A Short-Period Therapy with Subcutaneous Low-Dose IL-2 Plus High-Dose Melatonin to Correct Advanced Cancer-Related Lymphocytopenia: Possible Impact on the Survival Time

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The psychoneuroendocrine-immunotherapy of cancer: Historical evolution and clinical results

The prognosis of the neoplastic diseases depends not only on the biogenetic characteristics of cancer cells but also on the immunological response of patients, which may influence the biological features of cancer cells themselves as well as the angiogenic processes. Moreover, the immune system in vivo is under a physiological psychoneuroendocrine (PNE) regulation, mainly mediated by the brain opioid system and the pineal gland. In more detail, the anticancer immunity is stimulated by the pineal hormone melatonin (MLT) and inhibited by the opioid system, namely, through a mu-opioid receptor. Several alterations involving the pineal endocrine function and the opioid system have been described in cancer patients, which could play a role in tumor progression itself. Therefore, the pharmacological correction of cancer progression-related anomalies could contribute to control cancer diffusion, namely, the pineal endocrine deficiency and the hyperactivity of brain opioid system. In fact, the administration of pharmacological doses of the only MLT has already been proven to prolong the 1-year survival in untreatable metastatic cancer patients. Better results may be achieved by associating other pineal indoles to MLT, mu-opioid antagonists, cannabinoids, beta-carbolines. Moreover, these neuroendocrine combinations may be successfully associated with antitumor cytokines, such as interleukin (IL)-2 and IL-12, as a PNE-immune cancer therapy as well as with antitumor plants as PNE-phytotherapy of cancer in an attempt to propose possible anticancer treatments also to patients with disseminated cancer and untreatable according to the standard oncology

Systemic Corticosteroids for Treating Respiratory Diseases: Less Is Better, but… When and How Is It Possible in Real Life?

Abstract Systemic corticosteroids (CSs), a keystone in pulmonology, are drugs with strong antiinflammatory activity. They are cheap, easily available, and accessible, but with common and serious side effects. Moreover, the use of exogenous CSs may suppress the hypothalamic–pituitary–adrenal (HPA) axis, predisposing to adrenal insufficiency. Safe CS treatment is a challenge of pharmacological research. This narrative review examined the indications of CSs in some respiratory diseases, analyzing what types, dosages, and length of treatment are required as the dosage and duration of CS treatments need to be minimized. Chronic maintenance treatments with CSs are associated with poor prognosis, but they are still prescribed in patients with severe asthma, Chronic obstructive pulmonary disease (COPD), and interstitial lung diseases. When CS discontinuation is not possible, all efforts should be made to achieve clinically meaningful reductions. Guidelines suggest the use of methylprednisolone at a dose of 20–40 mg/day or equivalent for up to 10 days in subjects with COVID-19 pneumonia (but not other respiratory viral diseases) and respiratory failure, exacerbations of asthma, and COPD. Some guidelines suggest that CS treatment shorter than 10–14 days can be abruptly stopped, strictly monitoring subjects with unexplained symptoms after CS withdrawal, who should promptly be tested for adrenal insufficiency (AI) and eventually treated. CSs are often used in severe community-acquired pneumonia associated with markedly increased serum inflammation markers, in acute respiratory distress syndrome (ARDS), in septic shock unresponsive to hydro-saline replenishment and vasopressors, and acute exacerbations of interstitial lung diseases. As these cases often require higher doses and longer duration of CS treatment, CS tapering should be gradual and, when useful, supported by an evaluation of HPA axis function

A preliminar study of a neuroimmune regimen with lowdose angiotensin 1-7 plus melatonin to improve the safety of covid 19 vaccine

Abstract: In experimental conditions, it has been demonstrated that vaccine efficacy and the toxicity is depending on cytokine-induced immunoinflammatory response, and that they may be modulate through a neuroimmune approach, which neuroendocrine agents, such as the pineal hormone melatonin (MLT) and the enzymatic product of ACE2, the angiotensin 1-7 (Ang 1-7). On these bases, a preliminary study was planned to evaluate the influence of an oral peri-vaccination regimen with MLT plus Ang 1-7 on the subjective safety of Covid19 Pfizer-BioNTech (PF) and AstraZeneca (AZ) vaccines. The study included 60 subjects, 30 of whom received PF vaccine, while the other 30 subjects were treated by AZ vaccine. Both groups of subjects were randomized to receive the only vaccine or vaccine plus Ang 1-7 (0.5 mg/day in the morning) and MLT (10 mg/day in the evening) regimen, starting 3 days prior to vaccine and for the successive 4 days. The percentage of episodes of fever higher than 38°C, asthenia and myalgia were significantly reduced by the concomitant administration of Ang 1-7 plus MLT. This preliminary study shows the possibility to modulate the safety of Covid19 vaccine through a neuroimmune approach consisting of Ang 1-7 plus MLT. Further studies will be required to confirm these data, and to evaluate the impact not only on the safety, but also on the efficacy of Covid19 vaccination.

