ALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates.... Show moreALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates. Growing evidence suggests that the combination of drug and immune therapies greatly improves patient survival; however, due to the low immunogenicity of the tumors, ALK-positive patients do not respond to currently available immunotherapies. Tumor-associated macrophages (TAMs) play a crucial role in facilitating lung cancer growth by suppressing tumoricidal immune activation and absorbing chemotherapeutics. However, they can also be programmed toward a pro-inflammatory tumor suppressive phenotype, which represents a highly active area of therapy development. Iron loading of TAMs can achieve such reprogramming correlating with an improved prognosis in lung cancer patients. We previously showed that superparamagnetic iron oxide nanoparticles containing core-cross-linked polymer micelles (SPION-CCPMs) target macrophages and stimulate pro-inflammatory activation. Here, we show that SPION-CCPMs stimulate TAMs to secrete reactive nitrogen species and cytokines that exert tumoricidal activity. We further show that SPION-CCPMs reshape the immunosuppressive Eml4-Alk lung tumor microenvironment (TME) toward a cytotoxic profile hallmarked by the recruitment of CD8+ T cells, suggesting a multifactorial benefit of SPION-CCPM application. When intratracheally instilled into lung cancer-bearing mice, SPION-CCPMs delay tumor growth and, after first line therapy with a TKI, halt the regrowth of relapsing tumors. These findings identify SPIONs-CCPMs as an adjuvant therapy, which remodels the TME, resulting in a delay in the appearance of resistant tumors. Show less
Chen, Y.; Nieuwendijk, A.M.C.H. van den; Wu, L.; Moran, E.; Skoulikopoulou, F.; Riet, V. van; ... ; Armstrong, Z.W.B. 2023
Increasing knowledge of the impacts of pesticides on soil ecological communities is fundamental to a comprehensive understanding of the functional changes in the global agroecosystem industry. In... Show moreIncreasing knowledge of the impacts of pesticides on soil ecological communities is fundamental to a comprehensive understanding of the functional changes in the global agroecosystem industry. In this study, we examined microbial community shifts in the gut of the soil-dwelling organism Enchytraeus crypticus and functional shifts in the soil microbiome (bacteria and viruses) after 21 d of exposure to difenoconazole, one of the main fungicides in intensified agriculture. Our results demonstrated reduced body weight and increased oxidative stress levels of E. crypticus under difenoconazole treatment. Meanwhile, difenoconazole not only altered the composition and structure of the gut microbial community, but also interfered with the soil-soil fauna microecology stability by impairing the abundance of beneficial bacteria. Using soil metagenomics, we revealed that bacterial genes encoding detoxification and viruses encoding carbon cycle genes exhibited a dependent enrichment in the toxicity of pesticides via metabolism. Taken together, these findings advance the understanding of the ecotoxicological impact of residual difenoconazole on the soil-soil fauna micro-ecology, and the ecological importance of virus-encoded auxiliary metabolic genes under pesticide stress. Show less
Purpose To describe the adverse events associated with brolucizumab, in particular the sequence of intraocular inflammation (IOI), retinal vasculitis (RV), and/or retinal vascular occlusion (RO)... Show morePurpose To describe the adverse events associated with brolucizumab, in particular the sequence of intraocular inflammation (IOI), retinal vasculitis (RV), and/or retinal vascular occlusion (RO).Methods This was an unmasked post hoc analysis of the randomized HAWK/HARRIER clinical trials. Patients with neovascular AMD in the brolucizumab arms of the trials were included. IOI-related adverse events reported by study investigators were analyzed to determine early signs and the time course of IOI-related adverse events, using a subgroup of patients with definite/probable IOI cases identified in an independent unmasked post hoc review by an external safety review committee. A limited literature review on MI following anti-VEGF therapy was also conducted.Results Among 50 patients with definite/probable IOI cases identified by the safety review committee, 12 had RV or RO adverse events reported by the investigators. For 6 of 12, IOI (other than RV) was reported before RV or RO. The duration from the first IOI adverse event to the first RV or RO adverse event ranged from 16 to 171 days for 5 patients and was 553 days for 1 patient. Four of the 6 patients received >= 1 brolucizumab injection on or after the date of the first IOI adverse event and before the first RV or RO adverse event.Conclusions IOI may precede RV or RO in some patients treated with brolucizumab. Show less
Context. The physical and chemical conditions in Class 0/I protostars are fundamental in unlocking the protostellar accretion process and its impact on planet formation.Aims: The aim is to... Show moreContext. The physical and chemical conditions in Class 0/I protostars are fundamental in unlocking the protostellar accretion process and its impact on planet formation.Aims: The aim is to determine which physical components are traced by different molecules at subarcsecond scales (<100-400 au).Methods: We used a suite of Atacama Large Millimeter/submillimeter Array (ALMA) datasets in band 6 (1 mm), band 5 (1.8 mm), and band 3 (3 mm) at spatial resolutions 0.