Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.

A Role for the Bone Marrow Microenvironment in Drug Resistance of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease with a poor prognosis and remarkable resistance to chemotherapeutic agents. Understanding resistance mechanisms against currently available drugs helps to recognize the therapeutic obstacles. Various mechanisms of resistance to chemotherapy or targeted inhibitors have been described for AML cells, including a role for the bone marrow niche in both the initiation and persistence of the disease, and in drug resistance of the leukemic stem cell (LSC) population. The BM niche supports LSC survival through direct and indirect interactions among the stromal cells, hematopoietic stem/progenitor cells, and leukemic cells. Additionally, the BM niche mediates changes in metabolic and signal pathway activation due to the acquisition of new mutations or selection and expansion of a minor clone. This review briefly discusses the role of the BM microenvironment and metabolic pathways in resistance to therapy, as discovered through AML clinical studies or cell line and animal models.

Anti-angiogenic Properties of Bevacizumab Improve Respiratory System Inflammation in Ovalbumin-Induced Rat Model of Asthma.

Studies on the bronchial vascular bed have revealed that the number of blood vessels in the lamina propria and under the mucosa of the lung tissue increases in patients suffering from mild to severe asthma. Thus, in this study, a new strategy was employed in respiratory system disorders by angiogenesis inhibition in an ovalbumin (OVA)-induced rat model of asthma. Twenty-one male Wistar albino rats, 8 weeks old, were randomly divided into three groups (n = 7 in each group), including (1) control group, (2) OVA-treated group, and (3) OVA + Bmab (bevacizumab drug). On days 1 and 8, 1 mg of OVA and aluminum hydroxide in sterile phosphate-buffered saline (PBS) were intraperitoneally injected to rats in groups 2 and 3. The control group was only subject to intraperitoneal injection of saline on days 1 and 8. One week after the last injection, the rats (groups 2 and 3) were exposed to OVA inhalation for 30 min at 2-day intervals from days 15 to 25. After sensitization and challenge with OVA, the OVA + Bmab group (group 3) were treated with a 5 mg/kg bevacizumab drug. Genes and protein expression of IL-1ß and TNF-α and the expression of vascular endothelial growth factor (VEGF) protein were assessed by real-time PCR and immunohistochemistry respectively, in lung tissue. OVA exposure increased mucosal secretion and inflammatory cell populations in lung tissue and OVA-specific IgE level in serum. Also, VEGF and cytokine factor expression were significantly elevated in the OVA-induced asthma model (p ≤ 0.05). However, rats in OVA + Bmab group showed significantly a decrease in VEGF and IL-1ß and TNF-α genes as well as proteins (p ≤ 0.05). The results showed that bevacizumab efficiently diminished bronchial inflammation via downregulation of VEGF expression, followed by inflammatory cells population and cytokines reduction. Angiogenesis inhibition in rats with induced asthma not only suppresses the inflammatory process through blocking VEGF expression but also inhibits the development of new blood vessels and progressing asthmatic attacks.

Bevacizumab regulates inflammatory cytokines and inhibits VEGFR2 signaling pathway in an ovalbumin-induced rat model of airway hypersensitivity.

BACKGROUND: Bevacizumab with anti-angiogenesis properties reduces the vascular endothelial growth factor (VEGF) level and has widely been used to treat various diseases such as lung diseases and chronic obstructive pulmonary disease (COPD). This study, therefore, aimed to consider the effects of bevacizumab on VEGF receptor 2 (VEGFR2) and lung inflammation of the ovalbumin-induced rat model of airway hypersensitivity. MATERIALS AND METHODS: Twenty-one male Wistar rats were randomly divided into 3 groups (n = 7 in each group): (1) control, (2) ovalbumin (OVA)-sensitized, and (3) OVA-sensitized with bevacizumab (OVA + Bmab). Groups 2 and 3 were sensitized with ovalbumin (OVA) and aluminum hydroxide on days 1, 8 and challenged with OVA on day 15 by atomization for 10 days (inhalation). After OVA sensitization, the OVA + Bmab was treated with bevacizumab for 2 weeks. VEGFR2 was semiquantitatively analyzed in the lungs by immunohistochemistry. VEGF was measured in the lung tissue by ELISA method. The mRNA of IL-10 and IL-6 lung tissue were measured by real-time PCR. RESULTS: Ovalbumin exposure promoted the expression of VEGF and resulted in inflammatory factors overexpression (p ≤ 0.05). However, rats in OVA + Bmab group showed significantly a decrease in VEGFR2 and IL-1ß, IL-6, TNFα, and an increase in IL-10 (p ≤ 0.05). CONCLUSION: The results show that bevacizumab efficiently diminishes bronchial inflammation via reducing the expression of VEGFR2, and IL-6 genes and enhancing the expression of IL-10 gene. Hence, bevacizumab could be considered as a potential candidate drug to control pathological conditions relevant to airway hypersensitivity.