Abstract
Four spacecraft have been sent to investigate the Saturnian system: Pioneer 11, Voyager 1, Voyager 2, and Cassini. By analyzing data acquired with these spacecraft together with Earth-based ...and Hubble Space Telescope satellite astrometry and Saturnian ring and satellite occultations, we constructed a model for the orientation and precession of Saturn’s pole and determined gravitational parameters of the system and the orbits of the Saturnian satellites. This article provides details of our analysis and its results.
Most patients with advanced-stage indolent non-Hodgkin lymphoma have multiple relapses. We assessed axicabtagene ciloleucel autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in ...relapsed or refractory indolent non-Hodgkin lymphoma.
ZUMA-5 is a single-arm, multicentre, phase 2 trial being conducted at 15 medical cancer centres in the USA and two medical cancer centres in France. Patients were eligible if they were aged 18 years or older, with histologically confirmed indolent non-Hodgkin lymphoma (follicular lymphoma or marginal zone lymphoma), had relapsed or refractory disease, previously had two or more lines of therapy (including an anti-CD20 monoclonal antibody with an alkylating agent), and an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients underwent leukapheresis and received conditioning chemotherapy (cyclophosphamide at 500 mg/m2 per day and fludarabine at 30 mg/m2 per day on days −5, −4, and −3) followed by a single infusion of axicabtagene ciloleucel (2 × 106 CAR T cells per kg) on day 0. The primary endpoint was overall response rate (complete response and partial response) assessed by an independent review committee per Lugano classification. The primary activity analysis was done after at least 80 treated patients with follicular lymphoma had been followed up for at least 12 months after the first response assessment at week 4 after infusion. The primary analyses were done in the per-protocol population (ie, eligible patients with follicular lymphoma who had 12 months of follow-up after the first response assessment and eligible patients with marginal zone lymphoma who had at least 4 weeks of follow-up after infusion of axicabtagene ciloleucel). Safety analyses were done in patients who received an infusion of axicabtagene ciloleucel. This study is registered with ClinicalTrials.gov, NCT03105336, and is closed to accrual.
Between June 20, 2017, and July 16, 2020, 153 patients were enrolled and underwent leukapheresis, and axicabtagene ciloleucel was successfully manufactured for all enrolled patients. As of data cutoff (Sept 14, 2020), 148 patients had received an infusion of axicabtagene ciloleucel (124 84% who had follicular lymphoma and 24 16% who had marginal zone lymphoma). The median follow-up for the primary analysis was 17·5 months (IQR 14·1–22·6). Among patients who were eligible for the primary analysis (n=104, of whom 84 had follicular lymphoma and 20 had marginal zone lymphoma), 96 (92%; 95% CI 85–97) had an overall response and 77 (74%) had a complete response. The most common grade 3 or worse adverse events were cytopenias (104 70% of 148 patients) and infections (26 18%). Grade 3 or worse cytokine release syndrome occurred in ten (7%) patients and grade 3 or 4 neurological events occurred in 28 (19%) patients. Serious adverse events (any grade) occurred in 74 (50%) patients. Deaths due to adverse events occurred in four (3%) patients, one of which was deemed to be treatment-related (multisystem organ failure).
Axicabtagene ciloleucel showed high rates of durable responses and had a manageable safety profile in patients with relapsed or refractory indolent non-Hodgkin lymphoma.
Kite, a Gilead Company
Adenosine is a constituent of many molecules of life; increased free extracellular adenosine indicates cell damage or metabolic stress. The importance of adenosine signaling in basal physiology, as ...opposed to adaptive responses to danger/damage situations, is unclear. We generated mice lacking all four adenosine receptors (ARs), Adora1-/-;Adora2a-/-;Adora2b-/-;Adora3-/- (quad knockout QKO), to enable investigation of the AR dependence of physiologic processes, focusing on body temperature. The QKO mice demonstrate that ARs are not required for growth, metabolism, breeding, and body temperature regulation (diurnal variation, response to stress, and torpor). However, the mice showed decreased survival starting at about 15 weeks of age. While adenosine agonists cause profound hypothermia via each AR, adenosine did not cause hypothermia (or bradycardia or hypotension) in QKO mice, indicating that AR-independent signals do not contribute to adenosine-induced hypothermia. The hypothermia elicited by adenosine kinase inhibition (with A134974), inosine, or uridine also required ARs, as each was abolished in the QKO mice. The proposed mechanism for uridine-induced hypothermia is inhibition of adenosine transport by uridine, increasing local extracellular adenosine levels. In contrast, adenosine 5'-monophosphate (AMP)-induced hypothermia was attenuated in QKO mice, demonstrating roles for both AR-dependent and AR-independent mechanisms in this process. The physiology of the QKO mice appears to be the sum of the individual knockout mice, without clear evidence for synergy, indicating that the actions of the four ARs are generally complementary. The phenotype of the QKO mice suggests that, while extracellular adenosine is a signal of stress, damage, and/or danger, it is less important for baseline regulation of body temperature.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lunar and terrestrial planet formation in the Grand Tack scenario Jacobson, S. A.; Morbidelli, A.
