Estimating the number of available states for normal and tumor tissues in gene expression space.

The topology of gene expression space for a set of 12 cancer types is studied by means of an entropy-like magnitude, which measures the volumes of the regions occupied by tumor and normal samples, i.e., the number of available states (genotypes) that can be classified as tumor-like or normal-like, respectively. Computations show that the number of available states is much greater for tumors than for normal tissues, suggesting the irreversibility of the progression to the tumor phase. The entropy is nearly constant for tumors, whereas it exhibits a higher variability in normal tissues, probably due to tissue differentiation. In addition, we show an interesting correlation between the fraction (tumor/normal) of available states and the overlap between the tumor and normal sample clouds, interpreted as a way of reducing the decay rate to the tumor phase in more ordered or structured tissues.

Disruption of white matter integrity and its relationship with cognitive function in non-severe traumatic brain injury.

Background: Impairment in cognitive function is a recognized outcome of traumatic brain injury (TBI). However, the degree of impairment has variable relationship with TBI severity and time post injury. The underlying pathology is often due to diffuse axonal injury that has been found even in mild TBI. In this study, we examine the state of white matter putative connectivity in patients with non-severe TBI in the subacute phase, i.e., within 10 weeks of injury and determine its relationship with neuropsychological scores. Methods: We conducted a case-control prospective study involving 11 male adult patients with non-severe TBI and an age-matched control group of 11 adult male volunteers. Diffusion MRI scanning and neuropsychological tests were administered within 10 weeks post injury. The difference in fractional anisotropy (FA) values between the patient and control groups was examined using tract-based spatial statistics. The FA values that were significantly different between patients and controls were then correlated with neuropsychological tests in the patient group. Results: Several clusters with peak voxels of significant FA reductions (p < 0.05) in the white matter skeleton were seen in patients compared to the control group. These clusters were located in the superior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus, and cingulum, as well as white matter fibers in the area of genu of corpus callosum, anterior corona radiata, superior corona radiata, anterior thalamic radiation and part of inferior frontal gyrus. Mean global FA magnitude correlated significantly with MAVLT immediate recall scores while matrix reasoning scores correlated positively with FA values in the area of right superior fronto-occipital fasciculus and left anterior corona radiata. Conclusion: The non-severe TBI patients had abnormally reduced FA values in multiple regions compared to controls that correlated with several measures of executive function during the sub-acute phase of TBI.

Scalable Bio Marker Combinations for Early Stroke Diagnosis: A Systematic Review.

Background: Acute stroke treatment is a time-critical process in which every minute counts. Laboratory biomarkers are needed to aid clinical decisions in the diagnosis. Although imaging is critical for this process, these biomarkers may provide additional information to distinguish actual stroke from its mimics and monitor patient condition and the effect of potential neuroprotective strategies. For such biomarkers to be effectively scalable to public health in any economic setting, these must be cost-effective and non-invasive. We hypothesized that blood-based combinations (panels) of proteins might be the key to this approach and explored this possibility through a systematic review. Methods: We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines for systematic review. Initially, the broader search for biomarkers for early stroke diagnosis yielded 704 hits, and five were added manually. We then narrowed the search to combinations (panels) of the protein markers obtained from the blood. Results: Twelve articles dealing with blood-based panels of protein biomarkers for stroke were included in the systematic review. We observed that NR2 peptide (antibody against the NR2 fragment) and glial fibrillary acidic protein (GFAP) are brain-specific markers related to stroke. Von Willebrand factor (vWF), matrix metalloproteinase 9 (MMP-9), and S100ß have been widely used as biomarkers, whereas others such as the ischemia-modified albumin (IMA) index, antithrombin III (AT-III), and fibrinogen have not been evaluated in combination. We herein propose the following new combination of biomarkers for future validation: panel 1 (NR2 + GFAP + MMP-9 + vWF + S100ß), panel 2 (NR2 + GFAP + MMP-9 + vWF + IMA index), and panel 3 (NR2 + GFAP + AT-III + fibrinogen). Conclusions: More research is needed to validate, identify, and introduce these panels of biomarkers into medical practice for stroke recurrence and diagnosis in a scalable manner. The evidence indicates that the most promising approach is to combine different blood-based proteins to provide diagnostic precision for health interventions. Through our systematic review, we suggest three novel biomarker panels based on the results in the literature and an interpretation based on stroke pathophysiology.

Gene expression rearrangements denoting changes in the biological state.

In many situations, the gene expression signature is a unique marker of the biological state. We study the modification of the gene expression distribution function when the biological state of a system experiences a change. This change may be the result of a selective pressure, as in the Long Term Evolution Experiment with E. Coli populations, or the progression to Alzheimer disease in aged brains, or the progression from a normal tissue to the cancer state. The first two cases seem to belong to a class of transitions, where the initial and final states are relatively close to each other, and the distribution function for the differential expressions is short ranged, with a tail of only a few dozens of strongly varying genes. In the latter case, cancer, the initial and final states are far apart and separated by a low-fitness barrier. The distribution function shows a very heavy tail, with thousands of silenced and over-expressed genes. We characterize the biological states by means of their principal component representations, and the expression distribution functions by their maximal and minimal differential expression values and the exponents of the Pareto laws describing the tails.

Short-term Tolerance of Nasally-administered NeuroEPO in Patients with Parkinson Disease.

