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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.
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Play spaces are important components of paediatric healthcare environments. They provide children with critical opportunities to experience the social, emotional, and developmental benefits of play while in healthcare settings for appointments or hospitalizations. These spaces can help to mitigate stress, provide a sense of normalcy in unfamiliar environments, and facilitate social engagement for children and their families. Given the benefits of play spaces in paediatric healthcare settings, it is important to understand how these spaces can be designed to enhance children's inclusion and quality of care. The aim of this scoping review was to explore the current understanding of paediatric play space design. Using search terms related to children, health care, and play space, six interdisciplinary databases were searched over a 30-year period. The search found 2,533 records from which eighteen were included for review. Findings suggest that although it is well-documented that play spaces offer valuable social and emotional benefits, little is known about the specific design features that can and should be incorporated to enhance play opportunities and ensure that they benefit all children and families. Further, the literature mostly considers play spaces in the context of designated play or recreational rooms. Scholars are encouraged to consider how play opportunities can be incorporated into the designs of paediatric healthcare environments beyond the boundaries of these rooms. Future studies should also consider the diversity of play space users, including children of varying ages and abilities, to create more accessible and inclusive paediatric play spaces for children and their families. Advancing knowledge on play space design can help to optimize the quality of these important spaces and to ensure their designs meaningfully enhance children's play experiences and quality of care.
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Eliminating mental health disparities requires simultaneously addressing numerous determinants of health, including social inequities. Although emphasis on multilevel change is growing, interventions typically involve separate efforts or people focusing on each level. We propose a trans-level conceptual model for mental health intervention that simultaneously facilitates change across multiple intersecting levels with four guiding principles: (1) emphasis on structural change; (2) involvement of people experiencing health and social inequities in achieving structural change by addressing the necessary preconditions of access to resources for basic needs, community membership and belonging, and knowledge or information to participate in social change efforts; (3) valuing and building on the expertise and strengths of individuals, families, and communities experiencing health inequities; and (4) dismantling unequal power dynamics of helping relationships through a focus on mutual learning and support and cocreation of change. Tracing the trajectory of a 23-year community-based mental health intervention partnership (the Refugee and Immigrant Well-Being Project), we illustrate the trans-level intervention model and describe its impact on individual mental health and sustainable change at multiple levels. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Head and Neck Squamous Cell Carcinoma (HNSCC) is a heterogeneous malignancy that remains a significant challenge in clinical management due to frequent treatment failures and pronounced therapy resistance. While metabolic dysregulation appears to be a critical factor in this scenario, comprehensive analyses of the metabolic HNSCC landscape and its impact on clinical outcomes are lacking. This study utilized transcriptomic data from four independent clinical cohorts to investigate metabolic heterogeneity in HNSCC and define metabolic pathway-based subtypes (MPS). In HPV-negative HNSCCs, MPS1 and MPS2 were identified, while MPS3 was enriched in HPV-positive cases. MPS classification was associated with clinical outcome post adjuvant radio(chemo)therapy, with MPS1 consistently exhibiting the highest risk of therapeutic failure. MPS1 was uniquely characterized by upregulation of glycan (particularly chondroitin/dermatan sulfate) metabolism genes. Immunohistochemistry and pilot mass spectrometry imaging analyses confirmed this at metabolite level. The histological context and single-cell RNA sequencing data identified the malignant cells as key contributors. Globally, MPS1 was distinguished by a unique transcriptomic landscape associated with increased disease aggressiveness, featuring motifs related to epithelial-mesenchymal transition, immune signaling, cancer stemness, tumor microenvironment assembly, and oncogenic signaling. This translated into a distinct histological appearance marked by extensive extracellular matrix remodeling, abundant spindle-shaped cancer-associated fibroblasts, and intimately intertwined populations of malignant and stromal cells. Proof-of-concept data from orthotopic xenotransplants replicated the MPS phenotypes on the histological and transcriptome levels. In summary, this study introduces a metabolic pathway-based classification of HNSCC, pinpointing glycan metabolism-enriched MPS1 as the most challenging subgroup that necessitates alternative therapeutic strategies.
