Ancestry-linked stromal variations impact breast epithelial cell invasion.

Breast cancer is a significant health challenge worldwide, and disproportionately affects women of African ancestry (AA) who experience higher mortality rates relative to other racial/ethnic groups. Several studies have pointed to biological factors that affect breast cancer outcomes. A recently discovered stromal cell population that expresses P ROCR, Z EB1 and P DGFRα (PZP cells) was found to be enriched in normal healthy breast tissue from AA donors, and only in tumor adjacent tissues from donors of European ancestry (EA).

SATURN: assessing the feasibility of utilising existing registries for real-world evidence data collection to meet patients, regulatory, health technology assessment and payer requirements.

Background: SATURN (Systematic Accumulation of Treatment practices and Utilisation, Real world evidence, and Natural history data) for the rare condition osteogenesis imperfecta (OI) has the objective to create a common core dataset by utilising existing, well-established data sources to meet the needs of the various stakeholders (physicians, registry/dataset owners, patients and patient associations, OI community leaders, European [EU] policymakers, regulators, health technology assessments [HTA]s, and healthcare systems including payers). This paper describes the steps taken to assess the feasibility of one existing OI registry (i.e.

Current situation of osteogenesis imperfecta in Spain: results from a Delphi study.

Background: Osteogenesis imperfecta (OI) is a rare disease characterized by low bone mass and bone fragility, associated with an increased risk of fractures, and skeletal and extra-skeletal symptoms that results in an impairment of health-related quality of life of OI patients. Since published studies on OI in Spain are limited, this study aimed to determine the epidemiology, assessed the disease burden, management and unmet needs of OI patients in Spain. Thirty-four experts in the management of patients with osteogenesis imperfecta completed two rounds of online consultation and reported real-life experience and data from Spanish hospitals.

The patient clinical journey and socioeconomic impact of osteogenesis imperfecta: a systematic scoping review.

Background: Osteogenesis imperfecta (OI) is a rare heritable connective tissue disorder primarily characterised by skeletal deformity and fragility, and an array of secondary features. The purpose of this review was to capture and quantify the published evidence relating specifically to the clinical, humanistic, and economic impact of OI on individuals, their families, and wider society.

Methods: A systematic scoping review of 11 databases (MEDLINE, MEDLINE in-progress, EMBASE, CENTRAL, PsycINFO, NHS EED, CEA Registry, PEDE, ScHARRHUd, Orphanet and Google Scholar), supplemented by hand searches of grey literature, was conducted to identify OI literature published 1st January 1995-18th December 2021.

Tumor-Derived Extracellular Vesicles: Multifunctional Entities in the Tumor Microenvironment.

Tumor cells release extracellular vesicles (EVs) that can function as mediators of intercellular communication in the tumor microenvironment. EVs contain a host of bioactive cargo, including membrane, cytosolic, and nuclear proteins, in addition to noncoding RNAs, other RNA types, and double-stranded DNA fragments. These shed vesicles may deposit paracrine information and can also be taken up by stromal cells, causing the recipient cells to undergo phenotypic changes that profoundly impact diverse facets of cancer progression.

Acute-Onset Footdrop Caused by Intraneural Ganglion Cyst of the Common Peroneal Nerve: The Effects of Extraneural Pressure Gradients on Cyst Propagation.

Ganglion cysts are relatively common entities, but intraneural ganglia within peripheral nerves are rare and poorly understood. We present a case of a 51-year-old man who presented with acute left dropfoot. Initial magnetic resonance imaging (MRI) was misinterpreted as common peroneal neuritis consistent with a traction injury corroborated by the patient's history.

Recruitment of DNA to tumor-derived microvesicles.

The shedding of extracellular vesicles (EVs) represents an important but understudied means of cell-cell communication in cancer. Among the currently described classes of EVs, tumor-derived microvesicles (TMVs) comprise a class of vesicles released directly from the cell surface. TMVs contain abundant cargo, including functional proteins and miRNA, which can be transferred to and alter the behavior of recipient cells.

Profiling and promise of supermeres.

Extracellular vesicles and particles have important roles in physiology and disease. Advances in isolation and characterization technologies have enabled the identification of new particles. Supermeres are the newest addition to the rapidly expanding repertoire of the cell secretome, and provide exciting opportunities for clinical translation.

Inhibition of N-Nitrosamine Formation in Drug Products: A Model Study.

Nitrosamines, in the absence of toxicological data, are regarded as potential mutagens and need to be controlled at nanogram levels in drug products. Recent high profile product withdrawals have increased regulatory scrutiny of nitrosamine formation assessments for marketed products and for new drug applications. Formation of nitrosamine in drug product is possible when nitrite and vulnerable amines are present.

The ins and outs of microvesicles.

Microvesicles are a heterogeneous group of membrane-enclosed vesicles that are released from cells into the extracellular space by the outward budding and pinching of the plasma membrane. These vesicles are loaded with multiple selectively sorted proteins and nucleic acids. Although interest in the clinical potential of microvesicles is increasing, there is only limited understanding of different types of microvesicles and the mechanisms involved in their formation.

A bi-radial approach to define the sagittal geometry of the healthy ankle.

Background: Previous descriptions of the sagittal geometry of the tibia and talus have involved single radius curves. The purpose of this investigation was to: determine if the sagittal curvature of the medial and lateral sides of the talus and tibia can be described by dividing the condyles into anterior and posterior regions, determine tibiotalar congruency, and categorize the morphological configurations of the talus and tibia.

Methods: Eighteen subjects underwent weightbearing CT scans and the osseous curvature was analyzed.

Breaking Bad: Extracellular Vesicles Provoke Tumorigenic Responses Under Oxygen Deprivation.

