Translational research : the journal of laboratory and clinical medicine
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Secondary lymphedema is a common complication of cancer treatment resulting in progressive fibroadipose tissue deposition, increased risk of infections, and, in rare cases, secondary malignancies. Until recently, the pathophysiology of secondary lymphedema was thought to be related to impaired collateral lymphatic formation after surgical injury. ⋯ In this review, we will discuss the evidence supporting this hypothesis and summarize recent publications demonstrating that lymphatic injury activates chronic immune responses that promote fibrosis and lymphatic leakiness, decrease collecting lymphatic pumping, and impair collateral lymphatic formation. We will review how chronic mixed T-helper cell inflammatory reactions regulate this process and how this response may be used to design novel therapies for lymphedema.
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Radiation-induced pulmonary fibrosis (RIPF) is a serious treatment complication that affects about 9%-30% cancer patients receiving radiotherapy for thoracic tumors. RIPF is characterized by progressive and irreversible destruction of lung tissues and deterioration of lung function, which can compromise quality of life and eventually lead to respiratory failure and death. ⋯ Recently, an increasing body of evidence suggests that induction of senescence by radiation may play an important role in RIPF and clearance of senescent cells (SnCs) with a senolytic agent, small molecule that can selectively kill SnCs, has the potential to be developed as a novel therapeutic strategy for RIPF. This review discusses some of these new findings to promote further study on the role of cellular senescence in RIPF and the development of senolytic therapeutics for RIPF.
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Pulmonary fibrosis refers to the development of diffuse parenchymal abnormalities in the lung that cause dyspnea, cough, hypoxemia, and impair gas exchange, ultimately leading to respiratory failure. Though pulmonary fibrosis can be caused by a variety of underlying etiologies, ranging from genetic defects to autoimmune diseases to environmental exposures, once fibrosis develops it is irreversible and most often progressive, such that fibrosis of the lung is one of the leading indications for lung transplantation. This review aims to provide a concise summary of the recent advances in our understanding of the genetics and genomics of pulmonary fibrosis, idiopathic pulmonary fibrosis in particular, and how these recent discoveries may be changing the clinical approach to diagnosing and treating patients with fibrotic interstitial lung disease.
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Prader-Willi syndrome (PWS) is a complex and multisystem neurobehavioral disorder. The molecular mechanism of PWS is deficiency of paternally expressed gene gene or genes from the chromosome 15q11-q13. Due to imprinted gene regulation, the same genes in the maternal chromosome 15q11-q13 are structurally intact but transcriptionally repressed by an epigenetic mechanism. ⋯ High content screening of small molecule libraries using cells derived from transgenic mice carrying the SNRPN-EGFP fusion protein has discovered that inhibitors of EHMT2/G9a, a histone 3 lysine 9 methyltransferase, are capable of reactivating expression of paternally expressed SNRPN and SNORD116 from the maternal chromosome, both in cultured PWS patient-derived fibroblasts and in a PWS mouse model. Treatment with an EMHT2/G9a inhibitor also rescues perinatal lethality and failure to thrive phenotypes in a PWS mouse model. These findings present the first evidence to support a proof-of-principle for epigenetic-based therapy for the PWS in humans.
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Prostate cancer growth is controlled by androgen receptor signaling via both androgen-dependent and androgen-independent pathways. Furthermore, the prostate is an immune competent organ with inflammatory changes both within the systemic and local environment contributing to the reprogramming of the prostatic epithelium with consistently elevated lymphocyte infiltration and proinflammatory cytokines being found in prostate cancer. ⋯ However, despite an increase in immune checkpoint inhibitors and inflammatory signaling blockades available for a range of cancer types, we are yet to see substantial progress in the treatment of prostate cancer. Therefore, this review aims to summarize the tumor microenvironment and its impact on androgen receptor signaling in prostate cancer.