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1.
Nat Immunol ; 17(12): 1361-1372, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27798618

RESUMO

Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders.


Assuntos
Infecções por Bactérias Gram-Negativas/imunologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Heme/metabolismo , Hemólise/imunologia , Macrófagos/imunologia , Fagocitose , Sepse/imunologia , Animais , Antibacterianos/uso terapêutico , Citoesqueleto/metabolismo , Feminino , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Fatores de Troca do Nucleotídeo Guanina/genética , Heme Oxigenase-1/genética , Hemólise/efeitos dos fármacos , Humanos , Evasão da Resposta Imune , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/efeitos dos fármacos , Quinina/uso terapêutico , Células RAW 264.7 , Sepse/tratamento farmacológico , Proteína cdc42 de Ligação ao GTP/metabolismo
2.
Development ; 150(3)2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36715020

RESUMO

Thyroid hormone and its receptor TRα1 play an important role in brain development. Several animal models have been used to investigate this function, including mice heterozygous for the TRα1R384C mutation, which confers receptor-mediated hypothyroidism. These mice display abnormalities in several autonomic functions, which was partially attributed to a developmental defect in hypothalamic parvalbumin neurons. However, whether other cell types in the hypothalamus are similarly affected remains unknown. Here, we used single-nucleus RNA sequencing to obtain an unbiased view on the importance of TRα1 for hypothalamic development and cellular diversity. Our data show that defective TRα1 signaling has surprisingly little effect on the development of hypothalamic neuronal populations, but it heavily affects hypothalamic oligodendrocytes. Using selective reactivation of the mutant TRα1 during specific developmental periods, we find that early postnatal thyroid hormone action seems to be crucial for proper hypothalamic oligodendrocyte maturation. Taken together, our findings underline the well-known importance of postnatal thyroid health for brain development and provide an unbiased roadmap for the identification of cellular targets of TRα1 action in mouse hypothalamic development.


Assuntos
RNA , Receptores alfa dos Hormônios Tireóideos , Camundongos , Animais , Receptores alfa dos Hormônios Tireóideos/genética , Receptores alfa dos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos , Glândula Tireoide , Hipotálamo/metabolismo
3.
Eur Eat Disord Rev ; 32(2): 350-362, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37936300

RESUMO

OBJECTIVE: Although inpatient treatment is highly effective for patients with bulimia nervosa (BN), some patients show a resurgence of symptoms and relapse after discharge. Therefore, the aim of this study is to evaluate the efficacy of a guided smartphone-based aftercare intervention following inpatient treatment to support recovery. METHOD: 172 female patients with BN (DSM-5: 307.51) will be randomized to receive a 16-week smartphone-based aftercare intervention (German version of 'Recovery Record') with therapist feedback as an add-on element to treatment as usual (TAU) or TAU alone. Assessments will take place at baseline (discharge, T0), during the intervention (after 4 weeks, T1), post-intervention (after 16 weeks, T2) and at 6-month follow-up (T3). Primary outcome will be remission at T2. Moderator and mediator analyses will investigate for whom the aftercare intervention suits best and how it works. CONCLUSIONS: This is the first randomized controlled trial to examine a guided smartphone-based aftercare intervention following inpatient treatment of patients with BN. We expect that this innovative aftercare intervention is highly accepted by the patients and that it has the potential to support recovery after inpatient treatment and thereby could contribute to improving aftercare for patients with BN.


