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Past research has established the value of social distancing as a means of deterring the spread of COVID-19 largely by examining aggregate level data. Locales in which efforts were undertaken to encourage distancing experienced reductions in their rate of transmission. However, these aggregate results tell us little about the effectiveness of social distancing at the level of the individual, which is the question addressed by the current research. Four months after participating in a study assessing their social distancing behavior, 2,120 participants indicated whether they had contracted COVID-19. Importantly, the assessment of social distancing involved not only a self-report measure of how strictly participants had followed social distancing recommendations but also a series of virtual behavior measures of social distancing. These simulations presented participants with graphical depictions mirroring specific real-world scenarios, asking them to position themselves in relation to others in the scene. Individuals' social distancing behavior, particularly as assessed by the virtual behavior measure, predicted whether they contracted COVID-19 during the intervening 4 mo. This was true when considering only participants who reported having tested positively for the virus and when considering additional participants who, although untested, believed that they had contracted the virus. The findings offer a unique form of additional evidence as to why individuals should practice social distancing. What the individual does matters, not only for the health of the collective, but also for the specific individual.
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COVID-19 , Simulação por Computador , Modelos Biológicos , Distanciamento Físico , SARS-CoV-2 , Autorrelato , Adulto , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/transmissão , Feminino , Seguimentos , Humanos , MasculinoRESUMO
Heme oxygenases (HOs) detoxify heme by oxidatively degrading it into carbon monoxide, iron, and biliverdin, which is reduced to bilirubin and excreted. Humans express two isoforms of HO: the inducible HO-1, which is upregulated in response to excess heme and other stressors, and the constitutive HO-2. Much is known about the regulation and physiological function of HO-1, whereas comparatively little is known about the role of HO-2 in regulating heme homeostasis. The biochemical necessity for expressing constitutive HO-2 is dependent on whether heme is sufficiently abundant and accessible as a substrate under conditions in which HO-1 is not induced. By measuring labile heme, total heme, and bilirubin in human embryonic kidney HEK293 cells with silenced or overexpressed HO-2, as well as various HO-2 mutant alleles, we found that endogenous heme is too limiting a substrate to observe HO-2-dependent heme degradation. Rather, we discovered a novel role for HO-2 in the binding and buffering of heme. Taken together, in the absence of excess heme, we propose that HO-2 regulates heme homeostasis by acting as a heme buffering factor that controls heme bioavailability. When heme is in excess, HO-1 is induced, and both HO-2 and HO-1 can provide protection from heme toxicity via enzymatic degradation. Our results explain why catalytically inactive mutants of HO-2 are cytoprotective against oxidative stress. Moreover, the change in bioavailable heme due to HO-2 overexpression, which selectively binds ferric over ferrous heme, is consistent with labile heme being oxidized, thereby providing new insights into heme trafficking and signaling.
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Heme Oxigenase (Desciclizante) , Heme , Biliverdina , Células HEK293 , Heme/metabolismo , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Ferro/metabolismo , Rim/metabolismoRESUMO
The in vitro formation of stable G-quadruplexes (G4s) in human rRNA was recently reported. However, their formation in cells and their cellular roles were not resolved. Here, by taking a chemical biology approach that integrates results from immunofluorescence, G4 ligands, heme-affinity reagents, and a genetically encoded fluorescent heme sensor, we report that human ribosomes can form G4s in vivo that regulate heme bioavailability. Immunofluorescence experiments indicate that the vast majority of extra-nuclear G4s are associated with rRNA. Moreover, titrating human cells with a G4 ligand alters the ability of ribosomes to bind heme and disrupts cellular heme bioavailability as measured by a genetically encoded fluorescent heme sensor. Overall, these results suggest that ribosomes play a role in regulating heme homeostasis.
