BACKGROUND & AIMS: PURPOSE:To identify genes preferentially expressed in the stem-cell-rich limbal epithelium of the rat cornea. METHODS:The limbal and central corneal epithelial cells of 6-week-old rats were isolated by microdissection. Serial analysis of gene expression (SAGE) libraries were constructed and analyzed, and in situ hybridization, reverse transcription-polymerase chain reaction (RT-PCR) and cDNA cloning were conducted by conventional procedures. RESULTS:The rat limbal and central corneal epithelial SAGE libraries consisted of 41,894 and 40,691 tags, respectively. After annotation, this was reduced to 759 transcripts specific for the limbal library and 844 transcripts specific for the central corneal library; 2292 transcripts overlapped. Transcripts encoding proteins with metabolic functions comprised the major functional category in both libraries. In situ hybridization and/or RT-PCR results of 12 of the most abundant, highly enriched transcripts in the limbal epithelium were in general agreement with the SAGE data and showed that these proteins are also expressed in the conjunctival epithelium. Interesting limbal-enriched transcripts encode WDNM1-like protein (similar to WDNM1/Expi, a putative secreted proteinase and inhibitor of metastasis), mesothelin (a cancer marker), marapsin (a trypsin-like serine protease that may control cell growth and migration), K4 and K15 (both cytokeratins), and membrane-spanning four-domain subfamily A member 8B. WDNM1-like protein was cloned and confirmed as a member of the four-disulfide core family. CONCLUSIONS:The SAGE results extend the database of genes expressed in the rodent cornea and suggest an association between several genes preferentially expressed in the limbal epithelium with cellular proliferation and migration.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:To study the temporal relationships between cytomegalovirus (CMV) viral load and specific UL97 mutations in polymorphonuclear leukocytes (PMNL) and plasma samples from a patient with AIDS who developed ganciclovir-resistant CMV retinitis.

METHODS:Sequential PMNL and plasma samples were analysed for determination of the CMV viral load using non-molecular methods and a quantitative polymerase chain reaction (PCR) assay. Screening of the same samples for the most common mutations conferring ganciclovir resistance was performed using nested PCR and restriction enzyme analysis.

RESULTS:At the time of progression of CMV retinitis (after 6 months of ganciclovir), a rapid increase in the CMV DNA load was found in both PMNL and plasma samples. This increase paralleled the emergence of a specific mutation (V594) in the same samples and recovery of ganciclovir-resistant blood isolates. In this patient, however, the only tests that substantially predicted the progression of CMV disease were the quantitative PCR assay using PMNL and to a lesser extent the pp65 antigenemia assay.

CONCLUSIONS:Quantitative evaluation of the CMV viral load in PMNL using sensitive assays such as PCR appears to be a promising approach for monitoring antiviral therapy in subjects with AIDS. In addition, common mutations conferring ganciclovir resistance can be detected directly in PMNL and plasma samples.

背景与目标： 目标 : 研究巨细胞病毒 (CMV) 病毒载量与多形核白细胞 (PMNL) 和血浆样本中特定UL97突变之间的时间关系，该患者患有更昔洛韦耐药的CMV视网膜炎。
方法 : 使用非分子方法和定量聚合酶链反应 (PCR) 分析方法分析了连续的PMNL和血浆样品，以确定CMV病毒载量。使用巢式PCR和限制性内切酶分析对相同样品进行了更昔洛韦抗性最常见突变的筛选。
结果 : 在CMV视网膜炎进展时 (更昔洛韦6个月后)，在PMNL和血浆样品中发现CMV DNA载量迅速增加。这种增加与同一样品中出现特定突变 (V594) 和更昔洛韦耐药血液分离株的回收平行。但是，在该患者中，唯一可以基本预测CMV疾病进展的测试是使用PMNL的定量PCR测定，以及在较小程度上使用pp65抗原血症测定。
结论 : 使用敏感的检测方法 (例如PCR) 定量评估PMNL中的CMV病毒载量似乎是监测艾滋病患者抗病毒治疗的有希望的方法。此外，可以直接在PMNL和血浆样品中检测到赋予更昔洛韦抗性的常见突变。

