Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells

Tumors often escape immune-mediated destruction by suppressing lymphocyte infiltration or effector function. New approaches are needed that overcome this suppression and thereby augment the tumoricidal capacity of tumor-reactive lymphocytes. The cytokine interleukin-15 (IL-15) promotes proliferation and effector capacity of CD8(+) T cells, natural killer (NK) cells, and NKT cells; however, it has a short half-life and high doses are needed to achieve functional responses in vivo. The biological activity of IL-15 can be dramatically increased by complexing this cytokine to its soluble receptor, IL-15R alpha. Here, we report that in vivo delivery of IL-15/IL-15R alpha complexes triggers rapid and significant regression of established solid tumors in two murine models. Despite a marked expansion of IL-2/IL-15R beta(+) cells in lymphoid organs and peripheral blood following treatment with IL-15/IL-15R alpha complexes, the destruction of solid tumors was orchestrated by tumor-resident rather than newly infiltrating CD8(+) T cells. Our data provide novel insights into the use of IL-15/IL-15R alpha complexes to relieve tumor-resident T cells from functional suppression by the tumor microenvironment and have significant implications for cancer immunotherapy and treatment of chronic infections.     

美国国家骨髓库20年回顾:成人无关供者造血干细胞移植

自1987年起,美国国家骨髓库(NMDP)提供了>30 000份URD-HCT,其中70%以上的受者是患有恶性血液病或获得性血液疾病的成人.在此期间发生很大变化,包括无偿捐献队伍的扩大、PBSCs采集、脐血库(UCB)的加入、HLA分型技术的进步、新药物的使用、低强度预处理(RIC)以及移植后免疫调节等.本文就过去20年NMDP成人受者HCT的数据及分析作一介绍.     

Histamine induces the neuronal hypertrophy and increases the mast cell density in gastrointestinal tract

Histamine is an endogenous biogenic amine that is synthesized from the basic amino acid histidine. Ability to mimic anaphylaxis is one of the first described functions of histamine and it has been demonstrated that histamine plays a significant role in the regulation of immune system and neuronal function, influences neuronal morphology and is involved in mast cells (MCs) chemotaxis. MCs as histamine releasers, may thus also interact with neuronal function. In the present study, we aimed to evaluate the role of histamine on mast cell density and neuronal morphology in the gastrointestinal tract of the mouse.Ten mice were daily injected intraperitoneally for 7 days with 20 mg/kg of histamine diluted in 0.5 ml physiological serum. After 7 days, mice were euthanised and samples from stomach, small bowel, colon and appendix were processed for histological examination. Immunohistochemistry was performed employing primary antibodies directed against triptase for mast cells and PGP 9.5 antigen for neuronal structures. The density of triptase and PGP 9.5 positive cells and the morphology of the ganglia were quantitatively evaluated by digital image analysis.The number of ganglia was higher in stomach, small bowel, colon and appendices of the histamine group when compared with the control group. Only in appendices and colon, the number of Schwann cells was significantly higher than that of the control group. The PGP 9.5 expression and the mean area of ganglia showed a significant increase only in appendices. In histamine group the MCs were clustered especially in the lamina propria. Mast cell density (MCD) was significantly higher than the control group in the small bowel, colon and appendices tissues.The intraperitoneally injection histamine increases the MCD and induces the neuronal hypertrophy and after the comparison of the organs in the gastrointestinal tract the results indicated the most effected organ as the appendices.     

A huge low-grade fibromyxoid sarcoma of small bowel mesentery simulating hyper immune splenomegaly syndrome: a case report and review of literature

Introduction

Low-grade fibromyxoid sarcoma (LGFMS) is a rare non epithelial tumour. It usually arises from the smooth muscles of the extremities. It is, however, occasionally reported to arise from other regions of the body.

