BACKGROUND & AIMS: :In this review, we focused on our studies of cancer dormancy in a murine B cell lymphoma and human breast cancer. Lifelong dormancy was induced in syngeneic mice by prior immunization to the idiotype of the tumor cell (TC) Ig before TC challenge. The mice maintained approximately 10(6) lymphoma cells in their spleen throughout their lifetime despite replication of the TCs at a reduced rate. Recurrences occurred randomly. Because of the balance between replication and cell death, we hypothesized that a similar balance might occur in long-term survivors of breast cancer when the risk of recurrences is very low. We developed a sensitive assay for circulating tumor cells (CTCs) which none were found in normal age-matched women. One third of patients, 7-22 years after mastectomy and without any evidence of disease, had CTCs. The half-life of these CTCs could be deduced from other studies as probably 2-3 hours. Hence, there was a precise balance between replication of TCs (presumably from micrometastases) and cell death. Therefore, a major population of clinically cured breast cancer patients have a chronic disease controlled by their own physiological mechanisms. We speculate on underlying mechanisms based both on studies in experimental models and clinical trials.

背景与目标： ：在这篇综述中，我们集中于对小鼠B细胞淋巴瘤和人类乳腺癌的癌症休眠研究。通过在TC攻击之前先对肿瘤细胞（TC）Ig的独特型进行免疫，可以在同系小鼠中终生休眠。尽管TCs的复制率降低了，但小鼠的一生中仍在脾脏中维持着约10（6）个淋巴瘤细胞。复发随机发生。由于复制和细胞死亡之间的平衡，我们假设当复发风险非常低时，长期存活的乳腺癌患者可能会发生类似的平衡。我们开发了一种循环肿瘤细胞（CTC）的灵敏检测方法，在正常年龄匹配的女性中没有发现。乳房切除术后7-22年且无任何疾病证据的三分之一患者患有CTC。这些CTC的半衰期可以从其他研究中推断出来，大概为2-3小时。因此，在TC的复制（可能来自微转移）和细胞死亡之间存在着精确的平衡。因此，大部分临床治愈的乳腺癌患者患有受其自身生理机制控制的慢性疾病。我们根据实验模型和临床试验研究潜在的机制。

BACKGROUND & AIMS: :Our objective was to follow the course of a dysmyelinating disease followed by partial recovery in transgenic mice using non-invasive high-resolution (117 x 117 x 70 microm) magnetic resonance (microMRI) and evoked potential of the visual system (VEP) techniques. We used JOE (for J37 golli overexpressing) transgenic mice engineered to overexpress golli J37, a product of the Golli-mbp gene complex, specifically in oligodendrocytes. Individual JOE transgenics and their unaffected siblings were followed from 21 until 75-days-old using non-invasive in vivo VEPs and 3D T2-weighted microMRI on an 11.7 T scanner, performing what we believe is the first longitudinal study of its kind. The microMRI data indicated clear, global hypomyelination during the period of peak myelination (21-42 days), which was partially corrected at later ages (>60 days) in the JOE mice compared to controls. These microMRI data correlated well with [Campagnoni AT (1995) "Molecular biology of myelination". In: Ransom B, Kettenmann H (eds) Neuroglia--a Treatise. Oxford University Press, London, pp 555-570] myelin staining, [Campagnoni AT, Macklin WB (1988) Cellular and molecular aspects of myelin protein gene-expression. Mol Neurobiol 2:41-89] a transient intention tremor during the peak period of myelination, which abated at later ages, and [Lees MB, Brostoff SW (1984) Proteins in myelin. In: Morell (ed) Myelin. Plenum Press, New York and London, pp 197-224] VEPs which all indicated a significant delay of CNS myelin development and persistent hypomyelination in JOE mice. Overall these non-invasive techniques are capable of spatially resolving the increase in myelination in the normally developing and developmentally delayed mouse brain.