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： 对脂多糖 (LPS) 响应的b细胞上的表面IgM连接抑制了终末分化和高速度Ig分泌，而对增殖没有影响。如这里所示，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中 “al-or-none” 抑制的细胞异质性。B细胞群体对IgM连接的不同敏感性似乎是由细胞环境局部决定的，与响应细胞的 “成熟度” 无关。因此，尽管长寿命的腹膜b细胞的抵抗力比脾b细胞高3至5倍，但脾脏中短寿命b细胞和长寿命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细胞的敏感性相差两个数量级，但从骨髓前b细胞体外分化的b细胞与脾b细胞一样具有抵抗力。此外，骨髓细胞培养上清液在此类细胞群体中恢复了高水平的敏感性。在显示出与佛波酯直接激活蛋白激酶C相同的剂量反应抑制曲线的细胞群体中，多价名义抗原再现了对IgM受体连接的不同敏感性。我们得出的结论是，对IgM连接的敏感性水平与b细胞的寿命或成熟度无关，但在体内受假定的组织因素的差异调节。

BACKGROUND & AIMS: :Establishment of angiogenic circuits that orchestrate blood vessel development and remodeling requires an exquisite balance between the activities of pro- and antiangiogenic factors. However, the logic that permits complex signal integration by vascular endothelium is poorly understood. We demonstrate that a "neuropeptide," neurokinin-B (NK-B), reversibly inhibits endothelial cell vascular network assembly and opposes angiogenesis in the chicken chorioallantoic membrane. Disruption of endogenous NK-B signaling promoted angiogenesis. Mechanistic analyses defined a multicomponent pathway in which NK-B signaling converges upon cellular processes essential for angiogenesis. NK-B-mediated ablation of Ca2+ oscillations and elevation of 3'-5' [corrected] cyclic adenosine monophosphate (cAMP) reduced cellular proliferation, migration, and vascular endothelial growth factor receptor expression and induced the antiangiogenic protein calreticulin. Whereas NK-B initiated certain responses, other activities required additional stimuli that increase cAMP. Although NK-B is a neurotransmitter/ neuromodulator and NK-B overexpression characterizes the pregnancy-associated disorder preeclampsia, NK-B had not been linked to vascular remodeling. These results establish a conserved mechanism in which NK-B instigates multiple activities that collectively oppose vascular remodeling.

背景与目标： : 建立协调血管发育和重塑的血管生成回路需要在促血管生成因子和抗血管生成因子的活性之间取得完美的平衡。然而，允许血管内皮进行复杂信号整合的逻辑知之甚少。我们证明了 “神经肽”，即神经激肽-B (nk-b) 可逆地抑制了内皮细胞血管网络的组装并反对鸡绒毛膜尿囊膜中的血管生成。内源性NK-B信号的破坏促进了血管生成。机理分析定义了一种多组分途径，其中nk-b信号传导会聚在血管生成必不可少的细胞过程上。Nk-b介导的Ca2振荡消融和3 '-5' [校正] 环磷酸腺苷 (cAMP) 升高降低了细胞增殖，迁移和血管内皮生长因子受体表达，并诱导了抗血管生成蛋白钙网蛋白。NK-B发起了某些反应，而其他活动则需要增加cAMP的额外刺激。尽管nk-b是一种神经递质/神经调节剂，并且nk-b过表达是妊娠相关疾病先兆子痫的特征，但nk-b与血管重塑无关。这些结果建立了一个保守的机制，其中NK-B引发了共同反对血管重塑的多种活动。

