Increased ACTL6A occupancy within mSWI/SNF chromatin remodelers drives human squamous cell carcinoma.

Mammalian SWI/SNF (BAF) chromatin remodelers play dosage-sensitive roles in many human malignancies and neurologic disorders. The gene encoding the BAF subunit actin-like 6a (ACTL6A) is amplified early in the development of many squamous cell carcinomas (SCCs), but its oncogenic role remains unclear. Here we demonstrate that ACTL6A overexpression leads to its stoichiometric assembly into BAF complexes and drives their interaction and engagement with specific regulatory regions in the genome. In normal epithelial cells, ACTL6A was substoichiometric to other BAF subunits. However, increased ACTL6A levels by ectopic expression or in SCC cells led to near saturation of ACTL6A within BAF complexes. Increased ACTL6A occupancy enhanced polycomb opposition genome-wide to activate SCC genes and facilitated the co-dependent loading of BAF and TEAD-YAP complexes on chromatin. Both mechanisms appeared to be critical and function as a molecular AND gate for SCC initiation and maintenance, thereby explaining the specificity of the role of ACTL6A amplification in SCCs.

Distress among cancer patients attending rehabilitation in the community.

PURPOSE: The aim of this study is to identify sources of distress among cancer patients attending rehabilitation in the community. METHODS: Participants were 430 patients recruited from a cancer rehabilitation center in Singapore between 2017 and 2018, who had rated their distress using the distress thermometer (DT) and indicated associated problems on the problem list. Chi-square tests were used to detect differences in the reported symptoms among three age groups. Exploratory factor analysis was used to identify symptom clusters. Partial correlational analysis was then performed to examine the relationship between distress, symptom clusters, and age controlling for gender and cancer type. RESULTS: About 30% of the participants reported distress ≥ 5 on the DT (mean 3.3 ± 2.5), and the mean number of problems endorsed was 8 ± 6. A higher total number of reported problems (r = .63) and younger age (r = - .21) were associated with increased distress. The younger age group also reported more problems surrounding emotions, finance, work/school, children-related issues, and physical symptoms such as sleep and nausea. Of the 12 factors identified, 9 psychosocial and physical symptom clusters correlated with distress (r ranging from .12 to .41). All results were statistically significant after adjustment (p ≤ 0.05). CONCLUSION: Younger survivors are more at risk of distress and report greater role functioning concerns related to childcare, partner relationship, and work participation. Age-tailored and multimodal interventions may be necessary to adequately address age-related differences and help coordinate management of multiple symptom clusters across physical and psychosocial concerns.

Cancer and radiation therapy: current advances and future directions.

In recent years remarkable progress has been made towards the understanding of proposed hallmarks of cancer development and treatment. However with its increasing incidence, the clinical management of cancer continues to be a challenge for the 21st century. Treatment modalities comprise of radiation therapy, surgery, chemotherapy, immunotherapy and hormonal therapy. Radiation therapy remains an important component of cancer treatment with approximately 50% of all cancer patients receiving radiation therapy during their course of illness; it contributes towards 40% of curative treatment for cancer. The main goal of radiation therapy is to deprive cancer cells of their multiplication (cell division) potential. Celebrating a century of advances since Marie Curie won her second Nobel Prize for her research into radium, 2011 has been designated the Year of Radiation therapy in the UK. Over the last 100 years, ongoing advances in the techniques of radiation treatment and progress made in understanding the biology of cancer cell responses to radiation will endeavor to increase the survival and reduce treatment side effects for cancer patients. In this review, principles, application and advances in radiation therapy with their biological end points are discussed.

An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency.

