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1.
OMICS ; 25(1): 1-12, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33305994

RESUMEN

Pharmacogenomics, nutrigenomics, vaccinomics, and the nascent field of plant omics are examples of variability science. They are embedded within an overarching framework of personalized medicine. Across these public health specialties, the significance and biology of the placebo response have been historically neglected. A placebo is any substance such as a sugar pill administered in the guise of medication, but one that does not have pharmacological activity. Placebos do have clinical effects, however, that can be substantive in magnitude and vary markedly from person-to-person depending, for example, on the type of disease, symptoms, or clinical trial design. Research over the past several decades attests to a genuine neurobiological basis for placebo effects. All drugs have placebo components that contribute to their overall treatment effect. Placebos are used in clinical trials as control groups to ascertain the net pharmacological effect of a drug candidate. Not only less well known but also relevant to rational therapeutics and personalized medicine is the nocebo. A nocebo effect occurs when an inert substance is administered in a context that induces negative expectations, worsening patients' symptoms. With the COVID-19 pandemic, there are high public expectations for new vaccines and medicines to end the contagion, while at the same time antiscience, post-truth, and antivaccine movements are worrisomely on the rise. These social movements, changes in public health cultures, and conditioned behavioral responses can trigger both placebo and nocebo effects. Hence, in clinical trials, forecasting and explaining placebo and nocebo variability are more important than ever for robust science and personalized health care. Against this overarching context, this article provides (1) a brief history of placebo and (2) a discussion on biology, mechanisms, and variability of placebo effects, and (3) discusses three emerging new concepts: placebogenomics, nocebogenomics, and augmented placebo, that is, the notion of a "placebo dose." We conclude with a roadmap for placebogenomics, its synergies with the nascent field of social pharmacology, and the ways in which a new taxonomy of drug and placebo variability can be anticipated in the next decade.


Asunto(s)
Ensayos Clínicos como Asunto , Efecto Placebo , Medicina de Precisión , Proyectos de Investigación , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/normas , Relación Dosis-Respuesta a Droga , Genómica/métodos , Humanos , Efecto Nocebo , Evaluación de Resultado en la Atención de Salud , Medicina de Precisión/métodos , Medicina de Precisión/normas
3.
Radiol Clin North Am ; 59(1): 129-138, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33222994

RESUMEN

Breast cancer screening is a recognized tool for early detection of the disease in asymptomatic women, improving treatment efficacy and reducing the mortality rate. There is raised awareness that a "one-size-fits-all" approach cannot be applied for breast cancer screening. Currently, despite specific guidelines for a minority of women who are at very high risk of breast cancer, all other women are still treated alike. This article reviews the current recommendations for breast cancer risk assessment and breast cancer screening in average-risk and higher-than-average-risk women. Also discussed are new developments and future perspectives for personalized breast cancer screening.


Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Mamografía/métodos , Medicina de Precisión/métodos , Mama/diagnóstico por imagen , Detección Precoz del Cáncer , Femenino , Humanos
4.
Eur J Epidemiol ; 35(12): 1115-1121, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33247797

RESUMEN

Risk prediction is one of the central goals of medicine. However, ultimate prediction-perfectly predicting whether individuals will actually get a disease-is still out of reach for virtually all conditions. One crucial assumption of ultimate personalized prediction is that individual risks in the relevant sense exist. In the present paper we argue that perfect prediction at the individual level will fail-and we will do so by providing pragmatic, epistemic, conceptual, and ontological arguments.


Asunto(s)
Medicina de Precisión/métodos , Ontologías Biológicas , Humanos , Filosofía , Valor Predictivo de las Pruebas , Probabilidad , Factores de Riesgo
5.
JAMA Netw Open ; 3(11): e2026921, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33211112