Philosophical transactions of the Royal Society of London. Series A: Mathematical, physical, and engineering sciences,
09/2014, Letnik:
372, Številka:
2024
Journal Article
Recenzirano
Odprti dostop
We present conclusions from a large number of N-body simulations of the giant impact phase of terrestrial planet formation. We focus on new results obtained from the recently proposed Grand Tack ...model, which couples the gas-driven migration of giant planets to the accretion of the terrestrial planets. The giant impact phase follows the oligarchic growth phase, which builds a bi-modal mass distribution within the disc of embryos and planetesimals. By varying the ratio of the total mass in the embryo population to the total mass in the planetesimal population and the mass of the individual embryos, we explore how different disc conditions control the final planets. The total mass ratio of embryos to planetesimals controls the timing of the last giant (Moon-forming) impact and its violence. The initial embryo mass sets the size of the lunar impactor and the growth rate of Mars. After comparing our simulated outcomes with the actual orbits of the terrestrial planets (angular momentum deficit, mass concentration) and taking into account independent geochemical constraints on the mass accreted by the Earth after the Moon-forming event and on the time scale for the growth of Mars, we conclude that the protoplanetary disc at the beginning of the giant impact phase must have had most of its mass in Mars-sized embryos and only a small fraction of the total disc mass in the planetesimal population. From this, we infer that the Moon-forming event occurred between approximately 60 and approximately 130 Myr after the formation of the first solids and was caused most likely by an object with a mass similar to that of Mars.
In the 10 years since our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors, no developments have led to major ...changes in the recommendations. However, there have been so many other developments that an update is needed. The fact that the structure of one of the adenosine receptors has recently been solved has already led to new ways of in silico screening of ligands. The evidence that adenosine receptors can form homo- and heteromultimers has accumulated, but the functional significance of such complexes remains unclear. The availability of mice with genetic modification of all the adenosine receptors has led to a clarification of the functional roles of adenosine, and to excellent means to study the specificity of drugs. There are also interesting associations between disease and structural variants in one or more of the adenosine receptors. Several new selective agonists and antagonists have become available. They provide improved possibilities for receptor classification. There are also developments hinting at the usefulness of allosteric modulators. Many drugs targeting adenosine receptors are in clinical trials, but the established therapeutic use is still very limited.
Earth and the Moon are shown here to have indistinguishable oxygen isotope ratios, with a difference in Δ'¹⁷ O of −1 ± 5 parts per million (2 standard error). On the basis of these data and our new ...planet formation simulations that include a realistic model for primordial oxygen isotopic reservoirs, our results favor vigorous mixing during the giant impact and therefore a high-energy, high-angular-momentum impact. The results indicate that the late veneer impactors had an average Δ'¹⁷ O within approximately 1 per mil of the terrestrial value, limiting possible sources for this late addition of mass to the Earth-Moon system.
Available COVID-19 mortality indices are limited to acute inpatient data. Using nationwide medical administrative data available prior to SARS-CoV-2 infection from the US Veterans Health ...Administration (VA), we developed the VA COVID-19 (VACO) 30-day mortality index and validated the index in two independent, prospective samples.
We reviewed SARS-CoV-2 testing results within the VA between February 8 and August 18, 2020. The sample was split into a development cohort (test positive between March 2 and April 15, 2020), an early validation cohort (test positive between April 16 and May 18, 2020), and a late validation cohort (test positive between May 19 and July 19, 2020). Our logistic regression model in the development cohort considered demographics (age, sex, race/ethnicity), and pre-existing medical conditions and the Charlson Comorbidity Index (CCI) derived from ICD-10 diagnosis codes. Weights were fixed to create the VACO Index that was then validated by comparing area under receiver operating characteristic curves (AUC) in the early and late validation cohorts and among important validation cohort subgroups defined by sex, race/ethnicity, and geographic region. We also evaluated calibration curves and the range of predictions generated within age categories. 13,323 individuals tested positive for SARS-CoV-2 (median age: 63 years; 91% male; 42% non-Hispanic Black). We observed 480/3,681 (13%) deaths in development, 253/2,151 (12%) deaths in the early validation cohort, and 403/7,491 (5%) deaths in the late validation cohort. Age, multimorbidity described with CCI, and a history of myocardial infarction or peripheral vascular disease were independently associated with mortality-no other individual comorbid diagnosis provided additional information. The VACO Index discriminated mortality in development (AUC = 0.79, 95% CI: 0.77-0.81), and in early (AUC = 0.81 95% CI: 0.78-0.83) and late (AUC = 0.84, 95% CI: 0.78-0.86) validation. The VACO Index allows personalized estimates of 30-day mortality after COVID-19 infection. For example, among those aged 60-64 years, overall mortality was estimated at 9% (95% CI: 6-11%). The Index further discriminated risk in this age stratum from 4% (95% CI: 3-7%) to 21% (95% CI: 12-31%), depending on sex and comorbid disease.
