Determination of human platelet antigen typing by molecular methods: Importance in diagnosis and early treatment of neonatal alloimmune thrombocytopenia

Neonatal alloimmune thrombocytopenia (NAIT) is the most common cause of severe thrombocytopenia and intracranial hemorrhage in the perinatal period. While the gold standard for making a diagnosis of NAIT is detection of a human platelet antigen (HPA)-specific antibody in maternal serum, together with identifying an incompatibility between the parents for the cognate HPA antigen, platelet genotyping is the gold standard method for HPA typing. Platelet genotyping is critical in screening at-risk fetuses for the presence ofthe HPA corresponding to the maternal antibody. In addition, platelet genotyping may play a role in population screening to identify women at risk for sensitization, and thus, fetuses at risk for NAIT. The most commonly used methods of platelet genotyping are sequence-specific primer-polymerase chain reaction (PCR-SSP), restriction fragment length polymorphism-PCR (PCR-RFLP), and TaqMan real-time PCR. PCR-SSP and PCR-RFLP are relatively inexpensive and technically simple methods, but they are not easily automated and require expertise for reliable interpretation of results. Newer methods that allow for multiplexing, automation, and easily interpretable results, such as bead arrays, are currently in development and available for research purposes.     

Targeting intrinsic apoptosis and other forms of cell death by BH3-mimetics in glioblastoma

Introduction: Novel approaches to treat malignant brain tumors are necessary since these neoplasms still display an unfavorable prognosis.

Areas covered: In this review, the authors summarize and analyze recent preclinical data that suggest that targeting intrinsic apoptosis may be a suitable strategy for the treatment of malignant gliomas. They focus on the anti-apoptotic Bcl-2 family members of proteins and the recent drug developments in that field with a special focus on BH3-mimetics. With the discovery of BH3-mimetics that interfere with anti-apoptotic Bcl-2 family members in the low nanomolar range significant excitement has been generated towards these class of inhibitors, such as ABT-737, ABT-263 and the most recent successor, ABT-199 which is most advanced with respect to clinical application. The authors discuss the more recent selective inhibitors of Bcl-xL and Mcl-1. Concerning Mcl-1, these novel classes of inhibitors have the potential to impact malignant gliomas since these tumors reveal increased levels of Mcl-1.

Expert opinion: The recent development of certain small molecules raises significant hope that intrinsic apoptosis might soon be efficiently targetable for malignancies of the central nervous system. That being said, additional studies are necessary to determine which of the BH3-mimetics might be most suitable.     

Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

Introduction

The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.

Methods

Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.

Results

Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.

Conclusions

Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.     

Differential impact of belatacept and cyclosporine A on central aortic blood pressure and arterial stiffness after renal transplantation

Calcineurin inhibitors (CNI) are potent vasoconstrictors and induce an acceleration of arteriosclerosis, thus contributing to the cardiovascular risk after renal transplantation. The study compares the impact of belatacept and cyclosporine A (CsA) on arterial stiffness and central aortic blood pressure. We performed a case–control study in 46 patients (23 on belatacept and 23 on CsA) matched for age, body mass index, time after transplantation, and time on dialysis prior to transplantation. Pulse wave analysis (SphygmoCor, AtCor^®) was used to assess central aortic blood pressure, aortic augmentation pressure, and pulse wave velocity (PWV) as a marker of arterial stiffness. Assessment of vascular function was performed after a minimum of 20 months and a median follow‐up of 81 months post‐transplant. Peripheral systolic and diastolic blood pressure did not significantly differ in the two groups (p > 0.05 each). The central aortic augmentation pressure was higher in the CsA group (12.7 mmHg vs. 7.3 mmHg, p = 0.048). PWV as a measure of arterial stiffness did not differ in the two groups. Thus, belatacept is not associated with a significant difference in arterial stiffness compared to CsA after a median of 81 months post‐transplant. It is associated, however, with a lower aortic augmentation pressure, a strong independent cardiovascular risk factor.