Immune Checkpoint Profiling in Humanized Breast Cancer Mice Revealed Cell-Specific LAG-3/PD-1/TIM-3 Co-Expression and Elevated PD-1/TIM-3 Secretion

Checkpoint blockade is particularly based on PD-1/PD-L1-inhibiting antibodies. However, an efficient immunological tumor defense can be blocked not only by PD-(L)1 but also by the presence of additional immune checkpoint molecules. Here, we investigated the co-expression of several immune checkpoint proteins and the soluble forms thereof (e.g., PD-1, TIM-3, LAG-3, PD-L1, PD-L2 and others) in humanized tumor mice (HTM) simultaneously harboring cell line-derived (JIMT-1, MDA-MB-231, MCF-7) or patient-derived breast cancer and a functional human immune system. We identified tumor-infiltrating T cells with a triple-positive PD-1, LAG-3 and TIM-3 phenotype. While PD-1 expression was increased in both the CD4 and CD8 T cells, TIM-3 was found to be upregulated particularly in the cytotoxic T cells in the MDA-MB-231-based HTM model. High levels of soluble TIM-3 and galectin-9 (a TIM-3 ligand) were detected in the serum. Surprisingly, soluble PD-L2, but only low levels of sPD-L1, were found in mice harboring PD-L1-positive tumors. Analysis of a dataset containing 3039 primary breast cancer samples on the R2 Genomics Analysis Platform revealed increased TIM-3, galectin-9 and LAG-3 expression, not only in triple-negative breast cancer but also in the HER2+ and hormone receptor-positive breast cancer subtypes. These data indicate that LAG-3 and TIM-3 represent additional key molecules within the breast cancer anti-immunity landscape

Terminology for Achilles tendon related disorders

The terminology of Achilles tendon pathology has become inconsistent and confusing throughout the years. For proper research, assessment and treatment, a uniform and clear terminology is necessary. A new terminology is proposed; the definitions hereof encompass the anatomic location, symptoms, clinical findings and histopathology. It comprises the following definitions: Mid-portion Achilles tendinopathy: a clinical syndrome characterized by a combination of pain, swelling and impaired performance. It includes, but is not limited to, the histopathological diagnosis of tendinosis. Achilles paratendinopathy: an acute or chronic inflammation and/or degeneration of the thin membrane around the Achilles tendon. There are clear distinctions between acute paratendinopathy and chronic paratendinopathy, both in symptoms as in histopathology. Insertional Achilles tendinopathy: located at the insertion of the Achilles tendon onto the calcaneus, bone spurs and calcifications in the tendon proper at the insertion site may exist. Retrocalcaneal bursitis: an inflammation of the bursa in the recess between the anterior inferior side of the Achilles tendon and the posterosuperior aspect of the calcaneus (retrocalcaneal recess). Superficial calcaneal bursitis: inflammation of the bursa located between a calcaneal prominence or the Achilles tendon and the skin. Finally, it is suggested that previous terms as Haglund’s disease; Haglund’s syndrome; Haglund’s deformity; pump bump (calcaneus altus; high prow heels; knobbly heels; cucumber heel), are no longer used

Meaning and Grammar of Nouns and Verbs

The papers collected in this book cover contemporary and original research on semantic and grammatical issues of nouns and noun phrases, verbs and sentences, and aspects of the combination of nouns and verbs, in a great variety of languages. A special focus is put on noun types, tense and aspect semantics, granularity of verb meaning, and subcompositionality. The investigated languages and language groups include Austronesian, East Asian, Slavic, German, English, Hungarian and Lakhota. The collection provided in this book will be of interest to researchers and advanced students specialising in the fields of semantics, morphology, syntax, typology, and cognitive sciences

