Defining the principles of T cell migration in structurally and mechanically complex tumor microenvironments is critical to understanding escape from antitumor immunity and optimizing T cell-related ...therapeutic strategies. Here, we engineered nanotextured elastic platforms to study and enhance T cell migration through complex microenvironments and define how the balance between contractility localization-dependent T cell phenotypes influences migration in response to tumor-mimetic structural and mechanical cues. Using these platforms, we characterize a mechanical optimum for migration that can be perturbed by manipulating an axis between microtubule stability and force generation. In 3D environments and live tumors, we demonstrate that microtubule instability, leading to increased Rho pathway-dependent cortical contractility, promotes migration whereas clinically used microtubule-stabilizing chemotherapies profoundly decrease effective migration. We show that rational manipulation of the microtubule-contractility axis, either pharmacologically or through genome engineering, results in engineered T cells that more effectively move through and interrogate 3D matrix and tumor volumes. Thus, engineering cells to better navigate through 3D microenvironments could be part of an effective strategy to enhance efficacy of immune therapeutics.
Contact guidance due to extracellular matrix architecture is a key regulator of carcinoma invasion and metastasis, yet our understanding of how cells sense guidance cues is limited. Here, using a ...platform with variable stiffness that facilitates uniaxial or biaxial matrix cues, or competing E-cadherin adhesions, we demonstrate distinct mechanoresponsive behavior. Through disruption of traction forces, we observe a profound phenotypic shift towards a mode of dendritic protrusion and identify bimodal processes that govern guidance sensing. In contractile cells, guidance sensing is strongly dependent on formins and FAK signaling and can be perturbed by disrupting microtubule dynamics, while low traction conditions initiate fluidic-like dendritic protrusions that are dependent on Arp2/3. Concomitant disruption of these bimodal mechanisms completely abrogates the contact guidance response. Thus, guidance sensing in carcinoma cells depends on both environment architecture and mechanical properties and targeting the bimodal responses may provide a rational strategy for disrupting metastatic behavior.
Abstract
Background
Posterior Reversible Encephalopathy Syndrome (PRES) is a neurotoxic state characterized by seizures, headache, vision change, paresis, and altered mental status. PRES has an ...important place in medicine due to the wide variety of causative diseases, infections, and medications that precipitate its mysterious onset. Although exposure to medications, particularly immunosuppressants, cancer chemotherapy, and biologic drugs, is a common occurrence in patients who develop PRES, Mepolizumab has never before been associated.
Case presentation
This report of a 67-year-old male patient outlines the first reported case of Mepolizumab-induced PRES in the literature.
Conclusions
Treatment of severe asthma, asthma-exacerbations, and diseases such as eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss) with Mepolizumab is rapidly gaining popularity ever since the drug’s recent FDA-approval. This report aims to raise awareness of this potentially life-threatening and previously unreported side effect of Mepolizumab since early identification of the causative agent is the key to preventing the severe neurologic disability and possible death that may occur from the delayed treatment of PRES.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Malignant hyperthermia susceptibility (MHS) and the associated condition malignant hyperthermia (MH) are rare but well-known disorders in the field of anesthesiology. MHS is usually determined by a ...history of a family member developing a positive episode during general anesthesia and then confirmed by an invasive caffeine halothane contracture test (CHCT). More recently, within the context of MH as a pharmacogenetic disorder, the question of whether or not MHS can be principally genetically determined is of high importance as knowledge of detailed pathogenesis may prevent against its largely invariable lethality if untreated. Thus, in this brief report, genetic terms, as well as updates in the genetics of MHS, will be reviewed in order to better understand both the condition and the current research.
This survey study compares the socioeconomic composition of the 2017 to 2019 matriculating medical student body with that of the US population, by self-identified race and ethnicity and by sex.
High-risk human papilloma virus (HPV) is a driver of the development of oropharyngeal squamous cell carcinomas (SCC), while its role in other head and neck subsites, including the oral cavity, is ...debated. HPV detection in tissue is assayed directly and indirectly using various methods, including p16 surrogate immunohistochemistry (IHC), polymerase chain reaction (PCR), and in-situ hybridization (ISH).
Case of a 76-year-old man presenting with a right retromolar trigone well-differentiated keratinizing SCC, which was resected with a free flap reconstruction and HPV/p16 testing.
Synchronous p16 IHC and HPV PCR testing of the primary tumor were negative and positive, respectively, whereas testing of a lymph node metastasis by both assays was negative. RNA ISH was negative in the primary tumor and in the lymph node metastasis.
HPV assessment of oropharyngeal SCCs, but not those of other subsites, should be performed by surrogate p16 IHC, with any additional HPV confirmational testing done at institutional discretion. Detection of transcriptionally active HPV E6/E7 RNA by ISH may represent a new gold standard.
PDF