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Quadruplex G , Ribossomos/metabolismo , Imunofluorescência , Células HEK293 , Heme/metabolismo , Homeostase , Humanos , Ligantes , Ligação Proteica , RNA Ribossômico/metabolismoRESUMO
BACKGROUND: Caregivers of children with cancer can experience stress when seeking care in the emergency department (ED). We sought to assess how caregivers prepare for and manage a medical emergency that arises in the community setting. METHODS: A qualitative evaluation of ED visit preparations taken by children with cancer and their caregivers using self-reported interactive toolkits. Eligible participants included children with cancer (age: 11 to 21 y) currently receiving therapy for cancer diagnosis with an ED visit (besides initial diagnosis) within the previous 2 months and caregivers of same. Participants received a paper toolkit, which were structured as experience maps with several generative activities. Toolkits were transcribed, thematically coded, and iteratively analyzed using NVivo 12.0 software. RESULTS: A total of 25 toolkits were received (7 children, 18 caregivers), with about three quarters of participants living >1 hour from the treating institution. Several important common themes and areas for improvement emerged. Themes included struggles with decision-making regarding when and where to seek ED care, preparing to go to the ED, waiting during the ED visit, repetition of information to multiple providers, accessing of ports, and provider-to-provider and provider-to-caregiver/patient communication. CONCLUSIONS: The information gained from this study has the potential to inform a tool to support this population in planning for and managing emergent medical issues. This tool has the potential to improve patient and caregiver satisfaction, patient-centered outcomes, and clinical outcomes.
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Cuidadores/psicologia , Comunicação , Tomada de Decisões , Serviço Hospitalar de Emergência/estatística & dados numéricos , Avaliação das Necessidades/estatística & dados numéricos , Neoplasias/terapia , Aceitação pelo Paciente de Cuidados de Saúde , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Neoplasias/psicologia , Inquéritos e QuestionáriosRESUMO
Comprehensive approaches to youth violence prevention are needed to simultaneously address multiple risk factors across socioecological levels. ThrYve (Together Helping Reduce Youth Violence for Equity) is a collaborative initiative focused on addressing broader factors influencing youth violence, including social determinants of health. Using a participatory approach, the development of ThrYve is examined through an empirical case study. Through a Systems Advisory Board (SAB), ThrYve deploys multiple strategies that support cross-sector collaboration involving over 40 partners across 13 community sectors. Based on the Institute of Medicine's model for public health action in communities, the SAB identified 87 change levers (i.e., program, policy, practice changes) to support community and systems-level improvements. As a result of the collaborative process, in the first couple of years, ThrYve facilitated 85 community actions and changes across sectors. The changes aligned with identified risk and resilience needs of the youth served in the community. The findings further support prior research, which suggests disparities related to gender may influence risk and resilience factors for youth violence. The study also indicates the importance of continuing to examine academic performance as a factor related to youth resilience.
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Desenvolvimento de Programas , Violência/prevenção & controle , Adolescente , Redes Comunitárias , Participação da Comunidade , Etnicidade/estatística & dados numéricos , Feminino , Humanos , Kansas , Masculino , Grupos Minoritários/estatística & dados numéricos , Avaliação de Programas e Projetos de Saúde , Saúde Pública , Características de ResidênciaRESUMO
Syntenin-1 is an essential multi-functional adaptor protein, which has multiple roles in membrane trafficking and exosome biogenesis, as well as scaffolding interactions with either the actin cytoskeleton or focal adhesions. However, how this functional multiplicity relates to syntenin-1 distribution in different endosome compartments or other intracellular locations and its underlying involvement in cancer pathogenesis have yet to be fully defined. To help facilitate the investigation of syntenin-1 biology, we developed two specific monoclonal antibodies (Synt-2C6 and Synt-3A11) to spatially distinct linear sequence epitopes on syntenin-1, which were each designed to be unique at the six-amino acid level. These antibodies produced very different intracellular staining patterns, with Synt-2C6 detecting endosomes and Synt-3A11 producing a fibrillar staining pattern suggesting a cytoskeletal localisation. Treatment of cells with Nocodazole altered the intracellular localisation of Synt-3A11, which was consistent with the syntenin-1 protein interacting with microtubules. In prostate tissue biopsies, Synt-3A11 defined atrophy and early-stage prostate cancer, whereas Synt-2C6 only showed minimal interaction with atrophic tissue. This highlights a critical need for site-specific antibodies and a knowledge of their reactivity to define differential protein distributions, interactions and functions, which may differ between normal and malignant cells.