Prior to infection, demographics and comorbid conditions can discriminate COVID-19 mortality risk overall and within age strata. The VACO Index reproducibly identified individuals at substantial risk of COVID-19 mortality who might consider continuing social distancing, despite relaxed state and local guidelines.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract We report on ephemerides for the satellites of Pluto based on the large set of astrometric measurements. Our orbit fit yielded the following masses with 1 σ uncertainties: GM Pluto = 869.3 ± ...0.4 km 3 s −2 , GM Charon = 106.1 ± 0.3 km 3 s −2 , GM Nix = 1.50 ± 0.52 × 10 −3 km 3 s −2 , GM Hydra = 2.01 ± 0.27 × 10 −3 km 3 s −2 , corresponding to the densities of ρ Pluto = 1.853 ± 0.004 g cm −3 , ρ Charon = 1.705 ± 0.006 g cm −3 , ρ Nix = 0.88 ± 0.31 g cm −3 , and ρ Hydra = 1.21 ± 0.19 g cm −3 . Masses of Kerberos and Styx remain unconstrained, and it is unlikely that we will be able to measure them even if we obtain abundant 1 mas precision astrometry during the next 20 yr. We summarize the results of orbit integration in terms of osculating and precessing ellipse model mean elements. All satellites reside in near-circular orbits, and Kerberos and Styx have 0.4 deg and 0.3 deg inclinations with respect to Charon’s orbit plane. The nodal regression periods for Kerberos and Hydra are ∼9 and ∼14 yr respectively. We found that Charon’s orbit pole can be approximated as: R.A. = 133.0073 + 0.0036 T deg, and decl. = –6.2449 + 2.5 × 10 −5 T deg, where T is Julian centuries from the epoch J2000, based on 5000 yr of orbit integration.
A2B Adenosine Receptor and Cancer Gao, Zhan-Guo; Jacobson, Kenneth A.
International journal of molecular sciences,
10/2019, Letnik:
20, Številka:
20
Journal Article
Recenzirano
Odprti dostop
There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors (GPCRs). Locally produced adenosine is a suppressant in anti-tumor immune ...surveillance. The A2BAR, coupled to both Gαs and Gαi G proteins, is one of the several GPCRs that are expressed in a significantly higher level in certain cancer tissues, in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are novel, potentially attractive anticancer agents. Several antagonists targeting A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various cancers, and the rationale of using A2BAR antagonists in cancer therapy.
One in 4 Americans >40 years of age takes a statin to reduce the risk of myocardial infarction, ischemic stroke, and other complications of atherosclerotic disease. The most effective statins produce ...a mean reduction in low-density lipoprotein cholesterol of 55% to 60% at the maximum dosage, and 6 of the 7 marketed statins are available in generic form, which makes them affordable for most patients. Primarily using data from randomized controlled trials, supplemented with observational data where necessary, this scientific statement provides a comprehensive review of statin safety and tolerability. The review covers the general patient population, as well as demographic subgroups, including the elderly, children, pregnant women, East Asians, and patients with specific conditions such as chronic disease of the kidney and liver, human immunodeficiency viral infection, and organ transplants. The risk of statin-induced serious muscle injury, including rhabdomyolysis, is <0.1%, and the risk of serious hepatotoxicity is ≈0.001%. The risk of statin-induced newly diagnosed diabetes mellitus is ≈0.2% per year of treatment, depending on the underlying risk of diabetes mellitus in the population studied. In patients with cerebrovascular disease, statins possibly increase the risk of hemorrhagic stroke; however, they clearly produce a greater reduction in the risk of atherothrombotic stroke and thus total stroke, as well as other cardiovascular events. There is no convincing evidence for a causal relationship between statins and cancer, cataracts, cognitive dysfunction, peripheral neuropathy, erectile dysfunction, or tendonitis. In US clinical practices, roughly 10% of patients stop taking a statin because of subjective complaints, most commonly muscle symptoms without raised creatine kinase. In contrast, in randomized clinical trials, the difference in the incidence of muscle symptoms without significantly raised creatinine kinase in statin-treated compared with placebo-treated participants is <1%, and it is even smaller (0.1%) for patients who discontinued treatment because of such muscle symptoms. This suggests that muscle symptoms are usually not caused by pharmacological effects of the statin. Restarting statin therapy in these patients can be challenging, but it is important, especially in patients at high risk of cardiovascular events, for whom prevention of these events is a priority. Overall, in patients for whom statin treatment is recommended by current guidelines, the benefits greatly outweigh the risks.
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