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1.
Reprod Biomed Online ; 41(6): 1055-1069, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33032906

RESUMEN

RESEARCH QUESTION: What is the proportion of chromosomally abnormal spermatozoa in men with a history of reproductive failure, including patients with normal karyotype and carriers of translocations? Should this analysis be included in a clinical setting to define the best treatment options for infertile couples? DESIGN: Aneuploidy for chromosomes XY, 13, 15, 16, 17, 18, 21, 22 was tested by fluorescent in-situ hybridization (FISH) in 1665 samples from couples with normal karyotype having had at least three previous IVF failures, miscarriages, or both (group-A). A FISH test was also carried out in 76 samples from carriers of translocations (group B) to detect the proportion of spermatozoa with unbalanced rearrangement. RESULTS: In group A, the lowest incidence of aneuploid sperm cells was found in men with normozoospermia (1.3%, range 0.09-6.31%) compared with men with moderate oligoasthenoteratozoospermia (2.1%, range 0.41-16.6%, P < 0.001), severe oligoasthenoteratozoospermia (4.7%, range 0.53-30.77, P < 0.001), microepididymal sperm aspiration (3.1%, range 1.19-24.24, P < 0.001) and testicular sperm extraction samples (5.8%, range 1.54-33.3, P < 0.001). In group B, the proportion of spermatozoa with unbalanced rearrangement was significantly higher in reciprocal (63%, range 10.0-87.6%) than in Robertsonian translocations (16%, range 4.3-51.0%, P < 0.001). CONCLUSIONS: Patients with poor prognosis of term pregnancy tend to generate high proportions of chromosomally abnormal spermatozoa, especially in severe male factor cases. Corresponding frequencies occur at wide ranges; therefore, the FISH test is needed to assess the proportion of spermatozoa with altered chromosome condition. A flowchart, which included the FISH test, was designed to assist clinicians guide couples with poor prognosis of pregnancy, on the most indicated treatment options.


Asunto(s)
Aberraciones Cromosómicas , Infertilidad Masculina/genética , Espermatozoides/metabolismo , Adulto , Aneuploidia , Heterocigoto , Humanos , Hibridación Fluorescente in Situ , Infertilidad Masculina/diagnóstico , Infertilidad Masculina/patología , Cariotipificación , Masculino , Pronóstico , Técnicas Reproductivas Asistidas , Análisis de Semen , Espermatozoides/patología , Translocación Genética
2.
Int J Mol Sci ; 20(15)2019 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-31349607

RESUMEN

Molecular mechanisms governing cell fate decision events in bone marrow mesenchymal stromal cells (MSC) are still poorly understood. Herein, we investigated the homeobox gene Prep1 as a candidate regulatory molecule, by adopting Prep1 hypomorphic mice as a model to investigate the effects of Prep1 downregulation, using in vitro and in vivo assays, including the innovative single cell RNA sequencing technology. Taken together, our findings indicate that low levels of Prep1 are associated to enhanced adipogenesis and a concomitant reduced osteogenesis in the bone marrow, suggesting Prep1 as a potential regulator of the adipo-osteogenic differentiation of mesenchymal stromal cells. Furthermore, our data suggest that in vivo decreased Prep1 gene dosage favors a pro-adipogenic phenotype and induces a "browning" effect in all fat tissues.


Asunto(s)
Regulación de la Expresión Génica , Proteínas de Homeodominio/genética , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Adipogénesis/genética , Tejido Adiposo/diagnóstico por imagen , Tejido Adiposo/metabolismo , Animales , Médula Ósea/diagnóstico por imagen , Médula Ósea/metabolismo , Diferenciación Celular/genética , Biología Computacional/métodos , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas de Homeodominio/metabolismo , Ratones , Osteogénesis/genética , Análisis de la Célula Individual , Microtomografía por Rayos X
3.
Hum Reprod ; 33(9): 1767-1776, 2018 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-30085138

