RESUMO
Los tumores de ovario en la edad pediátrica son raros, representan 1-5 % de los tumores infantiles, con una incidencia anual de 2,6 casos por cada 100.000 pacientes. La mayoría son benignos y se tratan de quistes funcionales, sin embargo, entre 10-20 % son malignos y generalmente se presentan en adolescentes; estos últimos, se dividen en 3 grupos: tumores epiteliales, germinales, y estromales o de células sexuales. Método: Estudio retrospectivo de tipo transversal, observacional, no experimental. Se analizaron los pacientes con diagnóstico de tumor de ovario, ingresados en el Servicio de Cirugía Pediátrica del Hospital de Niños "Dr. José Manuel de los Ríos", entre el 1 de enero de 2017 y 01 de julio de 2022. Resultados: 18 pacientes incluidos en el estudio, con edad media de 8,23 años (DE 4,77); los síntomas más frecuentes presentados al momento del ingreso fueron: aumento de volumen abdominal (52,94 %, 9 pacientes), y dolor abdominal (35,29 %, 6 pacientes), entre otros. Reporte patológico: 2 pacientes con quistes de ovario funcional (11,76 %) y 16 pacientes con tumor neoplásico (88,23 %), de los cuales 8 fueron germinales (53,33 %), 5 tumores epiteliales (33,33 %) y 2 pacientes con linfoma (13,33 %). Conclusión: Los tumores de ovario en general tienen una edad promedio de presentación de 8 años y los tumores neoplásicos se presentaron principalmente en adolescentes, siendo el tipo histológico más frecuente el tumor germinal y dentro de este grupo el teratoma quístico maduro. (AU)
Ovarian tumors in pediatric age are rare, representing 1-5 % of childhood tumors, with an annual incidence of 2.6 cases per 100,000 patients. Most of them are benign and functional cysts; however, between 10-20 % are malignant and generally occur in teenagers; the latter are divided into 3 groups: epithelial, germinal, and stromal or sex cell tumors. Methods: Retrospective, cross-sectional, observational, non-experimental study. Patients with a diagnosis of ovarian tumor, admitted to the Pediatric Surgery Service of the Children's Hospital "Dr. José Manuel de los Ríos", between January 01, 2017 and July 01, 2022, were analyzed. Results: 18 patients included in the study, with mean age 8.23 years (SD 4.77); the most frequent symptoms presented at admission were: increased abdominal volume (52.94 %, 9 patients), and abdominal pain (35.29 %, 6 patients), among others. Pathological report: 2 patients with functional ovarian cysts (11.76 %) and 16 patients with neoplastic tumor (88.23 %), of which 8 were germinal (53.33 %), 5 epithelial tumors (33.33 %) and 2 patients with lymphoma (13.33 %). Conclusion: Ovarian tumors in general have an average age of presentation of 8 years and neoplastic tumors occurred mainly in teenagers, the most common histological type being the germ cell tumor and within this group the mature cystic teratoma. (AU)
Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Neoplasias Ovarianas/diagnóstico , Pediatria , Biópsia , Estudos Transversais , Estudos Retrospectivos , Doenças RarasRESUMO
In this issue paper, the authors refine the definition of water sustainability to account for temporal dynamics and spatial variability, identify specific challenges that must be resolved in the very near future to avoid catastrophic outcomes on levels ranging from economic disruption to survival of mankind, discuss related policy changes and potential effectiveness, and describe several technologies available to achieve water security and sustainability. While water quality certainly poses formidable challenges, in this piece we emphasize and address challenges associated with dynamic water supply availability. Our future as a society will depend upon how well and how rapidly we navigate these challenges in the coming years. As such, the main objective is to encourage private and public sector practitioners to consider revising existing programs, and to update current industry business models in a manner that promotes expedited solutions, alignment of beneficial goals, and motivates the biggest consumers of water to adopt modern data collection and decision support technologies.
