Interferon-α-2a

Synopsis

Interferons are intercellular signalling proteins which have antiviral, antitumour and immunomodulatory activities. Interferon-α-2a is a recombinant product which has antiproliferative effects on haemopoietic progenitor cells and haematological cell lines in vitro. These properties have led to its evaluation in the treatment of chronic myelogenous leukaemia (CML), a myeloproliferative disorder resulting from neoplastic transformation of a pluripotential haemopoietic stem cell and characterised by the presence of a chromosomal marker, the Philadelphia (Ph) chromosome, in the leukaemic cells. Clinical trials have demonstrated that interferon-α-2a (often given with or after cytoreductive chemotherapy), in common with other forms of interferon-α, can eliminate or reduce the proportion of Ph-positive cells in a number of patients with CML, as well as inducing haematological remission in the majority of cases. Higher rates of cytogenetic response were achieved in small groups of patients who had relapsed following allogeneic bone marrow transplant (BMT) and those who received low-dose cytarabine in combination with interferon-α-2a. Interferon-α-2a was superior to conventional chemotherapy [hydroxycarbamide (hydroxyurea) or busulfan] in a randomised multicentre study in 322 patients; it achieved a greater number of major cytogenetic responses (19 vs 1% of patients), a greater delay in disease progression and longer overall survival (median 72 vs 52 months). However, in another large comparative study interferon-α-2a or -2b was superior to busulfan, but not hydroxy carbamide, in prolonging survival. As with other types of interferon therapy, interferon-α-2a produces an acute influenza-like syndrome (fever, chills, myalgia, headache, arthralgia). Adverse effects during long term therapy include fatigue and anorexia (the most common events), and CNS disturbances. Serum neutralising antibodies to interferon-α-2a can usually be detected in around 20 to 25% of patients receiving the drug, but the clinical significance of this is unknown. Interferon-α therapy represents an important advance in the management of CML and is presently the only alternative to BMT (the preferred treatment option) for achieving long term complete cytogenetic remission and prolonging survival in this disease. Interferon-α-2a has been found to be effective in clinical trials and was superior to standard chemotherapy in one study. Although it appeared to be more effective than partially purified interferon-α, well-designed comparative studies are needed to demonstrate any differences in efficacy between different types of interferon-α. While only a small proportion of patients achieve long term cytogenetic remission with this agent and wider clinical experience is required, interferon-α-2a nevertheless can be considered a first-line therapy option in this disease, particularly in patients who cannot receive, or relapse following, BMT. Further research is also required to evaluate combination therapy with interferon-α and other agents.

Pharmacology

Interferon-α-2a is a recombinant interferon-α. These cytokines have direct antiproliferative effects on normal and chronic myelogenous leukaemia (CML) progenitor cells and haematological cell lines (CML, acute myelogenous leukaemia, Burkitt’s lymphoma, acute lymphocytic lymphoma, multiple myeloma) in vitro, and inhibit growth of experimental transplanted tumours in vivo. They also have immunomodulatory effects, including activation of monocytes and macrophages, induction of cell surface antigen expression, enhancement of natural killer cell and cytotoxic T-lymphocyte activity, and modulation of cytokine synthesis. Other effects include alteration of autonomic function and lipid metabolism. Postulated mechanisms for the apparent selective activity of interferon-α in CML include modulation of the bone marrow environment to allow restoration of normal control mechanisms and enhancement of immune recognition.

