Anti-telomerase T cells adoptive transfer

Commentary on the application of TERT-specific T cell adoptive cell therapy for cancer treatmen

Eine Methode zum Monitoring von säurebedingtem Zahnhartsubstanzverlust

Ziel der vorliegenden Untersuchung war es, eine Methode zu entwickeln, die das Monitoring von säurebedingtem Zahnhartsubstanzverlust unter Zuhilfenahme von Modellen ermöglicht. Das Prinzip der Messung beruht dabei auf der profilometrischen Erfassung eines oberflächlichen Zahnhartsubstanzverlustes in Relation zu einer unveränderlichen Referenzebene. Mit einer speziellen Stanze können Marker aus einer hochgoldhaltigen Legierung angefertigt und auf bukkalen und palatinalen Flächen adhäsiv befestigt werden. Dabei erlaubt das sternförmige Design des Markers die Beurteilung von 10 Messpunkten auf der angrenzenden Zahnhartsubstanz. Die Ecken und die gegenüberliegenden Spitzen des Sterns geben fünf Messstrecken vor, die durch entsprechende Ausrichtung des Profilometers reproduzierbar abgetastet werden können. Nach der graphischen Darstellungen der Messstrecken kann der mittlere Höhenunterschied zwischen Markeroberfläche und Zahnoberfläche ermittelt werden. Dabei dienen die Markeroberfläche, die Ecke und die Spitze als Referenzebene bzw. -punkte. In Vorversuchen zeigten wiederholte Messungen eines an einem plangeschliffenen Zahn befestigten Markers bei einem mittleren Höhenunterschied von 148,7 µm eine Standardabweichung von 2,2 µm und damit eine gute Reproduzierbarkeit der Messmethode. Wiederholte Messungen eines entsprechenden durch Abformung gewonnenen Epoxidharzmodells (\u27Blue Star\u27) ergaben einen mittleren Höhenunterschied von 143,8 µm bei einer vergleichbaren Standardabweichung von 2,9 µm (n.s.). Messungen von \u27Blue Star\u27-Modellen aus fünf verschiedenen Abformungen wiesen einen Mittelwert von 144,5 µm und eine geringfügig höhere Standardabweichung von 3,9 µm gegenüber dem Originalmodell auf (n.s.), während die Messungen eines weiteren Epoxidharzes (Stycast) mit einem Mittelwert von 160,15 µm signifikant größere Höhenunterschiede (p 0,01), eine höhere Standardabweichung von 11,1 µm und nur schwache Korrelationskoeffizenten aufwiesen. Wiederholte Messungen eines Markers auf einem gewölbten Zahn zeigten zwar eine höhere Standardabweichung (±4,7 µm) als das plane Urmodell, jedoch ergaben sich wie in den ersten drei Gruppen hohe Korrelationskoeffizienten. Für die Simulation der Messmethode unter klinischen Bedingungen wurde ein Modell, bestehend aus 14 karies- und füllungsfreien menschlichen Zähnen (vier Molaren, vier Prämolaren, zwei Eckzähnen, zwei lateralen und zwei zentralen Inzisivi), vorbereitet. Die Zähne wurden bukkal und palatinal mit Markern versehen. Die Erosionen wurden durch 0,05 molare Zitronensäure in Erosionsstufen von 20, 60 und 120 Minuten erzeugt. Nach jeder Erosionsstufe erfolgte die Abformung mit Polyethergummi (Impregum) und die Herstellung eines Epoxidharzmodells (\u27Blue Star\u27). Anschließend erfolgte die profilometrische Vermessung. Um den Mineralverlust zu beurteilen, wurde die Ausgangssituation mit der ersten, zweiten und dritten Erosionsstufe verglichen. In den meisten Fällen ließen sich nach jeder Erosionsstufe signifikante bis sehr signifikante Unterschiede feststellen. Die Ergebnisse zeigen, dass signifikante Resultate etwa bei einer mittleren Differenz von 15 µm zu erwarten sind. Insgesamt steht eine gut untersuchte und hinreichend genaue Meßmethode zum klinischen Monitoring von säurebedingten Zahnhartsubstanzverlusten zur Verfügung

Monocytes in the Tumor Microenvironment

Immunotherapy has revolutionized cancer treatment over the past decade. Nonetheless, prolonged survival is limited to relatively few patients. Cancers enforce a multifaceted immune-suppressive network whose nature is progressively shaped by systemic and local cues during tumor development. Monocytes bridge innate and adaptive immune responses and can affect the tumor microenvironment through various mechanisms that induce immune tolerance, angiogenesis, and increased dissemination of tumor cells. Yet monocytes can also give rise to antitumor effectors and activate antigen-presenting cells. This yin-yang activity relies on the plasticity of monocytes in response to environmental stimuli. In this review, we summarize current knowledge of the ontogeny, heterogeneity, and functions of monocytes and monocyte-derived cells in cancer, pinpointing the main pathways that are important for modeling the immunosuppressive tumor microenvironment

Breaking the Immune Complexity of the Tumor Microenvironment Using Single-Cell Technologies

: Tumors are not a simple aggregate of transformed cells but rather a complicated ecosystem containing various components, including infiltrating immune cells, tumor-related stromal cells, endothelial cells, soluble factors, and extracellular matrix proteins. Profiling the immune contexture of this intricate framework is now mandatory to develop more effective cancer therapies and precise immunotherapeutic approaches by identifying exact targets or predictive biomarkers, respectively. Conventional technologies are limited in reaching this goal because they lack high resolution. Recent developments in single-cell technologies, such as single-cell RNA transcriptomics, mass cytometry, and multiparameter immunofluorescence, have revolutionized the cancer immunology field, capturing the heterogeneity of tumor-infiltrating immune cells and the dynamic complexity of tenets that regulate cell networks in the tumor microenvironment. In this review, we describe some of the current single-cell technologies and computational techniques applied for immune-profiling the cancer landscape and discuss future directions of how integrating multi-omics data can guide a new "precision oncology" advancement

