Precision Measurement of the Helium Flux in Primary Cosmic Rays of Rigidities 1.9 GV to 3 TV with the Alpha Magnetic Spectrometer on the International Space Station.

Knowledge of the precise rigidity dependence of the helium flux is important in understanding the origin, acceleration, and propagation of cosmic rays. A precise measurement of the helium flux in primary cosmic rays with rigidity (momentum/charge) from 1.9 GV to 3 TV based on 50 million events is presented and compared to the proton flux. The detailed variation with rigidity of the helium flux spectral index is presented for the first time. The spectral index progressively hardens at rigidities larger than 100 GV. The rigidity dependence of the helium flux spectral index is similar to that of the proton spectral index though the magnitudes are different. Remarkably, the spectral index of the proton to helium flux ratio increases with rigidity up to 45 GV and then becomes constant; the flux ratio above 45 GV is well described by a single power law.

Precision Measurement of the Proton Flux in Primary Cosmic Rays from Rigidity 1 GV to 1.8 TV with the Alpha Magnetic Spectrometer on the International Space Station.

A precise measurement of the proton flux in primary cosmic rays with rigidity (momentum/charge) from 1 GV to 1.8 TV is presented based on 300 million events. Knowledge of the rigidity dependence of the proton flux is important in understanding the origin, acceleration, and propagation of cosmic rays. We present the detailed variation with rigidity of the flux spectral index for the first time. The spectral index progressively hardens at high rigidities.

Electron and positron fluxes in primary cosmic rays measured with the alpha magnetic spectrometer on the international space station.

Precision measurements by the Alpha Magnetic Spectrometer on the International Space Station of the primary cosmic-ray electron flux in the range 0.5 to 700 GeV and the positron flux in the range 0.5 to 500 GeV are presented. The electron flux and the positron flux each require a description beyond a single power-law spectrum. Both the electron flux and the positron flux change their behavior at ∼30 GeV but the fluxes are significantly different in their magnitude and energy dependence. Between 20 and 200 GeV the positron spectral index is significantly harder than the electron spectral index. The determination of the differing behavior of the spectral indices versus energy is a new observation and provides important information on the origins of cosmic-ray electrons and positrons.

High statistics measurement of the positron fraction in primary cosmic rays of 0.5-500 GeV with the alpha magnetic spectrometer on the international space station.

A precision measurement by AMS of the positron fraction in primary cosmic rays in the energy range from 0.5 to 500 GeV based on 10.9 million positron and electron events is presented. This measurement extends the energy range of our previous observation and increases its precision. The new results show, for the first time, that above ∼200 GeV the positron fraction no longer exhibits an increase with energy.

Precision Measurement of the (e

We present a measurement of the cosmic ray (e^{+}+e^{-}) flux in the range 0.5 GeV to 1 TeV based on the analysis of 10.6 million (e^{+}+e^{-}) events collected by AMS. The statistics and the resolution of AMS provide a precision measurement of the flux. The flux is smooth and reveals new and distinct information. Above 30.2 GeV, the flux can be described by a single power law with a spectral index γ=-3.170±0.008(stat+syst)±0.008(energy scale).

Quantitative shape analysis of chemoresistant colon cancer cells: correlation between morphotype and phenotype.

Morphological, qualitative observations allow pathologists to correlate the shape the cells acquire with the progressive, underlying neoplastic transformation they are experienced. Cell morphology, indeed, roughly scales with malignancy. A quantitative parameter for characterizing complex irregular structures is the Normalized Bending Energy (NBE). NBE provides a global feature for shape characterization correspondent to the amount of energy needed to transform the specific shape under analysis into its lowest energy state. We hypothesized that a chemotherapy resistant cancer cell line would experience a significant change in its shape, and that such a modification might be quantified by means of NBE parameterization. We checked out the usefulness of a mathematical algorithm to distinguish wild and 5-fluorouracil (5-FU)-resistant colon cancer HCT-8 cells (HCT-8FUres). NBE values, as well as cellular and molecular parameters, were recorded in both cell populations. Results demonstrated that acquisition of drug resistance is accompanied by statistically significant morphological changes in cell membrane, as well as in biological parameters. Namely, NBE increased progressively meanwhile cells become more resistant to increasing 5-FU concentrations. These data indicate how tight the relationships between morphology and phenotype is, and they support the idea to follow a cell transition toward a drug-resistant phenotype by means of morphological monitoring.

