Immune Checkpoint Inhibitor Toxicities

Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.     

三列凹顶藻中倍半萜成分的研究

目的从三列凹顶藻Laurenciatristicha中寻找具有多样性结构的倍半萜化学成分,供药理活性筛选。方法采用凝胶柱色谱、硅胶柱色谱、重结晶和高效液相色谱等方法进行分离;借助包括一维和二维NMR等波谱方法和X-单晶衍射鉴定化合物的结构;用MTT法对得到的化合物进行细胞毒活性评价。结果分离得到5个倍半萜类化合物,分别鉴定为海兔阿普里素(aplysin,)、海兔阿普里醇(aplysinol,)、去溴海兔阿普里醇(debro-moaplysinol,)、凹顶藻联苯(laurebiphenyl,)、约翰斯顿醇(johnstonol,);在人肿瘤细胞株HCT-8、Bel-7402、BGc-823、A549和HeLa模型上,化合物对所有细胞株均显示毒性,化合物对HeLa细胞显示中等强度的细胞毒活性,其他化合物对所有细胞株均无明显毒性,IC50均大于10.0μg/mL。结论化合物~均为首次从三列凹顶藻中得到,化合物对HeLa细胞具有中等强度的选择性细胞毒活性,化合物对所有细胞株均显示毒性。     

Changes in T .lymphocyte subsets after severe traumatic brain inJury

BACKGROUND： Besides local changes of cranial parenchymal cells, hemorrhage, etc., severe traumatic brain injuries also cause the changes of total body fluid and various functions, and the changes of lymphocytes and T lymphocyte subsets should be paid more attention to. OBJECTIVE： To reveal the changing laws of T lymphocyte subsets after severe traumatic brain injury, and compare with mild to moderate brain injury. DESIGN： A comparative observation. SETTINGS： Department of Neurosurgery, Longgang District Buji People＇s Hospital of Shenzhen City; Central Laboratory of Shenzhen Hospital of Prevention and Cure for Chronic Disease. PARTICIPANTS： All the subjects were selected from the Department of Neurosurgery, Longgang District Buji People＇s Hospital of Shenzhen City from August 2002 to August 2005. Thirty patients with severe brain injury, whose Glasgow coma score （GCS） was ≤ 8 points, were taken as the experimental group, including 21 males and 9 females, aging 16 - 62 years. Meanwhile, 30 patients with mild traumatic brain injury were taken as the control group （GCS ranged 14- 15 points）, including 18 males and 12 females, aging 15 -58 years. All the subjects were in admission at 6 hours after injury, without disease of major organs before injury Informed consents were obtained from all the patients or their relatives. METHODS： （1） The T lymphocytes and the subsets in peripheral blood were detected with immunofluorescent tricolor flow cytometry at l, 3, 7 and 14 days after injury in both groups. （2） The conditions of pulmonary infections were observed at 4 days after injury. The differences of measurement data were compared with the t test. MAIN OUTCOME MEASURES： Changes of T lymphocytes subsets at 1 - 14 days after severe and mild or moderate traumatic injury. RESULTS： Finally, 28 and 25 patients with mild to moderate traumatic brain injury, whereas 25 and 21 patients with severe traumatic brain injury were analyzed at 7 and 14 days respectively, and the missed ones died due to the development of disease. （1） Changes of T lymphocyte subsets： At 1 and 3 days after injury, CD3, CD4, CD8, CD4/CD8 began to decrease, whereas CD8 increased in the experimental group, which were very significantly different from those in the control group （t =2.77 - 3.26, P 〈 0.01）, and began to recover at 7 days, which were significantly different from those in the control group （t = 2.06 - 2.24, P 〈 0.05）, and generally recovered to the normal levels at 14 days （P 〉 0.05）. （2） Conditions of pulmonary infections： At 4 days after injury, the rate of pulmonary infection was significantly different between the experimental group and control group [73% （22/30）, 0, x2=37.29, P 〈 0.01]. CONCLUSION： Patients with severe traumatic brain injury suffer from damages of cellular immune function at early period （within 7 days）, and they are easily to be accompanied by pulmonary infections.     

胸腺肽α1对老年晚期恶性肿瘤患者细胞免疫功能的影响

目的 :观察胸腺肽α1对老年恶性肿瘤患者细胞免疫功能的影响。方法 :30例老年恶性肿瘤患者 ,用胸腺肽α1治疗 2个月 ,第 1个月每日 1.6 mg,第 2个月隔日 1.6 mg,均为皮下注射 ,观察治疗前后 T细胞亚群及 NK细胞、患者生活质量、血常规及肝肾功能变化。结果 :30例患者用胸腺肽α1前 ,CD4、CD4 /CD8、NK细胞分别为 (32 .33± 6 .2 5 ) %、(0 .77± 0 .2 3) %、(16 .0 5± 6 .79) % ,治疗后为 (39.4 2± 9.2 6 ) %、(1.19± 0 .5 3) %、(2 4 .37± 8.2 3) %。治疗前后比较均有显著意义 (P<0 .0 5 ) ,患者生活质量分值治疗后比治疗前显著提高 (P<0 .0 5 )。结论 :胸腺肽α1能提高老年晚期恶性肿瘤患者的细胞免疫功能 ,是较理想的免疫增强剂。     

