RESUMO
In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Robust droplet-based, single-cell simultaneous determination of gene expression and immune repertoire indicated that PDO TILs accurately preserved the original tumor T cell receptor (TCR) spectrum. Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity. Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immuno-oncology investigations within the TME and facilitate personalized immunotherapy testing.
Assuntos
Modelos Imunológicos , Neoplasias Experimentais/imunologia , Organoides/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Animais , Antígeno B7-H1/imunologia , Técnicas de Cocultura , Feminino , Humanos , Imunoterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Organoides/patologiaRESUMO
We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.
Assuntos
Neoplasias/patologia , Aneuploidia , Cromossomos/genética , Análise por Conglomerados , Ilhas de CpG , Metilação de DNA , Bases de Dados Factuais , Humanos , MicroRNAs/metabolismo , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , RNA Mensageiro/metabolismoRESUMO
Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFß signaling, p53 and ß-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.
Assuntos
Bases de Dados Genéticas , Neoplasias/patologia , Transdução de Sinais/genética , Genes Neoplásicos , Humanos , Neoplasias/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMO
We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.
Assuntos
Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Idoso , Análise por Conglomerados , Metilação de DNA , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Músculo Liso/patologia , RNA Longo não Codificante/genética , Análise de Sobrevida , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/terapiaRESUMO
Oncogenic mutations in isocitrate dehydrogenases 1 and 2 (IDH1/2) produce 2-hydroxyglutarate (2HG), which inhibits dioxygenases that modulate chromatin dynamics. The effects of 2HG have been reported to sensitize IDH tumors to poly-(ADP-ribose) polymerase (PARP) inhibitors. However, unlike PARP-inhibitor-sensitive BRCA1/2 tumors, which exhibit impaired homologous recombination, IDH-mutant tumors have a silent mutational profile and lack signatures associated with impaired homologous recombination. Instead, 2HG-producing IDH mutations lead to a heterochromatin-dependent slowing of DNA replication accompanied by increased replication stress and DNA double-strand breaks. This replicative stress manifests as replication fork slowing, but the breaks are repaired without a significant increase in mutation burden. Faithful resolution of replicative stress in IDH-mutant cells is dependent on poly-(ADP-ribosylation). Treatment with PARP inhibitors increases DNA replication but results in incomplete DNA repair. These findings demonstrate a role for PARP in the replication of heterochromatin and further validate PARP as a therapeutic target in IDH-mutant tumors.
Assuntos
Proteína BRCA1 , Neoplasias , Humanos , Proteína BRCA1/genética , Heterocromatina/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteína BRCA2/genética , Recombinação Homóloga/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Mutação , Isocitrato Desidrogenase/genéticaRESUMO
Scientists have been trying to identify every gene in the human genome since the initial draft was published in 2001. In the years since, much progress has been made in identifying protein-coding genes, currently estimated to number fewer than 20,000, with an ever-expanding number of distinct protein-coding isoforms. Here we review the status of the human gene catalogue and the efforts to complete it in recent years. Beside the ongoing annotation of protein-coding genes, their isoforms and pseudogenes, the invention of high-throughput RNA sequencing and other technological breakthroughs have led to a rapid growth in the number of reported non-coding RNA genes. For most of these non-coding RNAs, the functional relevance is currently unclear; we look at recent advances that offer paths forward to identifying their functions and towards eventually completing the human gene catalogue. Finally, we examine the need for a universal annotation standard that includes all medically significant genes and maintains their relationships with different reference genomes for the use of the human gene catalogue in clinical settings.
