BACKGROUND & AIMS: :Etanercept is a recombinant human soluble tumor necrosis factor (TNF-alpha) receptor fusion protein that inhibits TNF-alpha, a major mediator in the pathogenesis of graft-versus-host disease (GVHD). The purpose of our study was to evaluate the safety and efficacy of etanercept therapy in 21 patients with steroid-refractory acute GVHD (aGVHD) (n = 13) and chronic GVHD (cGVHD) (n = 8). Etanercept 25 mg was given subcutaneously twice weekly for 4 weeks followed by 25 mg weekly for 4 weeks. At the time of initiation of etanercept, 14 patients had skin, 13 had gastro-intestinal, 5 had liver, 5 had pulmonary, and 4 had oral involvement. Twelve patients (57%) completed 12 doses of therapy. Overall, 11 of 21 patients (52%) responded to the treatment with etanercept, including 6 patients (46%) with aGVHD [n = 4 complete response (CR), n = 2 partial response (PR)] and 5 patients (62%) with cGVHD (n = 1 CR, n = 4 PR). Clinical responses were most commonly seen in patients with refractory gut aGVHD with 55% of the patients having a CR and 9% having a PR. CMV reactivation occurred in 48% of patients, bacterial infections in 14% of patients, and fungal infections in 19% of patients. Fourteen patients (67%) were alive after a median follow-up of 429 days (range 71-1007 days) since initiation of etanercept. Seven patients died, 3 of infections, 2 of refractory aGVHD, and 2 of disease progression. In conclusion, our preliminary data indicate that etanercept is well tolerated and can induce a high response rate in patients with steroid-refractory aGVHD and cGVHD, particularly in the setting of GI involvement.

背景与目标： ：Etanercept是一种重组人类可溶性肿瘤坏死因子（TNF-alpha）受体融合蛋白，可抑制TNF-alpha（一种在移植物抗宿主病（GVHD）发病机理中的主要介体）。本研究的目的是评估依那西普治疗21例激素抵抗性急性GVHD（aGVHD）（n = 13）和慢性GVHD（cGVHD）（n = 8）患者的安全性和有效性。每周两次皮下给予Etanercept 25 mg，持续4周，然后每周25 mg，持续4周。依那西普开始治疗时，有14例皮肤，13例胃肠，5例肝，5例肺，4例经口受累。 12名患者（57％）完成了12剂治疗。总体上，在21名患者中有11名患者（52％）对依那西普治疗有反应，包括6名患者（46％）患有aGVHD [n = 4完全缓解（CR），n = 2部分缓解（PR）]和5例（62 ％）和cGVHD（n = 1 CR，n = 4 PR）。临床反应最常见于顽固性肠aGVHD患者，其中55％的患者为CR，9％的患者为PR。 CMV重新激活发生在48％的患者中，细菌感染发生在14％的患者中，而真菌感染发生在19％的患者中。自依那西普开始中位随访429天（71-1007天）后，有14名患者（67％）还活着。 7例患者死亡，3例感染，2例难治性aGVHD死亡，2例疾病进展。总之，我们的初步数据表明，依那西普耐受性好，在类固醇难治性aGVHD和cGVHD患者中可引起较高的应答率，尤其是在胃肠道受累的情况下。

BACKGROUND & AIMS: :The extracellular calcium-sensing receptor (CaR) is usually associated with systemic Ca(2+) homeostasis, but the CaR is also expressed in many other tissues, including pancreatic islets of Langerhans. In the present study, we have used human islets and an insulin-secreting cell line (MIN6) to investigate the effects of CaR activation using the calcimimetic R-568, a CaR agonist that activates the CaR at physiological concentrations of extracellular Ca(2+). CaR activation initiated a marked but transient insulin secretory response from both human islets and MIN6 cells at a sub-stimulatory concentration of glucose, and further enhanced glucose-induced insulin secretion. CaR-induced insulin secretion was reduced by inhibitors of phospholipase C or calcium-calmodulin-dependent kinases, but not by a protein kinase C inhibitor. CaR activation was also associated with an activation of p42/44 mitogen-activated protein kinases (MAPK), and CaR-induced insulin secretion was reduced by an inhibitor of p42/44 MAPK activation. We suggest that the beta-cell CaR is activated by divalent cations co-released with insulin, and that this may be an important mechanism of intra-islet communication between beta-cells.