Therapeutic Use

Clinical trials have demonstrated that interferon-α-2a can eliminate or reduce the numbers of Philadelphia (Ph)-positive cells in a proportion of patients with CML, and induces haematological remission in the majority of cases, in common with other forms of interferon-α. In many studies, interferon-α-2a was administered with or following hydroxy carbamide (hydroxyurea) or, less commonly, busulfan. No studies have formally compared different interferon-a subtypes, but comparison with a historical control group suggested that interferon-α-2a produced cytogenetic response more rapidly, and in a higher proportion of patients, than partially purified interferon-α. In preliminary studies, higher rates of cytogenetic response were achieved in patients who had relapsed following allogeneic BMT and in patients who received interferon-α-2a in combination with cytarabine. Interferon-α-2a was compared with conventional chemotherapy (hydroxycarbamide or busulfan) in 2 randomised multicentre studies, in 322 and 513 Ph-positive patients with chronic phase CML. In the first study, interferon-α-2a ≥9 MU/day induced significantly more major cytogenetic responses (elimination of Ph-positive cells or a 67 to 99% decrease in the proportion of these cells) than conventional chemotherapy (19 vs 1% of patients on intent-to-treat analysis). It also produced a greater delay in disease progression (median >72 vs 45 months) and longer overall survival (median 72 vs 52 months). The second study included a higher proportion of high-risk patients and used a lower interferon dosage; interferon-α-2a (68% of patients) or 2b (32% of patients) 5 MU/m²/day produced a relatively low cytogenetic response rate (5% complete responses). It was significantly superior to busulfan but not hydroxycarbamide in terms of survival (5-year survival rates 59 vs 32 vs 44% of patients). Minimal residual disease (persistence of small numbers of Ph-positive cells) can be detected with more sensitive assay methods, such as polymerase chain reaction assay, in most patients who are shown to be in complete cytogenetic remission by conventional cytogenetic tests following interferon-α therapy. It is not clear whether this has any impact on survival.

Tolerability

As with other types of interferon-α, interferon-α-2a produces an influenza-like syndrome, consisting of fever, chills, myalgia, headache, arthralgia and sweating within 4 to 8 hours of administration, although tolerance to many of these effects tends to develop during long term therapy. Long term adverse effects of interferon-α therapy include fatigue and anorexia (the dose-limiting toxicities), CNS disorders, including changes in behaviour, cognition, mood, memory and personality, and disturbed lipid metabolism. Induction of autoimmune reactions, with possible exacerbation or induction of diseases associated with MHC class I or II antigens (e.g. psoriasis, systemic lupus erythematosus and autoimmune thyroid disease), has also been reported. A similar pattern of events has been reported with interferon-α-2a. Serum neutralising antibodies to interferon-α-2a can usually be detected in around 20 to 25% of patients receiving the drug, depending on route and duration of therapy, type of disease and assay technique, but their clinical significance is unknown. Preliminary data suggest that seroconversion may be more common in patients receiving interferon-α-2a than in those receiving interferon-α-2b or the lymphoblastoid interferon-α-Nl.

Dosage and Administration

The optimal dosage and duration of interferon-α-2a therapy for the treatment of CML is yet to be established, and depends on individual patient factors. The manufacturer’s recommended starting dosage in adults with CML is 3MU/day, given by subcutaneous or intramuscular injection, and escalated to 6 MU/day on day 4, and to 9 MU/day on day 7. This can be reduced to a 3 times weekly schedule once response has been achieved. The efficacy, tolerability and optimum dosage of interferon-α-2a in children has not been established. Contraindications to interferon-α-2a therapy include severe renal or hepatic dysfunction, epilepsy, impaired CNS function, severe pre-existing cardiac disease or history of cardiac illness, and recent or current treatment with immunosuppressive agents other than short term ‘steroid withdrawal’. Interferon-α-2a can induce effects on the CNS and may impair performance of certain tasks, such as driving and operating machinery, and may interact with centrally-acting drugs. Periodic neuropsychiatric and haematological monitoring is recommended during treatment. Interferon-α-2a may also potentiate neurotoxic, haematotoxic or cardiotoxic effects of previously or concurrently administered drugs and may affect oxidative metabolism of some drugs.     

