研究。

BACKGROUND & AIMS: :Our recent study demonstrated that defects in p110delta result in B-cell immunodeficiency that is very similar to that observed in BTK-deficient mice. We revealed that the p110delta fit the B-cell signal transduction complex and played a non-redundant role in the development and function of B cells. In humans, most children with primary B-cell immunodeficiency have mutations in the BTK, whereas a few have defects in the components of the B-cell signal transduction complex. But little is known about the genetic variation of p110delta in children with defects in B-cell immunodeficiency of unknown aetiology. Sixteen patients from 15 unrelated families and 112 normal controls underwent sequence analysis to identify genetic variations of the p110delta. Allele frequency in each group was also analysed and compared. We identified five single base-pair polymorphic nucleotide exchanges in both patient and control groups with similar allele frequencies, which did not contribute to the immunodeficiency. Three of them are novel (m.953A>G, m.1200C>T and m.1561A>G), and the m.953A>G and m.1561A>G nucleotide exchanges are non-synonymous (N253S and T456A, respectively). The novel m.1561A>G was in complete linkage disequilibrium with the known m.873A>G in our study of Taiwanese group. In addition, one novel single base-pair missense mutation, m.3256G>A (E1021K), was identified in one boy with typical clinical features of primary B-cell immunodeficiency and could not be found in either his family or the normal control population. By atomic structural analysis of the amino acid as well as the alignment comparison between species, it resulted in the replacement of the negative-charged amino acid E with the positive-charged amino acid K at codon 1021, located in the highly conservative and important catalytic functional domain. Our findings could shed light on further understanding the polymorphisms of p110delta in B-cell immunodeficiency and different populations. Moreover, the 3256G>A missense mutation raised the attention and warranted further extensive analysis to elucidate the role of p110delta in human immunodeficiency.

背景与目标： : 我们最近的研究表明，p110delta的缺陷导致b细胞免疫缺陷，这与BTK缺陷小鼠中观察到的非常相似。我们揭示了p110delta符合b细胞信号转导复合物，并且在b细胞的发育和功能中起着非冗余的作用。在人类中，大多数患有原发性b细胞免疫缺陷的儿童在BTK中存在突变，而少数儿童在b细胞信号转导复合物的成分中存在缺陷。但是，对于病因不明的b细胞免疫缺陷儿童中p110delta的遗传变异知之甚少。来自15个无关家庭和112个正常对照的16名患者进行了序列分析，以鉴定p110delta的遗传变异。还对各组的等位基因频率进行了分析和比较。我们在患者组和对照组中鉴定出五个具有相似等位基因频率的单碱基对多态性核苷酸交换，这对免疫缺陷没有贡献。其中三个是新颖的 (m.953A>G，m.1200C>T和m.1561A>G)，而m.953A>G和m.1561A>G核苷酸交换是非同义的 (分别为N253S和T456A)。在我们对台湾组的研究中，新颖的m.1561A>G与已知的m.873A>G完全处于连锁不平衡状态。此外，在一名具有原发性b细胞免疫缺陷典型临床特征的男孩中鉴定出一个新的单碱基对错义突变m.3256G>A (E1021K)，在其家人或正常对照人群中均找不到。通过氨基酸的原子结构分析以及物种之间的比对比较，它导致负电荷氨基酸E被密码子1021位的正电荷氨基酸K取代，位于高度保守和重要的催化功能域。我们的发现可能有助于进一步了解b细胞免疫缺陷和不同人群中p110delta的多态性。此外，3256G>A错义突变引起了人们的注意，并需要进一步广泛的分析来阐明p110delta在人类免疫缺陷中的作用。

BACKGROUND & AIMS: Rabbits predominantly rearrange the most 3'VH gene (VH1); thus combinatorial diversity is very limited. In man and mouse, the most 3'DH gene, DQ52, is preferentially rearranged early in B-cell development. To test whether this preference for rearranging a DH gene segment based on 3' end proximity exists in rabbit, we cloned and sequenced the rabbit DQ52 gene. The 11 base pair coding region sequence is identical to a published mouse DQ52, and 81.8% similar to the human sequence. It is localized approximately 805 bp upstream of the JH1 gene. However, the 3' recombination signal sequence has an atypical nonamer. We prepared mRNA from 15- to 28-day fetal rabbits and amplified expressed VDJ sequences of mu mRNA by RT-PCR. The PCR products with VDJ rearrangements were cloned and sequenced. As expected, 44 of 45 VDJ sequences reflected use of the 3' VH1a2 gene, but the DQ52 gene was utilized very infrequently, if at all. We found only one VDJ sequence from 28-day fetal liver B-cells with 8 bp that matched the germline DQ52 sequence. Instead of expressing DQ52, another DH gene, Df was frequently expressed. We cloned the genomic Df gene and localized it about 32 kb upstream of the JH region. Thus, in contrast to man and mouse, rabbits preferentially express a DH gene located in the middle of the DH region early in B cell ontogeny. This may correlate with more frequent initial rearrangement of VH to DH in rabbit B cells.

