BACKGROUND & AIMS: :The human immunodeficiency virus type-1 (HIV-1) envelope (Env) proteins that mediate membrane fusion represent a major target for the development of new AIDS therapies. Three classes of Env-mediated membrane fusion inhibitors have been described that specifically target the pre-hairpin intermediate conformation of gp41. Class 2 inhibitors bind to the C-terminal heptad repeat (C-HR) of gp41. The single example of a class 3 inhibitor targets the trimeric N-terminal heptad repeat (N-HR) of gp41 and has been postulated to sequestrate the N-HR of the pre-hairpin intermediate through the formation of fusion incompetent heterotrimers. Here, we show that N(CCG)-gp41, a class 2 inhibitor, and N36(Mut(e,g)), a class 3 inhibitor, synergistically inhibit Env-mediated membrane fusion for several representative HIV-1 strains (X4 and R5) in both a cell fusion assay (with membrane-bound CD4) and an Env-pseudo-typed virus neutralization assay. The mechanistic, as well as potential therapeutic, implications of these observations for HIV-Env-mediated membrane fusion are discussed.

背景与目标： : 介导膜融合的人类免疫缺陷病毒1型 (HIV-1) 包膜 (Env) 蛋白是开发新的AIDS疗法的主要目标。已经描述了三类Env介导的膜融合抑制剂，它们专门针对gp41的发夹前中间构象。2类抑制剂与gp41的C端七药重复 (c-hr) 结合。3类抑制剂的单个实例针对gp41的三聚体N末端七位重复序列 (n-hr)，并已被假定通过形成融合无能的异三聚体来隔离发夹前中间体的n-hr。在这里，我们显示了2类抑制剂N(CCG)-gp41和3类抑制剂N36(Mut(e，g))，在细胞融合试验 (具有膜结合的CD4) 和Env-伪型病毒中和试验中，协同抑制几种代表性HIV-1菌株 (X4和R5) 的Env介导的膜融合。讨论了这些观察结果对HIV-Env介导的膜融合的机理以及潜在的治疗意义。

BACKGROUND & AIMS: Using in vivo microdialysis techniques, the effects of RTI-55 and/or cocaine on extracellular dopamine (DA) concentrations were measured in the nucleus accumbens (NACC) of freely moving rats. In control animals, cocaine (20 mg/kg) increased NACC DA approximately 458% 60 minutes following administration, returning to baseline values within 200 minutes. Similarly, RTI-55 administration (0.25 mg/kg) increased NACC DA levels approximately 347%. When combined, however, cocaine further increased NACC DA to 705% of baseline values when given 4 hours following RTI-55. This increase was significantly larger than cocaine alone (P < 0.05). In addition, chronic RTI-55 administration (5 days) further potentiated cocaine's ability to increase NACC DA (783%) but this did not reach statistical significance (P > 0.1) compared to acute RTI55/cocaine animals. These findings indicate that RTI-55, a drug that binds directly to the dopamine transporter (DAT) with higher affinity than cocaine, does not appear to be effective in attenuating cocaine's effects on NACC dopamine levels. In fact, acute RTI-55 potentiates cocaine's effects on NACC DA.

背景与目标： 使用体内微透析技术，在自由运动的大鼠伏隔核 (NACC) 中测量了RTI-55和/或可卡因对细胞外多巴胺 (DA) 浓度的影响。在对照动物中，可卡因 (20 mg/kg) 在给药后约60分钟458% 增加NACC DA，在200分钟内恢复到基线值。类似地，RTI-55施用 (0.25 mg/kg) 使NACC DA水平增加约347%。然而，当合并时，当RTI-55后4小时给予时，可卡因进一步增加NACC DA至基线值的705%。这一增加显著大于单独使用可卡因 (P <0.05)。此外，慢性RTI-55给药 (5天) 进一步增强了可卡因增加NACC DA (783%) 的能力，但与急性RTI55/可卡因动物相比，这没有达到统计学意义 (P> 0.1)。这些发现表明，RTI-55是一种直接与多巴胺转运蛋白 (DAT) 结合的药物，其亲和力高于可卡因，似乎无法有效减轻可卡因对NACC多巴胺水平的影响。实际上，急性RTI-55增强了可卡因对NACC DA的影响。