RESUMEN

STUDY QUESTION: Does preimplantation genetic testing for aneuploidy (PGT-A) by comprehensive chromosome screening (CCS) of the first and second polar body to select embryos for transfer increase the likelihood of a live birth within 1 year in advanced maternal age women aged 36-40 years planning an ICSI cycle, compared to ICSI without chromosome analysis? SUMMARY ANSWER: PGT-A by CCS in the first and second polar body to select euploid embryos for transfer does not substantially increase the live birth rate in women aged 36-40 years. WHAT IS KNOWN ALREADY: PGT-A has been used widely to select embryos for transfer in ICSI treatment, with the aim of improving treatment effectiveness. Whether PGT-A improves ICSI outcomes and is beneficial to the patients has remained controversial. STUDY DESIGN, SIZE, DURATION: This is a multinational, multicentre, pragmatic, randomized clinical trial with intention-to-treat analysis. Of 396 women enroled between June 2012 and December 2016, 205 were allocated to CCS of the first and second polar body (study group) as part of their ICSI treatment cycle and 191 were allocated to ICSI treatment without chromosome screening (control group). Block randomization was performed stratified for centre and age group. Participants and clinicians were blinded at the time of enrolment until the day after intervention. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile couples in which the female partner was 36-40 years old and who were scheduled to undergo ICSI treatment were eligible. In those assigned to PGT-A, array comparative genomic hybridization (aCGH) analysis of the first and second polar bodies of the fertilized oocytes was performed using the 24sure array of Illumina. If in the first treatment cycle all oocytes were aneuploid, a second treatment with PB array CGH was offered. Participants in the control arm were planned for ICSI without PGT-A. Main exclusion criteria were three or more previous unsuccessful IVF or ICSI cycles, three or more clinical miscarriages, poor response or low ovarian reserve. The primary outcome was the cumulative live birth rate after fresh or frozen embryo transfer recorded over 1 year after the start of the intervention. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 205 participants in the chromosome screening group, 50 (24%) had a live birth with intervention within 1 year, compared to 45 of the 191 in the group without intervention (24%), a difference of 0.83% (95% CI: -7.60 to 9.18%). There were significantly fewer participants in the chromosome screening group with a transfer (relative risk (RR) = 0.81; 95% CI: 0.74-0.89) and fewer with a miscarriage (RR = 0.48; 95% CI: 0.26-0.90). LIMITATIONS, REASONS FOR CAUTION: The targeted sample size was not reached because of suboptimal recruitment; however, the included sample allowed a 90% power to detect the targeted increase. Cumulative outcome data were limited to 1 year. Only 11 patients out of 32 with exclusively aneuploid results underwent a second treatment cycle in the chromosome screening group. WIDER IMPLICATIONS OF THE FINDINGS: The observation that the similarity in birth rates was achieved with fewer transfers, less cryopreservation and fewer miscarriages points to a clinical benefit of PGT-A, and this form of embryo selection may, therefore, be considered to minimize the number of interventions while producing comparable outcomes. Whether these benefits outweigh drawbacks such as the cost for the patient, the higher workload for the IVF lab and the potential effect on the children born after prolonged culture and/or cryopreservation remains to be shown. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the European Society of Human Reproduction and Embryology. Illumina provided microarrays and other consumables necessary for aCGH testing of polar bodies. M.B.'s institution (UZBrussel) has received educational grants from IBSA, Ferring, Organon, Schering-Plough, Merck and Merck Belgium. M.B. has received consultancy and speakers' fees from Organon, Serono Symposia and Merck. G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, IBSA, Glycotope, Abbott and Gedeon-Richter as well as personal fees from VitroLife, NMC Healthcare, ReprodWissen, BioSilu and ZIVA. W.V., C.S., P.M.B., V.G., G.A., M.D., T.E.G., L.G., G.Ka., G.Ko., J.L., M.C.M., M.P., A.S., M.T., K.V., J.G. and K.S. declare no conflict of interest. TRIAL REGISTRATION NUMBER: NCT01532284. TRIAL REGISTRATION DATE: 7 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 25 June 2012.


