癫癎发作诱发的程序性细胞死亡机制与神经细胞坏死的关系

目的　探讨癫发作激发的程序性细胞死亡机制是否参与癫发作所致的神经细胞坏死过程。方法　利用Sprague Dawley大鼠 ,经腹腔内注射毛果云香碱 (pilocarpine)制作癫发作模型。在实验 2 4h和 72h ,脑灌流固定后 ,取脑进行检测。经HE和TUNEL染色 ,在光镜下 ,观察神经细胞死亡 ,并采用免疫组织化学方法检测Bax和Bcl 2基因表达。结果　癫发作 2 4h和 72h,在大鼠海马CA1 区 ,细胞损伤形态上是细胞坏死。但癫发作 72h ,在海马CA1 区 ,TUNEL阳性的坏死细胞数明显增多 ,与对照组比较差异有显著性 (P <0 .0 0 1 ) .癫发作后 72h ,Bax表达显著增高 ,与对照组比较差异有显著性 (P <0 .0 0 1 ) ,而Bcl 2表达无增高 ,Bcl 2 /Bax比值降低。结论　癫发作所致的迟发性神经细胞坏死伴有程序性细胞死亡机制     

Ätiopathogenese des Diabetes mellitus Typ 1

Type 1 diabetes mellitus results from a progressive loss of pancreatic beta cells. Environmental factors such as exposure to cow's milk protein and toxins such as nitrosamines are thought to play a pivotal role in the development of type 1 diabetes by influencing the penetrance of diabetes susceptibility genes. As one additional environmental factor viruses have long been considered to play a part in type 1 diabetes.The production of cytokines such as tumour necrosis factor-alpha (TNF), interleukin-1 beta (Il-1) and the synthesis of nitric oxide (NO) are known to lead to the destruction of beta cells which results in the development of diabetes. The destruction of pancreatic beta cells is thought to be a consequence of cytokine-induced programmed cell death. The molecular mechanisms and the cell's machinery leading to and enhancing apoptosis/programmed cell death have been elucidated. It has become evident that a number of independent and distinct signaling pathways involving proteins and enzymes such as STATs, tyrosine kinases and small G-proteins are all involved in regulating a network of intracellular enzymes, called caspases/interleukin converting enzymes (ICEs) that direct a cell's progression towards death. The production of pro-inflammatory cytokines is thought to be a consequence of the disruption of the finely tuned immune balance of Th1-helper and Th2-helper T lymphocytes. This derangement of the immune system leads to the selective activation of beta-cell-cytotoxic effector T cells. It is hoped that the knowledge of the aetiopathogenesis of type 1 diabetes will help to further develop strategies to prevent and ultimately cure the disease.     

PD-1 对小鼠内毒素血症的保护作用及其机制研究

目的：革兰阴性细菌感染所致的多器官衰竭/功能障碍综合征仍是目前发达国家和发展中国家儿童死亡的主要原因之一,发病机制尚不明确。本研究探讨了具有负性免疫调节作用的免疫球蛋白超家族的成员程序性死亡受体-1（programmed death-1,PD-1）对革兰阴性细菌的主要致病成分脂多糖（LPS）所致内毒素血症的保护作用及可能的相关机制。方法PD-1+/+和PD-1/小鼠各10只经腹腔注射LPS（10 mg/kg）,观察其 72 h 存活情况;另对PD-1+/+和PD-1/小鼠各40只经腹腔注射LPS（5 mg/kg）,分别在注射前（0 h）及注射后1.5、3、6 h 采血,用ELISA检测血浆中多种炎性成分的含量。结果PD-1/小鼠在接受大剂量 LPS注射后,存活率明显低于PD-1+/+小鼠。注射5 mg/kg LPS后,PD-1/小鼠生成的具有促炎作用的介质TNF-α、IL-1β、IL-12及IL-17高于PD-1+/+小鼠。结论 PD-1对LPS所致的内毒素血症具有保护作用,可能是通过调节炎性成分的生成来实现的。［中国当代儿科杂志,2010,12(10)：812-815］     

Low Frequency of Programmed Death Ligand 1 Expression in Pediatric Cancers

Programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) pathway blockade has become a promising therapeutic target in adult cancers. We evaluated PD‐L1 expression and tumor‐infiltrating CD8⁺ T cells in formalin‐fixed, paraffin‐embedded tumor specimens from 53 untreated pediatric patients with eight cancer types: neuroblastoma, extracranial malignant germ cell tumor, hepatoblastoma, germinoma, medulloblastoma, renal tumor, rhabdomyosarcoma, and atypical teratoid/rhabdoid tumor. One rhabdomyosarcoma with the shortest survival exhibited membranous PD‐L1 expression and germinoma contained abundant tumor‐infiltrating CD8⁺ T cells and PD‐L1‐positive macrophages. The PD‐1/PD‐L1 pathway tended to be inactive in pediatric cancers.     