Assuntos
Água Subterrânea , Abastecimento de ÁguaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) typically presents as metastatic disease at diagnosis and remains refractory to treatment. Next-generation sequencing efforts have described the genomic landscape, classified molecular subtypes, and confirmed frequent alterations in major driver genes, with coexistent alterations in KRAS and TP53 correlating with the highest metastatic burden and poorest outcomes. However, translating this information to guide therapy remains a challenge. By integrating genomic analysis with an arrayed RNAi druggable genome screen and drug profiling of a KRAS/TP53 mutant PDAC cell line derived from a patient-derived xenograft (PDCL), we identified numerous targetable vulnerabilities that reveal both known and novel functional aspects of pancreatic cancer biology. A dependence on the general transcription and DNA repair factor TFIIH complex, particularly the XPB subunit and the CAK complex (CDK7/CyclinH/MAT1), was identified and further validated utilizing a panel of genomically subtyped KRAS mutant PDCLs. TFIIH function was inhibited with a covalent inhibitor of CDK7/12/13 (THZ1), a CDK7/CDK9 kinase inhibitor (SNS-032), and a covalent inhibitor of XPB (triptolide), which led to disruption of the protein stability of the RNA polymerase II subunit RPB1. Loss of RPB1 following TFIIH inhibition led to downregulation of key transcriptional effectors of KRAS-mutant signaling and negative regulators of apoptosis, including MCL1, XIAP, and CFLAR, initiating caspase-8 dependent apoptosis. All three drugs exhibited synergy in combination with a multivalent TRAIL, effectively reinforcing mitochondrial-mediated apoptosis. These findings present a novel combination therapy, with direct translational implications for current clinical trials on metastatic pancreatic cancer patients. Significance: This study utilizes functional genetic and pharmacological profiling of KRAS-mutant pancreatic adenocarcinoma to identify therapeutic strategies and finds that TFIIH inhibition synergizes with TRAIL to induce apoptosis in KRAS-driven pancreatic cancer.
Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Quinases Ciclina-Dependentes/genética , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias PancreáticasRESUMO
The oncogene Ras and the tumor suppressor gene p53 are frequently co-mutated in human cancer and mutations in Ras and p53 can cooperate to generate a more malignant cell state. To discover novel druggable targets for cancers carrying co-mutations in Ras and p53, we performed arrayed, kinome focused siRNA and oncology drug phenotypic screening utilizing a set of syngeneic Ras mutant squamous cell carcinoma (SCC) cell lines that also carried co-mutations in selected p53 pathway genes. These cell lines were derived from SCCs from carcinogen-treated inbred mice which harbored germline deletions or mutations in Trp53, p19Arf, Atm, or Prkdc. Both siRNA and drug phenotypic screening converge to implicate the phosphoinositol kinases, receptor tyrosine kinases, MAP kinases, as well as cell cycle and DNA damage response genes as targetable dependencies in SCC. Differences in functional kinome profiles between Ras mutant cell lines reflect incomplete penetrance of Ras synthetic lethal kinases and indicate that co-mutations cause a rewiring of survival pathways in Ras mutant tumors. This study describes the functional kinomic landscape of Ras/p53 mutant chemically-induced squamous cell carcinoma in both the baseline unperturbed state and following DNA damage and nominates candidate therapeutic targets, including the Nek4 kinase, for further development.
Assuntos
Carcinoma de Células Escamosas , Proteína Supressora de Tumor p53 , Proteínas ras , Animais , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Humanos , Camundongos , Mutação , RNA Interferente Pequeno , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas ras/genéticaRESUMO
The main objective of our study was to understand the impact of immune cell composition and the tumor-reactivity of tumor infiltrating lymphocytes (TIL) in HPV-positive (HPV+) and HPV-negative (HPV-) head and neck squamous cell carcinoma (HNSCC). TIL cultures were established from primary HNSCC tumors, the T cell subsets were phenotypically characterized using flow cytometry, and Interferon (IFN)-γ ELISA assay was used to determine TIL function. NanoString Immune Profiler was used to determine an immune signature by HPV-status, and multiplex immunohistochemistry (MIHC) was used to quantify immune cell distributions and their spatial relationships. Results showed that HPV+ and HPV- HNSCC had similar capacity to expand IFN-γ reactive TIL populations, and these TIL populations had similar characteristics. NanoString analysis revealed increased differential expression of genes related to B cell functions in HPV+ HNSCC, which were significant at a Benjamini-Yekutieli adjusted p-value of < 0.001. MIHC also displayed increased CD8+ T cell and CD19/CD20+ B cell densities in the tumor region of HPV+ HNSCC as opposed to HPV- HNSCC (p < 0.01). Increases in a combined metric of tumor B cell content and stromal plasma cell content was associated with increased progression-free survival in HPV- HNSCC patients treated with immune checkpoint inhibitor therapy (p = 0.03). In summary, TIL populations expanded from HPV+ and HPV- HNSCC displayed similar IFN-γ reactivity. However, we identified a strong B-cell signature present within HPV+ HNSCC, and higher B and plasma cell content associated with improved PFS in HPV- HNSCC patients treated with immune checkpoint inhibitors.