背景与目标： 兔子主要重排最3'VH基因 (VH1); 因此组合多样性非常有限。在人和小鼠中，最3'DH基因DQ52在b细胞发育的早期优先重排。为了测试兔子中是否存在基于3' 末端邻近度重新排列DH基因片段的偏好，我们克隆并测序了兔子DQ52基因。11个碱基对编码区序列与已发表的小鼠DQ52相同，并且81.8% 类似于人序列。它位于JH1基因上游约805 bp。但是，3' 重组信号序列具有非典型的非amer。我们从15至28天的胎兔中制备了mRNA，并通过rt-pcr扩增了mu mRNA的VDJ表达序列。克隆并测序具有VDJ重排的PCR产物。正如预期的那样，在45个VDJ序列中，有44个反映了3'vh1a2基因的使用，但是DQ52基因很少被使用 (如果有的话)。我们从28天的胎儿肝b细胞中发现只有一个VDJ序列，其8 bp与种系DQ52序列匹配。Df不表达另一个DH基因DQ52，而是经常表达。我们克隆了基因组Df基因，并将其定位在JH区域上游约32 kb。因此，与人和小鼠相比，兔子在b细胞个体发育早期优先表达位于DH区域中部的DH基因。这可能与兔b细胞中VH到DH的更频繁的初始重排有关。

BACKGROUND & AIMS: :Long-term cold exposure (5-7 days) is known to induce concomitant increases in the levels of adrenomedullary tyrosine hydroxylase (TH) RNA, protein, and enzyme activity. In this report, we compare the time courses of these changes and investigate the effects of cold exposure on the levels of biopterin, the cofactor required for tyrosine hydroxylation. After only 1 h of cold exposure, TH mRNA abundance increased 71% compared with nonstressed controls. Increases in total cellular TH RNA levels were maximal (threefold over control values) within 3-6 h of cold exposure and remained elevated throughout the duration of the experiment (72 h). TH protein levels increased rapidly after 24 h of cold exposure and reached a maximal value threefold above that of controls at 48-72 h. Despite the relatively rapid and large elevations in TH RNA and protein content, only modest increases in TH activity were detected during the initial 48 h of cold exposure. Adrenomedullary biopterin increased rapidly after the onset of cold exposure, rising to a level approximately twofold that of the nonstressed controls at 24 h, and remained at this level throughout the duration of the stress period. Taken together, the results of this time course study indicate that cold-induced alterations in adrenal TH activity are mediated by multiple cellular control mechanisms, which may include pre- and posttranslational regulation. Our findings also suggest that cold stress-induced increases in the levels of the TH cofactor may represent another key event in the sympathoadrenal system's response to cold stress.

背景与目标： : 已知长期冷暴露 (5-7天) 会引起肾上腺髓质酪氨酸羟化酶 (TH) RNA，蛋白质和酶活性的同时增加。在本报告中，我们比较了这些变化的时间过程，并研究了冷暴露对酪氨酸羟基化所需的辅因子生物蝶呤水平的影响。冷暴露仅1小时后，与无应激对照相比，TH mRNA丰度71% 增加。在冷暴露的3-6小时内，总细胞TH RNA水平的增加最大 (是对照值的三倍)，并且在整个实验期间 (72小时) 保持升高。冷暴露24小时后，TH蛋白水平迅速增加，并在48-72小时达到对照组的三倍的最大值。尽管TH RNA和蛋白质含量的升高相对较快且较大，但在冷暴露的最初48小时内仅检测到TH活性的适度增加。冷暴露开始后，肾上腺髓质生物蝶呤迅速增加，在24小时时升至非应激对照的大约两倍，并在整个应激期内保持在该水平。总之，该时间过程研究的结果表明，冷诱导的肾上腺TH活性的改变是由多种细胞控制机制介导的，其中可能包括翻译前和翻译后的调节。我们的发现还表明，冷应激引起的TH辅因子水平的增加可能是交感肾上腺系统对冷应激反应的另一个关键事件。