BACKGROUND & AIMS: :Bovine lactoferricin (LfcinB) is a cationic antimicrobial peptide that kills Jurkat T-leukemia cells by the mitochondrial pathway of apoptosis. However, the process by which LfcinB triggers mitochondria-dependent apoptosis is not well understood. Here, we show that LfcinB-induced apoptosis in Jurkat T-leukemia cells was preceded by LfcinB binding to, and progressive permeabilization of the cell membrane. Colloidal gold electron microscopy revealed that LfcinB entered the cytoplasm of Jurkat T-leukemia cells prior to the onset of mitochondrial depolarization. LfcinB was not internalized by endocytosis because endocytosis inhibitors did not prevent LfcinB-induced cytotoxicity. Furthermore, intracellular delivery of LfcinB via fusogenic liposomes caused the death of Jurkat T-leukemia cells, as well as normal human fibroblasts. Collectively, these findings suggest that LfcinB caused damage to the cell membrane that allowed LfcinB to enter the cytoplasm of Jurkat T-leukemia cells and mediate cytotoxicity. In addition, confocal microscopy showed that intracellular LfcinB co-localized with mitochondria in Jurkat T-leukemia cells, while flow cytometry and colloidal gold electron microscopy showed that LfcinB rapidly associated with purified mitochondria. Furthermore, purified mitochondria treated with LfcinB rapidly lost transmembrane potential and released cytochrome c. We conclude that LfcinB-induced apoptosis in Jurkat T-leukemia cells resulted from cell membrane damage and the subsequent disruption of mitochondrial membranes by internalized LfcinB.

背景与目标： 牛乳铁蛋白 (LfcinB) 是一种阳离子抗菌肽，可通过线粒体凋亡途径杀死Jurkat T-白血病细胞。然而，LfcinB触发线粒体依赖性细胞凋亡的过程尚不清楚。在这里，我们显示LfcinB诱导的Jurkat T白血病细胞凋亡之前，LfcinB与细胞膜结合并逐渐通透。胶体金电子显微镜显示，在线粒体去极化开始之前，LfcinB进入了Jurkat T-白血病细胞的细胞质。由于内吞作用抑制剂不能阻止LfcinB诱导的细胞毒性，因此LfcinB不会被内吞作用内化。此外，通过融合脂质体在细胞内递送LfcinB会导致Jurkat T-白血病细胞以及正常人成纤维细胞死亡。总的来说，这些发现表明LfcinB对细胞膜造成了损害，使LfcinB进入Jurkat T-白血病细胞的细胞质并介导了细胞毒性。此外，共聚焦显微镜显示细胞内LfcinB与线粒体共定位于Jurkat T-白血病细胞，而流式细胞术和胶体金电子显微镜显示LfcinB与纯化的线粒体迅速相关。此外，用LfcinB处理的纯化线粒体迅速失去跨膜电位并释放细胞色素c。我们得出结论，LfcinB诱导的Jurkat T-白血病细胞凋亡是由细胞膜损伤和随后内在化的LfcinB破坏线粒体膜引起的。