RESUMEN

Importance: Fragmented DNA is continuously released into the circulation following apoptosis and necrosis of both cancerous and noncancerous cells; when it is released by cancer cells, it is specifically known as circulating tumor DNA (ctDNA). Previous studies have suggested that ctDNA can reflect tumor burden and guide potential therapeutic targets. Objective: To determine the association of ctDNA with breast cancer disease-free survival (DFS) and progression-free survival in early, locally advanced, and metastatic breast cancer. Data Sources: An electronic search was conducted using the Cochrane Library, ScienceDirect, PubMed, and Embase from July 30, 2019, to October 31, 2019; all languages were included. The following search terms were used: ctDNA OR circulating tumor DNA OR liquid biopsy AND breast cancer OR breast carcinoma OR breast tumor AND prognosis OR survival. All titles were screened, and the appropriate abstracts were reviewed. If any data were missing, the authors contacted the study authors for permission to access data and extrapolate hazard ratios (HRs). Study Selection: To be included in the analysis, the studies had to meet the following prespecified inclusion criteria: (1) a ctDNA blood sample was measured; (2) DFS, progression-free survival, or relapse-free survival was reported as an HR; and (3) the patient population only had breast cancer. Retrospective and prospective observational cohort studies were included. Data Extraction and Synthesis: Two authors (C.C. and C.F.) independently reviewed the literature. All data were recorded independently by both authors and were compared at the end of the reviewing process to limit selection bias. Duplicates were removed and any disparities were clarified. Data were pooled using a fixed-effects or random-effects model according to the study heterogeneity. This study adhered to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE). Main Outcomes and Measures: The primary outcome was the association of ctDNA with DFS or relapse-free survival in breast cancer. Secondary outcomes focused on subgroup analysis in the setting of early breast cancer and metastatic breast cancer. Results: From a total of 263 publications found using the predefined search terms, data from 8 studies (3.0%) reporting on 739 patients in total were suitable for inclusion. Circulating tumor DNA gene variation detection (both before and after treatment) was statistically significantly associated with shorter DFS (HR, 4.44; 95% CI, 2.29-8.61; P < .001). Detection of ctDNA was statistically significantly associated with a reduction in DFS in both the early breast cancer subgroup (HR, 8.32; 95% CI, 3.01-22.99; P < .001) and the metastatic or locally advanced subgroup (HR, 1.91; 95% CI, 1.35-2.71; P < .001). Pretreatment and posttreatment plasma sample collection was analyzed in both early and metastatic groups. The posttreatment group encompassed both surgical and oncologic therapy. Pretreatment plasma detection of ctDNA was statistically significantly associated with reduced DFS (HR, 3.30; 95% CI, 1.98-5.52; P < .001). Posttreatment sampling of ctDNA failed to achieve statistical significance (HR, 8.17; 95% CI, 1.01-65.89; P = .05). Conclusions and Relevance: In this systematic review and meta-analysis, elevated plasma ctDNA was associated with a high risk of relapse. This finding suggests that plasma ctDNA may provide an excellent method to stratify risk and personalize patient follow-up.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , ADN Tumoral Circulante/genética , Cuidados Posteriores , Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , ADN Tumoral Circulante/sangre , Supervivencia sin Enfermedad , Femenino , Humanos , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Recurrencia Local de Neoplasia/genética , Estadificación de Neoplasias , Estudios Observacionales como Asunto , Medicina de Precisión/métodos , Pronóstico , Supervivencia sin Progresión , Estudios Prospectivos , Estudios Retrospectivos
7.
Rev Med Suisse ; 16(716): 2259-2263, 2020 Nov 25.
Artículo en Francés | MEDLINE | ID: mdl-33237643

RESUMEN

As a result of advances in pharmacogenomics (PGx), the paradigm that a single dose of a drug is extrapolated to an entire population is set to change. Personalising drug prescriptions according to individual genomic determinants would make it possible to increase the effectiveness and tolerance of treatments. In Switzerland, any doctor can prescribe validated PGx tests for five actionable drugs : abacavir, carbamazepine, thiopurines [azathioprine], fluoropyrimidines [5-FU, capecitabine] and irinotecan. Such an approach presupposes that PGx data are shared with trained clinicians and that prescribing aids can guide them.


