Discovery and characterization of a new class of NAD+-independent SIRT1 activators.

The activity of sirtuin 1 (SIRT1, a member of the NAD+-dependent deacetylases family) decreases during aging as NAD+ levels naturally decline, thus increasing the risk of several age-associated diseases. Several sirtuin-activating compounds (STACs) have been developed to counteract the age-associated reduction in SIRT1 activity, and some of them are currently under development in clinical trials. STACs induce SIRT1 activation, either through allosteric activation of the enzyme in the presence of NAD+, or by increasing NAD+ levels by inhibiting its degradation or by supplying a key precursor in biosynthesis. In this study, we have identified (E)-2'-des-methyl sulindac analogues as a novel class of STACs that act also in the absence of NAD+, a peculiar behavior demonstrated through enzymatic and mass spectrometry experiments, both in vitro and in cell lines. The activation of the SIRT1 pathway was confirmed in vivo through gene expression and metabolomics analysis. Our data suggest that these compounds could serve as candidate leads for a novel therapeutic strategy aimed at addressing a key metabolic deficiency that may contribute to metabolic and age-associated diseases.

Temporal Structures in Positron Spectra and Charge-Sign Effects in Galactic Cosmic Rays.

We present the precision measurements of 11 years of daily cosmic positron fluxes in the rigidity range from 1.00 to 41.9 GV based on 3.4×10^{6} positrons collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The positron fluxes show distinctly different time variations from the electron fluxes at short and long timescales. A hysteresis between the electron fluxes and the positron fluxes is observed with a significance greater than 5σ at rigidities below 8.5 GV. On the contrary, the positron fluxes and the proton fluxes show similar time variation. Remarkably, we found that positron fluxes are modulated more than proton fluxes with a significance greater than 5σ for rigidities below 7 GV. These continuous daily positron fluxes, together with AMS daily electron, proton, and helium fluxes over an 11-year solar cycle, provide unique input to the understanding of both the charge-sign and mass dependencies of cosmic rays in the heliosphere.

Temporal Structures in Electron Spectra and Charge Sign Effects in Galactic Cosmic Rays.

We present the precision measurements of 11 years of daily cosmic electron fluxes in the rigidity interval from 1.00 to 41.9 GV based on 2.0×10^{8} electrons collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The electron fluxes exhibit variations on multiple timescales. Recurrent electron flux variations with periods of 27 days, 13.5 days, and 9 days are observed. We find that the electron fluxes show distinctly different time variations from the proton fluxes. Remarkably, a hysteresis between the electron flux and the proton flux is observed with a significance of greater than 6σ at rigidities below 8.5 GV. Furthermore, significant structures in the electron-proton hysteresis are observed corresponding to sharp structures in both fluxes. This continuous daily electron data provide unique input to the understanding of the charge sign dependence of cosmic rays over an 11-year solar cycle.

Properties of Daily Helium Fluxes.

We present the precision measurement of 2824 daily helium fluxes in cosmic rays from May 20, 2011 to October 29, 2019 in the rigidity interval from 1.71 to 100 GV based on 7.6×10^{8} helium nuclei collected with the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. The helium flux and the helium to proton flux ratio exhibit variations on multiple timescales. In nearly all the time intervals from 2014 to 2018, we observed recurrent helium flux variations with a period of 27 days. Shorter periods of 9 days and 13.5 days are observed in 2016. The strength of all three periodicities changes with time and rigidity. In the entire time period, we found that below ∼7 GV the helium flux exhibits larger time variations than the proton flux, and above ∼7 GV the helium to proton flux ratio is time independent. Remarkably, below 2.4 GV a hysteresis between the helium to proton flux ratio and the helium flux was observed at greater than the 7σ level. This shows that at low rigidity the modulation of the helium to proton flux ratio is different before and after the solar maximum in 2014.

The Discovery of a Low-energy Excess in Cosmic-Ray Iron: Evidence of the Past Supernova Activity in the Local Bubble.