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The NIMH-funded Multilevel Community-Based Mental Health Intervention to Address Structural Inequities and Adverse Disparate Consequences of COVID-19 Pandemic on Latinx Immigrants and African Refugees study aims to advance the science of multilevel interventions to reduce the disparate, adverse mental health, behavioral, and socioeconomic consequences of the COVID-19 pandemic that are a result of complex interactions between underlying structural inequities and barriers to health care. The study tests three nested levels of intervention: 1) an efficacious 4-month advocacy and mutual learning model (Refugee and Immigrant Well-being Project, RIWP); 2) engagement with community-based organizations (CBOs); and 3) structural policy changes enacted in response to the pandemic. This community-based participatory research (CBPR) study builds on long-standing collaboration with five CBOs. By including 240 Latinx immigrants and 60 African refugees recruited from CBO partners who are randomly assigned to treatment-as-usual CBO involvement or the RIWP intervention and a comparison group comprised of a random sample of 300 Latinx immigrants, this mixed methods longitudinal waitlist control group design study with seven time points over 36 months tests the effectiveness of the RIWP intervention and engagement with CBOs to reduce psychological distress, daily stressors, and economic precarity and increase protective factors (social support, access to resources, English proficiency, cultural connectedness). The study also tests the ability of the RIWP intervention and engagement with CBOs to increase access to the direct benefits of structural interventions. This paper reports on the theoretical basis, design, qualitative and quantitative analysis plan, and power for the study.
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COVID-19 , Emigrantes e Inmigrantes , Salud Mental , Refugiados , Humanos , COVID-19/epidemiología , Hispánicos o Latinos , Pandemias , Refugiados/psicología , Población Negra , Disparidades en el Estado de SaludRESUMEN
Culturally and contextually valid measurement of psychological distress is critical, given the increasing numbers of forcibly displaced people and transnational migration. This study replicates an inductive process that elicited culturally specific expressions, understandings, and idioms of distress among Afghans to develop culturally specific measures of distress for Great Lakes Africans and Iraqis and expands this methodology to include a focus on the contexts of refugees resettled in the United States. To create the measures, we adapted Miller et al.'s (2006) model for the Afghan Symptom Checklist (ASCL) and conducted 18 semistructured qualitative interviews that attended to refugees' multiple settings; the impact of potentially traumatic events initially and postresettlement; and the experiences and impact of resettlement stressors. We tested the newly developed measures and existing ASCL with 280 recently resettled refugees (< 3 years) from Afghanistan, the Great Lakes region of Africa, and Iraq to assess factor structure, reliability, and construct validity. We successfully replicated and adapted a process for creating culturally specific measures of distress to create reliable and valid scales that consider culturally and contextually specific distress among several groups of forcibly displaced people. Our results highlight the salience of individuals' social contexts and how they are manifested as idioms of distress, bringing together two key areas of research: the social construction of mental health and social determinants of mental health. These findings have implications for improving measurement of psychological distress and for developing multilevel interventions that are culturally resonant and address factors beyond the individual level. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Refugiados , Humanos , Refugiados/psicología , Femenino , Masculino , Adulto , Irak/etnología , Afganistán/etnología , Distrés Psicológico , Reproducibilidad de los Resultados , Adulto Joven , Great Lakes Region , Estados Unidos , Estrés Psicológico/psicología , Estrés Psicológico/etnología , Adolescente , Persona de Mediana Edad , Investigación CualitativaRESUMEN
Alternative solutions to mineral fertilizers and pesticides that reduce the environmental impact of agriculture are urgently needed. Arbuscular mycorrhizal fungi (AMF) can enhance plant nutrient uptake and reduce plant stress; yet, large-scale field inoculation trials with AMF are missing, and so far, results remain unpredictable. We conducted on-farm experiments in 54 fields in Switzerland and quantified the effects on maize growth. Growth response to AMF inoculation was highly variable, ranging from -12% to +40%. With few soil parameters and mainly soil microbiome indicators, we could successfully predict 86% of the variation in plant growth response to inoculation. The abundance of pathogenic fungi, rather than nutrient availability, best predicted (33%) AMF inoculation success. Our results indicate that soil microbiome indicators offer a sustainable biotechnological perspective to predict inoculation success at the beginning of the growing season. This predictability increases the profitability of microbiome engineering as a tool for sustainable agricultural management.