″5-3″ for 16 protostellar sources. For a subset of sources, Atacama Compact Array (ACA) data at band 6 with a spatial resolution of 6″ were added. The availability of low- and high-excitation lines and data on small and larger scales, is important to understand the full picture.Results: The protostellar envelope is well traced by C18O, DCO+, and N2D+, which stems from the freeze-out of CO governing the chemistry at envelope scales. Molecular outflows are seen in classical shock tracers such as SiO and SO, but ice-mantle products such as CH3OH and HNCO that are released with the shock are also observed. The molecular jet is a key component of the system. It is only present at the very early stages, and it is prominent not only in SiO and SO, but occasionally also in H2CO. The cavity walls show tracers of UV-irradiation such as C2H, c-C3H2 and CN. In addition to showing emission from complex organic molecules (COMs), the hot inner envelope also presents compact emission from small molecules such as H2S, SO, OCS, and H13CN, which most likely are related to ice sublimation and high-temperature chemistry.Conclusions: Subarcsecond millimeter-wave observations allow us to identify these (simple) molecules that best trace each of the physical components of a protostellar system. COMs are found both in the hot inner envelope (high-excitation lines) and in the outflows (lower-excitation lines) with comparable abundances. COMs can coexist with hydrocarbons in the same protostellar sources, but they trace different components. In the near future, mid-infrared observations with JWST-MIRI will provide complementary information about the hottest gas and the ice-mantle content, at unprecedented sensitivity and at resolutions comparable to ALMA for the same sources. Show less
Gaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in beta-glucocerebrosidase (GBA). Current treatments require rapid disease diagnosis and a means of monitoring... Show moreGaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in beta-glucocerebrosidase (GBA). Current treatments require rapid disease diagnosis and a means of monitoring therapeutic efficacy, both of which may be supported by the use of GBA-targeting activity-based probes (ABPs). Here, we report the synthesis and structural analysis of a range of cyclophellitol epoxide and aziridine inhibitors and ABPs for GBA. We demonstrate their covalent mechanism-based mode of action and uncover binding of the new N-functionalised aziridines to the ligand binding cleft. These inhibitors became scaffolds for the development of ABPs; the O6-fluorescent tags of which bind in an allosteric site at the dimer interface. Considering GBA's preference for O6- and N-functionalised reagents, a bi-functional aziridine ABP was synthesized as a potentially more powerful imaging agent. Whilst this ABP binds to two unique active site clefts of GBA, no further benefit in potency was achieved over our first generation ABPs. Nevertheless, such ABPs should serve useful in the study of GBA in relation to GD and inform the design of future probes. Show less
Sun, Z.; Qiao, D.; Shi, Y.; Barz, M.; Liu, L.; Chen, Y. 2021
It remains unclear how the precise length of one-dimensional nanovehicles influences the characters of vaccination. Here, a unimolecular nanovehicle with tailored size and aspect ratio (AR) is... Show moreIt remains unclear how the precise length of one-dimensional nanovehicles influences the characters of vaccination. Here, a unimolecular nanovehicle with tailored size and aspect ratio (AR) is applied to deliver CpG oligodeoxynucleotide, a Toll-like receptor (TLR) 9 agonist, as an adjuvant of recombinant hepatitis B virus surface antigen (rHBsAg), for treating chronic hepatitis B (CHB). Cationic nanovehicles with fixed width (ca. 45 nm) but varied length (46 nm-180 nm), AR from 1 to 4, are prepared through controlled polymerization and are loaded with CpG by electrostatic interaction. We reveal that the nanoadjuvant with AR = 2 shows the highest retention in proximal lymph nodes. Importantly, it is more easily internalized into antigen-presenting cells and accumulates in the late endosome, where TLR9 is located. Such a nanoadjuvant exhibits the strongest immune response with rHBsAg to clear the hepatitis B virus in the CHB mouse model, showing that the AR of nanovehicles governs the efficiency of vaccination. Show less
Background The hallmarks of cancer provide a highly cited and well-used conceptual framework for describing the processes involved in cancer cell development and tumourigenesis. However, methods... Show moreBackground The hallmarks of cancer provide a highly cited and well-used conceptual framework for describing the processes involved in cancer cell development and tumourigenesis. However, methods for translating these high-level concepts into data-level associations between hallmarks and genes (for high throughput analysis), vary widely between studies. The examination of different strategies to associate and map cancer hallmarks reveals significant differences, but also consensus. Results Here we present the results of a comparative analysis of cancer hallmark mapping strategies, based on Gene Ontology and biological pathway annotation, from different studies. By analysing the semantic similarity between annotations, and the resulting gene set overlap, we identify emerging consensus knowledge. In addition, we analyse the differences between hallmark and gene set associations using Weighted Gene Co-expression Network Analysis and enrichment analysis. Conclusions Reaching a community-wide consensus on how to identify cancer hallmark activity from research data would enable more systematic data integration and comparison between studies. These results highlight the current state of the consensus and offer a starting point for further convergence. In addition, we show how a lack of consensus can lead to large differences in the biological interpretation of downstream analyses and discuss the challenges of annotating changing and accumulating biological data, using intermediate knowledge resources that are also changing over time. Show less
