Synergistic activity of combined inhibition of anti-apoptotic molecules in B-cell precursor ALL

Targeting BCL-2, a key regulator of survival in B-cell malignancies including precursor B-cell acute lymphoblastic leukemia, has become a promising treatment strategy. However, given the redundancy of anti-apoptotic BCL-2 family proteins (BCL-2, BCL-XL, MCL-1), single targeting may not be sufficient. When analyzing the effects of BH3-mimetics selectively targeting BCL-XL and MCL-1 alone or in combination with the BCL-2 inhibitor venetoclax, heterogeneous sensitivity to either of these inhibitors was found in ALL cell lines and in patient-derived xenografts. Interestingly, some venetoclax-resistant leukemias were sensitive to the MCL-1-selective antagonist S63845 and/or BCL-XL-selective A-1331852 suggesting functional mutual substitution. Consequently, co-inhibition of BCL-2 and MCL-1 or BCL-XL resulted in synergistic apoptosis induction. Functional analysis by BH3-profiling and analysis of protein complexes revealed that venetoclax-treated ALL cells are dependent on MCL-1 and BCL-XL, indicating that MCL-1 or BCL-XL provide an Achilles heel in BCL-2-inhibited cells. The effect of combining BCL-2 and MCL-1 inhibition by venetoclax and S63845 was evaluated in vivo and strongly enhanced anti-leukemia activity was found in a pre-clinical patient-derived xenograft model. Our study offers in-depth molecular analysis of mutual substitution of BCL-2 family proteins in acute lymphoblastic leukemia and provides targets for combination treatment in vivo and in ongoing clinical studies.

A P-61 Black Widow Inspired Palladium Biladiene Complex for Efficient Sensitization of Singlet Oxygen Using Visible Light

Photodynamic therapy (PDT) is a promising treatment option that ablates cancerous cells and tumors via photoinduced sensitization of singlet oxygen. Over the last few decades, much work has been devoted to the development of new photochemotherapeutic agents for PDT. A wide variety of macrocyclic tetrapyrrole based photosensitizers have been designed, synthesized and characterized as PDT agents. Many of these complexes have a variety of issues that pose a barrier to their use in humans, including biocompatibility, inherent toxicity, and synthetic hurdles. We have developed a non-traditional, non-cyclic, and non-aromatic tetrapyrrole ligand scaffold, called the biladiene (DMBil1), as an alternative to these traditional photosensitizer complexes. Upon insertion of a heavy atom such as Pd2+ center, Pd[DMBil1] generates singlet oxygen in substantial yields (ΦΔ = 0.54, λexc = 500 nm) when irradiated with visible light. To extend the absorption profile for Pd[DMBil1] deeper into the phototherapeutic window, the tetrapyrrole was conjugated with alkynyl phenyl groups at the 2- and 18-positions (Pd[DMBil2-PE]) resulting in a significant redshift while also increasing singlet oxygen generation (ΦΔ = 0.59, 600 nm). To further modify the dialkynyl-biladiene scaffold, we conjugated a 1,8-diethynylanthracene with to the Pd[DMBil1] tetrapyrrole in order to further extend the compound’s π-conjugation in a cyclic loop that spans the entire tetrapyrrole unit. This new compound (Pd[DMBil2-P61]) is structurally reminiscent of the P61 Black Widow aircraft and absorbs light into the phototherapeutic window (600–900 nm). In addition to detailing the solid-state structure and steady-state spectroscopic properties for this new biladiene, photochemical sensitization studies demonstrated that Pd[DMBil2-P61] can sensitize the formation of 1O2 with quantum yields of ΦΔ = 0.84 upon irradiation with light λ = 600 nm. These results distinguish the Pd[DMBil2-P61] platform as the most efficient biladiene-based singlet oxygen photosensitizer developed to date. When taken together, the improved absorption in the phototherapeutic window and high singlet oxygen sensitization efficiency of Pd[DMBil2-P61] mark this compound as a promising candidate for future study as an agent of photodynamic cancer therapy.

Replication and Spread of Oncolytic Herpes Simplex Virus in Solid Tumors

Oncolytic herpes simplex virus (oHSV) is a highly promising treatment for solid tumors. Intense research and development efforts have led to first-in-class approval for an oHSV for melanoma, but barriers to this promising therapy still exist that limit efficacy. The process of infection, replication and transmission of oHSV in solid tumors is key to obtaining a good lytic destruction of infected cancer cells to kill tumor cells and release tumor antigens that can prime anti-tumor efficacy. Intracellular tumor cell signaling and tumor stromal cells present multiple barriers that resist oHSV activity. Here, we provide a review focused on oncolytic HSV and the essential viral genes that allow for virus replication and spread in order to gain insight into how manipulation of these pathways can be exploited to potentiate oHSV infection and replication among tumor cells.

Research progress of the application of mesenchymal stem cells in chronic inflammatory systemic diseases

Chronic inflammatory systemic diseases are the result of the body's immune imbalance, with a long course and recurring episodes. Immunosuppressants are the main treatment, but not all patients respond well to it. Being capable of both self-renewal and differentiation into multiple tissue cells and low immunogenicity, mesenchymal stem cell is a promising treatment for chronic inflammatory systemic diseases. In this article, we describe the research progress and clinical application of mesenchymal stem cells in chronic inflammatory systemic diseases and look for influencing factors and biomarkers that can predict the outcome of patient with mesenchymal stem cell transplantation.

