L-1416, a novel MDR reversing agent with possible reduced calcium antagonism

BackgroundMultidrug efflux transporter P-glycoprotein (P-gp) is highly expressed on membrane of tumor cells and supposed to be implicated in the resistance to tumor chemotherapy. However, currently none of P-gp inhibitors has been approved by Food and Drug Administration not only due to toxicity but also lack of efficacy in clinical trials.MethodsTo solve the problem, our lab synthesized a novel compound named 1416 [1-(2,6-dimethylphenoxy)-3,4-dimethoxyphenylethylamino) propane hydrochloride] with the hope of high P-gp inhibition and low side effects. Caco-2 cell monolayer and tumor bearing mice were used to evaluate the P-gp inhibition of 1416 in vitro and in vivo, respectively. One of its potential side effects, calcium antagonism was also evaluated.ResultsResults showed that 1416 showed a similar P-gp inhibition as verapamil in Caco-2 cell monolayer. No significant difference was observed in antitumor enhancement when the optical isomers of 1416 (D-1416 and L-1416) were co-administered with vinblastine. In calcium antagonism, L-1416 showed less calcium inhibition than both D-1416 and verapamil.ConclusionThe novel compound 1416 could significantly increase the antitumor effects of cytotoxic drugs and one of its optical isomers, L-1416, might be more promising due to its potential low calcium antagonism.     

First-Line Mammalian Target of Rapamycin Inhibition in Metastatic Renal Cell Carcinoma: An Analysis of Practice Patterns From the International Metastatic Renal Cell Carcinoma Database Consortium

Introduction/BackgroundApproval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting.Patients and MethodsWe performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS).ResultsWe identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients.ConclusionPoor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made.     

Dual-target inhibitors of bromodomain-containing protein 4 (BRD4) in cancer therapy: Current situation and future directions

Bromodomain-containing protein 4 (BRD4) is emerging as a therapeutic target that acts synergistically with other targets of small-molecule drugs in cancer. Therefore, the discovery of potential new dual-target inhibitors of BRD4 may be a promising strategy for cancer therapy. In this review, we highlight a series of strategies to design therapeutic dual-target inhibitors of BRD4 that focus on the synergistic functions of this protein. Drug combinations that exploit synthetic lethality, protein–protein interactions, functional complementarity, and blocking of resistance mechanisms could ultimately overcome the barriers inherent to the development of BRD4 inhibitors as future cancer drugs.     

An Update on the Clinical Development of Proprotein Convertase Subtilisin Kexin 9 Inhibitors,Novel Therapeutic Agents for Lowering Low‐Density Lipoprotein Cholesterol

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an essential role in the degradation of low‐density lipoprotein C (LDL‐C) receptors, and PCSK9 inhibitors have recently emerged as a potential treatment option to reduce LDL‐C. Our paper reviewed the current available Phase II clinical trials of PCSK9 inhibitors for the treatment of dyslipidemia. A second objective of this review was to evaluate the potential clinical role of PCSK9 inhibitors in the management of dyslipidemia. Studies evaluating the efficacy and safety of any PCSK9 inhibitors in patients with dyslipidemia were included. The monoclonal antibodies REGN727/SAR236553 and AMG145 have the most published clinical data. Seven phase II trials were retrieved that evaluated the efficacy and safety of REGN727/SAR236553 or AMG145 in patients with either hypercholesterolemia or heterozygous familial hypercholesterolemia (HeFH). These two agents significantly decreased LDL‐C levels either as monotherapy or in combination with other lipid‐lowering agents. REGN727/SAR236553 and AMG145 have been well tolerated. The ongoing phase III trials of these two agents are summarized. REGN727/SAR236553 and AMG145 have demonstrated the potential to further decrease LDL‐C levels when added to conventional lipid‐lowering therapy. Morbidity and mortality data are required to define their roles in clinical practice.     

大黄附子汤对重症急性胰腺炎小鼠肠道微皱褶细胞变化的影响

目的研究大黄附子汤对重症急性胰腺炎(SAP)小鼠肠道微皱褶细胞(M细胞)变化的影响，为大黄附子汤临床防治SAP提供理论基础。 方法选取40只健康SPF级C57BL/6J雄性小鼠，随机分为4组(每组10只)：空白对照组、大黄附子汤对照组、SAP组、大黄附子汤治疗组，其中SAP组和大黄附子汤治疗组分别以3.5 g/kg剂量腹腔注射20% L-精氨酸，空白对照组和大黄附子汤对照组注射等剂量的等渗盐水；于造模后12、24、36 h，空白对照组和SAP组给予等渗盐水0.2 mL，大黄附子汤对照组和治疗组给予大黄附子汤0.2 mL灌肠，均于造模完成48 h后处死取材，使用ELISA检测血清淀粉酶、内毒素、IL-1β及TNF-α含量，取回肠及胰腺组织行HE染色、评分，免疫组化染色检测M细胞特异性蛋白GP2并评分。 结果(1)一般情况：对照组腹腔注射后小鼠一般情况好，精神状态良好，能正常进水，四肢活动自如，行动未受影响；SAP组小鼠腹腔注射后一般情况差，精神萎靡，反应迟钝，行动迟缓，呼吸急促，拱背收腹，饮水减少。(2)SAP组淀粉酶、内毒素、IL-1β及TNF-α水平较对照组明显升高(P<0.05)；与SAP组进行对比，大黄附子汤治疗组血清淀粉酶、内毒素、IL-1β及TNF-α水平出现显著下降(P<0.05)。(3)HE染色：SAP组胰腺及回肠组织坏死严重，可见大量白细胞浸润。大黄附子汤治疗组胰腺及回肠组织轻度坏死，可见少量中性粒细胞等白细胞浸润。(4)免疫组化染色：SAP组与对照组相比GP2表达降低(P<0.05)；相较于SAP组，大黄附子汤治疗组GP2的表达水平升高(P<0.05)。 结论大黄附子汤治疗可改善作为肠道免疫应答起始的M细胞数量与功能，增强肠道免疫应答，减轻肠免疫屏障损伤，减少内毒素入血，改善SAP症状。     