BACKGROUND & AIMS: :Bacterial sepsis is a serious life-threatening condition caused by an excessive immune response to infection. B-1 cells differ from conventional B-2 cells by their distinct phenotype and function. A subset of B-1 cells expressing CD5, known as B-1a cells, exhibits innate immune activity. Here we report that B-1a cells play a beneficial role in sepsis by mitigating exaggerated inflammation through a novel mechanism. Using a mouse model of bacterial sepsis, we found that the numbers of B-1a cells in various anatomical locations were significantly decreased. Adoptive transfer of B-1a cells into septic mice significantly attenuated systemic inflammation and improved survival, whereas B-1a cell-deficient CD19-/- mice were more susceptible to infectious inflammation and mortality. We also demonstrated B-1a cells produced ample amounts of IL-10 which controlled excessive inflammation and the mice treated with IL-10-deficient B-1a cells were not protected against sepsis. Moreover, we identified a novel intracellular signaling molecule, cAMP-response element binding protein (CREB), which serves as a pivotal transcription factor for upregulating IL-10 production by B-1a cells in sepsis through its nuclear translocation and binding to putative responsive elements on IL-10 promoter. Thus, the benefit of B-1a cells in bacterial sepsis is mediated by CREB and the identification of CREB in B-1a cells reveals a potential avenue for treatment in bacterial sepsis.

背景与目标： : 细菌性败血症是由于对感染的过度免疫反应而引起的严重威胁生命的疾病。B-1细胞与常规B-2细胞的区别在于其独特的表型和功能。表达CD5的B-1细胞的子集 (称为B-1a细胞) 表现出先天免疫活性。在这里，我们报告B-1a细胞通过一种新的机制减轻过度的炎症在败血症中发挥有益的作用。使用细菌败血症的小鼠模型，我们发现不同解剖位置的B-1a细胞数量显着减少。将B-1a细胞过继转移至脓毒症小鼠可显著减轻全身性炎症并改善存活率，而B-1a细胞缺陷型CD19-/-小鼠更容易感染感染性炎症和死亡率。我们还证明了B-1a细胞产生足够量的控制过度炎症的IL-10，并且用IL-10-deficient B-1a细胞处理的小鼠不能防止败血症。此外，我们鉴定了一种新的细胞内信号分子，cAMP反应元件结合蛋白 (CREB)，它是脓毒症中B-1a细胞通过其核易位和与IL-10启动子上推定的反应元件结合而上调IL-10产生的关键转录因子。因此，细菌败血症中B-1a细胞的益处由CREB介导，并且B-1a细胞中CREB的鉴定揭示了治疗细菌败血症的潜在途径。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :Chronic hepatitis B virus (HBV) infection afflicts millions worldwide with cirrhosis and liver cancer. HBV e-antigen (HBeAg), a clinical marker for disease severity, is a nonparticulate variant of the protein (core antigen, HBcAg) that forms the building-blocks of capsids. HBeAg is not required for virion production, but is implicated in establishing immune tolerance and chronic infection. Here, we report the crystal structure of HBeAg, which clarifies how the short N-terminal propeptide of HBeAg induces a radically altered mode of dimerization relative to HBcAg (∼140° rotation), locked into place through formation of intramolecular disulfide bridges. This structural switch precludes capsid assembly and engenders a distinct antigenic repertoire, explaining why the two antigens are cross-reactive at the T cell level (through sequence identity) but not at the B cell level (through conformation). The structure offers insight into how HBeAg may establish immune tolerance for HBcAg while evading its robust immunogenicity.

背景与目标： : 慢性乙型肝炎病毒 (HBV) 感染困扰全球数百万肝硬化和肝癌。HBV e抗原 (HBeAg)，疾病严重程度的临床标志物，是形成衣壳的基础结构的蛋白质 (核心抗原，HBcAg) 的非颗粒变体。HBeAg不需要用于病毒粒子的产生，但与建立免疫耐受和慢性感染有关。在这里，我们报告了HBeAg的晶体结构，该结构阐明了HBeAg的短N端前肽如何诱导相对于HBcAg的二聚化模式发生根本改变 (〜140 ° 旋转)，并通过形成分子内二硫键锁定到位。这种结构转换阻止了衣壳的组装并产生了独特的抗原库，解释了为什么这两种抗原在T细胞水平 (通过序列同一性) 而不是在b细胞水平 (通过构象) 交叉反应。该结构提供了深入了解HBeAg如何在逃避其强大的免疫原性的同时建立对HBcAg的免疫耐受性。