BACKGROUND & AIMS: :In Escherichia coli at least five enzyme activities required for the beta-oxidation of fatty acids are associated with a multienzyme complex composed of two subunits in alpha 2 beta 2 conformation (A. Pramanik et al., J. Bacteriol. 137:469-473, 1979). In the present work, the DNA sequence of the genes encoding these two subunits, fadB and fadA, has been determined. The direction of transcription was from fadB to fadA rather than from fadA to fadB, as suggested previously (S. K. Spratt et al., J. Bacteriol. 158:535-542, 1984). Only 10 nucleotides separated the coding sequences for the two peptides, confirming the suggestion that these genes form an operon. The peptides encoded by fadB and fadA were 729 amino acids and 387 amino acids, respectively, in length. The larger and smaller peptides had predicted molecular masses of 79,678 and 40,876 Da, respectively. Recently, the sequence of the fadA gene was published in a separate report (Yang et al., J. Biol. Chem. 265:10424-10429, 1990). In this work, most of the DNA sequence for fadA was confirmed, and 10 errors were corrected. Three of these nucleotide changes resulted in five amino acid residue changes predicted in the carboxy terminus of the fadA-encoded peptide. By comparison to other peptide sequences, the alpha subunit encoded within fadB had 31% perfect identity with the rat peroxisomal enoyl-coenzyme A:hydratase-3-hydroxyacyl-coenzyme A dehydrogenase trifunctional enzyme over the entire length of the two peptides. In agreement with the work of Yang et al., the beta subunit encoded within fadA had 35 to 45% perfect identity with five thiolase genes from different eucaryotic sources over the entire length of the peptide.

背景与目标： 在大肠杆菌中，脂肪酸的 β-氧化所需的至少五种酶活性与由 α2β2构象中的两个亚基组成的多酶复合物相关 (a.Pramanik等人，J. Bacteriol. 137:469-473，1979)。在本工作中，已经确定了编码这两个亚基fadB和fadA的基因的DNA序列。转录的方向是从fadB到fadA，而不是从fadA到fadB，如前所述 (S. K. Spratt等人，J. Bacteriol. 158:535-542，1984)。只有10个核苷酸分离了两个肽的编码序列，证实了这些基因形成操纵子的暗示。fadB和fadA编码的肽长度分别为729个氨基酸和387个氨基酸。较大和较小的肽分别预测79,678和40,876 Da的分子量。最近，fadA基因的序列发表在单独的报告中 (Yang等人，J. Biol. Chem. 265:10424-10429，1990)。在这项工作中，fadA的大部分DNA序列得到了确认，并纠正了10个错误。这些核苷酸变化中的三个导致fadA编码肽的羧基末端预测的五个氨基酸残基变化。与其他肽序列相比，fadB内编码的 α 亚基与大鼠过氧化物酶体烯酰辅酶a具有31% 完美的同一性: 在两个肽的整个长度上hydratase-3-hydroxyacyl-coenzyme脱氢酶三官能酶。与Yang等人的工作一致，在fadA内编码的 β 亚基在肽的整个长度上与来自不同真核来源的五个硫解酶基因具有35至45% 完美的同一性。

BACKGROUND & AIMS: :Although the considerable progress against gastric cancer, it remains a complex lethal disease defined by peculiar histological and molecular features. The purpose of the present study was to investigate pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expressions, and analyze their possible correlations with clinicopathological factors. The expression patterns were examined by immunohistochemistry in 47 patients, 27 evaluated of intestinal-type, and 20 of diffuse-type, with a mean follow up of 56 months and by Western blot in AGS, N87, KATO-III, and YCC-2, -3, -16 gastric cell lines. Overall, stomach cancer showed EZH2 correlated with high levels of p53, Ki-67, and cytoplasmic pRb2/p130 (P < 0.05, and P < 0.01, respectively). Increased expression of EZH2 was found in the intestinal-type and correlated with the risk of distant metastasis (P < 0.05 and P < 0.01, respectively), demonstrating that this protein may have a prognostic value in this type of cancer. Interestingly, a strong inverse correlation was observed between p27(KIP1) expression levels and the risk of advanced disease and metastasis (P < 0.05), and a positive correlation between the expression levels of p21(WAF1) and low-grade (G1) gastric tumors (P < 0.05), confirming the traditionally accepted role for these tumor-suppressor genes in gastric cancer. Finally, a direct correlation was found between the expression levels of nuclear pRb2/p130 and low-grade (G1) gastric tumors that was statistically significant (P < 0.05). Altogether, these data may help shed some additional light on the pathogenetic mechanisms related to the two main gastric cancer histotypes and their invasive potentials.

背景与目标： : 尽管在抗胃癌方面取得了长足的进步，但它仍然是一种由特殊的组织学和分子特征定义的复杂致死疾病。本研究的目的是调查pRb2/p130，VEGF，EZH2，p53，p16(INK4A)，p27(KIP1)，p21(WAF1)，Ki-67表达，并分析其与临床病理因素的可能相关性。通过免疫组织化学检查了47例患者的表达模式，其中27例被评估为肠型，20例被评估为弥漫型，平均随访56个月，并通过Western blot在AGS，N87，KATO-III和YCC-2中进行了检测，-3，-16胃细胞系。总体而言，胃癌显示EZH2与高水平的p53，Ki-67和细胞质pRb2/p130相关 (分别为P <0.05和P <0.01)。在肠型中发现EZH2的表达增加，并且与远处转移的风险相关 (分别为P <0.05和P <0.01)，表明该蛋白可能在此类癌症中具有预后价值。有趣的是，p27(KIP1) 表达水平与晚期疾病和转移风险之间存在很强的负相关 (P <0.05)，而p21(WAF1) 表达水平与低度 (G1) 胃肿瘤之间存在正相关 (P <0.05)，证实了这些肿瘤抑制基因在胃癌中的传统作用。最后，发现核pRb2/p130的表达水平与低级别 (G1) 胃肿瘤之间存在直接相关性，具有统计学意义 (P <0.05)。总之，这些数据可能有助于进一步阐明与两种主要胃癌组织类型及其侵袭潜力有关的致病机制。

BACKGROUND & AIMS: :Group B streptococcal (GBS) infections are the leading cause of bacterial disease and death among newborns in the United States and an important cause of morbidity among peripartum women and nonpregnant adults with chronic medical conditions. Disease in infants usually presents as sepsis, pneumonia or meningitis but also may include cellulitis or osteomyelitis. In 1990, GBS infections caused an estimated 7600 serious illnesses and 310 deaths among U.S. infants aged < or = 90 days; infections among infants aged < 7 days (i.e., early-onset disease) accounted for approximately 80% of these illnesses. To determine the incidence of GBS disease during 1993-1995, CDC conducted surveillance for this disease in an aggregate population of 12.5 million persons with 190,000 annual live-born infants. This report summarizes the findings of surveillance in this population, which indicate that a statistically significant decline in the incidence of early-onset GBS disease occurred in some surveillance areas.

背景与目标： : B组链球菌 (GBS) 感染是美国新生儿细菌性疾病和死亡的主要原因，也是围产期妇女和患有慢性疾病的未怀孕成年人发病的重要原因。婴儿的疾病通常表现为败血症，肺炎或脑膜炎，但也可能包括蜂窝织炎或骨髓炎。1990年，GBS感染在 <或 = 90天的美国婴儿中导致估计7600种严重疾病和310例死亡; <7天的婴儿 (即早发疾病) 感染约占这些疾病的80%。为了确定1993-1995年期间GBS疾病的发生率，CDC对1250万名每年有190,000名活产婴儿的人群进行了该疾病的监测。该报告总结了该人群的监测结果，这表明在某些监测地区，早发性GBS疾病的发病率在统计学上显着下降。

BACKGROUND & AIMS: :B-cell memory is provided by populations of quiescent memory B cells and long-lived plasma cells. Whereas it is clear that both of these cell populations arise from germinal centres, the signals and circumstances that trigger germinal-centre B cells to enter and then persist in memory compartments are poorly defined. Here, I propose that germinal centres produce memory B cells and plasma cells throughout the immune response and that memory B cells arise by the emigration of B cells that are chosen at random from the pool available in the germinal centre. The ability of such emigrants to survive as memory B cells depends on their germinal-centre 'history', with the persistence of high-affinity B-cell variants being favoured.

