176 research outputs found
Advances in non-small cell lung cancer mechanomedicine: deciphering the signaling networks that govern tumor-TME interactions
No full textCells from the tumor microenvironment (TME) interact with tumor cells in non-small cell lung cancer (NSCLC) to form a reciprocal crosstalk which influences tumor growth, proliferation, metastasis and multidrug response. This crosstalk is modulated by TME mechanical inputs, which elicit the processes of mechanosensing and mechanotransduction. Recent advances in unveiling these signaling networks establish the interdisciplinary field of mechanomedicine to exploit emerging diagnostic, predictive and therapeutic tools for more effective NSCLC treatments. © The Author(s) 2024
Distinct spatiotemporal dynamics of CD8<sup>+</sup> T cell-derived cytokines in the tumor microenvironment
No full textCells in the tumor microenvironment (TME) influence each other through secretion and sensing of soluble mediators, such as cytokines and chemokines. While signaling of interferon γ (IFNγ) and tumor necrosis factor α (TNFα) is integral to anti-tumor immune responses, our understanding of the spatiotemporal behavior of these cytokines is limited. Here, we describe a single cell transcriptome-based approach to infer which signal(s) an individual cell has received. We demonstrate that, contrary to expectations, CD8+ T cell-derived IFNγ is the dominant modifier of the TME relative to TNFα. Furthermore, we demonstrate that cell pools that show abundant IFNγ sensing are characterized by decreased expression of transforming growth factor β (TGFβ)-induced genes, consistent with IFNγ-mediated TME remodeling. Collectively, these data provide evidence that CD8+ T cell-secreted cytokines should be categorized into local and global tissue modifiers, and describe a broadly applicable approach to dissect cytokine and chemokine modulation of the TME.Pattern Recognition and Bioinformatic
Awareness on the Prevention and Treatment of Malaria among Residents in Abraka, Delta State, Nigeria
No full textNigeria, the most populous nation in the Sub-Saharan African region,
remains ravaged with a high occurrence of malaria infections which
accounts for one-fourth of malaria cases globally. Communal awareness
is important in the total eradication of malaria in Africa and the
world at large. This study is to ascertain the awareness of individuals
in Abraka communities on the transmission, prevention and treatment of
malaria. A cross-sectional survey was carried out among people of
Abraka, Delta State, Nigeria, using 200 structured questionnaires. Data
was presented as percentage (%) using descriptive statistics. Majority
of the respondents were females (51%), 83.5% practiced Christianity,
63% of the subjects are single, and a total of 60.4% either into
business, employed or selfemployed with 38% being students. Eighty-nine
percent (89%) of the respondents indicated that mosquito bite is the
mode of transmission of malaria and 82.5% of the respondents stated
that refuse dump is the major factor that breed mosquito. A large
number of the respondents (95%) have been engaged in one or more
malaria preventive (control) methods. A greater percent (30%) commonly
used artesunate in treating malaria, while 25% took Coartem\uae
(artemether/lumefantrine), 23% took Lonart\uae
(artemether/lumefantrine), 10% took quinine and 12% had other drugs
they took for the treatment of malaria. There was much awareness on the
spread, prevention and treatment of malaria in Abraka, Delta State
Combining Mass Cytometry Data by CyTOFmerge Reveals Additional Cell Phenotypes in the Heterogeneous Ovarian Cancer Tumor Microenvironment: A Pilot Study
No full textThe prognosis of high-grade serous ovarian carcinoma (HGSOC) is poor, and treatment selection is challenging. A heterogeneous tumor microenvironment (TME) characterizes HGSOC and influences tumor growth, progression, and therapy response. Better characterization with multidimensional approaches for simultaneous identification and categorization of the various cell populations is needed to map the TME complexity. While mass cytometry allows the simultaneous detection of around 40 proteins, the CyTOFmerge MATLAB algorithm integrates data sets and extends the phenotyping. This pilot study explored the potential of combining two datasets for improved TME phenotyping by profiling single-cell suspensions from ten chemo-naïve HGSOC tumors by mass cytometry. A 35-marker pan-tumor dataset and a 34-marker