BACKGROUND & AIMS: :MicroRNAs (miRs), a class of non-coding RNAs that are 18‑25 nucleotides in length, serve as key regulators in the development and progression of human cancers. Previously, miR‑503 has been implicated in breast cancer. However, the underlying mechanism of miR‑503 in regulating the proliferation and invasion of breast cancer cells remains largely unknown. In the present study, reverse transcription‑quantitative polymerase chain reaction analysis indicated that the expression of miR‑503 was significantly reduced in breast cancer tissues compared with their matched adjacent normal tissues. Furthermore, miR‑503 expression levels were markedly reduced in T2‑T4 stage breast cancer, compared with T1 stage. Insulin‑like growth factor 1 receptor (IGF‑1R) was further identified as a novel target of miR‑503. Overexpression of miR‑503 significantly suppressed the protein expression levels of IGF‑1R. Furthermore, it inhibited the proliferation and invasion of human breast cancer MCF‑7 cells, as assessed by MTT and Transwell assays, respectively. However, restoration of IGF‑1R expression markedly ameliorated the suppressive effects of miR‑503 overexpression on MCF‑7 cell proliferation and invasion, indicating that miR‑503 inhibits breast cancer cell proliferation and invasion at least partially via directly targeting IGF‑1R. Furthermore, the mRNA and protein expression levels of IGF‑1R were demonstrated to be significantly increased in breast cancer tissues compared with their matched adjacent normal tissues. In addition, IGF‑1R mRNA expression levels were reversely correlated with miR‑503 expression levels in breast tumors, suggesting that the upregulation of IGF‑1R may be due to downregulation of miR‑503 in breast cancer. In conclusion, the present study expanded the understanding of the regulatory mechanism of miR‑503 in breast cancer, and implicates the miR‑503/IGF‑1R axis as a potential therapeutic target for breast cancer.

背景与目标： : microrna (miRs) 是一类长度为18-25个核苷酸的非编码rna，是人类癌症发生和发展的关键调节剂。以前，mir-503与乳腺癌有关。然而，mir-503在调节乳腺癌细胞增殖和侵袭中的潜在机制在很大程度上仍然未知。在本研究中，逆转录定量聚合酶链反应分析表明，与匹配的邻近正常组织相比，乳腺癌组织中mir-503的表达显着降低。此外，与T1期相比，T2-T4期乳腺癌的mir-503表达水平显著降低。胰岛素样生长因子1受体 (igf ‑ 1R) 被进一步鉴定为mir-503的新靶标。Mir-503的过表达显著抑制igf ‑ 1R的蛋白表达水平。此外，它抑制人乳腺癌mcf ‑ 7细胞的增殖和侵袭，分别通过MTT和tranwell分析评估。然而，igf ‑ 1R表达的恢复显著改善了mir-503过表达对mcf ‑ 7细胞增殖和侵袭的抑制作用，表明mir-503至少部分通过直接靶向igf ‑ 1R来抑制乳腺癌细胞增殖和侵袭。此外，与匹配的邻近正常组织相比，乳腺癌组织中igf ‑ 1R的mRNA和蛋白表达水平显着增加。此外，igf ‑ 1R mRNA表达水平与乳腺肿瘤中的503表达水平呈反向相关，这表明igf ‑ 1R的上调可能是由于乳腺癌中mir-503的下调所致。总之，本研究扩大了对乳腺癌中mir-503调控机制的理解，并暗示mir-503/igf ‑ 1R轴是乳腺癌的潜在治疗靶标。

BACKGROUND & AIMS: :Wounds are known to serve as portals of entry for group A Streptococcus (GAS). Subsequent tissue colonization is mediated by interactions between GAS surface proteins and host extracellular matrix components. We recently reported that the streptococcal collagen-like protein-1, Scl1, selectively binds the cellular form of fibronectin (cFn) and also contributes to GAS biofilm formation on abiotic surfaces. One structural feature of cFn, which is predominantly expressed in response to tissue injury, is the presence of a spliced variant containing extra domain A (EDA/EIIIA). We now report that GAS biofilm formation is mediated by the Scl1 interaction with EDA-containing cFn. Recombinant Scl1 proteins that bound cFn also bound recombinant EDA within the C-C' loop region recognized by the α(9)β(1) integrin. The extracellular 2-D matrix derived from human dermal fibroblasts supports GAS adherence and biofilm formation. Altogether, this work identifies and characterizes a novel molecular mechanism by which GAS utilizes Scl1 to specifically target an extracellular matrix component that is predominantly expressed at the site of injury in order to secure host tissue colonization.

