A Couch Mounted Smartphone-based Motion Monitoring System for Radiation Therapy.

Purpose: Surface-guided radiation-therapy (SGRT) systems are being adopted into clinical practice for patient setup and motion monitoring. However, commercial systems remain cost prohibitive to resource-limited clinics around the world. Our aim is to develop and validate a smartphone-based application using LiDAR cameras (such as on recent Apple iOS devices) for facilitating SGRT in low-resource centers.

Tissue tension permits β-catenin phosphorylation to drive mesoderm specification in human embryonic stem cells.

The role of morphogenetic forces in cell fate specification is an area of intense interest. Our prior studies suggested that the development of high cell-cell tension in human embryonic stem cells (hESC) colonies permits the Src-mediated phosphorylation of junctional β-catenin that accelerates its release to potentiate Wnt-dependent signaling critical for initiating mesoderm specification. Using an ectopically expressed nonphosphorylatable mutant of β-catenin (Y654F), we now provide direct evidence that impeding tension-dependent Src-mediated β-catenin phosphorylation impedes the expression of Brachyury (T) and the epithelial-to-mesenchymal transition (EMT) necessary for mesoderm specification.

Multiomics and spatial mapping characterizes human CD8 T cell states in cancer.

Clinically relevant immunological biomarkers that discriminate between diverse hypofunctional states of tumor-associated CD8 T cells remain disputed. Using multiomics analysis of CD8 T cell features across multiple patient cohorts and tumor types, we identified tumor niche-dependent exhausted and other types of hypofunctional CD8 T cell states. CD8 T cells in "supportive" niches, like melanoma or lung cancer, exhibited features of tumor reactivity-driven exhaustion (CD8 T).

GBM tumors are heterogeneous in their fatty acid metabolism and modulating fatty acid metabolism sensitizes cancer cells derived from recurring GBM tumors to temozolomide.

Glioblastoma is a highly lethal grade of astrocytoma with very low median survival. Despite extensive efforts, there is still a lack of alternatives that might improve these prospects. We uncovered that the chemotherapeutic agent temozolomide impinges on fatty acid synthesis and desaturation in newly diagnosed glioblastoma.

High Endothelial Venules: A Vascular Perspective on Tertiary Lymphoid Structures in Cancer.

High endothelial venules (HEVs) are specialized postcapillary venules composed of cuboidal blood endothelial cells that express high levels of sulfated sialomucins to bind L-Selectin/CD62L on lymphocytes, thereby facilitating their transmigration from the blood into the lymph nodes (LN) and other secondary lymphoid organs (SLO). HEVs have also been identified in human and murine tumors in predominantly CD3T cell-enriched areas with fewer CD20B-cell aggregates that are reminiscent of tertiary lymphoid-like structures (TLS). While HEV/TLS areas in human tumors are predominantly associated with increased survival, tumoral HEVs (TU-HEV) in mice have shown to foster lymphocyte-enriched immune centers and boost an immune response combined with different immunotherapies.

EPH/EPHRIN regulates cellular organization by actomyosin contractility effects on cell contacts.

EPH/EPHRIN signaling is essential to many aspects of tissue self-organization and morphogenesis, but little is known about how EPH/EPHRIN signaling regulates cell mechanics during these processes. Here, we use a series of approaches to examine how EPH/EPHRIN signaling drives cellular self-organization. Contact angle measurements reveal that EPH/EPHRIN signaling decreases the stability of heterotypic cell:cell contacts through increased cortical actomyosin contractility.

The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+ and androgen receptor-positive metastatic or locally advanced breast cancer.

Purpose: Androgen receptor (AR) expression occurs in up to 86% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers. In vitro, AR inhibitors enhance antitumor activity of trastuzumab, an anti-HER2 antibody, in trastuzumab-resistant HER2+ cell lines. This open-label, single-arm, phase II study evaluated the efficacy and safety of enzalutamide, an AR-signaling inhibitor, in patients with advanced HER2+ AR+ breast cancer previously treated with trastuzumab.

Membrane Tension Locks In Pluripotency.

In this issue of Cell Stem Cell, De Belly et al. (2021) and Bergert et al. (2021) reveal that membrane tension regulates the pluripotent state via endocytosis-mediated ERK signaling.

The metabolism of cancer cells during metastasis.

Metastasis formation is the major cause of death in most patients with cancer. Despite extensive research, targeting metastatic seeding and colonization is still an unresolved challenge. Only recently, attention has been drawn to the fact that metastasizing cancer cells selectively and dynamically adapt their metabolism at every step during the metastatic cascade.

Mechanical Tension Promotes Formation of Gastrulation-like Nodes and Patterns Mesoderm Specification in Human Embryonic Stem Cells.

Embryogenesis is directed by morphogens that induce differentiation within a defined tissue geometry. Tissue organization is mediated by cell-cell and cell-extracellular matrix (ECM) adhesions and is modulated by cell tension and tissue-level forces. Whether cell tension regulates development by modifying morphogen signaling is less clear.

Patterning the Geometry of Human Embryonic Stem Cell Colonies on Compliant Substrates to Control Tissue-Level Mechanics.

Human embryonic stem cells demonstrate a unique ability to respond to morphogens in vitro by self-organizing patterns of cell fate specification that correspond to primary germ layer formation during embryogenesis. Thus, these cells represent a powerful tool with which to examine the mechanisms that drive early human development. We have developed a method to culture human embryonic stem cells in confined colonies on compliant substrates that provides control over both the geometry of the colonies and their mechanical environment in order to recapitulate the physical parameters that underlie embryogenesis.

