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Multiple System Atrophy is a severe neurodegenerative disorder which is characterized by a variable clinical presentation and a broad neuropathological spectrum. The pathogenic mechanisms are almost completely unknown. In the present study, we established a cellular model of MSA by using fibroblasts’ primary cultures and performed several experiments to investigate the causative mechanisms of the disease, with a particular focus on mitochondrial functioning. Fibroblasts’ analyses (7 MSA-P, 7 MSA-C and 6 healthy controls) displayed several anomalies in patients: an impairment of respiratory chain activity, in particular for succinate Coenzyme Q reductase (p < 0.05), and a reduction of complex II steady-state level (p < 0.01); a reduction of Coenzyme Q10 level (p < 0.001) and an up-regulation of some CoQ10 biosynthesis enzymes, namely COQ5 and COQ7; an impairment of mitophagy, demonstrated by a decreased reduction of mitochondrial markers after mitochondrial inner membrane depolarization (p < 0.05); a reduced basal autophagic activity, shown by a decreased level of LC3 II (p < 0.05); an increased mitochondrial mass in MSA-C, demonstrated by higher TOMM20 levels (p < 0.05) and suggested by a wide analysis of mitochondrial DNA content in blood of large cohorts of patients. The present study contributes to understand the causative mechanisms of Multiple System Atrophy. In particular, the observed impairment of respiratory chain activity, mitophagy and Coenzyme Q10 biosynthesis suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of the disease. Furthermore, these findings will hopefully contribute to identify novel therapeutic targets for this still incurable disorder.

© 2018 American Medical Association. All rights reserved. IMPORTANCE Studies of neoadjuvant chemotherapy regimens using anthracyclines followed by taxanes have reported a doubling of pathological complete remission (pCR) rates compared with anthracycline-based regimens alone. A reverse sequence did not reduce activity. Nab-paclitaxel is an albumin-bound nanoparticle of paclitaxel that allows for safe infusion without premedication, and its use led to a significantly higher rate of pCR in the GeparSepto trial. OBJECTIVE To determine whether nab-paclitaxel improves the outcomes of early and locally advanced human epidermal growth factor receptor 2 (ERBB2/HER2)-negative breast cancer compared with paclitaxel when delivered in a neoadjuvant setting. DESIGN, SETTING, AND PARTICIPANTS In this multicenter, open-label study, in collaboration with Grupo Español de Investigación en Cáncer de Mama (GEICAM) and Breast Cancer Research Center-Western Australia (BCRC-WA), patients with newly diagnosed and centrally confirmed ERBB2/HER2-negative breast cancer were recruited. Participants were randomly allocated to paclitaxel, 90 mg/m 2 (349 patients), or nab-paclitaxel, 125 mg/m 2 (346 patients). The 2 drugs were given on weeks 1, 2, and 3 followed by 1 week of rest for 4 cycles before 4 cycles of an anthracycline regimen per investigator choice. MAIN OUTCOMES AND MEASURES The primary end point was the rate of pCR, defined as absence of invasive cells in the breast and axillary nodes (ie, ypT0/is ypN0) at the time of surgery. A secondary end point was to assess tolerability and safety of the 2 regimens. RESULTS From May 2013 to March 2015, 814 patients were registered to the study; 695 patients met central confirmation eligibility and were randomly allocated to receive either paclitaxel (349), or nab-paclitaxel (346) (median age, 50 years; range, 25-79 years). The intention-to-treat analysis of the primary end point pCR revealed that the improved pCR rate after nab-paclitaxel (22.5

