Myeloid expression of adenosine a2A receptor suppresses T and NK cell responses in the solid tumor microenvironment

High concentrations of adenosine in tumor microenvironments inhibit antitumor cytotoxic lymphocyte responses. Although T cells express inhibitory adenosine A2A receptors (A2AR) that suppress their activation and inhibit immune killing of tumors, a role for myeloid cell A2ARs in suppressing the immune response to tumors has yet to be investigated. In this study, we show that the growth of transplanted syngeneic B16F10 melanoma or Lewis lung carcinoma cells is slowed in Adora2af/f-LysMCre+/- mice, which selectively lack myeloid A2ARs. Reduced melanoma growth is associated with significant increases in MHCII and IL12 expression in tumor-associated macrophages and with >90% reductions in IL10 expression in tumor-associated macrophages, dendritic cells (DC), and Ly6C+ or Ly6G+ myeloid-derived suppressor cells (MDSC). Myeloid deletion of A2ARs significantly increases CD44 expression on tumor-associated T cells and natural killer (NK) cells. Depletion of CD8+ T cells or NK cells in tumor-bearing mice indicates that both cell types initially contribute to slowing melanoma growth in mice lacking myeloid A2A receptors, but tumor suppression mediated by CD8+ T cells is more persistent. Myeloid-selective A2AR deletion significantly reduces lung metastasis of melanomas that express luciferase (for in vivo tracking) and ovalbumin (as a model antigen). Reduced metastasis is associated with increased numbers and activation of NK cells and antigen-specific CD8+ T cells in lung in filtrates. Overall, the findings indicate that myeloid cell A2ARs have direct myelosuppressive effects that indirectly contribute to the suppression of T cells and NK cells in primary and metastatic tumor microenvironments. The results indicate that tumor-associated myeloid cells, including macrophages, DCs, and MDSCs all express immunosuppressive A2ARs that are potential targets of adenosine receptor blockers to enhance immune killing of tumors. ©2014 AACR

The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity

ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol efflux from cells and regulates intracellular cholesterol homeostasis. Here we demonstrate a role of ABCG1 as a mediator of tumour immunity. Abcg1-/- mice have dramatically suppressed subcutaneous MB49-bladder carcinoma and B16-melanoma growth and prolonged survival. We show that reduced tumour growth in Abcg1-/- mice is myeloid cell intrinsic and is associated with a phenotypic shift of the macrophages from a tumour-promoting M2 to a tumour-fighting M1 within the tumour. Abcg1-/- macrophages exhibit an intrinsic bias towards M1 polarization with increased NF-κB activation and direct cytotoxicity for tumour cells in vitro. Overall, our study demonstrates that the absence of ABCG1 inhibits tumour growth through modulation of macrophage function within the tumour, and illustrates a link between cholesterol homeostasis and cancer. © 2015 Macmillan Publishers Limited. All rights reserved

Hair-thread strangulation syndrome in childhood: a systematic review.

Hair-thread strangulation syndrome describes the constriction of a body part by a tightly wound hair or thread. This research aims to review the literature about this entity. A systematic review was performed to characterise hair-thread strangulation syndrome in subjects aged ≤16 years. This pre-registered review (PROSPERO ID: CRD42022363996) followed the PRISMA methodology. Subjects with digital strangulation were significantly younger (median = 4.0 [interquartile range: 2.0-6.1] months; n = 143) than females with genital strangulation (9.0 [6.8-11] years; n = 36), males with genital strangulation (5.1 [1.9-8.0] years; n = 36), and subjects with non-digital and non-genital strangulation (24 [13-48] months; n = 11). Digital strangulation was followed by an amputation in five (3.5%) and a reconstructive surgical intervention in seven (4.9%) cases. Sequelae occurred in four (11%) cases after female genital strangulation: clitoris autoamputation (n = 2) and surgical removal of a necrotic labium minus (n = 2). Severe complications were observed in 14 (39%) cases with male genital strangulation: urethral fistula (n = 7), urethral transection (n = 2), and partial penile autoamputation (n = 5). A partial uvular autoamputation was observed in one case (9.0%) with non-digital and non-genital strangulation. Early recognition and management are crucial to avoid sequelae or long-term care in hair-thread strangulation syndrome