Interferon-α-2a

Interferon-alpha-2a, a single interferon-alpha subtype manufactured by use of recombinant DNA technology, has immmunomodulatory, antiviral and antiproliferative properties. It is a beneficial treatment for about 30% of patients with well-compensated chronic hepatitis C. Biochemical responses [defined as normalisation of serum alanine aminotransferase (ALT) levels] are achieved in 37 to 76% of patients at the end of treatment with interferon-alpha-2a at dosages of 3 to 6MU 3 times weekly (given intramuscularly or subcutaneously) for 6 to 12 months. In contrast, evidence of disease remission is seldom observed in untreated patients. Improvements in liver histology in patients receiving interferon-alpha-2a are associated with complete biochemical responses to the drug. Virological responses (defined as an absence of hepatitis C-RNA in the serum) occur in up to 86% of patients after treatment with interferon-alpha-2a 3 to 6MU 3 times weekly for 12 months. After cessation of interferon-alpha-2a therapy, a considerable proportion of treatment responders experience disease reactivation. Rates of sustained biochemical response are generally higher after 12 months' therapy (27 to 57%) than after 6-month courses of treatment (27 to 30%). The long term efficacy of interferon-alpha-2a in patients with chronic hepatitis C is improved by the concomitant administration of ribavirin. Interferon-alpha-2a shows efficacy similar to that of interferon-alpha-2b or interferon-alpha-n1 in patients with chronic hepatitis C. During the first few days of therapy with interferon-alpha-2a (or other forms of interferon-alpha), most patients experience a transient 'influenza-like' reaction, characterised by fatigue, fever, chills and headache. These symptoms are usually alleviated by paracetamol (acetaminophen). Lethargy, mild myelosuppression, alopecia and neuropsychiatric symptoms are dose-limiting adverse effects that may occur during longer term therapy. Severe adverse effects, experienced by <2% of interferon-alpha-2a recipients, include severe depression, seizures and generalised bacterial infections. Autoimmune thyroid dysfunction develops in 3 to 12% of patients during treatment with interferon-alpha-2a. Conclusion. Interferon-alpha-2a produces sustained responses in about 30% of adults with chronic hepatitis C. Its efficacy appears to be similar to that of other interferon-alpha products. Thus, the drug remains a useful first-line treatment option for adults with well-compensated chronic hepatitis C. Further research into the optimal dosage of interferon-alpha-2a and its role in combination with other agents is likely to contribute towards future advances in the management of chronic hepatitis C.     

肌肽减轻H_2O_2诱导的N2a细胞损伤

目的探究肌肽对H2O2诱导的N2a细胞损伤的保护作用及其机制。方法将N2a细胞分为对照组、损伤组(给予H2O2)和肌肽保护组(预先加入肌肽)。用相差显微镜观察了细胞形态,用免疫荧光染色和免疫印迹实验检测细胞AKT1和FAS-L的蛋白表达。结果肌肽显著增加了N2a细胞增殖能力(P0.05);与对照组比较,H2O2损伤组细胞形态发生明显改变,细胞皱缩,胞膜变厚并出现发泡现象;而肌肽保护组细胞形态较损伤组明显改善;免疫荧光染色和免疫印迹实验显示,损伤组AKT1的表达显著低于对照组,FAS-L的表达显著高于对照组。而肌肽保护组AKT1的表达显著高于对照组,FAS-L的表达显著低于对照组(P0.05)。结论肌肽能够减轻N2a细胞对H2O2诱导的细胞损伤。     

福氏2a痢疾菌单克隆抗体的研制

福氏痢疾菌的抗原组成极为复杂,非但在福氏菌群间,而且与其他肠道菌也有较多的共同抗原成分。各种抗原成分在痢疾菌的免疫、致病等过程中的作用与功能尚不完全清楚。为了探讨这一问题,我们应用杂交瘤技术试图制备抗福氏痢疾菌不同抗原决定簇的单克隆抗体。 骨髓瘤细胞株NS—1。基础免疫,福氏2a活菌悬液0.5×10~7个菌,于第1及第8天IP注     

Is Health Locus of Control a 3-factor or a 2-factor construct?

Although the Multidimensional Health Locus of Control (MHLC) scales are commonly used, uncertainty about their factorial validity still remains. In the present study, confirmatory factor analyses of a French-Canadian adaptation of the Multidimensional Health Locus of Control scales (MHLC) were conducted to compare in a non-clinical group of 224 adults two factor models. Multigroup analyses were also conducted using this group and a clinical group of 132 diabetics to assess the equivalence of the MHLC factor structure across these two groups. A 3-factor model postulating an internal, external, and chance dimension, and accounting for measurement errors provided the best fit to the data. Multigroup analyses failed to support the equivalence of the MHLC factor loadings across the non-clinical and clinical group. These findings suggest that comparisons of MHLC scores across such groups may be problematic. © 1996 John Wiley & Sons, Inc.     

