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1.
Nat Commun ; 12(1): 2383, 2021 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-33888713

RESUMEN

Immune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors may limit the benefit of their combination with ICB. Here we employ an unbiased kinome-wide siRNA screen to reveal that HER3, is essential for the proliferation of most HNSCC cells that do not harbor PIK3CA mutations. Indeed, we find that persistent tyrosine phosphorylation of HER3 and PI3K recruitment underlies aberrant PI3K/AKT/mTOR signaling in PIK3CA wild type HNSCCs. Remarkably, antibody-mediated HER3 blockade exerts a potent anti-tumor effect by suppressing HER3-PI3K-AKT-mTOR oncogenic signaling and concomitantly reversing the immune suppressive tumor microenvironment. Ultimately, we show that HER3 inhibition and PD-1 blockade may provide a multimodal precision immunotherapeutic approach for PIK3CA wild type HNSCC, aimed at achieving durable cancer remission.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor ErbB-3/antagonistas & inhibidores , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Femenino , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/patología , Humanos , /uso terapéutico , Inmunoterapia/métodos , Ratones , Mutación , Medicina de Precisión/métodos , Receptor de Muerte Celular Programada 1/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-3/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Serina-Treonina Quinasas TOR/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Am J Hum Genet ; 108(4): 535-548, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33798442

RESUMEN

Genome sequencing is enabling precision medicine-tailoring treatment to the unique constellation of variants in an individual's genome. The impact of recurrent pathogenic variants is often understood, however there is a long tail of rare genetic variants that are uncharacterized. The problem of uncharacterized rare variation is especially acute when it occurs in genes of known clinical importance with functionally consequential variants and associated mechanisms. Variants of uncertain significance (VUSs) in these genes are discovered at a rate that outpaces current ability to classify them with databases of previous cases, experimental evaluation, and computational predictors. Clinicians are thus left without guidance about the significance of variants that may have actionable consequences. Computational prediction of the impact of rare genetic variation is increasingly becoming an important capability. In this paper, we review the technical and ethical challenges of interpreting the function of rare variants in two settings: inborn errors of metabolism in newborns and pharmacogenomics. We propose a framework for a genomic learning healthcare system with an initial focus on early-onset treatable disease in newborns and actionable pharmacogenomics. We argue that (1) a genomic learning healthcare system must allow for continuous collection and assessment of rare variants, (2) emerging machine learning methods will enable algorithms to predict the clinical impact of rare variants on protein function, and (3) ethical considerations must inform the construction and deployment of all rare-variation triage strategies, particularly with respect to health disparities arising from unbalanced ancestry representation.


Asunto(s)
Variación Genética/genética , Genética Médica , Genómica , Aprendizaje Automático , Errores Innatos del Metabolismo/genética , Farmacogenética , Medicina de Precisión , Genoma Humano/genética , Humanos , Recién Nacido
3.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800786

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is known as a highly aggressive malignant disease. Prognosis for patients is notoriously poor, despite improvements in surgical techniques and new (neo)adjuvant chemotherapy regimens. Early detection of PDAC may increase the overall survival. It is furthermore foreseen that precision medicine will provide improved prognostic stratification and prediction of therapeutic response. In this review, omics-based discovery efforts are presented that aim for novel diagnostic and prognostic biomarkers of PDAC. For this purpose, we systematically evaluated the literature published between 1999 and 2020 with a focus on protein- and protein-glycosylation biomarkers in pancreatic cancer patients. Besides genomic and transcriptomic approaches, mass spectrometry (MS)-based proteomics and glycomics of blood- and tissue-derived samples from PDAC patients have yielded new candidates with biomarker potential. However, for reasons discussed in this review, the validation and clinical translation of these candidate markers has not been successful. Consequently, there has been a change of mindset from initial efforts to identify new unimarkers into the current hypothesis that a combination of biomarkers better suits a diagnostic or prognostic panel. With continuing development of current research methods and available techniques combined with careful study designs, new biomarkers could contribute to improved detection, prognosis, and prediction of pancreatic cancer.


Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma Ductal Pancreático/diagnóstico , Glicómica/métodos , Glicoproteínas/análisis , Espectrometría de Masas/métodos , Proteínas de Neoplasias/análisis , Neoplasias Pancreáticas/diagnóstico , Proteómica/métodos , Líquidos Corporales/química , Carcinoma Ductal Pancreático/química , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidad , Toma de Decisiones Clínicas , Diagnóstico Diferencial , Detección Precoz del Cáncer , Humanos , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/epidemiología , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidad , Pancreatitis Crónica/diagnóstico , Lesiones Precancerosas/diagnóstico , Medicina de Precisión , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Factores de Riesgo
4.
Chimia (Aarau) ; 75(4): 296-299, 2021 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-33902798

RESUMEN

Nanotheranostics combine the use of nanomaterials and biologically active compounds to achieve diagnosis and treatment at the same time. To date, severe limitations compromise the use of nanotheranostic systems as potent nanomaterials are often incompatible with potent biomolecules. Herein we emphasize how a novel type of polymersome clusters loaded with active molecules can be optimized to obtain an efficient nanotheranostic platform. Polymersomes loaded with enzymes and specific dyes, respectively and exposing complementary DNA strands at their external surface formed clusters by means of DNA hybridization. We describe factors at the molecular level and other conditions that need to be optimized at each step of the cluster formation to favor theranostic efficiency.