Selective Targeting of the G2/M Cell Cycle Checkpoint to Improve the Therapeutic Index of Radiotherapy

Despite tremendous advances in radiotherapy techniques, allowing dose escalation to tumour tissues and sparing of organs at risk, cure rates from radiotherapy or chemoradiotherapy remain suboptimal for most cancers. In tandem with our growing understanding of tumour biology, we are beginning to appreciate that targeting the molecular response to radiation-induced DNA damage holds great promise for selective tumour radiosensitisation. In particular, approaches that inhibit cell cycle checkpoint controls offer a means of exploiting molecular differences between tumour and normal cells, thereby inducing so-called cancer-specific synthetic lethality. In this overview, we discuss cellular responses to radiation-induced damage and discuss the potential of using G2/M cell cycle checkpoint inhibitors as a means of enhancing tumour control rates.     

Long-term activation of the innate immune system in atherosclerosis

Efforts to reverse the pathologic consequences of vulnerable plaques are often stymied by the complex treatment resistant pro-inflammatory environment within the plaque. This suggests that pro-atherogenic stimuli, such as LDL cholesterol and high fat diets may impart longer lived signals on (innate) immune cells that persist even after reversing the pro-atherogenic stimuli. Recently, a series of studies challenged the traditional immunological paradigm that innate immune cells cannot display memory characteristics. Epigenetic reprogramming in these myeloid cell subsets, after exposure to certain stimuli, has been shown to alter the expression of genes upon re-exposure. This phenomenon has been termed trained innate immunity or innate immune memory. The changed responses of ‘trained’ innate immune cells can confer nonspecific protection against secondary infections, suggesting that innate immune memory has likely evolved as an ancient mechanism to protect against pathogens. However, dysregulated processes of immunological imprinting mediated by trained innate immunity may also be detrimental under certain conditions as the resulting exaggerated immune responses could contribute to autoimmune and inflammatory diseases, such as atherosclerosis. Pro-atherogenic stimuli most likely cause epigenetic modifications that persist for prolonged time periods even after the initial stimulus has been removed. In this review we discuss the concept of trained innate immunity in the context of a hyperlipidemic environment and atherosclerosis. According to this idea the epigenome of myeloid (progenitor) cells is presumably modified for prolonged periods of time, which, in turn, could evoke a condition of continuous immune cell over-activation.     

Development of an immune function assay by measuring intracellular adenosine triphosphate (iATP) levels in mitogen-stimulated CD4+ T lymphocytes

We developed an immune function assay for monitoring CD4+ T cells activity based on changes in intracellular adenosine triphosphate (iATP) levels after phytohemagglutinin (PHA) stimulation. Blood samples were obtained from 40 healthy subjects and 30 RTRs and incubated with 5 µg/mL of PHA for 15–18 hr at 37°C and 5% CO₂. Afterward, the CD4+ T cells were separated by antibody-coated magnetic beads and lysed. Then, iATP content in unstimulated and stimulated conditions was measured by luciferin-luciferase reaction using a log-log standard curve. The iATP levels showed significant increase in CD4+ T cells in both healthy persons (mean: 550 ± 142 ng/mL vs. 109 ± 54 ng/mL) and RTRs (mean: 394 ± 160 ng/mL vs. 52 ± 37 ng/mL) after PHA stimulation (P < 0.001). However, the iATP production in RTRs was significantly lower than that in healthy individuals; both prior to and after stimulation with PHA (P < 0.001). No gender-specific difference in iATP production was observed between women and men subjects. This rapid and low-cost assay reflects the degree of immune cell function through assessment of CD4+ T cells activation. Thus, it can be used for evaluation of immune system status in immunodeficient individuals as well as in immunosuppressed transplant recipients who needs drug adjustment.     

Acquired Factor VIII Inhibitor: A Rare Etiology for Bruisability and Anemia

Acquired factor VIII inhibitor is a very rare cause of easy bruisability, muscular hematomas, and subsequent anemia in the elderly patient population. The incidence of acquired factor VIII inhibitor is one in one million. Here we report an elderly patient who presented to the hospital for bruising easily fatigue and was found to have acquired factor VIII inhibitor on further investigation. He responded to the treatment appropriately, and hemostasis was achieved successfully with recombinant VII concentrates and eradication of the inhibitor with Imuran and steroid combination.