RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies.

Immune checkpoint inhibitors (ICI) are commonly associated with thyroid immune-related adverse events, yet the mechanism has not been fully elucidated. We aimed to further explore the mechanism of ICI-induced thyroid dysfunction by assessing changes induced in the thyroid transcriptome by ICI treatment (αPD-1/αPD-L1) in a lung cancer murine model. RNA-sequencing of thyroid tissues revealed 952 differentially expressed genes (DEGs) with αPD-1 treatment (|fold-change| ≥1.

Targeted nanoparticles modify neutrophil function .

Neutrophils play critical roles in a broad spectrum of clinical conditions. Accordingly, manipulation of neutrophil function may provide a powerful immunotherapeutic approach. However, due to neutrophils characteristic short half-life and their large population number, this possibility was considered impractical.

The Bilateral Interplay between Cancer Immunotherapies and Neutrophils' Phenotypes and Sub-Populations.

Immunotherapy has become a leading modality for the treatment of cancer, but despite its increasing success, a substantial number of patients do not benefit from it. Cancer-related neutrophils have become, in recent years, a subject of growing interest. Distinct sub-populations of neutrophils have been identified at advanced stages of cancer.

The dual role of neutrophils in cancer.

For the past decade, the role and importance of neutrophils in cancer is being increasingly appreciated. Research has focused on the ability of cancer-related neutrophils to either support tumor growth or interfere with it, showing diverse mechanisms through which the effects of neutrophils take place. In contrast to the historic view of neutrophils as terminally differentiated cells, mounting evidence has demonstrated that neutrophils are a plastic and diverse population of cells.

Tumor-Derived Factors Differentially Affect the Recruitment and Plasticity of Neutrophils.

Neutrophils play a key role in cancer biology. In contrast to circulating normal-density neutrophils (NDN), the amount of low-density neutrophils (LDN) significantly increases with tumor progression. The correlation between these neutrophil subpopulations and intratumoral neutrophils (TANs) is still under debate.

Tumor-Associated Neutrophils Drive B-cell Recruitment and Their Differentiation to Plasma Cells.

A major mechanism through which neutrophils have been suggested to modulate tumor progression involves the interaction and subsequent modulation of other infiltrating immune cells. B cells have been found to infiltrate various cancer types and play a role in tumor immunity, offering new immunotherapy opportunities. Nevertheless, the specific impact of tumor-associated neutrophils (TAN) on B cells has largely been overlooked.

Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression.

Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms.

NETosis in cancer: a critical analysis of the impact of cancer on neutrophil extracellular trap (NET) release in lung cancer patients vs. mice.

Neutrophils play a major role in tumor biology. Among other functions, neutrophils can release extracellular traps (NETs), mesh-like structures of decondensed chromatin fibers, in a process termed NETosis. Originally characterized as an antimicrobial mechanism, NETosis has been described in cancer, but cancer-related predisposition is not clear.

Circulating neutrophil subsets in advanced lung cancer patients exhibit unique immune signature and relate to prognosis.

The accumulation of circulating low-density neutrophils (LDN) has been described in cancer patients and associated with tumor-supportive properties, as opposed to the high-density neutrophils (HDN). Here we aimed to evaluate the clinical significance of circulating LDN in lung cancer patients, and further assessed its diagnostic vs prognostic value. Using mass cytometry (CyTOF), we identified major subpopulations within the circulating LDN/HDN subsets and determined phenotypic modulations of these subsets along tumor progression.

Tumour-associated neutrophils in patients with cancer.

The role and importance of neutrophils in cancer has become increasingly apparent over the past decade. Neutrophils accumulate in the peripheral blood of patients with cancer, especially in those with advanced-stage disease, and a high circulating neutrophil-to-lymphocyte ratio is a robust biomarker of poor clinical outcome in various cancers. To date, most studies investigating the role of neutrophils in cancer have involved animal models or investigated the function of circulating human neutrophils.

Microenvironmental Cues Determine Tumor Cell Susceptibility to Neutrophil Cytotoxicity.

We have recently shown that neutrophil antitumor cytotoxicity is Ca dependent and is mediated by TRPM2, an HO-dependent Ca channel. However, neutrophil antitumor activity is dependent on context and is manifested in the premetastatic niche, but not at the primary site. We therefore hypothesized that expression of TRPM2 and the consequent susceptibility to neutrophil cytotoxicity may be associated with the epithelial/mesenchymal cellular state.

Cancer-related circulating and tumor-associated neutrophils - subtypes, sources and function.

In recent years, the role of neutrophils in cancer biology has been a matter of increasing interest. Many patients with advanced cancer show high levels of neutrophilia, tumor neutrophils are connected to dismal prognosis, and the neutrophil-to-lymphocyte ratio has been introduced as a significant prognostic factor for survival in many types of cancer. Neutrophils constitute an important portion of the infiltrating immune cells in the tumor microenvironment, but controversy has long surrounded the function of these cells in the context of cancer.

TRPM2 Mediates Neutrophil Killing of Disseminated Tumor Cells.

