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Disease relapse or progression is a major cause of death following umbilical cord blood (UCB) transplantation (UCBT) in patients with high-risk, relapsed or refractory acute lymphoblastic leukemia (ALL). Adoptive transfer of donor-derived T cells modified to express a tumor-targeted chimeric antigen receptor (CAR) may eradicate persistent disease after transplantation. Such therapy has not been available to UCBT recipients, however, due to the low numbers of available UCB T cells and the limited capacity for ex vivo expansion of cytolytic cells. We have developed a novel strategy to expand UCB T cells to clinically relevant numbers in the context of exogenous cytokines. UCB-derived T cells cultured with interleukin (IL)-12 and IL-15 generated >150-fold expansion with a unique central memory/effector phenotype. Moreover, UCB T cells were modified to both express the CD19-specific CAR, 1928z, and secrete IL-12. 1928z/IL-12 UCB T cells retained a central memory-effector phenotype and had increased antitumor efficacy in vitro. Furthermore, adoptive transfer of 1928z/IL-12 UCB T cells resulted in significantly enhanced survival of CD19 + tumor-bearing SCID-Beige mice. Clinical translation of CAR-modified UCB T cells could augment the graft-versus-leukemia effect after UCBT and thus further improve disease-free survival of transplant patients with B-cell ALL.

Controlling the strain in two-dimensional （2D） materials is an interesting avenue to tailor the mechanical properties of nanoelectromechanical systems. Here, we demonstrate a technique to fabricate ultrathin tantalum oxide nanomechanical resonators with large stress by the laser oxidation of nano-drumhead resonators composed of tantalum diselenide （TaSe2）, a layered 2D material belonging to the metal dichalcogenides. Before the study of their mechanical properties with a laser interferometer, we verified the oxidation and crystallinity of the freely suspended tantalum oxide using high-resolution electron microscopy. We demonstrate that the stress of tantalum oxide resonators increases by 140 MPa （with respect to pristine TaSe2 resonators）, which causes an enhancement in the quality factor （14 times larger） and resonance frequency （9 times larger） of these resonators.

In July 2022, the ongoing monkeypox (MPX) outbreak was declared a public health emergency of international concern. Modified vaccinia Ankara—Bavarian Nordic (MVA-BN, also known as Imvamune, JYNNEOS or Imvanex) is a third-generation smallpox vaccine that is authorized and in use as a vaccine against MPX. To date, there are no data showing MPX virus (MPXV)-neutralizing antibodies in vaccinated individuals nor vaccine efficacy against MPX. Here we show that MPXV-neutralizing antibodies can be detected after MPXV infection and after historic smallpox vaccination. However, a two-shot MVA-BN immunization series in non-primed individuals yields relatively low levels of MPXV-neutralizing antibodies. Dose-sparing of an MVA-based influenza vaccine leads to lower MPXV-neutralizing antibody levels, whereas a third vaccination with the same MVA-based vaccine significantly boosts the antibody response. As the role of MPXV-neutralizing antibodies as a correlate of protection against disease and transmissibility is currently unclear, we conclude that cohort studies following vaccinated individuals are necessary to assess vaccine efficacy in at-risk populations. Historic smallpox vaccination and monkeypox virus (MPXV) infection elicit MPXV-neutralizing antibodies, but MPXV-neutralizing antibodies are less frequent and of lower magnitude after vaccination with MVA-BN—the vaccine approved and in use for protection against MPXV and smallpox.

Photographic multi-station observations of 47 Leonid meteors are presented that were obtained from two ground locations in Spain during the 1999 meteor storm. We find an unresolved compact cluster of radiants at α = 153.67 ± 0.05 and δ = 21.70 ± 0.05 for a mean solar longitude of 235.282 (J2000). The position is identical to that of the Nov. 17/18 outburst of 1998, which implies that both are due to comet 55P/Tempel-Tuttle's ejecta from 1899. We also find a halo which contains about 28% of all meteors. The spatial distribution of radiant positions appears to be Lorentzian, with a similar fraction of meteors in the profile wings as the meteor storm activity curve.

Immune checkpoint inhibitors have revolutionised cancer treatment by offering durable responses to many patients with solid and haematological cancers. The high prices and increasing use of immune checkpoint inhibitors put considerable strain on health-care budgets globally. This financial strain could jeopardise patients’ access to these anti-cancer therapies. However, substantial evidence suggests that immune checkpoint inhibitors are being administered at doses that exceed the minimum dose required for maximum anti-tumour efficacy. Therefore, investigating and implementing the most cost-effective dosing strategies for immune checkpoint inhibitors are urgently necessary. This Personal View provides an overview of existing data on immune checkpoint inhibitor pharmacology and (novel) dosing strategies for anti-PD-1 therapy with nivolumab and pembrolizumab, with a special focus on cost-effectiveness and saving potential. Furthermore, specific recommendations to guide health-care professionals are provided, through the process of prescribing, rounding, preparing, and administering nivolumab and pembrolizumab in the most practical and cost-effective way possible.