Assuntos
Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Neoplasias de Cabeça e Pescoço/complicações , Humanos , Imunidade , Linfócitos do Interstício Tumoral , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismoRESUMO
PURPOSE: Definitive or postoperative chemoradiation (CRT) is curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a deintensification strategy, we studied primary transoral surgery (TOS) and reduced postoperative radiation therapy (RT) in intermediate-risk HPV+ OPC. METHODS: E3311 is a phase II randomized trial of reduced- or standard-dose postoperative RT for resected stage III-IVa (American Joint Committee on Cancer-seventh edition) HPV+ OPC, determined by pathologic parameters. Primary goals were feasibility of prospective multi-institutional study of TOS for HPV+ OPC, and oncologic efficacy (2-year progression-free survival) of TOS and adjuvant therapy in intermediate-risk patients after resection. TOS plus 50 Gy was considered promising if the lower limit of the exact 90% binomial confidence intervals exceeded 85%. Quality of life and swallowing were measured by functional assessment of cancer therapy-head and neck and MD Anderson Dysphagia Index. RESULTS: Credentialed surgeons performed TOS for 495 patients. Eligible and treated patients were assigned as follows: arm A (low risk, n = 38) enrolled 11%, intermediate risk arms B (50 Gy, n = 100) or C (60 Gy, n = 108) randomly allocated 58%, and arm D (high risk, n = 113) enrolled 31%. With a median 35.2-month follow-up for 359 evaluable (eligible and treated) patients, 2-year progression-free survival Kaplan-Meier estimate is 96.9% (90% CI, 91.9 to 100) for arm A (observation), 94.9% (90% CI, 91.3 to 98.6]) for arm B (50 Gy), 96.0% (90% CI, 92.8 to 99.3) for arm C (60 Gy), and 90.7% (90% CI, 86.2 to 95.4) for arm D (66 Gy plus weekly cisplatin). Treatment arm distribution and oncologic outcome for ineligible or step 2 untreated patients (n = 136) mirrored the 359 evaluable patients. Exploratory comparison of functional assessment of cancer therapy-head and neck total scores between arms B and C is presented. CONCLUSION: Primary TOS and reduced postoperative RT result in outstanding oncologic outcome and favorable functional outcomes in intermediate-risk HPV+ OPC.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Cisplatino/uso terapêutico , Inibidor p16 de Quinase Dependente de Ciclina/análise , Neoplasias Orofaríngeas/terapia , Papillomaviridae/isolamento & purificação , Faringectomia , Radioterapia de Intensidade Modulada , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Quimiorradioterapia Adjuvante , Cisplatino/efeitos adversos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/química , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Faringectomia/efeitos adversos , Intervalo Livre de Progressão , Estudos Prospectivos , Radioterapia de Intensidade Modulada/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/química , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Fatores de TempoRESUMO
PURPOSE: Human papillomavirus (HPV) infection drives the development of some head and neck squamous cell carcinomas (HNSCC). This disease is rapidly increasing in incidence worldwide. Although these tumors are sensitive to treatment, approximately 10% of patients fail therapy. However, the mechanisms that underlie treatment failure remain unclear. EXPERIMENTAL DESIGN: We performed RNA sequencing (RNA-seq) on tissues from matched primary- (pHNSCC) and metachronous-recurrent cancers (rHNSCC) to identify transcriptional differences to gain mechanistic insight into the evolutionary adaptations of metachronous-recurrent tumors. We used HPV-related HNSCC cells lines to investigate the effect of (i) NRF2 overexpression on growth in vitro and in vivo, (ii) oxidative phosphorylation (OXPHOS) inhibition using IACS-010759 on NRF2-dependent cells, and (iii) combination of cisplatin and OXPHOS inhibition. RESULTS: The OXPHOS pathway is enriched in recurrent HPV-associated HNSCC and may contribute to treatment failure. NRF2-enriched HNSCC samples from The Cancer Genome Atlas (TCGA) with enrichment in OXPHOS, fatty-acid metabolism, Myc, Mtor, reactive oxygen species (ROS), and glycolytic signaling networks exhibited worse survival. HPV-positive HNSCC cells demonstrated sensitivity to the OXPHOS inhibitor, in a NRF2-dependent manner. Further, using murine xenograft models, we identified NRF2 as a driver of tumor growth. Mechanistically, NRF2 drives ROS and mitochondrial respiration, and NRF2 is a critical regulator of redox homeostasis that can be crippled by disruption of OXPHOS. NRF2 also mediated cisplatin sensitivity in endogenously overexpressing primary HPV-related HNSCC cells. CONCLUSIONS: These results unveil a paradigm-shifting translational target harnessing NRF2-mediated metabolic reprogramming in HPV-related HNSCC.