雌激素对H_2O_2所致N2a细胞损伤的保护作用

目的探讨雌激素对氧自由基(H_2O_2)所致野生型鼠成神经瘤细胞株(N2a)损伤的保护作用及机制。方法应用H_2O_2制作N2a细胞凋亡的细胞模型,采用细胞计数、酶组织化学、免疫细胞化学方法,检测在雌激素作用下,神经细胞的形态结构、细胞活性和细胞早期凋亡的相关性变化。结果细胞计数结果显示,雌激素组的细胞数量[(0.60±0.12)个/mL(×10~4)]高于其它组,雌激素加H_2O_2组的细胞数量[(0.51±0.11]×104个/mL)明显高于H2O2组[(0.30±0.09)×10~4个/mL],组间差异有统计学意义(P0.05)。免疫细胞化学染色显示,Akt1阳性反应在雌激素组最强,在H2O2组最弱,但雌激素加H_2O_2组与正常对照组Akt1的表达没有明显差别,介于两者之间。Fasl呈相反变化。Caspase3酶活性检测结果显示,H_2O_2组Caspase3酶活性最高,雌激素加H_2O_2组Caspase3酶活性明显降低,其差别有统计学意义(P0.01)。结论雌激素有促进N2a细胞生长的作用,并可保护H_2O_2对N2a细胞的损伤且可以对抗凋亡。     

Does COX2-dependent PGE2 play a role in neuropathic pain?

Neuropathic pain (NeP) is a common chronic pain state with unmet medical needs. Due to poorly defined underlying mechanisms, current therapies for NeP are far from satisfactory. Mounting evidence suggests that long-term plasticity in pain signaling pathways underpins the pathogenesis of NeP. Inflammatory responses in injured nerves have been recognized as important events initially sensitizing nociceptive neurons and subsequently inducing long-term plasticity in the dorsal root ganglion. Inflammatory cells such as invading macrophages and Schwann cells produce a wide array of inflammatory mediators. Cyclooxygenase 2-dependent prostaglandin E2 (COX2/PGE2) is one of the important mediator abundantly produced in injured nerves and involved in the genesis of NeP. In this mini-review, we highlight possible novel mechanisms underlying the role of COX2/PGE2 in injured nerves in the genesis of NeP. Long lasting COX2/PGE2 in injured nerves may induce chronic effects on nociceptors to facilitate the synthesis of pain-related molecules by stimulating 'en passant' injured or spared axons. COX2/PGE2 may also induce chronic effects on local inflammatory cells in injured nerves to facilitate the synthesis of inflammatory mediators via autocrine and paracrine pathways. COX2/PGE2 in injured nerves and downstream PGE2 EP receptor signaling should be considered as therapeutic targets to more effectively treat chronic NeP.     

Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine

Background:Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019(Covid-19)pandemic of infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).A candidate vaccine,Ad26.COV2.S,is a recombinant,replication-incompetent adenovirus serotype 26(Ad26)vector encoding a full-length and stabilized SARS-CoV-2 spike protein.     

Ankylosing spondylitis: a beta2m-deposition disease?

To explain the strong association between HLA-B27 and ankylosing spondylitis, we suggest that the release of beta(2)-microglobulin (beta(2)m) from a subpopulation of cell surface-expressed HLA-B27 molecules leads to beta(2)m-deposition within synovia and to the initiation of an inflammatory process, which culminates in destructive spondyloarthropathy.     

miR-16促进Neuro2a细胞的凋亡

目的 检测过表达miR-16对小鼠Neuro2a细胞周期和凋亡的影响,探讨miR-16在肿瘤发病过程中的可能机制.方法 构建能够在细胞中过表达miR-16的真核表达载体pcDNA3.1-miR-16,利用Real-time PCR验证了表达载体的过表达效应.应用pcDNA3.1-miR-16载体转染Neuro2a细胞,...     

Is autoimmunity a side-effect of interleukin 2 production?