背景与目标： : b细胞记忆是由静态记忆b细胞和长寿命浆细胞群体提供的。尽管很明显，这两个细胞群体都来自生发中心，但触发生发中心b细胞进入并随后持续存在于记忆室中的信号和环境却定义不明确。在这里，我建议生发中心在整个免疫反应中产生记忆b细胞和浆细胞，并且记忆b细胞是通过从生发中心可用的库中随机选择的b细胞的迁移而产生的。这种移民作为记忆b细胞生存的能力取决于其生发中心的 “历史”，而高亲和力b细胞变体的持久性受到青睐。

BACKGROUND & AIMS: BACKGROUND:Several studies described the benefits of the heparin-surface-modified intraocular tens (HSM IOL) with regard to the reduced inflammation in routine extracapsular cataract extractions. However, limited information is available about the advantages of the HSM IOL in patients with an intraocular inflammation. AIM:To assess the eventual benefits of the HSM IOL compared to the regular polymethylmethacrylate intraocular lens (PMMA IOL) in patients with uveitis. METHODS:A retrospective study of 43 patients with uveitis of various origins who underwent an extracapsular cataract extraction (24 with HSM, 19 with PMMA IOL). The activity of intraocular inflammation, visual acuity, eventual complications, and medications were examined. Standardized follow-up dates were used (before surgery, one and fourteen days, five and eleven months after surgery.) RESULTS:No difference in the inflammatory, activity was noted between HSM and PMMA groups; neither at short term clinical evaluation, nor at five months after surgery. Despite a slightly better visual acuity in the HSM group before surgery, no long term differences were observed. After surgery the increase in visual acuity was similar for both groups, as well as the frequency of cystoid macular oedema (CMO) and synechiae. Fewer patients in HSM group required Nd:YAG posterior capsulotomy, but the difference was not significant. CONCLUSION:No clinical advantage was found when the HSM IOL was compared with the regular PMMA IOL in 43 patients with uveitis.

背景与目标：

BACKGROUND & AIMS: :Tumor-infiltrating stroma cells (TISC) as well as tumors themselves are thought to be involved in tumor-related immunosuppression, which is one of the critical mechanisms of tumor escape from immune surveillance. However, preparation of TISC is difficult because of the small proportion of TISC in established tumors. Thus, the cells thought to be involved in tumor-related immunosuppression are generally prepared from spleens or draining lymph nodes in tumor-bearing mice. In this study, we developed a method for directly preparing TISC from established tumors in order to analyze their function. Using green fluorescent protein (GFP) transgenic (Tg) mice and C57BL/6 mice transplanted with bone marrow (BM) cells of GFPTg mice, we detected three subpopulations of TISC: one is compatible with immature myeloid cells (ImC) derived from BM and the two other subpopulations, CD11b(+) cells and CD11b(-) cells, do not originate from BM. The TISC including these subpopulations but not each subpopulation independently after culturing with tumors in the presence of GM-CSF could suppress T cell proliferation induced by anti-CD3. In our system, tumors did not inhibit T cell responses directly, but unknown factors from tumors affected immunosuppression by TISC.

背景与目标： : 肿瘤浸润的基质细胞 (TISC) 以及肿瘤本身被认为与肿瘤相关的免疫抑制有关，这是肿瘤逃避免疫监视的关键机制之一。然而，由于TISC在已建立的肿瘤中的比例较小，因此很难制备TISC。因此，被认为与肿瘤相关的免疫抑制有关的细胞通常是从荷瘤小鼠的脾脏或引流淋巴结中制备的。在这项研究中，我们开发了一种从已建立的肿瘤中直接制备TISC的方法，以分析其功能。使用绿色荧光蛋白 (GFP) 转基因 (Tg) 小鼠和C57BL/6小鼠移植了GFPTg小鼠的骨髓 (BM) 细胞，我们检测到了TISC的三个亚群: 一个与BM衍生的未成熟髓样细胞 (ImC) 相容，另外两个亚群，CD11b(+) 细胞和CD11b(-) 细胞不起源于BM。在gm-csf存在下用肿瘤培养后，包括这些亚群但不是每个亚群的TISC可以抑制anti-CD3诱导的T细胞增殖。在我们的系统中，肿瘤没有直接抑制T细胞反应，但是肿瘤的未知因素会影响TISC的免疫抑制。