Introduction Insulin resistance (IR) is associated with polycystic ovary syndrome (PCOS). Oxidative stress (OS) is, in turn, related to IR. Studies in PCOS evidenced an increase in OS markers, but they are mainly performed in obese patients, while the complex picture of normal weight PCOS is still poorly investigated. Matherials and Methods To investigate OS in PCOS and relationship with hormonal and metabolic picture, we performed a case-control study in 2 PCOS groups: normal weight (N-PCOS, n=21, age 18-25 ys, mean±SEM BMI 20.7±0.2 kg/m2) and obese (OB-PCOS, n=15, 20-30 ys, BMI 32.8±1.1), compared with control groups matched for BMI: normal (N-C, n=10, 20-30 ys, BMI 21.6±0.9) and obese (OB-C, n=20, 21-31ys, BMI 36.8±1.0). Malondialdehyde (MDA) in blood plasma and peripheral mononuclear cells, obtained by density-gradient centrifugation, was assayed spectrophotometrically by TBARS assay. CoenzymeQ10 (CoQ10) in plasma and cells was assayed by HPLC. Plasma Total Antioxidant Capacity (TAC) was also measured by spectrophotometric method. Results PCOS patients exhibited higher Testosterone levels than controls, but OB-PCOS had highest HOMA (Homeostasis Model Assessment) index, suggesting marked insulin resistance. Despite plasma MDA levels were not significantly different (N-PCOS 3380±346.94 vs. N-C 7 120±541.66; OB-PCOS 5 517.5±853.9 vs. OB. 3 939.66±311.2 pmol/ml), intracellular MDA levels were significantly higher in N-PCOS than controls (mean 3 259±821.5 vs. 458±43.2 pmol/106/cells) and higher than OB-PCOS, although not significantly (1363.1±412.8 pmol/106/cells). Intracellular CoenzymeQ10 was higher in N-PCOS than in N-C, but the highest levels were found in OB-C. Conclusions Our data, while confirming the presence of OS in obese PCOS patients in agreement with literature, suggest that OS could be present also in normal weight PCOS, but it can be revealed in tissue rather than in plasma. The relationship with metabolic status remains to be established, but could be

A small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives was initially developed to optimize the antitrypanosomatid profile of the multitarget hit compound B6 (1). The whole series was evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and two compounds (14 and 21) showed good activity, despite a concomitant mammalian cytotoxicity. Furthermore, a subset also inhibited the glycolytic TbGAPDH enzyme in vitro. In light of these results and aware of the antitumor properties of quinones, the anticancer potential of some selected derivatives was investigated. Intriguingly, the tested compounds displayed antitumor activity, while being less toxic against noncancerous cells. The observed cytotoxic potency was ascribed to a multitarget mechanism of action accounting for hGAPDH inhibition and mitochondrial toxicity. Overall, the development of further derivatives, able to finely modulate multiple pathways of cancer or parasite cell metabolism, might lead to more effective treatments against these devastating diseases. (Figure Presented).

Due to the importance of intestinal transport in pharmacological studies and the emerging role of intestinal signalling activity in the gut-liver axis, we have developed a new method to investigate intestinal transport and liver signalling using cell and serum free mesenteric perfusion system in the rat. The method regarding bile acid active absorption was validated, then, the portal venous content was examined for fibroblast growth factor 15(FGF15), a putative signalling protein produced by the ileal enterocytes following bile acid absorption. After isolation and cannulation of the relevant vessels (abdominal aorta and portal vein), the abdominal aorta and the terminal ileum were infused with respectively Krebs-Ringer solution and tauroursodeoxycholate (TUDCA) and the absorption was assessed by its recovery in the portal vein. After immunoblot, liquid chromatography and mass spectrometry analysis were performed both on gel bands digestion products and on portal outflow samples in order to evaluate if negligible amounts of FGF15 were present in the portal circulation. TUDCA absorption was efficient, intestinal morphology and oxygen consumption were normal. Despite accurate analysis, we could not find FGF15. Our method proved to be reliable for studying the active bile acid absorption. It is also suitable to identify molecules produced by enterocytes and transferred to the portal circulation in response to absorption of different substances such as nutrients or drugs. Since FGF15 was not recovered we suggest the possibilities that this protein is produced in very little amounts, poorly transferred outside the cell, or that it is extremely unstable and rapidly degraded.