Investigational therapies for the treatment of spinal muscular atrophy

Introduction: Currently, there is no cure available for the hereditary neurodegenerative disease proximal spinal muscular atrophy (SMA), which is the number one genetic killer in early childhood. However, growing knowledge of SMA pathophysiology has opened new avenues for potential therapeutic interventions.

Areas covered: This review summarizes a variety of investigational therapeutic approaches for SMA. Focusing on the current state-of-the-art applications, the authors discuss the outcome of the first clinical interventions and compare the first results from the newest strategies. The achievements of the investigational drugs highlighted in this article were deduced from original articles, pharmaceutical company press releases and clinical trial results.

Expert opinion: Nearly two decades after the discovery of the disease causing gene survival motor neuron 1, many therapeutic options for SMA have been developed, some of which made it to clinical trials but could not prove their promising experimental results. Recently, big research efforts from academia, government and the pharmaceutical industry have led to the development of highly promising compounds that are currently in clinical trials, and which could lead to feasible treatment options in the future.     

Sustained remission of multi-line relapsed extranodal NK/T-cell lymphoma,nasal type,following sintilimab and chidamide: A case report

Introduction:There is currently no optimal treatment modality for refractory or relapsed Extranodal NK/T-cell lymphoma, nasal type (ENKTL). In recent years, programmed cell death protein 1 (PD-1)/programmed cell – ligand 1 pathway blockade and histone deacetylase inhibitors have emerged as promising strategies for refractory or relapsed ENKTL. Accumulating evidence has shown that therapeutic effects of anti-PD-1 antibody could be enhanced by histone deacetylase inhibitors.Patient Concerns:A 52-year-old male patient was diagnosed with stage I ENKTL by biopsy on February 2010.Diagnosis:positron emission tomography–computed tomography (PET-CT) and biopsy were used to diagnose relapsed ENKTL in 2014.Interventions:The patient was treated with radiotherapy and six cycles of etoposide, prednisone, vincristine (Oncovin), cyclophosphamide and doxorubicin hydrochloride and achieved complete remission (CR) by PET-CT in August 2010. In November 2014, the patient was diagnosed with relapsed stage IV ENKTL and was treated with six cycles of alternative chemotherapy with the regimen of steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide and pegaspargase plus Gemcitabine, Oxaliplatin along with radiotherapy. The patient achieved remission and was placed on thalidomide maintenance treatment. Upon suspicion of relapse suggested by PET-CT, Autologous stem cell transplant was performed after BCNU, etoposide, Ara-C, and melphalan preconditioning on February 2016. Following relapse again in December 2016, the lesions of left femur were treated with radiotherapy and he received anti-PD-1 antibody. He was treated with 4 cycles of pegaspargase plus Gemcitabine, Oxaliplatin on August 2017. The patient''s condition improved. He received maintenance and consolidation therapy including lenalidomide, radiotherapy of the right nasal cavity and paranasal sinuses and antigen-specific reactive T cell infusions. PET-CT imaging showed there was high metabolic activity signal in the distal end of right femoral on August 2018 and the treatment regimen was adjusted to radiotherapy of the distal end of right femoral and systemic treatment of PD-1 antibody Sintilimab and chidamide 30 mg. After 5 months post-treatment, biopsy of nasopharynx showed no lymphoma cells. The patient continued the treatment of Sintilimab and chidamide 20 mg.Outcomes:PET-CT imaging showed his lesions obtained remission after 8 months post-treatment.Conclusion:Thus, combination of sintilimab and chidamide can be used to treat relapsed ENKTL following treatment failure from chemo-, radio-, and immuno-therapy. A clinical trial has been launched.     

Novel oral histone deacetylase inhibitor,MPT0E028, displays potent growth-inhibitory activity against human B-cell lymphoma in vitro and in vivo

Histone deacetylase (HDAC) inhibitor has been a promising therapeutic option in cancer therapy due to its ability to induce growth arrest, differentiation, and apoptosis. In this study, we demonstrated that MPT0E028, a novel HDAC inhibitor, reduces the viability of B-cell lymphomas by inducing apoptosis and shows a more potent HDAC inhibitory effect compared to SAHA, the first HDAC inhibitor approved by the FDA. In addition to HDACs inhibition, MPT0E028 also possesses potent direct Akt targeting ability as measured by the kinome diversity screening assay. Also, MPT0E028 reduces Akt phosphorylation in B-cell lymphoma with an IC₅₀ value lower than SAHA. Transient transfection assay revealed that both targeting HDACs and Akt contribute to the apoptosis induced by MPT0E028, with both mechanisms functioning independently. Microarray analysis also shows that MPT0E028 may regulate many oncogenes expression (e.g., TP53, MYC, STAT family). Furthermore, in vivo animal model experiments demonstrated that MPT0E028 (50–200 mg/kg, po, qd) prolongs the survival rate of mice bearing human B-cell lymphoma Ramos cells and inhibits tumor growth in BJAB xenograft model. In summary, MPT0E028 possesses strong in vitro and in vivo activity against malignant cells, representing a potential therapeutic approach for cancer therapy.     

Arginine bioavailability and endothelin-1 system in the regulation of vascular function of umbilical vein endothelial cells from intrauterine growth restricted newborns

Background and aims

Intrauterine growth restriction (IUGR) is a major risk factor for perinatal morbidity and mortality, leading to long-term adverse cardiovascular outcomes. The present study aimed to investigate the potential mechanisms in IUGR-associated vascular endothelial dysfunction.

组蛋白修饰与干扰素γ应答基因调控的关系

目的应用染色质免疫沉淀技术研究组蛋白修饰与干扰素γ应答基因调控的关系。方法用实时定量聚合酶链反应对Hela细胞中干扰素γ诱导蛋白-10（IP—10）的mRNA水平进行定量检测，用染色质免疫沉淀技术结合实时定量聚合酶链反应对IP—10基因调控区的组蛋白乙酰化水平进行定量检测。结果干扰素γ可以诱导IP—10活化，使其mRNA水平显著升高，随着IP-10基因的激活，其调控区干扰素刺激应答元件位点的组蛋白H4发生了去乙酰化，组蛋白去乙酰化酶抑制剂可抑制或阻断这两种变化。结论组蛋白去乙酰化酶引起的组蛋白H4去乙酰化与干扰素γ激活IP—10基因有关。