Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax

Background The BCL2 inhibitor venetoclax has shown efficacy in several hematologic malignancies, with the greatest response rates in indolent blood cancers such as chronic lymphocytic leukaemia. There is a lower response rate to venetoclax monotherapy in diffuse large B-cell lymphoma (DLBCL).Methods We tested inhibitors of cap-dependent mRNA translation for the ability to sensitise DLBCL and mantle cell lymphoma (MCL) cells to apoptosis by venetoclax. We compared the mTOR kinase inhibitor (TOR-KI) MLN0128 with SBI-756, a compound targeting eukaryotic translation initiation factor 4G1 (eIF4G1), a scaffolding protein in the eIF4F complex.Results Treatment of DLBCL and MCL cells with SBI-756 synergised with venetoclax to induce apoptosis in vitro, and enhanced venetoclax efficacy in vivo. SBI-756 prevented eIF4E-eIF4G1 association and cap-dependent translation without affecting mTOR substrate phosphorylation. In TOR-KI-resistant DLBCL cells lacking eIF4E binding protein-1, SBI-756 still sensitised to venetoclax. SBI-756 selectively reduced translation of mRNAs encoding ribosomal proteins and translation factors, leading to a reduction in protein synthesis rates in sensitive cells. When normal lymphocytes were treated with SBI-756, only B cells had reduced viability, and this correlated with reduced protein synthesis.Conclusions Our data highlight a novel combination for treatment of aggressive lymphomas, and establishes its efficacy and selectivity using preclinical models.Subject terms: B-cell lymphoma, Molecular medicine     

Inhibition of tissue-nonspecific alkaline phosphatase protects against medial arterial calcification and improves survival probability in the CKD-MBD mouse model

Medial arterial calcification (MAC) is a major complication of chronic kidney disease (CKD) and an indicator of poor prognosis. Aortic overexpression of tissue-nonspecific alkaline phosphatase (TNAP) accelerates MAC formation. The present study aimed to assess whether a TNAP inhibitor, SBI-425, protects against MAC and improves survival probability in a CKD-mineral and bone disorder (MBD) mouse model. CKD-MBD mice were divided in three groups: vehicle, SBI-10, and SBI-30. They were fed a 0.2% adenine and 0.8% phosphorus diet from 14 to 20 weeks of age to induce CKD, followed by a high-phosphorus (0.2% adenine and 1.8% phosphorus) diet for another 6 weeks. At 14–20 weeks of age, mice in the SBI-10 and SBI-30 groups were given 10 and 30 mg/kg SBI-425 by gavage once a day, respectively, while vehicle-group mice were given distilled water as vehicle. Control mice were fed a standard chow (0.8% phosphorus) between the ages of 8 and 20 weeks. Computed tomography imaging, histology, and aortic tissue calcium content revealed that, compared to vehicle animals, SBI-425 nearly halted the formation of MAC. Mice in the control, SBI-10 and SBI-30 groups exhibited 100% survival, which was significantly better than vehicle-treated mice (57.1%). Aortic mRNA expression of Alpl, encoding TNAP, as well as plasma and aortic tissue TNAP activity, were suppressed by SBI-425 administration, whereas plasma pyrophosphate increased. We conclude that a TNAP inhibitor successfully protected the vasculature from MAC and improved survival rate in a mouse CKD-MBD model, without causing any adverse effects on normal skeletal formation and residual renal function. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Prior exposure to aged and diluted sidestream cigarette smoke impairs bronchiolar injury and repair.

The bronchiolar injury/repair response to naphthalene (NA) in mice includes acute distal airway epithelial injury that is followed by epithelial proliferation and redifferentiation, which result in repair of the epithelium within 14 days. To test whether prior exposure to aged and diluted sidestream cigarette smoke (TS) would alter the injury/repair response of the airway epithelium, adult mice were exposed to either filtered air (FA) or smoke for 5 days before injection with either corn oil carrier (CO) or naphthalene. Mice were killed 1 and 14 days after naphthalene injury. Lung and lobar bronchus were examined and measured using high-resolution epoxyresin sections. The control group (FACOFA) that was exposed to filtered air/corn oil/filtered air contained airway epithelium similar to untreated controls at all airway levels. The group exposed to tobacco smoke/corn oil/filtered air (TSCOFA) contained some rounded cells in the small airways and some expansion of the lateral intercellular space in the larger airways. Necrotic or vacuolated cells were not observed. As expected, the epithelium in the group exposed to filtered air/naphthalene/filtered air (FANAFA) contained many light-staining vacuolated Clara cells and squamated ciliated cells within distal bronchioles during the acute injury phase. Repair (including redifferentiation of epithelial cells and restoration of epithelial thickness) was nearly complete 14 days after injury. The extent of Clara cell injury, as assessed in lobar bronchi, was not different between the four groups. Although the FANAFA group contained greater initial injury in the distal airways at 1 day, the group exposed to tobacco smoke/naphthalene/filtered air (TSNAFA) had the least amount of epithelial repair at 14 days after naphthalene treatment; many terminal bronchioles contained abundant squamated undifferentiated epithelium. We conclude that tobacco smoke exposure prior to injury (1) does not change the target site or target cell type of naphthalene injury, since Clara cells in terminal bronchioles are still selectively injured; (2) results in slightly diminished acute injury from naphthalene in distal bronchioles; and (3) delays bronchiolar epithelial repair.     