BACKGROUND & AIMS: :The aim of this study was to analyse the acting forces and moments induced by a special orthodontic appliance, the Pendulum K, for molar distalization in the transverse and sagittal planes. The purpose-designed test set-up (artificial maxilla with anchorage unit and two electrothermodynamic molars, an electronic measuring unit, a unit with force-moment sensor, an analogue/digital converter, and a data read-out unit) allowed simulation of in vivo conditions on the one hand and precise determination of the force systems on the other. The appliances investigated were three specimens of the Pendulum K. In vitro measurement of the resulting force systems revealed that the forces and moments in the transverse and sagittal planes remained almost constant over a 3 mm measuring increment when the distal screw was continuously activated (10 activations/mm). Without reactivation of the incorporated distal screw, however, a marked decline in the force systems was recorded. The Pendulum K allows translatory distalization of the upper molars and thus dental arch expansion, dispensing with the need for permanent teeth to be extracted, subject to a corresponding indication. This is achieved by continuous adjustment of an incorporated distal screw and by specific pre-activations of the Pendulum springs.

背景与目标： : 这项研究的目的是分析由特殊的正畸矫治器摆K引起的作用力和力矩，以在横向和矢状平面中使磨牙远侧。目的设计的测试装置 (带有锚固单元和两个电热磨牙的人造上颌骨，一个电子测量单元，一个带力-力矩传感器的单元，一个模拟/数字转换器，和数据读出单元) 一方面可以模拟体内条件，另一方面可以精确确定力系统。所研究的器具是摆锤K的三个样本。所得力系统的体外测量表明，当远端螺钉连续激活 (10个激活/mm) 时，在3毫米测量增量内，横向和矢状平面中的力和力矩几乎保持恒定。但是，如果不重新激活合并的远端螺钉，则记录到力系统明显下降。摆锤K允许上磨牙的平移远端化，从而使牙弓扩张，从而无需拔出恒牙，但要有相应的指示。这是通过连续调节结合的远端螺钉和通过摆簧的特定预激活来实现的。

BACKGROUND & AIMS: :Heat shock protein 90 (HSP90) is required for structural folding and maintenance of conformational integrity of various proteins, including several associated with cellular signaling. Recent studies utilizing 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, demonstrated an antitumor effect in solid tumors. To test whether HSP90 could be targeted in multiple myeloma (MM) patients, we first investigated expression of HSP90 by immunofluorescence and flow cytometric analysis in a myeloma cell line (U266) and primary myeloma cells. Following demonstration of HSP90 expression in myeloma cells, archival samples of 32 MM patients were analysed by immunoperoxidase staining. Myeloma cells in all patients showed strong cytoplasmic expression of HSP90 in all samples and 55% also demonstrated concurrent nuclear immunopositivity. Treatment of U266 and primary MM cells with 17AAG resulted in significantly increased apoptosis compared to untreated control cells. Analysis of anti-apoptotic BCL2 family proteins and akt in MM cells incubated with 17-AAG revealed down-regulation of BCL-2, BCL-XL, MCL-1 and akt. Furthermore, although a low concentration of bortezomib resulted in no cell death, a combination of 17AAG and bortezomib treatment revealed a synergistic apoptotic effect on the U266 cell line. These data suggest that targeted inhibition of HSP90 may prove to be a valid and innovative strategy for the development of future therapeutic options for MM patients.

背景与目标： : 热休克蛋白90 (HSP90) 是各种蛋白质的结构折叠和构象完整性维持所必需的，包括与细胞信号传导相关的几种。利用HSP90抑制剂17-allylamino-17-demethoxygeldanamycin (17-AAG) 的最新研究表明，在实体瘤中具有抗肿瘤作用。为了测试HSP90是否可以靶向多发性骨髓瘤 (MM) 患者，我们首先通过免疫荧光和流式细胞仪分析研究了HSP90在骨髓瘤细胞系 (U266) 和原发性骨髓瘤细胞中的表达。在证明骨髓瘤细胞中HSP90表达后，通过免疫过氧化物酶染色分析了32 MM患者的档案样本。所有患者的骨髓瘤细胞在所有样品中均显示出HSP90的强细胞质表达，并且55% 还显示出同时的核免疫阳性。与未处理的对照细胞相比，用17AAG处理U266和原代MM细胞可显着增加细胞凋亡。对与17-aag孵育的MM细胞中抗凋亡BCL2家族蛋白和akt的分析表明，BCL-2，BCL-XL，MCL-1和akt下调。此外，尽管低浓度的硼替佐米不会导致细胞死亡，但17AAG和硼替佐米的组合治疗显示出对U266细胞系的协同凋亡作用。这些数据表明，靶向抑制HSP90可能被证明是开发MM患者未来治疗选择的有效且创新的策略。