Asunto(s)
Prescripciones de Medicamentos/normas , Genómica , Farmacogenética , Medicina de Precisión/métodos , Humanos , Médicos , Suiza
8.
PLoS One ; 15(11): e0242418, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33196659

RESUMEN

BACKGROUND: People with chronic conditions have complex healthcare needs that lead to challenges for adequate healthcare provision. Current healthcare services do not always respond adequately to their needs. A modular perspective, in particular providing visualization of the modular service architecture, is promising for improving the responsiveness of healthcare services to the complex healthcare needs of people with chronic conditions. The modular service architecture provides a comprehensive representation of the components and modules of healthcare provision. In this study, we explore this further in a qualitative multiple case study on healthcare provision for children with Down syndrome in the Netherlands. METHODS: Data collection for four cases involved 53 semi-structured interviews with healthcare professionals and 21 semi-structured interviews with patients (the parents of children with Down syndrome as proxy). In addition, we gathered data by means of practice observations and analysis of relevant documents. The interviews were audio-recorded, transcribed verbatim and analyzed utilizing the Miles and Huberman approach. RESULTS: Our study shows that the perspectives on healthcare provision of professionals and patients differ substantially. The visualization of the modular service architecture that was based on the healthcare professionals' perspective provided a complete representation of (para)medical outcomes relevant to the professionals' own discipline. In contrast, the modular service architecture based on the patients' perspective, which we define as a person-centered modular service architecture, provided a representation of the healthcare service that was primarily based on functional outcomes and the overall wellbeing of the patients. CONCLUSION: Our study shows that visualization of the modular service architecture can be a useful tool to better address the complex needs and requirements of people with a chronic condition. We suggest that a person-centered modular service architecture that focuses on functional outcomes and overall wellbeing, enables increased responsiveness of healthcare services to people with complex healthcare needs and provision of truly person-centered care.


Asunto(s)
Atención Integral de Salud/métodos , Prestación de Atención de Salud/métodos , Síndrome de Down/terapia , Niño , Enfermedad Crónica , Femenino , Instituciones de Salud/tendencias , Personal de Salud/tendencias , Humanos , Masculino , Países Bajos , Padres , Medicina de Precisión/métodos , Investigación Cualitativa
9.
Tumour Biol ; 42(10): 1010428320965284, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33028168

RESUMEN

Glucose, as the main consuming nutrient of the body, faces different destinies in cancer cells. Glycolysis, oxidative phosphorylation, and pentose phosphate pathways produce different glucose-derived metabolites and thus affect cells' bioenergetics differently. Tumor cells' dependency to aerobic glycolysis and other cancer-specific metabolism changes are known as the cancer hallmarks, distinct cancer cells from normal cells. Therefore, these tumor-specific characteristics receive the limelight as targets for cancer therapy. Glutamine, serine, and fatty acid oxidation together with 5-lipoxygenase are main pathways that have attracted lots of attention for cancer therapy. In this review, we not only discuss different tumor metabolism aspects but also discuss the metabolism roles in the promotion of cancer cells at different stages and their difference with normal cells. Besides, we dissect the inhibitors potential in blocking the main metabolic pathways to introduce the effective and non-effective inhibitors in the field.


Asunto(s)
Antineoplásicos/uso terapéutico , Metabolismo Energético/efectos de los fármacos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Medicina de Precisión , Antineoplásicos/farmacología , Ciclo del Ácido Cítrico/efectos de los fármacos , Metabolismo Energético/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Humanos , Terapia Molecular Dirigida/métodos , Neoplasias/etiología , Neoplasias/patología , Fosforilación Oxidativa/efectos de los fármacos , Vía de Pentosa Fosfato/efectos de los fármacos , Medicina de Precisión/métodos
10.
Medicine (Baltimore) ; 99(44): e22874, 2020 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-33126335

