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Objective: To investigate the use of the National Cancer Institute's hollow fiber assay (HFA) to evaluate and prioritize novel treatment strategies for clinical trials in the Ewing's sarcoma family of tumors (ESFT).Study Design: The growth and morphology of ESFT cell lines in hollow fibers (HFs) was characterized in vitro and in vivo. Reliability and reproducibility were evaluated using doxorubicin.Results: The numbers of viable cells in all 6 ESFT cell lines increased with time in vitro (0 to 96 hours). The SKES-1 and A673 cell lines grew exponentially after implantation of HFs in nude mice at subcutaneous and intraperitoneal sites. ESFT cells formed highly organized distinctive morphology within the HFs in vitro and in vivo. The number of viable ESFT cells within the HFs decreased in a time-dependent (24 to 96 hours) and dose-dependent (1 to 10 mg/kg) manner after treatment with doxorubicin in vivo.Conclusions: The HFA is a versatile short-term in vivo model that may be exploited to predict efficacy of potential anticancer agents in ESFT cells. Tumor markers and pharmacodynamic endpoints may be quantified in the pure population of ESFT cells from within the HFs. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly., (© 2024 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Growth of cancer cells in vitro can be attenuated by genetically inactivating selected metabolic pathways. However, loss-of-function mutations in metabolic pathways are not negatively selected in human cancers, indicating that these genes are not essential in vivo. We hypothesize that spontaneous mutations in 'metabolic genes' will not necessarily produce functional defects because mutation-bearing cells may be rescued by metabolite exchange with neighboring wild-type cells via gap junctions. Using fluorescent substances to probe intercellular diffusion, we show that colorectal cancer (CRC) cells are coupled by gap junctions assembled from connexins, particularly Cx26. Cells with genetically inactivated components of pH regulation ( SLC9A1 ), glycolysis ( ALDOA ), or mitochondrial respiration ( NDUFS1 ) could be rescued through access to functional proteins in co-cultured wild-type cells. The effect of diffusive coupling was also observed in co-culture xenografts. Rescue was largely dependent on solute exchange via Cx26 channels, a uniformly and constitutively expressed isoform in CRCs. Due to diffusive coupling, the emergent phenotype is less heterogenous than its genotype, and thus an individual cell should not be considered as the unit under selection, at least for metabolite-handling processes. Our findings can explain why certain loss-of-function mutations in genes ascribed as 'essential' do not influence the growth of human cancers., Competing Interests: SM, JM, AH, JK, EB, AH, GA, WB, PS No competing interests declared, (© 2022, Monterisi et al.)

