Targeting CD83 in mantle cell lymphoma with anti-human CD83 antibody

Objectives: Effective antibody–drug conjugates (ADCs) provide potent targeted cancer therapies. CD83 is expressed on activated immune cells including B cells and is a therapeutic target for Hodgkin lymphoma. Our objective was to determine CD83 expression on non-Hodgkin lymphoma (NHL) and its therapeutic potential to treat mantle cell lymphoma (MCL) which is currently an incurable NHL. Methods: We analysed CD83 expression on MCL cell lines and the lymph node/bone marrow biopsies of MCL patients. We tested the killing effect of CD83 ADC in vitro and in an in vivo xenograft MCL mouse model. Results: CD83 is expressed on MCL, and its upregulation is correlated with the nuclear factor κB (NF-κB) activation. CD83 ADC kills MCL in vitro and in vivo. Doxorubicin and cyclophosphamide (CP), which are included in the current treatment regimen for MCL, enhance the NF-κB activity and increase CD83 expression on MCL cell lines. The combination of CD83 ADC with doxorubicin and CP has synergistic killing effect of MCL. Conclusion: This study provides evidence that a novel immunotherapeutic agent CD83 ADC, in combination with chemotherapy, has the potential to enhance the efficacy of current treatments for MCL

Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens

The characterization of human dendritic cell (DC) subsets is essential for the design of new vaccines. We report the first detailed functional analysis of the human CD141+ DC subset. CD141+ DCs are found in human lymph nodes, bone marrow, tonsil, and blood, and the latter proved to be the best source of highly purified cells for functional analysis. They are characterized by high expression of toll-like receptor 3, production of IL-12p70 and IFN-β, and superior capacity to induce T helper 1 cell responses, when compared with the more commonly studied CD1c+ DC subset. Polyinosine-polycytidylic acid (poly I:C)–activated CD141+ DCs have a superior capacity to cross-present soluble protein antigen (Ag) to CD8+ cytotoxic T lymphocytes than poly I:C–activated CD1c+ DCs. Importantly, CD141+ DCs, but not CD1c+ DCs, were endowed with the capacity to cross-present viral Ag after their uptake of necrotic virus-infected cells. These findings establish the CD141+ DC subset as an important functionally distinct human DC subtype with characteristics similar to those of the mouse CD8α+ DC subset. The data demonstrate a role for CD141+ DCs in the induction of cytotoxic T lymphocyte responses and suggest that they may be the most relevant targets for vaccination against cancers, viruses, and other pathogens

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Optimization of Sensing and Feedback Control for Vibration/Flutter of Rotating Disk by PZT Actuators via Air Coupled Pressure

In this paper, a feedback control mechanism and its optimization for rotating disk vibration/flutter via changes of air-coupled pressure generated using piezoelectric patch actuators are studied. A thin disk rotates in an enclosure, which is equipped with a feedback control loop consisting of a micro-sensor, a signal processor, a power amplifier, and several piezoelectric (PZT) actuator patches distributed on the cover of the enclosure. The actuator patches are mounted on the inner or the outer surfaces of the enclosure to produce necessary control force required through the airflow around the disk. The control mechanism for rotating disk flutter using enclosure surfaces bonded with sensors and piezoelectric actuators is thoroughly studied through analytical simulations. The sensor output is used to determine the amount of input to the actuator for controlling the response of the disk in a closed loop configuration. The dynamic stability of the disk-enclosure system, together with the feedback control loop, is analyzed as a complex eigenvalue problem, which is solved using Galerkin’s discretization procedure. The results show that the disk flutter can be reduced effectively with proper configurations of the control gain and the phase shift through the actuations of PZT patches. The effectiveness of different feedback control methods in altering system characteristics and system response has been investigated. The control capability, in terms of control gain, phase shift, and especially the physical configuration of actuator patches, are also evaluated by calculating the complex eigenvalues and the maximum displacement produced by the actuators. To achieve a optimal control performance, sizes, positions and shapes of PZT patches used need to be optimized and such optimization has been achieved through numerical simulations

Promoting the Near-Infrared-II Fluorescence of Diketopyrrolopyrrole-Based Dye for In Vivo Imaging via Donor Engineering

Small-molecule dyes for fluorescence imaging in the second near-infrared region (NIR-II, 900–1880 nm) hold great promise in clinical applications. Constructing donor–acceptor–donor (D–A–D) architectures has been recognized to be a feasible strategy to achieve NIR-II fluorescence. However, the development of NIR-II dyes via such a scheme is hampered by the lack of high-performance electron acceptors and donors. Diketopyrrolopyrrole (DPP), as a classic organic optoelectronic material, enjoys strong light absorption, high fluorescence quantum yield (QY), and facile derivatization. Nevertheless, its application in the NIR-II imaging field has been hindered by its limited electron-withdrawing ability and the aggregation-caused quenching (ACQ) effect resulting from the planar structure of DPP. Herein, with DPP as an electron acceptor and through donor engineering, we have successfully designed and synthesized a DPP-based dye named T-27, in which the strong D–A interaction confers excellent NIR absorption and high-brightness NIR-II fluorescence tail emission. By strategically introducing long alkyl chains on the donor unit to increase intermolecular spacing and reduce the influence of solvent molecules, T-27 exhibits an improved anti-ACQ effect in aqueous solutions. After being encapsulated into DSPE-PEG2000, T-27 nanoparticles (NPs) show a relative NIR-II fluorescence QY of 3.4% in water, representing the highest value among the DPP-based NIR-II dyes reported to date. The outstanding photophysical properties of T-27 NPs enable multimode NIR-IIa bioimaging under 808 nm excitation. As such, the T-27 NPs can distinguish mouse femoral vein and artery and achieve cerebral vascular microscopic imaging with a penetrating depth of 800 μm, demonstrating the capability for high-resolution deep-tissue imaging. This work holds significant potential in the field of bioimaging and provides a new strategy for developing bright NIR-II dyes