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Background: Current treatments for people with obesity emphasise the need for person-centred approaches that consider complex biopsychosocial factors and value the lived experience of people when attempting to lose weight. Methods: Narrative interviews (n = 20) were conducted with people living with obesity to explore the causes of their weight gain and their expectations and engagement with treatment at a Weight Management Clinic. A mixed inductive and deductive qualitative analysis identified utterances that represented psychological constructs used to understand self-appraisal and health behaviour. A narrative analysis was used to situate these findings in the context of a participant's life story. Results: Locus of control was a dominant construct evidenced through a person's attributional style and self-efficacy. Transcripts represented a heightened sense of self-understanding and shifts in control, and styles of attribution and efficacy resulted in either stasis or self-actualisation. The Stages of Change model could be applied to narratives to ascertain a patient's motivation to access treatment. Importantly, narrative interviews also allowed for the consideration of how a person's systemic context influenced their weight. Conclusion: Narrative interaction supports both self- and shared understandings of the causes and consequences of obesity for individuals, in a non-blaming or shaming manner. It provides an opportunity to enhance engagement through tailored, person-centred treatments. [ABSTRACT FROM AUTHOR]

Background: Mismatch‐repair (MMR)/microsatellite instability (MSI) status has therapeutic implications in endometrial cancer (EC). The authors evaluated the concordance of testing and factors contributing to MMR expression heterogeneity. Methods: Six hundred sixty‐six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut‐L homolog 1 (MLH1) methylation. Select samples underwent whole‐transcriptome analysis and next‐generation sequencing. MMR expression of metastatic/recurrent sites was evaluated. Results: MSI testing identified 27.3% of cases as MSI‐high (n = 182), MMR IHC identified 25.1% cases as MMR‐deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut‐S homolog 6 [MSH6], n = 7; MLH1/PMS2, n = 1). MSH6‐associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR‐deficient cases and 9% in MMR‐proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial–mesenchymal transition. Conclusions: Subclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR‐deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker‐directed therapy. Plain Language Summary: Endometrial cancer is the most common gynecologic cancer, and 20%–40% of tumors have a defect in DNA proofreading known as mismatch‐repair (MMR) deficiency.These results can be used to guide therapy.Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities.Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes.Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread.These MMR‐deficient cells may drive tumor behavior and the risk of spreading cancer. Intratumoral heterogeneity, including subclonal and heterogeneous mismatch‐repair (MMR) expression, can yield discordant results from diagnostic assays, such as immunohistochemistry and polymerase chain reaction‐based microsatellite instability testing. Within endometrial cancers, subclonal or heterogeneous MMR expression may be attributed to germline or somatic mutations in MMR proteins, and the authors demonstrate that these tumors are characterized by clonal selection favoring the propagation of MMR deficiency at sites of metastasis or recurrence. [ABSTRACT FROM AUTHOR]

Reading Recovery (RR) is a short-term, one-to-one intervention designed to help the lowest achieving readers in first grade. This article presents first-year results from the multisite randomized controlled trial (RCT) and implementation study under the $55 million Investing in Innovation (i3) Scale-Up Project. For the 2011-2012 school year, the estimated standardized effect of RR on students' Iowa Tests of Basic Skills (ITBS) Total Reading Scores was 0.69 standard deviations relative to the population of struggling readers eligible for RR under the i3 scale-up and 0.47 standard deviations relative to the nationwide population of all first graders. School-level implementation of RR was, in most respects, faithful to the RR "Standards and Guidelines," and the intensive training provided to new RR teachers was viewed as critical to successful implementation.