Since its launch, the Alpha Magnetic Spectrometer-02 (AMS-02) has delivered outstanding quality measurements of the spectra of cosmic-ray (CR) species ( p ¯ , e ±, and nuclei, 1H-8O, 10Ne, 12Mg, 14Si) which resulted in a number of breakthroughs. One of the latest long-awaited surprises is the spectrum of 26Fe just published by AMS-02. Because of the large fragmentation cross section and large ionization energy losses, most of CR iron at low energies is local and may harbor some features associated with relatively recent supernova (SN) activity in the solar neighborhood. Our analysis of the new AMS-02 results, together with Voyager 1 and ACE-CRIS data, reveals an unexpected bump in the iron spectrum and in the Fe/He, Fe/O, and Fe/Si ratios at 1-2 GV, while a similar feature in the spectra of He, O, and Si and in their ratios is absent, hinting at a local source of low-energy CRs. The found excess extends the recent discoveries of radioactive 60Fe deposits in terrestrial and lunar samples and in CRs. We provide an updated local interstellar spectrum (LIS) of iron in the energy range from 1 MeV nucleon-1 to ~10 TeV nucleon-1. Our calculations employ the GALPROP-HELMOD framework, which has proved to be a reliable tool in deriving the LIS of CR p ¯ , e -, and nuclei Z ⩽ 28.

Erratum: Properties of a New Group of Cosmic Nuclei: Results from the Alpha Magnetic Spectrometer on Sodium, Aluminum, and Nitrogen [Phys. Rev. Lett. 127, 021101 (2021)].

This corrects the article DOI: 10.1103/PhysRevLett.127.021101.

Properties of a New Group of Cosmic Nuclei: Results from the Alpha Magnetic Spectrometer on Sodium, Aluminum, and Nitrogen.

We report the properties of sodium (Na) and aluminum (Al) cosmic rays in the rigidity range 2.15 GV to 3.0 TV based on 0.46 million sodium and 0.51 million aluminum nuclei collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. We found that Na and Al, together with nitrogen (N), belong to a distinct cosmic ray group. In this group, we observe that, similar to the N flux, both the Na flux and Al flux are well described by the sums of a primary cosmic ray component (proportional to the silicon flux) and a secondary cosmic ray component (proportional to the fluorine flux). The fraction of the primary component increases with rigidity for the N, Na, and Al fluxes and becomes dominant at the highest rigidities. The Na/Si and Al/Si abundance ratios at the source, 0.036±0.003 for Na/Si and 0.103±0.004 for Al/Si, are determined independent of cosmic ray propagation.

Properties of Heavy Secondary Fluorine Cosmic Rays: Results from the Alpha Magnetic Spectrometer.

Precise knowledge of the charge and rigidity dependence of the secondary cosmic ray fluxes and the secondary-to-primary flux ratios is essential in the understanding of cosmic ray propagation. We report the properties of heavy secondary cosmic ray fluorine F in the rigidity R range 2.15 GV to 2.9 TV based on 0.29 million events collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. The fluorine spectrum deviates from a single power law above 200 GV. The heavier secondary-to-primary F/Si flux ratio rigidity dependence is distinctly different from the lighter B/O (or B/C) rigidity dependence. In particular, above 10 GV, the F/Si/B/O ratio can be described by a power law R^{δ} with δ=0.052±0.007. This shows that the propagation properties of heavy cosmic rays, from F to Si, are different from those of light cosmic rays, from He to O, and that the secondary cosmic rays have two classes.

Properties of Iron Primary Cosmic Rays: Results from the Alpha Magnetic Spectrometer.

We report the observation of new properties of primary iron (Fe) cosmic rays in the rigidity range 2.65 GV to 3.0 TV with 0.62×10^{6} iron nuclei collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. Above 80.5 GV the rigidity dependence of the cosmic ray Fe flux is identical to the rigidity dependence of the primary cosmic ray He, C, and O fluxes, with the Fe/O flux ratio being constant at 0.155±0.006. This shows that unexpectedly Fe and He, C, and O belong to the same class of primary cosmic rays which is different from the primary cosmic rays Ne, Mg, and Si class.

Periodicities in the Daily Proton Fluxes from 2011 to 2019 Measured by the Alpha Magnetic Spectrometer on the International Space Station from 1 to 100 GV.