背景与目标： ：细胞外钙敏感受体（CaR）通常与全身性Ca（2）稳态相关，但该CaR在许多其他组织中也表达，包括Langerhans的胰岛。在本研究中，我们已经使用人类胰岛和胰岛素分泌细胞系（MIN6）来研究使用拟钙剂R-568（CaR激动剂在生理浓度的细胞外Ca（2）激活CaR的CaR激活）的CaR激活的影响。 。 CaR激活在葡萄糖的亚刺激浓度下启动了来自人胰岛和MIN6细胞的显着但短暂的胰岛素分泌反应，并进一步增强了葡萄糖诱导的胰岛素分泌。 CaR诱导的胰岛素分泌通过磷脂酶C或钙钙调蛋白依赖性激酶的抑制剂降低，但不通过蛋白激酶C抑制剂降低。 CaR激活还与p42 / 44丝裂原激活的蛋白激酶（MAPK）激活相关，并且CaR诱导的胰岛素分泌被p42 / 44 MAPK激活的抑制剂减少。我们建议β细胞CaR被与胰岛素共释放的二价阳离子激活，这可能是β细胞之间胰岛内通讯的重要机制。

BACKGROUND & AIMS: Tyrosine phosphorylation of the nicotinic acetylcholine receptor (AChR) is associated with an altered rate of receptor desensitization and also may play a role in agrin-induced receptor clustering. We have demonstrated a previously unsuspected interaction between Torpedo AChR and the adaptor protein Grb2. The binding is mediated by the Src homology 2 (SH2) domain of Grb2 and the tyrosine-phosphorylated delta subunit of the AChR. Dephosphorylation of the delta subunit abolishes Grb2 binding. A cytoplasmic domain of the delta subunit contains a binding motif (pYXNX) for the SH2 domain of Grb2. Indeed, a phosphopeptide corresponding to this region of the delta subunit binds to Grb2 SH2 fusion proteins with relatively high affinity, whereas a peptide lacking phosphorylation on tyrosine exhibits no binding. Grb2 is colocalized with the AChR on the innervated face of Torpedo electrocytes. Furthermore, Grb2 specifically copurifies with AChR solubilized from postsynaptic membranes. These data suggest a novel role for tyrosine phosphorylation of the AChR in the initiation of a Grb2-mediated signaling cascade at the postsynaptic membrane.

背景与目标： 烟碱样乙酰胆碱受体（AChR）的酪氨酸磷酸化与受体脱敏率的改变有关，也可能在凝集素诱导的受体簇中起作用。我们已经证明了鱼雷AChR和衔接蛋白Grb2之间以前没有想到的相互作用。结合是由Grb2的Src同源2（SH2）域和AChR的酪氨酸磷酸化的δ亚基介导的。 δ亚基的去磷酸化消除了Grb2结合。 δ亚基的胞质结构域包含Grb2的SH2结构域的结合基序（pYXNX）。实际上，对应于δ亚基的该区域的磷酸肽以相对高的亲和力结合到Grb2 SH2融合蛋白上，而在酪氨酸上缺乏磷酸化的肽则没有结合。 Grb2与AChR在鱼雷电池的神经支配面上共定位。此外，Grb2与从突触后膜溶解的AChR特异共纯化。这些数据表明，AChR的酪氨酸磷酸化在突触后膜的Grb2介导的信号级联反应的起始中起着新的作用。

BACKGROUND & AIMS: Ligation of surface IgM on B cells responding to lipopolysaccharide (LPS) suppresses terminal differentiation and high-rate Ig secretion with no effect on proliferation. As shown here, different B cell populations show characteristic mean values of ligand concentration required for 50% inhibition, with Gaussian distributions of sensitivity to IgM receptor ligation that reflect cellular heterogeneity of 'al-or-none' inhibitions in single cells. Differential sensitivity of B cell populations to IgM ligation seems to be locally determined by the cellular environment and unrelated to the 'maturity' of the responding cells. Thus, while long-lived peritoneal B cells are 3- to 5-fold more resistant than splenic B cells, there is no difference in sensitivity between short- and long-lived B cells in the spleen. Furthermore, while B cells in bone marrow and spleen differ in sensitivity by two orders of magnitude, B cells differentiated in vitro from bone marrow pre-B cells are as resistant as splenic B cells. Moreover, bone marrow cell culture supernatants restore a high level of sensitivity in such cell populations. Differential sensitivity to IgM receptor ligation is reproduced by multivalent nominal antigen, in cell populations that show identical dose-response inhibition curves to direct activation of protein kinase C by phorbol esters. We conclude that the level of sensitivity to IgM ligation is independent of the life span or maturity of the B cell, but differentially regulated in vivo by putative tissue factors.