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Microbiota , Micorrizas , Micorrizas/fisiología , Suelo , Raíces de Plantas/microbiología , Agricultura/métodosRESUMEN
Introduction: Mesenchymal stem cells (MSCs) are considered to be the most promising stem cell type for cell-based therapies in regenerative medicine. Based on their potential to home to diseased body sites following a therapeutically application, these cells could (i) differentiate then into organ-specific cell types to locally restore injured cells or, most prominently, (ii) foster tissue regeneration including immune modulations more indirectly by secretion of protective growth factors and cytokines. As tissue-resident stem cells of mesenchymal origin, these cells are morphologically and even molecularly- at least concerning the classical marker genes- indistinguishable from similar lineage cells, particularly fibroblasts. Methods: Here we used microarray-based gene expression and global DNA methylation analyses as well as accompanying computational tools in order to specify differences between MSCs and fibroblasts, to further unravel potential identity genes and to highlight MSC signaling pathways with regard to their trophic and immunosuppressive action. Results: We identified 1352 differentially expressed genes, of which in the MSCs there is a strong signature for e.g., KRAS signaling, known to play essential role in stemness maintenance, regulation of coagulation and complement being decisive for resolving inflammatory processes, as well as of wound healing particularly important for their regenerative capacity. Genes upregulated in fibroblasts addressed predominately transcription and biosynthetic processes and mapped morphological features of the tissue. Concerning the cellular identity, we specified the already known HOX code for MSCs, established a potential HOX code for fibroblasts, and linked certain HOX genes to functional cell-type-specific properties. Accompanied methylation profiles revealed numerous regions, especially in HOX genes, being differentially methylated, which might provide additional biomarker potential. Discussion: Conclusively, transcriptomic together with epigenetic signatures can be successfully be used for the definition (cellular identity) of MSCs versus fibroblasts as well as for the determination of the superior functional properties of MSCs, such as their immunomodulatory potential.
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Genes Homeobox , Células Madre Mesenquimatosas , Perfilación de la Expresión Génica , Células Cultivadas , Fibroblastos/metabolismo , Células Madre Mesenquimatosas/metabolismoRESUMEN
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.
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Large scale databases are critical for helping scientists decipher long-term patterns in human evolution. This paper describes the conception and development of such a research database and illustrates how big data can be harnessed to formulate new ideas about the past. The Role of Culture in Early Expansions of Humans (ROCEEH) is a transdisciplinary research center whose aim is to study the origins of culture and the multifaceted aspects of human expansions across Africa and Eurasia over the last three million years. To support its research, the ROCEEH team developed an online tool named the ROCEEH Out of Africa Database (ROAD) and implemented its web-based applications. ROAD integrates geographical data as well as archaeological, paleoanthropological, paleontological and paleobotanical content within a robust chronological framework. In fact, a unique feature of ROAD is its ability to dynamically link scientific data both spatially and temporally, thereby allowing its reuse in ways that were not originally conceived. The data stem from published sources spanning the last 150 years, including those generated by the research team. Descriptions of these data rely on the development of a standardized vocabulary and profit from online explanations of each table and attribute. By synthesizing legacy data, ROAD facilitates the reuse of heritage data in novel ways. Database queries yield structured information in a variety of interoperable formats. By visualizing data on maps, users can explore this vast dataset and develop their own theories. By downloading data, users can conduct further quantitative analyses, for example with Geographic Information Systems, modeling programs and artificial intelligence. In this paper, we demonstrate the innovative nature of ROAD and show how it helps scientists studying human evolution to access datasets from different fields, thereby connecting the social and natural sciences. Because it permits the reuse of "old" data in new ways, ROAD is now an indispensable tool for researchers of human evolution and paleogeography.