We present the precision measurement of the daily proton fluxes in cosmic rays from May 20, 2011 to October 29, 2019 (a total of 2824 days or 114 Bartels rotations) in the rigidity interval from 1 to 100 GV based on 5.5×10^{9} protons collected with the Alpha Magnetic Spectrometer aboard the International Space Station. The proton fluxes exhibit variations on multiple timescales. From 2014 to 2018, we observed recurrent flux variations with a period of 27 days. Shorter periods of 9 days and 13.5 days are observed in 2016. The strength of all three periodicities changes with time and rigidity. The rigidity dependence of the 27-day periodicity is different from the rigidity dependences of 9-day and 13.5-day periods. Unexpectedly, the strength of 9-day and 13.5-day periodicities increases with increasing rigidities up to ∼10 GV and ∼20 GV, respectively. Then the strength of the periodicities decreases with increasing rigidity up to 100 GV.

Properties of Neon, Magnesium, and Silicon Primary Cosmic Rays Results from the Alpha Magnetic Spectrometer.

We report the observation of new properties of primary cosmic rays, neon (Ne), magnesium (Mg), and silicon (Si), measured in the rigidity range 2.15 GV to 3.0 TV with 1.8×10^{6} Ne, 2.2×10^{6} Mg, and 1.6×10^{6} Si nuclei collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. The Ne and Mg spectra have identical rigidity dependence above 3.65 GV. The three spectra have identical rigidity dependence above 86.5 GV, deviate from a single power law above 200 GV, and harden in an identical way. Unexpectedly, above 86.5 GV the rigidity dependence of primary cosmic rays Ne, Mg, and Si spectra is different from the rigidity dependence of primary cosmic rays He, C, and O. This shows that the Ne, Mg, and Si and He, C, and O are two different classes of primary cosmic rays.

Deciphering the Local Interstellar Spectra of Secondary Nuclei with the Galprop/Helmod Framework and a Hint for Primary Lithium in Cosmic Rays.

Local interstellar spectra (LIS) of secondary cosmic-ray (CR) nuclei, lithium, beryllium, boron, and partially secondary nitrogen, are derived in the rigidity range from 10 MV to ~200 TV using the most recent experimental results combined with state-of-the-art models for CR propagation in the Galaxy and in the heliosphere. The lithium spectrum appears somewhat flatter at high energies compared to other secondary species, which may imply a primary lithium component. Two propagation packages, GALPROP and HelMod, are combined to provide a single framework that is run to reproduce direct measurements of CR species at different modulation levels, and at both polarities of the solar magnetic field. An iterative maximum-likelihood method is developed that uses GALPROP-predicted LIS as input to HelMod, which provides the modulated spectra for specific time periods of the selected experiments for the model-data comparison. The proposed LIS accommodates the low-energy interstellar spectra measured by Voyager 1, the High Energy Astrophysics Observatory-3 (HEAO-3), and the Cosmic Ray Isotope Spectrometer on board of the Advanced Composition Explorer (ACE/CRIS), as well as the high-energy observations by the Payload for Antimatter Matter Exploration and Light-nuclei Astrophysics (PAMELA), Alpha Magnetic Spectrometer-02 (AMS-02), and earlier experiments that are made deep in the heliosphere. The interstellar and heliospheric propagation parameters derived in this study are consistent with our earlier results for propagation of CR protons, helium, carbon, oxygen, antiprotons, and electrons.

Knowledge, attitudes, representations and declared practices of nurses and physicians about obesity in a university hospital: training is essential.

In the context of a worldwide obesity epidemic, healthcare providers play a key role in obesity management. Knowledge of current guidelines and attitudes to prevent stigmatization are especially important. This study aimed to assess knowledge, attitudes, beliefs, perception of opportunity for intervention, declared practices and need for training and material of nurses and physicians about obesity in a Swiss University Hospital. A total of 834 physicians and nurses filled an online survey. The questionnaire was based on literature, exploratory interviews and expert committee review. It was pre-tested with 15 physicians and nurses. Participants declared a low level of negative attitudes towards individuals living with obesity. However, the results highlighted a lack of knowledge to diagnose obesity in adults and children, as well as confidence and training to care of patients with obesity. One-third of providers did not know how to calculate body mass index. Half of providers felt it was part of their role to take care of patients with obesity, even if 55% of them had the feeling that they did not have adequate training. Nurses and physicians working in a university hospital showed a low level of negative attitudes but a lack of knowledge and skills on obesity management. Training should be improved in this population to insure adequate and coherent messages and equal access to evidence-based treatment for patients living with obesity.