Fractal analysis in a systems biology approach to cancer.

Cancer is a highly complex disease due to the disruption of tissue architecture. Thus, tissues, and not individual cells, are the proper level of observation for the study of carcinogenesis. This paradigm shift from a reductionist approach to a systems biology approach is long overdue. Indeed, cell phenotypes are emergent modes arising through collective non-linear interactions among different cellular and microenvironmental components, generally described by "phase space diagrams", where stable states (attractors) are embedded into a landscape model. Within this framework, cell states and cell transitions are generally conceived as mainly specified by gene-regulatory networks. However, the system's dynamics is not reducible to the integrated functioning of the genome-proteome network alone; the epithelia-stroma interacting system must be taken into consideration in order to give a more comprehensive picture. Given that cell shape represents the spatial geometric configuration acquired as a result of the integrated set of cellular and environmental cues, we posit that fractal-shape parameters represent "omics" descriptors of the epithelium-stroma system. Within this framework, function appears to follow form, and not the other way around.

Nebulized myo-inositol increases mucus clearance in patients with Bronchiectasis: a retrospective study.

OBJECTIVE: This retrospective study aimed at ascertaining the clinical usefulness of nebulized myo-inositol in the management of patients affected by bronchiectasis. PATIENTS AND METHODS: 19 patients, aged between 63 and 73 years old, with bronchiectasis, were treated for 15 days with nebulized myo-inositol or placebo. Lung functionality [forced expiratory volume in the 1st second (FEV1)], solid content of expectorate, and surfactant tension were analyzed. RESULTS: All patients treated with nebulized myo-inositol had a significant decrease in the percentage of solid content in the expectorate (T0 7.9±2.8% vs. T1 5.2±2.7%; p<0.001) and surfactant tension (T0 81.5±6.9 mN/m vs. T1 77.4±7.2 mN/m; p<0.001). Among treated patients, these variations correlated with FEV1 (rs=- 0.79; p<0.01) and forced expiratory flow at 25-75% of FVC (FEF25-75%) (rs=-0.81; p<0.01) scores. Also, variation of surfactant tension correlated with FEV1 (rs= -0.74; p<0.05) score. CONCLUSIONS: Nebulized myo-inositol increases lung functionality and mucus clearance in patients affected by bronchiectasis.

Does Alpha-lipoic acid improve effects on polycystic ovary syndrome?

Alpha-lipoic acid (ALA) plays a key role in many physiological processes, exerting anti-inflammatory, immunomodulatory, antioxidant, detoxifying, and insulin sensitizing activities. Since ALA improves insulin resistance (IR), it has been suggested that ALA could be beneficial it in the treatment of PCOS. The natural polyol myo-Inositol (myo-Ins) and its isomers (D-Chiro-Inositol, D-Chiro-Ins) has proven to improve PCOS features and clinical outcome, according to a compelling body of available studies. Few studies have proposed to strengthen the inositol effect by associating ALA. ALA does not seem to influence significantly reproductive hormones, while its beneficial effects are presumably restricted to the metabolic features of insulin resistant PCOS women. Therefore, ALA usefulness in improving inositol activity still awaits convincingly confirmation.  Experimental studies as well as proper randomized clinical trials, should be specifically tailored to assess this hypothesis. In absence of reliable evidence, ALA should not be recommended in the routinary clinical management of PCOS, even if associated to myo-Ins.

Measuring the incidence, prevalence and genetic relatedness of hepatitis C infections among a community recruited sample of injecting drug users, using dried blood spots.