急性高容量性血液稀释对妇科肿瘤患者围术期T淋巴细胞亚群的影响

目的探讨急性高容量性血液稀释(AHH)对妇科肿瘤患者围手术期T淋巴细胞亚群的影响.方法40例ASAⅠ～Ⅱ级的妇科肿瘤手术病人随机分成两组:高容量性血液稀释组(A组)在切皮前30分钟内输入6%羟乙基淀粉液1000ml;对照组(C组)常规输液,不实施血液稀释.分别与麻醉诱导前、手术结束后、术后24小时抽取静脉血,用流式细胞仪测定T淋巴细胞亚群CD3 、CD4 、CD8 及CD4 /CD8 细胞百分率.结果两组病人手术结束后(T1)、手术后第1天(T2)与麻醉诱导前(T0)比较:T淋巴细胞亚群CD3 、CD4 及CD4 CD8 均明显降低(P＜0.01或P＜0.05),CD8 无显著性变化;但A组手术结束后和手术后第1天CD3 、CD4 及CD4 /CD8 明显高于C组(P＜0.05).结论术前采用急性高容量性血液稀释(AHH),可显著改善妇科肿瘤患者T淋巴细胞的免疫功能.     

Changes in the Eeg Background Activity of Children with Acute Lymphoblastic Leukemia During Cytotoxic Therapy

Thirteen children with acute lymphoblastic leukemia (ALL) were investigated before and during cytotoxic therapy. EEG findings were correlated with the clinical course and the therapy protocol and compared with normal data obtained from 295 healthy children. Frequency analysis of the background activity of the EEG revealed an initial slowing of the background activity prior to therapy and further slowing each time a combination of vincristine (VCR), daunorubicine (DAU) or adriblastine (ADR), prednisone (FRED), and L-asparaginase (L-ASP) was administered. The slowing of the background activity correlated only with the administration of these drugs. DAU, ADR, and FRED are not known to influence the EEG; therefore, VCR and L-ASP remain the primary candidates responsible for the central nervous system alteration.     

人端粒酶逆转录酶在肿瘤免疫治疗中的应用

寻找有效的抗原表位是近期肿瘤免疫治疗的热点．人端粒酶逆转录酶(hTERT)的免疫学特性使其成为肿瘤免疫治疗中一个吸引人的目标。从人和鼠系统获得的数据证实，细胞毒淋巴细胞(CTL)能识别hTERT特异的肽并杀死多种组织类型hTERT表达的肿瘤细胞。由于hTERT在人肿瘤组织中的广泛表达，在极少正常组织的低水平表达，临床试验已开始检验将hTERT作为肿瘤免疫治疗目标的可行程度。近期树突状细胞(DC)转运系统及其相关技术的发展和成熟提供了一个快速有效筛选抗原肽的方法。     

乌贼墨诱生小鼠细胞毒因子活性的检测

用乌贼墨处理小鼠后，采集血清。经体外细胞毒实验证明：乌贼墨诱生的血清对人和鼠的肿瘤细胞株均有不同程度的杀伤作用。这一结果提示：乌贼墨可能具有诱生内源性细胞毒因子产生的活性。     

Immunohistochemical characterization of cellular infiltrates in squamous cell carcinoma and Bowen's disease occurring in one patient.

We investigated populations of the infiltrating cells in Bowen's disease (BD) and squamous cell carcinoma (SCC), both of which arose in the same patient, using the Avidin-Biotin-peroxidase complex method with eight monoclonal antibodies. T lymphocytes were most predominant among infiltrating cells; NK cells, B cells, and monocytes were rarely seen in either BD or SCC. Analysis of subsets of the infiltrating T lymphocytes revealed that the number of suppressor/cytotoxic (s/c) T cells was twice that of helper/inducer (h/i) T cells in BD, while the number of s/c T cells was lower than that of h/i T cells in SCC. The immunohistochemical results in the present case differed from those of predominant infiltration of h/i T cells and of s/c T cells in three other reports of BD and SCC. These results suggest that the population of the cellular infiltrates may be modulated by the nature of tumors and by the immuno-competent state of the hosts.     

A Comparative Study on the Effect of BCG-PSN and Thymopeptides on T-lymphocyte Subsets of Normal and Immunosuppressed Mice

Polysaccharidenucleicacidfractionofbacilluscalmetteguerin (BCG PSN ,SiqikangInjection)andthymopeptidesarenowtwowidelyusedimmunomod ulatorsinclinicalpractice .Theyareusuallyusedasanadjuvanttherapyforvirusinfection ,autoimmunediseasesandneoplasms ,whichhavebeenclinicallyprovedtobeeffective .Somereportsdemonstratedthattheybothcanstimulatetheproliferationanddif ferentiationofT lymphocytes.However ,theexactmechanismshavenotbeenelucidatedyet .InordertocomparetheirmodulatingmechanismsonT lympho c…