Assuntos
Genes , Genoma Humano , Anotação de Sequência Molecular , Isoformas de Proteínas , Humanos , Genoma Humano/genética , Anotação de Sequência Molecular/normas , Anotação de Sequência Molecular/tendências , Isoformas de Proteínas/genética , Projeto Genoma Humano , Pseudogenes , RNA/genéticaRESUMO
Pharmacogenomic testing has emerged as an aid in clinical decision making for psychiatric providers, but more data is needed regarding its utility in clinical practice and potential impact on patient care. In this cross-sectional study, we determined the real-world prevalence of pharmacogenomic actionability in patients receiving psychiatric care. Potential actionability was based on the prevalence of CYP2C19 and CYP2D6 phenotypes, including CYP2D6 allele-specific copy number variations (CNVs). Combined actionability additionally incorporated CYP2D6 phenoconversion and the novel CYP2C-TG haplotype in patients with available medication data. Across 15,000 patients receiving clinical pharmacogenomic testing, 65% had potentially actionable CYP2D6 and CYP2C19 phenotypes, and phenotype assignment was impacted by CYP2D6 allele-specific CNVs in 2% of all patients. Of 4114 patients with medication data, 42% had CYP2D6 phenoconversion from drug interactions and 20% carried a novel CYP2C haplotype potentially altering actionability. A total of 87% had some form of potential actionability from genetic findings and/or phenoconversion. Genetic variation detected via next-generation sequencing led to phenotype reassignment in 22% of individuals overall (2% in CYP2D6 and 20% in CYP2C19). Ultimately, pharmacogenomic testing using next-generation sequencing identified potential actionability in most patients receiving psychiatric care. Early pharmacogenomic testing may provide actionable insights to aid clinicians in drug prescribing to optimize psychiatric care.
RESUMO
In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or TIGIT+) CD4+ T-cells and PD-1+CD8+ T-cells in NLPHL compared to cHL. This included T-cells that rosetted with lymphocyte predominant (LP) and Hodgkin Reed-Sternberg (HRS) cells. In NLPHL, intra-tumoral PD-1+CD4+ T-cells frequently expressed TCF-1, a marker of heightened T-cell response to ICB. The peripheral blood signatures between HLs were also distinct, with higher levels of PD-1+TIGIT+ in TH1, TH2, and regulatory CD4+ T-cells in NLPHL versus cHL. Circulating PD-1+CD4+ had high levels of TCF-1. Notably, in both lymphomas, highly expanded populations of clonal TIGIT+PD-1+CD4+ and TIGIT+PD-1+CD8+ T-cells in the blood were also present in the TME, indicating that immune-checkpoint expressing T-cells circulated between intra-tumoral and blood compartments. In in vitro assays, ICB was capable of reducing rosette formation around LP and HRS cells, suggesting that disruption of rosetting may be a mechanism of action of ICB in HL. Overall, results indicate that further evaluation of ICB is warranted in NLPHL.
RESUMO
To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.
Assuntos
Linfoma não Hodgkin , Qualidade de Vida , Humanos , Feminino , Estados Unidos/epidemiologia , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Linfoma não Hodgkin/diagnóstico , Linfócitos B/patologia , PrognósticoRESUMO
Salmonella enterica continues to be a leading cause of foodborne morbidity worldwide. A quantitative risk assessment model was developed to evaluate the impact of pathogen enumeration and serotyping strategies on public health after consumption of undercooked contaminated ground turkey in the USA. The risk assessment model predicted more than 20,000 human illnesses annually that would result in ~700 annual reported cases. Removing ground turkey lots contaminated with Salmonella exceeding 10 MPN/g, 1 MPN/g, and 1 MPN/25 g would decrease the mean number of illnesses by 38.2, 73.1, and 95.0%, respectively. A three-class mixed sampling plan was tested to allow the detection of positive lots above threshold levels with 2-6 (c = 1) and 3-8 samples per lot (c = 2) using 25-g and 325-g sample sizes for a 95% probability of rejecting a contaminated lot. Removal of positive lots with the presence of highly virulent serotypes would decrease the number of illnesses by 44.2-87.0%. Based on these model prediction results, risk management strategies should incorporate pathogen enumeration and/or serotyping. This would have a direct impact on illness incidence linking public health outcomes with measurable food safety objectives, at the cost of diverting production lots.