This document is a reply to a previous article discussing the significance of tumors with "unusual staining" from mismatch repair (MMR) immunohistochemistry (IHC) in endometrial cancer. The authors agree that ongoing conversation and multiple testing strategies are needed to improve outcomes for patients. They also emphasize the importance of quality assurance in performing and interpreting MMR IHC, including uniform fixation and grossing protocols. The authors acknowledge the potential benefits of primary assessment of MMR IHC staining on biopsy specimens but note that in their cohort, preoperative biopsies were performed outside their institution and MMR IHC was not performed on these specimens. They also discuss the interpretation of MSI testing in endometrial cancer and the use of the Promega panel for clarifying cases that are MSI-low on the National Cancer Institute panel. Further research is needed to define optimal testing for MMR-deficient/MSI endometrial cancer and predict response to immunotherapy. [Extracted from the article]

Background: Genomic studies have revealed that multiple genes are mutated at varying frequency in endometrial cancer (EC); however, the relevance of many of these mutations is poorly understood. An EC-specific recurrent mutation in the MAX transcription factor p.His28Arg was recently discovered. We sought to assess the functional consequences of this hotspot mutation and determine its association with cancer-relevant phenotypes.Methods: MAX was sequenced in 509 endometrioid ECs, and associations between mutation status and clinicopathologic features were assessed. EC cell lines stably expressing MAXH28R were established and used for functional experiments. DNA binding was examined using electrophoretic mobility shift assays and chromatin immunoprecipitation. Transcriptional profiling was performed with microarrays. Murine flank (six to 11 mice per group) and intraperitoneal tumor models were used for in vivo studies. Vascularity of xenografts was assessed by MECA-32 immunohistochemistry. The paracrine pro-angiogenic nature of MAXH28R-expressing EC cells was tested using microfluidic HUVEC sprouting assays and VEGFA enzyme-linked immunosorbent assays. All statistical tests were two-sided.Results: Twenty-two of 509 tumors harbored mutations in MAX, including 12 tumors with the p.His28Arg mutation. Patients with a MAX mutation had statistically significantly reduced recurrence-free survival (hazard ratio = 4.00, 95% confidence interval = 1.15 to 13.91, P = .03). MAXH28R increased affinity for canonical E-box sequences, and MAXH28R-expressing EC cells dramatically altered transcriptional profiles. MAXH28R-derived xenografts statistically significantly increased vascular area compared with MAXWT and empty vector tumors (P = .003 and P = .008, respectively). MAXH28R-expressing EC cells secreted nearly double the levels of VEGFA compared with MAXWT cells (P = .03, .005, and .005 at 24, 48, and 72 hours, respectively), and conditioned media from MAXH28R cells increased sprouting when applied to HUVECs.Conclusion: These data highlight the importance of MAX mutations in EC and point to increased vascularity as one mechanism contributing to clinical aggressiveness of EC. [ABSTRACT FROM AUTHOR]

BACKGROUND Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but typically is associated with low rates of metastasis and high survival rates. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals die each year of this disease. METHODS Because it is difficult to predict which cSCCs are more likely to metastasize, and because to the best of the authors' knowledge there are no targeted therapies specifically designated for patients with metastatic cSCC, exome and/or targeted sequencing of 18 metastatic and 10 primary cSCCs was performed to identify mutations that were more frequent in metastatic tumors and might be targeted for therapeutic benefit. The authors compared their results with published sequencing results of an additional 223 primary tumors and 68 metastatic cSCCs. RESULTS The authors identified genes demonstrating higher mutation frequencies in metastatic cSCC compared with primary tumors, including the chromatin remodeling gene lysine methyltransferase 2D ( KMT2D) and the classic skin tumor suppressor tumor protein p53 ( TP53), which was found to be mutated in 54% of primary tumors compared with 85% of metastatic tumors ( P<.0001). CONCLUSIONS These studies appear to uncover potential pathways that are important in metastatic cSCC and that broaden understanding of the biology contributing to aggressive tumor behavior. These results may lead to new therapeutic strategies. Cancer 2017;123:1184-1193. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Preclinical Research Phenylmethimazole (C10) is an inhibitor of Toll ‐ like receptor (TLR3 and TLR4) expression and signaling. In this study, we carried out a detailed investigation of the effect of C10 on TLR4 and its molecular signaling products in RAW 264.7 macrophages using quantitative real ‐ time polymerase chain reaction (PCR), ELISA and cell toxicity assays, a set of in vitro assays that may be used to screen future C10 analogs. C10 exhibited an inhibitory effect on TLR4 MyD88 ‐ dependent and MyD88 ‐ independent pathways. Within the TLR4 pathway, C10 inhibited the expression of cytokines, cytokine receptors, kinases, adapter molecules and transcription factors, suggesting a pathway ‐ wide inhibitory effect. We also found that C10 dose ‐ dependently inhibited the expression of TLR4 signaling products, specifically IL ‐ 6, inducible nitric oxide (NO) synthase and IFNβ. Additionally, pre ‐ treatment of RAW 264.7 cells with C10 resulted in protection from lipopolysaccharide (LPS) insults, suggesting C10 may be bound to the target thus exhibiting activity during/following LPS stimulation. Also, dimethyl sulfoxide, the solvent for C10 exhibited inhibitory effect on TLR4 signaling products independent from the effects of C10. Combined, this study enhances understanding of the actions of action on TLR4 signaling pathway providing a path for the development of new C10 analogs for inhibiting TLR expression and signaling. [ABSTRACT FROM AUTHOR]