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Inteligencia Artificial , Sistemas de Información Geográfica , Humanos , Bases de Datos Factuales , Programas Informáticos , ÁfricaRESUMEN
This mixed-methods study examines mechanisms connecting the deployment of economic, social, and health care resources to emotional distress and physical health outcomes. Examining such mechanisms is critical for informing strategies, policies, and other interventions for reducing health disparities and improving refugee health in the United States and other resettlement contexts. Data for this study were collected as part of a randomized control trial in a mid-sized city in the Southwestern United States. Two-hundred ninety recently resettled (< 3 years) refugee adults from 143 households were enrolled in the study (36.2% Afghan, 32.8% Iraqi/Syrian, and 31.0% Great Lakes African; 52% women). Qualitative interview data were collected via semistructured interviews. A longitudinal structural equation path model of quantitative data from three time points over 12 months tested hypotheses that emerged from qualitative findings. In semistructured interviews, refugees in the United States (a) attributed the development of worse or new physical health problems to postresettlement stressors related to financial instability and limited social support that contributed to their emotional distress and (b) reported several barriers to accessing health care in the United States, including insufficient knowledge of health care resources, inadequate patient-provider communication, and navigating complex American health insurance systems, all of which exacerbated their physical health problems. Guided by these qualitative findings, longitudinal quantitative data revealed that: (a) postmigration stressors were associated with emotional distress and poor self-reported physical health, (b) emotional distress mediated the association between postmigration stressors and global health satisfaction, and (c) emotional distress was negatively associated with global health satisfaction. Findings document stressors refugees experience in the context of the unique environment created by the American health care system and how these stressors contribute to poor physical health through increased emotional distress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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Refugiados , Adulto , Estados Unidos , Humanos , Femenino , Masculino , Refugiados/psicología , Accesibilidad a los Servicios de Salud , Composición Familiar , Sudoeste de Estados Unidos , Evaluación de Resultado en la Atención de SaludRESUMEN
Background: The purpose of this paper is to report on the implementation of an evidence-based model, VIVA, which was developed to translate physical activity (PA) recommendations to rural environments and was scaled-up to 12 rural communities across New Mexico. Our longitudinal qualitative research describes processes of planned adaptation in the rural context with an exploration of inner and outer context adaptations that consider important implementation constructs including leadership, partnership and collaboration. Materials & methods: An enhanced version of the RE-AIM framework was used to formulate community-level engagement and process questions essential to implementation science. Qualitative methods, using a thematic approach that included both inductive and deductive coding with attention to processes, was used to explore adaptation at the community level. Data included semi-structured interviews with 17 community leaders at baseline and 10 at follow-up, fieldnotes, and technical assistance tracking forms. Analysis was conducted with NVivo qualitative data analysis software. Results: Analysis demonstrated how planned adaptation of the implementation model was critical to dissemination in rural communities. Understanding and adapting to local context-including geography, culture, economics-is essential for implementation. Inner context constructs, recognized as important across implementation models, including leadership, partnerships and political engagement were found to be key to implementation success. Moreover, we provide concrete examples of the range and complexity of these issues in rural communities, and how these shaped implementation uptake and success. Discussion: Studying processes of planned adaptation in rural contexts will further implementation science efforts to move evidence into practice. It is essential to incorporate planned adaptation to local, community contexts to create models which are simple to encourage adoption, are evidence-based, and are adaptable to local conditions without compromising the integrity of the evidence-based model.