BACKGROUND & AIMS: :Fludarabine and alemtuzumab are routinely used for treatment of B-cell chronic lymphocytic leukemia (B-CLL). The present study aimed to compare the expression of signaling molecules and cytokine production by T cells of B-CLL patients in long-term unmaintained remission/plateau phase following fludarabine or alemtuzumab treatment with that of indolent/untreated B-CLL patients and healthy donors. The frequency and intensity of TCR-CD3zeta chain, p56lck, p59fyn, ZAP-70, PI3-kinase and interferon (IFN)-gamma/interleukin (IL)-4 production in CD4 and CD8 T cells was examined by flow cytometry. T-cell function was assessed by stimulation with purified protein derivative (PPD) and phytohemagglutinin (PHA). Despite a reduction in number, the expression of IFN-gamma/IL-4 in T-cells in patients was significantly higher than in healthy donors. The intensity of most signaling molecules in treated patients was relatively unaffected vs. healthy donors but lower than untreated-indolent patients. However, the total number of T cells which expressed each of the signaling molecules was decreased in patients, with no difference between fludarabine- and alemtuzumab-treated patients. The T-cell response to PHA but not PPD was reduced in treated patients. The results suggest that, despite some alterations in signaling molecules and a reduction in T-cell number, overall T-cell functions may be relatively well preserved long-term after treatment with fludarabine and alemtuzumab.

背景与目标： : 氟达拉滨和阿仑单抗通常用于治疗b细胞慢性淋巴细胞白血病 (b-cll)。本研究旨在比较在氟达拉滨或阿仑单抗治疗后长期未维持缓解/平台期的b-cll患者的T细胞与惰性/未治疗的b-cll患者和健康的T细胞的信号分子表达和细胞因子产生供体。通过流式细胞术检查CD4和CD8 T细胞中TCR-CD3zeta链，p56lck，p59fyn，ZAP-70，PI3-kinase和干扰素 (IFN)-γ/白细胞介素 (IL)-4产生的频率和强度。通过纯化蛋白衍生物 (PPD) 和植物血凝素 (PHA) 刺激来评估T细胞功能。尽管数量减少，但患者T细胞中IFN-γ/IL-4的表达显着高于健康供体。与健康供体相比，接受治疗的患者中大多数信号分子的强度相对不受影响，但低于未经治疗的惰性患者。然而，在患者中表达每种信号分子的T细胞总数减少，而氟达拉滨和阿仑单抗治疗的患者之间没有差异。在治疗的患者中，T细胞对PHA的反应降低，但对PPD的反应降低。结果表明，尽管信号分子发生了一些变化，T细胞数量减少，但在用氟达拉滨和阿仑单抗治疗后，总体T细胞功能可能长期保持良好。

BACKGROUND & AIMS: :Professional antigen-presenting cells (APC) are able to process and present exogenous antigen leading to the activation of T cells. Antigen-immunoglobulin (Ig)G complexes (IC) are much more efficiently processed and presented than soluble antigen. Dendritic cells (DC) are known for their ability to take up and process immune complex (IC) via FcgammaR, and they have been shown to play a crucial role in IC-processing onto major histocompatibility complex (MHC) class I as they contain a specialized cross-presenting transport system required for MHC class I antigen-processing. However, the MHC class II-antigen-processing pathway is distinct. Therefore various other professional APC, like macrophages and B cells, all displaying FcgammaR, are thought to present IC-delivered antigen in MHC class II. Nonetheless, the relative contribution of these APC in IC-facilitated antigen-presentation for MHC class II in vivo is not known. Here we show that, in mice, both macrophages and DC, but not B cells, efficiently capture IC. However, only DC, but not macrophages, efficiently activate antigen-specific MHC class II restricted CD4(+) T cells. These results indicate that mainly DC and not other professional APC, despite expressing FcgammaR and MHC class II, contribute significantly to IC-facilitated T cell activation in vivo under steady-state conditions.