背景与目标： : 已知伤口是A组链球菌 (GAS) 的入口。随后的组织定植是由气体表面蛋白和宿主细胞外基质成分之间的相互作用介导的。我们最近报道了链球菌胶原蛋白样蛋白1 Scl1选择性地结合纤连蛋白 (cFn) 的细胞形式，并且还有助于在非生物表面上形成气体生物膜。cFn的一个结构特征主要是对组织损伤的反应，是存在包含额外结构域a (EDA/EIIIA) 的剪接变体。我们现在报告气体生物膜的形成是由Scl1与含EDA的cFn相互作用介导的。结合cFn的重组Scl1蛋白也结合了由 α(9)β(1) 整联蛋白识别的c-c' 环区域内的重组EDA。源自人类真皮成纤维细胞的细胞外2-D基质支持气体粘附和生物膜形成。总之，这项工作确定并表征了一种新的分子机制，通过该机制，GAS利用Scl1特异性靶向主要在损伤部位表达的细胞外基质成分，以确保宿主组织定植。

BACKGROUND & AIMS: :A series of twenty-five derivatives of tetrahydro-β-carbolines 1-3 was synthesized and assayed on FAAH and TRPV1 and TRPA1 channels. Four carbamates, that is, 5a,c,e, and 9b inhibited FAAH with significant potency and interacted also effectively with TRPV1 and TRPA1 nociceptive receptors, while ureas 7b,d,f, and 8a,b were endowed with specific submicromolar TRPV1 modulating activities.

背景与目标： : 合成了一系列25种四氢-β-carbolines 1-3衍生物，并在FAAH和TRPV1和TRPA1通道上进行了测定。四种氨基甲酸酯，即5a，c，e和9b以显着的效力抑制FAAH，并且还与TRPV1和TRPA1伤害性受体有效相互作用，而ureas 7b，d，f和8a，b具有特定的亚微摩尔TRPV1调节活性。

BACKGROUND & AIMS: :Treatment for multiple myeloma (MM) has significantly advanced in the last decade with the introduction of proteasome inhibitors and immunomodulatory therapies. Unfortunately, MM continues to cause significant morbidity and most patients eventually succumb to the disease. As in other areas of cancer, immunotherapy in MM has also evolved and holds promise to deliver long-lasting remissions or even cure. The signaling lymphocyte activation molecules (SLAM) family of surface proteins represents a group of potential targets for immunotherapy in MM as some of the family members are expressed consistently on plasma cells and also on myeloma propagating pre-plasma cells. Here, we review the SLAM family members in detail, describe their tissue distribution, biologic pathways, as well as relevant pre-clinical studies and clinical trials in MM. Our review demonstrates the value of SLAM family receptors as potential targets for anti-myeloma immunotherapies and outlines how immunotherapeutic approaches can be developed.

背景与目标： : 随着蛋白酶体抑制剂和免疫调节疗法的引入，多发性骨髓瘤 (MM) 的治疗在过去十年中有了显着进步。不幸的是，MM继续引起显着的发病率，大多数患者最终屈服于该疾病。与其他癌症领域一样，MM的免疫疗法也在不断发展，并有望提供持久的缓解甚至治愈。表面蛋白的信号淋巴细胞活化分子 (SLAM) 家族代表了MM中免疫疗法的一组潜在靶标，因为某些家族成员在浆细胞和骨髓瘤传播前浆细胞上一致表达。在这里，我们详细回顾了SLAM家族成员，描述了他们的组织分布，生物学途径，以及相关的临床前研究和MM的临床试验。我们的评论证明了SLAM家族受体作为抗骨髓瘤免疫疗法的潜在靶标的价值，并概述了如何开发免疫治疗方法。