Asunto(s)
Aneuploidia , Hibridación Genómica Comparativa/métodos , Transferencia de Embrión/estadística & datos numéricos , Cuerpos Polares , Adulto , Tasa de Natalidad , Método Doble Ciego , Transferencia de Embrión/métodos , Femenino , Humanos , Infertilidad/terapia , Análisis de Intención de Tratar , Nacimiento Vivo/epidemiología , Embarazo , Factores de Riesgo , Inyecciones de Esperma Intracitoplasmáticas/métodos , Inyecciones de Esperma Intracitoplasmáticas/estadística & datos numéricos
4.
Reprod Biomed Online ; 28(1): 125-32, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24268726

RESUMEN

National legislations represent one of the main factors influencing access to assisted reproduction treatment. The Italian situation in the last decade is an example of how the treatment of patients for preimplantation genetic diagnosis (PGD) was more dependent on regulators than on medical choices. This report analysed how the changes in Italian regulation affected the number of PGD referrals to this study centre, as well as their decision to opt for cross-border reproductive care (CBRC). The analysis showed that during the period in which PGD was actually not performed because of the restriction imposed by the Italian law on IVF (from 24 February 2004 to 7 May 2009) there was a significant decrease in the number of referrals asking for PGD (2.5% of total referrals) compared with the previous years (3.3%; P < 0.025) and following years when PGD was legalized (5.1%; P < 0.001). The number of couples opting for CBRC had an opposite trend, reaching a maximum when PGD was banned from Italian centres (55 couples), whereas after the readmission of PGD, only eight couples went abroad for treatment. Concomitantly, since May 2009, the proportion of couples performing a PGD cycle in this centre has constantly increased.


Asunto(s)
Fertilización In Vitro/legislación & jurisprudencia , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/epidemiología , Turismo Médico/estadística & datos numéricos , Diagnóstico Preimplantación/estadística & datos numéricos , Femenino , Fertilización In Vitro/estadística & datos numéricos , Enfermedades Genéticas Congénitas/prevención & control , Humanos , Italia/epidemiología , Turismo Médico/legislación & jurisprudencia , Turismo Médico/tendencias , Embarazo , Derivación y Consulta/estadística & datos numéricos
5.
Cancer Res Commun ; 4(3): 919-937, 2024 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-38546390

RESUMEN

Lung cancer is the leading cause of cancer deaths. Lethal pulmonary adenocarcinomas (ADC) present with frequent mutations in the EGFR. Genetically engineered murine models of lung cancer expedited comprehension of the molecular mechanisms driving tumorigenesis and drug response. Here, we systematically analyzed the evolution of tumor heterogeneity in the context of dynamic interactions occurring with the intermingled tumor microenvironment (TME) by high-resolution transcriptomics. Our effort identified vulnerable tumor-specific epithelial cells, as well as their cross-talk with niche components (endothelial cells, fibroblasts, and tumor-infiltrating immune cells), whose symbiotic interface shapes tumor aggressiveness and is almost completely abolished by treatment with Unesbulin, a tubulin binding agent that reduces B cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) activity. Simultaneous magnetic resonance imaging (MRI) analysis demonstrated decreased tumor growth, setting the stage for future investigations into the potential of novel therapeutic strategies for EGFR-mutant ADCs. SIGNIFICANCE: Targeting the TME is an attractive strategy for treatment of solid tumors. Here we revealed how EGFR-mutant landscapes are affected at the single-cell resolution level during Unesbulin treatment. This novel drug, by targeting cancer cells and their interactions with crucial TME components, could be envisioned for future therapeutic advancements.


Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Ratones , Células Endoteliales , Microambiente Tumoral/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Comunicación Celular , Receptores ErbB/genética
6.
J Cell Physiol ; 228(4): 879-89, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23018864