Monitoring hepatitis C virus (HCV) infection among injecting drug users (IDUs) in the community is complicated by difficulties in obtaining biological specimens and biases in recruitment and follow-up. This study examined the utility of dried blood spot (DBS) specimens from IDUs recruited using respondent-driven sampling (RDS). Active IDUs underwent a computer-assisted interview and provided a DBS sample, tested for HCV antibody (anti-HCV) and HCV-RNA. HCV incidence was estimated from the proportion of anti-HCV-negative subjects found HCV-RNA-positive and estimates of the duration of this state. Results were adjusted according to RDS derived sample weights. HCV-RNA testing was performed on 288 DBS samples; 173 were anti-HCV-positive (54% weighted), of which 70 (42%, 95%CI 34-50% weighted) were RNA-negative indicating cleared infection. Among the 115 anti-HCV-negatives, 14 were RNA-positive suggesting an incidence of 38-47 per 100pyrs. Incident infections were younger than anti-HCV-negative and prevalent infections: 25 vs. 29 and 34, respectively. Incidence was highest among individuals with poor needle exchange coverage. One hundred and fourteen were genotyped (60 1a, 46 3a): a cluster of 14 had homology of >98.5% including 10 incident infections. Public health surveillance of HCV among IDUs could be enhanced through the collection of DBS samples with appropriate recruitment approaches. DBS allow differentiation between individuals with cleared infections, ongoing infection and those recently infected. They also enable virus characterization at genotype and nucleotide level. This would allow surveillance to inform development of harm reduction interventions, and the international evidence base for these.

The use of D-chiro-Inositol in clinical practice.

OBJECTIVE: D-chiro-Inositol has been widely used in clinical practice to induce ovulation in women with polycystic ovary syndrome. Only recent evidence established that this molecule acts through two different mechanisms, with potentially different outcomes. On the one hand, under a metabolic perspective, D-chiro-Inositol improves insulin signaling, thus restoring physiological insulin levels in resistant subjects. On the other hand, at a cellular level, it downregulates the expression of steroidogenic enzyme aromatase, which is responsible for the conversion of androgens to estrogens. MATERIALS AND METHODS: We reviewed current literature in different databases, searching for D-chiro-Inositol in relation with one of the following keywords: myo-inositol, PCOS, infertility, insulin resistance, aromatase, androgen and inositol, testosterone, estrogen and inositol, estradiol, hypogonadotropic hypogonadism, fat tissue, estrogens and cancer, anovulation, uterine myoma, endometriosis, endometrial hyperplasia. RESULTS: D-Chiro-Inositol treatment may be helpful in restoring physiological hormonal levels in various clinical disorders. However, D-Chiro-Inositol intervention should be carefully designed to avoid possible undesired side effects stemming from its multiple mechanisms of action. CONCLUSIONS: We evaluated the optimal D Chiro-Inositol administration for different pathologies, defining dosages and timing. Even though further studies are required to validate our preliminary results, this paper is primarily intended to guide researchers through some of the pathways of D-Chiro-Inositol.

Zebrafish embryo extracts enhance 5-FU anti-cancer effects upon breast cancer cells.

OBJECTIVE: The inhibition of the metastatic capability of cancer cells is a pivotal aim of current anticancer strategies. We investigated herein the anti-migrating and anti-invasive properties of Zebrafish embryo extracts (SL) - an integrative formula comprising morphogenetic factors extracted from zebrafish embryos - alone or in association with 5-Fluoro-Uracil (5-FU), when added to metastatic breast cancer cells (MDA-MB-231) and in normal epithelial breast cells (MCF10A) committed toward an inflammatory phenotype upon TGF-ß1 stimulation. MATERIALS AND METHODS: Invasiveness, migrating capability, cytoskeleton architecture and related molecular factors involved in the epithelial-mesenchymal transition were studied after treatment with 5-FU, with and without SL. RESULTS: Remarkably, in both circumstances, embryo extracts amplify the migratory inhibition triggered by the anticancer drug 5-Fu. The fact that such an effect is noticed in normal as well as in cancerous cells suggests that the critical target of embryo extracts is specifically represented by the migrating/invasive phenotype. However, while 5-FU was unable in antagonizing the invasiveness of cancerous cells, the association with SL can significantly impair the invasive capability of tumor cells. These findings are noticeably associated with the reversion of the EMT phenotype in SL-treated cells, as documented by the contemporary downregulation of TCTP and some EMT-related molecular effectors, like α-SMA and Vimentin. CONCLUSIONS: Embryo fish extracts significantly counteract the migrating and invasive phenotype of cancerous and inflammatory breast cells treated with the chemotherapeutic drug 5-FU. The availability of a compound able to amplify 5-Fu activity while significantly hampering the invasive phenotype of breast cancer should provide invaluable benefits, namely if we consider that this compound is substantially deprived of side-effects.

