Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature;mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form...Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature;mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging;a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.展开更多
Hepatocellular carcinoma(HCC)is the most frequent primary liver tumor worldwide and,despite regional therapeutic and diagnostic differences,it stands among the three most lethal cancers found in humans.Resection or ab...Hepatocellular carcinoma(HCC)is the most frequent primary liver tumor worldwide and,despite regional therapeutic and diagnostic differences,it stands among the three most lethal cancers found in humans.Resection or ablative treatments,together with liver transplant,are the most successful clinical approaches,frequently ensuring complete HCC healing and the best survival rates.However,curative techniques are applicable only in patients at early stages of the disease(limits:one nodule≤5 cm in diameter or not more than three nodules all less than 3 cm in diameter).1 A significant percentage of HCC patients(≥50%)have a more advanced stage at diagnosis and must rely on less effective treatment or palliative care,thus signifying the need for alternative systemic therapies.Sorafenib,a tyrosine kinase inhibitor(TKI)was the first effective HCC drug treatment discovered after negative results were obtained with canonical cytotoxic chemotherapy.In 2018 lenvatinib,another TKI,was approved in the USA as a first line treatment for HCC.Recently immunotherapy combining the checkpoint inhibitor,atezolizumab with the VEGF-antibody bevacizumab,has improved survival rates compared with previous TKI-based monotherapies.2 Despite treatment improvements,1-year survival is attained by only two-thirds of patients,thus prompting investigation of more effective therapies for advanced stage HCC.展开更多
基金Indiana University Collaborative Research GrantIndiana Clinical and Translational Sciences Institute,No.NIH UL1TR001108,No.NIH R01 AR069657,No.NIH R01AR060863 and No.NIH R01AG060621
文摘Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature;mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging;a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.
基金supported by the Hickam Endowed Chair,Gastroenterology,Medicine,Indiana University,the Indiana University Health to Dr Alpini,and the Indiana University School of Medicine Strategic Research Initiative to Drs Alpini and Francis and the Senior Career Scientist Award(IK6 BX004601)to Dr Alpinithe Career Scientist Award(IK6BX005226)to Dr Francis.
文摘Hepatocellular carcinoma(HCC)is the most frequent primary liver tumor worldwide and,despite regional therapeutic and diagnostic differences,it stands among the three most lethal cancers found in humans.Resection or ablative treatments,together with liver transplant,are the most successful clinical approaches,frequently ensuring complete HCC healing and the best survival rates.However,curative techniques are applicable only in patients at early stages of the disease(limits:one nodule≤5 cm in diameter or not more than three nodules all less than 3 cm in diameter).1 A significant percentage of HCC patients(≥50%)have a more advanced stage at diagnosis and must rely on less effective treatment or palliative care,thus signifying the need for alternative systemic therapies.Sorafenib,a tyrosine kinase inhibitor(TKI)was the first effective HCC drug treatment discovered after negative results were obtained with canonical cytotoxic chemotherapy.In 2018 lenvatinib,another TKI,was approved in the USA as a first line treatment for HCC.Recently immunotherapy combining the checkpoint inhibitor,atezolizumab with the VEGF-antibody bevacizumab,has improved survival rates compared with previous TKI-based monotherapies.2 Despite treatment improvements,1-year survival is attained by only two-thirds of patients,thus prompting investigation of more effective therapies for advanced stage HCC.