RESUMEN

Human stromal stem cell populations reside in different tissues and anatomical sites, however a critical question related to their efficient use in regenerative medicine is whether they exhibit equivalent biological properties. Here, we compared cellular and molecular characteristics of stromal stem cells derived from the bone marrow, at different body sites (iliac crest, sternum, and vertebrae) and other tissues (dental pulp and colon). In particular, we investigated whether homeobox genes of the HOX and TALE subfamilies might provide suitable markers to identify distinct stromal cell populations, as HOX proteins control cell positional identity and, together with their co-factors TALE, are involved in orchestrating differentiation of adult tissues. Our results show that stromal populations from different sources, although immunophenotypically similar, display distinct HOX and TALE signatures, as well as different growth and differentiation abilities. Stromal stem cells from different tissues are characterized by specific HOX profiles, differing in the number and type of active genes, as well as in their level of expression. Conversely, bone marrow-derived cell populations can be essentially distinguished for the expression levels of specific HOX members, strongly suggesting that quantitative differences in HOX activity may be crucial. Taken together, our data indicate that the HOX and TALE profiles provide positional, embryological and hierarchical identity of human stromal stem cells. Furthermore, our data suggest that cell populations derived from different body sites may not represent equivalent cell sources for cell-based therapeutical strategies for regeneration and repair of specific tissues.


Asunto(s)
Diferenciación Celular/genética , Genes Homeobox , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , Células del Estroma/citología , Células del Estroma/fisiología , Células de la Médula Ósea/citología , Pulpa Dental/citología , Expresión Génica , Proteínas de Homeodominio/genética , Humanos , Células del Estroma/metabolismo
7.
Eur Spine J ; 22 Suppl 6: S979-84, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24061975

RESUMEN

PURPOSE: Due to their properties and characteristics human mesenchymal stem cells (MSCs) appear to have great therapeutic potential. Many different populations of MSCs have been described and to understand whether they have equivalent biological properties is a critical issue for their therapeutic application. METHODS: We proposed to analyze the in vitro growth kinetics of MSCs derived from different body sites (iliac crest bone marrow, vertebrae bone marrow, colon mucosa, dental pulp). RESULTS: Mesenchymal stem cells derived from vertebrae can be maintained in culture for a greater number of steps and they also generate mature cells of all mesenchymal lineages with greater efficiency, when induced into osteogenic, adipogenic and chondrogenic differentiation. CONCLUSIONS: The ability of vertebrae-derived MSCs in terms of expansion and differentiation is very interesting at the light of a clinical application for bone fusion in spine surgery.


Asunto(s)
Células de la Médula Ósea/citología , Células Madre Mesenquimatosas/citología , Columna Vertebral/citología , Diferenciación Celular , Células Cultivadas , Humanos
8.
J Cell Mol Med ; 15(1): 63-71, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19912439

RESUMEN

Experimental data suggest that cell-based therapies may be useful for cardiac regeneration following ischaemic heart disease. Bone marrow (BM) cells have been reported to contribute to tissue repair after myocardial infarction (MI) by a variety of humoural and cellular mechanisms. However, there is no direct evidence, so far, that BM cells can generate cardiac stem cells (CSCs). To investigate whether BM cells contribute to repopulate the Kit(+) CSCs pool, we transplanted BM cells from transgenic mice, expressing green fluorescent protein under the control of Kit regulatory elements, into wild-type irradiated recipients. Following haematological reconstitution and MI, CSCs were cultured from cardiac explants to generate 'cardiospheres', a microtissue normally originating in vitro from CSCs. These were all green fluorescent (i.e. BM derived) and contained cells capable of initiating differentiation into cells expressing the cardiac marker Nkx2.5. These findings indicate that, at least in conditions of local acute cardiac damage, BM cells can home into the heart and give rise to cells that share properties of resident Kit(+) CSCs.


Asunto(s)
Células de la Médula Ósea/citología , Diferenciación Celular , Cardiopatías/cirugía , Miocitos Cardíacos/fisiología , Miocitos Cardíacos/trasplante , Células Madre/fisiología , Animales , Animales Recién Nacidos , Western Blotting , Células de la Médula Ósea/metabolismo , Femenino , Cardiopatías/patología , Ratones , Ratones Transgénicos , ARN Mensajero/genética , Regeneración , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
9.
Commun Biol ; 4(1): 370, 2021 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-33854168

RESUMEN

Lung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas.