背景与目标： ：我们的目标是通过非侵入性高分辨率（117 x 117 x 70 microm）磁共振（microMRI）和诱发视觉系统（VEP）技术追踪转基因小鼠的运动异常，然后部分恢复。我们使用经工程改造过表达Golli-mbp基因复合物产物Golli J37（特别是在少突胶质细胞中）的JOE（用于J​​37 golli过表达）转基因小鼠。从21岁到75天大，使用11.7 T扫描仪上的非侵入性体内VEP和3D T2加权显微MRI对个体JOE转基因及其未受影响的兄弟姐妹进行跟踪研究，我们认为这是同类研究中的首次纵向研究。显微MRI数据表明，在峰值髓鞘形成期（21-42天）期间出现了明显的整体性低髓鞘形成，与对照组相比，JOE小鼠在以后的年龄（> 60天）中得到了部分纠正。这些显微MRI数据与[Campagnoni AT（1995）“髓鞘形成的分子生物学”）有很好的相关性。在：Ransom B，Kettenmann H（eds）Neuroglia-专着中。牛津大学出版社，伦敦，第555-570页]髓磷脂染色，[Campagnoni AT，Macklin WB（1988）髓磷脂蛋白基因表达的细胞和分子方面。 [Mol Neurobiol 2：41-89]在髓鞘形成高峰期发生短暂的意向性震颤，此现象在以后的年龄有所减轻，[Lees MB，Brostoff SW（1984）蛋白在髓鞘中。在：莫雷尔（编辑）髓磷脂。 [Plenum Press，纽约和伦敦，第197-224页] VEP均表明JOE小鼠的CNS髓磷脂发育显着延迟和持续性髓鞘减少。总体而言，这些非侵入性技术能够在空间上解决正常发育和发育迟缓的小鼠大脑中髓鞘形成的增加。

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： ：肿瘤浸润基质细胞（TISC）以及肿瘤本身都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，由于在已建立的肿瘤中TISC的比例很小，因此TISC的制备是困难的。因此，通常被认为与肿瘤相关的免疫抑制有关的细胞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）小鼠和移植有GFPTg小鼠骨髓（BM）细胞的C57BL / 6小鼠，我们检测到TISC的三个亚群：一个与源自BM的未成熟髓样细胞（ImC）相容。其他两个亚群CD11b（）细胞和CD11b（-）细胞并非源自BM。在存在GM-CSF的情况下与肿瘤培养后，TISC包括这些亚群，但并非每个亚群独立地抑制由抗CD3诱导的T细胞增殖。在我们的系统中，肿瘤并未直接抑制T细胞反应，但来自肿瘤的未知因素影响了TISC的免疫抑制。

BACKGROUND & AIMS: :Intrathecal injection of mice with substance P or its C-terminal fragments evokes a well documented behavioral syndrome characterized by caudally-directed biting and scratching. We have previously shown that repeated injections of substance P result in naloxone-sensitive desensitization to this substance P-induced behavior, possibly through interactions of N-terminal fragments of substance P with mu opiate binding sites. The present investigation tests the hypothesis that substance P metabolites play a role in the development of desensitization to substance P by using the biting and scratching behavioral paradigm. While substance P-induced behaviors are produced by as little as 1 pmol of substance P, repeated injections of 7.5 pmol at 60-s intervals was found to be the minimum dose capable of causing desensitization. The C-terminal peptides, substance P3-11 and substance P5-11, elicited substance P-like behaviors, but repeated injection of these compounds did not result in desensitization to this behavior. In contrast to C-terminal fragments, intrathecal injection of N-terminal fragments, (substance P1-4, substance P1-7 and substance P1-9), did not elicit any overt substance P-like behaviors when administered alone, but when co-administered with substance P, decreased the magnitude of substance P-induced behaviors in a dose-related fashion. Various peptidase inhibitors significantly inhibited the catabolism of co-administered substance P. Co-administration of substance P with peptidase inhibitors enhanced and prolonged the substance P-induced behavioral episode, but also prevented the development of substance P-induced desensitization. Together these results support the hypothesis that the accumulation of endogenously generated N-terminal metabolites of substance P mediate desensitization to substance P-induced behaviors in the spinal cord. Substance P metabolism may therefore decrease ongoing substance P activity both by the hydrolysis of the C-terminal portion of substance P as well as by the production of N-terminal metabolites that are capable of inhibiting the effects of substance P.