Assuntos
Alphapapillomavirus , Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Animais , Neoplasias de Cabeça e Pescoço/genética , Humanos , Camundongos , Recidiva Local de Neoplasia/genética , Fosforilação Oxidativa , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genéticaRESUMO
The present work addresses some fundamental aspects in the preparation of protein-conjugated gold nanoparticles, in order to ensure an appropriate final product. Ten broadly available and/or easy to implement analytical tools were benchmarked and compared in their capacity to provide reliable and conclusive information for each step of the procedure. These techniques included transmission electron microscopy, UV/VIS spectroscopy, dynamic light scattering, zeta-potential, Fourier-transformed infrared spectroscopy, colloidal stability titration, end-point colloidal stability analysis, cyclic voltammetry, agarose gel electrophoresis and size-exclusion chromatography (SEC). Four different proteins widely used as adaptors or blocking agents were tested, together with 13 nm gold nanoparticles containing different surface chemistries. Among all tested techniques, some of the least popular among nanomaterial scientists probed to be the most informative, including colloidal stability, gel electrophoresis and SEC; the latter being also an efficient purification procedure. These three techniques provide low-cost, low time consuming, sensitive and robust ways to assess the success of the nanoparticle bioconjugation steps, especially when used in adequate combinations.
RESUMO
Costa Rica is a bright spot of primary healthcare (PHC) performance, providing first-contact accessibility and continuous, comprehensive, coordinated, and patient-centered care to its citizens. Previous research hypothesized that strong data collection and use for quality improvement are central to Costa Rica's success. Using qualitative data from 40 interviews with stakeholders across the Costa Rican healthcare system, this paper maps the various data streams at the PHC level and delineates how these data are used to make decisions around insuring and improving the quality of PHC delivery. We describe four main types of PHC data: individual patient data, population health data, national healthcare delivery data, and local supplementary healthcare delivery data. In particular, we find that the Healthcare Delivery Performance Index-a ranking of the nation's 106 Health Areas using 15 quality indicators-is utilized by Health Area Directors to create quality improvement initiatives, ranging from education and coaching to optimization of care delivery and coordination. By ranking Health Areas, the Index harnesses providers' intrinsic motivation to stimulate improvement without financial incentives. We detail how a strong culture of valuing data as a tool for improving population health and robust training for personnel have enabled effective data collection and use. However, we also find that the country's complex data systems create unnecessary duplication and can inhibit efficient data use. Costa Rica's experience with data collection, analysis, and use for quality improvement hold important lessons for PHC in other public sector systems.
Assuntos
Atenção Primária à Saúde , Melhoria de Qualidade , Costa Rica , Coleta de Dados , Atenção à Saúde , HumanosRESUMO
Turkevich method is one of the most employed techniques to synthesize gold nanoparticles. Despite its simplicity, the mechanism has been an issue of debate over the past years. The general belief is that particles are formed by a classical nucleation and growth theory, originally described by LaMer's model. In the present work, we provide new experimental evidences that supports either LaMer's theory and their detractors. In the former model, it is proposed that particles are generated by a burst nucleation form the initial 'seeds', from which their growth in a second and quasi-independent step. Instead, our experiments (DLS, UV/VIS and TEM measurements) support the idea that nanoparticles 'seeds' tend to form large intermediate clusters at the beginning of the synthesis, that afterwards disassemble to yield the final nanoparticles. However, unlike other reports, we propose that during the cluster formation the particles do not coalesce, instead they come close to each other without losing their identity. As the synthesis continues, these clusters are progressively separated into the final particles. As a consequence, a path to synthesize ultra-narrow size nanoparticles is provided, along with their stability against salt aggregation, and shelf-time. We found that these ultra-homogeneous nanoparticles are stable for several months, making them suitable for many applications in the biomedical and analytical research.