Inositol and pulmonary function. Could myo-inositol treatment downregulate inflammation and cytokine release syndrome in SARS-CoV-2?

The outbreak of Sars-CoV-2 (COVID-19) poses serious challenges to people's health worldwide. The management of the disease is mostly supportive, and respiratory failure from acute respiratory distress syndrome is the leading cause of death in a significant proportion of affected patients. Preliminary data point out that dramatic increase in IL-6 and subsequent cytokine release syndrome may account for the development of fatal interstitial pneumonia. Inhibition of IL-6 by blocking its specific receptor with monoclonal antibodies has been advocated as a promising attempt. Here we assess the potential utility of myo-Inositol, a polyol already in use for treating the newborn Respiratory Distress Syndrome, in downregulating the inflammatory response upon Sars-CoV-2 infection. Myo-Inositol proved to reduce IL-6 levels in a number of conditions and to mitigate the inflammatory cascade, while being devoid of any significant side effects. It is tempting to speculate that inositol could be beneficial in managing the most dreadful effects of Sars-CoV-2 infection.

Inhibitory effects of Vitamin D on inflammation and IL-6 release. A further support for COVID-19 management?

The ongoing worldwide pandemic of Coronavirus disease 2019 (COVID-19), raised the urgency to address knowledge gaps and to establish evidence for improving management and control of this viral infection. Throughout a keen analysis of the World Health Organization (WHO) most updated data, a gender-specific difference in the occurrence of infection was determined, which seems to correlate with patient's vitamin D status. Therefore, our purpose is to provide insights into the nutritional importance of vitamin D for its immunomodulatory effect, in order to help counteracting the COVID-19 pandemic. Novel interesting findings suggest that vitamin D, by inducing progesterone-induced blocking factor (PIBF), might regulate the immune response and also modulate cytokine IL-6, which appears to be increased in COVID-19 infections. Therefore, in addition to the standard recommendations to prevent the infection, supplementation of vitamin D might be considered an approach to help counteracting this global epidemic.

Changes in the properties of Bacillus thuringiensis after prolonged culture in a rich medium.

AIM: To investigate the effect of repeated culture in a rich medium on certain genetic, metabolic, pathogenic and structural characteristics of fresh isolates of Bacillus thuringiensis. METHODS AND RESULTS: Four strains of B. thuringiensis, which had been isolated in vegetative form from leaf surfaces, were grown for 500 generations in batch culture in a rich medium. One of the strains, S4g, differed from the parent in the following respects: greater cell width; changed plasmid profile; complete loss of ability to produce delta-endotoxins; loss of ability to produce beta-exotoxin and disruption of vip3 gene; radically different fatty acid composition; and altered metabolic activity. Two of the other evolved strains (S1g and S6g) showed differences in fatty acid profiles compared with the parents. Genetic finger-printing showed that there were also mutations in the cry genes of two of the evolved strains (S1g and S2g). The delta-endotoxins of strain S6g were significantly less toxic to the larvae of Pieris brassica compared with those of the parent and it also differed in the plasmid content. CONCLUSION: Radical and unpredictable changes can occur in fresh isolates of B. thuringiensis when subjected to growth in the laboratory. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first analysis of a Gram positive and biotechnologically significant bacterium after repeated laboratory culture. It is of great relevance to the biotechnological exploitation of B. thuringiensis that prolonged growth of environmental isolates on laboratory culture media can have profound effects on their structure, genome and virulence determinants.

