Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia

Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative capacity and low intracellular ATP resulting from abnormal mitochondrial function were described. : The present study aimed at evaluating the ability of the mitochondria-targeted compound SS-31 to counteract muscle wasting and altered metabolism in C26-bearing (C26) mice either receiving chemotherapy (OXFU: oxaliplatin plus 5-fluorouracil) or not. : Mitochondrial dysfunction in C26-bearing (C26) mice associated with alterations of cardiolipin fatty acid chains. Selectively targeting cardiolipin with SS-31 partially counteracted body wasting and prevented the reduction of glycolytic myofiber area. SS-31 prompted muscle mitochondrial succinate dehydrogenase (SDH) activity and rescued intracellular ATP levels, although it was unable to counteract mitochondrial protein loss. Progressively increased dosing of SS-31 to C26 OXFU mice showed transient (21 days) beneficial effects on body and muscle weight loss before the onset of a refractory end-stage condition (28 days). At day 21, SS-31 prevented mitochondrial loss and abnormal autophagy/mitophagy. Skeletal muscle, liver and plasma metabolomes were analyzed, showing marked energy and protein metabolism alterations in tumor hosts. SS-31 partially modulated skeletal muscle and liver metabolome, likely reflecting an improved systemic energy homeostasis. : The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabolism for the prevention of cancer cachexia. With this in mind, prospective multi-modal therapies including SS-31 are warranted

Targeting mitochondria by ss-31 ameliorates the whole body energy status in cancer-and chemotherapy-induced cachexia

Objective: Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative ca-pacity and low intracellular ATP resulting from abnormal mitochondrial function were described. Methods: The present study aimed at evaluating the ability of the mitochondria-targeted compound SS-31 to counteract muscle wasting and altered metabolism in C26-bearing (C26) mice either receiv-ing chemotherapy (OXFU: oxaliplatin plus 5-fluorouracil) or not. Results: Mitochondrial dysfunction in C26-bearing (C26) mice associated with alterations of cardiolipin fatty acid chains. Selectively targeting cardiolipin with SS-31 partially counteracted body wasting and prevented the reduction of glycolytic myofiber area. SS-31 prompted muscle mitochondrial succinate dehydrogenase (SDH) activity and rescued intracellular ATP levels, although it was unable to counteract mitochondrial protein loss. Progressively increased dosing of SS-31 to C26 OXFU mice showed transient (21 days) beneficial effects on body and muscle weight loss before the onset of a refractory end-stage condi-tion (28 days). At day 21, SS-31 prevented mitochondrial loss and abnormal autophagy/mitophagy. Skeletal muscle, liver and plasma metabolomes were analyzed, showing marked energy and protein metabolism alterations in tumor hosts. SS-31 partially modulated skeletal muscle and liver metab-olome, likely reflecting an improved systemic energy homeostasis. Conclusions: The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabo-lism for the prevention of cancer cachexia. With this in mind, prospective multi-modal therapies including SS-31 are warranted

Is there a relationship between weather conditions and aortic dissection?

BACKGROUND: Bleeding and rupture of blood vessels has been correlated with weather conditions in the past. This is the first study in the world literature with the aim of investigating the relationship between atmospheric pressure and temperature with the presentation of aortic dissection. METHODS: The dates of all emergency aortic dissection repairs from 1996–2002 in a regional cardiothoracic unit at Blackpool Victoria Hospital were obtained. Hourly temperature and pressure data from a regional weather station for this time period was supplied by the Meteorological Office. The mean and standard deviation of hourly temperature and pressure data for that month were compared to the mean and standard deviation of the data 24 and 48 hours prior to the aortic dissection. RESULTS: 26 patients were found to have been operated on during the time period studied. There was no statistically significant correlation between temperature or atmospheric pressure readings, and the incidence of aortic dissection, using a Bonferonni-corrected significance p-value of 0.005 CONCLUSION: This study is the first to examine the relationship between atmospheric pressure, temperature and dissecting thoracic aorta. No statistically significant relationship was demonstrable

IKKα Is a p63 Transcriptional Target Involved in the Pathogenesis of Ectodermal Dysplasias