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Anticorpos Monoclonais/análise , Neoplasias da Próstata/patologia , Sinteninas/análise , Animais , Linhagem Celular , Linhagem Celular Tumoral , Mapeamento de Epitopos/métodos , Epitopos , Humanos , Imunoquímica/métodos , Masculino , Modelos Moleculares , Neoplasias da Próstata/diagnósticoRESUMO
Background. The obesity epidemic has led to an increase in prediabetes in youth, causing a serious public health concern. Education on diabetes risk and initiation of lifestyle change are the primary treatment modalities. There are few existing age-appropriate health education tools to address diabetes prevention for high-risk youth. Aim. To develop an age-appropriate health education tool(s) to help youth better understand type 2 diabetes risk factors and the reversibility of risk. Method. Health education tool development took place in five phases: exploration, design, analysis, refinement, and process evaluation. Results. The project resulted in (1) booklet designed to increase knowledge of risk, (2) meme generator that mirrors the booklet graphics and allows youth to create their own meme based on their pancreas' current mood, (3) environmental posters for clinic, and (4) brief self-assessment that acts as a conversation starter for the health educators. Conclusion. Patients reported high likability and satisfaction with the health education tools, with the majority of patients giving the materials an "A" rating. The process evaluation indicated a high level of fidelity and related measures regarding how the health education tools were intended to be used and how they were actually used in the clinic setting.
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Diabetes Mellitus Tipo 2/prevenção & controle , Educação em Saúde/organização & administração , Estado Pré-Diabético/epidemiologia , Adolescente , Glicemia , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Estilo de Vida , Masculino , Folhetos , Fatores de Risco , Autoavaliação (Psicologia)RESUMO
INTRODUCTION/BACKGROUND: Patient-reported outcome measures (PROMs) for hypospadias care are lacking, and most existing instruments were developed without patient input. OBJECTIVE: The objective of this study was to 1) use our previously developed Hypospadias Journal for concept elicitation in a sample of adolescent and young adult hypospadias patients and 2) develop a new hypospadias PROM. STUDY DESIGN: We recruited English-speaking males ages 13-30 living in the United States with a self-reported history of hypospadias through targeted advertisements on Facebook and Instagram from March to June 2022. Using a Qualtrics screening survey ineligible respondents were identified using automated fraud detection and manual review. Consenting participants were sent an electronic Hypospadias Journal containing brief creative writing exercises and multiple-choice scales to facilitate participant reflections about genital appearance, urination, sexual function, and psychosocial well-being. Demographics were summarized using descriptive statistics. Human-centered design researchers synthesized the journals' key themes to 1) create an affinity diagram with hypospadias-related quality of life (QOL) domains and 2) draft items for the PROM covering each domain and sub-domain. Journal participants were asked to complete a survey to 1) rank hypospadias QOL domains, subdomains, and draft items for the PROM, and 2) explore their preferences for item phrasing. In a small group virtual interview, a urologist and a hypospadias patient reviewed and revised draft PROM items, and a final PROM was created. RESULTS: Of the 411 completed screening surveys, 391 were ineligible. Journals were sent to 20 eligible participants. Of these, 12 completed journals: 8 adults; 4 adolescents (11 surgical/1 non-surgical): 66.7% White, 8.3% Black, 16.7% Asian, 8.3% >1 race. The meatal location was distal for 41.7%, proximal for 41.7%, unknown/missing for 16.7%. We identified four hypospadias-related quality-of-life domains and 13 respective sub-domains (Extended Summary Figure) of these, two were novel domains: 1) knowledge about the condition/treatment and comfort with treatment decision, and 2) impact on relationships with caregivers, medical providers, and sexual partners. A final PROM prototype, the Patient Assessment Tool for Hypospadias (PATH) was created, covering all QOL domains identified by participants. DISCUSSION: We created a simple, brief hypospadias PROM to screen for salient topics to be addressed by providers in the clinical setting. Limitations include the small sample size and limited clinical details about participants. CONCLUSIONS: Our study provides a hypospadias PROM that is ready for psychometric assessment in a larger sample.