Cell death in normal and abnormal development

Research over the past 50 years has consistently documented that cell death is an integral part of both normal development and the etiology of birth defects; however, the significance of this cell death has been, until recently, unclear. Research published during the past 15 years has now shown that programmed cell death (PCD) and teratogen-induced cell death are genetically controlled processes (apoptosis) that play important roles in both normal and abnormal development. Therefore, the purpose of this review is to highlight what is known about PCD and teratogen-induced cell death and their relationships to the mechanisms of apoptosis and abnormal development.     

自噬与神经系统疾病研究进展

自噬是将细胞质组分运输至溶酶体的细胞内降解系统,参与物质及能量的循环,同时自噬作为一种细胞死亡方式被称为Ⅱ型程序性死亡.近年来研究表明自噬参与神经系统疾病尤其是神经退行性疾病、缺血缺氧、脑外伤、惊厥等疾病的病理生理过程.     

Severe cytokine release syndrome in a patient receiving PD‐1‐directed therapy

Cytokine release syndrome (CRS) is a phenomenon of immune hyperactivation described in the setting of cellular and bispecific T‐cell engaging immunotherapy. Checkpoint blockade using anti‐programmed cell death 1 (anti‐PD‐1) inhibitors is an approach to antitumor immune system stimulation. A 29‐year‐old female with alveolar soft part sarcoma developed severe CRS after treatment with anti‐PD‐1 therapy. CRS was characterized by high fevers, encephalopathy, hypotension, hypoxia, hepatic dysfunction, and evidence of coagulopathy, and resolved after infusion of the interleukin‐6 inhibitor tocilizumab and corticosteroids.     

The basic biology of apoptosis and its implications for pediatric surgery.

Apoptosis, or programmed cell death, is an evolutionarily conserved and highly regulated process of nonfunctional cell death. Through this process, the body disposes of unwanted cells by self-destruction: it is our final defense against damaged cells. In the last decades, many of the essential pathways that control this phenomenon have been elucidated. Apoptosis plays an important role in developmental processes, as well as in cellular homeostasis. This process is known to be accelerated or diminished in many pathologic states. Therefore the understanding of apoptotic regulation has significant clinical ramifications. This article reviews the basic understanding of programmed cell death with respect to areas of interest to pediatric surgeons, including: Hirschsprung disease, intestinal atresias, testicular disorders, short bowel syndrome, ischemia-reperfusion injury and pediatric oncology. Pro or antiapoptotic interventions may become a future target for cell and organ protection in patients suffering from these diseases.     

PD‐1 inhibition in congenital pigment synthesizing metastatic melanoma

A newborn female child was born with a congenital pigment synthesizing melanoma of the scalp. Further workup revealed metastatic disease within the liver, lungs, and left tibia. Whole exome sequencing was performed on multiple samples that revealed one somatic mutation, lysine methyltransferase 2C (KMT2C), at low allelic frequency but no v‐Raf murine sarcoma viral oncogene homolog B (BRAF), NF‐1 mutation. Programmed death ligand 1 was moderately expressed. Treatment was initiated with the programmed cell death protein 1 inhibitor nivolumab. The patient tolerated this treatment well with minimal toxicity. She is now over a year out from initial diagnosis, continuing on nivolumab, with stable disease.     

Expression of programmed death-1 and its ligands in the liver of biliary atresia

Background

An aberrant immune response is the predominant pathogenetic factor in biliary atresia (BA). Programmed death-1 (PD-1) and its two ligands, programmed death ligand-1 and programmed death ligand-2 (PD-L1 and PD-L2, respectively) play an important inhibitory role in immune reactions. We aimed to illustrate the expression of these molecules in BA.

