Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial.

Objective: This study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality. Methods: A multi-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18-80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 µg rEGF + 3.5 mg GHRP6 i.v., n=10), II (75 µg rEGF + 5 mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6 months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index and modified Rankin scale (mRS)] outcomes. Results: The study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8-11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06-1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03-1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by their moderate to strong effect size. At 6 months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis including merged treated groups and utility-weighted mRS also showed a benefit of this combined therapy. Conclusion: EGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study. Clinical Trial Registration: RPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.

Cell-Free Filtrates (CFF) as Vectors of a Transmissible Pathologic Tissue Memory Code: A Hypothetical and Narrative Review.

Cellular memory is a controversial concept representing the ability of cells to "write and memorize" stressful experiences via epigenetic operators. The progressive course of chronic, non-communicable diseases such as type 2 diabetes mellitus, cancer, and arteriosclerosis, is likely driven through an abnormal epigenetic reprogramming, fostering the hypothesis of a cellular pathologic memory. Accordingly, cultured diabetic and cancer patient-derived cells recall behavioral traits as when in the donor's organism irrespective to culture time and conditions. Here, we analyze the data of studies conducted by our group and led by a cascade of hypothesis, in which we aimed to validate the hypothetical existence and transmissibility of a cellular pathologic memory in diabetes, arteriosclerotic peripheral arterial disease, and cancer. These experiments were based on the administration to otherwise healthy animals of cell-free filtrates prepared from human pathologic tissue samples representative of each disease condition. The administration of each pathologic tissue homogenate consistently induced the faithful recapitulation of: (1) Diabetic archetypical changes in cutaneous arterioles and nerves. (2) Non-thrombotic arteriosclerotic thickening, collagenous arterial encroachment, aberrant angiogenesis, and vascular remodeling. (3) Pre-malignant and malignant epithelial and mesenchymal tumors in different organs; all evocative of the donor's tissue histopathology and with no barriers for interspecies transmission. We hypothesize that homogenates contain pathologic tissue memory codes represented in soluble drivers that "infiltrate" host's animal cells, and ultimately impose their phenotypic signatures. The identification and validation of the actors in behind may pave the way for future therapies.

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.

Manifestaciones bucales por radioterapia en pacientes geriátricos con cáncer de cabeza y cuello / Oral manifestations due to radiotherapy in geriatric patients with head and neck cancer

Introducción: los efectos adversos severos son la causa principal de las interrupciones en las sesiones de radioterapia, lo cual repercute negativamente en el beneficio terapéutico esperado de estas intervenciones. Por tanto, la participación del estomatólogo en el diseño y ejecución de los protocolos de tratamiento estomatológico en pacientes con cáncer es tan importante como lo es el esquema de la terapia oncoespecífica. El control de las condiciones bucales desfavorables previo al comienzo del tratamiento constituye un factor de protección y condiciona la continuidad y el éxito terapéutico. Objetivos: identificar los eventos adversos a consecuencia del tratamiento radioionizante y determinar la relación entre los eventos adversos y las condiciones bucales preexistentes en pacientes geriátricos con cáncer de cabeza y cuello. Métodos: se realizó un estudio descriptivo, prospectivo y longitudinal en 72 pacientes geriátricos con cáncer de cabeza y cuello tributarios de radioterapia. Se evaluó el estado de salud bucal previo al inicio del tratamiento y durante este, basado en la guía de criterios comunes de toxicidad. Las variables estudiadas fueron edad, género, sitio topográfico, etapa clínica, estado de salud bucal, severidad de los efectos adversos e interrupciones de la radioterapia. El procesamiento de los datos se realizó utilizando el programa SPSS 11.0 y Epidat. Resultados: el 67 por ciento de los pacientes estaba comprendido en el grupo etario de 60-69 años, el 70 por ciento eran hombres. El 67 por ciento de todos los pacientes examinados tenían una condición bucal desfavorable y de ellos el 56 por ciento tuvo que interrumpir el tratamiento radioterapéutico. A partir de la sesión de radioterapia número 20 correspondiente a 40 Gy, todos los pacientes presentaron al menos un efecto adverso. Los principales eventos adversos fueron disgeusia, xerostomía y radiomucositis. Se demostró una asociación significativa entre los efectos adversos por radioterapia y el estado desfavorable de las condiciones bucales previo al inicio del tratamiento. Conclusiones: los resultados indican que la evaluación bucal estomatológica antes, durante y después de la terapia oncoespecífica debe constituir una práctica habitual en la atención de pacientes con cáncer de cabeza y cuello, pues la interrupción del tratamiento radiante por el agravamiento de los efectos adversos conspira contra la efectividad de esta terapéutica(AU)