背景与目标： 鞘内注射P物质或其C端片段会引起行为异常综合征，其特征是尾巴定向咬伤和抓挠。先前我们已经表明，重复注射P物质可能导致纳洛酮对这种P物质诱导的行为敏感，这可能是由于P物质的N末端片段与阿片结合位点的相互作用所致。本研究检验了以下假设，即物质P代谢产物通过使用咬和抓挠行为范式在对物质P脱敏的发展中起作用。虽然物质P诱导的行为仅由1 pmol的物质P产生，但发现以60秒的间隔重复注射7.5 pmol是能够引起脱敏的最小剂量。 C末端肽（物质P3-11和物质P5-11）引起了物质P样的行为，但是重复注射这些化合物不会导致对该行为的脱敏。与C末端片段相反，鞘内注射N末端片段（物质P1-4，物质P1-7和物质P1-9）在单独给药时不会引起任何明显的P样行为，但在联合给药时与物质P一起给药，以剂量相关的方式降低了物质P诱导的行为的幅度。各种肽酶抑制剂可显着抑制物质P共同给药的分解代谢。物质P与肽酶抑制剂的共同给药增强并延长了物质P引起的行为发作，但也阻止了物质P引起的脱敏。这些结果共同支持以下假设：内源性生成的P物质的N末端代谢产物的积累介导了对P物质诱导的脊髓行为的脱敏。因此，P物质的代谢可能会通过P物质的C末端部分水解以及产生能够抑制P物质作用的N末端代谢产物而降低正在进行的P物质活动。

BACKGROUND & AIMS: :CD5 (Ly-1) B cells are a minor subpopulation in mouse spleen and are thought to be responsible for the production of natural autoantibodies to bromelain-treated autologous erythrocytes (Br-RBC). Here it is shown that substantial numbers of conventional, CD5-negative, splenic B cells also secrete these antibodies in CBA and (NZB x NZW)F1 mice, whereas in NZB and BALB/c mice they are all produced by the CD5 B-cell population. However, stimulation with bacterial lipopolysaccharide in vivo preferentially activates the CD5 B-cell group to anti-Br-RBC antibody secretion.

背景与目标： ：CD5（Ly-1）B细胞是小鼠脾脏中的次要亚群，被认为负责产生与菠萝蛋白酶处理的自体红细胞（Br-RBC）的天然自身抗体。在此表明，大量常规的CD5阴性脾脏B细胞也在CBA和（NZB x NZW）F1小鼠中分泌这些抗体，而在NZB和BALB / c小鼠中，它们都是由CD5 B细胞产生的人口。但是，在体内用细菌脂多糖刺激可优先激活CD5 B细胞基团以分泌抗Br-RBC抗体。

BACKGROUND & AIMS: :Female mice deficient in steroid 5alpha-reductase type 1 have a decreased litter size. The average litter in homozygous deficient females is 2.7 pups vs. 8.0 pups in wild type controls. Oogenesis, fertilization, implantation, and placental morphology appear normal in the mutant animals. Fetal loss occurs between gestation days 10.75 and 11.0 commensurate with a midpregnancy surge in placental androgen production and an induction of 5alpha-reductase type 1 expression in the decidua of wild type mice. Plasma levels of androstenedione and testosterone are 2- to 3-fold higher on gestation day 9, and estradiol levels are chronically elevated by 2- to 3-fold throughout early and midgestation in the knockout mice. Administration of an estrogen receptor antagonist or inhibitors of aromatase reverse the high rate of fetal death in the mutant mice, and estradiol treatment of wild type pregnant mice causes fetal wastage. The results suggest that in the deficient mice, a failure to 5alpha-reduce androgens leads to their conversion to estrogens, which in turn causes fetal death in midgestation. These findings indicate that the 5alpha-reduction of androgens in female animals plays a crucial role in guarding against estrogen toxicity during pregnancy.

背景与目标： ：缺乏1型甾体5α-还原酶的雌性小鼠的窝产仔数减少。纯合缺陷型雌性的平均产仔数为2.7头，而野生型对照为8.0头。在突变动物中，卵子发生，受精，着床和胎盘形态正常。胎儿丢失发生在妊娠10.75至11.0天之间，与胎盘雄激素产生的中期妊娠激增和野生型小鼠蜕膜中5α-还原酶1型表达的诱导相称。在淘汰的第9天，雄烯二酮和睾丸激素的血浆水平升高了2至3倍，而在早期和中期妊娠期，雌二醇水平长期升高了2至3倍。在突变小鼠中，雌激素受体拮抗剂或芳香化酶抑制剂的使用可以逆转高死亡率的胎儿死亡，而雌二醇治疗野生型妊娠小鼠会造成胎儿的浪费。结果表明，在缺陷小鼠中，未能通过5α-还原雄激素导致其转化为雌激素，进而导致妊娠中期胎儿死亡。这些发现表明，雌性动物体内雄激素的5α-还原在预防妊娠期雌激素毒性中起着至关重要的作用。