Methods

Liver specimens were obtained from infants with BA during the Kasai procedure (early BA) and liver transplantation (late BA). Intrahepatic expression of PD- 1, PD-L1, and PD-L2 were examined by immunostaining and compared with that in patients with neonatal hepatitis syndrome and normal controls. The correlation between the expression levels of these molecules in the liver and clinicopathological parameters was analyzed for each group.

Results

Enhanced expression of PD-1 and its ligands occurred in the livers with early BA. In the BA-affected livers, PD-1 was correlated with the degree of peri-biliary inflammation, while PD-L2 was linked more directly with portal fibrosis. None of the three molecules was correlated with the prognosis of the Kasai procedure in patients with early BA.

Conclusions

Only PD-1 and PD-L1 are involved in the immune reactions of early BA. Elucidation of the detailed role of PD-L2 in BA requires further research.

     

铁死亡在新生儿缺氧缺血性脑损伤中的研究进展

新生儿缺氧缺血性脑损伤是导致新生儿死亡和婴幼儿伤残的常见病因,但机制复杂,缺乏特异治疗手段。铁死亡作为一种新型程序性细胞死亡方式,已成为一种新的治疗靶点而逐渐在临床上引起重视。该文围绕与铁死亡及缺氧缺血性脑损伤均密切相关的铁代谢异常、胱氨酸/谷氨酸反向转运体功能异常和脂质过氧化物调控异常的研究进展进行综述。     

Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory,metastatic hepatocellular carcinoma

Although checkpoint inhibitor therapies have demonstrated significant efficacy in many malignancies, they have not been well studied in patients with a history of solid organ transplant. We describe two patients with recurrent, refractory, and progressive advanced fibrolamellar hepatocellular carcinoma (HCC) following orthotopic liver transplantation who received programmed cell death protein 1 (PD‐1) inhibitor, nivolumab, on a patient access, off‐label basis. Both rapidly developed irreversible acute liver rejection shortly after starting therapy, and ultimately died. While checkpoint inhibitors clearly have tremendous potential as a targeted therapy, they should be avoided or used with extreme caution in the context of an organ transplant.     

Dramatic response to nivolumab in xeroderma pigmentosum skin tumor

We report the case of a 6‐year‐old female with xeroderma pigmentosum (XP) who developed a nonoperable scalp tumor, treated with anti‐programmed cell death protein 1 (anti‐PD‐1) therapy (nivolumab). She presented with a sarcomatoid carcinoma of the scalp with bone lysis as well as vascular and meningeal contact. Nivolumab was initiated because it has emerged as a promising immunotherapy. We observed a dramatic tumor response with excellent tolerance. However, while on nivolumab therapy she developed two large skin melanomas and several squamous cell carcinomas, which have been resected. These results demonstrate that cancer immunotherapy in patients with XP can be impressive but complex and warrants further investigation.     

Antimitochondrial agents: a new class of anticancer agents]

Over the last 2 decades, the role of apoptosis in anticancer agent cytotoxicity has become clear. Defects in the regulation of apoptosis (programmed cell death) make important contributions to the pathogenesis and progression of most cancers and leukemias. Apoptosis defects also have a key role in cell resistance to chemotherapy. Mitochondria play a central part in cell death in response to anticancer agents. Most of these agents target mitochondria via caspases or other regulator elements of the apoptotic machinery. Nevertheless, some anticancer agents, already in clinical use (paclitaxel, vinblastine, lonidamine, etoposide, arsenic trioxide) or in pre-clinical development (betulinic acid, MT21), directly target and permeabilize mitochondria. The acknowledgement of mitochondria as a new target for anticancer agents provides a new way to bypass cancer cell chemoresistance.     

Increased cerebrospinal fluid concentrations of soluble Fas (CD95/Apo-1) in hydrocephalus.

BACKGROUND AND AIMS: The ventricular enlargement observed in children with chronically raised intracranial pressure (ICP) causes a secondary loss of brain tissue. In animal studies of hydrocephalus, programmed cell death (apoptosis) has been found as a major mechanism of neuronal injury. One of the regulators of the apoptotic cell death programme is the receptor mediated Fas/Fas ligand interaction. METHODS: The apoptosis regulating cytokines soluble Fas (sFas) and soluble Fas ligand (sFasL) were studied in the cerebrospinal fluid (CSF) of 31 hydrocephalic children undergoing shunt surgery for symptomatic hydrocephalus and 18 controls. RESULTS: High concentrations of sFas were observed in children with hydrocephalus (median 252 ng/ml); in controls sFas was below the detection limit (0.5 ng/ml). sFasL was undetectable in all but one sample. CONCLUSION: High concentrations of sFas in the CSF of children with hydrocephalus suggest intrinsic sFas production, potentially antagonising pressure mediated Fas activation.     