Assuntos
Bulimia Nervosa , Smartphone , Humanos , Feminino , Bulimia Nervosa/terapia , Resultado do Tratamento , Assistência ao Convalescente/métodos , Pacientes Internados , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto
4.
Am J Perinatol ; 2023 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-36898409

RESUMO

OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare, multisystem disease that primarily affects women of reproductive age. Disease progression has been linked to estrogen exposure, and as such many patients are advised to avoid pregnancy. Data are limited regarding the interaction between LAM and pregnancy, and as such we performed a systematic review to summarize available literature reporting outcomes of pregnancies complicated by maternal LAM. STUDY DESIGN: This was a systematic review including randomized controlled trials, observational studies, systematic reviews, case reports, clinical practice guidelines, and quality improvement studies with full-text manuscripts or abstracts in the English language with primary data on pregnant or postpartum patients with LAM. The primary outcome was maternal outcomes during pregnancy as well as pregnancy outcomes. Secondary outcomes were neonatal outcomes and long-term maternal outcomes. This search occurred in July 2020 and included MEDLINE, Scopus, clinicaltrials.gov, Embase, and Cochrane Central. Risk of bias was ascertained using the Newcastle-Ottawa Scale. Our systematic review was registered with PROSPERO as protocol number CRD 42020191402. RESULTS: A total of 175 publications were identified in our initial search; ultimately 31 studies were included. Six (19%) studies were retrospective cohort studies and 25 (81%) studies were case reports. Patients diagnosed during pregnancy had worse pregnancy outcomes compared to those diagnosed with LAM prior to pregnancy. Multiple studies reported a significant risk of pneumothoraces during pregnancy. Other significant risks included preterm delivery, chylothoraces, and pulmonary function deterioration. A proposed strategy for preconception counseling and antenatal management is provided. CONCLUSION: Patients diagnosed with LAM during pregnancy generally experience worse outcomes including recurrent pneumothoraces and preterm delivery as compared to patients with a LAM diagnosis prior to pregnancy. Given that there are limited studies available, and that the majority are low-quality evidence and subject to bias, further investigation of the interaction between LAM and pregnancy is warranted to guide patient care and counseling. KEY POINTS: · Data are limited on the effects of lymphangioleiomyomatosis on pregnancy outcomes.. · We performed a systematic review to summarize pregnancy outcomes complicated by LAM.. · Patients diagnosed with LAM during pregnancy experience worse outcomes..

5.
Eur J Contracept Reprod Health Care ; 27(3): 174-179, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34870553

RESUMO

OBJECTIVE: The aim of the study was to investigate the differences in reliable contraceptive use between black women and white women with maternal cardiac disease. METHODS: The study comprised a retrospective cohort of women with maternal cardiac disease managed by the University of Alabama at Birmingham (UAB) Comprehensive Pregnancy and Heart Program (CPHP). Women were included if they had attended one or more prenatal visits at the UAB CPHP and delivered at the UAB hospital between March 2015 and June 2019. The primary outcome was reliable contraceptive use within 2 months postpartum, defined by receipt of long-acting reversible contraception (i.e., an intrauterine contraceptive device or an etonogestrel implant) or female sterilisation. All outcomes were compared based on self-reported race. RESULTS: One hundred and forty-nine women met the inclusion criteria. Black women (n = 63) were more likely than white women (n = 86) to use reliable contraception (65% vs 43%; p = 0.008). Black women were less likely than white women to be undecided or decline contraception at the time of admission (13% vs 27%; p = 0.037). There was no difference in reliable contraceptive use between black women (n = 20, 63%) and white women (n = 23, 72%) with modified World Health Organisation (WHO) class III/IV lesions (p = 0.42). CONCLUSION: Black women with maternal cardiac disease were more likely than white women to receive reliable contraception. Interventions to prevent unintended pregnancy in women with maternal cardiac disease should focus on improving reliable contraceptive use, especially for women with modified WHO class III/IV lesions.