RESUMO
Head and neck squamous cell carcinoma (HNSCC) associated with high-risk human papilloma virus (HPV) infection is a growing clinical problem. The WEE1 kinase inhibitor AZD1775 (WEE1i) overrides cell cycle checkpoints and is being studied in HNSCC regimens. We show that the HPV16 E6/E7 oncoproteins sensitize HNSCC cells to single-agent WEE1i treatment through activation of a FOXM1-CDK1 circuit that drives mitotic gene expression and DNA damage. An isogenic cell system indicated that E6 largely accounts for these phenotypes in ways that extend beyond p53 inactivation. A targeted genomic analysis implicated FOXM1 signaling downstream of E6/E7 expression and analyses of primary tumors and The Cancer Genome Atlas (TCGA) data revealed an activated FOXM1-directed promitotic transcriptional signature in HPV+ versus HPV- HNSCCs. Finally, we demonstrate the causality of FOXM1 in driving WEE1i sensitivity. These data suggest that elevated basal FOXM1 activity predisposes HPV+ HNSCC to WEE1i-induced toxicity and provide mechanistic insights into WEE1i and HPV+ HNSCC therapies.
Assuntos
Proteínas de Ciclo Celular/efeitos dos fármacos , Proteína Forkhead Box M1/metabolismo , Infecções por Papillomavirus/tratamento farmacológico , Proteínas Tirosina Quinases/efeitos dos fármacos , Pirazóis/antagonistas & inibidores , Pirimidinonas/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Proteína Quinase CDC2/metabolismo , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço , Humanos , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Repressoras/metabolismo , Regulação para CimaRESUMO
As the world strives to achieve universal health coverage by 2030, countries must build robust healthcare systems founded on strong primary healthcare (PHC). In order to strengthen PHC, country governments need actionable guidance about how to implement health reform. Costa Rica is an example of a country that has taken concrete steps towards successfully improving PHC over the last two decades. In the 1990s, Costa Rica implemented three key reforms: governance restructuring, geographic empanelment, and multidisciplinary teams. To understand how Costa Rica implemented these reforms, we conducted a process evaluation based on a validated implementation science framework. We interviewed 39 key informants from across Costa Rica's healthcare system in order to understand how these reforms were implemented. Using the Exploration Preparation Implementation Sustainment (EPIS) framework, we coded the results to identify Costa Rica's key implementation strategies and explore underlying reasons for Costa Rica's success as well as ongoing challenges. We found that Costa Rica implemented PHC reforms through strong leadership, a compelling vision and deliberate implementation strategies such as building on existing knowledge, resources and infrastructure; bringing together key stakeholders and engaging deeply with communities. These reforms have led to dramatic improvements in health outcomes in the past 25 years. Our in-depth analysis of Costa Rica's specific implementation strategies offers tangible lessons and examples for other countries as they navigate the important but difficult work of strengthening PHC.
