Notes

Mesoplankton through the North Atlantic: Structure and also enviromentally friendly drivers at Fifty nine.5th leeway.
benefits participants' clinical practice as well as psychological well-being.
Healthcare organisations now integrate patient feedback into value-based compensation formulas. This research considered Stanford Healthcare's same-day feedback, a programme designed to evaluate the patient experience. Specifically, how did patients with cancer interviewed in the programme assess their physicians? Furthermore, how did assessments differ across emotional, physical, practical and informational needs when interviewed by volunteer patient and family partners (PAFPs) versus hospital staff?

Integral to this research was Communication Accommodation Theory (CAT), which suggests individuals adjust interactions based on conversational roles, needs and understanding. Previous influential research was conducted by Frosch
(2012) and Di Bartolo
(2017), who revealed barriers to patient-physician communication, and Baker
(2011) who associated CAT with these interactions. However, we still did not know if patients alter physician assessments between interviewers.

This mixed methods study worked with 190 oncology unit patient interviews from 2009 to 2017. Open-ended interview responses underwent thematic analysis. When compared with hospital staff, PAFPs collected more practical and informational needs from patients. PAFPs also collected more verbose responses that resembled detailed narratives of the patients' hospital experiences. This study contributed insightful patient perspectives of physician care in a novel hospital programme.
This mixed methods study worked with 190 oncology unit patient interviews from 2009 to 2017. Open-ended interview responses underwent thematic analysis. When compared with hospital staff, PAFPs collected more practical and informational needs from patients. PAFPs also collected more verbose responses that resembled detailed narratives of the patients' hospital experiences. This study contributed insightful patient perspectives of physician care in a novel hospital programme.The study population within phase III clinical trials leading to approval of new cancer agents should ideally more closely mirror the population who will ultimately receive these agents. Although the number of females participating in clinical trials has increased over the past several decades, females are still under-represented in preclinical studies, in early phase clinical trials and even in some later phase cancer clinical trials. In the USA, this is particularly true for women from minority populations and elderly women. In this review, we review gender and sex disparities in cancer trials, the reasons for these disparities, the barriers to clinical trial enrolment and ways to improve diversity in cancer clinical trials.Cancer research and cancer care require deliberate attention to racial diversity. Here we comment on the ongoing issues of diversity and racism in cancer research.Therapeutic checkpoint antibodies blocking programmed death receptor 1/programmed death ligand 1 (PD-L1) signaling have radically improved clinical outcomes in cancer. However, the regulation of PD-L1 expression on tumor cells is still poorly understood. Here we show that intratumoral copper levels influence PD-L1 expression in cancer cells. Deep analysis of the The Cancer Genome Atlas database and tissue microarrays showed strong correlation between the major copper influx transporter copper transporter 1 (CTR-1) and PD-L1 expression across many cancers but not in corresponding normal tissues. Copper supplementation enhanced PD-L1 expression at mRNA and protein levels in cancer cells and RNA sequencing revealed that copper regulates key signaling pathways mediating PD-L1-driven cancer immune evasion. Conversely, copper chelators inhibited phosphorylation of STAT3 and EGFR and promoted ubiquitin-mediated degradation of PD-L1. Copper-chelating drugs also significantly increased the number of tumor-infiltrating CD8+ T and natural killer cells, slowed tumor growth, and improved mouse survival. Overall, this study reveals an important role for copper in regulating PD-L1 and suggests that anticancer immunotherapy might be enhanced by pharmacologically reducing intratumor copper levels. SIGNIFICANCE These findings characterize the role of copper in modulating PD-L1 expression and contributing to cancer immune evasion, highlighting the potential for repurposing copper chelators as enhancers of antitumor immunity. GRAPHICAL ABSTRACT http//cancerres.aacrjournals.org/content/canres/80/19/4129/F1.large.jpg.Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that has proven refractory to immunotherapy. Previously, treatment with the DNA hypomethylating drug decitabine (5-aza-dC; DAC) extended survival in the KPC-Brca1 mouse model of PDAC. Here we investigated the effects of DAC in the original KPC model and tested combination therapy with DAC followed by immune checkpoint inhibitors (ICI). Four protocols were tested PBS vehicle, DAC, ICI (anti-PD-1 or anti-VISTA), and DAC followed by ICI. For each single-agent and combination treatment, tumor growth was measured by serial ultrasound, tumor-infiltrating lymphoid and myeloid cells were characterized, and overall survival was assessed. Single-agent DAC led to increased CD4+ and CD8+ tumor-infiltrating lymphocytes (TIL), PD1 expression, and tumor necrosis while slowing tumor growth and modestly increasing mouse survival without systemic toxicity. RNA-sequencing of DAC-treated tumors revealed increased expression of Chi3l3 (Ym1), reflecting an increase in a subset of tumor-infiltrating M2-polarized macrophages. While ICI alone had modest effects, DAC followed by either of ICI therapies additively inhibited tumor growth and prolonged mouse survival. The best results were obtained using DAC followed by anti-PD-1, which extended mean survival from 26 to 54 days (P less then 0.0001). In summary, low-dose DAC inhibits tumor growth and increases both TILs and a subset of tumor-infiltrating M2-polarized macrophages in