BACKGROUND & AIMS: BACKGROUND:P21-activated kinase 1 (PAK1) stimulates growth and metastasis of colorectal cancer (CRC) through activation of multiple signalling pathways. Up-regulation of CRC stem cell markers by PAK1 also contributes to the resistance of CRC to 5-fluorouracil. The aim of this study was to investigate the effect of PAK1 depletion and inhibition on the immune system and on intestinal tumour formation in APC∆14/+ mice. METHODS:The PAK1 KO APC∆14/+ mice were generated by cross-breeding of PAK1 KO mice with APC∆14/+ mice. Splenic lymphocytes were analysed by flow cytometry, and immunohistochemical staining. The numbers of intestinal tumours were counted. Blood cells were also counted. RESULTS:Compared to APC+/+ mice, the numbers of both T- and B- lymphocytes were reduced in the spleen of APC∆14/+ mice. Depletion of PAK1 in APC∆14/+ mice increased the numbers of splenic T- and B- lymphocytes and decreased the numbers of intestinal tumours. Treatment of APC∆14/+ mice with PF-3758309, a PAK inhibitor reduced the numbers of intestinal tumours and increased the numbers of blood lymphocytes. CONCLUSION:Depletion of active PAK1 up-regulates the immune system of APC∆14/+ mice and suppresses intestinal tumour development. These observations suggest an important role for PAK1 in the immune response to tumours.

背景与目标：

BACKGROUND & AIMS: :Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is organised into minichromosomes by histone and non-histone proteins. Remodelling of minichromosomes is crucial for the regulation of HBV replication, which is dependent on the presence of the hepatitis B virus X protein (HBx). However, the mechanisms of HBx-dependent HBV replication remain obscure. The objective of this study was to investigate the mechanism of HBx-dependent HBV replication through the pathway of chromatin remodelling. The role of HBx was investigated by transfecting human HepG2 cells with the linear full-length HBV genome (wild-type) or HBx-deficient mutant HBV DNA (HBx mutant). Our results showed that although the formation of cccDNA was not affected by HBx, HBV replication, transcription and antigen secretion were all significantly reduced, resulting from the absence of HBx. The acetylation, mono-methylation and phosphorylation of cccDNA-bound histone H3 were associated with HBV replication. In addition, the levels of cccDNA-bound methylated, phosphorylated and acetylated histone H3 decreased sharply in HBx mutant HBV DNA. HBx modulated not only the status of acetylation but also the methylation and phosphorylation of histone H3 bound to the cccDNA during HBV replication in HepG2 cells. These findings suggest that HBx plays an important role in modulating the remodelling of minichromosomes related to HBV replication and it may regulate viral replication through the pathway of chromatin remodelling.

背景与目标： : 乙型肝炎病毒 (HBV) 共价闭合环状DNA (cccDNA) 由组蛋白和非组蛋白组织成微小染色体。微型染色体的重塑对于HBV复制的调节至关重要，这取决于乙型肝炎病毒X蛋白 (HBx) 的存在。然而，HBx依赖性HBV复制的机制仍然不清楚。这项研究的目的是通过染色质重塑途径研究HBx依赖性HBV复制的机制。通过用线性全长HBV基因组 (野生型) 或HBx缺陷型突变型HBV DNA (HBx突变型) 转染人HepG2细胞来研究HBx的作用。我们的结果表明，尽管cccDNA的形成不受HBx的影响，但由于HBx的缺失，HBV复制，转录和抗原分泌均显着降低。cccDNA结合组蛋白H3的乙酰化，单甲基化和磷酸化与HBV复制有关。此外，HBx突变HBV DNA中cccDNA结合的甲基化，磷酸化和乙酰化组蛋白H3的水平急剧下降。HBx不仅调节乙酰化状态，而且调节HepG2细胞中HBV复制过程中与cccDNA结合的组蛋白H3的甲基化和磷酸化。这些发现表明，HBx在调节与HBV复制相关的微小染色体的重塑中起着重要作用，它可能通过染色质重塑途径调节病毒复制。

BACKGROUND & AIMS: :Cognitive dysfunction syndrome is a major disease affecting old cats and is the consequence of severe and irreversible loss of brain cells and brain atrophy. The present study focused on the hypothesis that the optimal strategy for promoting successful brain ageing is to target risk factors associated with brain ageing and dementia. We used a nutritional strategy involving supplementation with a blend of nutrients (antioxidants, arginine, B vitamins and fish oil) to test this hypothesis. Middle-aged and old cats between 5·5 and 8·7 years of age were assigned to cognitively equivalent control or treatment groups based on prior cognitive experience and performance on baseline cognitive tests. The cats in the treatment group were maintained on a diet supplemented with the nutrient blend and the cats in the control group were maintained on the identical base diet without the additional supplementation. After an initial wash-in period, all cats were tested on a battery of cognitive test protocols. The cats fed the test diet showed significantly better performance on three of four test protocols: a protocol assessing egocentric learning, a protocol assessing discrimination and reversal learning and a protocol focused on acquisition of a spatial memory task. The results support the hypothesis that brain function of middle-aged and old cats can be improved by the nutrient blend that was selected to minimise or eliminate the risk factors associated with brain ageing and dementia.