BACKGROUND & AIMS: :Following surgery, the hormone dependence of breast tumors is exploited for therapy using antagonists such as tamoxifen, although occasional hormone-resistant clones do appear. Another chemotherapeutic strategy uses microtubule inhibitors such as taxanes. Unfortunately, these agents elicit toxicities such as leukocytopenia, diarrhea, alopecia, and peripheral neuropathies and are also associated with the emergence of drug resistance. We have previously described a tubulin-binding, natural compound, noscapine, that was nontoxic and triggered apoptosis in many cancer types albeit at 10 mumol/L or higher concentrations depending on the cell type. We now show that a synthetic analogue of noscapine, 9-bromonoscapine, is approximately 10-fold to 15-fold more potent than noscapine in inhibiting cell proliferation and induces apoptosis following G2-M arrest in hormone-insensitive human breast cancers (MDA-MB-231). Furthermore, a clear loss of mitochondrial membrane potential, release of cytochrome c, activation of the terminal caspase-3, and the cleavage of its substrates such as poly(ADP-ribose) polymerase, suggest an intrinsic apoptotic mechanism. Taken together, these data point to a mitochondrially mediated apoptosis of hormone-insensitive breast cancer cells. Human tumor xenografts in nude mice showed significant tumor volume reduction and a surprising increase in longevity without signs of obvious toxicity. Thus, our data provide compelling evidence that 9-bromonoscapine can be useful for the therapy of hormone-refractory breast cancer.

背景与目标： ：手术后，尽管偶尔出现激素抵抗性克隆，但利用他莫昔芬等拮抗剂开发了乳腺肿瘤的激素依赖性疗法。另一种化学治疗策略是使用微管抑制剂，例如紫杉烷类。不幸的是，这些药物引起毒性，例如白细胞减少，腹泻，脱发和周围神经病，并且还与耐药性的出现有关。先前我们已经描述了微管蛋白结合的天然化合物Noscapine，尽管在10μmol/ L或更高的浓度（取决于细胞类型）下，但在许多类型的癌症中均无毒并引发细胞凋亡。我们现在显示，Noscapine的合成类似物9-bromonoscapine在抑制细胞增殖方面比Noscapine的效力高约10倍至15倍，并在激素不敏感的人类乳腺癌（MDA-MB -231）。此外，线粒体膜电位的明显损失，细胞色素c的释放，末端caspase-3的活化以及其底物（如聚（ADP-核糖）聚合酶）的裂解表明了内在的凋亡机制。综上所述，这些数据表明了激素不敏感的乳腺癌细胞由线粒体介导的凋亡。裸鼠中的人类肿瘤异种移植物显示出明显的肿瘤体积减少和寿命的惊人增加，而没有明显的毒性迹象。因此，我们的数据提供了令人信服的证据，表明9-溴莫可可碱可用于治疗激素难治性乳腺癌。

BACKGROUND & AIMS: :The nature of the primary genetic defects in ob/ob and db/db mice are unknown. Both the obese (ob) and diabetes (db) mutations produce similar, multicomponent obese-hyperinsulinemic syndromes when maintained in the same strain of mouse. In an attempt to find differences between these mutations in neuroendocrine function affecting the islets of Langerhans or the pituitary, tissue content of four neuropeptides that are known to be capable of influencing the rate of insulin secretion was examined in obese (ob/ob) and diabetes (db/db) mice. In the first study, C57BL/6Job/ob and control males were studied at 3, 4, and 11 weeks of age. In the second study, db/db mice of both sexes and two inbred strains (C57BL/6J and C57BL/KsJ), which differ markedly in the severity of expression of the diabetes phenotype, were studied at 3 weeks of age, before the development of hyperglycemia and secondary consequences thereof. Immunoreactive peptides were measured in acetic acid extracts of pancreas and pituitary. No differences between male ob/ob and db/db mice of the C57BL/6J strain were found. Marked sex differences in lean control mice were found at 3 weeks of age in pancreatic Met-enkephalin-LI and galanin-LI (with two- to threefold higher content in males). Low pancreatic content (50% to 70% lower than in control mice) of galanin-LI, Met-enkephalin-LI and Leu-enkephalin-LI was associated with hyperinsulinemia in male B6 ob/ob and db/db mice at 3 weeks of age, though not in B6 db/db females and not in BKs db/db mice of either sex.(ABSTRACT TRUNCATED AT 250 WORDS)