Because it has a role in lymphocyte activation, interleukin 2 (IL-2) has been tried as a therapeutic agent in several types of immune dysfunction in animals and man. Here, Georg Wick and his colleagues discuss the possibility that IL-2 production initiates and perpetuates autoimmune disease, and express caution about the clinical use of IL-2.     

miR-181a过表达加重H2O2诱导的HUVECs损伤

目的研究miR-181a在过氧化氢(H_2O_2)损伤的人脐静脉内皮细胞(HUVECs)中的表达,并探讨miR-181a对H_2O_2诱导的HUVECs活性和凋亡的影响及其机制。方法 MTT法和流式细胞计量术测定HUVECs活性和凋亡;RT-qCR和Western blot测定miR-181a和X连锁凋亡抑制蛋白(XIAP)mRNA及蛋白的表达;Targetscan软件预测miR-181a和XIAP的靶向关系,利用双荧光素酶报告分析和Western blot加以验证。结果 1)H_2O_2呈剂量依赖性抑制HUVECs活性并促进凋亡(P0.05);2)miR-181a在H_2O_2处理的HUVECs中显著升高(P0.05);3)敲低miR-181a可明显促进H_2O_2诱导的HUVECs活性并抑制细胞凋亡(P0.05);4)miR-181a能够与XIAP靶向结合;5)miR-181a过表达可抑制H_2O_2诱导的HUVECs活性并促进细胞凋亡,外源过表达XIAP可减轻miR-181a调控的HUVECs活性和凋亡。结论 miR-181a通过靶向XIAP抑制H_2O_2诱导的HUVECs活性,并促进细胞凋亡,加重HUVECs损伤。     

Association of Variants in PPARγ2, IGF2BP2, and KCNQ1 with a Susceptibility to Gestational Diabetes Mellitus in a Korean Population

Purpose

Patients with gestational diabetes mellitus (GDM) have been reported to exhibit the same genetic susceptibility as that observed in those with type 2 diabetes mellitus (T2DM). Recent polymorphism studies have shown that several genes are related to T2DM and GDM. The aim of this study was to examine whether certain candidate genes, previously shown to be associated with T2DM, also offer a specific genetic predisposition to GDM.

Materials and Methods

The current study was conducted in 136 Korean pregnant women, who gave birth at Gil Hospital, from October 2008 to May 2011. These study subjects included 95 subjects with GDM and 41 non-diabetic controls. We selected the specific genes of PPARγ², IGF2BP2, and KCNQ1 for study and amplified them using the polymerase chain reaction. This was followed by genotyping for single nucleotide polymorphisms. We then compared the genotype frequencies between patients with GDM and non-diabetic controls using the χ² test. We obtained and analyzed clinical information using Student''s t-test, and statistical analyses were conducted using logistic regression with SPSS Statistics software, version 19.0.

Results

Significant differences were observed in maternal age, body mass index, weight gain and weight at time of delivery between the groups compared. Among pregnant women, polymorphisms in PPARγ² and IGF2BP2 were shown to be highly correlated with GDM occurrence, whereas no correlation was found for KCNQ1 polymorphisms.

Conclusion

Our results indicated that genetic polymorphisms could also be of value in predicting the occurrence and diagnosis of GDM.     

Severe phenotype of neurofibromatosis type 2 in a patient with a 7.4-MB constitutional deletion on chromosome 22: possible localization of a neurofibromatosis type 2 modifier gene?

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder predisposing to multiple neoplastic lesions with the hallmark of schwannoma arising at the eighth cranial nerve. NF2 shows a distinct clinical variability, with a mild and a severe form of the disease. The NF2 gene is mutated in constitutional DNA of affected patients from NF2 families and in sporadic cases. Comprehensive mutation analyses in patients with severe and mild phenotypes revealed mutations in only 34%-66%. In the remaining fraction, the genetic mechanism behind the development of NF2 is unknown. Analyses of germline mutations do not provide a conclusive explanation for the observed clinical heterogeneity of NF2. It can therefore be hypothesized that other factors, e.g., modifier gene(s), contribute to the development of a more severe NF2 phenotype. We report a mentally retarded patient with the severe form of NF2 who displays a 7.4 million base pair deletion on chromosome 22. We performed a full genetic characterization of this case using heterozygozity analysis of 41 markers from chromosome 22, detailed FISH mapping of deletion breakpoints, allelotyping of all other chromosomes, and sequencing of the NF2 gene in tumor DNA. Two genomically large deletions similar in size (700-800 kb), which encompass the entire NF2 gene, have been reported previously in mildly affected NF2 patients. The centromeric breakpoints of these deletions were similar to the centromeric breakpoint in the present case. However, the deletion in our patient extends over a much larger distance toward the telomere of 22q. Our results support the existence of NF2 modifier gene(s) and suggest that such a putative locus maps to a 6.5-MB interval on 22q, between D22S32 and the MB gene.     