Asunto(s)
ADN , Nanoestructuras , Medicina de Precisión
5.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809456

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case.


Asunto(s)
Esclerosis Amiotrófica Lateral/enzimología , Esclerosis Amiotrófica Lateral/inmunología , Linfocitos/inmunología , Mutación/genética , Medicina de Precisión , Superóxido Dismutasa-1/genética , Ácidos/metabolismo , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/genética , Autofagia/genética , Línea Celular Transformada , Metabolismo Energético , Femenino , Heterocigoto , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Metabolómica , Persona de Mediana Edad , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Consumo de Oxígeno , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Superóxido Dismutasa-1/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo
7.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33810246

RESUMEN

Autoimmune disease development depends on multiple factors, including genetic and environmental. Abnormalities such as sialylation levels and/or quality have been recently highlighted. The adjunction of sialic acid at the terminal end of glycoproteins and glycolipids is essential for distinguishing between self and non-self-antigens and the control of pro- or anti-inflammatory immune reactions. In autoimmunity, hyposialylation is responsible for chronic inflammation, the anarchic activation of the immune system and organ lesions. A detailed characterization of this mechanism is a key element for improving the understanding of these diseases and the development of innovative therapies. This review focuses on the impact of sialylation in autoimmunity in order to determine future treatments based on the regulation of hyposialylation.


Asunto(s)
Autoanticuerpos/metabolismo , Enfermedades Autoinmunes/inmunología , Procesamiento Proteico-Postraduccional , Ácidos Siálicos/metabolismo , Animales , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/terapia , Humanos , Inmunofenotipificación/métodos , Medicina de Precisión/métodos , Ácidos Siálicos/inmunología
8.
J Surg Oncol ; 123(6): 1395-1404, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33831247

RESUMEN

The annual incidence of pancreatic cancer is nearly 50,000 patients. The 5-year overall survival is only 9%, and there remains a great need for better therapy. A subset of these patients presents with locally advanced disease. Multidisciplinary therapy has evolved to include some combination of systemic chemotherapy, locoregional radiation, and surgery in select patients with excellent biology. This review will address the thoughtful evidence-based and individualized approach to these patients.


Asunto(s)
Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/terapia , Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Quimioradioterapia , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Manejo de la Enfermedad , Medicina Basada en la Evidencia , Fluorouracilo/administración & dosificación , Humanos , Irinotecán/administración & dosificación , Leucovorina/administración & dosificación , Terapia Neoadyuvante , Oxaliplatino/administración & dosificación , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Medicina de Precisión
9.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809749

RESUMEN

Metastatic castration-resistant prostate cancer (mCRPC) represents a condition of progressive disease in spite of androgen deprivation therapy (ADT), with a broad spectrum of manifestations ranging from no symptoms to severe debilitation due to bone or visceral metastatization. The management of mCRPC has been profoundly modified by introducing novel therapeutic tools such as antiandrogen drugs (i.e., abiraterone acetate and enzalutamide), immunotherapy through sipuleucel-T, and targeted alpha therapy (TAT). This variety of approaches calls for unmet need of biomarkers suitable for patients' pre-treatment selection and prognostic stratification. In this scenario, imaging with positron emission computed tomography (PET/CT) presents great and still unexplored potential to detect specific molecular and metabolic signatures, some of whom, such as the prostate specific membrane antigen (PSMA), can also be exploited as therapeutic targets, thus combining diagnosis and therapy in the so-called "theranostic" approach. In this review, we performed a web-based and desktop literature research to investigate the prognostic and theranostic potential of several PET imaging probes, such as 18F-FDG, 18F-choline and 68Ga-PSMA-11, also covering the emerging tracers still in a pre-clinical phase (e.g., PARP-inhibitors' analogs and the radioligands binding to gastrin releasing peptide receptors/GRPR), highlighting their potential for defining personalized care pathways in mCRPC.