Introduction: severe adverse effects are the main cause for interrupting radiotherapy sessions, a fact that has a negative repercussion in the therapeutically benefit expected from theses interventions. Therefore, the dental surgeon's involvement in designing and practicing these dental management protocols in patients with cancer is so important as the oncospecific therapies scheme. The control of unfavorable oral conditions before treatment is a protection factor and conditions therapeutic continuation and success. Objectives: to identify adverse events as a result of radioionic treatment and determine the relationship between adverse events and pre-existing oral conditions in geriatric patients with head and neck cancer. Methods: adescriptive, prospective and longitudinal study was carried out in 72 geriatric patients with head and neck cancer and who were receiving radiotherapy. The oral health status was evaluated right before and during treatment, based on the guidelines of common toxicity criteria. The variables studied were age, gender, topographic site, clinical stage, oral health status, severity of adverse effects and interruptions of radiotherapy. Data processing was performed using the programs SPSS 11.0 and Epidat. Results: 67 percent of the patients were included in the age group of 60-69 years, 70 percent were men. 67 percent of all examined patients had an oral condition that was unfavorable and, out of these, 56 percent had to interrupt the radiotherapeutic treatment. From the radiotherapy session number 20 on, corresponding to 40 Gy, all the patients presented at least one adverse effect. The main adverse events were dysgeusia, xerostomia and radiomucositis. A significant association was proved between the adverse effects of radiotherapy and the unfavorable oral conditions prior to the start of treatment. Conclusions: the results indicate that oral assessment in dentistry before, during and after oncoespecific therapy should be a common practice in the care of patients with head and neck cancer, since the interruption of radiotherapy due to the worsening of adverse effects negatively influence the effectiveness of this therapy(AU)

Diabetic Foot Ulcers and Epidermal Growth Factor: Revisiting the Local Delivery Route for a Successful Outcome.

Soon after epidermal growth factor (EGF) discovery, some in vivo models appeared demonstrating its property to enhance cutaneous wound healing. EGF was the first growth factor (GF) introduced in the clinical arena as a healing enhancer, exerting its mitogenic effects on epithelial, fibroblastoid, and endothelial cells via a tyrosine kinase membrane receptor. Compelling evidences from the 90s documented that, for EGF, locally prolonged bioavailability and hourly interaction with the receptor were necessary for a successful tissue response. Eventually, the enthusiasm on the clinical use of EGF to steer the healing process was wiped out as the topical route to deliver proteins started to be questioned. The simultaneous in vivo experiments, emphasizing the impact of the parenterally administered EGF on epithelial and nonepithelial organs in terms of mitogenesis and cytoprotection, rendered the theoretical fundamentals for the injectable use of EGF and shaped the hypothesis that locally infiltrating the diabetic ulcers would lead to an effective healing. Although the diabetic chronic wounds microenvironment is hostile for local GFs bioavailability, EGF local infiltration circumvented the limitations of its topical application, thus expanding its therapeutic prospect. Our clinical pharmacovigilance and basic studies attest the significance of the GF local infiltration for chronic wounds healing.

Role of epidermal growth factor and growth hormone-releasing peptide-6 in acceleration of renal tissue repair after kanamycin overdosing in rats.