Asunto(s)
Bencimidazoles/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Células Epiteliales/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Pirazinas/farmacología , Células A549 , Animales , Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Terapia Molecular Dirigida , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , RNA-Seq , Análisis de la Célula Individual , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Haematologica ; 94(3): 318-25, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19181779

RESUMEN

BACKGROUND: The transcriptional regulation of stem cell genes is still poorly understood. Kit, encoding the stem cell factor receptor, is a pivotal molecule for multiple types of stem/progenitor cells. We previously generated mouse lines expressing transgenic green fluorescent protein under the control of Kit promoter/first intron regulatory elements, and we demonstrated expression in hematopoietic progenitors. DESIGN AND METHODS: In the present work we investigated whether the transgene is also expressed in hematopoietic stem cells of adult bone marrow and fetal liver. To this purpose, we tested, in long-term repopulating assays, cell fractions expressing different levels of green fluorescent protein within Kit-positive or SLAM-selected populations. RESULTS: The experiments demonstrated transgene expression in both fetal and adult hematopoietic stem cells and indicated that the transgene is transcribed at distinctly lower levels in hematopoietic stem cells than in pluripotent and committed progenitors. CONCLUSIONS: These results, together with previous data, show that a limited subset of DNA sequences drives gene expression in number of stem cell types (hematopoietic stem cells, primordial germ cells, cardiac stem cells). Additionally, our results might help to further improve high level purification of hematopoietic stem cells for experimental purposes. Finally, as the Kit/green fluorescent protein transgene is expressed in multiple stem cell types, our transgenic model provides powerful in vivo system to track these cells during development and tissue regeneration.


Asunto(s)
Proteínas Fluorescentes Verdes/metabolismo , Células Madre Hematopoyéticas/metabolismo , Proteínas Proto-Oncogénicas c-kit/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Animales , Médula Ósea/metabolismo , Trasplante de Médula Ósea , Separación Celular , Ensayo de Unidades Formadoras de Colonias , Femenino , Citometría de Flujo/métodos , Proteínas Fluorescentes Verdes/genética , Células Madre Hematopoyéticas/citología , Hígado/embriología , Hígado/metabolismo , Masculino , Ratones , Ratones Transgénicos , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo
11.
Sci Rep ; 7(1): 15573, 2017 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-29138456

RESUMEN

Transcriptional regulators are crucial in adipocyte differentiation. We now show that the homeodomain-containing transcription factor Prep1 is a repressor of adipogenic differentiation since its down-regulation (DR) in both ex vivo bone marrow-derived mesenchymal stromal cells (MSC) and in vitro 3T3-L1 preadipocytes significantly increases their adipogenic differentiation ability. Prep1 acts at a stage preceding the activation of the differentiation machinery because its DR makes cells more prone to adipogenic differentiation even in the absence of the adipogenic inducers. Prep1 DR expands the DNA binding landscape of C/EBPß (CCAAT enhancer binding protein ß) without affecting its expression or activation. The data indicate that Prep1 normally acts by restricting DNA binding of transcription factors to adipogenic enhancers, in particular C/EBPß.


Asunto(s)
Adipogénesis/genética , Proteína beta Potenciadora de Unión a CCAAT/genética , Diferenciación Celular/genética , Proteínas de Homeodominio/genética , Células 3T3-L1 , Adipocitos/citología , Adipocitos/metabolismo , Animales , Células de la Médula Ósea/citología , Proteínas de Unión al ADN/genética , Elementos de Facilitación Genéticos/genética , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/patología , Ratones
13.
Eur J Obstet Gynecol Reprod Biol ; 207: 211-213, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27832922

RESUMEN

Infertility is a condition affecting an increasing number of individuals all over the world. In recent years, this phenomenon has spread across both western countries and developing countries, thus developing the features of a pandemic. For this reason, the World Health Organization (WHO) acknowledged that infertility should be considered a disease to all intents and purposes, as it diminishes the health and wellbeing of the individuals who suffers from it. At present, the most effective means to contain the spread of infertility are essentially prevention and Assisted Reproductive Technologies (ART). With reference to the latter, although most of these techniques are routinely used in the majority of countries, they are still subject to medical, ethical and political debates. There are huge variations noted when the regulatory legislation adopted by different countries to govern infertility treatment in various countries all over the world are reviewed. In fact, it has to be recognized that ART legislation depends on a variety of factors, such as social structure, political choices, ethical issues and religious beliefs. This makes it apparently impossible to create a standard regulation for different countries, especially in case of controversial issues like gamete and embryo donation, embryo cryopreservation or surrogacy.