How HIV treatment advances affect the cost-effectiveness of prevention.

OBJECTIVE: The cost-effectiveness of an HIV prevention program depends, in part, on its potential to avert HIV-related medical care costs. Recent advances in antiretroviral therapy have made HIV/AIDS treatment both more effective and more costly, which might make HIV prevention either more or less cost-effective. The objective of the present study was to explicate the relationship between the effectiveness and costs of HIV treatment and the cost-effectiveness of HIV prevention programs. METHODS: A basic analytic framework was used to compare the cost-effectiveness of HIV prevention interventions with respect to different HIV/AIDS medical care scenarios. Algebra was used to calculate a cost-effectiveness threshold that distinguishes prevention programs that become more cost-effective when therapeutic advances simultaneously increase or decrease the cost and effectiveness of treatment from those that become less cost-effective. Recent estimates of the costs and consequences of combination antiretroviral therapy were used to illustrate the calculation method. RESULTS: The advent of combination antiretroviral therapies for HIV has increased the cost-effectiveness of some, but not all, HIV prevention interventions. CONCLUSIONS: Whether a particular prevention program becomes more or less cost-effective as a consequence of advancements in the medical treatment of HIV/AIDS depends upon the specific characteristics of both the program and the therapy.     

胎盘早剥产妇、新生儿血及脐血中组织因子和组织因子途径抑制物的变化

目的:检测胎盘早剥产妇血、新生儿血及脐血组织因子及组织因子途径抑制物蛋白的变化,以及这些变化对其凝血功能的影响。方法:收集2006-10/2007-04在中山大学附属第一医院产科的胎盘早剥产妇血(足月或早产不限)、分娩胎儿的脐带血及新生儿血标本各11例,4例为足月产,其余均为胎龄29～36周早产标本,男婴5份,女婴6份。正常对照15份来自同期广州市妇婴医院产妇及分娩胎儿。标本收集时间母亲血为分娩前24h内、脐血为分娩即刻、新生儿血为出生后2h内抽取,排除标准为产妇本次分娩前无血液系统疾病史,未使用过对凝血功能产生影响的药物,采用酶联免疫吸附方法测定血浆组织因子及组织因子途径抑制物抗原水平,并与正常分娩产妇对照组进行比较。病理及正常标本均经产妇及家属知情同意后获得。结果:①胎盘早剥产妇血、新生儿血及脐血血浆中组织因子测定值明显高于正常对照组(P<0.05)。②胎盘早剥产妇血、新生儿血浆及脐血中组织因子途径抑制物测定值较正常分娩产妇降低,差异具有显著性意义(P<0.01)。③胎盘早剥产妇血、新生儿和脐血组织因子途径抑制物/组织因子比值均较正常分娩产妇明显降低(P<0.01)。结论:胎盘早剥时产妇血、脐血及新生儿血促凝血活性增强,抗凝血活性降低,与其高凝状态相关。     

Erratum to: Population pharmacokinetic modelling of doxorubicin and doxorubicinol in children with cancer: is there a relationship with cardiac troponin profiles?

Cancer Chemotherapy and Pharmacology -     

Sexual Risk Behavior In Men Attending Mardi Gras Celebrations In New Orleans,Louisiana

Previous research with travelers points to higher risk behaviors during vacations. Relative to their day-to-day lives, leisure travelers have more free time to pursue sexual activities and are likely to engage in higher rates of substance use than when at home. Risk behaviors during vacation have not been thoroughly examined in men who have sex with men (MSM), a key group at risk for HIV. The present investigation examined substance use, sexual risk behaviors, and components of the Information-Motivation-Behavioral Skills (IMB) Model in MSM attending Mardi Gras celebrations in New Orleans. Almost half of the sexually active men reported having sex with a partner of unknown HIV status while in New Orleans and a similar number did not disclose their own HIV status to all of their sexual partners. Drug use and excessive alcohol use were associated with unprotected sex (ps < .05). Components of the IMB model also predicted sexual risk behavior: individuals with more accurate HIV transmission information reported fewer unprotected sex acts, and motivation to engage in sexual activity on vacation was associated with more unprotected sex (ps < .05). Findings suggest that some MSM on vacation are placing themselves at risk for HIV. Traditional HIV prevention interventions do not readily lend themselves for use with transient populations. New intervention approaches are needed to reduce sexual risk behaviors in persons traveling for leisure.