Mammalian SWI/SNF [also called BAF (Brg/Brahma-associated factors)] ATP-dependent chromatin remodeling complexes are essential for formation of the totipotent and pluripotent cells of the early embryo. In addition, subunits of this complex have been recovered in screens for genes required for nuclear reprogramming in Xenopus and mouse embryonic stem cell (ES) morphology. However, the mechanism underlying the roles of these complexes is unclear. Here, we show that BAF complexes are required for the self-renewal and pluripotency of mouse ES cells but not for the proliferation of fibroblasts or other cells. Proteomic studies reveal that ES cells express distinctive complexes (esBAF) defined by the presence of Brg (Brahma-related gene), BAF155, and BAF60A, and the absence of Brm (Brahma), BAF170, and BAF60C. We show that this specialized subunit composition is required for ES cell maintenance and pluripotency. Our proteomic analysis also reveals that esBAF complexes interact directly with key regulators of pluripotency, suggesting that esBAF complexes are specialized to interact with ES cell-specific regulators, providing a potential explanation for the requirement of BAF complexes in pluripotency.

Surgery for atlanto-axial (C1-2) involvement or instability in nasopharyngeal carcinoma patients.

Nasopharyngeal cancer (NPC) is a common malignancy affecting Asian countries, especially the Chinese population. Treatment regimes and results have improved over the years with better overall survival outcome data. Radiotherapy with or without chemotherapy is successful in many patients. Local recurrences are treated with nasopharyngectomy or another course of radiotherapy. The upper cervical spine and skull base can also be involved in NPC patients. Possible aetiologies are osteoradionecrosis, chronic infection and tumour invasion. This article reviews the NPC involvement of C1-2 due to the various pathologies as well as the diagnostic and surgical treatment strategies. Three clinical cases that were surgically treated are discussed along with a review of the current literature.

Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma.

UNLABELLED: The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic-activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. In total, 23 of 65 (35.4%) cases harbored JAK3 mutations. Functional characterization of the JAK3 mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth. Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs. SIGNIFICANCE: Gene mutations causing NKTCL have not been fully identified. Through exome sequencing, we identified activating mutations of JAK3 that may play a significant role in the pathogenesis of NKTCLs. Our findings have important implications for the management of patients with NKTCLs.

Psychometric properties of reverse-scored items on the CES-D in a sample of ethnically diverse older adults.

Reverse-scored items on assessment scales increase cognitive processing demands and may therefore lead to measurement problems for older adult respondents. In this study, the objective was to examine possible psychometric inadequacies of reverse-scored items on the Center for Epidemiologic Studies Depression Scale (CES-D) when used to assess ethnically diverse older adults. Using baseline data from a gerontologic clinical trial (n = 460), we tested the hypotheses that the reversed items on the CES-D (a) are less reliable than nonreversed items, (b) disproportionately lead to intraindividually atypical responses that are psychometrically problematic, and (c) evidence improved measurement properties when an imputation procedure based on the scale mean is used to replace atypical responses. In general, the results supported the hypotheses. Relative to nonreversed CES-D items, the 4 reversed items were less internally consistent, were associated with lower item-scale correlations, and were more often answered atypically at an intraindividual level. Further, the atypical responses were negatively correlated with responses to psychometrically sound nonreversed items that had similar content. The use of imputation to replace atypical responses enhanced the predictive validity of the set of reverse-scored items. Among older adult respondents, reverse-scored items are associated with measurement difficulties. It is recommended that appropriate correction procedures such as item readministration or statistical imputation be applied to reduce the difficulties.

Hormone receptors and HER-2 status as surrogates for breast cancer molecular subtypes prognosticate for disease control in node negative Asian patients treated with breast conservation therapy.

