Rectal neuroendocrine tumours and the role of emerging endoscopic techniques

Rectal neuroendocrine tumours represent a rare colorectal tumour with a 10 fold increased prevalence due to incidental detection in the era of colorectal screening. Patient outcomes with early diagnosis are excellent. However endoscopic recognition of this lesion is variable and misdiagnosis can result in suboptimal endoscopic resection with subsequent uncertainty in relation to optimal long-term management. Endoscopic techniques have shown particular utility in managing this under-recognized neuroendocrine tumour.     

The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls

Recent studies suggest that the heart possesses an innate immune system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses, within the heart. The extant literature suggests that this intrinsic stress response system is mediated, at least in part, by a family of pattern recognition receptors, most notably the Toll-like receptors. Although the innate immune system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if innate immune signaling becomes sustained and/or excessive; in which case, the salutary effects of activation of these pathways are contravened by the known deleterious effects of inflammatory signaling. Herein, the biology of innate immune signaling in the heart is reviewed, as well as the literature suggesting that the innate immune system is involved in the pathogenesis of atherosclerosis, acute coronary syndromes, stroke, viral myocarditis, sepsis, ischemia/reperfusion injury, and heart failure. The review concludes by discussing new therapies that are being developed to modulate the innate immune system.     

The role of stem cell factor (c-kit ligand) and inflammatory cytokines in pulmonary mast cell activation

Mast cells play a critical role in allergic airway responses via IgE- specific activation and release of potent inflammatory mediators. In the present study, we have isolated and characterized primary mast cell lines derived from the upper airways of normal mice. The primary mast cell lines were grown and maintained by incubation with interleukin-3 (IL-3) and stem cell factor (SCF) and shown to be c-kit (SCF receptor) positive by flow cytometry. Subsequently, we examined the proliferation of both airway and bone marrow derived mast cell lines in response to inflammatory and hematopoietic cytokines, including SCF, IL-1, IL-3, interferon-gamma, IL-4, and IL-10. The results from the pulmonary mast cell lines were compared with those from bone marrow derived mast cells. Pulmonary mast cell lines were capable of proliferating in response to IL-3, IL-4, IL-10, and SCF, whereas the combination of SCF with the other cytokines did not increase the response over SCF alone. In contrast, the bone marrow-derived mast cells proliferated strongest to SCF or IL-3, but only modestly to IL-4 and IL-10. Furthermore, the combination of SCF with IL-3, but not the other cytokines, exhibited an increase in bone marrow-derived mast cell proliferation. Cytokine- specific stimulation of histamine release in the airway-derived and bone marrow-derived mast cells showed parallel results. SCF was the only cytokine shown to induce substantial histamine release. However, when certain nonhistamine releasing cytokines were combined with SCF, a synergistic increase in histamine release was induced in upper airway, but not bone marrow-derived mast cells. The results of these studies suggest that cytokines differentially modulate induction of proliferation and degranulation of bone marrow and upper airway-derived mast cells and may further indicate a cytokine activational cascade in tissue mast cells.     

干细胞因子在骨髓干细胞心肌内移植治疗中的作用研究

目的探讨干细胞因子（SCF）在骨髓干细胞心肌内移植中的作用机制及对移植治疗的影响。方法对急性心肌梗死（AMI）大鼠进行骨髓干细胞心肌内移植治疗,RT—PCR方法检测骨髓中SCF表达水平的变化,并用SCF表达水平不同的骨髓干细胞进行心肌内移植治疗,超声心动图检测心脏结构、功能的变化;ELISA方法检测心肌组织、血和骨髓中SCF蛋白水平的变化。结果AMI1周时骨髓中SCF mRNA表达明显降低（P〈0．01）,接受移植治疗大鼠骨髓中SCF mRNA表达未出现降低。不同SCF表达水平的骨髓干细胞进行心肌内移植治疗均能使心脏射血分数达到70％,各组之间差异无统计学意义。移植治疗后1周血清中SCF蛋白的表达水平明显低于正常对照（P〈0．05）。结论骨髓干细胞心肌内移植可能通过SCF产生骨髓动员作用;心肌梗死或曾接受移植治疗个体的骨髓干细胞同样可用于心肌内移植治疗,不影响心功能的改善。     

The role of neuroendocrine system in the pathogenesis of rheumatic diseases (minireview)