背景与目标： ：ob / ob和db / db小鼠的主要遗传缺陷的性质尚不清楚。肥胖（ob）和糖尿病（db）突变在同一小鼠品系中均会产生相似的多成分肥胖-高胰岛素血症综合征。为了发现影响兰格罕氏岛或垂体胰岛的神经内分泌功能的这些突变之间的差异，在肥胖和肥胖（ob / ob）和糖尿病患者中，对四种已知能够影响胰岛素分泌速率的神经肽的组织含量进行了检查。 （db / db）小鼠。在第一个研究中，研究了C57BL / 6Job / ob和对照男性在3、4和11周的年龄。在第二项研究中，在发育前的3周龄研究了性别和两种自交系（C57BL / 6J和C57BL / KsJ）的db / db小鼠，它们在糖尿病表型的表达严重程度上有显着差异。高血糖及其继发后果。在胰腺和垂体的乙酸提取物中测量了免疫反应性肽。在C57BL / 6J株的雄性ob / ob和db / db小鼠之间未发现差异。在瘦瘦对照小鼠中，在三周龄的胰腺Met-脑啡肽-LI和甘丙肽-LI中发现明显的性别差异（雄性含量高2至3倍）。在3周龄的雄性B6 ob / ob和db / db小鼠中，甘丙肽-LI，Met-脑啡肽-LI和亮-脑啡肽-LI的胰腺含量低（比对照小鼠低50％至70％）与高胰岛素血症相关。年龄，但不是在B6 db / db雌性中，也不是在BK s db / db两种性别的小鼠中。（摘要以250字截断）

BACKGROUND & AIMS: :Cyclic GMP metabolism has been investigated in the retinas of mice that are heterozygous for a 'photoreceptor dystrophy' gene and have a lowered concentration of cGMP in their photoreceptor cells. The concentration of rhodopsin, retinal morphology and guanylate cyclase kinetics were normal. Cyclic GMP phosphodiesterase had a lowered affinity for cGMP. In accord with previous observations, chelation of exogenous calcium had no effect on cGMP levels in light-adapted retinas but increased them in dark-adapted tissue. The difference between cGMP concentrations in heterozygous and normal retinas in the dark was then eliminated. It was concluded that a modulator of cGMP phosphodiesterase activity is most likely to be causing the lowered steady-state level of cGMP in heterozygous retinas and that calcium is not involved.

背景与目标： ：已经对小鼠视网膜中的循环GMP代谢进行了研究，这些小鼠对于“感光器营养不良”基因是杂合的，并且其感光细胞中cGMP的浓度降低。视紫红质的浓度，视网膜形态和鸟苷酸环化酶动力学均正常。环状GMP磷酸二酯酶对cGMP的亲和力较低。与以前的观察结果一致，外源钙的螯合对光适应性视网膜中cGMP的含量没有影响，但在黑暗适应性组织中却增加了。然后消除了黑暗中杂合子和正常视网膜中cGMP浓度之间的差异。结论是，cGMP磷酸二酯酶活性的调节剂最有可能导致杂合性视网膜中cGMP的稳态水平降低，并且不涉及钙。

BACKGROUND & AIMS: :Venous valves play a crucial role in blood circulation, promoting the one-way movement of blood from superficial and deep veins towards the heart. By preventing retrograde flow, venous valves spare capillaries and venules from being subjected to damaging elevations in pressure, especially during skeletal muscle contraction. Pathologically, valvular incompetence or absence of valves are common features of venous disorders such as chronic venous insufficiency and varicose veins. The underlying causes of these conditions are not well understood, but congenital venous valve aplasia or agenesis may play a role in some cases. Despite progress in the study of cardiac and lymphatic valve morphogenesis, the molecular mechanisms controlling the development and maintenance of venous valves remain poorly understood. Here, we show that in valved veins of the mouse, three gap junction proteins (Connexins, Cxs), Cx37, Cx43, and Cx47, are expressed exclusively in the valves in a highly polarized fashion, with Cx43 on the upstream side of the valve leaflet and Cx37 on the downstream side. Surprisingly, Cx43 expression is strongly induced in the non-valve venous endothelium in superficial veins following wounding of the overlying skin. Moreover, we show that in Cx37-deficient mice, venous valves are entirely absent. Thus, Cx37, a protein involved in cell-cell communication, is one of only a few proteins identified so far as critical for the development or maintenance of venous valves. Because Cxs are necessary for the development of valves in lymphatic vessels as well, our results support the notion of common molecular pathways controlling valve development in veins and lymphatic vessels.