RESUMEN

BACKGROUND: Asymptomatic cryptococcal antigenemia is a state of cryptococcal infection commonly seen in immunocompromised HIV-infected persons. Without early intervention, a proportion of HIV-infected persons with cryptococcal antigenemia may go on to develop cryptococcosis, especially cryptococcal meningitis, which is associated with high mortality. The benefits of antifungal intervention and optimal therapeutic intervention regimens for HIV-infected persons with cryptococcal antigenemia remain controversial. We therefore designed the present study in order to investigate the necessity of, and the optimal regimens for antifungal intervention in the clinical management of cryptococcal antigenemia in HIV-infected populations. METHODS/DESIGN: This study will be an open-labeled, multi-center, prospective, randomized controlled trial, and 450 eligible participants will be randomized into a control arm and 2 intervention arms at a 1:1:1 ratio, with 150 subjects in each arm. Participants in the control arm will not receive antifungal treatment during the study period. Participants in intervention arm 1 will receive oral fluconazole 800 mg/day for 2 weeks, followed by 400 mg/day for 8 weeks and 200 mg/day for 42 weeks, and participants in intervention arm 2 will receive oral fluconazole 400 mg/day for 52 weeks. The primary outcome is the incidence of CM among the 3 groups during the study period. The secondary outcomes include the differences in all-cause mortality, proportion of patients reverting to blood CrAg negativity, change of CrAg titers, and adverse events among the 3 groups during the follow-up period. DISCUSSION: We envisage that the results of this study will reveal the necessity of, and the optimal therapeutic regimens for, antifungal intervention in clinical management of HIV-infected patients with cryptococcal antigenemia. TRIAL REGISTRATION: The study was registered as one of the 12 clinical trials under a general project at the Chinese Clinical Trial Registry on February 1, 2019, and the registration number of the general project is ChiCTR1900021195.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Protocolos Clínicos , Criptococosis/diagnóstico , Factores de Tiempo , Infecciones Oportunistas Relacionadas con el SIDA/etiología , Infecciones Oportunistas Relacionadas con el SIDA/fisiopatología , Síndrome de Inmunodeficiencia Adquirida/fisiopatología , Criptococosis/etiología , Criptococosis/fisiopatología , Femenino , Humanos , Masculino , Medicina de Precisión/métodos
11.
Proc Natl Acad Sci U S A ; 117(45): 28316-28327, 2020 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-33106429

RESUMEN

Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of copper: positron-emitting copper-64 (64Cu, t 1/2 = 12.7 h) and beta particle-emitting copper-67 (67Cu, t 1/2 = 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels-Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a 67Cu-labeled Tz radioligand ([67Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [67Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [67Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [64Cu]Cu-MeCOSar-Tz and [67Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz.


Asunto(s)
Radioisótopos de Cobre/farmacología , Radioisótopos de Cobre/uso terapéutico , Medicina de Precisión/métodos , Radioinmunoterapia/métodos , Animales , Anticuerpos , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Reacción de Cicloadición , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunoconjugados , Ratones , Ratones Desnudos , Tomografía de Emisión de Positrones/métodos , Radioisótopos/farmacología , Radioisótopos/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Surgery ; 168(6): 987-992, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33039110

RESUMEN

BACKGROUND: The Lombardy region suffered severely during the acute phase of the coronavirus disease 2019 outbreak in Italy (Mar-Apr 2020) with 16,000 diagnosed coronavirus disease 2019-related deaths (49% of the total coronavirus disease 2019-related deaths in Italy). In the area surrounding Pavia during the critical stage of the outbreak (Mar-Apr 2020), 1,225 of the documented 4,200 deaths were related to coronavirus disease 2019 infection, with a mortality rate of 181/100,000 inhabitants and an increase in deaths of 138% compared with the same period during previous years. Our aim was to report the experience of the Department of Vascular Surgery of Pavia (Lombardy, Italy), including the lessons learned and future perspectives regarding the management of coronavirus disease 2019 patients who developed severe acute ischemia with impending lower limb loss or deep vein thrombosis. MATERIALS AND METHODS: We carried out a retrospective data collection of coronavirus disease 2019 patients with severe acute ischemia of the lower limbs or deep vein thrombosis, which we observed in our department during the period March 1, 2020, to April 30, 2020. Primary outcomes of the analysis were postoperative mortality for all patients and amputation rates only in those coronavirus disease 2019 patients suffering from acute lower limb ischemia. Secondary outcomes were the prevalence of the disease among admitted coronavirus disease 2019 patients, and any possible correlation among inflammatory parameters, thrombolytic status, and the presence of acute ischemia or deep vein thrombosis. RESULTS: We observed 38 patients (28 male) with severe coronavirus disease 2019 infection (6 with lower limb arterial thrombosis and 32 with deep vein thrombosis). The median patient age was 64 years (range 30-94 y). In the arterial group, 3 had thrombosis on plaque and 3 on healthy arteries ("simple" arterial thrombosis). All underwent operative or hybrid (open/endo) revascularization; 1 patient died from major organ failure and 1 patient underwent major amputation. In the deep vein thrombosis group, 9 (28%) patients died from major organ failure, despite aggressive medical therapy. In patients with simple arterial thrombosis and those with deep vein thrombosis, we observed a decrease in inflammatory parameters (C-reactive protein) and in D-dimer and fibrinogen after aggressive therapy (P <.001). CONCLUSION: Our study confirms that critically ill, coronavirus disease 2019 patients who develop arterial and deep vein thrombosis have a high risk of mortality, but, if treated properly, there is an improvement in overall survival, especially in patients of 60 years of age or younger.