INTRODUCTION: No neuroprotective treatment has been able to successfully halt the progression of Parkinson disease or prevent development of associated complications. Recombinant erythropoetin (EPO), an erythropoiesis-stimulating agent originally indicated in anemia, produced and manufactured in Cuba (iorEPOCIM, CIMAB S.A, Havana, Cuba) has neuroprotective properties. NeuroEPO is a new nasal formulation of recombinant EPO with a low content of sialic acid and without hematopoietic effects. It has neuroprotective effects in animal models. OBJECTIVE: Evaluate short-term tolerance of intranasal NeuroEPO in patients with Parkinson disease. METHODS: As part of a monocentric randomized placebo-controlled double-blind study (registered at www.clinicaltrials.gov number NCT04110678), 26 patients with Parkinson disease (stages 1 and 2 on Hoehn & Yahr Scale), were randomly divided into two groups: NeuroEPO (n = 15) and placebo (n = 11), both treated intranasally either with the drug (1 mL, at a concentration of 1 mg/mL of NeuroEPO) or placebo once a week for 5 weeks. At each application, we recorded any adverse events and blood pressure. To assess potential hematopoietic effects of the drug, hematological and biochemical variables were evaluated one week before and one week after the intervention. RESULTS: There were no significant differences (p = 0.22) between the two groups in terms of frequency of adverse events (20.0% in NeuroEPO and 9.1% in placebo groups). Three patients in NeuroEPO presented nausea, and one vomited (possibly due to the patient's positioning during drug application). One patient in placebo group reported polyuria and nasal irritation. In both groups, the adverse events were mild, brief, required no treatment and did not present sequelae. CONCLUSIONS: Nasally administered NeuroEPO for five weeks in patients with Parkinson disease stages 1 and 2 on Hoehn & Yahr Scale is well tolerated.

Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review.

Insulin plays a major neuroprotective and trophic function for cerebral cell population, thus countering apoptosis, beta-amyloid toxicity, and oxidative stress; favoring neuronal survival; and enhancing memory and learning processes. Insulin resistance and impaired cerebral glucose metabolism are invariantly reported in Alzheimer's disease (AD) and other neurodegenerative processes. AD is a fatal neurodegenerative disorder in which progressive glucose hypometabolism parallels to cognitive impairment. Although AD may appear and progress in virtue of multifactorial nosogenic ingredients, multiple interperpetuative and interconnected vicious circles appear to drive disease pathophysiology. The disease is primarily a metabolic/energetic disorder in which amyloid accumulation may appear as a by-product of more proximal events, especially in the late-onset form. As a bridge between AD and type 2 diabetes, activation of c-Jun N-terminal kinase (JNK) pathway with the ensued serine phosphorylation of the insulin response substrate (IRS)-1/2 may be at the crossroads of insulin resistance and its subsequent dysmetabolic consequences. Central insulin axis bankruptcy translates in neuronal vulnerability and demise. As a link in the chain of pathogenic vicious circles, mitochondrial dysfunction, oxidative stress, and peripheral/central immune-inflammation are increasingly advocated as major pathology drivers. Pharmacological interventions addressed to preserve insulin axis physiology, mitochondrial biogenesis-integral functionality, and mitophagy of diseased organelles may attenuate the adjacent spillover of free radicals that further perpetuate mitochondrial damages and catalyze inflammation. Central and/or peripheral inflammation may account for a local flood of proinflammatory cytokines that along with astrogliosis amplify insulin resistance, mitochondrial dysfunction, and oxidative stress. All these elements are endogenous stressor, pro-senescent factors that contribute to JNK activation. Taken together, these evidences incite to identify novel multi-mechanistic approaches to succeed in ameliorating this pandemic affliction.

Cellular Senescence as the Pathogenic Hub of Diabetes-Related Wound Chronicity.

Diabetes is constantly increasing at a rate that outpaces genetic variation and approaches to pandemic magnitude. Skin cells physiology and the cutaneous healing response are progressively undermined in diabetes which predisposes to lower limb ulceration, recidivism, and subsequent lower extremities amputation as a frightened complication. The molecular operators whereby diabetes reduces tissues resilience and hampers the repair mechanisms remain elusive. We have accrued the notion that diabetic environment embraces preconditioning factors that definitively propel premature cellular senescence, and that ulcer cells senescence impair the healing response. Hyperglycemia/oxidative stress/mitochondrial and DNA damage may act as major drivers sculpturing the senescent phenotype. We review here historical and recent evidences that substantiate the hypothesis that diabetic foot ulcers healing trajectory, is definitively impinged by a self-expanding and self-perpetuative senescent cells society that drives wound chronicity. This society may be fostered by a diabetic archetypal secretome that induces replicative senescence in dermal fibroblasts, endothelial cells, and keratinocytes. Mesenchymal stem cells are also susceptible to major diabetic senescence drivers, which accounts for the inability of these cells to appropriately assist in diabetics wound healing. Thus, the use of autologous stem cells has not translated in significant clinical outcomes. Novel and multifaceted therapeutic approaches are required to pharmacologically mitigate the diabetic cellular senescence operators and reduce the secondary multi-organs complications. The senescent cells society and its adjunctive secretome could be an ideal local target to manipulate diabetic ulcers and prevent wound chronification and acute recidivism. This futuristic goal demands harnessing the diabetic wound chronicity epigenomic signature.