Deciphering the Local Interstellar Spectra of Primary Cosmic-Ray Species with helmod.

Local interstellar spectra (LIS) of primary cosmic ray (CR) nuclei, such as helium, oxygen, and mostly primary carbon are derived for the rigidity range from 10 MV to ~200 TV using the most recent experimental results combined with the state-of-the-art models for CR propagation in the Galaxy and in the heliosphere. Two propagation packages, GALPROP and helmod, are combined into a single framework that is used to reproduce direct measurements of CR species at different modulation levels, and at both polarities of the solar magnetic field. The developed iterative maximum-likelihood method uses GALPROP-predicted LIS as input to helmod, which provides the modulated spectra for specific time periods of the selected experiments for model-data comparison. The interstellar and heliospheric propagation parameters derived in this study are consistent with our prior analyses using the same methodology for propagation of CR protons, helium, antiprotons, and electrons. The resulting LIS accommodate a variety of measurements made in the local interstellar space (Voyager 1) and deep inside the heliosphere at low (ACE/CRIS, HEAO-3) and high energies (PAMELA, AMS-02).

Solution of Heliospheric Propagation: Unveiling the Local Interstellar Spectra of Cosmic-ray Species.

Local interstellar spectra (LIS) for protons, helium, and antiprotons are built using the most recent experimental results combined with state-of-the-art models for propagation in the Galaxy and heliosphere. Two propagation packages, GALPROP and HelMod, are combined to provide a single framework that is run to reproduce direct measurements of cosmic-ray (CR) species at different modulation levels and at both polarities of the solar magnetic field. To do so in a self-consistent way, an iterative procedure was developed, where the GALPROP LIS output is fed into HelMod, providing modulated spectra for specific time periods of selected experiments to compare with the data; the HelMod parameter optimization is performed at this stage and looped back to adjust the LIS using the new GALPROP run. The parameters were tuned with the maximum likelihood procedure using an extensive data set of proton spectra from 1997 to 2015. The proposed LIS accommodate both the low-energy interstellar CR spectra measured by Voyager 1 and the high-energy observations by BESS, Pamela, AMS-01, and AMS-02 made from the balloons and near-Earth payloads; it also accounts for Ulysses counting rate features measured out of the ecliptic plane. The found solution is in a good agreement with proton, helium, and antiproton data by AMS-02, BESS, and PAMELA in the whole energy range.

Metronomic chemotherapy with oral vinorelbine (mVNR) and capecitabine (mCAPE) in advanced HER2-negative breast cancer patients: is it a way to optimize disease control? Final results of the VICTOR-2 study.

PURPOSE: The VICTOR-1 study demonstrated that the all-oral metronomic combination of vinorelbine and capecitabine is highly active and well tolerated in hormone receptor-positive/HER2-negative patients. The VICTOR-2 study was designed to confirm these results. METHODS: Patients received mVNR 40 mg three times a week and mCAPE 500 mg three times a day, continuously. The primary endpoint was the clinical benefit rate (CBR); secondary endpoints were toxicity, objective response rate (ORR), and progression-free survival (PFS). RESULTS: Eighty patients were evaluable for the primary efficacy analysis. Median age was 65.3 years; most patients had HR-positive tumors (65 %). The CBR was 45.7 % (95 % CI 28.8-63.4) and 51.1 % (95 % CI 35.8-66.3) in first- and ≥ second-line therapy, respectively. The ORR was 35.5 % in first-line (95 % CI 19.2-54.6) and 25.6 % in ≥second-line (95 % CI 13.5-41.2). The median duration of response was 11.3 and 6.4 months and PFS rates at 1 year were 24.3 and 22.2 %, respectively. In triple-negative breast cancer patients (N = 28, 35 %) a lower, but clinically relevant CBR (35.7, 95 % CI 18.6-55.9) was observed. The main toxicities per cycle were non-febrile neutropenia (1.1 %), hand-foot syndrome (1.0 %), nausea and vomiting (1.0 %), leucopenia (0.8 %), fatigue (0.7 %), and diarrhea (0.4 %). CONCLUSION: The VICTOR-2 study confirms the clinical activity of mVNR and mCAPE in HER2-negative breast cancer patients, suggesting that the easy schedule of administration, which requires monthly blood tests and limits patients' dependence on hospitals, and the low cost of the drugs are valuable elements, even for countries with limited access to innovative or expensive drugs.

