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1.
J Mol Diagn ; 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38925456

RESUMO

PMS2 is one of the DNA-mismatch repair genes included in routine genetic testing for Lynch syndrome and colorectal, ovarian, and endometrial cancers. PMS2 is also included in the American College of Medical Genetics and Genomics' List of Secondary Findings Genes in the context of clinical exome and genome sequencing. However, sequencing of PMS2 by short-read-based next-generation sequencing technologies is complicated by the presence of the pseudogene PMS2CL, and is often supplemented by long-range-based approaches, such as long-range PCR or long-read-based next-generation sequencing, which increases the complexity and cost. This article describes a bioinformatics homology triage workflow that can eliminate the need for long-read-based testing for PMS2 in the vast majority of patients undergoing exome sequencing, thus simplifying PMS2 testing and reducing the associated cost.

2.
Clin Auton Res ; 33(4): 533-537, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37294472

RESUMO

INTRODUCTION: The interplay between the sympathetic and parasympathetic branches of the autonomic nervous system contribute to adequate hemodynamic responses to stressors, reflected by the variation in intervals between heart beats, known as heart rate variability. The sex hormones estrogen and progesterone have been shown to affect autonomic function. The extent to which autonomic function may vary between different hormone phases of the natural menstrual cycle and how this relationship may differ in women taking oral contraceptives has yet to be fully elucidated. PURPOSE: To investigate differences in heart rate variability between the early follicular and early luteal phases of the menstrual cycle in naturally menstruating women and in oral contraceptive pill users. METHODS: Twenty-two young (22 ± 3 years), healthy women who were naturally menstruating or taking oral contraceptive pills participated in this study. Heart rate variability was measured at rest and during two sympathomimetic stressors: isometric handgrip exercise and cold pressor test. RESULTS: The proportion of successive NN intervals that differ by more than 50 ms was higher in oral contraceptive pill users during the placebo pill phase. Absolute high-frequency power was higher in the naturally menstruating women during the early luteal phase, relative to the early follicular phase. Other indices of vagal modulation were not different at rest or during sympathetic activation between hormone phases or groups. CONCLUSIONS: Vagal modulation may be increased in the early luteal menstrual cycle phase. Further,oral contraceptive use does not appear to adversely affect this modulation in young, healthy women.


Assuntos
Força da Mão , Menstruação , Humanos , Feminino , Frequência Cardíaca , Ciclo Menstrual/fisiologia , Anticoncepcionais Orais/efeitos adversos , Hormônios
3.
J Hepatol ; 79(2): 378-393, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37061197

RESUMO

BACKGROUND & AIMS: The prevalence of non-alcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) is rising rapidly, yet its underlying mechanisms remain unclear. Herein, we aim to determine the role of hypoxia-inducible lipid droplet associated protein (HILPDA)/hypoxia-inducible gene 2 (HIG2), a selective inhibitor of intracellular lipolysis, in NASH-driven HCC. METHODS: The clinical significance of HILPDA was assessed in human NASH-driven HCC specimens by immunohistochemistry and transcriptomics analyses. The oncogenic effect of HILPDA was assessed in human HCC cells and in 3D epithelial spheroids upon exposure to free fatty acids and either normoxia or hypoxia. Lipidomics profiling of wild-type and HILPDA knockout HCC cells was assessed via shotgun and targeted approaches. Wild-type (Hilpdafl/fl) and hepatocyte-specific Hilpda knockout (HilpdaΔHep) mice were fed a Western diet and high sugar in drinking water while receiving carbon tetrachloride to induce NASH-driven HCC. RESULTS: In patients with NASH-driven HCC, upregulated HILPDA expression is strongly associated with poor survival. In oxygen-deprived and lipid-loaded culture conditions, HILPDA promotes viability of human hepatoma cells and growth of 3D epithelial spheroids. Lack of HILPDA triggered flux of polyunsaturated fatty acids to membrane phospholipids and of saturated fatty acids to ceramide synthesis, exacerbating lipid peroxidation and apoptosis in hypoxia. The apoptosis induced by HILPDA deficiency was reversed by pharmacological inhibition of ceramide synthesis. In our experimental mouse model of NASH-driven HCC, HilpdaΔHep exhibited reduced hepatic steatosis and tumorigenesis but increased oxidative stress in the liver. Single-cell analysis supports a dual role of hepatic HILPDA in protecting HCC cells and facilitating the establishment of a pro-tumorigenic immune microenvironment in NASH. CONCLUSIONS: Hepatic HILPDA is a pivotal oncometabolic factor in the NASH liver microenvironment and represents a potential novel therapeutic target. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH, chronic metabolic liver disease caused by buildup of fat, inflammation and damage in the liver) is emerging as the leading risk factor and the fastest growing cause of hepatocellular carcinoma (HCC), the most common form of liver cancer. While curative therapeutic options exist for HCC, it frequently presents at a late stage when such options are no longer effective and only systemic therapies are available. However, systemic therapies are still associated with poor efficacy and some side effects. In addition, no approved drugs are available for NASH. Therefore, understanding the underlying metabolic alterations occurring during NASH-driven HCC is key to identifying new cancer treatments that target the unique metabolic needs of cancer cells.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/metabolismo , Ceramidas/metabolismo , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Hipóxia/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Microambiente Tumoral
4.
Sci Total Environ ; 878: 162832, 2023 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-36924960

