米卡芬净预防血液系统恶性肿瘤患者侵袭性真菌感染有效性和安全性的Meta分析

目的系统评价米卡芬净预防血液系统恶性肿瘤患者侵袭性真菌感染(IFIs)的有效性及安全性,为临床治疗提供循证参考。方法计算机检索PubMed、Embase、Cochrane图书馆、中国知网(CNKI)、万方数据,检索时限为建库起至2021年1月,收集米卡芬净(试验组)对比常规抗真菌药物(两性霉素B及三唑类抗真菌药,对照组)的随机对照试验(RCT),对符合纳入标准的临床研究进行资料提取并采用Cochrane系统评价员手册5.0.2进行质量评价后,采用Rev Man 5.3统计软件对突破性IFIs、真菌感染死亡率、全因死亡率及因不良反应停药的发生率进行Meta分析。结果共纳入9项RCT,合计2 479例患者。Meta分析结果显示,试验组患者突破性IFIs发生率[OR=0.74,95%CI(0.50,1.07),P=0.11]、真菌感染死亡率[OR=0.73,95%CI(0.46,1.17),P=0.19]和全因死亡率[OR=0.94,95%CI(0.69,1.28),P=0.7]与对照组相比,差异无统计学意义;因不良反应停药的发生率[OR=0.46,95%CI(0.32,0.66),P<0.0001]显著低于对照组,差异有统计学意义。结论米卡芬净用于预防血液系统恶性肿瘤患者IFIs的效果与两性霉素B及三唑类抗真菌药物相当,且安全性更高。     

单克隆抗体药物与血液系统恶性肿瘤的治疗

单克隆抗体凭借其特异性强、副作用较小的优点,越来越广泛地应用于疾病的诊断与治疗。单克隆抗体药物在血液系统恶性肿瘤的治疗中也发挥了重要作用。目前,经美国食品与药品管理局(FDA)批准用于治疗血液系统恶性肿瘤的单克隆抗体药物已有六种,在临床取得良好的治疗效果。单克隆抗体药物主要通过对肿瘤细胞的直接杀伤作用、抗体依赖性细胞介导的细胞毒性反应(ADCC)、补体依赖性细胞毒性反应(CDC)和改变信号通路等机制达到治疗肿瘤的效果。另外,将单克隆抗体与放射性核素、化疗药物和毒素等偶联,用于肿瘤等疾病的靶向治疗研究,成为生物治疗领域的热点。该文对近年来国际上用于血液系统恶性肿瘤治疗的单克隆抗体药物进行了概括和总结,讨论了治疗性单克隆抗体药物存在的问题和应用前景。     

表观遗传学修饰在血液肿瘤中的研究进展

血液肿瘤作为一类常见恶性肿瘤疾病主要包括各类白血病、多发性骨髓瘤以及恶性淋巴瘤.随着现代社会高速发展,人群发病率呈逐年升高趋势,且发病年龄逐渐低龄化,发病原因与环境因素以及遗传因素密不可分.近年来研究发现,表观遗传学修饰在血液肿瘤发生发展的过程中扮演了重要角色,一些相关修饰基因作为血液肿瘤的治疗靶点在临床应用上取得了重要进展.针对近年来表观遗传学修饰在血液肿瘤中的研究新进展,本文将系统综述DNA甲基化、组蛋白修饰、非编码RNA及RNA修饰等在血液肿瘤发病机制方面的研究进展.     

The role of HSP27 in the development of drug resistance of gastrointestinal malignancies: Current status and perspectives

Heat-shock protein 27 (HSP27) is a chaperone molecule that plays a critical role in the refolding and activity of several proteins responsible for cancer cell drug toxicity. Upregulation of HSP27 is associated with decreased drug sensitivity as well as poorer survival in gastrointestinal (GI) malignancies. It is, therefore, possible that HSP27 may be of value in the assessment of prognostic and therapeutic efficacy in the treatment of GI cancers. Pharmacological and biological inhibitors of HSP27 enhance tumor cell chemosensitivity. This review summarizes the potential role of HSP27 in chemotherapy drug resistance and the therapeutic potential of HSP27 inhibitors as a novel strategy in the treatment of GI cancers.     

