Cravenfraser4127

The efficacy of zebularine was abolished in nude mice and in cGAS-/- or STING-/- mice, indicating its dependency on host immunity. Analysis of tumor cells indicates upregulation of interferon-stimulated genes (ISGs) following zebularine administration. Zebularine promoted infiltration of CD8 T cells and natural killer (NK) cells into tumor and therefore suppressed tumor growth. This study unveils the role of zebularine in sensitizing the cGAS-STING pathway to promote anti-tumor immunity and provides the foundation for further therapeutic development.The immunosuppressive tumor microenvironment (TME) is a formidable barrier to the success of adoptive cell therapies for solid tumors. Oncolytic immunotherapy with engineered adenoviruses (OAd) may disrupt the TME by infecting tumor cells, as well as surrounding stroma, to improve the functionality of tumor-directed chimeric antigen receptor (CAR)-T cells, yet efficient delivery of OAds to solid tumors has been challenging. Here we describe how mesenchymal stromal cells (MSCs) can be used to systemically deliver a binary vector containing an OAd together with a helper-dependent Ad (HDAd; combinatorial Ad vector [CAd]) that expresses interleukin-12 (IL-12) and checkpoint PD-L1 (programmed death-ligand 1) blocker. CAd-infected MSCs deliver and produce functional virus to infect and lyse lung tumor cells while stimulating CAR-T cell anti-tumor activity by release of IL-12 and PD-L1 blocker. The combination of this approach with administration of HER.2-specific CAR-T cells eliminates 3D tumor spheroids in vitro and suppresses tumor growth in two orthotopic lung cancer models in vivo. Treatment with CAd MSCs increases the overall numbers of human T cells in vivo compared to CAR-T cell only treatment and enhances their polyfunctional cytokine secretion. These studies combine the predictable targeting of CAR-T cells with the advantages of cancer cell lysis and TME disruption by systemic MSC delivery of oncolytic virotherapy incorporation of immunostimulation by cytokine and checkpoint inhibitor production through the HDAd further enhances anti-tumor activity.Epithelial-mesenchymal transition (EMT) is reported to involve in the crosstalk between tumor cells and tumor-associated macrophages (TAMs). Exosomes are considered as important mediators of orchestrating intercellular communication. However, the underlying mechanisms by which EMT-colorectal cancer (CRC) cells promote the M2 polarization of TAMs remain less understood. In this study, we found that EMT-CRC cells promoted the M2-like polarization of macrophages by directly transferring exosomes to macrophages, leading to a significant increase of the microRNA-106b-5p (miR-106b) level in macrophages. Mechanically, an increased level of miR-106b activated the phosphatidylinositol 3-kinase (PI3K)γ/AKT/mammalian target of rapamycin (mTOR) signaling cascade by directly suppressing programmed cell death 4 (PDCD4) in a post-transcription level, contributing to the M2 polarization of macrophages. Activated M2 macrophages, in a positive-feedback manner, promote EMT-mediated migration, invasion, and metastasis of CRC cells. Clinically, miR-106b was significantly elevated in CRC tissues and negatively correlated with the levels of PDCD4 in CRC specimens, and high expression of exosomal miR-106b in plasma was significantly associated with the malignant progression of CRC. Taken together, our results indicate that exosomal miR-106b derived from EMT-CRC cells has an important role in intercellular communication for inducing M2 macrophage polarization, illuminating a novel mechanism underlying CRC progression and offering potential targets for prevention of CRC metastasis.

Operative hysteroscopy requires elevated intrauterine pressures, which could lead to the spread of malignant cells into the peritoneal cavity. Currently, there is a paucity of data analyzing clinical outcomes in endometrial cancer after hysteroscopic morcellation with newer equipment. In this study, we sought to determine whether there are increased rates of positive peritoneal cytology, lymphovascular space invasion, or surgical upstaging in patients undergoing hysteroscopic morcellation compared with alternative endometrial biopsy methods.

A retrospective chart review of patients from 2013-2018 was performed. The exclusion criteria included biopsy at outside institution, stage IV endometrial cancer known before biopsy, and missing data regarding biopsy method and histology. Peritoneal cytology results, lymphovascular space invasion, and surgical staging were compared by method of biopsy and histology using chi-square and Kruskal-Wallis tests.

The patients included in this study were accrued from the Kr low grade and high grade, respectively).

Our study demonstrates that hysteroscopy with morcellation is a safe diagnostic method for low- and high-grade endometrial pathologic conditions and does not lead to increased dissemination of malignant cells, lymphovascular space invasion, or upstaging of patients.

Our study demonstrates that hysteroscopy with morcellation is a safe diagnostic method for low- and high-grade endometrial pathologic conditions and does not lead to increased dissemination of malignant cells, lymphovascular space invasion, or upstaging of patients.Digital technologies have a significant role in collecting, filtering and disseminating information, allowing for social, healthcare and economic activities even in the context of highly restrictive public health measures in the current COVID-19 pandemic. selleck kinase inhibitor As personal contact is greatly reduced, they also create a shared informational landscape, allowing for a shared threat response. This is a difficult task, since truthfulness of content that leads to actionable knowledge is impossible to consistently validate. So, not only that curation of information is rarely congruent with pressing health issues, but digital spaces may also become fertile ground for misinformation and disinformation, contributing to the devastating effects of an infodemic. Digital intermediaries are useful exactly because their representation of reality is not a true construct, but a result of purposely curated information. However, they are active, dynamic epistemological agents with their own logic and aim. In dealing with a pandemic, we should reconsider the ways how our digital informational landscapes are created and sustained.