Team building and hidden costs of control

In a laboratory experiment, we investigate the interaction of two prominent firm strategies to increase worker effort: team building and control. We compare a team-building treatment where subjects initially play a coordination game to gain common experience (CE) with an autarky treatment where subjects individually perform a task (NCE). In both treatments, subjects then play two-player control games where agents provide costly effort and principals can control to secure a minimum effort. CE agents always outperform NCE agents. Conditional on control, however, CE agents’ effort is crowded out more strongly, with the effect being most pronounced for agents who successfully coordinated in the team-building exercise. Differential reactions to control perceived as excessive is one explanation for our findings

Climatic conditions and habitats in Belső-Somogy, Külső-Somogy and Zselic as vegetation-based landscape regions II. Temperature and precipitation sensitivity of woodlands

In our study climatic sensitivity of significant woody habitats are discussed in the territory of vegetation based landscape regions of South Transdanubia, including Belső-Somogy, Külső-Somogy and Zselic. Selected bioclimatic variables are used to characterize regional and habitat climate surfaces and envelopes by habitat occurrence. Gaussian probability curves were fitted, using long term (1961-1990) data for yearly and quarterly temperature and precipitation variables, representing general and extreme climatic conditions. Studied woodlands are sufficiently integrated into the climate surface and envelopes of the region, according to multipeaks of bioclimatic indices. Among woody habitat types, riverine and swamp woodlands (J) turned to be the most climate sensitive habitats, due to their few peaks with extreme values by numerous bioclimatic indices, especially yearly and quarterly precipitation variables. Mesic deciduous woodlands (K) are no directly climate sensitive on temperature relations, but they are like on the short time quarterly precipitation. Peaks of dry closed deciduous woodlands (L) and other tree dominated habitats (R) are completely fitted to regional climate surfaces and envelopes, so they have no significant climate sensitivity by any analysed bioclimatic variable

Functional Response Trait Analysis Improves Climate Sensitivity Estimation in Beech Forests at a Trailing Edge

Functional response traits influence the ability of species to colonize and thrive in a habitat and to persist under environmental challenges. Functional traits can be used to evaluate environment-related processes and phenomena. They also help to interpret distribution patterns, especially under limiting ecological conditions. In this study, we investigate landscape-scale functional distribution responses of beech forests in a climatic transitional zone in Europe. We construct empirical density distribution responses for beech forests by applying coping-resilience-failure climatic traits based on 27 bioclimatic variables, resulting in prevalence-decay-exclusion distribution response patterns. We also perform multivariate exploratory cluster analysis to reveal significant sets of response patterns from the resilience and adaptation aspects. Temperature-related distribution responses presented a prevalence-dominated functional pattern, with Annual mean temperature indicating the most favorable adaptation function. Precipitation indices showed climate-limited response patterns with the dominance of extinction function. Considering regional site-specific climate change projections, these continental beech forests could regress moderately due to temperature increase in the near future. Our results also suggest that both summer and winter precipitation could play a pivotal role in successful resilience. Functions and variables that indicate climate sensitivity can serve as a useful starting point to develop adaptation measures for regional forest management

Climatic conditions of semi-natural habitats in BelsőSomogy, Külső-Somogy and Zselic regions I. Climatic surface and climatic envelope of woodlands

In our study bioclimatic variables calculated from long-term temperature and precipitation data (1960-1990) were applied in order to define climatic surfaces and climatic envelope of significant woody habitat types in three vegetation-based hilly landscape of South Transdanubia (Belső-Somogy, Külső-Somogy, Zselic). Certain differencies can be observed in the climatic surface of the regions. Külső-Somogy is the most extreme region by all the bioclimatic indeces, Zselic is the most balanced by precipitation and Belső-Somogy is similar by the temperature indeces. Climatic envelopes of main woody habitat types (J – riverine and swamp woodlands, K – mesic deciduous woodlands, L – dry closed deciduous woodlands, R – other tree dominated habitats) are considerably overlapping by the selected bioclimatic variables. Precipitation must be a significant role in the existence of woody habitat types according to the landscape region. Values of temperature are valid in a narrower range without any differentiation by the habitats or landscapes