Conjugation of DM1 to anti-CD30 antibody has potential antitumor activity in CD30-positive hematological malignancies with lower systemic toxicity

ABSTRACT

An anti-CD30 antibody-drug conjugate incorporating the antimitotic agent DM1 and a stable SMCC linker, anti-CD30-MCC-DM1, was generated as a new antitumor drug candidate for CD30-positive hematological malignancies. Here, the in vitro and in vivo pharmacologic activities of anti-CD30-MCC-DM1 (also known as F0002-ADC) were evaluated and compared with ADCETRIS (brentuximab vedotin). Pharmacokinetics (PK) and the safety profiles in cynomolgus monkeys were assessed. Anti-CD30-MCC-DM1 was effective in in vitro cell death assays using CD30-positive lymphoma cell lines. We studied the properties of anti-CD30-MCC-DM1, including binding, internalization, drug release and actions. Unlike ADCETRIS, anti-CD30-MCC-DM1 did not cause a bystander effect in this study. In vivo, anti-CD30-MCC-DM1 was found to be capable of inducing tumor regression in subcutaneous inoculation of Karpas 299 (anaplastic large cell lymphoma), HH (cutaneous T-cell lymphoma) and L428 (Hodgkin’s disease) cell models. The half-lives of 4 mg/kg and 12 mg/kg anti-CD30-MCC-DM1 were about 5 days in cynomolgus monkeys, and the tolerated dose was 30 mg/kg in non-human primates, supporting the tolerance of anti-CD30-MCC-DM1 in humans. These results suggest that anti-CD30-MCC-DM1 presents efficacy, safety and PK profiles that support its use as a valuable treatment for CD30-positive hematological malignancies.     

Extracellular vesicles: Their functions in plant–pathogen interactions

Extracellular vesicles (EVs) are rounded vesicles enclosed by a lipid bilayer membrane, released by eukaryotic cells and by bacteria. They carry various types of bioactive substances, including nucleic acids, proteins, and lipids. Depending on their cargo, EVs have a variety of well‐studied functions in mammalian systems, including cell‐to‐cell communication, cancer progression, and pathogenesis. In contrast, EVs in plant cells (which have rigid walls) have received very little research attention for many decades. Increasing evidence during the past decade indicates that both plant cells and plant pathogens are able to produce and secrete EVs, and that such EVs play key roles in plant–pathogen interactions. Plant EVs contains small RNAs (sRNAs) and defence‐related proteins, and may be taken up by pathogenic fungi, resulting in reduced virulence. On the other hand, EVs released by gram‐negative bacteria contain a wide variety of effectors and small molecules capable of activating plant immune responses via pattern‐recognition receptor‐ and BRI1‐ASSOCIATED RECEPTOR KINASE‐ and SUPPRESSOR OF BIR1‐mediated signalling pathways, and salicylic acid‐dependent and ‐independent processes. The roles of EVs in plant–pathogen interactions are summarized in this review, with emphasis on important molecules (sRNAs, proteins) present in plant EVs.     

肠道微生态在血液肿瘤发生发展中的作用研究进展

肠道微生态在血液肿瘤的发生、发展及预后中起到了至关重要的作用。近年来, 动物和临床研究取得了很大的进展。肠道微生物不仅能诱导基因突变和异常免疫反应导致淋巴瘤发生, 还可以通过慢性炎症促进慢性淋巴细胞白血病(chronic lymphoblastic leukemia, CLL)的发展, 扰乱细胞增殖和凋亡的平衡, 引发异常的固有和适应性免疫反应。肠道中普雷沃菌通过白细胞介素17(IL-17)促进多发性骨髓瘤(multiple myeloma, MM)的发展, 且特定肠道微生物可以水解尿素生成L-谷氨酰胺(Gln)促进MM的进展。血液肿瘤的治疗可以造成肠道微生态失调。因此, 维持肠道微生态的稳定对治疗效果和疾病预后具有重要意义。粪菌移植(fecal microbiota transplantation, FMT)可以纠正肠道微生态失衡, 具有广阔的临床应用前景。

     

Therapeutic application of extracellular vesicles in kidney disease: promises and challenges

Extracellular vesicles (EVs) are nanosized, membrane‐bound vesicles released from different cells. Recent studies have revealed that EVs may participate in renal tissue damage and regeneration through mediating inter‐nephron communication. Thus, the potential use of EVs as therapeutic vector has gained considerable interest. In this review, we will discuss the basic characteristics of EVs and its role in nephron cellular communication. Then, the application of EVs as therapeutic vector based on its natural content or as carriers of drug, in acute and chronic kidney injury, was discussed. Finally, perspectives and challenges of EVs in therapy of kidney disease were described.     

Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain

Homeostasis relies heavily on effective cell-to-cell communication. In the central nervous system (CNS), probably more so than in other organs, such communication is crucial to support and protect neurons especially during ageing, as well as to control inflammation, remove debris and infectious agents. Emerging evidence indicates that extracellular vesicles (EVs) including endosome-derived exosomes and fragments of the cellular plasma membrane play a key role in intercellular communication by transporting messenger RNA, microRNA (miRNA) and proteins. In neurodegenerative diseases, secreted vesicles not only remove misfolded proteins, but also transfer aggregated proteins and prions and are thus thought to perpetuate diseases by ‘infecting’ neighbouring cells with these pathogenic proteins. Conversely, in other CNS disorders signals from stressed cells may help control inflammation and inhibit degeneration. EVs may also reflect the status of the CNS and are present in the cerebrospinal fluid indicating that exosomes may act as biomarkers of disease. That extracellular RNA and in particular miRNA, can be transferred by EV also indicates that these vesicles could be used as carriers to specifically target the CNS to deliver immune modulatory drugs, neuroprotective agents and anti-cancer drugs. Here, we discuss the recent evidence indicating the potential role of exosomes in neurological disorders and how knowledge of their biology may enable a Trojan-horse approach to deliver drugs into the CNS and treat neurodegenerative and other disorders of the CNS.     

Exosomes in Genitourinary Cancers: Emerging Mediators of Drug Resistance and Promising Biomarkers

Drug resistance presents a major obstacle in the treatment of genitourinary cancers. Exosomes as the medium of intercellular communication serve important biological functions and play essential roles in pathological processes, including drug response. Through the transfer of bioactive cargoes, exosomes can modulate drug resistance via multiple mechanisms. This review attempts to elucidate the mechanisms of exosomal cargoes with reference to tumor drug resistance, their role in genitourinary cancers, and their potential clinical applications as candidate biomarkers in liquid biopsy.     

Advances in haplo-identical stem cell transplantation in adults with high-risk hematological malignancies

Allogeneic bone marrow transplant is a life-saving procedure for adults and children that have high-risk or relapsed hematological malignancies. Incremental advances in the procedure, as well as expanded sources of donor hematopoietic cell grafts have significantly improved overall rates of success. Yet, the outcomes for patients for whom suitable donors cannot be found remain a significant limitation. These patients may benefit from a hematopoietic cell transplant wherein a relative donor is fully haplotype mismatched. Previously this procedure was limited by graft rejection, lethal graft-versus-host disease, and increased treatmentrelated toxicity. Recent approaches in haplo-identical transplantation have demonstrated significantly improved outcomes. Based on years of incremental preclinical research into this unique form of bone marrow transplant, a range of approaches have now been studied in patients in relatively large phase Ⅱ trials that will be summarized in this review.     

Phosphatase of regenerating liver in hematopoietic stem cells and hematological malignancies

The phosphatases of regenerating liver (PRLs), consisting PRL1, PRL2 and PRL3, are dual-specificity protein phosphatases that have been implicated as biomarkers and therapeutic targets in several solid tumors. However, their roles in hematological malignancies are largely unknown. Recent findings demonstrate that PRL2 is important for hematopoietic stem cell self-renewal and proliferation. In addition, both PRL2 and PRL3 are highly expressed in some hematological malignancies, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Moreover, PRL deficiency impairs the proliferation and survival of leukemia cells through regulating oncogenic signaling pathways. While PRLs are potential novel therapeutic targets in hematological malignancies, their exact biological function and cellular substrates remain unclear. This review will discuss how PRLs regulate hematopoietic stem cell behavior, what signaling pathways are regulated by PRLs, and how to target PRLs in hematological malignancies. An improved understanding of how PRLs function and how they are regulated may facilitate the development of PRL inhibitors that are effective in cancer treatment.     