Assuntos
Reforma dos Serviços de Saúde , Cobertura Universal do Seguro de Saúde , Costa Rica , Atenção à Saúde , HumanosRESUMO
PURPOSE: Understanding the role of transoral surgery in oropharyngeal cancer (OPC) requires prospective, randomized multi-institutional data. Meticulous evaluation of surgeon expertise and surgical quality assurance (QA) will be critical to the validity of such trials. We describe a novel surgeon credentialing and QA process developed to support the ECOG-ACRIN Cancer Research Group E3311 (E3311) and report outcomes related to QA. PATIENTS AND METHODS: E3311 was a phase II randomized clinical trial of transoral surgery followed by low- or standard-dose, risk-adjusted post-operative therapy with stage III-IVa (AJCC 7th edition) HPV-associated OPC. In order to be credentialed to accrue to this trial, surgeons were required to demonstrate active hospital credentials and technique-specific surgical expertise with ≥20 cases of transoral resection for OPC. In addition, 10 paired operative and surgical pathology reports from the preceding 24 months were reviewed by an expert panel. Ongoing QA required <10% rate of positive margins, low oropharyngeal bleeding rates, and accrual of at least one patient per 12 months. Otherwise surgeons were placed on hold and not permitted to accrue until re-credentialed using a new series of transoral resections. RESULTS: 120 surgeons trained in transoral minimally invasive surgery applied for credentialing for E3311 and after peer-review, 87 (73%) were approved from 59 centers. During QA on E3311, positive final pathologic margins were reported in 19 (3.8%) patients. Grade III/IV and grade V oropharyngeal bleeding was reported in 29 (5.9%) and 1 (0.2%) of patients. CONCLUSIONS: We provide proof of concept that a comprehensive credentialing process can support multicenter transoral head and neck surgical oncology trials, with low incidence of positive margins and *grade III/V oropharyngeal bleeding.
Assuntos
Neoplasias Orofaríngeas/cirurgia , Garantia da Qualidade dos Cuidados de Saúde/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , CirurgiõesRESUMO
Introducción: Es conocida la capacidad de los fractales estadísticos en la evaluación de la complejidad de diferentes sistemas cuya dinámica pueda ser evaluada a partir de las frecuencias de una variable; para esto, se utiliza la medida de la dimensión fractal estadística, la cual puede ser calculada con la ley de Zipf-Mandelbrot. Esta ley matemática ha sido aplicada en cardiología para evaluar el grado de complejidad de la dinámica cardíaca. En el presente trabajo se aplicó la ley de Zipf-Mandelbrot junto con la metodología diagnóstica desarrollada previamente para evaluar dinámicas cardíacas normales y con enfermedad aguda. Materiales y métodos: Se tomaron 15 registros Holter; 10 con diagnóstico normal y 5 con patologías agudas de pacientes de la Unidad de Cuidados Intensivos. Se organizaron jerárquicamente las frecuencias de aparición de las frecuencias cardíacas de cada dinámica en rangos de a 15 lat/min, en busca del comportamiento hiperbólico necesario para la aplicación de la ley de Zipf-Mandelbrot. Posteriormente se realizó una linealización y se obtuvo la dimensión fractal estadística para cada dinámica. Resultados: Los valores de la dimensión fractal estadística para una dinámica cardíaca aguda variaron entre 0.4925 y 0.6061, mientras que para una dinámica normal variaron entre 0.7134 y 0.9749, evidenciando la diferenciación entre ambos grupos. Conclusiones: El comportamiento fractal estadístico de la dinámica cardíaca fue corroborado, de igual forma la pérdida de complejidad para las dinámicas agudas respecto a las dinámicas normales
Background: The capacity of statistical fractals in the evaluation of the complexity of different systems whose dynamics can be evaluated from the frequencies of a variable is known. This is why the measure of the statistical fractal dimension is used, which can be calculated with the Zipf-Mandelbrot law, this mathematical law has been applied in cardiology evaluating the degree of complexity of cardiac dynamics. In the present work, the Zipf-Mandelbrot law was applied together with the diagnostic methodology previously developed to evaluate normal cardiac dynamics and acute disease. Material and methods: 15 Holter records were taken; 10 with normal diagnosis and 5 with acute pathologies of patients of the Intensive Care Unit. The frequencies of occurrence of the heart frequencies of each dynamics were organized hierarchically in ranges of 15 lat/min, in search of the hyperbolic behavior required for the application of the law of Zipf-Mandelbrot. Subsequently, a linearization was performed and the statistical fractal dimension was obtained for each dynamics. Results: The values of the statistical fractal dimension for acute cardiac dynamics varied between 0.4925 and 0.6061, whereas for normal dynamics they varied between 0.7134 and 0.9749, evidencing the differentiation between both groups. Conclusions: The statistical fractal behavior of the cardiac dynamics was corroborated, as well as the loss of complexity for the acute dynamics with respect to the normal dynamics
Assuntos
Humanos , Eletrocardiografia Ambulatorial , Fractais , Cardiopatias , Frequência Cardíaca , Unidades de Terapia IntensivaRESUMO
The use of the thermodynamic formalism in the investigation of biochemical reactions constitutes one of the key analysis in bioenergetics, and the first step in such analysis is the selection of the adequate reference state. For biochemistry majors, thermodynamic analysis based on the chemical reference state is used in Physical Chemistry courses, while the biological and biochemical reference states are used in Biochemistry courses. As these definitions are introduced in different courses, it is difficult that students can understand the need to select a reference state as a first step in the energy analysis of a system. The lack of suitable examples in textbooks to illustrate the importance of the adequate selection of the reference state in a thermodynamic analysis, promoted the present analysis of the energetic role of pyrophosphate (PPi) in comparison with adenosine-triphosphate in different ambient conditions, namely, the early PPi world (better described by the chemical reference state), the enclosed systems like the cells (better described by the biological reference state), and the actual thioester world (better described by the biochemical reference state). This example not only provides a new interesting point of view on the evolution of two biochemical fuels but also represents a biochemical example in which the use of different reference states can illustrate a single process from different points of views.