Asunto(s)
/complicaciones , Pandemias , Medicina de Precisión/métodos , Medición de Riesgo/métodos , Trombosis/etiología , Tromboembolia Venosa/etiología , Adulto , Anciano , Anciano de 80 o más Años , Arterias , Femenino , Estudios de Seguimiento , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Trombosis/epidemiología , Procedimientos Quirúrgicos Vasculares , Tromboembolia Venosa/epidemiología
13.
Bull Cancer ; 107(11): 1161-1170, 2020 Nov.
Artículo en Francés | MEDLINE | ID: mdl-33070953

RESUMEN

Genomic instability is one of the main properties of tumour development, promoting first the acquisition of genetic alterations and thus carcinogenesis. Then, the chronic and anarchic proliferation of cancer cells also supports and contributes to this instability allowing a continuous evolution of the tumour. The accumulation of mutations resulting from that instability contributes to tumour heterogeneity that occurs in a specific environment. The resulting diversity of oncogenic drivers further complicates the characterization of the origin of cancer cells dysfunction and consequently therapeutic decision. However, the consideration of the molecular context in oncology has initiated the development of targeted therapies. Based on the concept of oncogene addiction and synthetic lethality, these new drugs require the characterization and identification of specific tumour biomarkers. Targeted therapies have thus considerably optimized patient management, improving efficiency and quality of life while limiting the side effects observed with conventional chemotherapies. However, despite significant clinical benefits, some major limitations to their administration remain. The study of the current issues related to these new therapeutic molecules is becoming crucial for patient management towards an improvement of personalized medicine.


Asunto(s)
Inestabilidad Genómica , Terapia Molecular Dirigida , Neoplasias/genética , Neoplasias/terapia , Biomarcadores de Tumor/análisis , Carcinogénesis/genética , Proliferación Celular , Interacción Gen-Ambiente , Humanos , Mutación , Neoplasias/patología , Medicina de Precisión/métodos
14.
Urol Clin North Am ; 47(4): 469-474, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33008497

RESUMEN

Multiple immunologic platforms have provided minimal impact in patients with metastatic castration-resistant prostate cancer, necessitating that novel approaches continue to be developed. Although checkpoint inhibitors have been largely ineffective, there remain small cohorts of patients who have durable responses but lack the conventional indicators for response to this class of drugs, that is, high mutational burden or significant genomic alterations, as seen in other solid tumors. This article presents an update on the evolution of immunotherapeutics that target a more lethal form of prostate cancer and provides the groundwork for future considerations as to how this field should proceed.


Asunto(s)
Quinasas Ciclina-Dependientes/genética , Regulación Neoplásica de la Expresión Génica , Inmunoterapia/métodos , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/terapia , Anciano , Productos Biológicos/uso terapéutico , Vacunas contra el Cáncer/administración & dosificación , Quinasas Ciclina-Dependientes/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Fenotipo , Medicina de Precisión/métodos , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/patología , Análisis de Supervivencia , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos
15.
Urol Clin North Am ; 47(4): 523-536, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33008501

RESUMEN

Personalized medicine uses a patient's genotype, environment, and lifestyle choices to create a tailored diagnosis and therapy plan, with the goal of minimizing side effects, avoiding lost time with ineffective treatments, and guiding preventative strategies. Although most precision medicine strategies are still within the laboratory phase of development, this article reviews the promising technologies with the greatest potential to improve the diagnosis and treatment options for male infertility, including sperm cell transplantation, genomic editing, and new biomarker assays, based on the latest proteomic and epigenomic studies.


