Anti-Angiogenic Therapy in ALK Rearranged Non-Small Cell Lung Cancer (NSCLC)

The management of advanced lung cancer has been transformed with the identification of targetable oncogenic driver alterations. This includes anaplastic lymphoma kinase (ALK) gene rearrangements. ALK tyrosine kinase inhibitors (TKI) are established first-line treatment options in advanced ALK rearranged non-small cell lung cancer (NSCLC), with several next-generation ALK TKIs (alectinib, brigatinib, ensartinib and lorlatinib) demonstrating survival benefit compared with the first-generation ALK TKI crizotinib. Still, despite high objective response rates and durable progression-free survival, drug resistance inevitably ensues, and treatment options beyond ALK TKI are predominantly limited to cytotoxic chemotherapy. Anti-angiogenic therapy targeting the vascular endothelial growth factor (VEGF) signaling pathway has shown efficacy in combination with platinum-doublet chemotherapy in advanced NSCLC without a driver alteration, and with EGFR TKI in advanced EGFR mutated NSCLC. The role for anti-angiogenic therapy in ALK rearranged NSCLC, however, remains to be elucidated. This review will discuss the pre-clinical rationale, clinical trial evidence to date, and future directions to evaluate anti-angiogenic therapy in ALK rearranged NSCLC.     

Linear B-Cell Epitope Prediction for In Silico Vaccine Design: A Performance Review of Methods Available via Command-Line Interface

Linear B-cell epitope prediction research has received a steadily growing interest ever since the first method was developed in 1981. B-cell epitope identification with the help of an accurate prediction method can lead to an overall faster and cheaper vaccine design process, a crucial necessity in the COVID-19 era. Consequently, several B-cell epitope prediction methods have been developed over the past few decades, but without significant success. In this study, we review the current performance and methodology of some of the most widely used linear B-cell epitope predictors which are available via a command-line interface, namely, BcePred, BepiPred, ABCpred, COBEpro, SVMTriP, LBtope, and LBEEP. Additionally, we attempted to remedy performance issues of the individual methods by developing a consensus classifier, which combines the separate predictions of these methods into a single output, accelerating the epitope-based vaccine design. While the method comparison was performed with some necessary caveats and individual methods might perform much better for specialized datasets, we hope that this update in performance can aid researchers towards the choice of a predictor, for the development of biomedical applications such as designed vaccines, diagnostic kits, immunotherapeutics, immunodiagnostic tests, antibody production, and disease diagnosis and therapy.     

Formulation and In Vivo Evaluation of Niosome-Encapsulated Daunorubicin Hydrochloride

ABSTRACT

The central aim of this present study was to modify the reverse evaporation process, such that an enhanced entrapment, with increased storage stability and prolonged release, could be achieved, and to translate these advantages to increased therapeutic efficacy of daunorubicin hydrochloride on Dalton's ascitic lymphoma. Niosomes prepared exhibited entrapment efficiency 20% higher than theoretically possible by the reverse evaporation process. The niosomes were found to be very stable at a storage temperature of 4°C for a duration of three months. Even the drug leakage was restricted to just 10%. The in vivo studies suggested a prolonged release of 20 hr. Niosomal daunorubicin hydrochloride exhibited an enhanced anti-tumor efficacy when compared to free drug. The niosomal formulation was able to destroy the Dalton's ascitic lymphoma cells in the peritoneum within the third day of treatment, while free drug took around six days and the process was incomplete. The hematological studies also prove that the niosomal formulation was superior to free drug treatment. An enhanced mean survival time was achieved by the niosomal formulation that finally substantiates the overall efficacy of the niosomal formulation. This study suggests that the multilamellar vesicles obtained by the presently utilized reverse evaporation process resulted in vesicles that resisted the immediate lysis in the Kupffer cells, whereby a prolonged drug concentration was achieved which enhanced the cell lysis. But the major factor responsible for the quicker onset of action could be the increased permeability of the niosomes into the cell membrane and the cytoplasm of the Dalton's ascitic lymphoma cells.     