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Heme b (iron protoporphyrin IX) is an essential but potentially cytotoxic cofactor, signaling molecule, and nutritional source of iron. Its importance in cell biology and metabolism is underscored by the fact that numerous diseases, including various cancers, neurodegenerative disorders, infectious diseases, anemias, and porphyrias, are associated with the dysregulation of heme synthesis, degradation, trafficking, and/or transport. Consequently, methods to measure, image, and quantify heme in cells are required to better understand the physiology and pathophysiology of heme. Herein, we describe fluorescence-based protocols to probe heme bioavailability and trafficking dynamics using genetically encoded fluorescent heme sensors in combination with various modalities, such as confocal microscopy, flow cytometry, and microplate readers. Additionally, we describe a protocol for measuring total heme and its precursor protoporphyrin IX using a fluorometric assay that exploits porphyrin fluorescence. Together, the methods described enable the monitoring of total and bioavailable heme to study heme homeostatic mechanisms in virtually any cell type and organism.
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Fluorometria , Heme , Heme/metabolismo , Fluorometria/métodos , Humanos , Protoporfirinas/metabolismo , Citometria de Fluxo/métodos , Microscopia Confocal/métodos , Disponibilidade Biológica , AnimaisRESUMO
The diagnosis of prostate cancer using histopathology is reliant on the accurate interpretation of prostate tissue sections. Current standards rely on the assessment of Haematoxylin and Eosin (H&E) staining, which can be difficult to interpret and introduce inter-observer variability. Here, we present a digital pathology atlas and online resource of prostate cancer tissue micrographs for both H&E and the reinterpretation of samples using a novel set of three biomarkers as an interactive tool, where clinicians and scientists can explore high resolution histopathology from various case studies. The digital pathology prostate cancer atlas when used in conjunction with the biomarkers, will assist pathologists to accurately grade prostate cancer tissue samples.
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Proteínas Adaptadoras de Transdução de Sinal , Proteínas Adaptadoras de Transporte Vesicular , Biomarcadores Tumorais , Neoplasias da Próstata , Sindecana-1 , Neoplasias da Próstata/patologia , Masculino , Humanos , Sindecana-1/análiseAssuntos
Fibrose Cística/fisiopatologia , Oxigênio/uso terapêutico , Respiração , Testes de Função Respiratória/métodos , Adolescente , Adulto , Testes Respiratórios , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Nitrogênio , Análise de Regressão , Taxa Respiratória , Software , Espirometria , Volume de Ventilação Pulmonar , Adulto JovemRESUMO
Effective stakeholder engagement increases research relevance and utility. Though published principles of community-based participatory research and patient-centered outcomes research offer guidance, few resources offer effective techniques to engage stakeholders and translate their engagement into improvements in research process and outcomes. The Indiana Clinical and Translational Sciences Institute (Indiana CTSI) is home to Research Jam (RJ), an interdisciplinary team of researchers, project management professionals, and design experts, that employs human-centered design (HCD) to engage stakeholders in the research process. Establishing HCD services at the Indiana CTSI has allowed for accessible and innovative stakeholder-engaged research. RJ offers services for stakeholder-informed study design, measurement, implementation, and dissemination. RJ's services are in demand to address research barriers pertaining to a diverse array of health topics and stakeholder groups. As a result, the RJ team has grown significantly with both institutional and extramural support. Researchers involved in RJ projects report that working with RJ helped them learn how to better engage with stakeholders in research and changed the way they approach working with stakeholders. RJ can serve as a potential model for effectively engaging stakeholders through HCD to improve translational research.
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Objective: How we communicate about obesity is critical as treatment paradigms shift upstream. We previously identified parental perceptions, concerns, beliefs, and communication preferences about early life obesity risk. We engaged parents of children 0 to 24 months of age and pediatricians from Indianapolis, Indiana, USA in the co-design of messages and tools that can be used to facilitate parent/provider conversations about early life obesity prevention. Methods: From April to June 2021, we conducted a series of co-design workshops with parents of children ages 0 to 24 months and pediatricians to identify their preferences for communicating obesity prevention in the setting of a pediatric well visit. Human-centered design techniques, including affinity diagraming and model building, were used to inform key elements of a communication model and communication strategy messages. These elements were combined and refined to create prototype tools that were subsequently refined using stakeholder feedback. Results: Parent participants included 11 mothers and 2 fathers: 8 white, 4 black, and 1 Asian; median age 33 years with 38% reporting annual household incomes less than $50,000. Pediatricians included 7 female and 6 male providers; 69% white. Through an iterative process of co-design, we created an exam room poster that addresses common misconceptions about infant feeding, sleep and exercise, and a behavior change plan to foster parent/provider collaboration focused on achieving children's healthy weight. Conclusions: Our hands-on, collaborative approach may ultimately improve uptake, acceptability and usability of early life obesity interventions by ensuring that parents remain at the center of prevention efforts.
