br Discussion br Conclusion The PERFECT trial shows that car

Discussion
Conclusion The PERFECT trial shows that cardiac tissue repair and restitution of left ventricular function can be successfully installed in ischemic heart disease by CABG surgery associated with presence of enhanced peripheral circulating CD133+EPC level. In addition, dysfunctional left ventricular post-infarct tissue may be recruited by the local injection of purified CD133+ BMDC. The induction of cardiac repair, however, is correlated to CD133+EPC release from bone marrow. Resistence of HSC/EPC to growth factor induction may be caused by elevated SH2B3 gene tsh receptor in non-responders. The diagnostic sensitivity of the responder vs. non-responder signature may be useful for diagnosis of deficient repair capacity in cardiovascular disease and for the preselection of patients for inductive stem cell therapy.
Limitations of the Study Main limitations of the study are: 1. Preterm closure of recruitment resulting in limited patient number for efficacy analysis. 2. Non-significant CD133+ effect on primary endpoint despite positive intermediate analysis. 3. Unknown mechanism of treatment unresponsiveness interfering with treatment intervention. 4. Need for further clinical evaluation of suspected blood/bone marrow suppression by SH2B3/lnk activator. 5. Predictive value of response signature in larger patient populations.
Declaration of Interests
Introduction Parkinson\'s disease is the second-most frequent neurodegenerative disease, with an incidence of approximately one per 1000 individuals. Parkinson\'s disease is caused by gradual cell death of dopaminergic neurons in the substantia nigra, and therapeutic chemicals or drugs that prevent this cell death are currently not available. In the early 1980s, certain numbers of drug users near San Francisco were observed manifesting Parkinson\'s disease phenotypes (Langston et al., 1983). The examination clarified that they suffered from accidental intoxication by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which was a contaminant in the drug they used. Later, it was found that 1-methyl-4-phenylpyridinium (MPP+), a metabolite of MPTP, but not MPTP itself, is specifically incorporated into dopaminergic neurons in the substantia nigra, where it inhibits mitochondrial complex I, suppresses ATP production, and ultimately kills the dopaminergic neurons in vivo, not only in humans but also in other animals, e.g. mice and rats (Dauer and Przedborski, 2003; Davis et al., 1979; Langston et al., 1983; Ramsay et al., 1991). These results have strongly implicated mitochondrial dysfunction or ATP decrease as a pathological mechanism in Parkinson\'s disease. Since then, MPTP has been widely used to experimentally create animal models of Parkinson\'s disease. The most well-known, if not invariable, pathological hallmark of Parkinson\'s disease is the presence of Lewy bodies, protein aggregates composed of α-synuclein, in dopaminergic neurons in the affected brain region (Dauer and Przedborski, 2003; Halliday et al., 2014; Polymeropoulos et al., 1997; Spillantini et al., 1997). Similar α-synuclein aggregates are also observed in cortical neurons in dementia with Lewy bodies and in glial cells in multisystem atrophy (Dauer and Przedborski, 2003; Halliday et al., 2014). These neurodegenerative diseases are collectively referred to as “α-synucleinopathies” (McCann et al., 2014). From a genetic point of view, 18 genetic loci have been linked to familial Parkinson\'s disease, and are named PARK1 to PARK18 (Klein and Westenberger, 2012; Lin and Farrer, 2014). PARK1 encodes α-synuclein itself (Klein and Westenberger, 2012; Lin and Farrer, 2014; Polymeropoulos et al., 1997). PARK2, PARK6, and PARK17 encode Parkin, PINK1, and VPS35, respectively (Kitada et al., 1998; Klein and Westenberger, 2012; Lin and Farrer, 2014; Sharma et al., 2012; Valente et al., 2004; Vilariño-Güell et al., 2011; Zimprich et al., 2011). It is noteworthy that both Parkin and PINK1 collaboratively function to maintain mitochondrial function (Pickrell and Youle, 2015), and that VPS35 also operates to maintain mitochondrial function (Tang et al., 2015; Wang et al., 2016). Furthermore, it has been shown that genetic manipulation to maintain mitochondrial functions renders mice resistant to MPTP-induced Parkinson\'s disease (Hasegawa et al., 2016a; Mudò et al., 2012). These lines of evidence again indicate that dysfunctional mitochondria and ATP decrease are underlying factors in the etiology of Parkinson\'s disease, and suggest a potential link between the production of α-synuclein aggregates and ATP decrease.