Tumors vs. Chronic Wounds: An Immune Cell's Perspective.

The wound repair program is tightly regulated and coordinated among different cell constituents including epithelial cells, fibroblasts, immune cells and endothelial cells following consecutive steps to ensure timely, and proper wound closure. Specifically, innate and adaptive immune cells are pivotal participants that also closely interact with the vasculature. Tumors are portrayed as wounds that do not heal because they undergo continuous stromal remodeling and vascular growth with immunosuppressive features to ensure tumor propagation; a stage that is reminiscent of the proliferative resolution phase in wound repair.

Regulation of Blood and Lymphatic Vessels by Immune Cells in Tumors and Metastasis.

Research over the last decades has provided strong evidence for the pivotal role of the tumor-associated blood and lymphatic vasculature in supporting immunoevasion and in subverting T cell-mediated immunosurveillance. Conversely, tumor blood and lymphatic vessel growth is in part regulated by the immune system, with infiltrating innate as well as adaptive immune cells providing both immunosuppressive and various angiogenic signals. Thus, tumor angiogenesis and escape of immunosurveillance are two cancer hallmarks that are tightly linked and interregulated by cell constituents from compartments secreting both chemokines and cytokines.

A tension-mediated glycocalyx-integrin feedback loop promotes mesenchymal-like glioblastoma.

Glioblastoma multiforme (GBMs) are recurrent lethal brain tumours. Recurrent GBMs often exhibit mesenchymal, stem-like phenotypes that could explain their resistance to therapy. Analyses revealed that recurrent GBMs have increased tension and express high levels of glycoproteins that increase the bulkiness of the glycocalyx.

The protective role of sphingosine-1-phosphate against the action of the vascular disrupting agent combretastatin A-4 3--phosphate.

Solid tumours vary in sensitivity to the vascular disrupting agent combretastatin A-4 3--phosphate (CA4P), but underlying factors are poorly understood. The signaling sphingolipid, sphingosine-1-phosphate (S1P), promotes vascular barrier integrity by promoting assembly of VE-cadherin/β-catenin complexes. We tested the hypothesis that tumour pre-treatment with S1P would render tumours less susceptible to CA4P.

Physical and Chemical Gradients in the Tumor Microenvironment Regulate Tumor Cell Invasion, Migration, and Metastasis.

Cancer metastasis requires the invasion of tumor cells into the stroma and the directed migration of tumor cells through the stroma toward the vasculature and lymphatics where they can disseminate and colonize secondary organs. Physical and biochemical gradients that form within the primary tumor tissue promote tumor cell invasion and drive persistent migration toward blood vessels and the lymphatics to facilitate tumor cell dissemination. These microenvironment cues include hypoxia and pH gradients, gradients of soluble cues that induce chemotaxis, and ions that facilitate galvanotaxis, as well as modifications to the concentration, organization, and stiffness of the extracellular matrix that produce haptotactic, alignotactic, and durotactic gradients.

Tissue mechanics promote IDH1-dependent HIF1α-tenascin C feedback to regulate glioblastoma aggression.

Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1). Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1α. We found that glioma aggression and patient prognosis correlate with HIF1α levels and the stiffness of a tenascin C (TNC)-enriched ECM.

Glioblastoma: Defining Tumor Niches.

Glioblastomas (GBM) are one of the most recalcitrant brain tumors because of their aggressive invasive growth and resistance to therapy. They are highly heterogeneous malignancies at both the molecular and histological levels. Specific histological hallmarks including pseudopalisading necrosis and microvascular proliferation distinguish GBM from lower-grade gliomas, and make GBM one of the most hypoxic as well as angiogenic tumors.

Nodular Fasciitis: Definitive Diagnosis by Fine Needle Aspiration.

Objectives: Nodular fasciitis (NF) is a self-limited, mass-forming, fibrous proliferation that can occur in the head and neck and may mimic malignancy. Fine-needle aspiration biopsy (FNAB) is a minimally invasive, rapid, accurate method of obtaining diagnostic material from head and neck masses. In this study, we verify the usefulness of FNAB in obtaining a definitive diagnosis of NF.

Agent Orange and long-term outcomes after radical prostatectomy.

Purpose: To investigate the association between Agent Orange (AO) exposure and long-term prostate cancer (PC) outcomes.

Material And Methods: Data from 1,882 men undergoing radical prostatectomy for PC between 1988 and 2011 at Veterans Affairs Health Care Facilities were analyzed from the Shared Equal Access Regional Cancer Hospital database. Men were stratified by AO exposure (binary).

Public interest in and acceptability of the prospect of risk-stratified screening for breast and prostate cancer.

Background: For risk-stratified screening to be implemented as a screening program for breast and prostate cancer it has to be accepted among the general population. Investigating public interest in stratified screening and its acceptability to the public is therefore essential since as yet little is known.

Method: Cross-sectional web survey sent to a sample of 10 000 individuals (20-74 years of age) representative of the Swedish population as registered in 2009.

Intertwined regulation of angiogenesis and immunity by myeloid cells.

Angiogenesis is a hallmark of cancer because its induction is indispensable to fuel an expanding tumor. The tumor microenvironment contributes to tumor vessel growth, and distinct myeloid cells recruited by the tumor have been shown not only to support angiogenesis but also to foster an immune suppressive environment that supports tumor expansion and progression. Recent findings suggest that the intertwined regulation of angiogenesis and immune modulation can offer therapeutic opportunities for the treatment of cancer.