APOE ε4: The most prevalent yet understudied risk factor for Alzheimer's disease

Brain pathology of Alzheimer's diseases (AD) and the genetics of autosomal dominant familial AD have been the “lamp posts” under which the AD field has been looking for therapeutic targets. Although this approach still remains valid, none of the compounds tested to date have produced clinically meaningful results. This calls for developing complementary therapeutic approaches and AD targets. The allele ε4 of apolipoprotein E4 (APOE ε4), is the most prevalent genetic risk factor for sporadic AD, and is expressed in more than half of the AD patients. However, in spite of its genetic prominence, the allele APOE ε4 and its corresponding protein product apoE4 have been understudied. We presently briefly discuss the reasons underlying this situation and review newly developed AD therapeutic approaches that target apoE4 and which pave the way for future studies.     

PREVENTION OF COLLAGEN INDUCED ARTHRITIS IN MICE BY TREATMENT WITH AN ANTIBODY DIRECTED AGAINST THE T CELL RECEPTOR αβ FRAMEWORK

Collagen induced arthritis (CIA) is an animal model of inflammatory polyarthritis. Type II collagen is the major matrix protein of hyaline cartilage. Susceptibility to CIA is linked to the Major Histocompatibility Complex Class II genes but the presence of T cells expressing specific variable beta (Vβ) chain of their T cell receptor (TCR) is also required. Pretreatment with the monoclonal antibody H57-597 directed against the TCR αβ framework prevented the onset of arthritis in the majority of animals. The depletion of the T cell population did not lead to any apparent health problems. These experiments demonstrate the important role of the αβ T cell and its receptors in the CIA model. Further, anti-TCR αβ antibodies may be of value in the therapy of autoreactive disorders.     

自然杀伤细胞抗肝癌的研究新进展

肝癌是最常见的恶性肿瘤之一,预后差,复发率高。免疫治疗已成为继手术、放疗、化疗后的第四种治疗模式,其中自然杀伤细胞可以在细胞、分子及基因水平抑制肿瘤转移及复发,在肝癌的免疫治疗中起关键性作用,在开展新的治疗模式以及提高肝癌患者生活质量方面具有很广阔的应用前景。     

尘螨主要变应原DNA疫苗对其提取液诱导小鼠肺部变应性炎症的免疫保护作用

目的　探讨尘螨主要变应原DNA疫苗对尘螨提取液诱导的小鼠肺部变应性炎症的免疫治疗作用。方法　分别构建表达Derp1和Derp 2的真核表达质粒pCMV Derp 1和pDerp 2 IRES Derp1。 30只BALB/c小鼠随机分为正常组 (6只 )、对照组 (12只 )、单质粒组 (6只 )和混合组 (6只 )。后三组分别用空白质粒、pDerp 2 IRES Derp 1或混合的pDerp 2 IRES Derp 1和pCMV Derp 1免疫 ,4周后用尘螨提取液致敏、激发 ,观察肺部炎症、计分、肺泡灌洗液 (BALF)细胞总数和分类计数 ;酶联免疫吸附法 (ELISA)检测BALF中白细胞介素 4 (IL 4 )和γ干扰素 (IFN γ)水平。结果　细胞总数和嗜酸细胞(EOS)计数 :混合组 [(6± 4 )× 10 5/ml、0 0 5± 0 0 4 ]和对照组 [(2 1± 13)× 10 5/L、1 80± 1 39]比较差异有显著性 (P <0 0 5 ) ;IL 4水平 :混合组 [(16 8± 2 33)g/L]与对照组 [(5 38± 2 5 6 )g/L]比较差异有显著性 (P<0 0 5 ) ,各组间IFN γ比较差异无显著性 (P >0 0 5 )。结论　尘螨主要变应原的DNA疫苗可有效抑制尘螨提取液诱导的肺部变应性炎症 ,能表达两个主要变应原的DNA疫苗其抑制变应性炎症效果优于只表达一种变应原的疫苗。     