Pentostatin for treatment of refractory autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS), a disorder of programmed cell death, could be due to a congenital defect in the Fas signaling pathway or other pathways for apoptosis. Most cases present with lymphoproliferation and certain autoimmune features such as thrombocytopenia, neutropenia, and anemia are due to excessive production of antibodies by B lymphocytes. Majority of cases present within the first few years of life. We report a case of ALPS presenting at birth which was refractory to splenectomy and immunosuppressive therapy, but responded to pentostatin followed by hematopoietic stem cell transplantation (HSCT).     

Apoptosis as a Possible Way of Destruction of Lymphoblasts After Glucocorticoid Treatment of Children with Acute Lymphoblastic Leukemia

Apoptosis (programmed cell death) is a physiologic phenomenon wherein the dying cell plays an active part in its own destruction. It has an important role in regulation of the balance of cell proliferation and cell death. The pharmacologic manipulation of apoptosk offers new possibilities for the prevention and treatment of cancer. One of the independent prognostic factors in the treatment of acute lymphoblastic leukemia is the sensitivity of the leukemic cells to corticosteroids. Apoptosis after glucocorticoid therapy is suggested as a prognostic factor in children with leukemia. Peripheral blood of children with acute leukemia was taken for morphologic and flow cytometric studies before and after the onset of prednisolone monotherapy. In most of the cases a positive correlation was observed between the decrease of blast numbers and the increase in apoptotic ratio in peripheral blood. In one case no response was observed either clinically or regarding apoptosis.     

Apoptosis as a Possible Way of Destruction of Lymphoblasts After Glucocorticoid Treatment of Children with Acute Lymphoblastic Leukemia

Apoptosis (programmed cell death) is a physiologic phenomenon wherein the dying cell plays an active part in its own destruction. It has an important role in regulation of the balance of cell proliferation and cell death. The pharmacologic manipulation of apoptosk offers new possibilities for the prevention and treatment of cancer. One of the independent prognostic factors in the treatment of acute lymphoblastic leukemia is the sensitivity of the leukemic cells to corticosteroids. Apoptosis after glucocorticoid therapy is suggested as a prognostic factor in children with leukemia. Peripheral blood of children with acute leukemia was taken for morphologic and flow cytometric studies before and after the onset of prednisolone monotherapy. In most of the cases a positive correlation was observed between the decrease of blast numbers and the increase in apoptotic ratio in peripheral blood. In one case no response was observed either clinically or regarding apoptosis.     

Prenatal blockade of vasoactive intestinal peptide alters cell death and synaptic equipment in the murine neocortex

Vasoactive intestinal peptide (VIP) is a potent growth factor that stimulates murine neocortical astrocyte genesis during the period of ontogenesis corresponding to premature delivery in humans. In rodents, part of the VIP supplied to the fetal brain is maternal VIP that crosses the placenta. If these data also apply to human brain development, premature newborns may be partly VIP-deficient because of loss of the maternal supply, and this may adversely affect their brain development. The goal of the present study was to determine the effects of VIP blockade during mouse neocortical astrocyte genesis on neuritic survival and maturation. VIP blockade by a specific VIP antagonist on embryonic d 17 and 18 induced transient, postnatal depletion of astrocytes in the upper neocortical layers. Combined use of in situ DNA fragmentation analysis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method, a marker of cell death); immunohistochemical detection of synaptophysin, microtubule-associated proteins, and neurofilaments; and quantification of mRNA for synaptophysin and N-methyl-D-aspartate R1 receptor subunit revealed that early VIP blockade significantly altered programmed neuritic death and impaired neuritic differentiation. VIP inhibition induced 1) exaggerated postnatal terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling of cortical neurons, 2) long-term overexpression of synaptophysin and N-methyl-D-aspartate R1 receptor subunit, and 3) long-term overexpression of microtubule-associated protein-5 and neurofilament 160 kD. Although the functional consequences of this deviant pattern of murine neocortical development remain to be determined, these data open up new avenues for investigating some of the cognitive deficits observed in human premature infants.