the KPC model of PDAC, and DAC followed by anti-PD-1 substantially prolongs survival. Because M2-polarized macrophages are predicted to antagonize antitumor effects, targeting these cells may be important to enhance the efficacy of combination therapy with DAC plus ICI. SIGNIFICANCE In a pancreatic cancer model, a DNA hypomethylating drug increases tumor-infiltrating effector T cells, increases a subset of M2 macrophages, and significantly prolongs survival in combination with immune checkpoint inhibitors.See related commentary by Nephew, p. 4610.Lung cancer is the leading cause of cancer-related deaths worldwide. The paralogous transcriptional cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ, also called WWTR1), the main downstream effectors of the Hippo signal transduction pathway, are emerging as pivotal determinants of malignancy in lung cancer. Traditionally, studies have tended to consider YAP and TAZ as functionally redundant transcriptional cofactors with similar biological impact. However, there is growing evidence that each of them also possesses distinct attributes. Here we sought to systematically characterize the division of labor between YAP and TAZ in non-small cell lung cancer (NSCLC), the most common histological subtype of lung cancer. Representative NSCLC cell lines as well as patient-derived data showed that the two paralogs orchestrated nonoverlapping transcriptional programs in this cancer type. YAP preferentially regulated gene sets associated with cell division and cell-cycle progression, whereas TAZ preferentially regulated genes associated with extracellular matrix organization. Depletion of YAP resulted in growth arrest, whereas its overexpression promoted cell proliferation. Likewise, depletion of TAZ compromised cell migration, whereas its overexpression enhanced migration. The differential effects of YAP and TAZ on key cellular processes were also associated with differential response to anticancer therapies. Uncovering the different activities and downstream effects of YAP and TAZ may thus facilitate better stratification of patients with lung cancer for anticancer therapies. SIGNIFICANCE Thease findings show that oncogenic paralogs YAP and TAZ have distinct roles in NSCLC and are associated with differential response to anticancer drugs, knowledge that may assist lung cancer therapy decisions.Elevated expression of EZH2, the enzymatic subunit of polycomb repressive complex 2 (PRC2), often occurs in cancer. EZH2 expression results in the silencing of genes that suppress tumor formation and metastasis through trimethylation of histone H3 at lysine 27 (H3K27me3) at their promoters. However, inhibitors of EZH2 enzymatic activity have not shown the expected efficacy against cancer in clinical trials, suggesting a need for other strategies to address EZH2 overexpression. Here, we show that SUMOylation, a posttranslational modification characterized by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins, enhances EZH2 transcription. Either knockdown of the SUMO-activating enzyme SAE2 or pharmacologic inhibition of SUMOylation resulted in decreased levels of EZH2 mRNA and protein as well as reduced H3K27me3 levels. SUMOylation regulated EZH2 expression by enhancing binding of the E2F1 transcriptional activator to the EZH2 promoter. Inhibition of SUMOylation not only resulted in reduced EZH2 mRNA and protein levels but also increased expression of genes silenced by EZH2, such as E-cadherin, which suppresses epithelial-mesenchymal transition and metastasis. In more than 6,500 patient tumor samples across different cancer types, expression of UBA2 and EZH2 was positively correlated. Taken together, our findings suggest that inhibition of SUMOylation may serve as a potential strategy to address EZH2 overexpression and improve current cancer therapeutic approaches. SIGNIFICANCE These findings provide important biological insights into the mechanism of EZH2 overexpression in cancers and suggest that inhibiting SUMOylation may improve current cancer therapeutic approaches.Tumor-associated macrophages (TAM) in the tumor microenvironment (TME) cooperate with cancer stem cells (CSC) to maintain stemness. We recently identified cluster of differentiation 44 (CD44) as a surface marker defining head and neck squamous cell carcinoma (HNSCC) CSC. PI3K-4EBP1-SOX2 activation and signaling regulate CSC properties, yet the upstream molecular control of this pathway and the mechanisms underlying cross-talk between TAM and CSC in HNSCC remain largely unknown. Because CD44 is a molecular mediator in the TME, we propose here that TAM-influenced CD44 signaling could mediate stemness via the PI3K-4EBP1-SOX2 pathway, possibly by modulating availability of hyaluronic acid (HA), the main CD44 ligand. HNSCC IHC was used to identify TAM/CSC relationships, and in vitro coculture spheroid models and in vivo mouse models were used to identify the influence of TAMs on CSC function via CD44. Patient HNSCC-derived TAMs were positively and negatively associated with CSC marker expression at noninvasive and invasive edge regions, respectively. TAMs increased availability of HA and increased cancer cell invasion. HA binding to CD44 increased PI3K-4EBP1-SOX2 signaling and the CSC fraction, whereas CD44-VCAM-1 binding promoted invasive signaling by ezrin/PI3K. In vivo, targeting CD44 decreased PI3K-4EBP1-SOX2 signaling, tumor growth, and CSC. TAM depletion in syngeneic and humanized mouse models also diminished growth and CSC numbers. Finally, a CD44 isoform switch regulated epithelial-to-mesenchymal plasticity as standard form of CD44 and CD44v8-10 determined invasive and tumorigenic phenotypes, respectively. ARS853 price We have established a mechanistic link between TAMs and CSCs in HNSCC that is mediated by CD44 intracellular signaling in response to extracellular signals. SIGNIFICANCE These findings establish a mechanistic link between tumor cell CD44, TAM, and CSC properties at the tumor-stroma interface that can serve as a vital area of focus for target and drug discovery.
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