Assuntos
Salmonella enterica , Salmonella , Animais , Humanos , Sorotipagem , Perus , Gestão de Riscos , Avaliação de Resultados em Cuidados de SaúdeRESUMO
The pivotal importance of workplace learning (WPL) within health professions education has elevated its understanding and improvement to a major research priority. From a sociocultural learning theory perspective, WPL is inherently situated and context-specific. This means that the health care settings in which (future) health care professionals are trained will impact how and what is learned. However, to what extent is the research performed thus far transferable across professional contexts, cultures and borders? To what extent has WPL research sufficiently addressed the contextual characteristics of WPL to enable the evaluation of its transferability? To what extent have methodological and theoretical approaches enabled the building of understanding across contexts? We propose that heightening the transferability of WPL research as well as opening up the conversation to more diverse WPL contexts, settings and cultures will require mapping context and theoretical engagement. To explore what theoretical engagement may afford to our understanding of the influence of context on WPL, we use two theories: Landscapes of Practice and Figured Worlds. These theories with sociocultural groundings provide concrete lenses to understand the interplay between the individual and the context. We conclude with implications for research and practice and advocate for more attention to research practices that may deepen our understanding and heighten the transferability of workplace learning research.
RESUMO
INTRODUCTION: Medical residents may be required to handle health care management (HCM) tasks alongside their clinical duties, despite not having received training to perform them. However, little research has been done on how medical residents acquire HCM skills at the workplace and how these experiences impact their learning. METHODS: We completed a qualitative research study using the Constructivist Grounded Theory approach inform by the Figured World theory. To gather data, we held focus groups and conducted semi-structured interviews with 22 medical residents from various disciplines and learning levels at Pontificia Universidad Javeriana. We utilised iterative data collection and analysis, constant comparison methods and theoretical sampling to construct our findings. RESULTS: We constructed two different worlds to represent how residents acquire HCM skills: the non-managing physician and the physician-as-manager. The former was characterised by a discourse that underplayed the role of the HCM tasks as part of residents' training, was full of negative interactions with the health care team and limited residents' agency. In the latter, residents collaborated and learned from health care team members, had supervisors who modelled how to incorporate HCM tasks into daily activities and expanded residents' agency. Residents developed their professional identity according to the world they were introduced into. DISCUSSION: Educational leaders must understand that the non-managing physician figured world gives residents a feeling of uprooting and discomfort when carrying out this type of tasks. To transform this world into the physician-as-manager, it is necessary to reconfigure some workplace hierarchies, consolidate interprofessional collaborations and change the discourse perpetuated by influential role models. Supervisors must also strengthen their knowledge of HCM and improve its integration into clinical practice. Any effort to train residents on HCM competencies could be lost if the workplace underscores their value in patient care.
Assuntos
Teoria Fundamentada , Internato e Residência , Pesquisa Qualitativa , Local de Trabalho , Humanos , Grupos Focais , Feminino , Masculino , Competência Clínica , AdultoRESUMO