[Consequences of space exploration for mankind]. / Le ricadute sull'uomo dell'esplorazione spaziale.

Space exploration obliges man to confront a hostile environment of cosmic radiation, microgravity, and magnetic field changes. Although the people who will go to Mars have been born, many new discoveries will be needed and new disciplines will have to be created before they can actually go there. All of this will have a tremendous impact on our health technology. For one thing, universities will work together with enterprises, creating a new way to carry out research. Space exploration has already generated new insight into osteoporosis, muscle atrophy, and motor coordination disorders. Space research has produced a long list of utilities including bone fixation devices and wheelchairs. Over the next 5 to 7 years, in the International Space Station many programs ranging from molecular biology to direct observation of human subjects will be developed. This will mean that, while awaiting the first expedition to Mars (which will take place after 2080), the collaboration of scientists with small and medium enterprises will continue to produce useful devices for people on earth.

Natural products - alpha-lipoic acid and acetyl-L-carnitine - in the treatment of chemotherapy-induced peripheral neuropathy.

OBJECTIVE: Cancer patients frequently experience Chemotherapy-Induced Peripheral Neuropathy (CIPN), as a typical side effect related to time of administration and dose of anticancer agents. Yet, CIPN pathophysiology is poorly understood, and there is a lack of well-tolerated pharmacological remedies helpful to prevent or treat it. Therefore, new safe and effective compounds are highly warranted, namely if based on an adequate understanding of the pathogenic mechanisms. MATERIAL AND METHODS: Herein we reviewed and discussed scientific data related to the beneficial role of some non-conventional treatments able to counteract CIPN, focusing our attention on alpha-lipoic acid (ALA) and L-acetyl-carnitine (LAC), two natural products that have been demonstrated to be promising preventive drugs. RESULTS: Although a growing body of in vitro and in vivo studies support ALA as a molecule able to counteract CIPN symptoms, mostly due to its antioxidant and anti-inflammatory properties, only two randomized clinical trials evaluated ALA usefulness in preventing chemotherapy-related neuropathy. Unfortunately, these studies were inconclusive and clinical outcomes showed to be highly dependent on the route of administration (oral versus or intravenous injection). LAC has demonstrated beneficial effects on both in vitro and in animal studies. Yet, some controversies aroused from randomized clinical trials. Indeed, while CIPN-patients treated with Taxane showed no benefit from LAC treatment, CIPN-patients treated with platinum compounds exhibit significant improvement of CIPN-related symptoms. Therefore, LAC treatment should be used, and thoroughly investigated only in patients treated with chemotherapy protocols Taxanes-free. CONCLUSIONS: Mechanisms of toxicity triggered by each single drug need to be deeply explored to better identify effective compounds to prevent or treat them. Moreover, additional experiments are mandatory to establish effective doses and length of treatment for each clinical situation in order to perform large and long-term randomized studies.

Inositol hexaphosphate (InsP6) as an effective topical treatment for patients receiving adjuvant chemotherapy after breast surgery.

OBJECTIVE: Oral treatment with inositol hexaphosphate (InsP6) has shown to be efficient in decreasing adverse effects in patients with breast cancer under chemotherapy. This study was aimed at evaluating and comparing the efficacy of topical InsP6 in improving quality of life in women treated with anticancer drugs. PATIENTS AND METHODS: The study was a double-blind, randomized controlled trial (RCT) with allocation concealment of 20 patients in two groups, one (experimental) applied 4% topical formulation of InsP6 once a day, whereas the second one (control) a gel containing hyaluronic acid. InsP6 therapy started 6 weeks after lumpectomy. Blood tests were monitored in both groups and quality of life was assessed using standardized QLQ-C30 and QLQ-BR23. RESULTS: Patients who applied InsP6 on the breast significantly improved their quality of life and functional status reducing side effects compared to control group; moreover, after treatment, a significant difference between the two groups was observed in the white blood cells and platelets count values. CONCLUSIONS: Topical InsP6 treatment has demonstrated to be effective and safe in preventing and/or mitigating chemotherapy-induced side effects as well as the preserving quality of life in women with ductal breast cancer.