Amylases are key enzymes in the processing of starch in many kingdoms of life. They are important catalysts in industrial biotechnology where they are applied in, among others, food processing and... Show moreAmylases are key enzymes in the processing of starch in many kingdoms of life. They are important catalysts in industrial biotechnology where they are applied in, among others, food processing and the production of detergents. In man amylases are the first enzymes in the digestion of starch to glucose and arguably also the preferred target in therapeutic strategies aimed at the treatment of type 2 diabetes patients through down-tuning glucose assimilation. Efficient and sensitive assays that report selectively on retaining amylase activities irrespective of the nature and complexity of the biomaterial studied are of great value both in finding new and effective human amylase inhibitors and in the discovery of new microbial amylases with potentially advantageous features for biotechnological application. Activity-based protein profiling (ABPP) of retaining glycosidases is inherently suited for the development of such an assay format. We here report on the design and synthesis of 1,6-epi-cyclophellitol-based pseudodisaccharides equipped with a suite of reporter entities and their use in ABPP of retaining amylases from human saliva, murine tissue as well as secretomes from fungi grown on starch. The activity and efficiency of the inhibitors and probes are substantiated by extensive biochemical analysis, and the selectivity for amylases over related retaining endoglycosidases is validated by structural studies. Show less
In tonal languages such as Mandarin, both lexical tone and sentence intonation are primarily signaled by F0. Their F0 encodings are sometimes in conflict and sometimes in congruency. The present... Show moreIn tonal languages such as Mandarin, both lexical tone and sentence intonation are primarily signaled by F0. Their F0 encodings are sometimes in conflict and sometimes in congruency. The present study investigated how tone and intonation, with F0 encodings in conflict or in congruency, are processed and how semantic context may affect their processing. To this end, tone and intonation identification experiments were conducted in both semantically neutral and constraining contexts. Results showed that the overall performance of tone identification was better than that of intonation. Specifically, tone identification was seldom affected by intonation information irrespective of semantic contexts. However, intonation identification, particularly question intonation, was susceptible to the final lexical tone identity and affected by the semantic context. In the semantically neutral context, questions ending with a rising tone and a falling tone were equally difficult to identify. In the semantically constraining context, questions ending with a falling tone were much better identified than those ending with a rising tone. This perceptual asymmetry suggests that top-down information provided by the semantically constraining context can play a facilitating role for listeners to disentangle intonational information from tonal information, but mainly in sentences with the lexical falling tone in the final position. Show less
Ahlgren, P.; Chen, Y.; Colliander, C.; Eck, N.J.P. van 2020
The effects of enhancing direct citations, with respect to publication–publication relatedness measurement, by indirect citation relations (bibliographic coupling, cocitation, and extended direct... Show moreThe effects of enhancing direct citations, with respect to publication–publication relatedness measurement, by indirect citation relations (bibliographic coupling, cocitation, and extended direct citations) and text relations on clustering solution accuracy are analyzed. For comparison, we include each approach that is involved in the enhancement of direct citations. In total, we investigate the relative performance of seven approaches. To evaluate the approaches we use a methodology proposed by earlier research. However, the evaluation criterion used is based on MeSH, one of the most sophisticated publication-level classification schemes available. We also introduce an approach, based on interpolated accuracy values, by which overall relative clustering solution accuracy can be studied. The results show that the cocitation approach has the worst performance, and that the direct citations approach is outperformed by the other five investigated approaches. The extended direct citations approach has the best performance, followed by an approach in which direct citations are enhanced by the BM25 textual relatedness measure. An approach that combines direct citations with bibliographic coupling and cocitation performs slightly better than the bibliographic coupling approach, which in turn has a better performance than the BM25 approach. Show less
Objective To evaluate the development and implementation of clinical practice guidelines for the management of depression globally.Methods We conducted a systematic review of existing guidelines... Show moreObjective To evaluate the development and implementation of clinical practice guidelines for the management of depression globally.Methods We conducted a systematic review of existing guidelines for the management of depression in adults with major depressive or bipolar disorder. For each identified guideline, we assessed compliance with measures of guideline development quality (such as transparency in guideline development processes and funding, multidisciplinary author group composition, systematic review of comparative efficacy research) and implementation (such as quality indicators). We compared guidelines from low- and middle-income countries with those from high-income countries.Findings We identified 82 national and 13 international clinical practice guidelines from 83 countries in 27 languages. Guideline development processes and funding sources were explicitly specified in a smaller proportion of guidelines from low- and middle-income countries (8/29; 28%) relative to high-income countries (35/58; 60%). Fewer guidelines (2/29; 7%) from low- and middle-income countries, relative to high-income countries (22/58; 38%), were authored by a multidisciplinary development group. A systematic review of comparative effectiveness was conducted in 31% (9/29) of low- and middle-income country guidelines versus 71% (41/58) of high-income country guidelines. Only 10% (3/29) of low- and middle-income country and 19% (11/58) of high-income country guidelines described plans to assess quality indicators or recommendation adherence.Conclusion Globally, guideline implementation is inadequately planned, reported and measured. Narrowing disparities in the development and implementation of guidelines in low- and middle-income countries is a priority. Future guidelines should present strategies to implement recommendations and measure feasibility, cost-effectiveness and impact on health outcomes. Show less