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Ejercicio Físico , Población Rural , Humanos , Investigación Cualitativa , Ambiente , New MexicoRESUMEN
Purpose: In prostate cancer, the indication to irradiate the pelvic lymphatic pathways in clinical node-negative patients is solely based on clinical nomograms. To define biological risk patterns of lymphatic spread, we studied DNA-methylation and genomic copy number in primary tumors and corresponding lymph nodes metastases. Methods/Patients: DNA-methylation and genomic copy number profiles of primary tumors (PT) and paired synchronous lymph node metastases (LN) from Gleason Score (GS)-6/7a (n = 20 LN-positive, n = 20 LN-negative) and GS-9/10 patients (LN-positive n = 20) after prostatectomy and lymphonodectomy were analyzed. Results: GS-6/7a pN0 PTs and GS-6/7a pN1 PTs differed in histone H3K27me3/H3K9me3 mediated methylation. PTs compared to LNs, in both, GS-6/7a pN1 and GS-9/10 pN1 patients showed large differences in DNA-methylation mediated by histones H3K4me1/2, in addition to copy number changes of chromosomal regions 11q13.1, 14q11.2 and 15q26.1. Between GS-6/7a pN1 and GS-9/10 pN1 patients, methylation levels differed more when comparing LNs than PTs. 16q21-22.1 was specifically lost in GS-9/10 pN0 PTs. Immune system-related pathways characterized the differences between PTs and LNs in both GS-6/7a pN1 and GS-9/10 pN1 patients. Comparing PTs and LKs between GS-6/7a pN1 and GS-9/10 pN1 patients revealed altered transmembrane and G-protein-coupled receptor signaling. Conclusions: Our data suggest that progression of prostate cancer, including lymphatic spread, is associated with histone-mediated DNA-methylation and we hypothesize a methylation signature predicting lymphatic spread in GS-6/7a patients from primary tumors. Lymphatic spread in GS-6/7a patients, flanked by DNA-methylation and CNA alterations, appears to be more complex than in GS-9/10 patients, in whom the primary tumors already appear to bear lymph node metastasis-enabling alterations.
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Despite intensive basic scientific, translational, and clinical efforts in the last decades, glioblastoma remains a devastating disease with a highly dismal prognosis. Apart from the implementation of temozolomide into the clinical routine, novel treatment approaches have largely failed, emphasizing the need for systematic examination of glioblastoma therapy resistance in order to identify major drivers and thus, potential vulnerabilities for therapeutic intervention. Recently, we provided proof-of-concept for the systematic identification of combined modality radiochemotherapy treatment vulnerabilities via integration of clonogenic survival data upon radio(chemo)therapy with low-density transcriptomic profiling data in a panel of established human glioblastoma cell lines. Here, we expand this approach to multiple molecular levels, including genomic copy number, spectral karyotyping, DNA methylation, and transcriptome data. Correlation of transcriptome data with inherent therapy resistance on the single gene level yielded several candidates that were so far underappreciated in this context and for which clinically approved drugs are readily available, such as the androgen receptor (AR). Gene set enrichment analyses confirmed these results, and identified additional gene sets, including reactive oxygen species detoxification, mammalian target of rapamycin complex 1 (MTORC1) signaling, and ferroptosis/autophagy-related regulatory circuits to be associated with inherent therapy resistance in glioblastoma cells. To identify pharmacologically accessible genes within those gene sets, leading edge analyses were performed yielding candidates with functions in thioredoxin/peroxiredoxin metabolism, glutathione synthesis, chaperoning of proteins, prolyl hydroxylation, proteasome function, and DNA synthesis/repair. Our study thus confirms previously nominated targets for mechanism-based multi-modal glioblastoma therapy, provides proof-of-concept for this workflow of multi-level data integration, and identifies novel candidates for which pharmacological inhibitors are readily available and whose targeting in combination with radio(chemo)therapy deserves further examination. In addition, our study also reveals that the presented workflow requires mRNA expression data, rather than genomic copy number or DNA methylation data, since no stringent correlation between these data levels could be observed. Finally, the data sets generated in the present study, including functional and multi-level molecular data of commonly used glioblastoma cell lines, represent a valuable toolbox for other researchers in the field of glioblastoma therapy resistance.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/tratamiento farmacológico , Temozolomida/uso terapéutico , Transducción de Señal , Pronóstico , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológicoRESUMEN
PURPOSE: Identification of molecularly-defined cancer subgroups and targeting tumor-specific vulnerabilities have a strong potential to improve treatment response and patient outcomes but remain an unmet challenge of high clinical relevance, especially in head and neck squamous cell carcinoma (HNSC). EXPERIMENTAL DESIGN: We established a UCHL1-related gene set to identify and molecularly characterize a UCHL1-related subgroup within TCGA-HNSC by integrative analysis of multi-omics data. An extreme gradient boosting model was trained on TCGA-HNSC based on GSVA scores for gene sets of the MSigDB to robustly predict UCHL1-related cancers in other solid tumors and cancer cell lines derived thereof. Potential vulnerabilities of UCHL1-related cancer cells were elucidated by an in-silico drug screening approach. RESULTS: We established a 497-gene set, which stratified the TCGA-HNSC cohort into distinct subgroups with a UCHL1-related or other phenotype. UCHL1-related HNSC were characterized by higher frequencies of genomic alterations, which was also evident for UCHL1-related cancers of other solid tumors predicted by the classification model. These data indicated an impaired maintenance of genomic integrity and vulnerability for DNA-damaging treatment, which was supported by a favorable prognosis of UCHL1-related tumors after radiotherapy, and a higher sensitivity of UCHL1-related cancer cells to irradiation or DNA-damaging compounds (e.g., Oxaliplatin). CONCLUSION: Our study established UCHL1-related cancers as a novel subgroup across most solid tumor entities with a unique molecular phenotype and DNA-damaging treatment as a specific vulnerability, which requires further proof-of-concept in pre-clinical models and future clinical trials.