Asunto(s)
Infertilidad Femenina/terapia , Infertilidad Masculina/terapia , Técnicas Reproductivas Asistidas , Adulto , Criopreservación/ética , Ectogénesis/ética , Transferencia de Embrión/efectos adversos , Transferencia de Embrión/ética , Embrión de Mamíferos , Europa (Continente) , Femenino , Conocimientos, Actitudes y Práctica en Salud , Accesibilidad a los Servicios de Salud/ética , Accesibilidad a los Servicios de Salud/legislación & jurisprudencia , Transición de la Salud , Humanos , Legislación Médica , Masculino , Embarazo , Religión , Derechos Sexuales y Reproductivos/educación , Derechos Sexuales y Reproductivos/legislación & jurisprudencia , Técnicas Reproductivas Asistidas/efectos adversos , Técnicas Reproductivas Asistidas/ética , Técnicas Reproductivas Asistidas/legislación & jurisprudencia , Técnicas Reproductivas Asistidas/normas , Madres Sustitutas , Obtención de Tejidos y Órganos/ética , Obtención de Tejidos y Órganos/legislación & jurisprudencia , Organización Mundial de la Salud
14.
Sci Transl Med ; 8(350): 350ra104, 2016 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-27488898

RESUMEN

Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPα (CCAAT/enhancer binding protein α) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBPα suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBPα expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBPα expression and positive expression of the oncogenic protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) have prognostic value. We also generated a lung-specific mouse model of C/EBPα deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBPα-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBPα is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBPα loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBPα and high BMI1.


Asunto(s)
Adenocarcinoma/patología , Adenocarcinoma/terapia , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Complejo Represivo Polycomb 1/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma del Pulmón , Animales , Proteína alfa Potenciadora de Unión a CCAAT/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Noqueados , Mutación/genética , Complejo Represivo Polycomb 1/genética , Proteínas Proto-Oncogénicas/genética
15.
J Histochem Cytochem ; 53(3): 273-6, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15750000

RESUMEN

The positions of chromosomes 18 and X fluorescence in situ hybridization signals were analyzed in blastomeres generated from human in vitro fertilization 3- to 4-day-old embryos after preimplantation screening of aneuploidy of chromosomes 13, 16, 18, 21, 22, X, and Y. Fluorescent signal localization compared with a three-dimensional sphere model of random signal distribution revealed significant differences, providing evidence of peripheral localization of chromosome 18 in aneuploid (p=0.0013) and aneuploid/euploid blastomeres (p=0.0011). No differences were found in localization of chromosome 18 in euploid and in chromosome X in euploid and aneuploid blastomeres.


Asunto(s)
Blastómeros/ultraestructura , Cromosomas Humanos Par 18 , Cromosomas Humanos X , Adulto , Aneuploidia , Blastocisto/ultraestructura , Núcleo Celular/ultraestructura , Femenino , Humanos , Hibridación Fluorescente in Situ , Diagnóstico Preimplantación
16.
Fertil Steril ; 104(2): 333-8, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26051093

RESUMEN

OBJECTIVE: To validate the use of clomiphene citrate in IVF when mild stimulation approaches are chosen to reduce patient discomfort, risk, and cost. DESIGN: Prospective cohort study. SETTING: Private IVF clinic. PATIENT(S): A total of 163 patients undergoing IVF and with a good prognosis (defined as ≤38 years old with normal ovarian reserve and normovulatory cycles, body mass index <29 kg/m(2), no previous assisted reproductive technology cycles, no severe endometriosis, no history of recurrent miscarriage, no endocrine/autoimmune diseases, and no surgical semen extraction). INTERVENTION(S): Mild stimulation using a fixed protocol of clomiphene citrate (100 mg/d from cycle days 3 to 7) in combination with low doses of gonadotropins (150 IU of recombinant FSH on cycle days 5, 7, and 9) and GnRH antagonist. MAIN OUTCOME MEASURE(S): The cumulative delivery rate per patient after three fresh and/or frozen embryo transfers and time to pregnancy. RESULT(S): No dropouts were observed. The cumulative delivery rate was 70%, and the mean time to pregnancy was 2.4 months. CONCLUSION(S): Mild stimulation using clomiphene citrate in combination with low doses of gonadotropins can be considered a realistic option for good-prognosis patients undergoing IVF.