比索洛尔提高心力衰竭大鼠心肌SERCA2a活性

目的观察比索洛尔对心力衰竭大鼠心肌肌浆网钙ATP酶2a(SERCA2a)活性的影响。方法腹腔注射阿霉素建立大鼠心力衰竭模型。实验分为对照组、假手术组、模型组、比索洛尔组、卡托普利组和比索洛尔+卡托普利组。检测心功能指标;ELISA法检测血浆脑钠肽水平;茎环状引物实时定量PCR检测心肌miR-25-3p表达水平;Western blot检测心肌SERCA2a和受磷蛋白(PLB)表达水平;定磷法测定心肌SERCA2a活性。结果与对照组比较,模型组大鼠心功能明显减退(P0.01),血浆脑钠肽水平和心肌miR-25-3p表达水平明显升高(P0.01),SERCA2a和PLB表达水平、SERCA2a/PLB比值和SERCA2a活性明显降低(P0.01);与模型组比较,比索洛尔组、卡托普利组和比索洛尔+卡托普利组大鼠心功能明显改善(P0.01),血浆脑钠肽水平和心肌miR-25-3p表达水平明显降低(P0.01),SERCA2a和PLB表达水平明显升高(P0.01);比索洛尔组和比索洛尔+卡托普利组SERCA2a/PLB比值和SERCA2a活性明显高于模型组(P0.05)。结论比索洛尔可以下调心肌miR-25-3p表达水平,提高SERCA2a和PLB表达水平,增强SERCA2a活性。     

腺苷A2a受体在炎症反应中的作用

腺苷广泛分布于全身各组织器官,可通过与细胞表面相应G-蛋白偶联受体结合发挥抑制炎症反应,对抗缺血/缺氧和免疫调节等生物学作用.目前发现腺苷受体有4种亚型,即A1R、A2aR、A2bR和A3R.其中A2a腺苷受体(A2aR)广泛分布于神经胶质细胞,巨噬细胞,树突状细胞,肥大细胞,自然杀伤细胞等免疫细胞及内皮细胞和上皮细胞中,在相应的腺苷配体作用下,可通过腺苷-腺苷受体系统介导炎症反应和发挥免疫调节作用.     

腺苷A2a受体在炎症反应中的作用

腺苷广泛分布于全身各组织器官,可通过与细胞表面相应G-蛋白偶联受体结合发挥抑制炎症反应,对抗缺血/缺氧和免疫调节等生物学作用.目前发现腺苷受体有4种亚型,即A1R、A2aR、A2bR和A3R.其中A2a腺苷受体(A2aR)广泛分布于神经胶质细胞,巨噬细胞,树突状细胞,肥大细胞,自然杀伤细胞等免疫细胞及内皮细胞和上皮细胞中,在相应的腺苷配体作用下,可通过腺苷-腺苷受体系统介导炎症反应和发挥免疫调节作用.     

干扰素α－2a治疗早期黑素瘤有效果

干扰素α－２ａ治疗早期黑素瘤有效果在美国临床肿瘤学协会会议上介绍的一项大型多中心研究的结果显示，在手术切除原发性黑素瘤之后，对早期黑素瘤患者使用干扰素α－２ａ的佐剂疗法，能够延长患者的发病间歇及生存时间。最近在法国的３１家医院完成了一项随机取样控制性...     

腺苷A2a受体在炎症反应中的作用

腺苷广泛分布于全身各组织器官,可通过与细胞表面相应G-蛋白偶联受体结合发挥抑制炎症反应,对抗缺血/缺氧和免疫调节等生物学作用.目前发现腺苷受体有4种亚型,即A1R、A2aR、A2bR和A3R.其中A2a腺苷受体(A2aR)广泛分布于神经胶质细胞,巨噬细胞,树突状细胞,肥大细胞,自然杀伤细胞等免疫细胞及内皮细胞和上皮细胞中,在相应的腺苷配体作用下,可通过腺苷-腺苷受体系统介导炎症反应和发挥免疫调节作用.