pan-immune dataset were analyzed separately and combined with the CyTOFmerge, merging 18 shared markers. While the merged analysis confirmed heterogeneity across patients, it also identified a main tumor cell subset, additionally to the nine identified by the pan-tumor panel. Furthermore, the expression of traditional immune cell markers on tumor and stromal cells was revealed, as were marker combinations that have rarely been examined on individual cells. This study demonstrates the potential of merging mass cytometry data to generate new hypotheses on tumor biology and predictive biomarker research in HGSOC that could improve treatment effectiveness.Pattern Recognition and Bioinformatic
Computational design of synthetic receptors with programmable signalling activity for enhanced cancer T cell therapy
No full textThe tumour microenvironment (TME) plays a key role in tumour progression, and soluble and cellular TME components can limit CAR-T cell function and persistence. Targeting soluble TME factors to enhance anti-tumour responses of engineered T cells through chimeric receptors is not broadly explored owing to the unpredictable signalling characteristics of synthetic protein receptors. Here we develop a computational protein design platform for the de novo bottom-up assembly of allosteric receptors with programmable input–output behaviours that respond to soluble TME factors with co-stimulation and cytokine signals in T cells, called TME-sensing switch receptor for enhanced response to tumours (T-SenSER). We develop two sets of T-SenSERs targeting vascular endothelial growth factor (VEGF) or colony-stimulating factor 1 (CSF1) that are both selectively enriched in a variety of tumours. Combination of CAR and T-SenSER in human T cells enhances anti-tumour responses in models of lung cancer and multiple myeloma, in a VEGF- or CSF1-dependent manner. Our study sets the stage for the accelerated development of synthetic biosensors with custom-built sensing and responses for basic and translational cell engineering applications.UPBARTHSSV-EN
Microfluidics meets 3D cancer cell migration
No full textAn early step of metastasis requires a complex and coordinated migration of invasive tumor cells into the surrounding tumor microenvironment (TME), which contains extracellular matrix (ECM). It is being appreciated that 3D matrix-based microfluidic models have an advantage over conventional in vitro and animal models to study tumor progression events. Recent microfluidic models have enabled recapitulation of key mechanobiological features present within the TME to investigate collective cancer cell migration and invasion. Microfluidics also allows for functional interrogation and therapeutic manipulation of specific steps to study the dynamic aspects of tumor progression. In this review, we focus on recent developments in cancer cell migration and how microfluidic strategies have evolved to address the physiological complexities of the TME to visualize migration modes adapted by various tumor cells.ChemE/Product and Process Engineerin
Comparative diversity of ammonia oxidizer 16S rRNA gene sequences in native, tilled, and successional soils
No full textAutotrophic ammonia oxidizer (AAO) populations in soils from native, tilled, and successional treatments at the Kellogg Biological Station Long-Term Ecological Research site in southwestern Michigan were compared to assess effects of disturbance on these bacteria. N fertilization effects on AAO populations were also evaluated with soils from fertilized microplots within the successional treatments. Population structures were characterized by PCR amplification of microbial community DNA with group-specific 16S rRNA gene (rDNA) primers, cloning of PCR products and clone hybridizations with group- specific probes, phylogenetic analysis of partial 16S rDNA sequences, and denaturing gradient gel electrophoresis (DGGE) analysis. Population sizes were estimated by using most- probable-number (MPN) media containing varied concentrations of ammonium sulfate. Tilled soils contained higher numbers than did native soils of culturable AAOs that were less sensitive to different ammonium concentrations in MPN media. Compared to sequences from native soils, partial 16S rDNA sequences from tilled soils were less diverse and grouped exclusively within Nitrosospira cluster 3. Native soils yielded sequences representing three different AAO clusters. Probes for Nitrosospira cluster 3 hybridized with DGGE blots from tilled and fertilized successional soils but not with blots from native or unfertilized successional soils. Hybridization results thus suggested a positive association between the Nitrosospira cluster 3 subgroup and soils amended with inorganic N. DGGE patterns for soils sampled from replicated plots of each treatment were nearly identical for tilled and native soils in both sampling years, indicating spatial and temporal reproducibility based on treatment. [KEYWORDS: Gradient gel-electrophoresis; grassland soils; bacteria; nitrification; populations; rates; pcr]