INTRODUCTION: Aminoglycosides nephrotoxicity limits their use in clinical practice. Growth hormone-releasing peptide-6 (GHRP6) and epidermal growth factor (EGF) have proven cytoprotective effects in various tissues, including the kidney. This study aimed to determine the cytoprotective effect of EGF and GHRP6 on glomerular, proximal tubular, and interstitial morphology in rats treated with an overdose of kanamycin. MATERIALS AND METHODS: Forty-four male Wistar adults rats were submitted to treatment for 20 days with sodium phosphate saline buffer (control group), kanamycin (kanamycin group), kanamycin and EGF (EGF group), kanamycin and GHRP6 (GHRP6 group), kanamycin, EGF, and GHRP6 (EGF-GHRP6 group). The kidneys were studied both during acute kidney injury (n = 19) and recovery phases (n = 25). The percentages of glomerular damage, tubular damage (reversible and irreversible changes), and interstitial damage were quantified in 10 histological fields per kidney using paraffin-embedded sections. RESULTS: The damage in the glomeruli, proximal tubules, and interstitium was less in the groups treated with the cytoprotective treatments than in kanamycin group during acute kidney injury. During the recovery phase, normal structure of several glomeruli and the interstitium was appreciated in the EGF and GHRP6 groups, although tissue repair was not as complete as it in the EGF-GHRP6 group. In the recovery phase, cytoprotective treatments accelerated the recovery of tubular damage and reversible tubular changes prevailed. CONCLUSIONS: These results confirm the cytoprotective properties of EGF and GHRP6 alone and in combination and suggest the possibility of using these agents to accelerate kidney tissue repair after aminoglycoside-induced renal damage.

Epidermal growth factor and growth hormone-releasing peptide-6: combined therapeutic approach in experimental stroke.

PURPOSE: Stroke is the second cause of mortality worldwide, with a high incidence of disability in survivors. Promising candidate drugs have failed in stroke trials. Combined therapies are attractive strategies that simultaneously target different points of stroke pathophysiology. The aim of this work is to determine whether the combined effects of epidermal growth factor (EGF) and growth hormone-releasing peptide-6 (GHRP6) can attenuate clinical signs and pathology in an experimental stroke model. METHODS: Brain global ischemia was generated in Mongolian gerbils by 15 minutes of carotid occlusion. After reperfusion, EGF, GHRP6 or EGF+GHRP6 were intraperitoneally administered. Clinical manifestations were monitored daily. Three days after reperfusion, animals were anesthetized and perfused with an ink solution. The anatomy of the Circle of Willis was characterized. Infarct volume and neuronal density were analyzed. RESULTS: EGF+GHRP6 co-administration reduced clinical manifestations and infarct volume and preserved neuronal density. No correlation was observed between the grade of anastomosis of the Circle of Willis and clinical manifestations in the animals receiving EGF+GHRP6, as opposed to the vehicle-treated gerbils. CONCLUSIONS: Co-treatment with EGF and GHRP6 affects both the clinical and pathological outcomes in a global brain ischemia model, suggesting a suitable therapeutic approach for the acute management of stroke.

Proinflammatory soluble interleukin-15 receptor alpha is increased in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease in which many cytokines have been implicated. In particular, IL-15 is a cytokine involved in the inflammatory processes and bone loss. The aim of this study was to investigate the existence in synovial fluid of soluble IL-15Rα, a private receptor subunit for IL-15 which may act as an enhancer of IL-15-induced proinflammatory cytokines. Soluble IL-15Rα was quantified by a newly developed enzyme-linked immunosorbent assay (ELISA) in samples of synovial fluid from patients with RA and osteoarthritis (OA). The levels of IL-15Rα were significantly increased in RA patients compared to OA patients. Also, we studied the presence of membrane-bound IL-15 in cells from synovial fluids, another element necessary to induce pro-inflammatory cytokines through reverse signaling. Interestingly, we found high levels of IL-6 related to high levels of IL-15Rα in RA but not in OA. Thus, our results evidenced presence of IL-15Rα in synovial fluids and suggested that its pro-inflammatory effect could be related to induction of IL-6.