BACKGROUND: Endocrine-resistant HR+/HER2- breast cancer (BC) and triple-negative BC (TNBC) are of interest for molecularly informed treatment due to their aggressive natures and limited treatment profiles. Patients of African Ancestry (AA) experience higher rates of TNBC and mortality than European Ancestry (EA) patients, despite lower overall BC incidence. Here, we compare the molecular landscapes of AA and EA patients with HR+/HER2- BC and TNBC in a real-world cohort to promote equity in precision oncology by illuminating the heterogeneity of potentially druggable genomic and transcriptomic pathways. METHODS: De-identified records from patients with TNBC or HR+/HER2- BC in the Tempus Database were randomly selected (N = 5000), with most having stage IV disease. Mutations, gene expression, and transcriptional signatures were evaluated from next-generation sequencing data. Genetic ancestry was estimated from DNA-seq. Differences in mutational prevalence, gene expression, and transcriptional signatures between AA and EA were compared. EA patients were used as the reference population for log fold-changes (logFC) in expression. RESULTS: After applying inclusion criteria, 3433 samples were evaluated (n = 623 AA and n = 2810 EA). Observed patterns of dysregulated pathways demonstrated significant heterogeneity among the two groups. Notably, PIK3CA mutations were significantly lower in AA HR+/HER2- tumors (AA = 34% vs. EA = 42%, P < 0.05) and the overall cohort (AA = 28% vs. EA = 37%, P = 2.08e-05). Conversely, KMT2C mutation was significantly more frequent in AA than EA TNBC (23% vs. 12%, P < 0.05) and HR+/HER2- (24% vs. 15%, P = 3e-03) tumors. Across all subtypes and stages, over 8000 genes were differentially expressed between the two ancestral groups including RPL10 (logFC = 2.26, P = 1.70e-162), HSPA1A (logFC = - 2.73, P = 2.43e-49), ATRX (logFC = - 1.93, P = 5.89e-83), and NUTM2F (logFC = 2.28, P = 3.22e-196). Ten differentially expressed gene sets were identified among stage IV HR+/HER2- tumors, of which four were considered relevant to BC treatment and were significantly enriched in EA: ERBB2_UP.V1_UP (P = 3.95e-06), LTE2_UP.V1_UP (P = 2.90e-05), HALLMARK_FATTY_ACID_METABOLISM (P = 0.0073), and HALLMARK_ANDROGEN_RESPONSE (P = 0.0074). CONCLUSIONS: We observed significant differences in mutational spectra, gene expression, and relevant transcriptional signatures between patients with genetically determined African and European ancestries, particularly within the HR+/HER2- BC and TNBC subtypes. These findings could guide future development of treatment strategies by providing opportunities for biomarker-informed research and, ultimately, clinical decisions for precision oncology care in diverse populations.
Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , População Negra/genética , Neoplasias da Mama/etnologia , Neoplasias da Mama/patologia , Mutação , Medicina de Precisão , Neoplasias de Mama Triplo Negativas/etnologia , Neoplasias de Mama Triplo Negativas/patologia , População BrancaRESUMO
Venous thromboembolism (VTE) associated with cancer (CAT) is a well-described complication of cancer and a leading cause of death in patients with cancer. The purpose of this study was to assess potential associations of molecular signatures with CAT, including tumor-specific mutations and the presence of clonal hematopoiesis. We analyzed deep-coverage targeted DNA-sequencing data of >14 000 solid tumor samples using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform to identify somatic alterations associated with VTE. End point was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis. Cause-specific Cox proportional hazards regression was used, adjusting for pertinent clinical covariates. Of 11 695 evaluable individuals, 72% had metastatic disease at time of analysis. Tumor-specific mutations in KRAS (hazard ratio [HR], 1.34; 95% confidence interval (CI), 1.09-1.64; adjusted P = .08), STK11 (HR, 2.12; 95% CI, 1.55-2.89; adjusted P < .001), KEAP1 (HR, 1.84; 95% CI, 1.21-2.79; adjusted P = .07), CTNNB1 (HR, 1.73; 95% CI, 1.15-2.60; adjusted P = .09), CDKN2B (HR, 1.45; 95% CI, 1.13-1.85; adjusted P = .07), and MET (HR, 1.83; 95% CI, 1.15-2.92; adjusted P = .09) were associated with a significantly increased risk of CAT independent of tumor type. Mutations in SETD2 were associated with a decreased risk of CAT (HR, 0.35; 95% CI, 0.16-0.79; adjusted P = .09). The presence of clonal hematopoiesis was not associated with an increased VTE rate. This is the first large-scale analysis to elucidate tumor-specific genomic events associated with CAT. Somatic tumor mutations of STK11, KRAS, CTNNB1, KEAP1, CDKN2B, and MET were associated with an increased risk of VTE in patients with solid tumors. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types.