背景与目标： : 认知功能障碍综合征是影响老猫的主要疾病，是严重且不可逆转的脑细胞丧失和脑萎缩的后果。本研究的重点是以下假设: 促进成功的大脑衰老的最佳策略是针对与大脑衰老和痴呆症相关的危险因素。我们使用了一种营养策略，包括补充营养素 (抗氧化剂，精氨酸，b族维生素和鱼油)，以检验这一假设。根据先前的认知经验和基线认知测试的表现，将5·5至8·7岁的中年和老年猫分配到认知上等效的对照组或治疗组。治疗组中的猫维持在补充营养混合物的饮食中，而对照组中的猫维持在相同的基础饮食中，而无需额外补充。在最初的冲洗期后，所有猫都接受了一系列认知测试协议的测试。喂养测试饮食的猫在四个测试协议中的三个协议中表现出明显更好的性能: 评估以自我为中心的学习的协议，评估歧视和逆转学习的协议以及专注于获取空间记忆任务的协议。结果支持以下假设: 可以通过选择营养混合物来改善中老年猫的脑功能，以最大程度地减少或消除与脑衰老和痴呆症相关的危险因素。

BACKGROUND & AIMS: :Sensitizing mutations in the epidermal growth factor receptor (EGFR) predict response to EGFR tyrosine kinase inhibitors (TKIs) and both first- and second-generation TKIs are available as first-line treatment options in patients with advanced EGFR-mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The T790M gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with EGFR T790M mutant lung cancer after failure of initial EGFR kinase therapy. Resistance mechanisms are being identified to these novel agents, and the treatment landscape of EGFR-mutant lung cancer continues to evolve. The sequence of EGFR TKIs may change in the future and combination therapies targeting resistance appear highly promising.

背景与目标： : 表皮生长因子受体 (EGFR) 的致敏突变可预测对EGFR酪氨酸激酶抑制剂 (TKIs) 的反应，并且第一代和第二代TKIs均可作为晚期EGFR突变型非小细胞肺癌患者的一线治疗选择。在重复活检和血浆循环肿瘤DNA中，最终的耐药性可通过多种机制识别。T790M网守突变负责几乎60% 的病例。许多第三代TKIs正在临床开发中，奥希替尼已获得美国食品药品监督管理局的批准，可用于治疗EGFR T790M突变型肺癌患者的初始EGFR激酶治疗失败。这些新药物的耐药机制正在被确定，并且EGFR突变型肺癌的治疗前景继续发展。EGFR TKIs的序列可能会在未来发生变化，针对耐药性的联合疗法似乎很有希望。

BACKGROUND & AIMS: :Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018-29. ©2017 AACR.See related commentary by Lakshmanan and Byrd, p. 940This article is highlighted in the In This Issue feature, p. 920.

背景与目标： : 布鲁顿酪氨酸激酶 (BTK) 将b细胞抗原受体 (BCR) 和Toll样受体与NF-κ B联系起来。BTK在原发性中枢神经系统 (CNS) 淋巴瘤 (PCNSL) 中的作用尚不清楚。我们使用ibrutinib (一流的BTK抑制剂) 对复发或难治性CNS淋巴瘤患者进行了I期临床试验。13例 (77% 例) PCNSL患者中有10例出现ibrutinib的临床反应，包括5例完全反应。唯一具有完全伊布替尼抗性的PCNSL在CARD11的卷曲螺旋结构域中具有突变，这是已知的伊布替尼抗性机制。不完全的肿瘤反应与b细胞抗原受体相关蛋白CD79B的突变有关。CD79B-mutant PCNSLs显示出哺乳动物雷帕霉素靶 (mTOR) 相关基因集的富集，并且PI3K/mTOR激活标记物的染色增加。抑制PI3K亚型p110α/p110δ 或mTOR与伊布替尼协同诱导CD79B-mutant PCNSL细胞死亡。意义: 伊布替尼在中枢神经系统复发或难治性b细胞淋巴瘤患者中具有重要活性。PCNSL的反应率大大高于CNS外弥漫性大b细胞淋巴瘤的报道，表明分子发病机制不同。BTK和PI3K/mTOR的联合抑制可能会增强CD79B-mutant人pcnsl中的伊布替尼反应。癌症椎间盘; 7(9); 1018-29。©2017 AACR。请参阅Lakshmanan和Byrd的相关评论，p。940本文在本刊功能第920页中突出显示。