Extracellular vesicles: Emerged as a promising strategy for regenerative medicine

Cell transplantation therapy has certain limitations including immune rejection and limited cell viability, which seriously hinder the transformation of stem cell-based tissue regeneration into clinical practice. Extracellular vesicles (EVs) not only possess the advantages of its derived cells, but also can avoid the risks of cell transplantation. EVs are intelligent and controllable biomaterials that can participate in a variety of physiological and pathological activities, tissue repair and regeneration by transmitting a variety of biological signals, showing great potential in cell-free tissue regeneration. In this review, we summarized the origins and characteristics of EVs, introduced the pivotal role of EVs in diverse tissues regeneration, discussed the underlying mechanisms, prospects, and challenges of EVs. We also pointed out the problems that need to be solved, application directions, and prospects of EVs in the future and shed new light on the novel cell-free strategy for using EVs in the field of regenerative medicine.     

Genes of multidrug resistance in haematological malignancies

Since the early 1970s, multiple drug resistance has been known to exist in cancer cells and is thought to be attributable to a membrane-bound, energy-dependent pump protein (P-glycoprotein [P-gp]) capable of extruding various related and unrelated chemotherapeutic drugs. The development of refractory disease in haematological malignancies is frequently associated with the expression of one or several multidrug resistance (MDR) genes. MDR1, multidrug resistance-associated protein (MRP) and lung-resistance protein (LRP) have been identified as important adverse prognostic factors. Recently it has become possible to reverse clinical MDR by blocking P-gp-mediated drug efflux. The potential relevance of these reversal agents of MDR as well as the potential new approaches to treat the refractory disease are discussed in this article. In addition, an array of different molecules and mechanisms by which resistant cells can escape the cytotoxic effect of anticancer drugs has now been identified. These molecules and mechanisms include apoptosis-related proteins and drug inactivation enzymes. Resistance to chemotherapy is believed to cause treatment failure in more than 50% patients. Clearly, if drug resistance could be overcome, the impact on survival would be highly significant. This review focuses on molecular mechanism of drug resistance in haematological malignancies with emphasis on molecules involved in MDR. In addition, it brings the survey of methods involved in determination of MDR, in particular P-gp/MDR1, MRP and LRP.     

Exosomes: New insights into cancer mechanisms

Exosomes are mobile extracellular vesicles with a diameter 40 to 150 nm. They play a critical role in several processes such as the development of cancers, intercellular signaling, drug resistance mechanisms, and cell-to-cell communication by fusion onto the cell membrane of recipient cells. These vesicles contain endogenous proteins and both noncoding and coding RNAs (microRNA and messenger RNAs) that can be delivered to various types of cells. Furthermore, exosomes exist in body fluids such as plasma, cerebrospinal fluid, and urine. Therefore, they could be used as a novel carrier to deliver therapeutic nucleic-acid drugs for cancer therapy. It was recently documented that, hypoxia promotes exosomes secretion in different tumor types leading to the activation of vascular cells and angiogenesis. Cancer cell-derived exosomes (CCEs) have been used as prognostic and diagnostic markers in many types of cancers because exosomes are stable at 4°C and −70°C. CCEs have many functional roles in tumorigenesis, metastasis, and invasion. Consequently, this review presents the data about the therapeutic application of exosomes and the role of CCEs in cancer invasion, drug resistance, and metastasis.     

国产两性霉素B抢先治疗血液病患者肺部侵袭性真菌感染的疗效与安全性分析

目的观察国产两性霉素B抢先治疗血液病患者侵袭性肺部真菌感染(以下简称IFI)的疗效与不良反应。方法回顾性分析我院2004年12月～2008年12月间,45例免疫功能低下IFI患者接受国产两性霉素B治疗的临床资料。结果 45例患者均应用两性霉素B治疗两周以上,最长应用时间为14周,中位数6周。总有效率为86.7%,不良反应主要有低钾血症、发热、转氨酶升高、肾功损害、胃肠道反应,根据WHO药物毒性分级标准均为I～II级毒性。结论国产两性霉素B对于血液病患者IFI临床诊断的抢先治疗疗效肯定,不良反应可耐受。