Intercellular communication is vital to tumor progression. In this issue of Developmental Cell, Bertolini et al. (2020) describe how small extracellular vesicles released from hypoxic mammary tumor cells facilitate intercellular communication, leading to alterations in mitochondrial dynamics and acquisition of invasive phenotypes in normal epithelial cells.

Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth.

Breast cancer brain metastases (BCBM) have a 5-20 year latency and account for 30% of mortality; however, mechanisms governing adaptation to the brain microenvironment remain poorly defined. We combine time-course RNA-sequencing of BCBM development with a Drosophila melanogaster genetic screen, and identify Rab11b as a functional mediator of metastatic adaptation. Proteomic analysis reveals that Rab11b controls the cell surface proteome, recycling proteins required for successful interaction with the microenvironment, including integrin β1.

Two critical thinking models-probing questions and conceptualization-adding 4 skillsets to the teacher's armamentarium.

Critical thinking is ubiquitous in patient care. One track for critical thinking develops skillsets emulating the thought process of the master clinician using probing questions and has been offered in treatment planning, literature search, and critique, risk assessment in caries and geriatrics, technology decision-making, EBD, and IPP. This paper offers 2 additional critical thinking skillsets following this emulation model in social work and ethics.

Spontaneous Rupture of Multiple Tendons in the Lower Extremity Following the Diagnosis of Lyme Disease.

Over a time frame of less than 1 year, a 23-year-old competitive horseback rider experienced a midsubstance tear of both the tibialis anterior and extensor hallucis longus tendons without inciting injury. It was after the second spontaneous tear that the patient's recent diagnosis of Lyme disease became the likely culprit. Often, patients with chronic Lyme disease present with an elaborate clinical picture that can mimic many more common diagnoses such as septic arthritis, transient synovitis, ligamentous sprain, and various other traumatic injuries.

An ARF6-Exportin-5 axis delivers pre-miRNA cargo to tumour microvesicles.

Tumour-derived microvesicles (TMVs) comprise a class of extracellular vesicles released from tumour cells that are now understood to facilitate communication between the tumour and the surrounding microenvironment. Despite their significance, the regulatory mechanisms governing the trafficking of bioactive cargos to TMVs at the cell surface remain poorly defined. Here we describe a molecular pathway for the delivery of microRNA (miRNA) cargo to nascent TMVs involving the dissociation of a pre-miRNA/Exportin-5 complex from Ran-GTP following nuclear export and its subsequent transfer to a cytoplasmic shuttle comprised of ARF6-GTP and GRP1.

Coordinated Regulation of Intracellular Fascin Distribution Governs Tumor Microvesicle Release and Invasive Cell Capacity.

Tumor cell invasion is one result of the bidirectional interactions occurring between tumor cells and the surrounding milieu. The ability of tumor cells to invade through the extracellular matrix is in part regulated by the formation of a class of protease-loaded extracellular vesicles, called tumor microvesicles (TMVs), which are released directly from the cell surface. Here we show that the actin bundling protein, fascin, redistributes to the cell periphery in a ternary complex with podocalyxin and ezrin, where it promotes TMV release.

Aberrant endocytosis leads to the loss of normal mitotic spindle orientation during epithelial glandular morphogenesis.

Epithelial cells form tissues with many functions, including secretion and environmental separation and protection. Glandular epithelial tissues comprise cysts and tubules that are formed from a polarized, single-epithelial cell layer surrounding a central, fluid-filled lumen. The pathways regulating key processes in epithelial tissue morphogenesis such as mitotic spindle formation are incompletely understood, but are important to investigate, as their dysregulation is a signature of epithelial tumors.

Extracellular Vesicles in Cancer: Purpose and Promise.

Extracellular vesicles refer collectively to a heterogeneous group of membrane-bound vesicles released from cells and loaded with bioactive proteins, nucleic acids, and lipids. The concept of extracellular vesicles has rapidly evolved from once being viewed as cellular debris to their recognition as packets of cellular information with considerable promise for clinical applications as biomarker platforms and therapeutic vehicles. These shed vesicles have emerged as critical mediators of intercellular communication in both local and distant microenvironments during normal physiological processes, as well as in orchestrating systemic pathophysiological events in disease.

Biology and biogenesis of shed microvesicles.

The ability of cells to transmit bioactive molecules to recipient cells and the extracellular environment is a fundamental requirement for both normal physiology and disease pathogenesis. It has traditionally been thought that soluble factors released from cells were responsible for this cellular signaling but recent research has revealed a fundamental role for microvesicles in this process. Microvesicles are heterogeneous membrane-bound sacs that are shed from the surface of cells into the extracellular environment in a highly regulated process.

Extracellular microvesicles and invadopodia mediate non-overlapping modes of tumor cell invasion.

Tumor cell invasion requires the molecular and physical adaptation of both the cell and its microenvironment. Here we show that tumor cells are able to switch between the use of microvesicles and invadopodia to facilitate invasion through the extracellular matrix. Invadopodia formation accompanies the mesenchymal mode of migration on firm matrices and is facilitated by Rac1 activation.

Tumor-derived microvesicles in the tumor microenvironment: How vesicle heterogeneity can shape the future of a rapidly expanding field.

Information transmission from tumor cells to non-tumor cells in the surrounding microenvironment via microvesicles is a more recently studied form of intercellular signaling that can have a marked impact on the tumor microenvironment. Tumor-derived microvesicles (TMVs) are packed with information including signaling proteins and nucleic acids, and can be taken up by target cells, enabling paracrine signaling. While previous research has focused on how vesicles released from pathologic cells differ from normal cells, the heterogeneity that exists within the TMV population itself is not fully characterized, and only beginning to be appreciated.