The dark side of tumor-associated endothelial cells

Angiogenesis is a hallmark of cancer and a requisite that tumors must achieve to fulfill their metabolic needs of nutrients and oxygen. As a critical step in cancer progression, the 'angiogenic switch' allows tumor cells to survive and grow, and provides them access to vasculature resulting in metastatic progression and dissemination. Tumor-dependent triggering of the angiogenic switch has critical consequences on tumor progression which extends from an increased nutrient supply and relies instead on the ability of the tumor to hijack the host immune response for the generation of a local immunoprivileged microenvironment. Tumor angiogenic-mediated establishment of endothelial anergy is responsible for this process. However, tumor endothelium can also promote immune tolerance by unbalanced expression of co-stimulatory and co-inhibitory molecules and by releasing soluble factors that restrain T cell function and induce apoptosis. In this review, we discuss the molecular properties of the tumor endothelial barrier and endothelial anergy and discuss the main immunosuppressive mechanisms triggered by the tumor endothelium. Lastly, we describe the current anti-angiogenic therapeutic landscape and how targeting tumor angiogenesis can contribute to improve clinical benefits for patients

Targeting tumour-reprogrammed myeloid cells: the new battleground in cancer immunotherapy

Tumour microenvironment is a complex ecosystem in which myeloid cells are the most abundant immune elements. This cell compartment is composed by different cell types, including neutrophils, macrophages, dendritic cells, and monocytes but also unexpected cell populations with immunosuppressive and pro-tumour roles. Indeed, the release of tumour-derived factors influences physiological haematopoiesis producing unconventional cells with immunosuppressive and tolerogenic functions such as myeloid-derived suppressor cells. These pro-tumour myeloid cell populations not only support immune escape directly but also assist tumour invasion trough non-immunological activities. It is therefore not surprising that these cell subsets considerably impact in tumour progression and cancer therapy resistance, including immunotherapy, and are being investigated as potential targets for developing a new era of cancer therapy. In this review, we discuss emerging strategies able to modulate the functional activity of these tumour-supporting myeloid cells subverting their accumulation, recruitment, survival, and functions. These innovative approaches will help develop innovative, or improve existing, cancer treatments

Erratum to: Energy from Nuclear Fission

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Failure envelopes of pile groups under combined axial-moment loading: Theoretical background and experimental evidence

Abstract The problem of failure envelopes of pile groups subjected to vertical and eccentric load is investigated both theoretically and experimentally. A critical review of literature works on failure envelopes for pile groups under combined axial-moment loading is first provided. Emphasis is placed on a recent, exact solution derived from theorems of limit analysis by idealizing piles as uniaxial rigid-perfectly plastic elements. The application of the relevant equations over a practical range of problems needs only the axial capacities in compression and uplift of the isolated piles. An intense program of centrifuge experiments carried out along with different load paths on annular shaped pile groups aimed at validating the equations pertinent to the above solution is presented and discussed. The endpoints of the load paths followed in the centrifuge lie approximately above the analytical failure envelope, giving confidence that the reference equations can be reliably adopted to assess the capacity of a pile group under combined axial-moment loading. Finally, the kinematics of the collapse mechanism observed experimentally is compared to that determined from the application of the reference theory

A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment

Myeloid-derived suppressor cells (MDSCs) constitute a plastic and heterogeneous cell population among immune cells within the tumour microenvironment (TME) that support cancer progression and resistance to therapy. During tumour progression, cancer cells modify their metabolism to sustain an increased energy demand to cope with uncontrolled cell proliferation and differentiation. This metabolic reprogramming of cancer establishes competition for nutrients between tumour cells and leukocytes and most importantly, among tumour-infiltrating immune cells. Thus, MDSCs that have emerged as one of the most decisive immune regulators of TME exhibit an increase in glycolysis and fatty acid metabolism and also an upregulation of enzymes that catabolise essential metabolites. This complex metabolic network is not only crucial for MDSC survival and accumulation in the TME but also for enhancing immunosuppressive functions toward immune effectors. In this review, we discuss recent progress in the field of MDSC-associated metabolic pathways that could facilitate therapeutic targeting of these cells during cancer progression

The Engagement Between MDSCs and Metastases: Partners in Crime

Tumor metastases represent the major cause of cancer-related mortality, confirming the urgent need to identify key molecular pathways and cell-associated networks during the early phases of the metastatic process to develop new strategies to either prevent or control distal cancer spread. Several data revealed the ability of cancer cells to establish a favorable microenvironment, before their arrival in distant organs, by manipulating the cell composition and function of the new host tissue where cancer cells can survive and outgrow. This predetermined environment is termed \u201cpre-metastatic niche\u201d (pMN). pMN development requires that tumor-derived soluble factors, like cytokines, growth-factors and extracellular vesicles, genetically and epigenetically re-program not only resident cells (i.e., fibroblasts) but also non-resident cells such as bone marrow-derived cells. Indeed, by promoting an \u201cemergency\u201d myelopoiesis, cancer cells switch the steady state production of blood cells toward the generation of pro-tumor circulating myeloid cells defined as myeloid-derived suppressor cells (MDSCs) able to sustain tumor growth and dissemination. MDSCs are a heterogeneous subset of myeloid cells with immunosuppressive properties that sustain metastatic process. In this review, we discuss current understandings of how MDSCs shape and promote metastatic dissemination acting in each fundamental steps of cancer progression from primary tumor to metastatic disease