Cytostatic Effects of Polyethyleneimine Surfaces on the Mesenchymal Stromal Cell Cycle

Polyelectrolytes assembled layer-by-layer (PEMs) are commonly used as functional coatings to build-up biological interfaces, particularly suitable as compatible layers for the interaction with a biological medium, providing suitable conditions to promote or prevent cell seeding while maintaining the phenotype. The proper assessment of the biocompatibility of PEMs and the elucidation of the related mechanisms are therefore of paramount importance. In this study, we report in detail the effect of two different PEM endings, polystyrene sulfonate (PSS) and polyethylenimine (PEI), respectively, on the cell adhesion, growth, and viability of human bone mesenchymal stromal cells (MSCs). The results have shown that PSS-ended substrates appear to be the most suitable to drive the cell adhesion and phenotype maintenance of MSCs, showing good biocompatibility. On the contrary, while the cells seem to adhere more quickly and strongly on the PEI-ended surfaces, the interaction with PEI significantly affects the growth and viability, reducing the cell spreading capability, by sequestering the adhesion molecules already in the very early steps of cell–substrate contact. These results point to the promotion of a cytostatic effect of PEI, rather than the often-claimed cytotoxicity

Psycho Neuroendocrino Immune (PNEI) therapy of cancer beyond melatonin

Abstract: The recent advances in psycho-neuroendocrino-immunology (PNEI) have demonstrated the existence of a natural anticancer neuroendocrine system, mainly expressed by the pineal gland, endocannabinoid system, oxytocin, and Ang 1-7. Moreover, cancer progression has appeared to be associated with a progressive decline in the pineal and cannabinoid system functions. A new approach to cancer therapy according to a PNEI strategy could simply consist of the correction of the main cancer-related neuroimmune and neuroendocrine alterations through the exogenous administration of the same human natural anticancer molecules, whose production declines with cancer progression. PNEI therapy of cancer, because of its complete lack of toxicity, could be applied also to patients, who failed to respond to the conventional anticancer treatments. Most data available up to now regard the treatment with the pineal anticancer hormone melatonin (MLT), whose efficacy has been proven to be a dose-dependent phenomenon. Preliminary results with other human antitumor molecules, mainly the pineal indole 5-MTT, cannabinoids, oxytocin and probably in particular Ang 1-7, could further amplify the already interesting results obtained with high-dose MLT alone in untreatable advanced cancer patients

A phase II study of the pineal hormones melatonin and 5-methoxytryptamine plus cannabidiol in association with angiotensin 1-7 in the treatment of advanced solid tumour patients eligible for the only best supportive care

Abstract: The recent advances in the investigation of tumour biology have demonstrated that the human body may produce several molecules provided by a natural anticancer activity without any toxicity, in particular the pineal hormones melatonin (MLT), 5-methoxytryptamine (5-MTT) and pinealine, the endogenous cannabinoids, oxytocin, and angiotensin 1-7 (Ang 1-7). Unfortunately, despite their well confirmed anticancer and non-toxic properties, very few clinical studies have been performed in an attempt to evaluate the potential therapeutic efficacy of the endogenous human anticancer molecules in the treatment of cancer patients, at least of those eligible for the only palliative therapy. Moreover, most studies have been generally limited to the use of the only pineal MLT. The present preliminary study was carried out to evaluate the anticancer efficacy of an oral administration of MLT (100 mg in the dark period) in association with 5-MTT (10 mg in the light period), the cannabinoid agent cannabidiol (CBD) ( 10 mg twice/day) and Ang 1-7 (0.5 mg/twice day) in a group of 14 untreatable advanced or metastatic cancer patients. The clinical response consisted of partial response (PR) in 2/14 (14%), and stable disease (SD) in 8/14 (57%). Then, a disease control (PR + SD) was achieved in 10/14 (71%), whereas the remaining 4/14 (29%) had a progressive disease. Moreover, disease control was associated with a significant increase in lymphocyte-to-monocyte ratio (LMR), by showing that the control of the neoplastic growth is mediated at least in part by an improvement in the antitumor immune status of cancer patients.The treatment was well tolerated in all patients, and in particular no important decline in blood pressure values occurred. On the contrary, a clear improvement in asthenia was obtained in 8/10 (80%) patients with important asthenia prior to study. This preliminary study may suggest that after the failure of the common standard anticancer therapies, the administration of the main endogenous anticancer neuroendocrine molecules, firstly MLT and Ang 1-7, could constitute an alternative approach to cancer patients instead of the simple best supportive care alone

Antimicrobial efficacy of cordless sonic or ultrasonic devices on Enterococcus faecalis-infected root canals