Assuntos
Anticoncepcionais Femininos , Cardiopatias , Anticoncepção , Anticoncepcionais Femininos/uso terapêutico , Feminino , Humanos , Gravidez , Gravidez não Planejada , Estudos Retrospectivos
6.
Int J Eat Disord ; 53(11): 1791-1800, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32841413

RESUMO

OBJECTIVE: The COVID-19 pandemic and the resulting public restrictions pose a psychological burden for humans worldwide and may be particularly detrimental for individuals with mental disorders. Therefore, the current study explored effects of the COVID-19 pandemic on eating disorder (ED) symptoms and other psychological aspects in former inpatients with anorexia nervosa (AN). METHOD: One-hundred and fifty-nine patients with AN-discharged from inpatient treatment in 2019-completed an online survey on contact history with COVID-19, changes in ED symptoms and other psychological aspects, health care utilization, and strategies patients employed to cope during the pandemic. RESULTS: Approximately 70% of patients reported that eating, shape and weight concerns, drive for physical activity, loneliness, sadness, and inner restlessness increased during the pandemic. Access to in-person psychotherapies and visits at the general practitioner (including weight checks) decreased by 37% and 46%, respectively. Videoconference therapy was used by 26% and telephone contacts by 35% of patients. Patients experienced daily routines, day planning and enjoyable activities as the most helpful among the most used coping strategies. DISCUSSION: The COVID-19 pandemic poses great challenges to patients with AN. ED-related thoughts and behaviors may be used as dysfunctional coping mechanisms to regain control over the current circumstances. E-mental health interventions appear to be promising for supporting AN patients during these hard times. Furthermore, interventions addressing symptoms of depression and anxiety, as well as intolerance of uncertainty might help them manage their ED symptoms.


Assuntos
Anorexia Nervosa/psicologia , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Adaptação Psicológica , Adolescente , Adulto , Anorexia Nervosa/terapia , Ansiedade/etiologia , COVID-19 , Estudos Transversais , Depressão/etiologia , Exercício Físico/psicologia , Feminino , Alemanha , Comportamentos Relacionados com a Saúde , Acessibilidade aos Serviços de Saúde , Inquéritos Epidemiológicos , Humanos , Saúde Mental , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Índice de Gravidade de Doença , Perfil de Impacto da Doença , Adulto Jovem
7.
Mol Cell Proteomics ; 17(12): 2518-2533, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30228193

RESUMO

Understanding cellular processes requires the determination of dynamic changes in the concentration of genetically nonmodified, endogenous proteins, which, to date, is commonly accomplished by end-point assays in vitro Molecular probes such as fluorescently labeled nanobodies (chromobodies, CBs) are powerful tools to visualize the dynamic subcellular localization of endogenous proteins in living cells. Here, we employed the dependence of intracellular levels of chromobodies on the amount of their endogenous antigens, a phenomenon, which we termed antigen-mediated CB stabilization (AMCBS), for simultaneous monitoring of time-resolved changes in the concentration and localization of native proteins. To improve the dynamic range of AMCBS we generated turnover-accelerated CBs and demonstrated their application in visualization and quantification of fast reversible changes in antigen concentration upon compound treatment by quantitative live-cell imaging. We expect that this broadly applicable strategy will enable unprecedented insights into the dynamic regulation of proteins, e.g. during cellular signaling, cell differentiation, or upon drug action.


Assuntos
Complexo Antígeno-Anticorpo/metabolismo , Antígenos/metabolismo , Anticorpos de Domínio Único/metabolismo , Anticorpos/metabolismo , Imunofluorescência , Células HeLa , Humanos , Lisossomos/metabolismo , Mutação Puntual/fisiologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Estabilidade Proteica , Proteólise , Ubiquitina/metabolismo , beta Catenina/metabolismo
8.
Psychother Psychosom Med Psychol ; 70(3-04): 112-121, 2020 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-31466116

RESUMO

Family-based therapy (FBT) is currently the most evidence-based treatment for adolescents with eating disorders. The aim of this review is to summarize previous research results regarding the efficacy of the manualized FBT according to Lock and Le Grange and to report on moderators and mediators. In 5 randomized controlled trials (RCTs) in anorexia nervosa (N=560) remission rates were between 21.2-42% at end of treatment, between 21.8-40% at 6-month follow-up, and between 29-49% at 12-month follow-up. Remission rates for patients with bulimia nervosa (2 RCTs, N=210) were 39%, 29-44% and 49% respectively. It would be desirable to replicate these results through independent working groups and in other countries. In addition, it would also be important to evaluate FBT in comparison to cognitive behavioral therapy and psychodynamic therapy, and to further explore strategies for non-responders.