RESUMO

Marine sponges play important roles in benthic ecosystems. More than providing shelter and food to other species, they help maintain water quality by regulating nitrogen and ammonium levels in the water, and bioaccumulate heavy metals. This system, however, is particularly sensitive to sudden environmental changes including catastrophic pollution event such as oil spills. Hundreds of oil platforms are currently actively extracting oil and gas in the Gulf of Mexico. To test the vulnerability of the benthic ecosystems to oil spills, we utilized the Caribbean reef sponge, Cinachyrella alloclada, as a novel experimental indicator. We have exposed organisms to crude oil and oil dispersant for up to 24 h and measured resultant gene expression changes. Our findings indicate that 1-hour exposure to water accommodated fractions (WAF) was enough to elicit massive shifts in gene expression in sponges and host bacterial communities (8052 differentially expressed transcripts) with the up-regulation of stress related pathways, cancer related pathways, and cell integrity pathways. Genes that were upregulated included heat shock proteins, apoptosis, oncogenes (Rab/Ras, Src, CMYC), and several E3 ubiquitin ligases. 24-hour exposure of chemically enhanced WAF (CE-WAF) had the greatest impact to benthic communities, resulting in mostly downregulation of gene expression (4248 differentially expressed transcripts). Gene deregulation from 1-hour treatments follow this decreasing trend of toxicity: WAF > CE-WAF > Dispersant, while the 24-hour treatment showed a shift to CE-WAF > Dispersant > WAF in our experiments. Thus, this study supports the development of Cinachyrella alloclada as a research model organism and bioindicator species for Florida reefs and underscores the importance of developing more efficient and safer ways to remove oil in the event of a spill catastrophe.


Assuntos
Poluição por Petróleo , Petróleo , Poríferos , Poluentes Químicos da Água , Animais , Petróleo/toxicidade , Ecossistema , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/análise
5.
J Clin Invest ; 130(3): 1185-1198, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31770109

RESUMO

High levels of ecto-5'-nucleotidase (CD73) have been implicated in immune suppression and tumor progression, and have also been observed in cancer patients who progress on anti-PD-1 immunotherapy. Although regulatory T cells can express CD73 and inhibit T cell responses via the production of adenosine, less is known about CD73 expression in other immune cell populations. We found that tumor-infiltrating NK cells upregulate CD73 expression and the frequency of these CD73-positive NK cells correlated with larger tumor size in breast cancer patients. In addition, the expression of multiple alternative immune checkpoint receptors including LAG-3, VISTA, PD-1, and PD-L1 was significantly higher in CD73-positive NK cells than in CD73-negative NK cells. Mechanistically, NK cells transport CD73 in intracellular vesicles to the cell surface and the extracellular space via actin polymerization-dependent exocytosis upon engagement of 4-1BBL on tumor cells. These CD73-positive NK cells undergo transcriptional reprogramming and upregulate IL-10 production via STAT3 transcriptional activity, suppressing CD4-positive T cell proliferation and IFN-γ production. Taken together, our results support the notion that tumors can hijack NK cells as a means to escape immunity and that CD73 expression defines an inducible population of NK cells with immunoregulatory properties within the tumor microenvironment.


