The progression of cancer is facilitated by infiltrating leukocytes which can either actively kill cancer cells or promote their survival. Our current understanding of leukocyte recruitment into ...tumors is largely limited to the adhesion molecules and chemokines expressed by conventional blood vessels that are lined by endothelial cells (ECs). However, cancer cells themselves can form their own vascular structures (a process known as vasculogenic mimicry (VM)); but whether they actively participate in the recruitment of leukocytes remains to be elucidated. Herein, we demonstrate that VM-competent human melanoma cell lines express multiple adhesion molecules (e.g. CD44, intercellular adhesion molecule (ICAM)-1 and junction adhesion molecules (JAMs)) and chemokines (e.g. CXCL8 and CXCL12) relevant for leukocyte recruitment. Microfluidic-based adhesion assays revealed that similar to ECs, VM-competent melanoma cells facilitate the rolling and adhesion of leukocytes, particularly monocytes, under conditions of shear flow. Moreover, we identified ICAM-1 to be a key participant in this process. Transwell assays showed that, similar to ECs, VM-competent melanoma cells facilitate monocyte transmigration toward a chemotactic gradient. Gene expression profiling of human melanoma patient samples confirmed the expression of numerous leukocyte capture adhesion molecules and chemokines. Finally, immunostaining of patient tissue microarrays revealed that tumors with high VM content also contained higher numbers of leukocytes (including macrophages). Taken together, this study suggests an underappreciated role of VM vessels in solid tumors via their active participation in leukocyte recruitment and begins to identify key adhesion molecules and chemokines that underpin this process.
This study aimed to develop a framework for optimising prostate intensity-modulated radiotherapy (IMRT) based on patient-specific tumour biology, derived from multiparametric MRI (mpMRI). The ...framework included a probabilistic treatment planning technique in the effort to yield dose distributions with an improved expected treatment outcome compared with uniform-dose planning approaches.
IMRT plans were generated for five prostate cancer patients using two inverse planning methods: uniform-dose to the planning target volume and probabilistic biological optimisation for clinical target volume tumour control probability (TCP) maximisation. Patient-specific tumour location and clonogen density information were derived from mpMRI and geometric uncertainties were incorporated in the TCP calculation. Potential reduction in dose to sensitive structures was assessed by comparing dose metrics of uniform-dose plans with biologically-optimised plans of an equivalent level of expected tumour control.
The planning study demonstrated biological optimisation has the potential to reduce expected normal tissue toxicity without sacrificing local control by shaping the dose distribution to the spatial distribution of tumour characteristics. On average, biologically-optimised plans achieved 38.6% (p-value: < 0.01) and 51.2% (p-value: < 0.01) reduction in expected rectum and bladder equivalent uniform dose, respectively, when compared with uniform-dose planning.
It was concluded that varying the dose distribution within the prostate to take account for each patient's clonogen distribution was feasible. Lower doses to normal structures compared to uniform-dose plans was possible whilst providing robust plans against geometric uncertainties. Further validation in a larger cohort is warranted along with considerations for adaptive therapy and limiting urethral dose.
Glioblastoma is one of the most common and lethal types of primary brain tumor. Despite aggressive treatment with chemotherapy and radiotherapy, tumor recurrence within 6-9 months is common. To ...overcome this, more effective therapies targeting cancer cell stemness, invasion, metabolism, cell death resistance and the interactions of tumor cells with their surrounding microenvironment are required. In this study, we performed a systematic review of the molecular mechanisms that drive glioblastoma progression, which led to the identification of 65 drugs/inhibitors that we screened for their efficacy to kill patient-derived glioma stem cells in two dimensional (2D) cultures and patient-derived three dimensional (3D) glioblastoma explant organoids (GBOs). From the screening, we found a group of drugs that presented different selectivity on different patient-derived in vitro models. Moreover, we found that Costunolide, a TERT inhibitor, was effective in reducing the cell viability in vitro of both primary tumor models as well as tumor models pre-treated with chemotherapy and radiotherapy. These results present a novel workflow for screening a relatively large groups of drugs, whose results could lead to the identification of more personalized and effective treatment for recurrent glioblastoma.
In this study we present results from immersion freezing experiments with size‐segregated mineral dust particles. Besides two already existing data sets for Arizona Test Dust (ATD), and Fluka ...kaolinite, we show two new data sets for illite‐NX, which consists mainly of illite, a clay mineral, and feldspar, a common crustal material. The experiments were carried out with the Leipzig Aerosol Cloud Interaction Simulator. After comparing the different dust samples, it became obvious that the freezing ability was positively correlated with the K‐feldspar content. Furthermore, a comparison of the composition of the ATD, illite‐NX, and feldspar samples suggests that within the K‐feldspars, microcline is more ice nucleation active than orthoclase. A coating with sulfuric acid leads to a decrease in the ice nucleation ability of all mineral dusts, with the effect being more pronounced for the feldspar sample.