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Migration processes encompass uncertainty, discrimination, racism, stigma, social isolation, lack of access to resources, fear of deportation, and family separation, having a critical impact on the health of Latinx/@ immigrants in the United States. It is essential to accurately measure the ways in which social, legal, economic, and political contexts impact mental health. This article discusses adaptation and use of discrimination and historical loss measures in a multilevel community-based advocacy, learning, and social support intervention (Immigrant Well-Being Project) with Latinx/@ immigrants in New Mexico, using participatory research approaches. Participants (n = 52) were recruited through community partner organizations and completed four qualitative and quantitative interviews over a 12-month period. The present analysis draws on the baseline quantitative data. Results show it is possible to adapt standardized measures of discrimination developed to assess the experiences of other racial/ethnic groups; however, the most common responses involved response options added by our research team. For the historical loss instrument, there was a high frequency of "never" answers for many items, suggesting that they were not relevant for participants or did not capture their experiences of loss. As with the discrimination measures, the items we added resonated the most with participants. The contexts of discrimination and loss for Latinx/@ immigrant populations are complex, thus the tools we use to measure these experiences and their impact on health must account for this complexity. This study contributes to these endeavors through involving community members in the conceptualization and measurement of discrimination and historical loss among Latinx/@ immigrants. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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Emigrantes e Inmigrantes , Hispánicos o Latinos , Salud Mental , Discriminación Social , Humanos , Hispánicos o Latinos/psicología , Grupos de Población , Racismo/psicología , Estados UnidosRESUMEN
OBJECTIVE: HPV-associated head and neck cancer is correlated with favorable prognosis; however, its underlying biology is not fully understood. We propose an explainable convolutional neural network (CNN) classifier, DeepClassPathway, that predicts HPV-status and allows patient-specific identification of molecular pathways driving classifier decisions. METHODS: The CNN was trained to classify HPV-status on transcriptome data from 264 (13% HPV-positive) and tested on 85 (25% HPV-positive) head and neck squamous carcinoma patients after transformation into 2D-treemaps representing molecular pathways. Grad-CAM saliency was used to quantify pathways contribution to individual CNN decisions. Model stability was assessed by shuffling pathways within 2D-images. RESULTS: The classification performance of the CNN-ensembles achieved ROC-AUC/PR-AUC of 0.96/0.90 for all treemap variants. Quantification of the averaged pathway saliency heatmaps consistently identified KRAS, spermatogenesis, bile acid metabolism, and inflammation signaling pathways as the four most informative for classifying HPV-positive patients and MYC targets, epithelial-mesenchymal transition, and protein secretion pathways for HPV-negative patients. CONCLUSION: We have developed and applied an explainable CNN classification approach to transcriptome data from an oncology cohort with typical sample size that allows classification while accounting for the importance of molecular pathways in individual-level decisions.
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Aprendizaje Profundo , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Masculino , Humanos , Redes Neurales de la Computación , Carcinoma de Células Escamosas de Cabeza y Cuello , Neoplasias de Cabeza y Cuello/genéticaRESUMEN
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.
Asunto(s)
Neoplasias de Cabeza y Cuello , Transcriptoma , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Humanos , Recurrencia Local de Neoplasia/genética , Pronóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/genéticaRESUMEN
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.