Assuntos
5'-Nucleotidase/imunologia , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Evasão Tumoral , Microambiente Tumoral/imunologia , Ligante 4-1BB/imunologia , Proteínas Ligadas por GPI/imunologia , Humanos , Células K562 , Células Matadoras Naturais/patologia , Linfócitos do Interstício Tumoral/patologia , Neoplasias/patologia
6.
Nature ; 498(7453): 246-50, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23728299

RESUMO

DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.


Assuntos
Montagem e Desmontagem da Cromatina , Cromatina/metabolismo , Dano ao DNA , Proteínas Nucleares/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Acetilação , Adenosina Trifosfatases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Cromatina/química , Cromatina/efeitos da radiação , Montagem e Desmontagem da Cromatina/efeitos da radiação , Reparo do DNA/efeitos da radiação , Proteínas de Ligação a DNA/metabolismo , Histonas/química , Histonas/metabolismo , Humanos , Lisina/química , Lisina/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Fosforilação/efeitos da radiação , Fator B de Elongação Transcricional Positiva/metabolismo , Isoformas de Proteínas/metabolismo , Radiação Ionizante , Transdução de Sinais/efeitos da radiação , Fatores de Transcrição/química , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética
7.
Fertil Steril ; 94(4): 1296-1301, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19608168

RESUMO

OBJECTIVE: To determine pharmacokinetic profiles of two times a day and three times a day dosage regimens of Endometrin, a micronized progesterone vaginal insert for luteal support in assisted reproductive technology, compared with a gel. DESIGN: A single-center, randomized, open-label, single-day, and multiple-day (5 days) parallel design pharmacokinetic study. SETTING: University clinical research unit. PATIENT(S): Three groups of six healthy subjects, ages 18 to 40 years. INTERVENTION(S): Endometrin vaginal inserts two times a day or three times a day, or gel daily. MAIN OUTCOME MEASURE(S): Pharmacokinetic profiles. RESULT(S): Progesterone serum concentrations increased rapidly following administration of Endometrin vaginal insert, producing higher peak concentrations (Cmax) and clearing faster than gel. On the single day of dosing, mean Cmax was 17.0+/-2.7 ng/mL in the two times a day group, 19.8+/-2.9 ng/mL in the three times a day group, and 6.82+/-1.69 ng/mL in the gel group. Endometrin treatments reached steady state within the first 2 days (24-36 hours), much more rapidly than the gel, which had not reached steady state by 5 days. At 5 days, the Endometrin treatments produced sustained progesterone concentrations exceeding 10 mg/mL across 24 hours. CONCLUSIONS: Endometrin vaginal inserts reached higher Cmax, produced greater systemic exposure (area under the curve 0-24), achieved steady state more rapidly, and cleared more rapidly after termination of therapy than the comparator.


Assuntos
Progesterona/administração & dosagem , Progesterona/farmacocinética , Cremes, Espumas e Géis Vaginais/administração & dosagem , Cremes, Espumas e Géis Vaginais/farmacocinética , Administração Intravaginal , Adolescente , Adulto , Fatores Etários , Formas de Dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Saúde , Humanos , Progesterona/sangue , Reprodução/efeitos dos fármacos , Reprodução/fisiologia , Técnicas de Reprodução Assistida , Fatores de Tempo , Adulto Jovem
8.
Fertil Steril ; 91(6): 2445-50, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18555224