BACKGROUND & AIMS: :Human hair follicle mesenchymal stem cells (hHF-MSCs) are capable of differentiating into smooth muscle cells (SMCs) in response to transforming growth factor-β (TGF-β), and thus can be used for cardiovascular tissue engineering and regenerative medicine. However, the precise molecular mechanisms underlying SMC conversion of hHF-MSCs are still undefined. MicroRNAs (miRNAs) are small noncoding RNAs that modulate gene expression post-transcriptionally by binding to the complementary sequences of targeted mRNAs. Accumulating evidence indicates that miRNAs are associated with SMC differentiation in vitro andin vivo. In this study, we revealed that miR-18b was significantly downregulated during TGF-β1-induced hHF-MSCs differentiation into SMC using miRNA array profiling and quantitative RT- PCR (qRT-PCR). Over-expression of miR-18b in hHF-MSCs led to remarkable downregulation of SMC-specific markers such as SMA and calponin proteins. On the contrary, inhibition of endogenous miR-18b by its antisense oligonucleotide antagomir-18b reversed the changes of SMA and calponin proteins. We also showed that SMAD2, a key transcription regulator in TGF-β signaling which was involved in SMC differentiation, is regulated by miR-18b. miR-18b could suppress the expression of SMAD2 protein by targeting the 3'UTR of SMAD2 gene without affecting its mRNA level in hHF-MSCs. Moreover, knockdown of SMAD2 by RNA interference could block the effect of inhibition of miR-18b on SMC differentiation, indicating that SMAD2 contributed to miR-18b mediated regulation of TGF-β-induced SMC differentiation. In conclusion, this study demonstrated that miR-18b regulated the TGF-β1-induced differentiation of hHF-MSCs into SMCs by targeting SMAD2 gene, and provided novel insights into the regulatory mechanisms of TGF-β-induced SMC differentiation.

背景与目标： : 人毛囊间充质干细胞 (hhf-mscs) 能够响应转化生长因子-β (TGF-β) 分化为平滑肌细胞 (SMCs)，因此可用于心血管组织工程和再生医学。然而，hHF-MSCs的SMC转化的确切分子机制仍未确定。Microrna (mirna) 是小的非编码rna，通过与靶向mrna的互补序列结合来调节转录后的基因表达。越来越多的证据表明，mirna在体外和体内与SMC分化有关。在这项研究中，我们揭示了使用miRNA阵列谱和定量rt-pcr (qRT-PCR) 在tgf-β1诱导的hHF-MSCs分化为SMC期间miR-18b显着下调。hHF-MSCs中miR-18b的过表达导致SMC特异性标记 (例如SMA和钙蛋白) 的显着下调。相反，其反义寡核苷酸对内源性miR-18b的抑制antagomir-18b逆转了SMA和钙蛋白的变化。我们还表明，SMAD2是参与SMC分化的TGF-β 信号传导中的关键转录调节剂，受miR-18b调节。miR-18b可以通过靶向SMAD2基因的3'UTR来抑制SMAD2蛋白的表达，而不影响其在hHF-MSCs中的mRNA水平。此外，通过RNA干扰敲除SMAD2可以阻断miR-18b对SMC分化的抑制作用，表明SMAD2有助于miR-18b介导的TGF-β 诱导的SMC分化的调节。总之，本研究表明，miR-18b通过靶向SMAD2基因调控了tgf-β1诱导的hHF-MSCs向SMC的分化，并为TGF-β 诱导的SMC分化的调控机制提供了新的见解。

BACKGROUND & AIMS: :Purine-binding proteins are of critical importance to all living organisms. Approximately 13% of the human genome is devoted to coding for purine-binding proteins. Given their importance, purine-binding proteins are attractive targets for chemotherapeutic intervention against a variety of disease states, particularly cancer. Modern computational and biophysical techniques, combined together in a structure-based drug design approach, aid immensely in the discovery of inhibitors of these targets. This review covers the process of modern structure-based drug design and gives examples of its use in discovery and development of drugs that target purine-binding proteins. The targets reviewed are human purine nucleoside phosphorylase, human epidermal growth factor receptor kinase, and human kinesin spindle protein.