Assuntos
Psiquiatria do Adolescente/métodos , Transtornos da Alimentação e da Ingestão de Alimentos/terapia , Adolescente , Adulto , Terapia Cognitivo-Comportamental , Terapia Familiar , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Development ; 142(10): 1879-84, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25968318

RESUMO

Chromobodies are intracellular nanoprobes that combine the specificity of antibodies with the convenience of live fluorescence imaging in a flexible, DNA-encoded reagent. Here, we present the first application of this technique to an intact living vertebrate organism. We generated zebrafish lines expressing chromobodies that trace the major cytoskeletal component actin and the cell cycle marker PCNA with spatial and temporal specificity. Using these chromobodies, we captured full localization dynamics of the endogenous antigens in different cell types and at different stages of development. For the first time, the chromobody technology enables live imaging of endogenous subcellular structures in an animal, with the remarkable advantage of avoiding target protein overexpression or tagging. In combination with improved chromobody selection systems, we anticipate a rapid adaptation of this technique to new intracellular antigens and model organisms, allowing the faithful description of cellular and molecular processes in their dynamic state.


Assuntos
Diagnóstico por Imagem/métodos , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Actinas/metabolismo , Animais , Ciclo Celular/fisiologia , Anticorpos de Domínio Único
10.
Cytotherapy ; 19(9): 1079-1095, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28734678

RESUMO

BACKGROUND: Cell-based therapies with autologous adipose tissue-derived cells have shown great potential in several clinical studies in the last decades. The majority of these studies have been using the stromal vascular fraction (SVF), a heterogeneous mixture of fibroblasts, lymphocytes, monocytes/macrophages, endothelial cells, endothelial progenitor cells, pericytes and adipose-derived stromal/stem cells (ASC) among others. Although possible clinical applications of autologous adipose tissue-derived cells are manifold, they are limited by insufficient uniformity in cell identity and regenerative potency. METHODS: In our experimental set-up, low-energy extracorporeal shock wave therapy (ESWT) was performed on freshly obtained human adipose tissue and isolated adipose tissue SVF cells aiming to equalize and enhance stem cell properties and functionality. RESULTS: After ESWT on adipose tissue we could achieve higher cellular adenosine triphosphate (ATP) levels compared with ESWT on the isolated SVF as well as the control. ESWT on adipose tissue resulted in a significantly higher expression of single mesenchymal and vascular marker compared with untreated control. Analysis of SVF protein secretome revealed a significant enhancement in insulin-like growth factor (IGF)-1 and placental growth factor (PLGF) after ESWT on adipose tissue. DISCUSSION: Summarizing we could show that ESWT on adipose tissue enhanced the cellular ATP content and modified the expression of single mesenchymal and vascular marker, and thus potentially provides a more regenerative cell population. Because the effectiveness of autologous cell therapy is dependent on the therapeutic potency of the patient's cells, this technology might raise the number of patients eligible for autologous cell transplantation.


Assuntos
Tecido Adiposo/citologia , Tratamento por Ondas de Choque Extracorpóreas/métodos , Células-Tronco/citologia , Trifosfato de Adenosina/metabolismo , Biomarcadores/metabolismo , Diferenciação Celular , Células Cultivadas , Humanos , Imunofenotipagem , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Placentário/metabolismo , Células-Tronco/fisiologia , Células Estromais/citologia , Células Estromais/fisiologia
11.
Cytotherapy ; 19(7): 849-860, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28454682