INTRODUCTION: Our study investigates whether an approximation of breast cancer molecular subtypes using the hormone receptors and HER-2 status prognosticates for disease control after breast conservation therapy (BCT) in node-negative Asian breast cancer patients. METHODS AND MATERIALS: We retrospectively reviewed 541 women with node-negative breast cancers treated with BCT between 1989 and 2007. Hormone receptors and HER-2 status were obtained from patients' histological report. All patients received radiotherapy. Thirty-six percent and 68% of women received chemotherapy and hormonal treatment respectively. RESULTS: Median follow-up of patients is 72 months. Five-year local recurrence free survival (LRFS) is 97.2% for the cohort but differs between subtypes: luminal A, 0.8%; luminal B, 1.4%; HER-2, 3.6% and basal-like, 12.7% (P = 0.047). The 5-year distant disease free survival (DDFS) is 96.4% for the cohort but differs between subtypes: luminal A, 98.2%; luminal B, 92.6%; HER-2, 89.5% and basal-like, 91.5% (P = 0.019). The 5-year disease free survival (DFS) is 94.4% for the cohort but differs between subtypes: luminal A, 97.4%; luminal B, 92.7%; HER-2, 86.3% and basal-like, 85.0% (P = 0.007). Univariate analysis with luminal A as baseline revealed an association of the other 3 subtypes with decreased DFS (P = 0.007), Hazard Ratio (HR) of 2.2, 4.4 and 3.3 to Luminal B, HER-2 and basal subtypes, respectively. On multivariate analysis, HER-2 subtype (AHR = 3.3, 95% CI, 1.1 to 9.8, P = 0.036) and basal-like subtype (HR = 3.5, 95% CI, 1.2 to 9.9, P = 0.019) prognosticate adversely for DFS. CONCLUSION: The combination of hormone receptors and HER-2 status can be used as surrogates for molecular subtypes in Asian breast cancer patients with node-negative disease to prognosticate LRFS, DFS and DDFS.

Enhanced NFATc1 nuclear occupancy causes T cell activation independent of CD28 costimulation.

TCR signals induce the nuclear localization of NFATc proteins, which are removed from the nucleus after rephosphorylation by glycogen synthase kinase 3 and other kinases. Rapid nuclear export might allow continuous monitoring of receptor occupancy, making the transcriptional response proportional to the duration of TCR/CD28 signaling. To investigate this possibility, we analyzed mice in which T cells express a NFATc1 variant (NFATc1(nuc)) with serine-to-alanine changes at the glycogen synthase kinase 3 phosphorylation sites. NFATc1(nuc) T cells have constitutively nuclear NFATc1, enhanced T cell activation in vivo, and calcineurin-independent proliferation in vitro. NFATc1(nuc) T cells are hypersensitive to TCR/CD3 stimulation, resulting in enhanced proliferation and cytokine production that is independent of CD28 costimulation. These results support the notion that CD28 inhibits nuclear export of NFATc transcription factors. In addition, NFATc1(nuc) destabilizes a positive feedback loop in which NFATc1 activates its own transcription as well as its targets, such as CD40 ligand and Th1/Th2 cytokines.

Identification of a polymorphic, neuron-specific chromatin remodeling complex.

A variety of chromatin remodeling complexes are thought to assist sequence-specific transcription factors. The complexes described to date are expressed ubiquitously, suggesting that they have general transcriptional functions. We show that vertebrate neurons have a specialized chromatin remodeling complex, bBAF, specifically containing the actin-related protein, BAF53b, which is first expressed in postmitotic neurons at about murine embryonic day 12.5 (E12.5). BAF53b is combinatorially assembled into polymorphic complexes with ubiquitous subunits including the two ATPases BRG1 and BRM. We speculate that bBAF complexes create neuronal-specific patterns of chromatin accessibility, thereby imparting new regulatory characteristics to ubiquitous sequence-specific transcription factors in neurons.

A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis.

The delicate leaflets that make up vertebrate heart valves are essential for our moment-to-moment existence. Abnormalities of valve formation are the most common serious human congenital defect. Despite their importance, relatively little is known about valve development. We show that the initiation of heart valve morphogenesis in mice requires calcineurin/NFAT to repress VEGF expression in the myocardium underlying the site of prospective valve formation. This repression of VEGF at E9 is essential for endocardial cells to transform into mesenchymal cells. Later, at E11, a second wave of calcineurin/NFAT signaling is required in the endocardium, adjacent to the earlier myocardial site of NFAT action, to direct valvular elongation and refinement. Thus, NFAT signaling functions sequentially from myocardium to endocardium within a valvular morphogenetic field to initiate and perpetuate embryonic valve formation. This mechanism also operates in zebrafish, indicating a conserved role for calcineurin/NFAT signaling in vertebrate heart valve morphogenesis.