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BACKGROUND: Premature infants are at increased risk of kidney-related complications, including acute kidney injury (AKI) and chronic kidney disease (CKD). The risk of CKD in prematurely born infants is underrecognized by health care teams and caregivers. Understanding how to communicate the risk of CKD to caregivers is essential for longitudinal clinical follow-up and adherence. OBJECTIVE: This study aimed to determine family caregiver attitudes toward kidney health and risk communication during a neonatal intensive care admission. We also sought to understand caregiver preferences for the communication of information surrounding the risk of CKD in premature infants. METHODS: We augmented standard qualitative group sessions with human-centered design methods to assess parent preferences and clinician perspectives. Caregivers recruited had a prematurely born child who spent time in the neonatal intensive care unit at Riley Hospital for Children in Indianapolis, Indiana, and experienced AKI or another kidney complication, which put them at risk for future CKD. We used a variety of specific design methods in these sessions, including card sorting, projective methods, experience mapping, and constructive methods. RESULTS: A total of 7 clinicians and 8 caregivers participated in 3 group sessions. Caregivers and clinicians readily acknowledged barriers to and drivers of long-term kidney monitoring as well as opportunities for communication of the risk of long-term kidney disease. Caregivers' primary concerns were for both the type and depth of information conveyed as well as the time at which it was communicated. Participants emphasized the importance of collaboration between the hospital care team and the primary care provider. Participant input was synthesized into several prototype concepts and, ultimately, into a rough prototype of a website and an informational flyer. CONCLUSIONS: Caregivers of premature infants are open to communication about kidney health during their neonatal admission. The next phase of this work will translate caregivers' preferences into family-centered communication tools and test their efficacy in the neonatal intensive care unit.
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Heme b (iron protoporphyrin IX) plays important roles in biology as a metallocofactor and signaling molecule. However, the targets of heme signaling and the network of proteins that mediate the exchange of heme from sites of synthesis or uptake to heme dependent or regulated proteins are poorly understood. Herein, we describe a quantitative mass spectrometry (MS)-based chemoproteomics strategy to identify exchange labile hemoproteins in human embryonic kidney HEK293 cells that may be relevant to heme signaling and trafficking. The strategy involves depleting endogenous heme with the heme biosynthetic inhibitor succinylacetone (SA), leaving putative heme-binding proteins in their apo-state, followed by the capture of those proteins using hemin-agarose resin, and finally elution and identification by MS. By identifying only those proteins that interact with high specificity to hemin-agarose relative to control beaded agarose in an SA-dependent manner, we have expanded the number of proteins and ontologies that may be involved in binding and buffering labile heme or are targets of heme signaling. Notably, these include proteins involved in chromatin remodeling, DNA damage response, RNA splicing, cytoskeletal organization, and vesicular trafficking, many of which have been associated with heme through complementary studies published recently. Taken together, these results provide support for the emerging role of heme in an expanded set of cellular processes from genome integrity to protein trafficking and beyond.