RESUMO

BACKGROUND AIMS: Lipedema is a hormone-related disease of women characterized by enlargement of the extremities caused by subcutaneous deposition of adipose tissue. In healthy patients application of autologous adipose tissue-derived cells has shown great potential in several clinical studies for engrafting of soft tissue reconstruction in recent decades. The majority of these studies have used the stromal vascular fraction (SVF), a heterogeneous cell population containing adipose-derived stromal/stem cells (ASC), among others. Because cell identity and regenerative properties might be affected by the health condition of patients, we characterized the SVF cells of 30 lipedema patients in comparison to 22 healthy patients. METHODS: SVF cells were analyzed regarding cell yield, viability, adenosine triphosphate content, colony forming units and proliferative capacity, as well as surface marker profile and differentiation potential in vitro. RESULTS: Our results demonstrated a significantly enhanced SVF cell yield isolated from lipedema compared with healthy patients. In contrast, the adipogenic differentiation potential of SVF cells isolated from lipedema patients was significantly reduced compared with healthy patients. Interestingly, expression of the mesenchymal marker CD90 and the endothelial/pericytic marker CD146 was significantly enhanced when isolated from lipedema patients. DISCUSSION: The enhanced number of CD90+ and CD146+ cells could explain the increased cell yield because the other tested surface marker were not reduced in lipedema patients. Because the cellular mechanism and composition in lipedema is largely unknown, our findings might contribute to a better understanding of its etiology.


Assuntos
Tecido Adiposo/patologia , Lipedema/patologia , Células Estromais/citologia , Trifosfato de Adenosina/metabolismo , Adipogenia/fisiologia , Tecido Adiposo/citologia , Adulto , Antígeno CD146/metabolismo , Estudos de Casos e Controles , Diferenciação Celular , Células Cultivadas , Feminino , Humanos , Pessoa de Meia-Idade , Células-Tronco/citologia , Células-Tronco/patologia , Células Estromais/metabolismo , Células Estromais/patologia , Antígenos Thy-1/metabolismo
12.
Mol Cell Proteomics ; 14(3): 707-23, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25595278

RESUMO

ß-catenin is the key component of the canonical Wnt pathway and plays a crucial role in a multitude of developmental and homeostatic processes. The different tasks of ß-catenin are orchestrated by its subcellular localization and participation in multiprotein complexes. To gain a better understanding of ß-catenin's role in living cells we have generated a new set of single domain antibodies, referred to as nanobodies, derived from heavy chain antibodies of camelids. We selected nanobodies recognizing the N-terminal, core or C-terminal domain of ß-catenin and applied these new high-affinity binders as capture molecules in sandwich immunoassays and co-immunoprecipitations of endogenous ß-catenin complexes. In addition, we engineered intracellularly functional anti-ß-catenin chromobodies by combining the binding moieties of the nanobodies with fluorescent proteins. For the first time, we were able to visualize the subcellular localization and nuclear translocation of endogenous ß-catenin in living cells using these chromobodies. Moreover, the chromobody signal allowed us to trace the accumulation of diffusible, hypo-phosphorylated ß-catenin in response to compound treatment in real time using High Content Imaging. The anti-ß-catenin nanobodies and chromobodies characterized in this study are versatile tools that enable a novel and unique approach to monitor the dynamics of subcellular ß-catenin in biochemical and cell biological assays.


Assuntos
Camelídeos Americanos/imunologia , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/metabolismo , beta Catenina/química , beta Catenina/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , Núcleo Celular/metabolismo , Cromatografia de Afinidade , Citoplasma/metabolismo , Imunofluorescência/métodos , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Transporte Proteico
13.
Biochim Biophys Acta ; 1844(11): 1933-1942, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24792387