Assuntos
Trifosfato de Adenosina/metabolismo , Bioquímica/educação , Físico-Química/educação , Difosfatos/metabolismo , Animais , Bioquímica/normas , Físico-Química/normas , Metabolismo Energético , Humanos , Hidrólise , Valores de Referência , Estudantes , Termodinâmica , UruguaiRESUMO
Immune checkpoint inhibitors have demonstrated activity in recurrent/metastatic head and neck squamous cell cancer, but less is known regarding their long-term sequelae. We describe four patients who, after complete responses to anti-PD-1 therapy, developed complications requiring surgical intervention. Patient 1 is a 57-year-old female whose marked tumor regression exposed some mandibular hardware. Patient 2 is a 39-year-old male who developed an ulcerated buccal lesion with exposed mandible. Patient 3 is a 66-year-old male with craniofacial osteoradionecrosis. Patient 4 is a 71-year-old male who developed an exposed and fractured mandible. All patients successfully underwent surgical intervention and remain disease free. Laryngoscope, 129:E428-E433, 2019.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias de Cabeça e Pescoço/terapia , Nivolumabe/efeitos adversos , Procedimentos Cirúrgicos Otorrinolaringológicos/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Cicatrização/efeitos dos fármacos , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Complicações Pós-Operatórias , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismoRESUMO
The p53 gene is the most commonly mutated gene in solid tumors, but leveraging p53 status in therapy remains a challenge. Previously, we determined that p53 deficiency sensitizes head and neck cancer cells to AZD1775, a WEE1 kinase inhibitor, and translated our findings into a phase I clinical trial. Here, we investigate how p53 affects cellular responses to AZD1775 at the molecular level. We found that p53 modulates both replication stress and mitotic deregulation triggered by WEE1 inhibition. Without p53, slowing of replication forks due to replication stress is exacerbated. Abnormal, γH2AX-positive mitoses become more common and can proceed with damaged or underreplicated DNA. p53-deficient cells fail to properly recover from WEE1 inhibition and exhibit fewer 53BP1 nuclear bodies despite evidence of unresolved damage. A faulty G1-S checkpoint propagates this damage into the next division. Together, these deficiencies can intensify damages in each consecutive cell cycle in the drug. IMPLICATIONS: The data encourage the use of AZD1775 in combination with genotoxic modalities against p53-deficient head and neck squamous cell carcinoma.