背景与目标： ：静脉瓣膜在血液循环中起关键作用，促进血液从浅静脉和深静脉向心脏的单向运动。通过防止逆行流动，静脉瓣膜避免了毛细管和小静脉受到破坏性的压力升高，尤其是在骨骼肌收缩期间。病理上，瓣膜功能不全或瓣膜缺失是静脉疾病（例如慢性静脉功能不全和静脉曲张）的常见特征。这些情况的根本原因尚不清楚，但在某些情况下，先天性静脉瓣膜发育不全或发育不全可能起作用。尽管在心脏和淋巴瓣形态发生的研究方面取得了进展，但控制静脉瓣的发育和维持的分子机制仍知之甚少。在这里，我们显示在小鼠的带瓣静脉中，三种间隙连接蛋白（Connexins，Cxs），Cx37，Cx43和Cx47仅以高度极化的方式在瓣膜中表达，而Cx43在瓣膜的上游侧小叶和Cx37在下游侧。出人意料的是，在上层皮肤受伤之后，在浅静脉中的非瓣膜静脉内皮中强烈诱导了Cx43表达。此外，我们显示在Cx37缺陷小鼠中，完全没有静脉瓣膜。因此，Cx37是一种参与细胞-细胞通讯的蛋白质，是目前鉴定出的对静脉瓣膜的形成或维持至关重要的少数几种蛋白质之一。由于Cx也是淋巴管内瓣膜发育所必需的，因此我们的研究结果支持了控制静脉和淋巴管内瓣膜发育的常见分子途径的概念。

BACKGROUND & AIMS: :Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disease. Autoantibodies (autoAbs) against double-stranded DNA (ds DNA), the hallmark of lupus, are produced and maintained by the interaction between auto-reactive B cells and CD4+ T cells. This interplay is controlled by the CD28/CD80-86/CTLA-4 axis. Here we investigated whether selective blockade of CD28-CD80/86 co-stimulatory interactions abrogates lupus nephritis development in a murine model of SLE. To this aim, NZB/NZW F1 mice were treated for 3 months, either with an anti-CD28 Fab' fragment or a control Fab'-IgG. The effect of CD28 blockade on lupus nephritis onset, survival, production of anti-ds DNA antibodies and costimulatory molecules was evaluated. CD28 blockade prevented the development of lupus nephritis and prolonged survival during the 3-month treatment and 12 weeks after. Furthermore, the production of anti-ds DNA autoAbs was decreased. Lastly, the protective effect of CD28 blockade was associated with increased intrarenal expression of the immunoregulatory molecule, Indoleamine 2, 3-dioxygenase, of the co-inhibitory receptor programmed cell-Death - 1 (PD-1) and of its ligand programmed death ligand - 1 (PDL-1).In conclusion, CD28 blockade prevented the development of lupus nephritis in NZB/NZW F1 mice. This immunomodulatory strategy is a promising candidate for SLE therapy in humans.

背景与目标： 系统性红斑狼疮（SLE）是一种慢性全身性炎症性疾病。通过自身反应性B细胞和CD4 T细胞之间的相互作用来产生和维持针对双链DNA（ds DNA）（狼疮的标志）的自身抗体（autoAbs）。这种相互作用是由CD28 / CD80-86 / CTLA-4轴控制的。在这里，我们研究了CD28-CD80 / 86共刺激相互作用的选择性阻断是否消除了狼疮性肾炎在SLE鼠模型中的发展。为了这个目的，将NZB / NZW F1小鼠用抗CD28 Fab'片段或对照Fab'-IgG治疗3个月。评估了CD28阻断对狼疮肾炎发作，生存，抗ds DNA抗体产生和共刺激分子的影响。 CD28阻断可防止狼疮性肾炎的发生，并在3个月的治疗期间和12周后延长生存期。此外，抗ds DNA autoAb的产生减少。最后，CD28阻断的保护作用与免疫调节分子吲哚胺2、3-二加氧酶，共抑制受体编程的细胞死亡-1（PD-1）及其配体编程的死亡配体的肾内表达增加有关。 -1（PDL-1）。总之，CD28阻断可预防NZB / NZW F1小鼠的狼疮性肾炎。这种免疫调节策略是人类SLE治疗的有希望的候选者。