RESUMO

In biomedical research there is an ongoing demand for new technologies, which help to elucidate disease mechanisms and provide the basis to develop novel therapeutics. In this context a comprehensive understanding of cellular processes and their pathophysiology based on reliable information on abundance, localization, posttranslational modifications and dynamic interactions of cellular components is indispensable. Besides their significant impact as therapeutic molecules, antibodies are arguably the most powerful research tools to study endogenous proteins and other cellular components. However, for cellular diagnostics their use is restricted to endpoint assays using fixed and permeabilized cells. Alternatively, live cell imaging using fluorescent protein-tagged reporters is widely used to study protein localization and dynamics in living cells. However, only artificially introduced chimeric proteins are visualized, whereas the endogenous proteins, their posttranslational modifications as well as non-protein components of the cell remain invisible and cannot be analyzed. To overcome these limitations, traceable intracellular binding molecules provide new opportunities to perform cellular diagnostics in real time. In this review we summarize recent progress in the generation of intracellular and cell penetrating antibodies and their application to target and trace cellular components in living cells. We highlight recent advances in the structural formulation of recombinant antibody formats, reliable screening protocols and sophisticated cellular targeting technologies and propose that such intrabodies will become versatile research tools for real time cell-based diagnostics including target validation and live cell imaging. This article is part of a Special Issue entitled: Recent advances in molecular engineering of antibody.

14.
GigaByte ; 2024: gigabyte105, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38239770

RESUMO

The snake pipefish, Entelurus aequoreus (Linnaeus, 1758), is a northern Atlantic fish inhabiting open seagrass environments that recently expanded its distribution range. Here, we present a highly contiguous, near chromosome-scale genome of E. aequoreus. The final assembly spans 1.6 Gbp in 7,391 scaffolds, with a scaffold N50 of 62.3 Mbp and L50 of 12. The 28 largest scaffolds (>21 Mbp) span 89.7% of the assembly length. A BUSCO completeness score of 94.1% and a mapping rate above 98% suggest a high assembly completeness. Repetitive elements cover 74.93% of the genome, one of the highest proportions identified in vertebrates. Our demographic modeling identified a peak in population size during the last interglacial period, suggesting the species might benefit from warmer water conditions. Our updated snake pipefish assembly is essential for future analyses of the morphological and molecular changes unique to the Syngnathidae.

15.
Proteomics ; 13(6): 1010-5, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23401470

RESUMO

Antibodies that recognize PTMs of histones play a central role in epigenetic proteomic research. Modification-specific antibodies are employed in chromatin immunoprecipitation, for Western blotting and during the immunoprecipitation steps for MS-based global proteomic analyses. Knowledge about the antibodies' off-target binding is essential for the interpretation of experimental data. To address this challenge we developed a fast and cost efficient system for generating peptide bead arrays. We employed this method to establish a bead-based peptide array containing 384 peptides displaying phosphorylated, acetylated, methylated, and citrullinated N-terminal regions of histones H2A, H2B, H3 and H4 and controls. We profiled the binding of 40 PTM-specific antibodies important for epigenetic proteomic research.


Assuntos
Anticorpos/química , Histonas/química , Análise Serial de Proteínas/métodos , Processamento de Proteína Pós-Traducional , Sequência de Aminoácidos , Anticorpos/imunologia , Especificidade de Anticorpos , Epigênese Genética , Epitopos/química , Células HeLa , Histonas/imunologia , Histonas/metabolismo , Humanos , Peptídeos , Fosforilação , Ligação Proteica , Proteômica
16.
Urogynecology (Phila) ; 29(12): 946-952, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37195629