Asunto(s)
Clomifeno/administración & dosificación , Fármacos para la Fertilidad Femenina/administración & dosificación , Fertilización In Vitro/métodos , Inducción de la Ovulación/métodos , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Embarazo , Índice de Embarazo/tendencias , Estudios Prospectivos
17.
Biomed Res Int ; 2014: 926172, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25197669

RESUMEN

INTRODUCTION: Poor response to ovarian stimulation is still a major problem in IVF. The study presents a new stimulation protocol evaluated in a suppopulation of very difficult young poor ovarian responders. MATERIAL AND METHODS: The study consists in two sections. The first includes data from a randomized controlled study involving forty-three young patients with a poor ovarian response in at least two previous cycles (intended as cycle cancellation or with ≤3 collected oocytes). Patients were randomized in two groups: group A (control) received FSH (400 IU/day), while group B received the new stimulation protocol consisting in a sequential association of 150 IU r-LH for 4 days followed by 400 IU r-FSH/after downregulation with daily GnRh agonist. The second includes data from the overall results in 65 patients treated with the new protocol compared to their previous performance with conventional cycles (historical control). RESULTS: Both in the RCT and in the historical control study, LH pretreatment was able to decrease the cancellation rate, to improve the in vitro performance, and to significantly increase the live birth rates. CONCLUSIONS: LH pretreatment improved oocyte quantity and quality in young repeated poor responders selected in accordance with the Bologna criteria.


Asunto(s)
Fertilización In Vitro , Hormona Luteinizante/farmacología , Adulto , Femenino , Hormona Folículo Estimulante/farmacología , Humanos , Ovario/efectos de los fármacos , Inducción de la Ovulación , Resultado del Tratamiento
18.
Asian J Androl ; 14(4): 591-8, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22543677

RESUMEN

The objective of this study was to investigate whether medical therapy can reduce sperm aneuploidy levels and improve the results of intracytoplasmic sperm injection (ICSI) in patients with severe idiopathic oligoasthenoteratospermia (OAT). Thirty-three infertile couples requiring ICSI because of severe idiopathic OAT after at least one unsuccessful ICSI cycle were considered. Semen parameters (concentration, motility and morphology), the percentage of aneuploid sperm and the results of ICSI (the number of oocytes fertilized, embryos transferred, biochemical pregnancies, clinical pregnancies and live births) were compared before and after a 3-month course of treatment with L-carnitine 1 g given twice per day+acetyl-L-carnitine 500 mg given twice per day+one 30-mg cinnoxicam tablet every 4 days. Aneuploidy was assessed using fluorescent in situ hybridisation (FISH) performed on chromosomes X, Y, 13, 15, 16, 17, 18, 21 and 22. The results showed that 22 of the 33 patients had a reduced frequency of aneuploid sperm and improved sperm morphology after treatment (group 1), and 11 showed no change (group 2). The numbers of biochemical pregnancies, clinical pregnancies and live births were significantly higher in group 1 than in group 2. No significant difference was found between the groups regarding the numbers of oocytes fertilized and embryos transferred. The side effects were negligible. The numbers of ICSI pregnancies and live births in severe idiopathic OAT patients improved with a course of L-carnitine, acetyl-L-carnitine and cinnoxicam.