纵隔灰区淋巴瘤的研究进展

纵隔灰区淋巴瘤(mediastinal gray zone lymphoma)作为一个疾病实体,常不能依据现有的诊断标准进行分类.这类淋巴瘤同时具有纵隔弥漫大B细胞淋巴瘤(PMBL)和经典霍奇金淋巴瘤(cHL)的特征.在2008年WHO造血与淋巴组织肿瘤分类中将其命名为"B细胞淋巴瘤,不能分类,具有介于弥漫大B细胞淋巴瘤和经典霍奇金淋巴瘤之间的特征(BCLu)".BCLu具有独特的临床特点、免疫表型和分子遗传学特征,临床过程更具侵袭性,预后较差.目前尚无达成共识的治疗方案,可参照侵袭性B细胞淋巴瘤的方案化疗.     

Design, synthesis, and biological activity of urea derivatives as anaplastic lymphoma kinase inhibitors

In anaplastic large-cell lymphomas, chromosomal translocations involving the kinase domain of anaplastic lymphoma kinase (ALK), generally fused to the 5' part of the nucleophosmin gene, produce highly oncogenic ALK fusion proteins that deregulate cell cycle, apoptosis, and differentiation in these cells. Other fusion oncoproteins involving ALK, such as echinoderm microtubule-associated protein-like 4-ALK, were recently found in patients with non-small-cell lung, breast, and colorectal cancers. Recent research has focused on the development of inhibitors for targeted therapy of these ALK-positive tumors. Because kinase inhibitors that target the inactive conformation are thought to be more specific than ATP-targeted inhibitors, we investigated the possibility of using two known inhibitors, doramapimod and sorafenib, which target inactive kinases, to design new urea derivatives as ALK inhibitors. We generated a homology model of ALK in its inactive conformation complexed with doramapimod or sorafenib in its active site. The results elucidated why doramapimod is a weak inhibitor and why sorafenib does not inhibit ALK. Virtual screening of commercially available compounds using the homology model of ALK yielded candidate inhibitors, which were tested using biochemical assays. Herein we present the design, synthesis, biological activity, and structure-activity relationships of a novel series of urea compounds as potent ALK inhibitors. Some compounds showed inhibition of purified ALK in the high nanomolar range and selective antiproliferative activity on ALK-positive cells.     

肺黏膜相关淋巴组织型淋巴瘤的免疫组织化学和电镜观察

探讨肺黏膜相关淋巴组织型淋巴瘤（MALTLoma）的免疫表型和超微结构特点，对3例经开胸肺活检病理诊断的肺MALTLoma进行光镜和透射电镜观察以及免疫组化染色。光镜观察发现，瘤细胞主要由中心细胞样淋巴细胞、小淋巴细胞样瘤细胞组成；3例均有淋巴上皮性损伤和反应性淋巴滤泡以及淋巴滤泡的克隆化。免疫组化显示瘤细胞表达B细胞相关抗原。透射电镜观察发现，在支气管黏膜上皮和肺泡上皮细胞周围以及肺泡腔内有较多的淋巴细胞源性瘤细胞浸润，瘤细胞具有淋巴细胞的超微结构特点。对肺MALToma的超微结构观察为该瘤的研究提供了形态学依据，电镜观察对判断瘤细胞的来源和免疫表型有帮助。     

Expression and characterisation of recombinant human CD48 and isolation of a human anti‐CD48 monoclonal antibody by phage display

Human CD48, a membrane‐bound, glycosylphosphatidylinositol (GPI)‐linked glycoprotein, is a potential tumour target for the treatment of leukaemias and lymphomas. CD48 is expressed on T‐ and B‐cells, however <5% of CD34⁺ progenitor cells express CD48. A truncated, 45 kDa soluble form of the full length CD48 was expressed in Chinese hamster ovary (CHO) cells, and was shown to consist of a broad range of charge isoforms, with the most abundant isoforms between pI 4.5 and 5.0. The truncated form of CD48 was shown to bind to antibodies raised against native, GPI‐linked CD48 by surface plasmon resonance analysis. A synthetic, human, scFv immunoglobulin gene library was screened against recombinant CD48 by phage display, and an scFv antibody fragment, (designated N2A) was isolated after four rounds of biopanning. N2A was reassembled as a human IgG1 human monoclonal antibody, expressed in CHO cells and the binding of IgG1‐N2A to recombinant CD48 was confirmed by surface plasmon resonance. Flow cytometry studies of IgG1‐N2A binding to Raji cells showed the specificity of N2A for GPI‐linked CD48 was conserved, and presents the potential for IgG1‐N2A as a lead antibody candidate for the treatment of white blood cell malignancies. Copyright © 2005 Society of Chemical Industry