背景与目标： 响应脂多糖（LPS）的B细胞表面IgM的连接可抑制终末分化和高速率的Ig分泌，而对增殖没有影响。如此处所示，不同的B细胞群体显示出50％抑制所需的配体浓度的特征平均值，其对IgM受体连接的敏感性的高斯分布反映了单细胞“异或无”抑制的细胞异质性。 B细胞群体对IgM连接的差异敏感性似乎是由细胞环境局部决定的，并且与响应细胞的“成熟度”无关。因此，虽然长寿腹膜B细胞的抵抗力比脾脏B细胞高3至5倍，但脾脏中短寿和长寿B细胞之间的敏感性没有差异。此外，尽管骨髓和脾脏中的B细胞在敏感性方面相差两个数量级，但体外与骨髓前B细胞分化出的B细胞与脾脏B细胞一样具有抗性。而且，骨髓细胞培养物上清液在这种细胞群体中恢复了高水平的敏感性。在表现出相同剂量反应抑制曲线以直接通过佛波醇酯激活蛋白激酶C的细胞群体中，多价名义抗原重现了对IgM受体连接的不同敏感性。我们得出的结论是，对IgM结扎的敏感性水平与B细胞的寿命或成熟度无关，但在体内受假定的组织因子的调节。

BACKGROUND & AIMS: OBJECTIVE:The purpose of this study was to determine the expression of receptor activator of NFkappaB ligand (RANKL) and osteoprotegerin (OPG) associated with bone destruction in periapical cysts and granulomas. STUDY DESIGN:Forty human dental chronic periapical lesions were collected after periapical surgery. The lesions collected were fixed in 10% buffered formalin and histologically processed. At least 2 sections of each specimen were stained with hematoxylin and eosin for microscopic diagnosis. After that, 10 human periapical granulomas and 10 cysts were selected for immunohistochemical analysis for RANKL, OPG, and CD68+. RESULTS:Polymorphonuclear neutrophils, macrophages, endothelial cells, and lymphocytes were stained for RANKL and OPG in both lesions. Epithelial cells were also stained for RANKL and OPG in periapical cysts. Quantitative analysis was conducted and the results were expressed as a ratio of the number of immunostained cells over the total number of cells in the field (n = 100). The ratio of RANKL+/total cells was higher than OPG+/total cells in periapical granulomas (0.553 +/- 0.153 and 0.483 +/- 0.189, respectively; P < .0012; paired t test) and in cysts (0.519 +/- 0.09 and 0.339 +/- 0.117, respectively; P < .0001; paired t test). The ratios of OPG+/total cells (P < .0001; paired t test) and RANKL+/total cells (P < .0322; paired t test) were greater in granulomas than in cysts. However, the ratio RANKL+/OPG+ in granulomas (1.336 +/- 0.723) and cysts (1.404 +/- 0.385) was not significantly different. The ratio of CD68+/total cells was significantly higher in granulomas (0.381 +/- 0.040) than in cysts (0.307 +/- 0.068) (P < .0001; unpaired t test with Welch correction). CONCLUSION:Taking into account the limitations of the experimental approach employed, our findings indicate the presence of RANKL and OPG in cysts and granulomas, strongly suggesting the involvement of these gene products in the development of periapical lesions.

背景与目标： 目的：本研究的目的是确定与根尖周囊肿和肉芽肿中的骨破坏有关的NFκB配体（RANKL）和骨保护素（OPG）受体激活剂的表达。
研究设计：根尖周手术后收集了40例人类牙齿慢性根尖周病变。将收集的病灶固定在10％的福尔马林缓冲液中，并进行组织学处理。每个标本至少2个切片用苏木精和曙红染色以进行显微镜诊断。之后，选择10个人根尖肉芽肿和10个囊肿进行RANKL，OPG和CD68的免疫组织化学分析。
结果：在两个病变中，多形核中性粒细胞，巨噬细胞，内皮细胞和淋巴细胞均进行了RANKL和OPG染色。还对上皮周囊肿中的上皮细胞进行了RANKL和OPG染色。进行定量分析，结果表示为免疫染色细胞数与现场细胞总数之比（n = 100）。根尖肉芽肿中RANKL /总细胞的比率高于OPG /总细胞的比率（分别为0.553 /-0.153和0.483 /-0.189; P <.0012;成对t检验）和囊肿中（0.519 /-0.09和0.339 / -分别为0.117； P <.0001；成对t检验）。肉芽肿中OPG /总细胞（P <.0001；成对t检验）与RANKL /总细胞（P <.0322；成对t检验）的比率大于囊肿。然而，肉芽肿（1.336 /-0.723）和囊肿（1.404 /-0.385）中的RANKL / OPG比率没有显着差异。肉芽肿中CD68 /总细胞的比例（0.381 /-0.040）显着高于囊肿（0.307 /-0.068）（P <.0001；采用Welch校正的未配对t检验）。
结论：考虑到实验方法的局限性，我们的发现表明囊肿和肉芽肿中存在RANKL和OPG，强烈暗示这些基因产物参与了根尖周病变的发展。