背景与目标： : 专业抗原呈递细胞 (APC) 能够处理和呈递导致T细胞活化的外源性抗原。抗原-免疫球蛋白 (Ig)G复合物 (IC) 比可溶性抗原更有效地处理和呈现。树突状细胞 (DC) 以其通过FcgammaR吸收和处理免疫复合物 (IC) 的能力而闻名。并且它们已被证明在IC处理到主要组织相容性复合体 (MHC) I类上起着至关重要的作用，因为它们包含MHC I类抗原处理所需的专门交叉呈递转运系统。然而，MHC II类抗原处理途径是不同的。因此，其他各种专业的APC，如巨噬细胞和b细胞，都显示FcgammaR，被认为在MHC II类中呈现IC递送的抗原。尽管如此，这些APC在体内MHC II类的IC促进抗原呈递中的相对贡献尚不清楚。在这里，我们表明，在小鼠中，巨噬细胞和DC，但不是b细胞，有效地捕获IC。然而，只有DC，但不是巨噬细胞，有效激活抗原特异性MHC II类限制性CD4(+) T细胞。这些结果表明，尽管表达FcgammaR和MHC II类，但主要是DC而不是其他专业APC，在稳态条件下对IC促进的T细胞激活有显着贡献。

BACKGROUND & AIMS: :Priority setting of health interventions is often ad-hoc and resources are not used to an optimal extent. Underlying problem is that multiple criteria play a role and decisions are complex. Interventions may be chosen to maximize general population health, to reduce health inequalities of disadvantaged or vulnerable groups, ad/or to respond to life-threatening situations, all with respect to practical and budgetary constraints. This is the type of problem that policy makers are typically bad at solving rationally, unaided. They tend to use heuristic or intuitive approaches to simplify complexity, and in the process, important information is ignored. Next, policy makers may select interventions for only political motives. This indicates the need for rational and transparent approaches to priority setting. Over the past decades, a number of approaches have been developed, including evidence-based medicine, burden of disease analyses, cost-effectiveness analyses, and equity analyses. However, these approaches concentrate on single criteria only, whereas in reality, policy makers need to make choices taking into account multiple criteria simultaneously. Moreover, they do not cover all criteria that are relevant to policy makers. Therefore, the development of a multi-criteria approach to priority setting is necessary, and this has indeed recently been identified as one of the most important issues in health system research. In other scientific disciplines, multi-criteria decision analysis is well developed, has gained widespread acceptance and is routinely used. This paper presents the main principles of multi-criteria decision analysis. There are only a very few applications to guide resource allocation decisions in health. We call for a shift away from present priority setting tools in health--that tend to focus on single criteria--towards transparent and systematic approaches that take into account all relevant criteria simultaneously.

背景与目标： : 卫生干预措施的优先级设定通常是临时性的，资源的使用没有达到最佳程度。潜在的问题是，多个标准发挥作用，决策很复杂。可以选择干预措施，以最大程度地提高总体人口健康水平，减少弱势或弱势群体的健康不平等，ad/或应对威胁生命的情况，所有这些都涉及实际和预算方面的限制。这是政策制定者通常不善于理性地、没有帮助地解决的问题。他们倾向于使用启发式或直观的方法来简化复杂性，在此过程中，重要的信息被忽略。接下来，政策制定者可能只出于政治动机选择干预措施。这表明需要合理和透明的方法来确定优先级。在过去的几十年中，已经开发了许多方法，包括循证医学，疾病负担分析，成本效益分析和公平性分析。但是，这些方法仅集中在单个标准上，而实际上，决策者需要同时考虑多个标准来做出选择。此外，它们并未涵盖与决策者相关的所有标准。因此，有必要开发一种多标准方法来确定优先级，并且最近确实已将其确定为卫生系统研究中最重要的问题之一。在其他科学学科中，多准则决策分析得到了很好的发展，得到了广泛的认可，并被常规使用。本文介绍了多准则决策分析的主要原理。只有很少的应用程序来指导健康中的资源分配决策。我们呼吁从目前的卫生优先事项设定工具 (往往侧重于单一标准) 转向透明和系统的方法，同时考虑到所有相关标准。