The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance

It has been recently shown that increased oxidative phosphorylation, as reflected by increased mitochondrial activity, together with impairment of the mitochondrial stress response, can severely compromise hematopoietic stem cell (HSC) regeneration. Here we show that the NAD(+)-boosting agent nicotinamide riboside (NR) reduces mitochondrial activity within HSCs through increased mitochondrial clearance, leading to increased asymmetric HSC divisions. NR dietary supplementation results in a significantly enlarged pool of progenitors, without concurrent HSC exhaustion, improves survival by 80%, and accelerates blood recovery after murine lethal irradiation and limiting-HSC transplantation. In immune-deficient mice, NR increased the production of human leucocytes from hCD34+ progenitors. Our work demonstrates for the first time a positive effect of NAD(+)-boosting strategies on the most primitive blood stem cells, establishing a link between HSC mitochondrial stress, mitophagy, and stem-cell fate decision, and unveiling the potential of NR to improve recovery of patients suffering from hematological failure including post chemo- and radiotherapy.Peer reviewe

Pelvic Chondrosarcoma Treated by En Bloc Resection with Patient-Specific Osteotomy Guides and Reimplantation of the Extracorporeally Irradiated Bone as an Osseocartilaginous Structural Orthotopic Autograft: A Report of Two Cases with Description of the Surgical Technique

Primary tumors of the pelvis are considered difficult to treat due to the complex anatomy and the proximity of important neurovascular structures. The surgical armamentarium for the treatment of these tumors has evolved with the help of cutting-edge technology from debilitating hemipelvectomies to solutions such as precise resections guided by patient-specific instruments or computer navigation and reconstruction by modular prostheses, 3D-printed custom-made implants, or orthotopic autograft reimplantation after extracorporeal irradiation. Different combinations of these techniques have been described in the literature with various rates of success. We present two cases of pelvic chondrosarcomas successfully treated by a combination of periacetabular resection with patient-specific osteotomy guides and orthotopic reimplantation of the extracorporeally irradiated autograft resulting in retention of the native hip

Pelvic Chondrosarcoma Treated by En Bloc Resection with Patient-Specific Osteotomy Guides and Reimplantation of the Extracorporeally Irradiated Bone as an Osseocartilaginous Structural Orthotopic Autograft: A Report of Two Cases with Description of the Surgical Technique

Primary tumors of the pelvis are considered difficult to treat due to the complex anatomy and the proximity of important neurovascular structures. The surgical armamentarium for the treatment of these tumors has evolved with the help of cutting-edge technology from debilitating hemipelvectomies to solutions such as precise resections guided by patient-specific instruments or computer navigation and reconstruction by modular prostheses, 3D-printed custom-made implants, or orthotopic autograft reimplantation after extracorporeal irradiation. Different combinations of these techniques have been described in the literature with various rates of success. We present two cases of pelvic chondrosarcomas successfully treated by a combination of periacetabular resection with patient-specific osteotomy guides and orthotopic reimplantation of the extracorporeally irradiated autograft resulting in retention of the native hip

Life or limb: an international qualitative study on decision making in sarcoma surgery during the COVID-19 pandemic

Objectives The COVID-19 pandemic is unprecedented as a global crisis over the last century. How do specialist surgeons make decisions about patient care in these unprecedent times? Design Between April and May 2020, we conducted an international qualitative study. Sarcoma surgeons from diverse global settings participated in 60 min interviews exploring surgical decision making during COVID-19. Interview data were analysed using an inductive thematic analysis approach. Setting Participants represented public and private hospitals in 14 countries, in different phases of the first wave of the pandemic: Australia, Argentina, Canada, India, Italy, Japan, Nigeria, Singapore, Spain, South Africa, Switzerland, Turkey, UK and USA. Participants From 22 invited sarcoma surgeons, 18 surgeons participated. Participants had an average of 19 years experience as a sarcoma surgeon. Results 17/18 participants described a decision they had made about patient care since the start of the pandemic that was unique to them, that is, without precedence. Common to 'unique' decisions about patient care was uncertainty about what was going on and what would happen in the future (theme 1: the context of uncertainty), the impact of the pandemic on resources or threat of the pandemic to overwhelm resources (theme 2: limited resources), perceived increased risk to self (theme 3: duty of care) and least-worst decision making, in which none of the options were perceived as ideal and participants settled on the least-worst option at that point in time (theme 4: least-worst decision making). Conclusions In the context of rapidly changing standards of justice and beneficence in patient care, traditional decision-making frameworks may no longer apply. Based on the experiences of surgeons in this study, we describe a framework of least-worst decision making. This framework gives rise to actionable strategies that can support decision making in sarcoma and other specialised fields of surgery, both during the current crisis and beyond.Australian National Health and Medical Research Council Practitioner Fellowship [APP1154203]This work was supported by an Australian National Health and Medical Research Council Practitioner Fellowship held by PFMC (APP1154203). All authors were independent from funders, and all authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis

Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems

Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias) <sup>1,2</sup> . These processes are accompanied by an aberrant accumulation of mitochondria in HSCs <sup>3</sup> . The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of 'old' HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems