Adjuvant (chemo)radiotherapy for patients with head and neck cancer: can comorbidity risk scores predict outcome?

PURPOSE: This study compares the objective American Society of Anesthesiologists (ASA) and Adult Comorbidity Evaluation-27 (ACE-27) scores with the subjective Eastern Cooperative Oncology Group performance status (ECOG PS) for patient outcome prediction. METHODS: We retrospectively analyzed head and neck squamous cell carcinoma patients treated with adjuvant (chemo)radiotherapy at the LMU Munich from June 2008 to June 2015. The study focused on associations between patient outcomes; treatment failures; known risk factors (including human papillomavirus [HPV] status and tumor stage); and the comorbidity indices ECOG-PS, ASA score, and ACE-27. The Kaplan-Meier method and Cox proportional hazards model were used for survival analysis and identifying independent risk factors. RESULTS: A total of 302 patients were analyzed, 175 received concurrent chemotherapy. Median follow-up was 61.8 months, and median age at diagnosis was 61 years. The 3­ and 5­year overall survival (OS) and disease-free survival (DFS) rates were 70.5%/60.2% and 64.7%/57.6%, respectively. Both ACE-27 and ASA showed significant correlations with OS in univariate and multivariate analyses, while ECOG-PS was significant only in univariate analysis. ASA and ACE-27 scores were also significantly correlated with local and locoregional recurrence, but only HPV status and tumor stage were significant in multivariate models. CONCLUSION: ACE-27 and ASA score effectively categorize patients' risks in adjuvant radiotherapy for head and neck cancer, proving more predictive of overall survival than ECOG-PS. These results underscore the importance of objective comorbidity assessment and suggest further prospective studies.

Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes.

The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest KrasMUT levels underlying aggressive undifferentiated phenotypes. We also identify alternative oncogenic gains (Myc, Yap1 or Nfkb2), which collaborate with heterozygous KrasMUT in driving tumorigenesis, but have lower metastatic potential. Mechanistically, different oncogenic gains and dosages evolve along distinct evolutionary routes, licensed by defined allelic states and/or combinations of hallmark tumour suppressor alterations (Cdkn2a, Trp53, Tgfß-pathway). Thus, evolutionary constraints and contingencies direct oncogenic dosage gain and variation along defined routes to drive the early progression of PDAC and shape its downstream biology. Our study uncovers universal principles of Ras-driven oncogenesis that have potential relevance beyond pancreatic cancer.

Is cultural appropriateness culturally specific? Intersectional insights from a community-based participatory mental health intervention study conducted with diverse cultural groups.

Growing evidence supports the importance of culturally appropriate mental health interventions, yet it is not always feasible to develop culturally grounded interventions or adapt existing interventions for each cultural group. In addition, these approaches do not recognize the multiple intersecting aspects of culture and identity that individuals, families, and communities possess. Thus, an essential question is whether culturally appropriate mental health interventions have to be culturally specific. We address this question by examining processes of the Refugee Well-being Project (RWP), a community-based mental health intervention for refugees resettled in the United States, which included people from multiple cultural groups (Afghanistan, Great Lakes region of Africa, Iraq, and Syria) and was grounded in common experiences of forcibly displaced people from marginalized backgrounds. RWP incorporates a practice-based concept of culture, an intersectional view of identity, and a multilevel approach to address postmigration stressors. Semistructured qualitative interviews were conducted with 290 participants at preintervention, followed by interviews at three timepoints with a purposively selected subsample (n = 66). Additional interviews (n = 101) were conducted with refugee and student partners. Four themes demonstrated key principles for creating culturally appropriate interventions with diverse groups: (a) recognize cultural complexity in practice; (b) focus on how racism and discrimination are experienced in everyday life; (c) de-center dominant US culture; and (d) create an egalitarian, inclusive space to put principles into action. We conclude that mental health interventions implemented with multiple, diverse groups can be culturally appropriate and effective without being culturally specific.

Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20.

Hepatitis B virus (HBV) persists by depositing a covalently closed circular DNA (cccDNA) in the nucleus of infected cells that cannot be targeted by available antivirals. Interferons can diminish HBV cccDNA via APOBEC3-mediated deamination. Here, we show that overexpression of APOBEC3A alone is not sufficient to reduce HBV cccDNA that requires additional treatment of cells with interferon indicating involvement of an interferon-stimulated gene (ISG) in cccDNA degradation. Transcriptome analyses identify ISG20 as the only type I and II interferon-induced, nuclear protein with annotated nuclease activity. ISG20 localizes to nucleoli of interferon-stimulated hepatocytes and is enriched on deoxyuridine-containing single-stranded DNA that mimics transcriptionally active, APOBEC3A-deaminated HBV DNA. ISG20 expression is detected in human livers in acute, self-limiting but not in chronic hepatitis B. ISG20 depletion mitigates the interferon-induced loss of cccDNA, and co-expression with APOBEC3A is sufficient to diminish cccDNA. In conclusion, non-cytolytic HBV cccDNA decline requires the concerted action of a deaminase and a nuclease. Our findings highlight that ISGs may cooperate in their antiviral activity that may be explored for therapeutic targeting.

Effect of polishing and denture cleansers on the surface roughness of new-generation denture base materials and their color change after cleansing.

PURPOSE: To evaluate the effect of polishing and denture cleansers on the surface roughness (Ra ) of new-generation denture base materials that are additively, subtractively, and conventionally fabricated, while also assessing their color change after cleansing. MATERIAL AND METHODS: One hundred and fifty disk-shaped specimens (Ø10 × 2 mm) were prepared from five denture base materials (one subtractively manufactured nanographene-reinforced prepolymerized polymethylmethacrylate (PMMA) (SM-GC), one subtractively manufactured prepolymerized PMMA (SM-PM), two additively manufactured denture base resins (AM-DT and AM-ND), and one heat-polymerized PMMA (CV) (n = 30). The Ra of the specimens was measured before and after conventional laboratory polishing, while color coordinates were measured after polishing. Specimens were then divided into three subgroups based on the denture cleanser: distilled water, 1% sodium hypochlorite (NaOCl), and effervescent tablet (n = 10). The Ra and color coordinates were remeasured after nine cleansing cycles over a period of 20 days. The CIEDE2000 formula was used to calculate the color differences (ΔE00 ). Two-way analysis of variance (ANOVA) was used to analyze the Ra values before (n = 30) and after (n = 10) cleansing, while repeated measures ANOVA was used to analyze the Ra of material-time point pairs within each denture cleanser (n = 10). ΔE00 data after denture cleansing was also analyzed by using two-way ANOVA (n = 10) (α = 0.05). RESULTS: Before polishing, Ra varied significantly among the materials. SM-GC and SM-PM had the lowest and AM-ND the highest Ra values (P < 0.001). Polishing significantly reduced Ra of all materials (P < 0.001), and after polishing, Ra differences among materials were nonsignificant (P ≥ 0.072). Regardless of the denture cleanser, the Ra of AM-DT, AM-ND, and CV was the highest before polishing when different time points were considered (P < 0.001). After cleansing, AM-ND had the highest Ra of all the materials, regardless of the cleanser (P ≤ 0.017). AM-DT had higher Ra than SM-PM when distilled water (P = 0.040) and higher Ra than SM-GC, SM-PM, and CV when NaOCl was used (P < 0.001). The type of cleanser significantly influenced the Ra of AM-DT, AM-ND, and CV. For AM-DT, NaOCl led to the highest Ra and the tablet led to the lowest Ra (P ≤ 0.042), while for AM-ND, distilled water led to the lowest Ra (P ≤ 0.024). For CV, the tablet led to lower Ra than distilled water (P = 0.009). Color change varied among the materials. When distilled water was used, SM-GC had higher ΔE00 than SM-PM and AM-DT (P ≤ 0.034). When NaOCl was used, AM-ND had higher ΔE00 than SM-GC, SM-PM, and AM-DT, while CV and SM-GC had higher ΔE00 than SM-PM and AM-DT (P ≤ 0.039). Finally, when the tablet was used, AM-ND and CV had the highest ΔE00 , while AM-DT had lower ΔE00 than SM-GC (P ≤ 0.015). CONCLUSIONS: The tested materials had unacceptable surface roughness (>0.2 µm) before polishing. Roughness decreased significantly after polishing (<0.2 µm). Denture cleansers did not significantly affect the surface roughness of the materials, and roughness remained clinically acceptable after cleansing (<0.2 µm). Considering previously reported color thresholds, AM-ND and CV had unacceptable color change regardless of the denture cleanser, and the effervescent tablet led to perceptible, but acceptable color change for SM-GC, SM-PM, and AM-DT.

Simultaneous metabolite MALDI-MSI, whole exome and transcriptome analysis from formalin-fixed paraffin-embedded tissue sections.

Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) allows spatial analysis of proteins, metabolites, or small molecules from tissue sections. Here, we present the simultaneous generation and analysis of MALDI-MSI, whole-exome sequencing (WES), and RNA-sequencing data from the same formalin-fixed paraffin-embedded (FFPE) tissue sections. Genomic DNA and total RNA were extracted from (i) untreated, (ii) hematoxylin-eosin (HE) stained, and (iii) MALDI-MSI-analyzed FFPE tissue sections from three head and neck squamous cell carcinomas. MALDI-MSI data were generated by a time-of-flight analyzer prior to preprocessing and visualization. WES data were generated using a low-input protocol followed by detection of single-nucleotide variants (SNVs), tumor mutational burden, and mutational signatures. The transcriptome was determined using 3'-RNA sequencing and was examined for similarities and differences between processing stages. All data met the commonly accepted quality criteria. Besides SNVs commonly identified between differently processed tissues, FFPE-typical artifactual variants were detected. Tumor mutational burden was in the same range for tissues from the same patient and mutational signatures were highly overlapping. Transcriptome profiles showed high levels of correlation. Our data demonstrate that simultaneous molecular profiling of MALDI-MSI-processed FFPE tissue sections at the transcriptome and exome levels is feasible and reliable.

A transcriptomic map of EGFR-induced epithelial-to-mesenchymal transition identifies prognostic and therapeutic targets for head and neck cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) is both a driver oncogene and a therapeutic target in advanced head and neck squamous cell carcinoma (HNSCC). However, response to EGFR treatment is inconsistent and lacks markers for treatment prediction. This study investigated EGFR-induced epithelial-to-mesenchymal transition (EMT) as a central parameter in tumor progression and identified novel prognostic and therapeutic targets, and a candidate predictive marker for EGFR therapy response. METHODS: Transcriptomic profiles were analyzed by RNA sequencing (RNA-seq) following EGFR-mediated EMT in responsive human HNSCC cell lines. Exclusive genes were extracted via differentially expressed genes (DEGs) and a risk score was determined through forward feature selection and Cox regression models in HNSCC cohorts. Functional characterization of selected prognostic genes was conducted in 2D and 3D cellular models, and findings were validated by immunohistochemistry in primary HNSCC. RESULTS: An EGFR-mediated EMT gene signature composed of n = 171 genes was identified in responsive cell lines and transferred to the TCGA-HNSCC cohort. A 5-gene risk score comprising DDIT4, FADD, ITGB4, NCEH1, and TIMP1 prognosticated overall survival (OS) in TCGA and was confirmed in independent HNSCC cohorts. The EGFR-mediated EMT signature was distinct from EMT hallmark and partial EMT (pEMT) meta-programs with a differing enrichment pattern in single malignant cells. Molecular characterization showed that ITGB4 was upregulated in primary tumors and metastases compared to normal mucosa and correlated with EGFR/MAPK activity in tumor bulk and single malignant cells. Preferential localization of ITGB4 together with its ligand laminin 5 at tumor-stroma interfaces correlated with increased tumor budding in primary HNSCC tissue sections. In vitro, ITGB4 knock-down reduced EGFR-mediated migration and invasion and ITGB4-antagonizing antibody ASC8 impaired 2D and 3D invasion. Furthermore, a logistic regression model defined ITGB4 as a predictive marker of progression-free survival in response to Cetuximab in recurrent metastatic HNSCC patients. CONCLUSIONS: EGFR-mediated EMT conveyed through MAPK activation contributes to HNSCC progression upon induction of migration and invasion. A 5-gene risk score based on a novel EGFR-mediated EMT signature prognosticated survival of HNSCC patients and determined ITGB4 as potential therapeutic and predictive target in patients with strong EGFR-mediated EMT.

Tumor DNA-methylome derived epigenetic fingerprint identifies HPV-negative head and neck patients at risk for locoregional recurrence after postoperative radiochemotherapy.

Biomarkers with relevance for loco-regional therapy are needed in human papillomavirus negative aka HPV(-) head and neck squamous cell carcinoma (HNSCC). Based on the premise that DNA methylation pattern is highly conserved, we sought to develop a reliable and robust methylome-based classifier identifying HPV(-) HNSCC patients at risk for loco-regional recurrence (LR) and all-event progression after postoperative radiochemotherapy (PORT-C). The training cohort consisted of HPV-DNA negative HNSCC patients (n = 128) homogeneously treated with PORT-C in frame of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG) multicenter biomarker trial. DNA Methylation analysis was performed using Illumina 450 K and 850 K-EPIC microarray technology. The performance of the classifier was integrated with a series of biomarkers studied in the training set namely hypoxia-, 5-microRNA (5-miR), stem-cell gene-expression signatures and immunohistochemistry (IHC)-based immunological characterization of tumors (CD3/CD8/PD-L1/PD1). Validation occurred in an independent cohort of HPV(-) HNSCC patients, pooled from two German centers (n = 125). We identified a 38-methylation probe-based HPV(-) Independent Classifier of disease Recurrence (HICR) with high prognostic value for LR, distant metastasis and overall survival (P < 10-9 ). HICR remained significant after multivariate analysis adjusting for anatomical site, lymph node extracapsular extension (ECE) and size (T-stage). HICR high-risk tumors were enriched for younger patients with hypoxic tumors (15-gene signature) and elevated 5-miR score. After adjustment for hypoxia and 5-miR covariates, HICR maintained predicting all endpoints. HICR provides a novel mean for assessing the risk of LR in HPV(-) HNSCC patients treated with PORT-C and opens a new opportunity for biomarker-assisted stratification and therapy adaptation in these patients.

Analysis of genetic variants of frequently mutated genes in human papillomavirus-negative primary head and neck squamous cell carcinoma, resection margins, local recurrences and corresponding circulating cell-free DNA.

BACKGROUND: Head and neck squamous cell carcinoma remains a substantial burden to global health. Despite evolving therapies, 5-year survival is <50% and unlike in other cancers, reliable molecular biomarkers to guide treatment do not exist. METHODS: We performed targeted panel next-generation sequencing to analyse somatic variants from primary and recurrent tumour tissue, corresponding resection margins and cell-free DNA from intra-operatively collected plasma samples from eight patients with human papillomavirus-negative head and neck squamous cell carcinoma. Patients were primarily treated with curative-intent surgery and received subsequent adjuvant treatment. RESULTS: The most frequently mutated gene was TP53. Other mutated genes included NOTCH1, NF1 and CDKN2A among others. A total of 20.8% of variants were shared between primary tumour and resection margin. Out of all the variants detected, 37.5% were shared between cell-free DNA and primary tumour, whereas 12.5% were commonly found in cell-free DNA, primary tumour and resection margin. Mutational profiling was able to distinguish between a locoregional recurrence and a second primary tumour by identifying a different TP53 mutation in the primary tumour compared to the recurrent tumour in addition to private FBXW7 and CTNNB1 mutations. We also identified identical TP53 and PIK3CA mutations in another primary tumour and corresponding recurrence. CONCLUSION: Molecular profiling of cell-free DNA and resection margins has potential applications in clinical practice to guide future treatment decisions.

Innovative participatory bilingual data analysis with Latinx/@ immigrants: Language, power, and transformation.

OBJECTIVE: The insights of Latinx/@ immigrants are essential to developing interventions that better address complex multilevel phenomena impacting mental health. Despite important advances in methods that genuinely embody participatory research practices, attention to collaborative data collection, analysis, and dissemination are limited. Our aim is to describe the development and implementation of research practices to address these gaps through an emphasis on and understanding of the centrality of language in collaborative research processes. METHOD: Guided from the outset by community-based participatory research principles, our community-academic research partnership recognized the importance of developing and intentionally studying our collaborative processes. As part of an ethnographic interview study with 24 Latinx/@ immigrants, a community-university research team developed innovative methods, including practices related to research team meetings, data collection, analysis, and dissemination, which we documented through ongoing discussion and reflection. RESULTS: The resulting participatory research processes were grounded in a theoretical framework of praxis and language and included six innovative and iterative stages: (a) Establishing the research team, (b) planning the interview process/data collection, (c) developing the data analysis methodology, (d) interpreting findings to adapt the intervention, (e) integrating results of the participatory process into the analysis, and (f) data analysis for dissemination. CONCLUSIONS: A focus on praxis and language revealed how the language of research structures' power, meaning, feeling, collaboration, analysis, and transformation. We also found that bilingual participatory analytic processes have important implications with respect to achieving genuine inclusion in rigorous research that moves toward equity for Latinx/@ immigrants and other populations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Innovative radiation oncology Together - Precise, Personalized, Human : Vision 2030 for radiotherapy & radiation oncology in Germany.

PURPOSE: Scientific and clinical achievements in radiation, medical, and surgical oncology are changing the landscape of interdisciplinary oncology. The German Society for Radiation Oncology (DEGRO) working group of young clinicians and scientists (yDEGRO) and the DEGRO representation of associate and full professors (AKRO) are aware of the essential role of radiation oncology in multidisciplinary treatment approaches. Together, yDEGRO and AKRO endorsed developing a German radiotherapy & radiation oncology vision 2030 to address future challenges in patient care, research, and education. The vision 2030 aims to identify priorities and goals for the next decade in the field of radiation oncology. METHODS: The vision development comprised three phases. During the first phase, areas of interest, objectives, and the process of vision development were defined jointly by the yDEGRO, AKRO, and the DEGRO board. In the second phase, a one-day strategy retreat was held to develop AKRO and yDEGRO representatives' final vision from medicine, biology, and physics. The third phase was dedicated to vision interpretation and program development by yDEGRO representatives. RESULTS: The strategy retreat's development process resulted in conception of the final vision "Innovative radiation oncology Together - Precise, Personalized, Human." The first term "Innovative radiation oncology" comprises the promotion of preclinical research and clinical trials and highlights the development of a national committee for strategic development in radiation oncology research. The term "together" underpins collaborations within radiation oncology departments as well as with other partners in the clinical and scientific setting. "Precise" mainly covers technological precision in radiotherapy as well as targeted oncologic therapeutics. "Personalized" emphasizes biology-directed individualization of radiation treatment. Finally, "Human" underlines the patient-centered approach and points towards the need for individual longer-term career curricula for clinicians and researchers in the field. CONCLUSION: The vision 2030 balances the ambition of physical, technological, and biological innovation as well as a comprehensive, patient-centered, and collaborative approach towards radiotherapy & radiation oncology in Germany.

EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers.

Head and neck squamous cell carcinomas (HNSCCs) are characterized by outstanding molecular heterogeneity that results in severe therapy resistance and poor clinical outcome. Inter- and intratumoral heterogeneity in epithelial-mesenchymal transition (EMT) was recently revealed as a major parameter of poor clinical outcome. Here, we addressed the expression and function of the therapeutic target epidermal growth factor receptor (EGFR) and of the major determinant of epithelial differentiation epithelial cell adhesion molecule (EpCAM) in clinical samples and in vitro models of HNSCCs. We describe improved survival of EGFRlow/EpCAMhigh HNSCC patients (n = 180) and provide a molecular basis for the observed disparities in clinical outcome. EGF/EGFR have concentration-dependent dual capacities as inducers of proliferation and EMT through differential activation of the central molecular switch phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and EMT transcription factors (EMT-TFs) Snail, zinc finger E-box-binding homeobox 1 (Zeb1), and Slug. Furthermore, soluble ectodomain of EpCAM (EpEX) was identified as a ligand of EGFR that activates pERK1/2 and phosphorylated AKT (pAKT) and induces EGFR-dependent proliferation but represses EGF-mediated EMT, Snail, Zeb1, and Slug activation and cell migration. EMT repression by EpEX is realized through competitive modulation of pERK1/2 activation strength and inhibition of EMT-TFs, which is reflected in levels of pERK1/2 and its target Slug in clinical samples. Accordingly, high expression of pERK1/2 and/or Slug predicted poor outcome of HNSCCs. Hence, EpEX is a ligand of EGFR that induces proliferation but counteracts EMT mediated by the EGF/EGFR/pERK1/2 axis. Therefore, the emerging EGFR/EpCAM molecular cross talk represents a promising target to improve patient-tailored adjuvant treatment of HNSCCs.

Direct conversion of human fibroblasts into therapeutically active vascular wall-typical mesenchymal stem cells.

Cell-based therapies using adult stem cells are promising options for the treatment of a number of diseases including autoimmune and cardiovascular disorders. Among these, vascular wall-derived mesenchymal stem cells (VW-MSCs) might be particularly well suited for the protection and curative treatment of vascular damage because of their tissue-specific action. Here we report a novel method for the direct conversion of human skin fibroblasts towards MSCs using a VW-MSC-specific gene code (HOXB7, HOXC6 and HOXC8) that directs cell fate conversion bypassing pluripotency. This direct programming approach using either a self-inactivating (SIN) lentiviral vector expressing the VW-MSC-specific HOX-code or a tetracycline-controlled Tet-On system for doxycycline-inducible gene expressions of HOXB7, HOXC6 and HOXC8 successfully mediated the generation of VW-typical MSCs with classical MSC characteristics in vitro and in vivo. The induced VW-MSCs (iVW-MSCs) fulfilled all criteria of MSCs as defined by the International Society for Cellular Therapy (ISCT). In terms of multipotency and clonogenicity, which are important specific properties to discriminate MSCs from fibroblasts, iVW-MSCs behaved like primary ex vivo isolated VW-MSCs and shared similar molecular and DNA methylation signatures. With respect to their therapeutic potential, these cells suppressed lymphocyte proliferation in vitro, and protected mice against vascular damage in a mouse model of radiation-induced pneumopathy in vivo, as well as ex vivo cultured human lung tissue. The feasibility to obtain patient-specific VW-MSCs from fibroblasts in large amounts by a direct conversion into induced VW-MSCs could potentially open avenues towards novel, MSC-based therapies.

Curcuma longa hydrolate improves Nile tilapia survival in a recirculation rearing system, maintaining the animal homeostasis and modulating the gut microbial community.

This study aimed to evaluate the effects of the dietary supplementation Curcuma longa hydrolate on Nile tilapia (Oreochromis niloticus) reared in a recirculation system. Hemato-immunological parameters, growth performance, nitrogen and phosphorus retention, as well as body composition and its interaction with the intestinal microbiota, were studied. Nile tilapia fingerlings (120) were distributed randomly in 8 polyethylene tanks (40 L). The experimental units were divided into two treatments, in quadruplicate: commercial diet supplemented with 2.5% of C. longa hydrolate and commercial diet without supplementation (control). After 45 days, the treatment supplemented hydrolate showed higher survival than the control group, 95.25% and 82.22%, receptively. In the blood profile, fish supplemented with hydrolate had a higher count of total leukocytes and neutrophils, as well as mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration, than control group. The hydrolate group showed a substantial increase in the relative abundance of Cetobacterium and Romboutsia, as well as lower diversity in gut microbiota. The dietary addition of C. longa hydrolate for Nile tilapia seems to have a beneficial effect on gut microbiota, in addition to a likely positive effect on the physiological performance of Nile tilapia by maintaining intestinal homeostasis and promoting survival in reared conditions.

Metformin Protects against Radiation-Induced Acute Effects by Limiting Senescence of Bronchial-Epithelial Cells.

Radiation-induced damage to normal lung parenchyma remains a dose-limiting factor in thorax-associated radiotherapy (RT). Severe early and late complications with lungs can increase the risk of morbidity in cancer patients after RT. Herein, senescence of lung epithelial cells following RT-induced cellular stress, or more precisely the respective altered secretory profile, the senescence-associated secretory phenotype (SASP), was suggested as a central process for the initiation and progression of pneumonitis and pulmonary fibrosis. We previously reported that abrogation of certain aspects of the secretome of senescent lung cells, in particular, signaling inhibition of the SASP-factor Ccl2/Mcp1 mediated radioprotection especially by limiting endothelial dysfunction. Here, we investigated the therapeutic potential of a combined metformin treatment to protect normal lung tissue from RT-induced senescence and associated lung injury using a preclinical mouse model of radiation-induced pneumopathy. Metformin treatment efficiently limited RT-induced senescence and SASP expression levels, thereby limiting vascular dysfunctions, namely increased vascular permeability associated with increased extravasation of circulating immune and tumor cells early after irradiation (acute effects). Complementary in vitro studies using normal lung epithelial cell lines confirmed the senescence-limiting effect of metformin following RT finally resulting in radioprotection, while fostering RT-induced cellular stress of cultured malignant epithelial cells accounting for radiosensitization. The radioprotective action of metformin for normal lung tissue without simultaneous protection or preferable radiosensitization of tumor tissue might increase tumor control probabilities and survival because higher radiation doses could be used.

Randomized Controlled Trial of a Multilevel Intervention to Address Social Determinants of Refugee Mental Health.

Understanding processes that support the well-being of the unprecedented numbers of forcibly displaced people throughout the world is essential. Growing evidence documents post-migration stressors related to marginalization as key social determinants of refugee mental health. The goal of this RCT was to rigorously test a social justice approach to reducing high rates of distress among refugees in the United States. The 6-month multilevel, strengths-based Refugee Well-being Project (RWP) intervention brought together university students enrolled in a 2-semester course and recently resettled refugees to engage in mutual learning and collaborative efforts to mobilize community resources and improve community and systems responsiveness to refugees. Data collected from 290 Afghan, Great Lakes African, Iraqi, and Syrian refugees at four time points over 12 months were used to test the effectiveness of RWP to reduce distress (depression and anxiety symptoms) and increase protective factors (English proficiency, social support, connection to home and American cultures). Intention-to-treat analyses using multilevel modeling revealed significant intervention effects for all hypothesized outcomes. Results provide evidence to support social justice approaches to improving refugee mental health. Findings have implications for refugees worldwide, and for other immigrant and marginalized populations who experience inequities in resources and disproportionate exposure to trauma/stress.

Perceptions of water and sugar-sweetened beverage consumption habits among teens, parents and teachers in the rural south-western USA.

OBJECTIVE: The present research aimed to describe perceptions and behaviours around the consumption of water and sugar-sweetened beverages (SSB) by youths. DESIGN: A formative, qualitative study which conducted four focus groups. Transcripts were analysed and themes related to reasons youths drink SSB and water, and conversely do not drink SSB and water, were analysed to reveal thematic clusters around sensory factors, environment and policy, access, marketing and role model influences, and health risks. SETTING: A rural, tri-ethnic community in New Mexico, USA.ParticipantsMiddle- and high-school students, parents and teachers. RESULTS: Although youths and adults were aware of the health risks of soda, they did not translate this information to other SSB, including sports drinks and sweetened tea. Moreover, their perceptions of risks of dyes outweighed their concern with sugar. Youths and adults were aware of water's health benefits, but they focused on short-term benefits. Youths and adults perceived water as unappealing. Adults were also concerned with water safety and access. CONCLUSIONS: This formative research has implications for decreasing SSB consumption and simultaneously increasing water intake among youths in rural communities. Addressing unique access and safety concerns related to water in rural communities, as well as increasing awareness of the risks of all types of SSB, can work together in a positive feedback loop to change perceptions and behaviours with long-term health consequences. Specific policy suggestions include strengthening school policies to restrict all types of SSB and water promotion efforts that address access, safety and health benefits.

Family Separation and the Impact of Digital Technology on the Mental Health of Refugee Families in the United States: Qualitative Study.

BACKGROUND: Conflicts around the world have resulted in a record high number of refugees. Family separation is a critical factor that impacts refugee mental health. Thus, it is important to explore refugees' ability to maintain contact with family members across the globe and the ways in which they attempt to do so. It is increasingly common for refugees to use information and communication technologies (ICTs), which include mobile phones, the internet, and social media sites, such as Facebook, WhatsApp, Skype, and Viber, for these purposes. OBJECTIVE: The aim of this study was to explore refugees' perceptions of the impact of communication through ICTs on their mental health, the exercise of agency by refugees within the context of ICT use, especially their communication with their families, and logistical issues that affect their access to ICTs in the United States. METHODS: We used a constructivist grounded theory approach to analyze in-depth interviews of 290 adult refugee participants from different countries, who were enrolled in a randomized controlled trial of a community-based mental health intervention. RESULTS: Analyses showed that communication through ICTs had differing impacts on the mental health of refugee participants. ICTs, as channels of communication between separated families, were a major source of emotional and mental well-being for a large number of refugee participants. However, for some participants, the communication process with separated family members through digital technology was mentally and emotionally difficult. The participants also discussed ways in which they hide adversities from their families through selective use of different ICTs. Several participants noted logistical and financial barriers to communicating with their families through ICTs. CONCLUSIONS: These findings are important in elucidating aspects of refugee agency and environmental constraints that need to be further explicated in theories related to ICT use as well as in providing insight for researchers and practitioners involved in efforts related to migration and mental health.

A genomic copy number signature predicts radiation exposure in post-Chernobyl breast cancer.

Breast cancer is the second leading cause of cancer death among women worldwide and besides life style, age and genetic risk factors, exposure to ionizing radiation is known to increase the risk for breast cancer. Further, DNA copy number alterations (CNAs), which can result from radiation-induced double-strand breaks, are frequently occurring in breast cancer cells. We set out to identify a signature of CNAs discriminating breast cancers from radiation-exposed and non-exposed female patients. We analyzed resected breast cancer tissues from 68 exposed female Chernobyl clean-up workers and evacuees and 68 matched non-exposed control patients for CNAs by array comparative genomic hybridization analysis (aCGH). Using a stepwise forward-backward selection approach a non-complex CNA signature, that is, less than ten features, was identified in the training data set, which could be subsequently validated in the validation data set (p value < 0.05). The signature consisted of nine copy number regions located on chromosomal bands 7q11.22-11.23, 7q21.3, 16q24.3, 17q21.31, 20p11.23-11.21, 1p21.1, 2q35, 2q35, 6p22.2. The signature was independent of any clinical characteristics of the patients. In all, we identified a CNA signature that has the potential to allow identification of radiation-associated breast cancer at the individual level.

Expression of miRNA-26b-5p and its target TRPS1 is associated with radiation exposure in post-Chernobyl breast cancer.

Ionizing radiation is a well-recognized risk factor for the development of breast cancer. However, it is unknown whether radiation-specific molecular oncogenic mechanisms exist. We investigated post-Chernobyl breast cancers from radiation-exposed female clean-up workers and nonexposed controls for molecular changes. Radiation-associated alterations identified in the discovery cohort (n = 38) were subsequently validated in a second cohort (n = 39). Increased expression of hsa-miR-26b-5p was associated with radiation exposure in both of the cohorts. Moreover, downregulation of the TRPS1 protein, which is a transcriptional target of hsa-miR-26b-5p, was associated with radiation exposure. As TRPS1 overexpression is common in sporadic breast cancer, its observed downregulation in radiation-associated breast cancer warrants clarification of the specific functional role of TRPS1 in the radiation context. For this purpose, the impact of TRPS1 on the transcriptome was characterized in two radiation-transformed breast cell culture models after siRNA-knockdown. Deregulated genes upon TRPS1 knockdown were associated with DNA-repair, cell cycle, mitosis, cell migration, angiogenesis and EMT pathways. Furthermore, we identified the interaction partners of TRPS1 from the transcriptomic correlation networks derived from gene expression data on radiation-transformed breast cell culture models and sporadic breast cancer tissues provided by the TCGA database. The genes correlating with TRPS1 in the radiation-transformed breast cell lines were primarily linked to DNA damage response and chromosome segregation, while the transcriptional interaction partners in the sporadic breast cancers were mostly associated with apoptosis. Thus, upregulation of hsa-miR-26b-5p and downregulation of TRPS1 in radiation-associated breast cancer tissue samples suggests these molecules representing radiation markers in breast cancer.