The mathematical continuum: A haunting problematic
No full text© 2018 The Author(s) & Dept. of Mathematical Sciences, The University of Montana. The mathematical continuum has a number of formulations and technical definitions. Two of these reference the geometric line and the real number system. This conceptual coupling of line and number has been an enduring source for mathematical invention and paradox. The continuum captures the monstrous desire of mathematics, a desire to re-assemble the point with the line, the discrete with the continuous, the finite with the infinite. This paper explores how the continuum is a source of fundamental ambiguity fueling our desires and fears about mathematics
Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer
No full textTriple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of therapeutic targets. The paucity of effective treatment options motivated a number of studies to tackle this problem. Immunosuppressive cells infiltrated into the tumor microenvironment (TME) of TNBC are currently considered as candidates for new therapeutic targets. Myeloid-derived suppressor cells (MDSCs) have been reported to populate in the TME of TNBC, but their roles in the clinical and biological features of TNBC have not been clarified. This study identified that interleukin-34 (IL-34) released by TNBC cells is a crucial immunomodulator to regulate MDSCs accumulation in the TME. We provide evidence that IL-34 induces a differentiation of myeloid stem cells into monocytic MDSCs (M-MDSCs) that recruits regulatory T (Treg) cells, while suppressing a differentiation into polymorphonuclear MDSCs (PMN-MDSCs). As a result, the increase in M-MDSCs contributes to the creation of an immunosuppressive TME, and the decrease in PMN-MDSCs suppresses angiogenesis, leading to an acquisition of resistance to chemotherapy. Accordingly, blockade of M-MDSC differentiation with an estrogen receptor inhibitor or anti-IL-34 monoclonal antibody suppressed M-MDSCs accumulation causing retardation of tumor growth and restores chemosensitivity of the tumor by promoting PMN-MDSCs accumulation. This study demonstrates previously poorly understood mechanisms of MDSCs-mediated chemoresistance in the TME of TNBC, which is originated from the existence of IL-34, suggesting a new rationale for TNBC treatment
Phenotypic characterization by mass cytometry of the microenvironment in ovarian cancer and impact of tumor dissociation methods
No full textImproved molecular dissection of the tumor microenvironment (TME) holds promise for treating high-grade serous ovarian cancer (HGSOC), a gynecological malignancy with high mortality. Reliable disease-related biomarkers are scarce, but single-cell mapping of the TME could identify patient-specific prognostic differences. To avoid technical variation effects, however, tissue dissociation effects on single cells must be considered. We present a novel Cytometry by Time-of-Flight antibody panel for single-cell suspensions to identify individual TME profiles of HGSOC patients and evaluate the effects of dissociation methods on results. The panel was developed utilizing cell lines, healthy donor blood, and stem cells and was applied to HGSOC tissues dissociated by six methods. Data were analyzed using Cytobank and X-shift and illustrated by t-distributed stochastic neighbor embedding plots, heatmaps, and stacked bar and error plots. The panel distinguishes the main cellular subsets and subpopulations, enabling characterization of individual TME profiles. The dissociation method affected some immune (n = 1), stromal (n = 2), and tumor (n = 3) subsets, while functional marker expressions remained comparable. In conclusion, the panel can identify subsets of the HGSOC TME and can be used for in-depth profiling. This panel represents a promising profiling tool for HGSOC when tissue handling is considered.Pattern Recognition and Bioinformatic
- …