Assuntos
Neoplasias/complicações , Tromboembolia Venosa/etiologia , Idoso , Predisposição Genética para Doença , Genômica , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias/genética , Fatores de Risco , Tromboembolia Venosa/genéticaRESUMO
Chimeric antigen receptor (CAR) T-cells anti-CD30 is an innovative therapeutic option that has been used to treat cases of refractory/relapsed (R/R) classic Hodgkin lymphoma (CHL). Limited data are available regarding the CD30 expression status of patients who relapsed after this therapy. This is the first study to show decreased CD30 expression in R/R CHL in patients (n = 5) who underwent CAR T-cell therapy in our institution between 2018 and 2022. Although conventional immunohistochemical assays showed decreased CD30 expression in neoplastic cells in all cases (8/8) the tyramide amplification assay and RNAScope in situ hybridisation detected CD30 expression at different levels in 100% (n = 8/8) and 75% (n = 3/4), respectively. Hence, our findings document that certain levels of CD30 expression are retained by the neoplastic cells. This is not only of biological interest but also diagnostically important, as detection of CD30 is an essential factor in establishing a diagnosis of CHL.
Assuntos
Doença de Hodgkin , Imunoconjugados , Humanos , Doença de Hodgkin/patologia , Antígeno Ki-1/metabolismo , Imunoterapia Adotiva , Imunoconjugados/uso terapêuticoRESUMO
DUSP22 rearrangement (R) has been associated with a favorable outcome in systemic ALK-negative anaplastic large cell lymphoma (ALCL). However, a recent study found that patients with DUSP22-R ALK-negative ALCL have a poorer prognosis than was reported initially. In this study, we compared the clinicopathological features and outcomes of patients with ALKnegative ALCL with DUSP22-R (n=22) versus those without DUSP22-R (DUSP22-NR; n=59). Patients with DUSP22-R ALCL were younger than those with DUSP22-NR neoplasms (P=0.049). DUSP22-R ALK-negative ALCL cases were more often positive for CD15, CD8, and less frequently expressed pSTAT3Tyr705, PD-L1, granzyme B and EMA (all P<0.05). TP63 rearrangement (TP63-R) was detected in three of the 66 (5%) ALK-negative ALCL cases tested and none of these cases carried the DUSP22-R. Overall survival of patients with DUSP22-R ALCL was similar to that of the patients with DUSP22-NR neoplasms regardless of International Prognostic Index score, stage, age, or stem cell transplantation status (all P>0.05), but was significantly shorter than that of the patients with ALK-positive ALCL (median overall survival 53 months vs. undefined, P=0.005). Five-year overall survival rates were 40% for patients with DUSP22-R ALCL versus 82% for patients with ALK-positive ALCL. We conclude that DUSP22-R neoplasms represent a distinctive subset of ALK-negative ALCL. However, in this cohort DUSP22-R was not associated with a better clinical outcome. Therefore, we suggest that current treatment guidelines for this subset of ALK-negative ALCL patients should not be modified at present.
Assuntos
Linfoma Anaplásico de Células Grandes , Receptores Proteína Tirosina Quinases , Humanos , Quinase do Linfoma Anaplásico/genética , Receptores Proteína Tirosina Quinases/genética , Linfoma Anaplásico de Células Grandes/patologia , Imunofenotipagem , Prognóstico , Fosfatases de Especificidade Dupla/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/genéticaRESUMO
Oestrus ovis is an obligate parasite that causes myiasis in domestic ruminants, being commonly found in the Mediterranean area. From 2009 to 2019 a total of 3476 heads of culling sheep and goats from the Mediterranean coast of Spain were examined for the presence of O. ovis. The total prevalence was 56.3%, significantly higher in sheep than in goats (61.2% and 43%, respectively). Differences were found in the mean annual prevalence, with the highest value being registered in 2018 (61.7%) and the lowest in 2012 (50.3%). Autumn, for sheep, and winter, for goats, were the seasons with the highest number of infested specimens. Temperature, but not rainfall, was found to be associated with prevalence (p < 0.05). Most L1 were found in the anatomic region I (septum, meatus, and ventral conchae), while L2 and L3 were mainly located in regions II (nasopharynx, ethmoid labyrinth, and dorsal conchae), and III (sinuses). The overall intensity was 12.8 larvae per head, significantly higher in sheep (13.3) than in goats (3.5). Our results confirm the high prevalence of O. ovis in sheep and goats in this geographic area over the last decade, with the trend increasing in recent years in association with higher mean temperatures.