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Hemina , Proteoma , Humanos , Hemina/metabolismo , Proteínas Ligantes de Grupo Heme , Proteoma/metabolismo , Proteômica , Células HEK293 , Heme/metabolismoRESUMO
INTRODUCTION: Despite significant and known challenges to urinary and fecal incontinence (UI and FI, respectively) among children with spina bifida (SB) and their families, few studies have identified patient-centered measures and approaches to assessing them. This study represents the first stage of a larger study to develop a patient-centered goal-setting tool to guide incontinence management (Figure). Our aim was to understand patient experiences of UI and FI, and what goals should be included in the tool. METHODS: We used a qualitative research approach integrated with human-centered design methods. We recruited, in clinic and online, children with SB (8-17 years old) and parents (>=18 years old) of children with SB (8-17 years old). Online activities were analyzed by four experienced design researchers using affinity diagramming, group analysis and modeling activities (mind maps, challenge maps, experience maps). Recruitment and thematic qualitative analysis continued until saturation was reached. RESULTS: Seventeen children with SB participated (9 female, 12 shunted, 13 using bladder catheterizations, 6 using Malone antegrade continence enema, median age: 15 years old). Fifteen parents participated (13 mothers/2 fathers, median age: 42 years old), including six mother-child dyads. Five major themes each were identified for UI and FI experiences: (1) negative emotional impact of incontinence, (2) unpredictability of incontinence, (3) challenging/unpleasant incontinence management, (4) inconvenient/unreliable incontinence management, (5) UI management having unpleasant complications and FI putting much responsibility on parents. We identified six UI goal domains and five FI goal domains. Four overlapping domains included: accidents, independence, interruptions at school and social/friends. Unique domains were: urinary tract infections (UI), catheterizations (UI) and enemas (FI). COMMENT: Findings of our study improve our understanding of children's and parents' experiences associated with incontinence in SB and potential continence goals. CONCLUSIONS: Children with SB experience incontinence as distressing and unpredictable. Incontinence management can be challenging and unreliable. Patient-centered continence goals cluster in domains, indicating how incontinence intermeshes with other life areas and offering potential approaches to structure continence goals in a goals-selection tool.
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Incontinência Fecal , Disrafismo Espinal , Sistema Urinário , Humanos , Feminino , Adolescente , Adulto , Criança , Incontinência Fecal/etiologia , Incontinência Fecal/terapia , Pais , Disrafismo Espinal/complicações , Disrafismo Espinal/psicologia , MãesRESUMO
INTRODUCTION: No tools exist to help children with spina bifida (SB) describe their incontinence concerns and to help their providers account for them when evaluating management success. Our aim was to understand patients', parents', and clinicians' preferences about how a SB continence goal-selection tool (MyGoal-C) should look and function, and to create a tool prototype. METHODS: We used a qualitative research approach integrated with human-centered design methods. We recruited children with SB (8-17 years old), parents ( ≥ 18 years old) of children with SB (8-17 years old) in clinic and online, and urology healthcare providers at our institution. We surveyed children and parents, and conducted parent and provider Zoom-based prototyping sessions to iteratively design the app. Design researchers analyzed online activities using affinity diagramming, group analysis and modeling activities. Provider sessions were analyzed with qualitative thematic analysis based on grounded theory. Recruitment continued until saturation was reached. RESULTS: Thirteen children with SB participated (median age: 10 years old, 4 female, 9 shunted, 10 using bladder catheterizations). Thirty-seven parents participated (33 mothers, median age: 43 years old). Children and parents unanimously recommended an app and their comments generated 6 major theme domains: goal-setting process, in-app content, working toward goals, urology provider check-in, app customization, and using big data to improve future functionality. Twenty-one of the parents participated in 3 prototyping sessions with 6 breakout groups. The remaining 16 parents and 13 children then completed the Prototype Testing Survey, leading to a refined prototype and a visual flow map of the app experience (Figure). Feedback from 11 urology healthcare providers (7 female, 6 advanced practice providers) generated 8 themes: patient engagement/autonomy, clearly displaying results, integration into clinic workflow, not increasing clinical staff burden, potential clinician bias, parental involvement, limitations of the app, and future app adaptation. These cumulative data allowed for a construction of a final app prototype. COMMENT: Findings of our study lay the foundation for creating a goal-selection app that meets preferences and needs of children, parents, and providers. Next steps involve building the app, testing its usability and assessing it prospectively in a clinical setting. CONCLUSIONS: Children with SB and parents preferred an app to help them set and track continence goals. All stakeholders, including urology providers, offered complementary and mutually reinforcing feedback to guide the creation of an app prototype that would ultimately be integrated into a clinic visit.