BACKGROUND & AIMS: BACKGROUND:Obesity is associated with gut microbiota dysbiosis, disrupted intestinal barrier and chronic inflammation. Given the high and increasing prevalence of obesity worldwide, anti-obesity treatments that are safe, effective and widely available would be beneficial. We examined whether the medicinal mushroom Antrodia cinnamomea may reduce obesity in mice fed with a high-fat diet (HFD). METHODS:Male C57BL/6J mice were fed a HFD for 8 weeks to induce obesity and chronic inflammation. The mice were treated with a water extract of A. cinnamomea (WEAC), and body weight, fat accumulation, inflammation markers, insulin sensitivity and the gut microbiota were monitored. RESULTS:After 8 weeks, the mean body weight of HFD-fed mice was 39.8±1.2 g compared with 35.8±1.3 g for the HFD+1% WEAC group, corresponding to a reduction of 4 g or 10% of body weight (P<0.0001). WEAC supplementation reduced fat accumulation and serum triglycerides in a statistically significant manner in HFD-fed mice. WEAC also reversed the effects of HFD on inflammation markers (interleukin-1β, interleukin-6, tumor necrosis factor-α), insulin resistance and adipokine production (leptin and adiponectin). Notably, WEAC increased the expression of intestinal tight junctions (zonula occludens-1 and occludin) and antimicrobial proteins (Reg3g and lysozyme C) in the small intestine, leading to reduced blood endotoxemia. Finally, WEAC modulated the composition of the gut microbiota, reducing the Firmicutes/Bacteroidetes ratio and increasing the level of Akkermansia muciniphila and other bacterial species associated with anti-inflammatory properties. CONCLUSIONS:Supplementation with A. cinnamomea produces anti-obesogenic, anti-inflammatory and antidiabetic effects in HFD-fed mice by maintaining intestinal integrity and modulating the gut microbiota.

背景与目标： 背景：肥胖症与肠道菌群失调，肠壁屏障破坏和慢性炎症有关。鉴于世界范围内肥胖症的发病率不断上升，安全，有效和广泛使用的抗肥胖症治疗方法将是有益的。我们检查了药用蘑菇牛樟芝是否可以减少高脂饮食（HFD）喂养的小鼠的肥胖。
方法：雄性C57BL / 6J小鼠被喂食HFD 8周，以诱导肥胖和慢性炎症。用肉桂曲霉（WEAC）的水提取物治疗小鼠，并监测体重，脂肪堆积，炎症标志物，胰岛素敏感性和肠道菌群。
结果：8周后，喂食HFD的小鼠的平均体重为39.8±1.2 g，而喂食1％WEAC的HFD组的平均体重为35.8±1.3 g，相当于减少了4 g或体重的10％（P < 0.0001）。在HFD喂养的小鼠中，WEAC补充剂以统计学上显着的方式减少了脂肪积累和血清甘油三酯。 WEAC还逆转了HFD对炎症标志物（白介素-1β，白介素-6，肿瘤坏死因子-α），胰岛素抵抗和脂肪因子产生（瘦素和脂联素）的影响。值得注意的是，WEAC增加了小肠中肠紧密连接（小肠闭合带1和闭合蛋白）和抗菌蛋白（Reg3g和溶菌酶C）的表达，从而降低了血液内毒素血症。最后，WEAC调节了肠道菌群的组成，降低了Firmicutes / Bacteroidetes的比例，并增加了Akkermansia muciniphila和其他与抗炎特性相关的细菌的水平。
结论：补充肉桂曲霉可通过维持肠道完整性和调节肠道菌群，在喂食HFD的小鼠中产生抗肥胖，抗炎和抗糖尿病作用。