RESUMO

IMPORTANCE: Understanding patients' perceptions of symptoms and outcomes of urogynecologic surgery is essential for providing high-quality care. OBJECTIVE: The aim of the study was to assess association of pain catastrophizing with pelvic floor symptom distress and impact, postoperative pain, and voiding trial in patients undergoing urogynecologic surgery. STUDY DESIGN: Individuals whose self-identified gender was female and were undergoing surgery March 2020-December 2021 were included. Participants completed the Pain Catastrophizing Scale (range 0-52), Pelvic Floor Distress Inventory, and Pelvic Floor Impact Questionnaire preoperatively. Pain catastrophizing was score ≥30 and describes the tendency to magnify the overall threat of pain. Voiding trial failure was inability to void ≥2/3 of instilled volume (≤300 mL). The association between pain catastrophizing and symptom distress and impact was assessed with linear regression. A P < 0.05 is significant. RESULTS: Three hundred twenty patients were included (mean age, 60 years, 87% White). Forty-six of 320 participants (14%) had a pain catastrophizing score ≥30. The pain catastrophizing group had higher body mass index (33 ± 12 vs 29 ± 5), more benzodiazepine use (26% vs 12%), greater symptom distress (154 ± 58 vs 108 ± 60), and greater urogenital (59 ± 29 vs 47 ± 28), colorectal (42 ± 24 vs 26 ± 23), and prolapse (54 ± 24 vs 36 ± 24) subscale scores, all P ≤ 0.02. The pain catastrophizing group had greater impact (153 ± 72 vs 72 ± 64, P < 0.01) and urogenital (60 ± 29 vs 34 ± 28), colorectal (36 ± 33 vs 16 ± 26), and prolapse (57 ± 32 vs 22 ± 27) subscale scores, P < 0.01. Associations remained controlling for confounders ( P < 0.01). The pain catastrophizing group had higher 10-point pain scores (8 vs 6, P < 0.01) and was more likely to report pain at 2 weeks (59% vs 20%, P < 0.01) and 3 months (25% vs 6%, P = 0.01). Voiding trial failure did not differ (26% vs 28%, P = 0.98). CONCLUSIONS: Pain catastrophizing is associated with greater pelvic floor symptom distress and impact and postoperative pain but not voiding trial failure.


Assuntos
Neoplasias Colorretais , Diafragma da Pelve , Humanos , Feminino , Pessoa de Meia-Idade , Prolapso , Inquéritos e Questionários , Dor Pós-Operatória/diagnóstico
17.
NPJ Syst Biol Appl ; 9(1): 22, 2023 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-37270586

RESUMO

Pancreatic neuroendocrine tumors (PanNETs) are a rare tumor entity with largely unpredictable progression and increasing incidence in developed countries. Molecular pathways involved in PanNETs development are still not elucidated, and specific biomarkers are missing. Moreover, the heterogeneity of PanNETs makes their treatment challenging and most approved targeted therapeutic options for PanNETs lack objective responses. Here, we applied a systems biology approach integrating dynamic modeling strategies, foreign classifier tailored approaches, and patient expression profiles to predict PanNETs progression as well as resistance mechanisms to clinically approved treatments such as the mammalian target of rapamycin complex 1 (mTORC1) inhibitors. We set up a model able to represent frequently reported PanNETs drivers in patient cohorts, such as Menin-1 (MEN1), Death domain associated protein (DAXX), Tuberous Sclerosis (TSC), as well as wild-type tumors. Model-based simulations suggested drivers of cancer progression as both first and second hits after MEN1 loss. In addition, we could predict the benefit of mTORC1 inhibitors on differentially mutated cohorts and hypothesize resistance mechanisms. Our approach sheds light on a more personalized prediction and treatment of PanNET mutant phenotypes.


Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Humanos , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/terapia , Tumores Neuroendócrinos/metabolismo , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/metabolismo , Biologia de Sistemas , Fenótipo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética
18.
Blood ; 115(6): 1156-65, 2010 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-19965634