RESUMO

OBJECTIVE: To evaluate vaginal compared to intramuscular (IM) progesterone supplementation for luteal phase support after in vitro fertilization and embryo transfer (IVF-ET). DESIGN: Retrospective matched-samples comparative study. SETTING: Private infertility center. PATIENTS(S): Two hundred forty patients undergoing IVF-ET. INTERVENTION(S): Patients received either vaginal progesterone supplementation in the form of Endometrin 100 mg twice a day (n = 12), Endometrin 100 mg three times a day (n = 11), or Crinone 8% gel 90 mg every day (n = 17), or 50 mg every day IM progesterone in oil (n = 200). MAIN OUTCOME MEASURE(S): Clinical intrauterine pregnancy rates, pregnancy loss, and live birth rates. RESULT(S): Among patients using vaginal progesterone, there were no statistically significant differences in patient characteristics and clinical outcomes, regardless of the type of vaginal progesterone used. There were no differences in outcomes between the vaginal and IM progesterone treatment groups. There were 20 pregnancies (50.0%) among patients treated with vaginal progesterone and 103 pregnancies (51.5%) among matched IM progesterone patients. The live birth rates were 47% in the IM versus 47.5% in the vaginal progesterone groups. There were no statistically significant differences in miscarriage rates between groups. CONCLUSION(S): There are no significant differences in treatment outcomes between vaginal and IM progesterone supplementation, yielding similar clinical pregnancy, miscarriage, and live birth rates.


Assuntos
Transferência Embrionária/métodos , Fertilização in vitro/métodos , Progesterona/uso terapêutico , Aborto Espontâneo/epidemiologia , Coeficiente de Natalidade , Feminino , Humanos , Recém-Nascido , Injeções , Injeções Intramusculares , Gravidez , Resultado da Gravidez , Progesterona/administração & dosagem , Vagina
9.
Fertil Steril ; 91(4): 1012-7, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18371963

RESUMO

OBJECTIVE: To assess the efficacy and safety of a vaginal progesterone (P(4)) insert (Endometrin) for luteal support for assisted reproductive technology (ART). DESIGN: Multicenter, randomized, open-label (assessor-blinded) phase III clinical trial. SETTING: Twenty-five U.S. ART centers. PATIENT(S): A total of 1,211 ART patients randomized to three groups: Endometrin 100 mg twice daily (n = 404), Endometrin 100 mg three times daily (n = 404), and P(4) 90 mg 8% gel daily (n = 403). INTERVENTION(S): In vitro fertilization and ET were performed according to site-specific protocols. The day after oocyte retrieval, Endometrin or vaginal P(4) gel was begun for luteal support and continued for up to 10 weeks of pregnancy. MAIN OUTCOME MEASURE(S): Biochemical, clinical, and ongoing pregnancy and live birth rates. RESULT(S): Pregnancy rates were high and similar in all treatment groups, with biochemical rates exceeding 50%, clinical and ongoing rates >or=40%, and live birth rates at 35%-38%. The adverse event profiles were similar across groups. CONCLUSION(S): Pregnancy rates and live birth rates for Endometrin (twice daily and three times daily) were high and similar to those for P(4) gel. The adverse event profiles for both were similar to that for P(4) gel and primarily due to IVF stimulation and oocyte retrieval. Endometrin was safe and well tolerated.


Assuntos
Fertilização in vitro/métodos , Dispositivos Intrauterinos Medicados , Fase Luteal/efeitos dos fármacos , Menotropinas/administração & dosagem , Indução da Ovulação/métodos , Progesterona/administração & dosagem , Urofolitropina/administração & dosagem , Adolescente , Adulto , Combinação de Medicamentos , Feminino , Fármacos para a Fertilidade Feminina/administração & dosagem , Fármacos para a Fertilidade Feminina/efeitos adversos , Humanos , Dispositivos Intrauterinos Medicados/efeitos adversos , Menotropinas/efeitos adversos , Indução da Ovulação/efeitos adversos , Gravidez , Taxa de Gravidez , Progesterona/efeitos adversos , Progesterona/uso terapêutico , Método Simples-Cego , Resultado do Tratamento , Urofolitropina/efeitos adversos , Adulto Jovem
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