Unlike most cell types, many cancer cells survive at low extracellular pH (pHe), a chemical signature of tumors. Genes that facilitate survival under acid stress are therefore potential targets for cancer therapies. We performed a genome-wide CRISPR-Cas9 cell viability screen at physiological and acidic conditions to systematically identify gene knockouts associated with pH-related fitness defects in colorectal cancer cells. Knockouts of genes involved in oxidative phosphorylation (NDUFS1) and iron-sulfur cluster biogenesis (IBA57, NFU1) grew well at physiological pHe, but underwent profound cell death under acidic conditions. We identified several small-molecule inhibitors of mitochondrial metabolism that can kill cancer cells at low pHe only. Xenografts established from NDUFS1 -/- cells grew considerably slower than their wild-type controls, but growth could be stimulated with systemic bicarbonate therapy that lessens the tumoral acid stress. These findings raise the possibility of therapeutically targeting mitochondrial metabolism in combination with acid stress as a cancer treatment option., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Exosomes are secreted extracellular vesicles carrying diverse molecular cargos, which can modulate recipient cell behaviour. They are thought to derive from intraluminal vesicles formed in late endosomal multivesicular bodies (MVBs). An alternate exosome formation mechanism, which is conserved from fly to human, is described here, with exosomes carrying unique cargos, including the GTPase Rab11, generated in Rab11-positive recycling endosomal MVBs. Release of Rab11-positive exosomes from cancer cells is increased relative to late endosomal exosomes by reducing growth regulatory Akt/mechanistic Target of Rapamycin Complex 1 (mTORC1) signalling or depleting the key metabolic substrate glutamine, which diverts membrane flux through recycling endosomes. Vesicles produced under these conditions promote tumour cell proliferation and turnover and modulate blood vessel networks in xenograft mouse models in vivo. Their growth-promoting activity, which is also observed in vitro, is Rab11a-dependent, involves ERK-MAPK-signalling and is inhibited by antibodies against amphiregulin, an EGFR ligand concentrated on these vesicles. Therefore, glutamine depletion or mTORC1 inhibition stimulates release from Rab11a compartments of exosomes with pro-tumorigenic functions, which we propose promote stress-induced tumour adaptation., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Angiogenesis is a coordinated process tightly regulated by the balance between Delta-like-4 (DLL4) and Jagged-1 (JAG1) in endothelial cells. Here we show that galectin-3 (gal-3), a glycan-binding protein secreted by cancer cells under hypoxic conditions, triggers sprouting angiogenesis, assisted by hypoxic changes in the glycosylation status of endothelial cells that enhance binding to gal-3. Galectin-3's proangiogenic functions were found to be predominantly dependent on the Notch ligand JAG1. Differential direct binding to JAG1 was shown by surface plasmon resonance assay. Upon binding to Notch ligands, gal-3 preferentially increased JAG1 protein half-life over DLL4 and preferentially activated JAG1/Notch-1 signaling in endothelial cells. JAG1 overexpression in Lewis lung carcinoma cells accelerated tumor growth in vivo, but this effect was prevented in Lgals3-/- mice. Our findings establish gal-3 as a molecular regulator of the JAG1/Notch-1 signaling pathway and have direct implications for the development of strategies aimed at controlling tumor angiogenesis.

Background: Nurses play a crucial role in patient education and adaptation to having an implantable cardioverter defibrillator (ICD)., Objective: The aim of this study was to assess cardiology nurses' knowledge and confidence in providing education and support to ICD recipients., Methods: A cross-sectional descriptive survey was used to assess nurses' knowledge and experience caring for ICD recipients in 2 academic medical centers in the Pacific Northwest, using an instrument developed in 2004 in the United Kingdom., Results: Nurses (N = 74) worked on cardiology units or clinics, primarily held a baccalaureate degree or higher (85%), and had 16 years or more of nursing experience and 6 to 10 years of cardiology experience. The overall average knowledge score was 77%, with knowledge about modern ICD technology averaging 55%. Nurses' confidence, using 10-point scale, in preparing patients to receive an ICD implant was 6.32 ± 2.56, for preparing patients for discharge was 6.14 ± 2.43, and for providing education about ICD shocks was 6.63 ± 2.50. Nurses were most knowledgeable about factors that affect patient retention of knowledge and ICD-related environmental hazards. Nurses lacked knowledge about the basic ICD components, purpose of cardiac resynchronization, and dual-chamber ICDs. Factors associated with higher knowledge scores included past experience caring for a patient with an ICD and working in an electrophysiology outpatient clinic., Conclusions: The ICD knowledge of US nurses in 2015 was similar to that reported in the United Kingdom in 2004, with limited knowledge about the complexities of modern ICD devices. Such deficits in knowledge may affect the quality of education provided to ICD recipients in preparing them to live safely with an ICD.

Oscillating protein signals control the branching and expansion of blood vessels.

Angiogenesis has emerged as a critical process for tumour progression. Identifying key pathways involved in the regulation and promotion of angiogenesis has resulted in the development of numerous approaches targeting pro-angiogenic signalling pathways. The most prominent and characterised pro-angiogenic pathway is the vascular endothelial growth factor signalling pathway. This review will describe several inhibitors of angiogenesis currently in clinical trial and their various targets. Targeting pro-angiogenic pathways has improved outcome for many patients, however, the emerging problems with drug resistance with clinically approved angiogenic inhibitors will also be discussed in this review. It is hoped that identifying the causes of tumour re-growth and disease progression following treatment will enable future anti-angiogenic therapies to circumvent resistance., (Copyright © 2011 Elsevier Inc. All rights reserved.)