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Disrafismo Espinal , Urologia , Humanos , Criança , Feminino , Adulto , Adolescente , Objetivos , Pais , Inquéritos e Questionários , Disrafismo Espinal/complicaçõesRESUMO
The presence of intraductal carcinoma of the prostate (IDCP) correlates with late-stage disease and poor outcomes for patients with prostatic adenocarcinoma, but the accurate and reliable staging of disease severity remains challenging. Immunohistochemistry (IHC) has been utilised to overcome problems in assessing IDCP morphology, but the current markers have only demonstrated limited utility in characterising the complex biology of this lesion. In a retrospective study of a cohort of patients who had been diagnosed with IDCP, we utilised IHC on radical prostatectomy sections with a biomarker panel of Appl1, Sortilin and Syndecan-1, to interpret different architectural patterns and to explore the theory that IDCP occurs from retrograde spread of high-grade invasive prostatic adenocarcinoma. Cribriform IDCP displayed strong Appl1, Sortilin and Syndecan-1 labelling patterns, while solid IDCP architecture had high intensity Appl1 and Syndecan-1 labelling, but minimal Sortilin labelling. Notably, the expression pattern of the biomarker panel in regions of IDCP was similar to that of adjacent invasive prostatic adenocarcinoma, and also comparable to prostate cancer showing perineural and vascular invasion. The Appl1, Sortilin, and Syndecan-1 biomarker panel in IDCP provides evidence for the model of retrograde spread of invasive prostatic carcinoma into ducts/acini, and supports the inclusion of IDCP into the five-tier Gleason grading system.
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Carcinoma Intraductal não Infiltrante , Neoplasias da Próstata , Masculino , Humanos , Próstata/patologia , Carcinoma Intraductal não Infiltrante/patologia , Estudos Retrospectivos , Imuno-Histoquímica , Sindecana-1 , Neoplasias da Próstata/patologia , Gradação de TumoresRESUMO
Cutaneous melanoma is the deadliest form of skin neoplasm and its high mortality rates could be averted by early accurate detection. While the detection of melanoma is currently reliant upon melanin visualisation, research into melanosome biogenesis, as a key driver of pathogenesis, has not yielded technology that can reliably distinguish between atypical benign, amelanotic and melanotic lesions. The endosomal-lysosomal system has important regulatory roles in cancer cell biology, including a specific functional role in melanosome biogenesis. Herein, the involvement of the endosomal-lysosomal system in melanoma was examined by pooled secondary analysis of existing gene expression datasets. A set of differentially expressed endosomal-lysosomal genes was identified in melanoma, which were interconnected by biological function. To illustrate the protein expression of the dysregulated genes, immunohistochemistry was performed on samples from patients with cutaneous melanoma to reveal candidate markers. This study demonstrated the dysregulation of Syntenin-1, Sortilin and Rab25 may provide a differentiating feature between cutaneous melanoma and squamous cell carcinoma, while IGF2R may indicate malignant propensity in these skin cancers.
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Carcinoma de Células Escamosas , Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/patologia , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas/patologia , Lisossomos/genética , Lisossomos/patologia , Proteínas rab de Ligação ao GTP , Melanoma Maligno CutâneoRESUMO
Prostate cancer (PCa) development and progression relies on the programming of glucose and lipid metabolism, and this involves alterations in androgen receptor expression and signalling. Defining the molecular mechanism that underpins this metabolic programming will have direct significance for patients with PCa who have a poor prognosis. Here we show that there is a dynamic balance between sortilin and syndecan-1, that reports on different metabolic phenotypes. Using tissue microarrays, we demonstrated by immunohistochemistry that sortilin was highly expressed in low-grade cancer, while syndecan-1 was upregulated in high-grade disease. Mechanistic studies in prostate cell lines revealed that in androgen-sensitive LNCaP cells, sortilin enhanced glucose metabolism by regulating GLUT1 and GLUT4, while binding progranulin and lipoprotein lipase (LPL) to limit lipid metabolism. In contrast, in androgen-insensitive PC3 cells, syndecan-1 was upregulated, interacted with LPL and colocalised with ß3 integrin to promote lipid metabolism. In addition, androgen-deprived LNCaP cells had decreased expression of sortilin and reduced glucose-metabolism, but increased syndecan-1 expression, facilitating interactions with LPL and possibly ß3 integrin. We report a hitherto unappreciated molecular mechanism for PCa, which may have significance for disease progression and how androgen-deprivation therapy might promote castration-resistant PCa.