Interactions between the neuroendocrine and immune system play an important role in maintaining and restoring homeostasis. In susceptible individuals a dysfunction of the neuroendocrine system may be one of the risk factors involved in the pathogenesis of rheumatic diseases. Specific causes of altered neuroendocrine function are still not fully elucidated. Accumulation of genetical, environmental, behavioral and other risk factors during long preclinical period may result in chronic imbalances in homeostatic mechanisms maintained by neuroendocrine, microvascular and immune systems. Chronic inflammatory stress mediated by humoral and neural signals during active stages of the disease and autoantibodies against the structures of the neuroendocrine system may further participate in the neuroendocrine dysfunction. In a subset of patients with rheumatoid arthritis (RA), an assumed defect of the hypothalamic-pituitary-adrenocortical axis may be implicated in the pathogenesis. Results of some studies support the concept of adrenal dysfunction in women with premenopausal onset of the RA. Significantly lower levels of dehydroepiandrosterone sulfate (DHEAS) plasma levels of women who subsequently developed RA indicate that neuroendocrine dysfunction may be present already in preclinical period and thus are not only secondary due to ongoing inflammatory process. These findings are sketching the new prospects of possible primary prevention of RA in the future. The role of some other hormones including prolactin, growth hormone, sex hormones and involvement of autonomic nervous system in relation with the rheumatic diseases is also reviewed in the paper. Further research concerning their role in the pathogenesis of other rheumatic diseases will possibly provide new prospects in optimizing their therapy.     

The emerging role of the endocannabinoid system in endocrine regulation and energy balance

During the last few years, the endocannabinoid system has emerged as a highly relevant topic in the scientific community. Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors, named CB1 receptor and CB2 receptor, first discovered as the molecular targets of the psychotropic component of the plant Cannabis sativa, participate in the physiological modulation of many central and peripheral functions. CB2 receptor is mainly expressed in immune cells, whereas CB1 receptor is the most abundant G protein-coupled receptor expressed in the brain. CB1 receptor is expressed in the hypothalamus and the pituitary gland, and its activation is known to modulate all the endocrine hypothalamic-peripheral endocrine axes. An increasing amount of data highlights the role of the system in the stress response by influencing the hypothalamic-pituitary-adrenal axis and in the control of reproduction by modifying gonadotropin release, fertility, and sexual behavior. The ability of the endocannabinoid system to control appetite, food intake, and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the gastrointestinal tract, and, possibly, skeletal muscle. The relevance of the system is further strenghtened by the notion that drugs interfering with the activity of the endocannabinoid system are considered as promising candidates for the treatment of various diseases, including obesity.     

The role of stem cell transplantation in multiple myeloma

High-dose therapy with autologous stem cell transplantation (ASCT) has been extensively used in the past 15 years in multiple myeloma. The IFM 90 trial has shown that autologous bone marrow transplantation (BMT) is superior to conventional chemotherapy in terms of response rate, event free survival, overall survival. Several other randomized studies confirm that ASCT yields superior complete remission and event free survival rates. However, the benefit for overall survival is not always significant because some patients may receive high-dose therapy at the time of relapse. While ASCT appears to be the treatment of choice for younger patients, a number of questions have been addressed in the past few years (optimal conditioning regimen, best source of stem cells, impact of tandem autotransplants, role of maintenance therapy, results of transplantation in patients over 65 years of age or with renal failure). These issues are addressed in this review. Analysis of large cohorts of patients indicate that a low beta2 microglobulin level and the absence of chromosome 13 abnormalities are associated with a better outcome. However patients with a high-beta2 microglobulin level and chromosome 13 abnormalities, the prognosis is poor even after tandem transplantations. Allogeneic BMT is offered to a minority of younger patients with an HLA identical sibling. Initial series have shown a high-toxic death rate and no survival advantage compared to ASCT. However, allogeneic BMT is possibly the only curative therapy. Reports of CR achieved after infusion of donor lymphoid cells in patients relapsing after allogeneic BMT support the concept of graft versus myeloma effect. Therefore, the objectives of current studies is to reduce transplant related mortality by using earlier BMT, better selection of patients, better graft-versus host prophylaxis or non myeloablative conditioning regimens.     