Asunto(s)
Aneuploidia , Astenozoospermia/tratamiento farmacológico , Infertilidad Masculina/tratamiento farmacológico , Oligospermia/tratamiento farmacológico , Espermatozoides/citología , Espermatozoides/efectos de los fármacos , Adulto , Carnitina/uso terapéutico , Distribución de Chi-Cuadrado , Inhibidores de la Ciclooxigenasa/uso terapéutico , Femenino , Humanos , Masculino , Piroxicam/análogos & derivados , Piroxicam/uso terapéutico , Embarazo , Resultado del Embarazo , Índice de Embarazo , Recuento de Espermatozoides , Inyecciones de Esperma Intracitoplasmáticas , Motilidad Espermática , Estadísticas no Paramétricas , Complejo Vitamínico B/uso terapéutico
19.
Fertil Steril ; 97(5): 1067-1073.e1, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22386843

RESUMEN

OBJECTIVE: To evaluate the effects on human spermatozoa of freeze-drying, also known as lyophilization, and of cryopreservation in liquid nitrogen. DESIGN: Prospective experimental study. SETTING: Reproductive medicine unit and a private IVF center. PATIENT(S): Thirty healthy male donors. INTERVENTION(S): Sperm samples from 30 donors divided as two aliquots, one to be lyophilized and the other to be cryopreserved in liquid nitrogen. MAIN OUTCOME MEASURE(S): Assessment of count, motility, morphology, viability, DNA integrity, chromosomal status, and birefringence properties of lyophilized and cryopreserved human spermatozoa compared with the same parameters in the fresh sample. RESULT(S): Although sperm viability and motility were totally compromised after freeze-drying, the sperm chromatin structure was not altered in comparison with fresh samples, which demonstrated that the procedure did not affect DNA integrity. The sperm-head inner protoplasmic structures were also preserved, which was estimated by assessing the corresponding birefringence characteristics. After cryopreservation with liquid nitrogen, the motility, viability, and DNA integrity of spermatozoa were statistically significantly reduced compared with the fresh samples; the proportion of sperm cells with abnormal head birefringence increased meaningfully. CONCLUSION(S): The process of freeze-drying deeply damages cell membranes; however, unlike with liquid nitrogen preservation, it does not affect DNA integrity.


Asunto(s)
Ensamble y Desensamble de Cromatina , Criopreservación/métodos , Daño del ADN , Liofilización , Nitrógeno , Espermatozoides/patología , Adulto , Aneuploidia , Birrefringencia , Membrana Celular/patología , Supervivencia Celular , Humanos , Hibridación Fluorescente in Situ , Masculino , Nitrógeno/efectos adversos , Estudios Prospectivos , Recuento de Espermatozoides , Motilidad Espermática
20.
Biol Reprod ; 79(4): 667-73, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18562708

RESUMEN

Interdependence between sperm concentration, motility, morphology, and the percentage of aneuploid sperm was explored to test whether oligoasthenoteratospermia (OAT) may have a multiple origin in idiopathic infertile males. A total of 174 men (age, 35.8 +/- 4.3 yr) with idiopathic infertility were studied. Seven patients had nonobstructive azoospermia, 55 had severe OAT, 30 had OAT, 27 had isolated alterations of motility, 45 had alterations of morphology and of motility, and 10 had isolated alterations of morphology. The sperm morphology was assessed with strict criteria. The percentage of aneuploid sperm was assessed with fluorescent in situ hybridization for chromosomes X, Y, 13, 15, 16, 17, 18, 21, and 22. Relationships between sperm features, and the relationship between sperm features and aneuploidies were analyzed with multivariate regression analysis. Statistical analysis did not find any significant relationship between the percentage of typical forms and sperm concentration or between morphology and motility. On the other hand, a positive and significant relationship was found between sperm concentration and motility. The percentage of aneuploid sperm was inversely and significantly related to the percentage of typical forms but not to motility and concentration. Sperm morphology is an independent characteristic with respect to concentration and motility, whereas it showed a significant inverse relationship with respect to the percentage of aneuploid sperm. This means that idiopathic OAT may occur by means of at least two independent pathways, the first affecting concentration and/or motility and the second affecting morphology.


Asunto(s)
Astenozoospermia/complicaciones , Genes del Desarrollo/fisiología , Infertilidad Masculina/genética , Oligospermia/complicaciones , Adulto , Aneuploidia , Azoospermia/genética , Análisis Citogenético , Humanos , Infertilidad Masculina/etiología , Masculino , Recuento de Espermatozoides , Motilidad Espermática/genética
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