A Phase II study of CHIP in advanced squamous cell carcinoma of the cervix (a Gynecologic Oncology Group study)

Summary The Gynecologic Oncology Group (GOG) conducted a Phase II trial of CHIP, cis-dichloro-trance-dihydroxybis-(isopropylamine)-platinum IV, in patients with measurable advanced squamous cell carcinoma of the cervix. No prior therapy with cytotoxic drugs was permitted in patients entered into this trial. All patients had a GOG performance status of 2 or better.CHIP at a starting dose of 230 mg/m² was administered as a 30-minute IV infusion. Dose escalation was permitted to a maximum of 300 mg/m². Treatments were repeated every four weeks until disease progressed or until toxicity prohibited further therapy.Thirty-six evaluable patients were entered between January and July, 1984. Of these, 34 were evaluable for response. Four complete and three partial responses were observed (response rate 20.6%). No neurotoxicity was noted and only mild and reversible nephrotoxicity was reported. Grade 3 gastrointestinal toxicity was reported in twenty patients (56%). Dose-limiting toxicity was myelosuppression.CHIP is an active agent against squamous cell carcinoma of the cervix and appears to be less neurotoxic and nephrotoxic than cisplatin. Gastrointestinal toxicity was moderate and appears equal to that seen with cisplatin at a dose of 50 mg/m² given as a rapid IV infusion and more toxic than an equivalent dose of cisplatin administered over 24 hours. Randomized studies comparing CHIP and cisplatin are indicated to better define the relative therapeutic indices of these two compounds in the treatment of advanced squamous carcinoma of the cervix. Address for offprints: GOG Headquarters, Suite 1945, 1234 Market Street, Philadelphia, PA 19107.     

22例卵巢癌术中行腹腔热灌注化疗其游离癌细胞变化的观察

目的:探讨腹腔热灌注化疗(chemotherapeutic hyperthermic intraperitoneal perfusion CHIP)在卵巢癌治疗中的应用价值.方法:收集卵巢癌术后CHIP前后腹腔液中细胞并在电镜下进行观察.结果:电镜下CHIP前腹腔液中细胞密集,大多是癌细胞,癌细胞结构完整,细胞膜表面有微绒毛,细胞器形态正常,而CHIP后,腹腔液中仅见癌细胞碎片或炎性细胞,癌细胞完整性破坏,细胞核变性溶解,线粒体空泡变,细胞器形态异常,胞浆水肿.结论:卵巢癌术后CHIP能有效杀灭腹腔内游离癌细胞(Free cancer cell FCC),对预防卵巢癌术后腹腔内转移及复发具有重要意义.     

Digenic inheritance of STUB1 variants and TBP polyglutamine expansions explains the incomplete penetrance of SCA17 and SCA48

PurposeThis study aimed to unravel the genetic factors underlying missing heritability in spinocerebellar ataxia type 17 (SCA17) caused by polyglutamine-encoding CAG/CAA repeat expansions in the TBP gene. Alleles with >49 CAG/CAA repeats are fully penetrant. Most patients, however, carry intermediate TBP_41-49 alleles that show incomplete penetrance.MethodsUsing next-generation sequencing approaches, we investigated 40 SCA17/TBP_41-54 index patients, their affected (n = 55) and unaffected (n = 51) relatives, and a cohort of patients with ataxia (n = 292).ResultsAll except 1 (30/31) of the index cases with TBP_41-46 alleles carried a heterozygous pathogenic variant in the STUB1 gene associated with spinocerebellar ataxias SCAR16 (autosomal recessive) and SCA48 (autosomal dominant). No STUB1 variant was found in patients carrying TBP_47-54 alleles. TBP_41-46 expansions and STUB1 variants cosegregate in all affected family members, whereas the presence of either TBP_41-46 expansions or STUB1 variants individually was never associated with the disease.ConclusionOur data reveal an unexpected genetic interaction between STUB1 and TBP in the pathogenesis of SCA17 and raise questions on the existence of SCA48 as a monogenic disease with crucial implications for diagnosis and counseling. They provide a convincing explanation for the incomplete penetrance of intermediate TBP alleles and demonstrate a dual inheritance pattern for SCA17, which is a monogenic dominant disorder for TBP_≥47 alleles and a digenic TBP/STUB1 disease (SCA17-DI) for intermediate expansions.     

CHIP基因稳定转染人慢性髓系白血病K562细胞诱发有丝分裂异常

本研究旨在建立可稳定高效表达E3泛素连接酶CHIP（carboxyl terminus of Hsc70／Hsp70—interacting protein）的慢性髓系白血病细胞株K562细胞模型，以观察过表达CHIP对细胞生物学特性的影响。采用脂质体介导的方法，经G418筛选及有限稀释法成功建立了可稳定表达野生型CHIP及其TPR及U—box结构域缺失突变体的慢性髓系白血病K562细胞克隆。对过表达CHIP的K562细胞用MTT法检测体外增殖，流式细胞术检测细胞周期，Western blot法检测相关蛋白表达，瑞氏一姬姆萨染色进行细胞形态学观测。结果表明，过表达野生型CHIP对K562细胞体外增殖能力没有明显影响，细胞周期中G2／M期细胞比率增加，CHIP对BCR—ABL激酶的稳定性没有影响，但却明显导致细胞形态异常，表现为细胞体积增大及异常核细胞数目增多，出现异常有丝分裂相等，提示CHIP分子对细胞有丝分裂过程可能具有调控作用。结论：野生型CHIP可诱导K562细胞发生有丝分裂异常。     

Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications

The hepatic endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) are mixed-function oxidases engaged in the biotransformation of physiologically relevant endobiotics as well as of myriad xenobiotics of therapeutic and environmental relevance. P450 ER-content and hence function is regulated by their coordinated hemoprotein syntheses and proteolytic turnover. Such P450 proteolytic turnover occurs through a process known as ER-associated degradation (ERAD) that involves ubiquitin-dependent proteasomal degradation (UPD) and/or autophagic-lysosomal degradation (ALD). Herein, on the basis of available literature reports and our own recent findings of in vitro as well as in vivo experimental studies, we discuss the therapeutic and pathophysiological implications of altered P450 ERAD and its plausible clinical relevance. We specifically (i) describe the P450 ERAD-machinery and how it may be repurposed for the generation of antigenic P450 peptides involved in P450 autoantibody pathogenesis in drug-induced acute hypersensitivity reactions and liver injury, or viral hepatitis; (ii) discuss the relevance of accelerated or disrupted P450-ERAD to the pharmacological and/or toxicological effects of clinically relevant P450 drug substrates; and (iii) detail the pathophysiological consequences of disrupted P450 ERAD, contributing to non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) under certain synergistic cellular conditions.     

Clonal Hematopoiesis and therapy related MDS/AML

Clonal Hematopoiesis is defined as the presence of mutations in peripheral blood in the absence of myeloid malignancies and is thought to occur as a normal part of ageing due to the fitness advantage conferred by these mutations in an ageing hematopoietic compartment. Therapy related myeloid neoplasms are malignancies that occur after exposure to chemotherapy/radiation and are associated with poor survival. Clonal hematopoiesis mutations represent a pre malignant state that can be triggered by exposure to cytotoxic damage and rapid hematopoietic stem cell expansion. We discuss in this review clinical evidence of association of clonal hematopoiesis with risk of therapy related myeloid neoplasms, the underlying mechanisms of clonal expansion under different cellular stresses and recommendations on clinical follow up of patients with clonal hematopoiesis including possible strategies for prevention of therapy related myeloid neoplasms.     

Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response

The ubiquitin-proteasome system (UPS) is the major intracellular proteolytic mechanism controlling the degradation of misfolded/abnormal proteins. A common hallmark in amyotrophic lateral sclerosis (ALS) and in other neurodegenerative disorders is the accumulation of misfolded/abnormal proteins into the damaged neurons, leading to the formation of cellular inclusions that are mostly ubiquitin-positive. Although proteolysis is a complex mechanism requiring the participation of different pathways, the abundant accumulation of ubiquitinated proteins strongly suggests an important contribution of UPS to these neuropathological features. The use of cellular and animal models of ALS, particularly those expressing mutant SOD1, the gene mutation most represented in familiar ALS, has provided significant evidence for a role of UPS in protein inclusions formation and motor neuron death. This review will specifically discuss this piece of evidence and provide suggestions of potential strategies for therapeutic intervention. We will also discuss the finding that, unlike the constitutive proteasome subunits, the inducible subunits are overexpressed early during disease progression in SOD1 mice models of ALS. These subunits form the immunoproteasome and generate peptides for the major histocompatibility complex class I molecules, suggesting a role of this system in the immune responses associated with the pathological features of ALS. Since recent discoveries indicate that innate and adaptive immunity may influence the disease process, in this review we will also provide evidence of a possible connection between immune-inflammatory reactions and UPS function, in the attempt to better understand the etiopathology of ALS and to identify appropriate targets for novel treatment strategies of this devastating disease.     

Multiple functions of the E3 ubiquitin ligase CHIP in immunity

The carboxyl terminal of Hsp70-interacting protein (CHIP) is an E3 ubiquitin ligase that plays a pivotal role in the protein quality control system by shifting the balance of the folding-refolding machinery toward the degradative pathway. However, the precise mechanisms by which nonnative proteins are selected for degradation by CHIP either directly or indirectly via chaperone Hsp70 or Hsp90 are still not clear. In this review, we aim to provide a comprehensive model of the mechanism by which CHIP degrades its substrate in a chaperone-dependent or direct manner. In addition, through tight regulation of the protein level of its substrates, CHIP plays important roles in many physiological and pathological conditions, including cancers, neurological disorders, cardiac diseases, bone metabolism, immunity, and so on. Nonetheless, the precise mechanisms underlying the regulation of the immune system by CHIP are still poorly understood despite accumulating developments in our understanding of the regulatory roles of CHIP in both innate and adaptive immune responses. In this review, we also aim to provide a view of CHIP-mediated regulation of immune responses and the signaling pathways involved in the model described. Finally, we discuss the roles of CHIP in immune-related diseases.     

E3泛素连接酶CHIP与上皮性癌关系研究

泛素化修饰是机体一种非常重要的蛋白质翻译后修饰方式,其广泛参与细胞周期、DNA修复、信号转导、转录调控等生物学过程。近些年,蛋白质泛素化修饰在恶性肿瘤发生和发展中的作用,受到国内外广泛关注。尤其是E3泛素连接酶,它能特异性识别作用底物,泛素化修饰的特异性就取决于该连接酶。研究表明,E3泛素连接酶功能异常与恶性肿瘤等多种疾病的病理过程密切相关,因此分析特定的E3连接酶在恶性肿瘤中的作用和机制,有助于加深对恶性肿瘤发生、发展过程中分子机制的认识,为恶性肿瘤相关分子分类和治疗靶点提供实验基础。本文对E3泛素连接酶CHIP的功能,尤其与上皮性癌关系的研究进展进行综述。