Project description:Crimean-Congo hemorrhagic fever (CCHF) is the most prevalent tick-borne viral disease affecting humans. The disease is life-threatening in many regions of the developing world, including Africa, Asia, the Middle East, and Southern Europe. In line with the rapidly increasing disease prevalence, various vaccine strategies are under development. Despite a large number of potential vaccine candidates, there are no approved vaccines as of yet. This paper presents a detailed comparative analysis of current efforts to develop vaccines against CCHFV, limitations associated with current efforts, and future research directions.
Project description:Cancer represents a significant and persistent global health burden, with its impact underscored by its prevalence and devastating consequences. Whereas numerous oncogenes could contribute to cancer development, a group of transcription factors (TFs) are overactive in the majority of tumors. Targeting these TFs may also combat the downstream oncogenes activated by the TFs, making them attractive potential targets for effective antitumor therapeutic strategy. One such TF is yin yang 1 (YY1), which plays crucial roles in the development and progression of various tumors. In preclinical studies, YY1 inhibition has shown efficacy in inhibiting tumor growth, promoting apoptosis, and sensitizing tumor cells to chemotherapy. Recent studies have also revealed the potential of combining YY1 inhibition with immunotherapy for enhanced antitumor effects. However, clinical translation of YY1-targeted therapy still faces challenges in drug specificity and delivery. This review provides an overview of YY1 biology, its role in tumor development and progression, as well as the strategies explored for YY1-targeted therapy, with a focus on their clinical implications, including those using small molecule inhibitors, RNA interference, and gene editing techniques. Finally, we discuss the challenges and current limitations of targeting YY1 and the need for further research in this area.
Project description:Transfusional iron overload is a major target in the care of patients with transfusion-dependent thalassemia (TDT) and other refractory anemias. Iron accumulates in the liver, heart, and endocrine organs leading to a wide array of complications. In this review, we summarize the characteristics of the approved iron chelators, deferoxamine, deferiprone, and deferasirox, and the evidence behind the use of each, as monotherapy or as part of combination therapy. We also review the different guidelines on iron chelation in TDT. This review also discusses future prospects and directions in the treatment of transfusional iron overload in TDT whether through innovation in chelation or other therapies, such as novel agents that improve transfusion dependence.
Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic disease in which the lungs become irreversibly scarred, leading to declining lung function. As currently available drugs do not cure IPF, there remains a great medical need for more effective treatments. Perhaps this need could be addressed by gene therapies, which offer powerful and versatile ways to attenuate a wide range of processes involved in fibrosis. Despite the potential benefits of gene therapy, no one has reviewed the current state of knowledge regarding its application for treating IPF. We therefore analyzed publications that reported the use of gene therapies to treat pulmonary fibrosis in animals, as clinical studies have not been published yet. In this review, we first provide an introduction on the pathophysiology of IPF and the most well-established gene therapy approaches. We then present a comprehensive evaluation of published animal studies, after which we provide recommendations for future research to address challenges with respect to the selection and use of animal models as well as the development of delivery vectors and dosage forms. Addressing these considerations will bring gene therapies one step closer to clinical testing and thus closer to patients.
Project description:An understanding of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways has greatly changed the way metastatic renal cell carcinoma (RCC) is treated. Based on available phase III randomized trials, anti-VEGF agents such as sunitinib, sorafenib, bevacizumab-based therapy, and mTOR-targeted agents such as temsirolimus and everolimus have been used in the treatment armamentarium for this disease. Now that agents directed against these pathways have largely replaced immunotherapy as the standard of care, new questions have emerged and are the subject of ongoing clinical trials. The development of new targeted therapies including axitinib, pazopanib, cediranib, volociximab, tivozanib (AV-951), BAY 73-4506, and c-met inhibitors such as GSK1363089 and ARQ197 may potentially expand the list of treatment options. Sequential and combination targeted therapies are currently under investigation in advanced disease as are adjuvant and neo-adjuvant approaches around nephrectomy.