The transcription factor p63 plays a pivotal role in the development and differentiation of the epidermis and epithelial appendages. Indeed, mutations in p63 are associated with a group of ectodermal dysplasias characterized by skin, limb, and craniofacial defects. It was hypothesized that p63 exerts its functions by activating specific genes during epidermal development, which in turn regulate epidermal stratification and differentiation. We have identified I-kappaB kinase alpha (IKKα) as a direct transcriptional target of p63 that is induced at early phases of terminal differentiation of primary keratinocytes. We show that the ΔNp63 isoform is required for IKKα expression in differentiating keratinocytes and that mutant p63 proteins expressed in ectodermal dysplasia patients exhibit defects in inducing IKKα. Furthermore, we observed reduced IKKα expression in the epidermis of an ankyloblepharon ectodermal dysplasia clefting patient. Our data demonstrate that a failure to properly express IKKα may play a role in the development of ectodermal dysplasias

Incidence and outcome of infections after unrelated cord blood transplantation in patients with hematological malignancies: a long-term single center experience

Introduction: Unrelated cord blood (UCB) has become an alternative stem cell source for patients with hematological malignancies requiring allogeneic transplantation and lacking a HLA-matched donor. Infections after an UCB transplantation (UCBT) represent a leading cause of morbidity and mortality. The aim of this study was to evaluate the incidence, risk factors and outcome of infections occurring after an UCBT. Materials (or patients) and methods: We performed a retrospective study in 75 patients who received a UCBT at our center between July 1995 and July 2013: there were 51 children (median age 9 years, range 1-17) and 24 adults (median age 28 years, range 18-60). Patients were affected by high risk hematological malignancies: 22 had acute myeloid leukemia, 47 acute lymphoblastic leukemia and 6 chronic myeloid leukemia. All patients received a myeloablative conditioning regimen, in vivo T-cell depletion with antilymphocyte serum, and cyclosporine plus corticosteroid as GVHD prophylaxis. Fluconazole, acyclovir and ciprofloxacin were administered as prophylaxis for fungal, viral and bacterial infections, respectively. All patients underwent CMV antigenemia or DNAemia monitoring, while EBV DNAemia monitoring was performed since 2002 for the last 40 patients. Results: The incidences of bacteremia, proven/probable invasive fungal diseases (IFD), CMV infection, EBV infection and herpes zoster disease were 88%, 21%, 61%, 20% and 17% of transplants, respectively. Out of 80 bacterial isolates, 44% were Gram negative and 56% Gram positive. IFDs were caused by filamentous fungi in 62% of cases. Gastrointestinal CMV disease was documented in 4% of patients with virus infection. Out of 8 patients with EBV infection, 3 developed a posttransplant lymphoproliferative disorder (PTLD) (fatal in 2 cases). The distribution of the infections in the early (days 1- 40 from transplant), late (days 41- 100), very late (days 101 - 365) phases and after day 365 are detailed in Figure 1. Bacterial, fungal and CMV infections were documented mainly during the early engraftment phase, while EBV and herpes zoster infections were generally documented after day 100. The duration of pre-engraftment neutropenia did not correlate significantly with an increased infectious risk. Grade II-IV acute GVHD was significantly predictive of the development of an IFD (HR 0.28; IC: 0.09 – 0.87; P¼0.029). At a median follow-up of 10 years, 30 of 75 (40%) patients are still alive. Infections represented the primary cause of death in 24% of patients. The attributable mortality rate for bacterial and fungal infections accounted for 4.5% and 31%, respectively. Conclusion: Our study confirms the high rate of infectious complications occurring after an UCBT. In agreement with other experiences, the early engraftment phase represented the period at higher risk of bacterial, fungal and CMV infections. After this time period, a moderate risk of developing IFDs persists up to 6 months, especially in patients with GVHD. Infections by viruses other than CMV have been more frequently documented after the very late phase posttransplant. These epidemiological findings should be considered for the definition of tailored anti-fungal prophylaxis and virological pre-emptive strategies. Disclosure of Interest: None declared