Assuntos
Dípteros , Doenças das Cabras , Miíase , Doenças dos Ovinos , Ovinos , Animais , Prevalência , Doenças dos Ovinos/epidemiologia , Doenças dos Ovinos/parasitologia , Miíase/epidemiologia , Miíase/veterinária , Miíase/parasitologia , Larva , Cabras , Doenças das Cabras/epidemiologia , Doenças das Cabras/parasitologiaRESUMO
To prevent and control foodborne diseases, there is a fundamental need to identify the foods that are most likely to cause illness. The goal of this study was to rank 25 commonly consumed food products associated with Salmonella enterica contamination in the Central Region of Mexico. A multicriteria decision analysis (MCDA) framework was developed to obtain an S. enterica risk score for each food product based on four criteria: probability of exposure to S. enterica through domestic food consumption (Se); S. enterica growth potential during home storage (Sg); per capita consumption (Pcc); and food attribution of S. enterica outbreak (So). Risk scores were calculated by the equation Se*W1 +Sg*W2 +Pcc*W3 +So*W4 , where each criterion was assigned a normalized value (1-5) and the relative weights (W) were defined by 22 experts' opinion. Se had the largest effect on the risk score being the criterion with the highest weight (35%; IC95% 20%-60%), followed by So (24%; 5%-50%), Sg (23%; 10%-40%), and Pcc (18%; 10%-35%). The results identified chicken (4.4 ± 0.6), pork (4.2 ± 0.6), and beef (4.2 ± 0.5) as the highest risk foods, followed by seed fruits (3.6 ± 0.5), tropical fruits (3.4 ± 0.4), and dried fruits and nuts (3.4 ± 0.5), while the food products with the lowest risk were yogurt (2.1 ± 0.3), chorizo (2.1 ± 0.4), and cream (2.0 ± 0.3). Approaches with expert-based weighting and equal weighting showed good correlation (R2 = 0.96) and did not show significant differences among the ranking order in the top 20 tier. This study can help risk managers select interventions and develop targeted surveillance programs against S. enterica in high-risk food products.
Assuntos
Frutas , Sementes , Bovinos , Animais , México , Galinhas , Fatores de RiscoRESUMO
Neuroblastoma is a neural crest cell-derived pediatric tumor characterized by high inter- and intra-tumor heterogeneity, and by a poor outcome in advanced stages. Patient-derived xenografts (PDXs) have been shown to be useful models for preserving and expanding original patient biopsies in vivo, and for studying neuroblastoma biology in a more physiological setting. The maintenance of genetic, histologic, and phenotypic characteristics of the original biopsy along serial PDX passages in mice is a major concern regarding this model. Here we analyze consecutive PDX passages in mice, at both transcriptomic and histological levels, in order to identify potential changes or highlight similarities to the primary sample. We studied temporal changes using mRNA and miRNA expression and correlate those with neuroblastoma aggressiveness using patient-derived databases. We observed a shortening of tumor onset and an increase in proliferative potential in the PDXs along serial passages. This behavior correlates with changes in the expression of genes related to cell proliferation and neuronal differentiation, including signaling pathways described as relevant for neuroblastoma malignancy. We also identified new genes and miRNAs that can be used to stratify patients according to survival, and which could be potential new players in neuroblastoma aggressiveness. Our results highlight the usefulness of the PDX neuroblastoma model and reflect phenotypic changes that might be occurring in the mouse environment. These findings could be useful for understanding the progression of tumor aggressiveness in this pathology.