Project description:An understanding of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways has greatly changed the way metastatic renal cell carcinoma (RCC) is treated. Based on available phase III randomized trials, anti-VEGF agents such as sunitinib, sorafenib, bevacizumab-based therapy, and mTOR-targeted agents such as temsirolimus and everolimus have been used in the treatment armamentarium for this disease. Now that agents directed against these pathways have largely replaced immunotherapy as the standard of care, new questions have emerged and are the subject of ongoing clinical trials. The development of new targeted therapies including axitinib, pazopanib, cediranib, volociximab, tivozanib (AV-951), BAY 73-4506, and c-met inhibitors such as GSK1363089 and ARQ197 may potentially expand the list of treatment options. Sequential and combination targeted therapies are currently under investigation in advanced disease as are adjuvant and neo-adjuvant approaches around nephrectomy.
Project description:Stem cells have been part of the biomedical landscape since the early 1960s. However, the translation of stem cells to effective therapeutics have met significant challenges, especially for retinal diseases. The retina is a delicate and complex architecture of interconnected cells that are steadfastly interdependent. Degenerative mechanisms caused by acquired or inherited diseases disrupt this interconnectivity, devastating the retina and causing severe vision loss in many patients. Consequently, retinal differentiation of exogenous and endogenous stem cells is currently being explored as replacement therapies in the debilitating diseases. In this review, we will examine the mechanisms involved in exogenous stem cells differentiation and the challenges of effective integration to the host retina. Furthermore, we will explore the current advancements in trans-differentiation of endogenous stem cells, primarily Müller glia.
Project description:Internal tandem duplications (ITDs) of the gene encoding the Fms-Like Tyrosine kinase-3 (FLT3) receptor are present in approximately 25% of patients with acute myeloid leukemia (AML). The mutation is associated with poor prognosis, and the aberrant protein product has been hypothesized as an attractive therapeutic target. Various tyrosine kinase inhibitors (TKIs) have been developed targeting FLT3, but in spite of initial optimism the first generation TKIs tested in clinical studies generally induce only partial and transient hematological responses. The limited treatment efficacy generally observed may be explained by numerous factors; extensively pretreated and high risk cohorts, suboptimal pharmacodynamic and pharmacokinetic properties of the compounds, acquired TKI resistance, or the possible fact that inhibition of mutated FLT3 alone is not sufficient to avoid disease progression. The second-generation agent quizartinb is showing promising outcomes and seems better tolerated and with less toxic effects than traditional chemotherapeutic agents. Therefore, new generations of TKIs might be feasible for use in combination therapy or in a salvage setting in selected patients. Here, we sum up experiences so far, and we discuss the future outlook of targeting dysregulated FLT3 signaling in the treatment of AML.
Project description: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.
Project description:Neurofibromatosis type 1 (NF1) is a life-long neurocutaneous disorder characterized by a predisposition to tumor development, including cutaneous neurofibroma (cNF), the hallmark of the disease. cNF is a histologically benign, multicellular tumor formed in virtually most individuals with NF1. It is considered the most burdensome feature of the disorder due to their physical discomfort, cosmetically disfiguring appearance, and psychosocial burden. Management of cNF remains a challenge in the medical field. Effective medicinal treatment for cNF does not exist at this time. Trials aimed at targeting individual components of the neoplasm such as mast cells with Ketotifen have not shown much success. Physical removal or destruction has been the mainstay of therapy. Surgical removal gives excellent cosmetic results, but risk in general anesthesia may require trained specialists. Destructive laser such as CO2 laser is effective in treating hundreds of tumors at one time but has high risk of scarring hypopigmentation or hyperpigmentation that alter cosmetic outcomes. A robust, low-risk surgical technique has been developed, which may be performed in clinic using traditional biopsy tools that may be more accessible to NF1 patients worldwide than contemporary techniques including Er:YAG or Nd:YAG laser. In this review, specific recommendations for management of cNFs are made based on symptoms, clinical expertise, and available resources. Additionally, antiproliferative agents aimed at stimulating cellular quiescence are explored.