背景与目标： : 嘌呤结合蛋白对所有生物都至关重要。大约13% 的人类基因组致力于编码嘌呤结合蛋白。鉴于其重要性，嘌呤结合蛋白是针对各种疾病状态 (尤其是癌症) 的化学治疗干预的有吸引力的靶标。现代计算和生物物理技术结合在基于结构的药物设计方法中，极大地帮助发现了这些靶标的抑制剂。这篇综述涵盖了基于结构的现代药物设计的过程，并举例说明了其在发现和开发靶向嘌呤结合蛋白的药物中的用途。综述的目标是人嘌呤核苷磷酸化酶，人表皮生长因子受体激酶和人驱动蛋白纺锤体蛋白。

BACKGROUND & AIMS: :Nanomedicine formulations such as biodegradable nanoparticles (nps) and liposomes offer several advantages over traditional routes of administration: due to their small size, nanocarriers are able to selectively accumulate inside tumours or inflammatory tissues, resulting in improved drug efficacy and reduced side effects. To further augment targeting ability of nanoparticles towards tumour cells, specific ligands or antibodies that selectively recognise biomarkers over-expressed on cancer cells, can be attached to the surface either by chemical bond or by hydrophilic/hydrophobic interactions. In the present work, Herceptin (HER), a monoclonal antibody (mAb) able to selectively recognise HER-2 over-expressing tumour cells (such as breast and ovarian cancer cells), was absorbed on the surface of nanoparticles through hydrophilic/hydrophobic interactions. Nps were prepared by a modified single emulsion solvent evaporation method with five different polymers: three commercial polyesters (poly(ε-caprolactone) (PCL), poly (D,L-lactide) (PLA) and poly (D,L-lactide-co-.glycolide) (PLGA)) and two novel biodegradable polyesterurethanes (PURs) based on Poly(ε-caprolactone) blocks, synthesised with different chain extenders (1,4-cyclohexane dimethanol (CDM) and N-Boc-serinol). Polyurethanes were introduced as matrix-forming materials for nanoparticles due to their high chemical versatility, which allows tailoring of the materials final properties by properly selecting the reagents. All nps exhibited a small size and negative surface charge, suitable for surface functionalisation with mAb through hydrophilic/hydrophobic interactions. The extent of cellular internalisation was tested on two different cell lines: MCF-7 and SK-BR-3 breast cancer cells showing a normal and a high expression of the HER-2 receptor, respectively. Paclitaxel, a model anti-neoplastic drug, was encapsulated inside all nps, and release profiles and cytotoxicity on SK-BR-3 cells were also assessed. Interestingly, PUR nps were superior to commercial polyester-based nps in terms of higher cellular internalisation and cytotoxic activity on the tested cell lines. Results obtained warrants further investigation on the application of these PUR nps for controlled drug delivery and targeting.

背景与目标： : 纳米药物制剂 (例如可生物降解的纳米颗粒 (nps) 和脂质体) 比传统的给药途径具有多个优势: 由于其体积小，纳米载体能够选择性地在肿瘤或炎症组织内积聚，从而提高药物功效并减少副作用。为了进一步增强纳米颗粒对肿瘤细胞的靶向能力，可以通过化学键或通过亲水/疏水相互作用将选择性识别在癌细胞上过度表达的生物标志物的特异性配体或抗体附着到表面。在目前的工作中，赫赛汀 (HER) 是一种能够选择性识别HER-2过表达肿瘤细胞 (如乳腺癌和卵巢癌细胞) 的单克隆抗体 (mAb)，通过亲水/疏水相互作用被吸收在纳米颗粒的表面上。用五种不同的聚合物通过改进的单乳液溶剂蒸发法制备了Nps: 三种商业聚酯 (聚 (ε-己内酯) (PCL)，聚 (D，L-丙交酯) (PLA) 和聚 (D，L-丙交酯-co-乙交酯 (PLGA)) 和两种基于聚 (ε-己内酯) 嵌段的新型可生物降解的聚酯氨基甲酸酯 (PURs)，用不同的扩链剂 (1,4-环己烷二甲醇 (CDM) 和N-Boc-丝氨酸) 合成。由于聚氨酯具有很高的化学通用性，因此被引入作为纳米颗粒的基质形成材料，这可以通过适当选择试剂来调整材料的最终性能。所有np均显示出小尺寸和负表面电荷，适合通过亲水/疏水相互作用与mAb进行表面官能化。在两种不同的细胞系上测试了细胞内在化的程度: 分别显示正常和高表达HER-2受体的MCF-7和SK-BR-3乳腺癌细胞。将紫杉醇 (一种模型抗肿瘤药物) 封装在所有np中，并评估其释放特性和对SK-BR-3细胞的细胞毒性。有趣的是，PUR nps在测试细胞系上具有更高的细胞内在化和细胞毒性活性方面优于商业基于聚酯的nps。获得的结果值得进一步研究这些PUR np在受控药物输送和靶向方面的应用。