The Hsp60 peptide p277 enhances anti-CD3 mediated diabetes remission in non-obese diabetic mice

Type 1 diabetes (T1D) is characterized by the immune-mediated destruction of pancreatic beta cells leading to inadequate glycemic control. Trials with immunomodulatory monotherapies have shown that the disease course can in principle be altered. The observed preservation of endogenous insulin secretion however is typically transient and chronic treatment is often associated with significant side effects.Here we combined anti-CD3 with the Hsp60 peptide p277, two drugs that have been evaluated in Phase 3 trials, to test for enhanced efficacy. Female NOD mice with recent onset diabetes were given 5 μg anti-CD3 i.v., on three consecutive days in combination with 100 μg of p277 peptide in IFA s.c., once weekly for four weeks. Anti-CD3 alone restored normoglycemia in 44% of the mice while combination therapy with anti-CD3 and p277 induced stable remission in 83% of mice. The observed increase in protection occurred only in part through TLR2 signaling and was characterized by increased Treg numbers and decreased insulitis. These results have important implications for the design of combination therapies for the treatment of T1D.     

卡介苗膀胱灌注治疗致结核性前列腺脓肿1例

Morales等［1］于1976年报道应用卡介苗（bacillus Calmette-Guérin,BCG）治疗膀胱癌。目前BCG膀胱灌注是治疗非肌层浸润性膀胱癌的常用方法,但该治疗方法可引起一系列的并发症,包括结核性前列腺炎。BCG致结核性前列腺炎发展为前列腺脓肿罕见,国内外仅有少数个案报道,现将北京大学人民医院近期收治的1例卡介苗膀胱灌注治疗致前列腺脓肿的病例报告如下。     

Deciphering the role of transforming growth factor-beta 1 as a diagnostic-prognostic-therapeutic candidate against hepatocellular carcinoma

Transforming growth factor-beta (TGF-β) is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression. Among different ligands of the TGF-β family, TGF-β1 modulates most of its biological outcomes. Despite the abundant expression of TGF-β1 in the liver, steatosis to hepatocellular carcinoma (HCC) progression triggers elevated TGF-β1 levels, contributing to poor prognosis and survival. Additionally, elevated TGF-β1 levels in the tumor microenvironment create an immunosuppressive stage via various mechanisms. TGF-β1 has a prime role as a diagnostic and prognostic biomarker in HCC. Moreover, TGF-β1 is widely studied as a therapeutic target either as monotherapy or combined with immune checkpoint inhibitors. This review provides clinical relevance and up-to-date information regarding the potential of TGF-β1 in diagnosis, prognosis, and therapy against HCC.     

Role of modern radiotherapy in managing patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Several treatment options are available for managing HCC patients, classified roughly as local, local-regional, and systemic therapies. The high post-monotherapy recurrence rate of HCC urges the need for the use of combined modalities to increase tumor control and patient survival. Different international guidelines offer treatment recommendations based on different points of view and classification systems. Radiotherapy (RT) is a well-known local-regional treatment modality for managing many types of cancers, including HCC. However, only some of these treatment guidelines include RT, and the role of combined modalities is rarely mentioned. Hence, the present study reviewed clinical evidence for the use of different combined modalities in managing HCC, focusing on modern RT's role. Modern RT has an increased utility in managing HCC patients, mainly due to two driving forces. First, technological advancement (e.g., stereotactic body radiotherapy and advanced proton-beam therapy) enables precise delivery of radiation to increase tumor control and reduce side effects in the surrounding normal tissue. Second, the boom in developing target therapies and checkpoint-blockade immunotherapy prolongs overall survival in HCC patients, re-emphasizing the importance of local tumor control. Remarkably, RT combines with systemic therapies to generate the systemic therapy augmented by radiotherapy effect, a benefit now being actively investigated.