Does size matter?:Hospital volume and resource use in paediatric diabetes care

Aims: Paediatric diabetes care has become increasingly specialised due to the multidisciplinary approach and technological developments. Guidelines recommend sufficient experience of treatment teams. This study evaluates associations between hospital volume and resource use and hospital expenditure in Dutch children with diabetes. Methods: Retrospective cohort study using hospital claims data of 5082 children treated across 44 Dutch hospitals (2019–2020). Hospitals were categorised into three categories; small (≥20–100 patients), medium (≥100–200 patients) and large (≥200 patients). All-cause hospitalisations, consultations, technology and hospital expenditure were analysed and adjusted for age, sex, socio-economic status (SES) and hospital of treatment. Results: Fewer hospitalisations were observed in large hospitals compared to small hospitals (OR 0.48; [95% CI 0.32–0.72]; p &lt; 0.001). Median number of yearly paediatrician visits was 7 in large and 6 in small hospitals, the significance of which was attenuated in multilevel analysis (OR ≥7 consultations: 1.89; [95%CI 0.74–4.83]; p = 0.18). Technology use varies between individual hospitals, whereas pump usage and real-time continuous glucose monitoring showed no significant differences between hospital volumes. Mean overall expenditure was highest in medium-sized centres with €6434 per patient (IQR €2555–7955); the difference in diabetes care costs was not significant between hospital patient volumes. Conclusions: Care provision patterns vary by hospital patient volume. Large hospitals had the lowest hospitalisation rates. The use of diabetes technology was not different between hospital patient volumes. Medium-sized hospitals showed the highest overall expenditure, but diabetes care costs were similar across hospital volumes.</p

MID3: Mission Impossible or Model-Informed Drug Discovery and Development? Point-Counterpoint Discussions on Key Challenges

MID3: Mission Impossible, or Model‐Informed, Drug Discovery and Development? At the 2019 American Society for Clinical Pharmacology and Therapeutics (ASCPT) annual meeting, point‐counterpoint discussions were held on key challenges that limit, and future directions that enhance the adoption of model‐informed drug discovery and development (MID3) across the drug discovery, development, regulatory, and utilization continuum. We envision that the opportunities discussed and lessons learned from having contrasting perspectives on issues that lack consensus may aid our discipline in more effectively implementing MID3 principles

Hoigné's syndrome, an uncommon mimicker of anaphylaxis: Systematic literature review.

The term Hoigné's syndrome denotes a mimicker of anaphylaxis, which occurs immediately after the parenteral administration of a drug and is likely caused by non-thrombotic pulmonary and systemic drug micro-embolization. It has so far been documented uniquely in case reports and small case series. Because this condition has never been systematically evaluated, we performed a structured literature review (pre-registered as CRD42023392962). The search was carried out in Excerpta Medica, National Library of Medicine, and Google Scholar. Cases with features consistent with anaphylaxis, urticaria, angioedema, asthma, syncope, anxiety, or panic attack triggered by needle phobia, and local anesthetic systemic toxicity were excluded. For the final analysis, we retained reports published between 1951 and 2021, which presented 247 patients with Hoigné's syndrome: 37 children and 211 adults with a male: female ratio of 2.1 : 1.0. The patients presented within 1 min after parenteral administration of a drug (intramuscular penicillin in 90 % of the cases) with chest discomfort, shortness of breath, fear of death, psychomotor agitation, and auditory or visual hallucinations and impairment. Recovery occurred within 30 min. The diagnosis of Hoigné's syndrome was also established in five patients 66-91 years of age with pre-existing cardiovascular or pulmonary diseases, who suddenly died after the administration of penicillin despite not exhibiting the aforementioned symptoms. It was therefore speculated that pulmonary drug micro-embolization induced a lethal cardiovascular compromise in these individuals. Histologic investigations supporting this hypothesis were performed in only one case. The diagnosis of Hoigné's pulmonary drug micro-embolization was established also in five patients with pre-existing cardiovascular or pulmonary diseases, who suddenly died after the administration of penicillin despite not exhibiting the afore mentioned symptoms. Histologic investigations supporting this hypothesis were performed in only one case. In conclusion, Hoigné's syndrome is an uncommon non-immune-mediated reaction. This report seeks to promote broader awareness and knowledge regarding this alarming mimicker of anaphylaxis. Diagnosis relies solely on clinical evaluation