BACKGROUND & AIMS: :Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel therapeutic strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response of tumor cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I or serum-induced IGF-IR signaling in MM cells in vitro. The A12 as a single agent was demonstrated to exert modest to significant inhibition of tumor growth in vivo in various subcutaneous xenograft MM models. The A12 was also evaluated in a disseminated xenograft MM.1S NOD/SCID model as monotherapy or in combination with other drugs (bortezomib, melphalan) currently in clinical use. The tumor burden, as determined by luciferase bioimaging, was sharply decreased, and overall survival significantly prolonged when the therapies were combined. Immunohistochemical analysis demonstrated that the A12 treated tumors had significantly decreased vascularization compared to control tumors. Furthermore, most MM lines constitutively secreted significant quantities of VEGF, and this was enhanced following IGF-I treatment. Inhibition of IGF-IR by the A12 in vitro suppressed both constitutive and IGF-I-induced secretion of VEGF, indicating that a putative anti-angiogenic mechanism associated with the A12 treatment may contribute to its anti-tumor effect.

背景与目标： : 尽管许多多发性骨髓瘤 (MM) 患者最初对细胞毒性治疗有反应，但大多数最终复发。采用化疗与靶向生物制剂相结合的新型治疗策略可能会显着增强肿瘤细胞对治疗的反应。我们测试了针对MM的全人抗igf-ir抗体 (A12)，并在体外显示了对MM细胞中igf-i或血清诱导的igf-ir信号的特异性抑制。在各种皮下异种移植MM模型中，A12作为单一药物被证明对体内肿瘤生长具有适度至显着的抑制作用。还在播散性异种移植MM.1S NOD/SCID模型中评估了A12，作为单一疗法或与目前临床使用的其他药物 (硼替佐米，美法仑) 联合使用。通过荧光素酶生物成像确定的肿瘤负荷急剧降低，并且当联合治疗时，总生存期显着延长。免疫组织化学分析表明，与对照肿瘤相比，A12治疗的肿瘤血管形成明显减少。此外，大多数MM系组成型分泌了大量的VEGF，并且在igf-i治疗后这种情况得到了增强。体外A12抑制igf-ir抑制了组成型和igf-i诱导的VEGF分泌，表明与A12治疗相关的推定抗血管生成机制可能有助于其抗肿瘤作用。

BACKGROUND & AIMS: :A major traditional of antibacterial drugs is antibiotic which promotes more rapid release of the toxins from bacteria cells in human body, which causes severe infection. The thermostable direct hemolysin (TDH) has been proposed as a major virulence factor of Vibrio parahaemolyticus (Vp). This study covers the preparation of polymer microparticle-antibody conjugate for the development of a drug targeting approach for antibacterial drug delivery. The chemical binding of antibodies (ab) to latex bead of 0.2 mum diameter was performed by using a water-soluble carbodiimide technique. Confocal microscopy revealed that the bacteria were strongly absorbed by the latex beads with bound anti-Vp polyclonal antibody (pAb). Treatment with a latex bead bound both anti-Vp pAb and anti-TDH monoclonal antibody (mAb) significantly inhibited bacterial adherence to the Caco-2 cells (p < 0.01), and reduced TDH-induced cytotoxicity in histology. These preliminary results suggest that it may be possible to effectively protect against Vp infection by using this microparticle-antibody conjugate delivery system.