Assuntos
Neoplasias de Cabeça e Pescoço/genética , Mutação , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Proteína Supressora de Tumor p53/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Mitose/efeitos dos fármacosRESUMO
OBJECTIVES: (1) Report the patterns of cervical node positivity for HPVâ¯+â¯oropharyngeal squamous cell carcinoma (OPSCC) treated with transoral robotic surgery (TORS) and a unilateral level II-IV node dissection. (2) Investigate the regional failure rate following this operation. (3) Report the rate of pharyngocutaneous fistula (PCF) formation intraoperatively and postoperatively following TORS/neck dissection. METHODS: Retrospective case series of 88 patients with HPV+ OPSCC treated with TORS and simultaneous neck dissection levels II-IV at the University of Washington from 2010 to 2016. Primary endpoints were PCF, regional recurrence, disease-free survival (DFS), and overall survival (OS). RESULTS: The overall frequency of cervical node positivity was 93%, with 84% in level IIa, 7% in IIb, 23% in III, and 13% in IV. Two patients developed PCF intraoperatively, repaired with a local digastric flap, and no postoperative PCF occurred. Sixteen patients (18%) received surgery alone, 49 patients (56%) received adjuvant radiation, and 23 patients (26%) underwent adjuvant chemoradiation. DFS at 2â¯years was 95% and OS at 2â¯years was 100%. No concerning level Ib nodes were identified preoperatively or during surgery, and no regional failures occurred in this location. CONCLUSION: Our data suggests, in TORS for HPV+ OPSCC, neck dissection of levels II-IV accurately stages the neck pathologically and prevents regional recurrences, with adjuvant therapy when indicated, and survival outcomes are excellent. Single-staged operations did not result in any postoperative PCF. Avoiding dissection of level Ib with TORS oropharyngectomy limits morbidity to the marginal mandibular nerve and salivary function, and resulted in no postoperative fistulas with minimal reconstruction interventions.
Assuntos
Recidiva Local de Neoplasia/epidemiologia , Neoplasias Orofaríngeas/cirurgia , Infecções por Papillomavirus/cirurgia , Faringectomia/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Adulto , Idoso , Fístula Cutânea/epidemiologia , Fístula Cutânea/etiologia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática/diagnóstico , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Esvaziamento Cervical/efeitos adversos , Esvaziamento Cervical/métodos , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/patologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/mortalidade , Infecções por Papillomavirus/patologia , Faringectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Fístula do Sistema Respiratório/epidemiologia , Fístula do Sistema Respiratório/etiologia , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , TraqueiaRESUMO
BACKGROUND: Human papillomavirus-related (HPV-related) oropharyngeal squamous cell carcinomas (OPSCCs) have an excellent response rate to platinum-based chemoradiotherapy. Genomic differences between primary HPV-related OPSCCs that do or do not recur are unknown. Furthermore, it is unclear if HPV-related OPSCCs that recur share a genomic landscape with HPV-negative head and neck cancers (HNCs). METHODS: We utilized whole exome sequencing to analyze somatic nucleotide (SNVs) and copy number variants (CNVs) among a unique set of 51 primary HPV-related OPSCCs, including 35 that did not recur and 16 that recurred. We evaluated 12 metachronous recurrent OPSCCs (7 with paired primary OPSCCs) and 33 primary HPV-unrelated oral cavity and OPSCCs. RESULTS: KMT2D was the most frequently mutated gene among primary HPV-related OPSCCs (n = 51; 14%) and among metachronous recurrent OPSCCs (n = 12; 42%). Primary HPV-related OPSCCs that recurred shared a genomic landscape with primary HPV-related OPSCCs that did not recur. However, TSC2, BRIP1, NBN, and NFE2L2 mutations occurred in primary OPSCCs that recurred but not in those that did not recur. Moreover, primary HPV-related OPSCCs that recur harbor features of HPV-unrelated HNCs, notably including MAPK, JAK/STAT, and differentiation signaling pathway aberrations. Metachronous recurrent OPSCCs shared a genomic landscape with HPV-unrelated HNCs, including a high frequency of TP53, CASP8, FAT1, HLA-A, AJUBA, and NSD1 genomic alterations. CONCLUSION: Overall, primary HPV-related OPSCCs that recur share a genomic landscape with nonrecurrent OPSCCs. Metachronous recurrent OPSCCs share genomic features with HPV-negative HNCs. These data aim to guide future deescalation endeavors and functional experiments. FUNDING: This study is supported by the American Cancer Society (RSG TBG-123653), funding support for RAH (T32DC00018, Research Training in Otolaryngology, University of Washington), funds to EM from Seattle Translational Tumor Research (Fred Hutchinson Cancer Research Center), and center funds from the Fred Hutchinson Cancer Research Center to EM. UD is supported by the Department of Veterans Affairs, Biomedical Laboratory Research and Development (BLR&D), grant IO1-oo23456, and funds from the Pittsburgh Foundation and PNC Foundation.