Is the new WHO classification of neuroendocrine tumours useful for selecting an appropriate treatment?

BACKGROUND: Neuroendocrine tumours (NETs) are a rare and heterogeneous group of neoplasms. The most recent WHO classification provides clinical tools and indications to make the diagnosis and to suggest the correct treatment in different subgroups of patients. The aim of this trial was to apply the new classification criteria in clinical practice and, accordingly, to choose the most appropriate treatment. PATIENTS AND METHODS: Thirty-one evaluable patients, not previously treated, classified as advanced well differentiated NETs according to the new classification, were given long-acting release octreotide 30 mg every 28 days until evidence of disease progression. The treatment activity was evaluated according to objective, biochemical and symptomatic responses. Safety and tolerability were also assessed. RESULTS: Two partial objective tumour responses were obtained (6%), stabilization occurred in 16 patients (52%) and 95% of patients had a disease stabilisation lasting > or =6 months. However, eight patients showed rapid disease progression within 6 months of therapy and six patients after 6 months. Biochemical responses, evaluated by changes in serum chromogranine A levels were reported in 20/24 patients (83%). Symptomatic responses were observed in 6/14 patients (43%): a complete syndrome remission in one patient, partial syndrome remission in five patients, no change in four patients and progressive disease in four patients. The median overall survival was not reached, and the median time to disease progression was 18 months (range 1-49 months). The treatment was well tolerated, no severe adverse events were observed and no patient withdrew from the study because of adverse events. CONCLUSIONS: The WHO classification enables identification of low-grade NET patients who may be suitable for hormonal treatment. Octreotide LAR was seen to be effective in controlling the disease and was well tolerated. However, eight patients failed to respond to the treatment, despite histological evidence of a well differentiated tumour according to the new classification. This suggests that further histological examination should be carried out, especially in patients with visceral metastases and a short disease-free interval.

Accuracy and clinical correlates of two different methods for chromogranin A assay in neuroendocrine tumors.

Measurement of chromogranin A (CgA) plays a major role in the management of neuroendocrine tumors (NET); however, reliable assaying of CgA is made difficult by the rapid hydrolysis following its release into the bloodstream. This study was aimed at the assessment of two assays for CgA in NET patients. CgA was measured in 93 patients by means of an enzyme-linked immunosorbent assay (ELISA) and an immunoradiometric assay (IRMA). The specificity and sensitivity of CgA were evaluated in relation to tumor histology. The clinical accuracy of the two assays was evaluated by receiver-operating characteristic (ROC) curve analysis. Regression analysis demonstrated different immunoreactivity for CgA of the antibodies used in the two kits (r = 0.61). The two assays had different accuracy also in classifying patients according to their clinical condition (91% vs 64% specificity and 79% vs 79% sensitivity for the ELISA and IRMA assay, respectively) and tumor histology (81% vs 85% sensitivity for the ELISA and IRMA assays, respectively, in carcinoids; 92% vs 67% sensitivity for the ELISA and IRMA assays, respectively, in pancreatic islet cell tumors). The different clinical accuracy of the two assays was confirmed by the ROC analysis (AUC = 0.90 vs AUC = 0.87 for the ELISA and IRMA assays, respectively). In conclusion, because of the poor standardization of the commercially available measurement tools the clinical accuracy of CgA measurement depends on the assay used. This makes it difficult to compare CgA values measured with different kits and affects the clinical accuracy of the different assays for CgA.