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： ：通过减法克隆程序，从用怀孕母马血清促性腺激素（PMSG）引发的大鼠卵巢中分离出由促性腺激素立即诱导的基因。同源性分析显示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印迹分析表明，通过注射PMSG，大鼠SRBI mRNA水平在3小时内迅速而强烈地增加。原位杂交研究表明，SRBI mRNA在30 IU PMSG刺激6 h的未成熟大鼠卵巢的内膜细胞中被强烈诱导。在成年大鼠卵巢的黄体中也观察到了SRBI mRNA表达。这些发现表明，SRBI mRNA的表达受限于卵巢类固醇生成细胞类型并在其中被诱导，其中胆固醇被用作类固醇激素合成的底物。我们的数据有力地表明，SRBI可能通过介导HDL对胆固醇和卵巢黄体的选择性摄取来介导胆固醇的选择性摄取，从而在卵巢类固醇生成中发挥重要作用。

BACKGROUND & AIMS: :Burkholderia pseudomallei is a facultative intracellular pathogen and the causative agent of melioidosis, a spectrum of potentially fatal diseases endemic in Northern Australia and South-East Asia. We demonstrate that B. pseudomallei rapidly modifies infected macrophage-like cells in a manner analagous to osteoclastogenesis. These alterations include multinucleation and the expression by infected cells of mRNA for factors required for osteoclastogenesis: the chemokines monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 gamma (MIP-1gamma), 'regulated on activation normal T cell expressed and secreted' (RANTES) and the transcription factor 'nuclear factor of activated T-cells cytoplasmic 1' (NFATc1). An increase in expression of these factors was also observed after infection with Burkholderia thailandensis. Expression of genes for the osteoclast markers calcitonin receptor (CTR), cathepsin K (CTSK) and tartrate-resistant acid phosphatase (TRAP) was also increased by B. pseudomallei-infected, but not by B. thailandensis-infected cells. The expression by B. pseudomallei-infected cells of these chemokine and osteoclast marker genes was remarkably similar to cells treated with RANKL, a stimulator of osteoclastogenesis. Analysis of dentine resorption by B. pseudomallei-induced osteoclast-like cells revealed that demineralization may occur but that authentic excavation does not take place under the tested conditions. Furthermore, we identified and characterized lfpA (for lactonase family protein A) in B. pseudomallei, which shares significant sequence similarity with the eukaryotic protein 'regucalcin', also known as 'senescence marker protein-30' (SMP-30). LfpA orthologues are widespread in prokaryotes and are well conserved, but are phylogenetically distinct from eukaryotic regucalcin orthologues. We demonstrate that lfpA mRNA expression is dramatically increased in association with macrophage-like cells. Mutation of lfpA significantly reduced expression of the tested host genes, relative to the response to wild-type B. pseudomallei. We also show that lfpA is required for optimal virulence in vivo.

背景与目标： ：伪狂犬病是一种兼职的细胞内病原体，是类鼻oid病的病原体，类li虫病是北澳大利亚和东南亚流行的一系列潜在致命性疾病。我们证明假性芽孢杆菌以与破骨细胞发生类似的方式快速修饰感染的巨噬细胞样细胞。这些改变包括多核化和破骨细胞形成所需因子的感染细胞mRNA表达：趋化因子单核细胞趋化蛋白1（MCP-1），巨噬细胞炎性蛋白1γ（MIP-1gamma），“对激活的正常T细胞的表达和分泌”（RANTES）和转录因子“活化T细胞胞质1的核因子”（NFATc1）。在感染了伯克霍尔德菌之后，这些因子的表达也增加了。破伤风标记的降钙素受体（CTR），组织蛋白酶K（CTSK）和抗酒石酸的酸性磷酸酶（TRAP）的破骨细胞标志物的基因表达也增加了，而被泰国芽孢杆菌（B. thailandensis）感染的细胞却没有。这些趋化因子和破骨细胞标志物基因的经假芽孢杆菌感染的细胞的表达与破骨细胞形成刺激物RANKL处理的细胞非常相似。假性麦芽孢杆菌诱导的破骨细胞样细胞对牙本质吸收的分析表明，可能会发生脱矿质，但在测试条件下不会发生真正的挖掘。此外，我们在假苹果芽孢杆菌中鉴定并鉴定了lfpA（用于内酯酶家族蛋白A），它与真核蛋白“ regucalcin”（也称为“衰老标记蛋白-30”（SMP-30））具有显着的序列相似性。 LfpA直向同源物广泛存在于原核生物中，并且保守性很强，但在系统发育上与真核瑞古钙素直向同源物不同。我们证明，与巨噬细胞样细胞相关联，lfpA mRNA表达显着增加。相对于对野生型假单胞菌的反应，lfpA的突变显着降低了测试宿主基因的表达。我们还表明，lfpA是体内最佳毒力所必需的。