背景与目标： 抗菌药物的主要传统是抗生素，它促进人体细菌细胞中毒素的更快释放，从而引起严重的感染。已提出热稳定的直接溶血素 (TDH) 作为副溶血性弧菌 (Vp) 的主要毒力因子。这项研究涵盖了聚合物微粒-抗体偶联物的制备，用于开发用于抗菌药物递送的药物靶向方法。通过使用水溶性碳二亚胺技术进行抗体 (ab) 与直径为0.2的乳胶珠的化学结合。共聚焦显微镜显示，细菌被结合了抗Vp多克隆抗体 (pAb) 的乳胶珠强烈吸收。用结合抗Vp pAb和抗TDH单克隆抗体 (mAb) 的乳胶珠处理可显着抑制细菌对Caco-2细胞的粘附 (p <0.01)，并降低组织学中TDH诱导的细胞毒性。这些初步结果表明，通过使用这种微粒-抗体缀合物递送系统，有可能有效地预防Vp感染。

BACKGROUND & AIMS: :The organization of neuronal processes into a series of layers is a hallmark of many brain regions. Homophilic cell adhesion molecules of the cadherin family have been implicated in layer choice. How they contribute to the targeting of neurons to distinct layers remains unclear. Here we systematically explore the role of a classical cadherin, Drosophila N-cadherin (CadN), in the targeting of five classes of related neurons to a series of consecutive layers in the fly visual system. We show that CadN is required in lamina neurons at discrete developmental steps but not used in a layer-specific fashion. Local CadN expression patterns correlate with specific growth cone movements, and CadN expression on one growth cone in a specific layer is essential for the targeting of processes of another neuron to this layer. We propose that dynamic regulation of CadN enables this widely expressed protein to mediate specific local interactions during neural circuit assembly.

背景与目标： : 神经元过程组织成一系列层是许多大脑区域的标志。钙粘蛋白家族的同源细胞粘附分子与层选择有关。它们如何有助于将神经元靶向到不同的层尚不清楚。在这里，我们系统地探讨了经典钙粘蛋白果蝇N-钙粘蛋白 (CadN) 在将五类相关神经元靶向果蝇视觉系统中的一系列连续层中的作用。我们证明，在离散的发育步骤中，椎板神经元需要CadN，但不以层特定的方式使用。局部CadN表达模式与特定的生长锥运动相关，并且在特定层中的一个生长锥上的CadN表达对于将另一个神经元的过程靶向该层至关重要。我们建议对CadN的动态调节使这种广泛表达的蛋白质能够在神经回路组装过程中介导特定的局部相互作用。

BACKGROUND & AIMS: OBJECTIVE:Cytotoxic T lymphocytes (CTL) initially recognize target cells using the T-cell receptor (TCR), then strongly adhere to these cells by accessory molecules, and finally induce apoptosis by Fas ligand (FasL)/Fas or lyse by the granzyme/perforin system. We describe the development of gelatin beads carrying anti-tumor monoclonal antibody (mAb) and anti-Fas mAb mimicking the TCR and FasL, respectively. We hypothesized that these antibody-coated beads can be therapeutically utilized for the elimination of tumor cells. MATERIALS AND METHODS:We evaluated the cytotoxic activity of gelatin beads bearing CH11 (anti-Fas mAb) after incubation with several human leukemia cell lines. Cytotoxic activities were measured using colorimetric DNA fragmentation assay and lactate dehydrogenase (LDH) release assay. RESULTS:We demonstrated that the cytotoxic effects of anti-Fas mAb were markedly enhanced by fixation on gelatin beads. Microscopic examination showed that the beads attached to the target cells and induced their apoptosis. These effects were enhanced further by adding tumor-specific mAb. These in vitro properties of the beads were well reconstituted in the peritoneal cavity of mice. CONCLUSION:Although antibody-coated gelatin beads lack several important properties of natural CTL, such as differentiation, proliferation, and the functions of adhesion molecules, they mimic well the targeting and cytotoxic functions of natural CTL. Our findings suggest that antibody-carrying gelatin beads may be the first step toward the development of artificial CTL and can be applied, for example, to artificial dendritic and stroma cells for the development of novel biotherapeutic approaches.

背景与目标：

BACKGROUND & AIMS: :An amendment to this paper has been published and can be accessed via a link at the top of the paper.

背景与目标： : 本文的修正案已经发表，可以通过本文顶部的链接进行访问。