Asunto(s)
Genómica , Infertilidad Masculina/genética , Infertilidad Masculina/terapia , Medicina de Precisión/métodos , Biomarcadores/sangre , Terapia Combinada , Predicción , Humanos , Infertilidad Masculina/diagnóstico , Masculino , Proteómica , Medición de Riesgo , Resultado del Tratamiento
16.
Nat Commun ; 11(1): 5248, 2020 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-33067419

RESUMEN

Cancer has no borders: Generation and analysis of molecular data across multiple centers worldwide is necessary to gain statistically significant clinical insights for the benefit of patients. Here we conceived and standardized a proteotype data generation and analysis workflow enabling distributed data generation and evaluated the quantitative data generated across laboratories of the international Cancer Moonshot consortium. Using harmonized mass spectrometry (MS) instrument platforms and standardized data acquisition procedures, we demonstrate robust, sensitive, and reproducible data generation across eleven international sites on seven consecutive days in a 24/7 operation mode. The data presented from the high-resolution MS1-based quantitative data-independent acquisition (HRMS1-DIA) workflow shows that coordinated proteotype data acquisition is feasible from clinical specimens using such standardized strategies. This work paves the way for the distributed multi-omic digitization of large clinical specimen cohorts across multiple sites as a prerequisite for turning molecular precision medicine into reality.


Asunto(s)
Espectrometría de Masas/normas , Medicina de Precisión/normas , Línea Celular Tumoral , Femenino , Humanos , Espectrometría de Masas/métodos , Neoplasias Ováricas/química , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Medicina de Precisión/métodos , Proteoma/química , Proteoma/genética , Proteoma/metabolismo , Proteómica/métodos , Proteómica/normas , Estándares de Referencia , Flujo de Trabajo
17.
Med Sci (Paris) ; 36(10): 859-865, 2020 Oct.
Artículo en Francés | MEDLINE | ID: mdl-33026327

RESUMEN

Obesity is a complex, multifactorial disorder. About 5% of obese patients actually present with a monogenic form of obesity where only one mutation is sufficient to cause the disease. So far, the genes that have been found to be mutated in these monogenic forms play a key role in the leptin/melanocortin pathway which is mainly active in the hypothalamus and which regulates food intake and energy expenditure. Our laboratory has recently reported a novel monogenic form of obesity due to MRAP2 deficiency where, contrary to previously described monogenic forms of obesity, the carriers presented with hyperglycemia and hypertension in addition to obesity, suggesting that MRAP2 might play a pleiotropic role in metabolic tissues, in addition to its role in brain control of food intake and energy expenditure.


Asunto(s)
Regulación del Apetito/genética , Obesidad/genética , Animales , Predisposición Genética a la Enfermedad , Humanos , Leptina/genética , Leptina/metabolismo , Mutación/fisiología , Obesidad/patología , Obesidad/terapia , Medicina de Precisión/métodos , Medicina de Precisión/tendencias , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Receptor de Melanocortina Tipo 4/genética , Receptor de Melanocortina Tipo 4/metabolismo , Receptores de Leptina/genética , Receptores de Leptina/metabolismo
18.
Int J Nanomedicine ; 15: 7079-7096, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33061369

RESUMEN

Here, bismuth-based nanomaterials (Bi-based NMs) are introduced as promising theranostic agents to enhance image contrast as well as for the therapeutic gain for numerous diseases. However, understanding the interaction of such novel developed nanoparticles (NPs) within a biological environment is a requisite for the translation of any promising agent from the lab bench to the clinic. This interaction delineates the fate of NPs after circulation in the body. In an ideal setting, a nano-based therapeutic agent should be eliminated via the renal clearance pathway, meanwhile it should have specific targeting to a diseased organ to reach an effective dose and also to overcome off-targeting. Due to their clearance pathway, biodistribution patterns and pharmacokinetics (PK), Bi-based NMs have been found to play a determinative role to pass clinical approval and they have been investigated extensively in vivo to date. In this review, we expansively discuss the possible toxicity induced by Bi-based NMs on cells or organs, as well as biodistribution profiles, PK and the clearance pathways in animal models. A low cytotoxicity of Bi-based NMs has been found in vitro and in vivo, and along with their long-term biodistribution and proper renal clearance in animal models, the translation of Bi-based NMs to the clinic as a useful novel theranostic agent is promising to improve numerous medical applications.