BACKGROUND & AIMS: :We have previously shown that the interaction of Ca2+/calmodulin with the metabotropic glutamate receptor type 7 (mGluR7) promotes the G-protein-mediated inhibition of voltage-sensitive Ca2+ channels (VSCCs) seen upon agonist activation. Here, we performed a yeast two-hybrid screen of a new-born rat brain cDNA library using the cytoplasmic C-terminal tail of mGluR7 as bait and identified macrophage myristoylated alanine-rich c-kinase substrate (MacMARCKS) as a binding protein. The interaction was confirmed in vitro and in vivo by pull-down assays, immunoprecipitation, and colocalization of mGluR7 and MacMARCKS in transfected HEK293 cells and cultured cerebellar granule cells. Binding of MacMARCKS to mGluR7 was antagonized by Ca2+/calmodulin. In neurons, cotransfection of MacMARCKS with mGluR7, but not mGluR7 mutants unable to bind MacMARCKS, reduced the G-protein-mediated tonic inhibition of VSCCs in the absence of mGluR7 agonist. These results suggest that competitive interactions of Ca2+/calmodulin and MacMARCKS with mGluR7 control the tonic inhibition of VSCCs by G-proteins.

背景与目标： ：我们之前已经证明，Ca2 /钙调蛋白与7型代谢型谷氨酸受体（mGluR7）的相互作用促进了激动剂激活后G蛋白介导的对电压敏感Ca2通道（VSCC）的抑制。在这里，我们使用mGluR7的胞质C末端尾巴作为诱饵，对新生大鼠大脑cDNA文库进行了酵母双杂交筛选，并鉴定了巨噬细胞肉豆蔻酰化的富含丙氨酸的c激酶底物（MacMARCKS）作为结合蛋白。通过下拉测定，免疫沉淀以及mGluR7和MacMARCKS在转染的HEK293细胞和培养的小脑颗粒细胞中的共定位，在体外和体内证实了这种相互作用。 Ca2 /钙调蛋白可拮抗MacMARCKS与mGluR7的结合。在神经元中，将MacMARCKS与mGluR7共转染，但不能与不能结合MacMARCKS的mGluR7突变体共转染，可在没有mGluR7激动剂的情况下降低VSCC的G蛋白介导的强直抑制。这些结果表明Ca2 /钙调蛋白和MacMARCKS与mGluR7的竞争性相互作用控制了G蛋白对VSCC的强直抑制。

BACKGROUND & AIMS: :Receptor tyrosine kinases (RTKs) are critical for normal cell growth, differentiation, and development, but they contribute to various pathological conditions when disrupted. Activation of RTKs stimulates a plethora of pathways, including the ubiquitylation and endocytosis of the receptor itself. Although endocytosis terminates RTK signaling, it has emerged as a requisite step in RTK activation of signaling pathways. We have discovered that the endocytic scaffolding protein intersectin (ITSN) cooperated with epidermal growth factor receptor (EGFR) in the regulation of cell growth and signaling. However, a biochemical link between ITSN and EGFR was not defined. In this study, we demonstrate that ITSN is a scaffold for the E3 ubiquitin ligase Cbl. ITSN forms a complex with Cbl in vivo mediated by the Src homology (SH) 3 domains binding to the Pro-rich COOH terminus of Cbl. This interaction stimulates the ubiquitylation and degradation of the activated EGFR. Furthermore, silencing ITSN by RNA interference attenuated EGFR internalization as well as activation of the extracellular signal-regulated kinasemitogen-activated protein kinase pathway, thereby demonstrating the importance of ITSN in EGFR function. Given the cooperativity between ITSN and additional RTKs, these results point to an important evolutionarily conserved, regulatory role for ITSN in RTK function that is necessary for both signaling from receptors as well as the ultimate termination of receptor signaling.