The source ambiguity problem: Distinguishing the effects of grammar and processing on acceptability judgments

Judgments of linguistic unacceptability may theoretically arise from either grammatical deviance or significant processing difficulty. Acceptability data are thus naturally ambiguous in theories that explicitly distinguish formal and functional constraints. Here, we consider this source ambiguity problem in the context of Superiority effects: the dispreference for ordering a wh-phrase in front of a syntactically “superior” wh-phrase in multiple wh-questions, e.g., What did who buy? More specifically, we consider the acceptability contrast between such examples and so-called D-linked examples, e.g., Which toys did which parents buy? Evidence from acceptability and self-paced reading experiments demonstrates that (i) judgments and processing times for Superiority violations vary in parallel, as determined by the kind of wh-phrases they contain, (ii) judgments increase with exposure, while processing times decrease, (iii) reading times are highly predictive of acceptability judgments for the same items, and (iv) the effects of the complexity of the wh-phrases combine in both acceptability judgments and reading times. This evidence supports the conclusion that D-linking effects are likely reducible to independently motivated cognitive mechanisms whose effects emerge in a wide range of sentence contexts. This in turn suggests that Superiority effects, in general, may owe their character to differential processing difficulty

Many pion decays of rho(770) and omega(782) mesons in chiral theory

The decays rho(770) to 4 pi and omega(782) to 5pi are considered in detail in the approach based on the Weinberg Lagrangian obtained upon the nonlinear realization of chiral symmetry, added with the term induced by the anomalous Lagrangian of Wess and Zumino. The partial widths and excitation curves of the decays rho^0 to 2 pi^+ 2 pi^-, pi^+ pi^- 2 pi^0, rho^{+-} to 2 pi^{+-} pi^{-+} pi^0, rho^(+-} to pi^(+-} 3 pi^0 are evaluated for e^+e^- annihilation, photoproduction and tau lepton decays. The results of calculations are compared with the recent CMD-2 data on the decay rho^0 to 2 pi^+ 2 pi^- observed in e^+e^- annihilation. The omega to 5 pi decay widths and excitation curves in e^+e^- annihilation are obtained. The angular distributions for various combinations of the final pions in the decays rho to 4 pi and omega to 5 pi are written. The perspectives of the experimental study of the above decays in e^+e^- annihilation, tau lepton decays and photoproduction are discussed.Comment: Revtex, 32 pages including 11 ps figures. Replaced to fit the version published in Phys. Rev. D. Material rearranged, clarifying remarks and references added, typos fixe

Holocene Landscape Dynamics and Long-term Population Trends in the Levant

This paper explores long-term trends in human population and vegetation change in the Levant from the early to the late Holocene in order to assess when and how human impact has shaped the region’s landscapes over the millennia. To do so, we employed multiple proxies and compared archaeological, pollen and palaeoclimate data within a multi-scalar approach in order to assess how Holocene landscape dynamics change at different geographical scales. We based our analysis on 14 fossil pollen sequences and applied a hierarchical agglomerative clustering and community classification in order to define groups of vegetation types (e.g. grassland, wetland, woodland, etc.). Human impact on the landscape has been assessed by the analysis of pollen indicator groups. Archaeological settlement data and Summed Probability Distribution (SPD) of radiocarbon dates have been used to reconstruct long-term demographic trends. In this study, for the first time, the evolution of the human population is estimated statistically and compared with environmental proxies for assessing the interplay of biotic and abiotic factors in shaping the Holocene landscapes in the Levant