A randomized trial of Boswellia in association with betaine and myo-inositol in the management of breast fibroadenomas.

OBJECTIVE: Breast fibroadenoma is a common finding in young women and actually accounts for the majority of benign breast lumps. Fibroadenoma does not require any treatment unless clinical symptoms (mostly mastalgia) or histological markers of cancer risk (atypia) impose specific medical or surgical intervention. In symptomatic fibroadenoma, anti-estrogenic treatments provided evidence of success. Yet, these therapies are often associated with relevant side effects that lead to drug treatment discontinuation. Additionally, in such cases, relapse is a frequent issue. Therefore, an optimal strategy is still warranted. Boswellia, betaine and myo-inositol have already been proved to modulate different pathways - inflammatory, metabolic, oxidative and endocrine processes - in a wide array of human tissues. Based on that background, we hypothesized that these substances can effectively synergize in inducing the regression of fibroadenoma. PATIENTS AND METHODS: We included 64 patients ≤ 30 years of age with fibroadenoma. The patients were randomized into two groups. The experimental group was treated with an association of Boswellia, betaine, myo-inositol, B-group vitamins and N-acetylcysteine for 6 months; otherwise, the placebo group was treated only with B-group vitamins and N-acetylcysteine. Patients were monitored at the enrollment and the end of the study for evaluating the clinical response. RESULTS: A significant clinical improvement was observed in the experimental arm. Fibroadenoma median volume reduction averaged 17.86% in the experimental group and 5.96% in the placebo group. Moreover, 14 out of 36 (38.88%) patients showed a reduction of fibroadenoma volume compared to 5/28 (17.85%) observed in the placebo group (p = 0.005). CONCLUSIONS: A supplementation with Boswellia, betaine and myo-inositol reduces fibroadenoma dimension in young women. No relevant side effects have been recorded.

Hyaluronic acid and vitamins are effective in reducing vaginal atrophy in women receiving radiotherapy.

AIM: During the last decades, therapies targeting cervical cancer have been considerably improved. Surgery and radiotherapy (RT) represent the main common therapeutic approach in cervical cancer. In order to minimize the side effects of radiotherapy approach, several protocols have been developed such as brachytherapy (BRT). Among the side effects associated with RT, the vaginal atrophy is the most important and common one. Vaginal atrophy, in turn, leads to additional alterations like inflammation, associated to relevant symptoms such as itching, burning and dyspareunia. All these alterations heavily affect the quality of women's life. The aim of our study was to evaluate the toxicity induced by RT on vaginal mucosa, and the adjuvant action of a product containing LMWHA, vitamin A, and Vitamin E (Santes®, Lo.Li. Pharma, Rome, Italy). The introduction of adjuvant therapies may have likely had a relevant place in providing that result. METHODS: A prospective randomized study was designed. From October 2006 to October 2008, 45 women with a mean age 38 ± 6 years were enrolled. After surgery, all patients were treated with 4 weeks of RT and 4 weeks of BRT, concomitantly with chemiotherapy. They were randomly assigned in two groups: 23 women were treated with two suppositories (Santes®) per day for 4 months. For the first two months the preventive treatment was simultaneous to RT and BRT. Instead the control groups for composed by 22 patients and they did not undergo any treatment during RT. To evaluate the efficacy of Santes® treatment three biopsies were performed. RESULTS: At the second biopsy, after the BRT therapy, the treated group showed a statistically significant improvement (P<0.05 vs. control) on inflammation, cell atypia, fibrosis, mucositis and bleeding. At the third biopsy, two months after BRT, further statistically improvement were observed for all RT/BRT associated side effects. The treatment showed an efficacy also in terms of pain severity. CONCLUSION: Our data suggest that low molecular weight HA shows good performances in treating RT-damaged tissue and plays a key role in all steps of the healing process. Indeed the results shows that women exposed to RT treatments and simultaneously treated with Santes®, had an optimal resolution of vaginal atrophy and related symptoms.