Asunto(s)
Tomografía de Emisión de Positrones , Medicina de Precisión , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/terapia , Biomarcadores de Tumor/metabolismo , Humanos , Masculino , Metástasis de la Neoplasia , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/patología
10.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799513

RESUMEN

Squamous cell carcinomas of the lung, head and neck, esophagus, and cervix account for more than two million cases of cancer per year worldwide with very few targetable therapies available and minimal clinical improvement in the past three decades. Although these carcinomas are differentiated anatomically, their genetic landscape shares numerous common genetic alterations. Amplification of the third chromosome's distal portion (3q) is a distinguishing genetic alteration in most of these carcinomas and leads to copy-number gain and amplification of numerous oncogenic proteins. This area of the chromosome harbors known oncogenes involved in squamous cell fate decisions and differentiation, including TP63, SOX2, ECT2, and PIK3CA. Furthermore, novel targetable oncogenic kinases within this amplicon include PRKCI, PAK2, MAP3K13, and TNIK. TCGA analysis of these genes identified amplification in more than 20% of clinical squamous cell carcinoma samples, correlating with a significant decrease in overall patient survival. Alteration of these genes frequently co-occurs and is dependent on 3q-chromosome amplification. The dependency of cancer cells on these amplified kinases provides a route toward personalized medicine in squamous cell carcinoma patients through development of small-molecules targeting these kinases.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidad , Ensayos Clínicos como Asunto , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Neoplasias Esofágicas/enzimología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidad , Femenino , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Fosfatidilinositol 3-Quinasa/genética , Fosfatidilinositol 3-Quinasa/metabolismo , Medicina de Precisión/métodos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/genética , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Análisis de Supervivencia , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/mortalidad
11.
Wiad Lek ; 74(3 cz 2): 652-657, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33843629

RESUMEN

OBJECTIVE: The aim: Is to scientifically substantiate the concept of personalized medicine in the prevention of arterial hypertension (AH) among the adult population at the regional level. PATIENTS AND METHODS: Materials and methods: The study, after obtaining informed consent, involved 2000 patients, residents of Zaporizhzhia Region, including 1000 patients (average age 59±0.5 years, the ratio of men to women 1:1.22 people) with and 1000 patients (average age of whom is 62±0.7 years, the ratio of men to women is 1:1.1) without AH. The data of the sociological survey were processed, the methods of mathematical modeling, statistical, system analysis were applied. Odds ratio (OR) is determined by generally accepted methods with the calculation of 95% of confidence interval (CI). RESULTS: Results: The application of the concept of personalized medicine in the prevention of AH among the adult population has been scientifically substantiated by studying the associations between medical and social risk factors and the development of AH and determining on their basis 3 modules - "risk behavior", "adverse health factors" and "social determinants of the development of AH", based on stepwise multiple logistic regression analysis. CONCLUSION: Conclusions: It has been proved that the use of the final prognostic model of the development of arterial hypertension with the inclusion of the most significant risk factorshas high operational characteristics: sensitivity - 78.6%, specificity - 96.6%, positive predicative value - 95.85%, negative predicative value - 81.86%, the area under the ROC curve is 0.9623. The application of the concept of personalized medicine in the prevention of this disease among the adult population was substantiated by studying the associations between medical and social risk factors and the development of arterial hypertension.


Asunto(s)
Hipertensión , Medicina de Precisión , Adulto , Femenino , Humanos , Hipertensión/prevención & control , Masculino , Persona de Mediana Edad , Factores de Riesgo , Encuestas y Cuestionarios
12.
Anticancer Res ; 41(4): 1715-1726, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813375

RESUMEN

Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Treatment of MB is based on histopathological and molecular stratification, and includes surgical intervention, often with craniospinal irradiation and adjuvant chemotherapy. Unfortunately, however, this treatment leads to a high morbidity rate, and it does not cure all patients either, with around 30% succumbing to their disease. With improved cancer genomics and better molecular characterization, MB has been classified into four major subgroups, wingless-activated, sonic hedgehog-activated, Group 3, and Group 4, with each group consisting of additional subtypes. Recently disclosed genetic drivers of MB may in the future help improve treatment, and in this way reduce therapy-related toxicity. In this review, we describe the heterogeneity of the MB subgroups, and potential new options for targeted therapy.


Asunto(s)
Neoplasias Cerebelosas/terapia , Inmunoterapia , Meduloblastoma/terapia , Terapia Molecular Dirigida , Procedimientos Neuroquirúrgicos , Medicina de Precisión , Biomarcadores de Tumor/genética , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/patología , Quimioterapia Adyuvante , Niño , Preescolar , Irradiación Craneana , Femenino , Humanos , Inmunoterapia/efectos adversos , Lactante , Masculino , Meduloblastoma/genética , Meduloblastoma/mortalidad , Meduloblastoma/patología , Terapia Molecular Dirigida/efectos adversos , Procedimientos Neuroquirúrgicos/efectos adversos , Radioterapia Ayuvante , Resultado del Tratamiento
16.
Am J Bioeth ; 21(4): 80-83, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33825631
20.
Am J Bioeth ; 21(4): 94-97, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33825638
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