背景与目标： 受体酪氨酸激酶（RTKs）对于正常细胞的生长，分化和发育至关重要，但是当它们被破坏时，它们会导致各种病理状况。 RTK的激活刺激了许多途径，包括受体自身的泛素化和内吞作用。尽管内吞作用终止了RTK信号传导，但它已成为RTK激活信号通路的必要步骤。我们已经发现，内吞支架蛋白intersectin（ITSN）与表皮生长因子受体（EGFR）协同调节细胞生长和信号传导。但是，尚未定义ITSN和EGFR之间的生化联系。在这项研究中，我们证明了ITSN是E3泛素连接酶Cbl的支架。 ITSN在体内与Cbl形成复合物，该复合物是通过与Cbl的富含Pro的COOH末端结合的Src同源性（SH）3结构域介导的。这种相互作用刺激了活化的EGFR的泛素化和降解。此外，通过RNA干扰使ITSN沉默可以减弱EGFR的内在化以及细胞外信号调节激酶有丝分裂原激活的蛋白激酶途径的激活，从而证明了ITSN在EGFR功能中的重要性。考虑到ITSN和其他RTK之间的协作性，这些结果表明ITSN在RTK功能中具有重要的进化保守的调节作用，这对于来自受体的信号传导以及最终终止受体信号传导都是必需的。

BACKGROUND & AIMS: The exact mechanism for the decrease in intestinal calcium absorption with age is not yet understood. A decrease with age in serum 1,25-dihydroxyvitamin D (1,25(OH)2D) or a decrease in the intestinal vitamin D receptor (VDR) protein concentration are possible causes. The objective of this study was to examine the effect of age on these factors. Fifty-nine young women age 25-35 years were compared with 41 elderly women age 65-83 years who underwent measurements of VDR, calcium absorption using a 20 mg and 100 mg calcium carrier, and calciotropic hormones. Calcium absorption by both tests was lower in the elderly women compared with the young women (p < 0.05). Serum 1,25(OH)2D and duodenal VDR protein concentration were not significantly different between the two age groups. Serum 1,25(OH)2D correlated with the 20 mg calcium absorption test in both young (r = 0.35, p < 0.007) and elderly women (r = 0.58, p < 0.0001) and with the 100 mg calcium absorption in the elderly (r = 0.32; p < 0.05). VDR did not correlate with calcium absorption in young women or elderly women, nor did VDR correlate with serum 1,25(OH)2D and serum 25-hydroxyvitamin D. In summary, the decrease in calcium absorption cannot be explained by a decrease in intestinal VDR. The correlation between serum 1,25(OH)2D and both calcium absorption tests only accounts for 12-30% of the variance in the age-related change in the calcium absorption tests. Other factors, not yet understood, are responsible for the decline in calcium absorption with age.

背景与目标： 随着年龄的增长，肠道钙吸收减少的确切机制尚不清楚。血清1,25-二羟基维生素D（1,25（OH）2D）随着年龄的增长而减少或肠道维生素D受体（VDR）蛋白质的浓度降低是可能的原因。这项研究的目的是研究年龄对这些因素的影响。比较了59名年龄在25-35岁之间的年轻女性与41位年龄在65-83岁之间的女性，这些女性进行了VDR测量，使用20 mg和100 mg钙载体的钙吸收量以及亲钙性激素。与年轻女性相比，老年女性的两种测试中的钙吸收均较低（p <0.05）。在两个年龄组之间，血清1,25（OH）2D和十二指肠VDR蛋白浓度无显着差异。血清1,25（OH）2D与年轻（r = 0.35，p <0.007）和老年妇女（r = 0.58，p <0.0001）的20 mg钙吸收测试以及老年人的100 mg钙吸收相关（r ＝ 0.32； p ＜0.05）。 VDR与年轻妇女或老年妇女的钙吸收无关，也不与血清1,25（OH）2D和血清25-羟维生素D相关。 VDR。血清1,25（OH）2D与两种钙吸收测试之间的相关性仅占钙吸收测试中与年龄相关的变化方差的12％至30％。钙吸收随着年龄的增长而下降的其他原因尚不明确。

BACKGROUND & AIMS: :Several molecular-targeted therapeutics have been tested in clinical trials for the treatment of head and neck squamous cell carcinoma (HNSCC). Of these, therapeutics targeting the epidermal growth factor receptor (EGFR) have been studied most extensively and some agents have demonstrated measurable clinical effectiveness. However, molecular studies designed to define HNSCC patient subcohorts of likely responders to EGFR-targeted therapy have not identified molecular signatures that correlate with clinical response. Here, the authors summarise the relevant clinical findings and highlight reported molecular correlative studies for EGFR-targeted therapeutics for HNSCC. The authors focus especially on molecular markers evaluated for association with clinical response and include data from EGFR-targeted clinical studies in other cancer sites that they anticipate will be of interest to the head and neck cancer research and treatment communities.