RESUMO

Human plasmacytoid dendritic cells (pDCs) are crucially involved in the modulation of adaptive T-cell responses in the course of neoplastic, viral, and autoimmune disorders. In several of these diseases elevated extracellular levels of the serine protease granzyme B (GrB) are observed. Here we demonstrate that human pDCs can be an abundant source of GrB and that such GrB(+) pDCs potently suppress T-cell proliferation in a GrB-dependent, perforin-independent manner, a process reminiscent of regulatory T cells. Moreover, we show that GrB expression is strictly regulated on a transcriptional level involving Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), and STAT5 and that interleukin-3 (IL-3), a cytokine secreted by activated T cells, plays a central role for GrB induction. Moreover, we find that the immunosuppressive cytokine IL-10 enhances, while Toll-like receptor agonists and CD40 ligand strongly inhibit, GrB secretion by pDCs. GrB-secreting pDCs may play a regulatory role for immune evasion of tumors, antiviral immune responses, and autoimmune processes. Our results provide novel information about the complex network of pDC-T-cell interactions and may contribute to an improvement of prophylactic and therapeutic vaccinations.


Assuntos
Artrite Juvenil/imunologia , Células Dendríticas/metabolismo , Granzimas/fisiologia , Ativação Linfocitária/fisiologia , Linfócitos T/imunologia , Artrite Juvenil/patologia , Western Blotting , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Criança , Citotoxicidade Imunológica , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Interleucina-3/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais
19.
Cancers (Basel) ; 14(3)2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35158799

RESUMO

Richter syndrome (RS) is defined as the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, mostly diffuse large B-cell lymphoma (DLBCL). Despite intensive therapy, patients with RS have an unfavorable clinical outcome. The detailed pathobiology of Richter transformation still needs to be elucidated. Here, we report high mRNA and protein levels of CARD9 in the RS cell line U-RT1. Co-immunoprecipitation revealed the assembly of a CBM complex using CARD9 instead of CARD11. CARD9 is known to be an activator of NF-кB signaling in myeloid cells. U-RT1 Western blot analyses showed phosphorylation of IκB as well as IKK, indicating a constitutively active canonical NF-кB pathway. This was further supported by the significant reduction in cell viability and CYLD cleavage products after CARD9 siRNA knockdown. We also showed immunostaining for CARD9 in 53% of cases analyzed in a series of RS tissue specimens, whereas other lymphomas rarely show CARD9 expression. This is the first report on ectopic expression and function of CARD9 in an aggressive B-cell lymphoma. Our findings suggest that CARD9 may contribute to the pathogenesis of RS.

20.
Gynecol Oncol Rep ; 42: 101041, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35898199

RESUMO

Background: To determine whether race and ethnicity impacts patient adherence to follow-up for colposcopy after abnormal cervical cancer screening. Methods: This retrospective chart review included women that were randomly selected from patients presenting to our colposcopy clinic from 1/2019 to 12/2019. Inclusion criteria were females age ≥21 years-old and appropriate referral for colposcopy. Patients were grouped into three categories: (1) ADHERENT to follow-up if they came to their first scheduled appointment; (2) DELAYED if they presented more than three months from their original referral (usually missing 1-3 appointments); and (3) NOT ADHERENT if they did not show for their appointment after referral. Analysis was performed using SPSS v.26. Results: 284 women met inclusion criteria for the study. The majority of women were Black (65.2 %) followed by non-Hispanic Whites (20.0 %) and Latinx (14.8 %). Overall, 39.1 % were ADHERENT, 18.6 % were DELAYED, and 42.3 % were NOT ADHERENT. When compared with non-Hispanic White women, there was a significant difference between race/ethnicity and timing of follow-up (p = 0.03). Blacks were more likely to be NOT ADHERENT (45.9 %; p = 0.03), and Latinx and Blacks were the most likely to be DELAYED (35.7 % and 21.1 %; p = 0.03). Private insurance patients were more likely to be ADHERENT for care compared with un-/underinsured patients (78.9 vs 27.8 %, p = 0.0001). Conclusion: There is inadequate follow-up after abnormal cervical cancer screening across all races/ethnicities; however, lack of adherence is higher in Black patients. Moreover, 25% of Hispanic and Black women present in a delayed fashion. Culturally relevant assessments and interventions are needed to understand and address these gaps.

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