Case report

We report the case of a 32 year old man who complained of a progressive abdominal swelling of 4 months duration. There was associated abdominal discomfort and weight loss. Abdominal examination revealed a non-tender intra abdominal mass filling the abdomen completely. Abdominal ultrasound suggested a massive splenomegaly. Abdomina Computerized Tomography (CT) scan was not done due to financial constraints. At laparotomy, a large, pearl-coloured mass was found within the mesentery of the proximal jejunum, with dilated, tortuous vessels. It was resected along with the overlying 60cm of jejunum. It weighed 7.5kg. Histology and immunohistochemistry confirmed the diagnosis of lowgrade fibromyxoid sarcoma. Post-operative period was uneventful and there were no features of recurrent after 2 year of follow up.

Conclusion

LGFMS may cause a diagnostic dilemma, especially in a third world setting where preoperative diagnosis is hampered by lack of facilities and poverty. A high index of suspicion is needed for preoperative diagnosis, which is necessary for proper planning of the operation.     

Effects of evening light on body temperature

Abstract Six healthy male subjects aged 21–35 years participated in the present study. The subjects were exposed to dim light (150 lux) or bright light (3000 lux) at eye level, from 19.00 to 21.30 h for 5 days. Rectal temperature and wrist activity were monitored throughout the study period. Rectal temperature nadir was delayed significantly after the bright light exposure. Ease in sleep initiation and overall sleep quality, measured by questionnaire, were aggravated significantly by the evening bright light exposure. These results suggest that strong illumination at night may disturb nocturnal sleep.     

STUDIES ON PROTEIN FOLDING,UNFOLDING AND FLUCTUATIONS BY COMPUTER SIMULATION IV. Hydrophobic Interactions

The theoretical model of proteins on the two-dimensional square lattice, introduced previously, is extended to include the hydrophobic interactions. Two proteins, whose native conformations have different folded patterns, are studied. Units in the protein chains are classified into polar units and nonpolar units. If there is a vacant lattice point next to a nonpolar unit, it is interpreted as being occupied by solvent water and the entropy of the system is assumed to decrease by a certain amount. Besides these hydrophobic free energies, the specific longrange interactions studied in previous papers are assumed to be operative in a protein chain. Equilibrium properties of the folding and unfolding transitions of the two proteins are found to be similar, even though one of them was predicted, based on the one globule model of the transitions, to unfold through a significant intermediate state (or at least to show a tendency toward such a behavior), when the hydrophobic interactions are strongly weighted. The failure of this prediction led to the development of a more refined model of transitions; a non-interacting local structure model. The hydrophobic interactions assumed here have a character of non-specific long-range interactions. Because of this character the hydrophobic interactions have the effect of decelerating the folding kinetics. The deceleration effect is less pronounced in one of the two proteins, whose native conformation is stabilized by many pairs of medium-range interactions. It is therefore inferred that the medium-range interactions have the power to cope with the decelerating effect of the non-specific hydrophobic interactions.     

Hypoxia-inducible factor-1alpha expression in experimental cirrhosis: correlation with vascular endothelial growth factor expression and angiogenesis

Angiogenesis progresses together with fibrogenesis during chronic liver injury. Hypoxia-inducible factor-1alpha (HIF-1alpha), a master regulator of homeostasis, plays a pivotal role in hypoxia-induced angiogenesis through its regulation of vascular endothelial growth factor (VEGF). The association between hypoxia, angiogenesis and VEGF expression has been demonstrated in experimental cirrhosis. However, expression of HIF-1alpha has yet to be reported. The aim of this study was to investigate the significance of HIF-1alpha expression during experimental liver fibrosis and the relationships between HIF-1alpha expression, VEGF expression and angiogenesis. Cirrhosis was induced in male Wistar rats by intraperitoneal administration of diethyl nitrosamine (DEN) (100 mg/kg, once a week). The serial sections from liver tissues were stained with anti-HIF-1alpha, anti-VEGF and anti-CD34 antibodies before being measured by light microscopy. Our results showed that HIF-1alpha expression gradually increases according to the severity of fibrosis (p<0.01). Moreover, its expression was found to be correlated with angiogenesis (r=0.916) and VEGF expression (r=0.969). The present study demonstrates that HIF-1alpha might have a role in the development of angiogenesis via regulation of VEGF during experimental liver fibrogenesis and suggests that this factor could be a potential target in the manipulation of angiogenesis in chronic inflammatory diseases of the liver.