Key Points
The freezing ability of mineral dusts correlated with the K‐feldspar contentAmong feldspars, microcline shows a better ice nucleation ability than orthoclaseAfter coating, all investigated dusts feature a similar ice nucleation ability
Shipping contributes primary and secondary emission products to the atmospheric aerosol burden that have implications for climate, clouds, and air quality from regional to global scales. In this ...study we exam the potential impact of ship emissions with regards to ice nucleating particles. Particles that nucleate ice are known to directly affect precipitation and cloud microphysical properties. We have collected and analyzed particles for their ice nucleating capacity from a shipping channel outside a large Scandinavia port. We observe that ship plumes amplify the background levels of ice nucleating particles and discuss the larger scale implications. The measured ice nucleating particles suggest that the observed amplification is most likely important in regions with low levels of background particles. The Arctic, which as the sea ice pack declines is opening to transit and natural resource exploration and exploitation at an ever increasing rate, is highlighted as such a region.
Using the effective-range expansion for the two-body amplitudes may generate spurious sub-threshold poles outside of the convergence range of the expansion. In the infinite volume, the emergence of ...such poles leads to the breakdown of unitarity in the three-body amplitude. We discuss the extension of our alternative subtraction scheme for including effective range corrections in pionless effective field theory for spinless bosons to nucleons. In particular, we consider the neutron-deuteron system in the doublet S-wave channel explicitly.
Basal protein turnover, which largely relies on the degradation of ubiquitinated substrates, is instrumental for maintenance of muscle mass and function. However, the regulation of ubiquitinated ...protein degradation in healthy, nonatrophying skeletal muscle is still evolving, and potential tissue‐specific modulators remain unknown. Using an unbiased expression analysis of 34 putative autophagy genes across mouse tissues, we identified unc‐51 like autophagy activating kinase (Ulk)2, a homolog of the yeast autophagy related protein 1, as particularly enriched in skeletal muscle. Subsequent experiments revealed accumulations of insoluble ubiquitinated protein aggregates associated with the adaptors sequestosome 1 (SQSTM1, also known as p62) and next to breast cancer type 1 susceptibility protein gene 1 protein (NBR1) in adult muscles with ULK2 deficiency. ULK2 deficiency also led to impaired muscle force and caused myofiber atrophy and degeneration. These features were not observed in muscles with deficiency of the ULK2 paralog, ULK1. Furthermore, short‐term ULK2 deficiency did not impair autophagy initiation, autophagosome to lysosome fusion, or protease activities of the lysosome and proteasome. Altogether, our results indicate that skeletal muscle ULK2 has a unique role in basal selective protein degradation by stimulating the recognition and proteolytic sequestration of insoluble ubiquitinated protein aggregates associated with p62 and NBR1. These findings have potential implications for conditions of poor protein homeostasis in muscles as observed in several myopathies and aging.—Fuqua, J. D., Mere, C. P., Kronemberger, A., Blomme, J., Bae, D., Turner, K. D., Harris, M. P., Scudese, E., Edwards, M., Ebert, S. M., de Sousa, L. G. O., Bodine, S. C., Yang, L., Adams, C. M., Lira, V. A. ULK2 is essential for degradation of ubiquitinated protein aggregates and homeostasis in skeletal muscle. FASEB J. 33, 11735‐11745 (2019). www.fasebj.org
Adoptive T-cell therapy using autologous T cells genetically modified to express cancer-specific chimeric antigen receptors (CAR) has emerged as a novel approach for cancer treatment. CAR-T cell ...therapy has been approved in several major jurisdictions for treating refractory or relapsed cases of B-cell precursor acute lymphoblastic leukaemia and diffuse large B-cell lymphoma. However, in solid cancer patients, several clinical studies of CAR-T cell therapy have demonstrated minimal therapeutic effects, thus encouraging interest in better integrating CAR-T cells with other treatments such as conventional cytotoxic chemotherapy. Increasing evidence shows that not only do chemotherapy drugs have tumoricidal effects, but also significantly modulate the immune system. Here, we discuss immunomodulatory effects of chemotherapy drugs on circulating leukocyte populations, including their ability to enhance cytotoxic effects and preserve the frequency of CD8+ T cells and to deplete immunosuppressive populations including regulatory T cells and myeloid-derived suppressor cells. By modulating the abundance and phenotype of leukocytes in the blood (the ‘raw material’ for CAR-T cell manufacturing), we propose that prior chemotherapy could facilitate production of the most effective CAR-T cell products. Further research is required to directly test this concept and identify strategies for the optimal integration of CAR-T cell therapies with cytotoxic chemotherapy for solid cancers.
Glioblastoma is the most common form of primary brain tumour in adults. For more than a decade, conventional treatment has produced a relatively modest improvement in the overall survival of ...glioblastoma patients. The immunosuppressive mechanisms employed by neoplastic and non-neoplastic cells within the tumour can limit treatment efficacy, and this can include the secretion of immunosuppressive cytokines and chemokines. These factors can play a significant role in immune modulation, thus disabling anti-tumour responses and contributing to tumour progression. Here, we review the complex interplay between populations of immune and tumour cells together with defined contributions by key cytokines and chemokines to these intercellular interactions. Understanding how these tumour-derived factors facilitate the crosstalk between cells may identify molecular candidates for potential immunotherapeutic targeting, which may enable better tumour control and improved patient survival.
We present an unusual case of a female neonate presenting with a single midline pelvic cyst. Prenatal imaging was suggestive of multicystic dysplastic kidney (MCDK), but postnatal imaging was ...atypical for this diagnosis given the location and singular cyst noted. The patient ultimately underwent surgical exploration and was diagnosed with an ectopic MCDK. Ectopic MCDK should be considered in the differential diagnosis of unilocular cystic pelvic lesions identified in the perinatal period.
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