Aim The aim of the present study was to evaluate the immediate and residual antimicrobial activity of cordless sonic or ultrasonic devices on Enterococcus faecalis (E faecalis)-infected teeth. Methods A total of 140 single-rooted extracted teeth with E faecalis were grouped as follows (N = 15): conventional syringe irrigation with 3% sodium hypochlorite activated by ultrasonic device (group 1) or cordless ultrasonic device (group 2), EndoActivator (group 3) or without activation (group 4), conventional syringe irrigation with sterile bi-distilled water and ultrasonic device (group 5), EndoUltra (group 6), EndoActivator (group 7), or without activation (group 8). The remaining 20 teeth were used for positive and negative controls. Colony-forming units (CFU) and turbidity were recorded from bacteriological samples taken before and after irrigation and after 24 hours of re-incubation. Data were statistically analyzed using Student's t test, Mann-Whitney test, Kruskal-Wallis test, and Dunn's multiple comparison tests (P < .05). Results Groups 1 and 2 showed higher antimicrobial efficacy than groups 3 and 4 (P < .05). No bacteria reduction was found in groups 5-8 (P > .05). After 24 hours, regrowth of bacteria was not significantly different for all groups (P > .05). Conclusions Ultrasound produced lower CFU and turbidity after treatment and after re-incubation of 24 hours than sonic or no activation

Antimicrobial efficacy of cordless sonic or ultrasonic devices on Enterococcus faecalis-infected root canals

Aim The aim of the present study was to evaluate the immediate and residual antimicrobial activity of cordless sonic or ultrasonic devices on Enterococcus faecalis (E faecalis)-infected teeth. Methods A total of 140 single-rooted extracted teeth with E faecalis were grouped as follows (N = 15): conventional syringe irrigation with 3% sodium hypochlorite activated by ultrasonic device (group 1) or cordless ultrasonic device (group 2), EndoActivator (group 3) or without activation (group 4), conventional syringe irrigation with sterile bi-distilled water and ultrasonic device (group 5), EndoUltra (group 6), EndoActivator (group 7), or without activation (group 8). The remaining 20 teeth were used for positive and negative controls. Colony-forming units (CFU) and turbidity were recorded from bacteriological samples taken before and after irrigation and after 24 hours of re-incubation. Data were statistically analyzed using Student's t test, Mann-Whitney test, Kruskal-Wallis test, and Dunn's multiple comparison tests (P < .05). Results Groups 1 and 2 showed higher antimicrobial efficacy than groups 3 and 4 (P < .05). No bacteria reduction was found in groups 5-8 (P > .05). After 24 hours, regrowth of bacteria was not significantly different for all groups (P > .05). Conclusions Ultrasound produced lower CFU and turbidity after treatment and after re-incubation of 24 hours than sonic or no activation

A preliminary study of low-dose angiotensin 1-7 plus the pineal hormone melatonin in the treatment of human systemic diseases other than cancer and autoimmune pathologies

Abstract: The recent advances of the psychoneuroimmunology have demonstrated the existence of a physiological anti-inflammatory antitumor neuroendocrine axis, mainly constituted by the pineal gland through its indole hormone melatonin (MLT) and the ACE2-angiotensin 1-7 (Ang 1-7) system. Moreover, most human systemic diseases, including cancer, autoimmunity, metabolic, cardiovascular, and neurodegenerative pathologies, have appeared to be characterized by an endogenous deficiency in the functionless of the pineal gland and ACEACE2 system. Therefore, the exogenous correction of MLT and Ang 1-7 deficiency could improve the clinical control of human systemic diseases. On these bases, a preliminary study of MLT plus Ang 1-7 was planned in patients suffering from systemic alterations other than cancer and autoimmunity. The study included 33 consecutive patients, whose pathologies were, as follows: cardiovascular pathologies: 9; pulmonary diseases: 7; metabolic syndrome: 7; neurodegenerative pathologies: 10. Both Ang 1-7 and MLT were given orally, at a dose of 0.5 mg/day in the morning for Ang 1-7, and at a dose of 10 mg/day in the evening for MLT. The treatment was well tolerated in all patients, and no-therapy related toxicity occurred. On the contrary, most patients experienced a relief of anxiety and asthenia, and an improvement in both mood and quality of sleep. Moreover, most patients referred an increased diuresis. Blood pressure values progressively became within the normal range in hypertensive patients. On the same way, glucose and cholesterol levels progressively decrease on therapy in diabetic and hypercholesterolemic patients, respectively. Patients with pulmonary disturbance referred an important enhancement in the expectoration, with a following improvement in the respiratory symptomatology. Finally, an apparent improvement in cognitive and motor functions was achieved in patients with neurodegenerative pathologies. These preliminary results would suggest a future medical possibility to treat the human systemicdiseases by simply correcting their endogenous neuroendocrine deficiencies, mainly those involving the functions of the pineal gland and ACE2-Ang1-7 system