A Short Bout of Exercise Prior to Stroke Improves Functional Outcomes by Enhancing Angiogenesis
Authors: Leigh Monica Mantohac
Julian P Tuazon
Vanessa Castelli
Cesar V Borlongan
Jea Young Lee
Naoki Tajiri
Stefano Pianta
Journal: NeuroMolecular Medicine (2019)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Ischemic stroke; Neuroprotection; Physical activity; Stem cells; Vasculature.
Affiliations: Center of Excellence for Aging and Brain Repair, University of South Florida College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL, 33612, USA., Department of Neurophysiology & Brain Science, Graduate School of Medical Sciences & Medical School, Nagoya City University, Nagoya, 467-8601, Japan., Center of Excellence for Aging and Brain Repair, University of South Florida College of Medicine, 12901 Bruce B Downs Blvd, Tampa, FL, 33612, USA. .

Abstract:  Stroke remains a significant unmet clinical need with limited therapeutic options. The peculiar feature of ischemic stroke is the interruption in brain circulation, resulting in a cascade of detrimental cerebrovasculature alterations. Treatment strategies designed to maintain potency of the cerebrovasculature may protect against stroke. The present study assessed the effects of short bouts of exercise prior to stroke induction and characterized cerebral blood flow and motor functions in vivo. Adult Sprague-Dawley rats were exposed to a single short bout of exercise (30-min or 60-min forced running wheel) then subjected to transient middle cerebral artery occlusion (MCAO). Non-exercise stroke rats served as controls while non-stroke rats represented shams. Cerebral blood flow (CBF) was evaluated by laser Doppler at baseline (prior to MCAO), during MCAO, and during reperfusion. Behavioral tests using the elevated body swing test was conducted at baseline, day 0 (day of stroke), and at days 1 and 3 after stroke. Animals that received exercise displayed typical alterations in CBF after stroke, but exhibited improved motor performance compared to non-exercise rats. Exercised stroke rats showed a reduction in infarct size and an increased number of surviving cells in the peri-infarct area, with a trend towards prolonged duration of the exercise. Immunofluorescence staining and Western blot analysis of the peri-infarct area revealed increased levels of endothelial markers/angiogenesis markers, VEGF, VEGFR-2, and Ang-2, and endothelial progenitor cell marker CD34+ in exercise groups compared with the controls. These results demonstrated that prophylactic exercise affords neuroprotection possibly by improving cerebrovascular potency. 

Retracted: No

PubPeer comments:
 I am curious as to why the number of KD patients in Table 6 for the 0-4 Staging adds up to 29 and not 30. I am unable to find the supplementary data and am wondering if the individual tumor sizes could be released. Additionally, Table 5 seems a little confusing u2014 perhaps it is a typo? A decrease in tumor size in the KD group is expressed as a positive number (27mm), while a decrease in tumor size in the control group is expressed as a negative number (-6mm). Clearing this up would also help to evaluate the ranges of tumor size in Table 5. Does the **-34** number in the KD range indicate that 34mm was the highest amount of *growth* or the largest *decrease* in tumor size? ![file] , 
 **Multiple discrepancies regarding trial participant counts and disease staging**  The present study aimed to evaluate the effects of a KD in patients with locally advanced and metastatic breast cancer... Per the trial registration ,  Inclusion criteria: Patients with locally advanced and metastatic breast cancer (Stage III or IV)... **Yet, several data tables in the present article seem to indicate that early-stage patients were also included?** ![file] ![file] and ![file] Concerningly, if the data in tables 1 and 6 are correct (not to mention the discrepancies between them and the discrepancy with Figure 1 showing total of 30 vs 29 patients as mentioned in the above comment, the two study arms were vastly mismatched in terms of disease severity. A)The intervention arm had less than half as many stage 3 4 patients as the control arm, which makes a good comparison impossible. B)27 of 59 reported patients had stage 0-2 disease, which according to the registration inclusion criteria, should not have even been in the study at all? **Undisclosed conflict of interest**  The authors declare that they have no competing interests, yet Miriam Kalamian runs a business specifically selling ketogenic diet advice and books marketed to cancer patients. **Multiple unresolved unexplained issues with several publications related to this research:** https: doi.org 10.1080 01635581.2019.1650942 https: pubpeer.com publications 6D8E630964A59B12EA92637A5C396C As mentioned in  The use of ketogenic diets in cancer patients: a systematic review, Maximilian Ru00f6mer, Jennifer Du00f6rfler Jutta Huebner  10.1007 s10238-021-00710-2, **These inconsistencies raise serious concerns regarding the presented data.** Only Khodabakhshi et al. [23] found a significantly longer OS of the neoadjuvant treated subgroup of breast cancer patients. But said data are only presented as a Kaplanu2013Meier plot, without any further information, despite a p value of 0.04 and the claim of a higher survival rate in the KD group. It is also noteworthy that the follow-up time in this studyu2019s Kaplanu2013Meier plot appears to be 26 months. However, the recruitment started in 07 2017 and stopped in 10 2018. The finished article was received by the publishing journal in 02 2019. This is just 4 months after the last patient was recruited. The resulting follow-up is 19 months at most for the first patients recruited. Furthermore, the KD was only administered for 3 months. These inconsistencies raise serious concerns regarding the presented data. Additionally, no data were provided for the subgroup of metastatic patients in this publication. Even though the data from these patients were not published as an original publication, they are reported in a systematic review by Klement et al. [51]. Here, the patients in the KD group had a numerically shorter OS (pu2009=u20090.078). **FURTHER EXPLANATION CORRECTION BY AUTHORS AND EDITORS IS URGENTLY NEEDED, GIVEN THIS RESEARCH CONTINUES TO BE CITED IN SUBSEQUENT PUBLICATIONS BY THESE AND OTHER AUTHORS, PROMULGATING BASIC ERRORS, MISLEADING CLAIMS, AND DATA INCONSISTENCIES.** For example, a recent publication called  Ketogenic Diets and their Therapeutic Potential on Breast Cancer: A Systemic Review by Mohammed Jemal, Tewodros Shibabaw Molla, and Tadesse Asmamaw Dejenie https: www.ncbi.nlm.nih.gov labs pmc articles PMC8684375 ,