Climate, land use, and other anthropogenic and natural drivers have the potential to influence fire dynamics in many regions. To develop a mechanistic understanding of the changing role of these drivers and their impact on atmospheric composition, long-term fire records are needed that fuse information from different satellite and in situ data streams. Here we describe the fourth version of the Global Fire Emissions Database (GFED) and quantify global fire emissions patterns during 1997–2016. The modeling system, based on the Carnegie–Ames–Stanford Approach (CASA) biogeochemical model, has several modifications from the previous version and uses higher quality input datasets. Significant upgrades include (1) new burned area estimates with contributions from small fires, (2) a revised fuel consumption parameterization optimized using field observations, (3) modifications that improve the representation of fuel consumption in frequently burning landscapes, and (4) fire severity estimates that better represent continental differences in burning processes across boreal regions of North America and Eurasia. The new version has a higher spatial resolution (0.25°) and uses a different set of emission factors that separately resolves trace gas and aerosol emissions from temperate and boreal forest ecosystems. Global mean carbon emissions using the burned area dataset with small fires (GFED4s) were 2.2  ×  1015 grams of carbon per year (Pg C yr−1) during 1997–2016, with a maximum in 1997 (3.0 Pg C yr−1) and minimum in 2013 (1.8 Pg C yr−1). These estimates were 11 % higher than our previous estimates (GFED3) during 1997–2011, when the two datasets overlapped. This net increase was the result of a substantial increase in burned area (37 %), mostly due to the inclusion of small fires, and a modest decrease in mean fuel consumption (−19 %) to better match estimates from field studies, primarily in savannas and grasslands. For trace gas and aerosol emissions, differences between GFED4s and GFED3 were often larger due to the use of revised emission factors. If small fire burned area was excluded (GFED4 without the s for small fires), average emissions were 1.5 Pg C yr−1. The addition of small fires had the largest impact on emissions in temperate North America, Central America, Europe, and temperate Asia. This small fire layer carries substantial uncertainties; improving these estimates will require use of new burned area products derived from high-resolution satellite imagery. Our revised dataset provides an internally consistent set of burned area and emissions that may contribute to a better understanding of multi-decadal changes in fire dynamics and their impact on the Earth system. GFED data are available from http://www.globalfiredata.org.

During the past two decades, small-molecule kinase inhibitors have proven to be valuable in the treatment of solid and haematological tumours. However, because of their oral administration, the intrapatient and interpatient exposure to small-molecule kinase inhibitors (SMKIs) is highly variable and is affected by many factors, such as concomitant use of food and herbs. Food–drug interactions are capable of altering the systemic bioavailability and pharmacokinetics of these drugs. The most important mechanisms underlying food–drug interactions are gastrointestinal drug absorption and hepatic metabolism through cytochrome P450 isoenzymes. As food–drug interactions can lead to therapy failure or severe toxicity, knowledge of these interactions is essential. This Review provides a comprehensive overview of published studies involving food–drug interactions and herb–drug interactions for all registered SMKIs up to Oct 1, 2019. We critically discuss US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines concerning food-drug interactions and offer clear recommendations for their management in clinical practice.

In a multicenter, controlled trial, patients undergoing transplantation of a liver from a donor after circulatory death were randomly assigned to receive the liver after hypothermic oxygenated machine perfusion or conventional static cold storage. Hypothermic perfusion led to a lower risk of post-transplantation nonanastomotic biliary strictures.

Background: Potential drug–drug interactions (PDDIs) in patients with cancer are common, but have not previously been quantified for oral anticancer treatment. We assessed the prevalence and seriousness of potential PDDIs among ambulatory cancer patients on oral anticancer treatment. Methods: A search was conducted in a computer-based medication prescription system for dispensing oral anticancer drugs to outpatients in three Dutch centres. Potential drug–drug interactions were identified using electronic (Drug Interaction Fact software) and manual screening methods (peer-reviewed reports). Results: In the 898 patients included in the study, 1359 PDDIs were identified in 426 patients (46%, 95% confidence interval (CI)=42–50%). In 143 patients (16%), a major PDDI was identified. The drug classes most frequently involved in a major PDDI were coumarins and opioids. The majority of cases concerned central nervous system interactions, PDDIs that can cause gastrointestinal toxicity and prolongation of QT intervals. In multivariate analysis, concomitant use of more drugs (odds ratio (OR)=1.66, 95% CI=1.54–1.78, P <0001) and genito-urinary cancer (OR=0.25, 95% CI=0.12–0.52, P <0001) were risk factors. Conclusion: Potential drug–drug interactions are very common among cancer patients on oral cancer therapy. Physicians and pharmacists should be more aware of these potential interactions.