Interventional Bronchus Occlusion Using Amplatzer Devices – A Promising Treatment Option for Children with Persistent Air Leak

Background: Persistent air leak (PAL) is a severe complication of secondary spontaneous pneumothorax (SSP). Surgical interventions are usually successful when medical treatment fails, but can be associated with significant complications and loss of potentially recoverable lung parenchyma. Methods: Retrospective analysis of efficacy and safety of interventional bronchus occlusions (IBO) using Amplatzer devices (ADs) in children with PAL secondary to SSP. Results: Six patients (four males, 4–15 years of age) underwent IBO using ADs as treatment for PAL. Necrotizing pneumonia (NP) was the most common cause (n=4) of PAL. Three patients were previously healthy and three suffered from chronic lung disease. All patients required at least two chest tubes prior to the intervention for a duration of 15–43 days and all required oxygen or higher level of ventilatory support. In three cases, previous surgical interventions had been performed without success. All children improved after endobronchial intervention and we observed no associated complications. All chest tubes were removed within 5–25 days post IBO. In patients with PAL related to NP (n=4), occluders were removed bronchoscopically without re-occurrence of pneumothorax after a mean of 70 days (IQR: 46.5–94). Conclusion: IBO using ADs is a safe and valuable treatment option in children with PAL independent of disease severity and underlying cause. A major advantage of this procedure is its less invasiveness compared to surgery and the parenchyma- preserving approach.

Nanoconfined anti-oxidizing RAFT nitroxide radical polymer for reduction of Low-Density Lipoprotein oxidation

therosclerosis is a leading cause of death worldwide. Antioxidant therapy has been considered a promising treatment modality for atherosclerosis, since reactive oxygen species (ROS) play a major role in the...

Mushroom-Derived Bioactive-Based Nanoemulsion

Cancer is a class of disorders that is characterized by the abnormal growth of cells in an uncontrolled manner. In cancer progression, tumor cells have become highly heterogeneous, and they create a mixed population of cells with different molecular characteristics. The mushroom bioactive compounds have a rich biological activity including immunomodulatory, anticarcinogenic, antiviral, antioxidant, and anti-inflammatory, etc. Besides, conventional anticancer drugs and applied therapy have tremendous challenges and limitations such as poor solubility, narrow therapeutic window, cytotoxicity to normal tissues, etc., which may be the causes of treatment failure in cancer. A previous study reported mushroom bioactive compounds against cancer treatment. The chapter focuses on mushroom-derived bioactive compounds and possible implications in nanotechnology and, further, will be utilized for new advanced nanoemulsion techniques for the promising treatment of cancer.

A Promising Treatment Strategy for Lung Cancer: A Combination of Radiotherapy and Immunotherapy

Lung cancer is a leading cause of cancer-related deaths worldwide despite advances in treatment. In the past few decades, radiotherapy has achieved outstanding technical advances and is being widely used as a definitive, prophylactic, or palliative treatment of patients with lung cancer. The anti-tumor effects of radiotherapy are considered to result in DNA damage in cancer cells. Moreover, recent evidence has demonstrated another advantage of radiotherapy: the induction of anti-tumor immune responses, which play an essential role in cancer control. In contrast, radiotherapy induces an immunosuppressive response. These conflicting reactions after radiotherapy suggest that maximizing immune response to radiotherapy by combining immunotherapy has potential to achieve more effective anti-tumor response than using each alone. Immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4, programmed cell death-1/programmed death-ligand 1, and their inhibitors, have attracted significant attention for overcoming the immunosuppressive conditions in patients with cancer. Therefore, the combination of immune checkpoint inhibitors and radiotherapy is promising. Emerging preclinical and clinical studies have demonstrated the rationale for these combination strategies. In this review, we outlined evidence suggesting that combination of radiotherapy, including particle therapy using protons and carbon ions, with immunotherapy in lung cancer treatment could be a promising treatment strategy.

Gamma Knife Radiosurgery in the Management of Hypothalamic Glioma: A Case Report with Long-term Follow-up

Background Optic pathway/hypothalamic gliomas are rare pediatric brain tumors. The management paradigm for these challenging tumors includes chemotherapy, radiotherapy, or surgical resection, but the optimal management strategy remains elusive. Gamma Knife radiosurgery (GKRS) has emerged as a promising treatment for such lesions as documented by a small number of cases in the literature. Case Presentation Herein, we present a rare case of hypothalamic glioma in a 13-year-old girl who was referred to our service due to growth of a an incidentally diagnosed hypothalamic lesion following head injury at the age of 8 years. The lesion demonstrated hypointensity on T1 and hyperintensity on T2 without enhancement. Given the growth of the lesion on serial imaging, a stereotactic biopsy was performed demonstrating low-grade glioma. The patient underwent GKRS treatment with a marginal dose of 15 Gy at 50% isodose line for a tumor volume of 2.2 ml. Annual radiological surveillance over the next 17 years demonstrated a gradual shrinkage of the lesion until it completely disappeared. The patient is currently a healthy 31-year-old female without any visual, endocrine, or neurocognitive complaints. Conclusion The outcome obtained after extended follow-up in our patient highlights the safety and efficacy of GKRS in the management of hypothalamic gliomas in pediatrics, which in turn can avoid potentially serious complications of surgery in this vulnerable patient population in this sensitive location.