The role of stem cell transplantation in follicular lymphoma

With the introduction of novel treatments paradigms to if or when to use transplantation strategies for patients with follicular lymphoma have changed substantially. Autologous transplantation has been intensively evaluated as consolidation after first induction treatment with positive effects, however the introduction of Rituximab led to comparable improvements and HDT has been moved to relapse treatment. In this indication HDT was frequently use already at first relapse, but now is dominantly used in patients with a highrisk profile, e.g. failure of response, early or multiply relapse and/or signs of transformation. The ideal place for allogeneic transplantation is even harder to define, as the curative potential might be outweighed by the substantial side effect profile and the indication must always be discussed in the light of available alternatives. In consequence, transplantation strategies remain an important therapeutic instrument for patients with FL, however timing within the treatment course has to be defined individually.     

The changing role of stem cell transplantation in childhood

Over the past decade, relevant improvements and refinements have significantly changed the indications, technique and results obtained with allogeneic hematopoietic SCT (HSCT) in childhood. A fundamental turning point in the history of allogeneic HSCT is represented by the use of placental blood, which was first employed in 1988 in a patient with Fanconi anemia, successfully transplanted with cord blood cells from an HLA-identical sibling. Since then, thousands of children were given an allograft of cord blood-derived hematopoietic progenitors, mainly from an unrelated donor. This large clinical experience has documented that, as compared with BMT, cord blood transplantation (CBT) is associated with reduced incidence and severity of GvHD. The outcome of recipients given unrelated CBT has been reported to be at least as good as that of patients transplanted with either BM or peripheral blood mobilized cells of an unrelated volunteer. Another emerging strategy of HSCT is that of using HLA-partially matched relatives as donors of hematopoietic progenitors. The infusion of a huge number of positively in vitro-selected CD34+ cells, with the concomitant removal of T cells, has been demonstrated to permit sustained engraftment of donor hematopoiesis, without the occurrence of GvHD in the majority of patients transplanted from an HLA-disparate relative. In adults given this type of transplantation, the most favorable results have been reported for AMLs and when the donor displays alloreactivity of natural killer cells. It remains to be definitively proved whether these findings documented in adults maintain their value in pediatric patients transplanted from an HLA-disparate family donor. Finally, the last few years have witnessed the emergence of approaches of adoptive cell therapy aimed at optimizing the results of allograft through strategies able to reinforce immune competence against pathogens, as well as against tumor cells, or at modulating donor T-cell alloreactivity.     

The critical role of agrin in the hematopoietic stem cell niche

Hematopoiesis is the process leading to the sustained production of blood cells by hematopoietic stem cells (HSCs). Growth, survival, and differentiation of HSCs occur in specialized microenvironments called "hematopoietic niches," through molecular cues that are only partially understood. Here we show that agrin, a proteoglycan involved in the neuromuscular junction, is a critical niche-derived signal that controls survival and proliferation of HSCs. Agrin is expressed by multipotent nonhematopoietic mesenchymal stem cells (MSCs) and by differentiated osteoblasts lining the endosteal bone surface, whereas Lin(-)Sca1(+)c-Kit(+) (LSK) cells express the α-dystroglycan receptor for agrin. In vitro, agrin-deficient MSCs were less efficient in supporting proliferation of mouse Lin(-)c-Kit(+) cells, suggesting that agrin plays a role in the hematopoietic cell development. These results were indeed confirmed in vivo through the analysis of agrin knockout mice (Musk-L;Agrn(-/-)). Agrin-deficient mice displayed in vivo apoptosis of CD34(+)CD135(-) LSK cells and impaired hematopoiesis, both of which were reverted by an agrin-sufficient stroma. These data unveil a crucial role of agrin in the hematopoietic niches and in the cross-talk between stromal and hematopoietic stem cells.     

The emerging role of telomerase in cardiac muscle cell growth and survival

Most mammalian cells-excepting germ cells, tumor cells, and stem cells, that is-possess a finite replicative life span, manifested by the eventual cessation of cell proliferation. Clinically, this is germane not just to the overt derangements of cell growth in cancer, but also to organs such as the heart, in which the capacity for cell replacement and repair is insufficient to maintain organ function following cell death. Among the intrinsic mechanisms that control a conserved program of replicative senescence is the enzyme telomerase, which synthesizes the telomeric repeat for end-capping of each chromosome. The implications of telomerase for cardiac growth have recently begun to be defined. Other functions of telomerase, in maintaining genome integrity, also hold importance for cardiac muscle, as a novel means to suppress apoptosis and, thus, salvage myocardium following ischemic injury.