背景与目标： ：几种针对分子的疗法已在临床试验中用于治疗头颈部鳞状细胞癌（HNSCC）。其中，针对表皮生长因子受体（EGFR）的疗法已得到最广泛的研究，某些药物已证明可测量的临床有效性。然而，旨在定义可能对EGFR靶向治疗有反应的HNSCC患者亚组的分子研究尚未发现与临床反应相关的分子标志。在这里，作者总结了相关的临床发现，并着重报道了针对HNSCC的EGFR靶向治疗药物的分子相关研究。作者尤其关注评估与临床反应相关的分子标志物，并包括来自其他癌症部位针对EGFR的临床研究的数据，他们预期这将是头颈癌研究和治疗界感兴趣的数据。

BACKGROUND & AIMS: Interleukin-1 (IL-1) has been implicated in chronic and acute cerebral neuropathologies. IL-1 receptor antagonist (IL-1ra), a naturally occurring protein that binds to IL-1 receptors without inducing signal transduction, blocks several actions of IL-1. IL-1ra acts at the local level and it also circulates in the bloodstream. We now report evidence for a biological function of IL-1ra in the brain as an endogenous neuroprotective molecule. Cerebral expression of IL-1ra mRNA is induced rapidly by focal cerebral ischemia in rats, and inhibition of the action of IL-1ra, by passive immuno-neutralization, markedly enhances ischemic damage. To our knowledge this is the first report of an action of endogenous IL-1ra in the brain. Control of IL-1ra expression or action may therefore provide a useful therapeutic strategy to limit acute neurodegeneration.

背景与目标： 白介素-1（IL-1）已牵涉到慢性和急性脑神经病理学。 IL-1受体拮抗剂（IL-1ra）是一种与IL-1受体结合而不诱导信号转导的天然蛋白质，可阻断IL-1的多种作用。 IL-1ra在局部起作用，并且也在血液中循环。我们现在报告IL-1ra在脑中作为内源性神经保护分子的生物学功能的证据。大鼠局灶性脑缺血可快速诱导IL-1ra mRNA的脑表达，并且被动免疫中和抑制IL-1ra的作用可显着增强缺血性损伤。据我们所知，这是大脑中内源性IL-1ra作用的首次报道。因此，控制IL-1ra的表达或作用可能为限制急性神经变性提供了有用的治疗策略。

BACKGROUND & AIMS: :A structure-activity relationship (SAR) study was performed principally at the N1 position of N1-arylsulfonyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes, a new family of calcilytics acting at the calcium sensing receptor (CaSR). The most active compound in this series was the 4-(trifluoromethoxy)benzenesulfonyl derivative 7e, which displayed an IC50 of 5.4 +/- 0.5 microM with respect to the inhibition of calcium-induced tritiated inositol phosphate ([3H]IP) accumulation in Chinese hamster ovarian (CHO) cells expressing the CaSR. Replacement of the sulfonamide linkage of this compound by a carboxamide led to a 6-fold increase in activity (7m, IC50 = 0.9 +/- 0.2 microM). Among the carboxamides synthesized, one of the most active compounds was the 4-chlorophenylcarboxamide (1S,2S,1'R)-7n (Calhex 231, IC50 = 0.33 +/- 0.02 microM). The absolute configuration of (1S,2S,1'R)-7n was deduced from an X-ray crystallographic study of one of the diastereomers of compound 7d. The stereochemical preference for the (1S,2S,1'R)-isomers can be rationalized on the basis of a three-dimensional model of the calcilytic binding pocket of the CaSR. Removal of the C-1' methyl group or replacement of the 1-naphthyl group by a 2-naphthyl or biphenyl moiety led to appreciable loss of calcilytic activity. Compounds 7e, 7m, and Calhex 231 did not stimulate [3H]IP accumulation in CHO cells expressing or not expressing the CaSR.

背景与目标： ：结构-活性关系（SAR）研究主要在N1-芳基磺酰基-N2- [1-（1-（萘基）乙基]-反式-1,2-二氨基环己烷的N1位置进行，钙敏感受体（CaSR）。该系列中活性最高的化合物是4-（三氟甲氧基）苯磺酰基衍生物7e，在抑制中国仓鼠中钙诱导的tri化肌醇磷酸酯（[3H] IP）积累方面，其IC50为5.4 /-0.5 microM。表达CaSR的卵巢（CHO）细胞。该化合物的磺酰胺键被羧酰胺取代导致活性增加了6倍（7m，IC50 = 0.9 /-0.2 microM）。在合成的羧酰胺中，活性最高的化合物之一是4-氯苯基羧酰胺（1S，2S，1'R）-7n（Calhex 231，IC50 = 0.33 /-0.02 microM）。 （1S，2S，1'R）-7n的绝对构型是由化合物7d的一种非对映异构体的X射线晶体学研究得出的。 （1S，2S，1'R）异构体的立体化学偏好可以根据CaSR钙解结合口袋的三维模型来合理化。除去C-1′甲基或用2-萘基或联苯部分取代1-萘基导致明显的钙解活性损失。化合物7e，7m和Calhex 231不会刺激表达或不表达CaSR的CHO细胞中的[3H] IP积累。