Neutrophils play a critical role in cancer, with both protumor and antitumor neutrophil subpopulations reported. The antitumor neutrophil subpopulation has the capacity to kill tumor cells and limit metastatic spread, yet not all tumor cells are equally susceptible to neutrophil cytotoxicity. Because cells that evade neutrophils have greater chances of forming metastases, we explored the mechanism neutrophils use to kill tumor cells.

Tumor-associated neutrophils induce apoptosis of non-activated CD8 T-cells in a TNFα and NO-dependent mechanism, promoting a tumor-supportive environment.

The role of neutrophils in tumor progression has become in recent years a subject of growing interest. Tumor-associated neutrophils (TANs), which constitute an important portion of the tumor microenvironment, promote immunosuppression in advanced tumors by modulating the proliferation, activation and recruitment of a variety of immune cell types. Studies which investigated the consequences of manipulating TAN polarization suggest that the impact of these neutrophils on tumor progression is considerably mediated by and dependent on the presence of CD8 T-cells.

Neutrophils as active regulators of the immune system in the tumor microenvironment.

In recent years, the role of immune cells in tumor progression has been a matter of increasing interest. Neutrophils constitute an important portion of the immune cells infiltrating the tumor microenvironment. Traditionally viewed as the first line of defense against infections, it is now well accepted that neutrophils also have an important role in multiple aspects of cancer biology.

Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: A transcriptomics analysis of pro- vs. antitumor TANs.

It is becoming increasingly clear that tumor-associated neutrophils (TANs) play an important role in cancer biology, through direct impact on tumor growth and by recruitment of other cells types into the tumor. The function of neutrophils in cancer has been the subject of seemingly contradicting reports, pointing toward a dual role played by TANs in tumor progression. The existence of multiple neutrophil subsets, as well as phenotypic modulation of the neutrophils by various factors in the tumor microenvironment, has been shown.

Membrane-permeable tastants amplify β2-adrenergic receptor signaling and delay receptor desensitization via intracellular inhibition of GRK2's kinase activity.

Background: Amphipathic sweet and bitter tastants inhibit purified forms of the protein kinases GRK2, GRK5 and PKA activities. Here we tested whether membrane-permeable tastants may intracellularly interfere with GPCR desensitization at the whole cell context.

Methods: β2AR-transfected cells and cells containing endogenous β2AR were preincubated with membrane-permeable or impermeable tastants and then stimulated with isoproterenol (ISO).

Cerebral blood volume and vasodilation are independently diminished by aging and hypertension: a near infrared spectroscopy study.

Background: Senescent changes in brain microvascular circulation may cause or contribute to age-related cognitive decline. Such changes are promoted partly by aging, but also by chronic hypertension, a leading treatable cause of cognitive decline.

Objectives: We aimed to non-invasively detect in vivo the senescent changes in brain microvascular circulation associated with age and hypertension, and inquired whether decrements driven by aging would be exacerbated by chronic hypertension.

Absolute measurement of cerebral optical coefficients, hemoglobin concentration and oxygen saturation in old and young adults with near-infrared spectroscopy.

We present near-infrared spectroscopy measurement of absolute cerebral hemoglobin concentration and saturation in a large sample of 36 healthy elderly (mean age, 85 ± 6 years) and 19 young adults (mean age, 28 ± 4 years). Non-invasive measurements were obtained on the forehead using a commercially available multi-distance frequency-domain system and analyzed using a diffusion theory model for a semi-infinite, homogeneous medium with semi-infinite boundary conditions. Our study included repeat measurements, taken five months apart, on 16 elderly volunteers that demonstrate intra-subject reproducibility of the absolute measurements with cross-correlation coefficients of 0.

Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet--induced obesity in mice.

Objective: To identify, localize, and determine M1/M2 polarization of epidydimal adipose tissue (eAT) macrophages (Phis) during high-fat diet (HFD)-induced obesity.

Research Design And Methods: Male C57BL/6 mice were fed an HFD (60% fat kcal) or low-fat diet (LFD) (10% fat kcal) for 8 or 12 weeks. eATMPhis (F4/80(+) cells) were characterized by in vivo fluorescent labeling, immunohistochemistry, fluorescence-activated cell sorting, and quantitative PCR.

T-cell recruitment and Th1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice.

The role of adaptive immunity in obesity-associated adipose tissue (AT) inflammation and insulin resistance (IR) is controversial. We employed flow cytometry and quantitative PCR to assess T-cell recruitment and activation in epididymal AT (eAT) of C57BL/6 mice during 4-22 weeks of a high-fat diet (HFD (60% energy)). By week 6, eAT mass and stromal vascular cell (SVC) number increased threefold in mice fed HFD, coincident with onset of IR.

Inhibition of signal termination-related kinases by membrane-permeant bitter and sweet tastants: potential role in taste signal termination.

Sweet and bitter taste sensations are believed to be initiated by the tastant-stimulated T1R and T2R G protein-coupled receptor (GPCR) subfamilies, respectively, which occur in taste cells. Although such tastants, with their significantly diverse chemical structures (e.g.