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： 细菌败血症是一种严重的威胁生命的疾病，由对感染的过度免疫反应引起。 B-1细胞与常规B-2细胞的不同表型和功能不同。表达CD5的B-1细胞子集（称为B-1a细胞）表现出先天免疫活性。在这里，我们报告B-1a细胞通过新型机制缓解过度的炎症反应，在败血症中发挥有益作用。使用细菌性脓毒症的小鼠模型，我们发现各个解剖位置的B-1a细胞数量均明显减少。 B-1a细胞过继转移到败血性小鼠中可显着减轻全身性炎症并提高生存率，而B-1a细胞缺陷型CD19-/-小鼠更易感染传染性炎症和死亡。我们还证明了B-1a细胞产生了大量的IL-10，可控制过度的炎症，并且用IL-10-10缺乏的B-1a细胞治疗的小鼠没有败血症的保护。此外，我们鉴定了一种新型的细胞内信号分子cAMP反应元件结合蛋白（CREB），它是关键的转录因子，可通过其核易位并与假定的反应元件结合来上调脓毒症中B-1a细胞的IL-10产生。在IL-10启动子上。因此，B-1a细胞在细菌性败血症中的益处是由CREB介导的，B-1a细胞中CREB的鉴定揭示了在细菌性败血症中治疗的潜在途径。

BACKGROUND & AIMS: :Porcine enzootic pneumonia (PEP), which is caused by the fastidious bacterium Mycoplasma hyopneumoniae, is one of the most economically important diseases in the pig industry worldwide. Commercial bacterins provide only partial protection; therefore, the development of more efficient vaccines against PEP is necessary. In this study, the cellular and humoral immune responses elicited by DNA and recombinant subunit vaccines based on the P37, P42, P46 and P95 antigens of M. hyopneumoniae were evaluated after the intramuscular inoculation of BALB/c mice. The expression of the cytokines INFγ, TNFα and IL1 was evaluated by real-time RT-PCR in splenocytes from vaccinated mice. All antigens delivered as subunit vaccines, especially P42 and P95, and the pcDNA3/P46 DNA vaccine were able to elicit strong immune responses. These vaccines induced cellular immune responses and the production of antibodies able to react with native M. hyopneumoniae proteins. Because both cellular and humoral immune responses were induced, P42 and P95 are promising candidates for a recombinant subunit vaccine and P46 is a promising candidate for a DNA vaccine against PEP.

背景与目标： 猪传染性肺炎（PEP）是由细菌性猪肺炎支原体（Mycoplasma hyopneumoniae）引起的，是全球养猪业中最重要的经济疾病之一。商业细菌仅提供部分保护；因此，有必要开发出更有效的抗PEP疫苗。在这项研究中，肌肉注射BALB / c小鼠后，评估了基于猪肺炎支原体的P37，P42，P46和P95抗原的DNA和重组亚基疫苗引发的细胞和体液免疫反应。通过实时RT-PCR评估来自接种小鼠的脾细胞中细胞因子INFγ，TNFα和IL1的表达。所有作为亚单位疫苗提供的抗原，特别是P42和P95，以及pcDNA3 / P46 DNA疫苗都能够引起强烈的免疫反应。这些疫苗诱导细胞免疫反应，并产生能够与天然猪肺炎支原体蛋白反应的抗体。因为诱导了细胞和体液免疫应答，所以P42和P95是重组亚单位疫苗的有前途的候选者，而P46是抗PEP的DNA疫苗的有前途的候选者。

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： 背景：P21激活激酶1（PAK1）通过多种信号通路的激活刺激结直肠癌（CRC）的生长和转移。 PAK1对CRC干细胞标志物的上调也有助于CRC对5-氟尿嘧啶的抗性。这项研究的目的是研究PAK1的消耗和抑制对APC∆14 /小鼠免疫系统和肠道肿瘤形成的影响。
方法：PAK1 KO APC∆14 /小鼠是通过将PAK1 KO小鼠与APC∆14 /小鼠杂交而产生的。通过流式细胞术和免疫组织化学染色分析脾淋巴细胞。计算肠道肿瘤的数量。还对血细胞计数。
结果：与APC /小鼠相比，APC∆14 /小鼠脾脏中T淋巴细胞和B淋巴细胞的数量均减少。 APC∆14 /小鼠中PAK1的消耗增加了脾脏T-和B-淋巴细胞的数量，并减少了肠肿瘤的数量。用PAK抑制剂PF-3758309治疗APC∆14 /小鼠，可减少肠道肿瘤的数量并增加血液淋巴细胞的数量。
结论：活性PAK1的耗尽可上调APC∆14 /小鼠的免疫系统并抑制肠道肿瘤的发展。这些观察结果表明PAK1在对肿瘤的免疫应答中起重要作用。