BACKGROUND & AIMS: :Granulocyte colony-stimulating factor (GCSF) administration has been linked to the development of monosomy 7 in severe congenital neutropenia and aplastic anemia. We assessed the effect of pharmacologic doses of GCSF on monosomy 7 cells to determine whether this chromosomal abnormality developed de novo or arose as a result of favored expansion of a preexisting clone. Fluorescence in situ hybridization (FISH) of chromosome 7 was used to identify small populations of aneuploid cells. When bone marrow mononuclear cells from patients with monosomy 7 were cultured with 400 ng/ml GCSF, all samples showed significant increases in the proportion of monosomy 7 cells. In contrast, bone marrow from karyotypically normal aplastic anemia, myelodysplastic syndrome, or healthy individuals did not show an increase in monosomy 7 cells in culture. In bone marrow CD34 cells of patients with myelodysplastic syndrome and monosomy 7, GCSF receptor (GCSFR) protein was increased. Although no mutation was found in genomic GCSFR DNA, CD34 cells showed increased expression of the GCSFR class IV mRNA isoform, which is defective in signaling cellular differentiation. GCSFR signal transduction via the Jak/Stat system was abnormal in monosomy 7 CD34 cells, with increased phosphorylated signal transducer and activation of transcription protein, STAT1-P, and increased STAT5-P relative to STAT3-P. Our results suggest that pharmacologic doses of GCSF increase the proportion of preexisting monosomy 7 cells. The abnormal response of monosomy 7 cells to GCSF would be explained by the expansion of undifferentiated monosomy 7 clones expressing the class IV GCSFR, which is defective in signaling cell maturation.

背景与目标： ：粒细胞集落刺激因子（GCSF）的管理与严重先天性中性粒细胞减少和再生障碍性贫血的7号单体病的发展有关。我们评估了药理学剂量的GCSF对7号单体细胞的影响，以确定这种染色体异常是从头发展还是由于已有克隆的有利扩增而出现。 7号染色体的荧光原位杂交（FISH）用于鉴定少量非整倍体细胞。当用400 ng / ml GCSF培养来自第7号单体患者的骨髓单个核细胞时，所有样品均显示出第7号单体细胞的比例显着增加。相反，来自核型典型再生障碍性贫血，骨髓增生异常综合症或健康个体的骨髓在培养物中未显示单核7细胞的增加。在患有骨髓增生异常综合症和7号单体病的患者的CD34细胞中，GCSF受体（GCSFR）蛋白增加。尽管在基因组GCSFR DNA中未发现突变，但CD34细胞显示GCSFR IV类mRNA亚型的表达增加，这在信号细胞分化中是有缺陷的。通过Jak / Stat系统进行的GCSFR信号转导在7号单体CD34细胞中异常，磷酸化信号转导子的增加和转录蛋白STAT1-P的激活以及相对于STAT3-P的STAT5-P的增加。我们的结果表明，GCSF的药理剂量增加了先前存在的单核7细胞的比例。 7号单体细胞对GCSF的异常反应可以通过表达IV类GCSFR的未分化的7号单体克隆的扩增来解释，该克隆在信号细胞的成熟中是有缺陷的。

BACKGROUND & AIMS: :The pharmacological profile of MEN15596 or (6-methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide), a novel potent and selective tachykinin NK2 receptor antagonist endowed with oral activity, is described. At the human recombinant tachykinin NK2 receptor, MEN15596 showed subnanomolar affinity (pKi 10.1) and potently antagonized (pKB 9.1) the neurokinin A-induced intracellular calcium release. MEN15596 selectivity for the tachykinin NK2 receptor was assessed by binding studies at the recombinant tachykinin NK1 (pKi 6.1) and NK3 (pKi 6.4) receptors, and at a number of 34 molecular targets including receptors, transporters and ion channels. In isolated smooth muscle preparations MEN15596 showed a marked species selectivity at the tachykinin NK2 receptor with the highest antagonist potency in guinea-pig colon, human and pig bladder (pKB 9.3, 9.2 and 8.8, respectively) whereas it was three orders of magnitude less potent in the rat and mouse urinary bladder (pKB 6.3 and 5.8, respectively). In agreement with binding experiments, MEN15596 showed low potency in blocking selective NK1 or NK3 receptor agonist-induced contractions of guinea-pig ileum preparations (pA2