Purpose: Recent research indicates that physiotherapy interventions, such as exercise and manual therapy, may be effective in decreasing the frequency of side effects linked with breast cancer treatment, including fatigue, pain, nausea, and decreased quality of life. This systematic review aims to determine the efficacy of exercise therapy in reducing shoulder pain related to breast cancer treatment and to identify outcome measures that can be used to assess shoulder pain in this population. Methods: A systematic review of the current literature was conducted using portals such as the Physiotherapy Evidence Database (PEDro), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Ovid MEDLINE (1996 to April 2011), and Allied and Complementary Medicine (AMED) (1985 to April 2011). Databases were searched for relevant studies published up to April 2011. Participants in relevant studies were adults (&nvge;18 years of age) with a primary diagnosis of breast cancer at any point during the treatment of their disease. Results: Six articles were independently appraised by two blinded reviewers. Six studies met the inclusion criteria, each analyzing different types of exercise-shoulder/arm/scapular strengthening/stabilization, postural exercises, general exercises and conditioning, shoulder range-of-motion exercises, and lymphedema exercises-with respect to their efficacy in reducing shoulder pain related to breast cancer treatment. Conclusions: Results suggest that exercise targeting shoulder pain related to breast cancer treatment may be effective. However, definitive conclusions cannot be drawn due to the lack of methodological quality and homogeneity of the studies included. Clinicians should use valid outcome measures, such as the visual analogue scale and brief pain inventory, to evaluate the effectiveness of this treatment. [ABSTRACT FROM AUTHOR]

Background: Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but typically is associated with low rates of metastasis and high survival rates. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals die each year of this disease.Methods: Because it is difficult to predict which cSCCs are more likely to metastasize, and because to the best of the authors' knowledge there are no targeted therapies specifically designated for patients with metastatic cSCC, exome and/or targeted sequencing of 18 metastatic and 10 primary cSCCs was performed to identify mutations that were more frequent in metastatic tumors and might be targeted for therapeutic benefit. The authors compared their results with published sequencing results of an additional 223 primary tumors and 68 metastatic cSCCs.Results: The authors identified genes demonstrating higher mutation frequencies in metastatic cSCC compared with primary tumors, including the chromatin remodeling gene lysine methyltransferase 2D (KMT2D) and the classic skin tumor suppressor tumor protein p53 (TP53), which was found to be mutated in 54% of primary tumors compared with 85% of metastatic tumors (P<.0001).Conclusions: These studies appear to uncover potential pathways that are important in metastatic cSCC and that broaden understanding of the biology contributing to aggressive tumor behavior. These results may lead to new therapeutic strategies. Cancer 2017;123:1184-1193. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]