Asunto(s)
Bismuto/farmacocinética , Bismuto/toxicidad , Nanoestructuras/toxicidad , Animales , Humanos , Nanopartículas del Metal/toxicidad , Medicina de Precisión/métodos , Distribución Tisular
19.
Am J Hum Genet ; 107(4): 589-595, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-33007198

RESUMEN

In the post-genomic era, genomic medicine interventions as a key component of personalized medicine and tailored-made health care are greatly anticipated following recent scientific and technological advances. Indeed, large-scale sequencing efforts that explore human genomic variation have been initiated in several, mostly developed, countries across the globe, such as the United States, the United Kingdom, and a few others. Here, we highlight the successful implementation of large-scale national genomic initiatives, namely the Genome of Greece (GoGreece) and the DNA do Brasil (DNABr), aiming to emphasize the importance of implementing such initiatives in developing countries. Based on this experience, we also provide a roadmap for replicating these projects in other low-resource settings, thereby bringing genomic medicine in these countries closer to clinical fruition.


Asunto(s)
Genética Médica/organización & administración , Genoma Humano , Genómica/organización & administración , Salud Única/legislación & jurisprudencia , Medicina de Precisión/métodos , Brasil , Países en Desarrollo , Grecia , Secuenciación de Nucleótidos de Alto Rendimiento/economía , Humanos , Salud Pública/métodos , Reino Unido , Estados Unidos
20.
PLoS Med ; 17(10): e1003363, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33001984

RESUMEN

BACKGROUND: Metastatic breast cancer (mBC) is a heterogenous disease with increasing availability of targeted therapies as well as emerging genomic markers of therapeutic resistance, necessitating timely and accurate molecular characterization of disease. As a minimally invasive test, analysis of circulating tumour DNA (ctDNA) is well positioned for real-time genomic profiling to guide treatment decisions. Here, we report the results of a prospective testing program established to assess the feasibility of ctDNA analysis to guide clinical management of mBC patients. METHODS AND FINDINGS: Two hundred thirty-four mBC patients (median age 54 years) were enrolled between June 2015 and October 2018 at the Peter MacCallum Cancer Centre, Melbourne, Australia. Median follow-up was 15 months (range 1-46). All patient samples at the time of enrolment were analysed in real time for the presence of somatic mutations. Longitudinal plasma testing during the course of patient management was also undertaken in a subset of patients (n = 67, 28.6%), according to clinician preference, for repeated molecular profiling or disease monitoring. Detection of somatic mutations from patient plasma was performed using a multiplexed droplet digital PCR (ddPCR) approach to identify hotspot mutations in PIK3CA, ESR1, ERBB2, and AKT1. In parallel, subsets of samples were also analysed via next-generation sequencing (targeted panel sequencing and low-coverage whole-genome sequencing [LC-WGS]). The sensitivity of ddPCR and targeted panel sequencing to identify actionable mutations was compared. Results were discussed at a multidisciplinary breast cancer meeting prior to treatment decisions. ddPCR and targeted panel sequencing identified at least 1 actionable mutation at baseline in 80/234 (34.2%) and 62/159 (39.0%) of patients tested, respectively. Combined, both methods detected an actionable alteration in 104/234 patients (44.4%) through baseline or serial ctDNA testing. LC-WGS was performed on 27 patients from the cohort, uncovering several recurrently amplified regions including 11q13.3 encompassing CCND1. Increasing ctDNA levels were associated with inferior overall survival, whether assessed by ddPCR, targeted sequencing, or LC-WGS. Overall, the ctDNA results changed clinical management in 40 patients including the direct recruitment of 20 patients to clinical trials. Limitations of the study were that it was conducted at a single site and that 31.3% of participants were lost to follow-up. CONCLUSION: In this study, we found prospective ctDNA testing to be a practical and feasible approach that can guide clinical trial enrolment and patient management in mBC.


Asunto(s)
Neoplasias de la Mama/genética , ADN Tumoral Circulante/genética , Metástasis de la Neoplasia/genética , Australia , Biomarcadores de Tumor/sangre , Ácidos Nucleicos Libres de Células/genética , ADN Tumoral Circulante/sangre , Fosfatidilinositol 3-Quinasa Clase I/genética , Estudios de Cohortes , Receptor alfa de Estrógeno/genética , Femenino , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa Multiplex/métodos , Mutación , Medicina de Precisión/métodos , Proteínas Proto-Oncogénicas c-akt/genética , Receptor ErbB-2/genética
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