RESUMO
Infertility is a reproductive disease affecting one in six individuals that renders an individual unable to conceive. One cause of infertility is diminished ovarian reserve (DOR), which reduces the quantity and/or quality of a female's oocyte pool. Although typically indicating normal ovarian aging during the late 30s and early 40s, DOR can also impact younger women, increasing their risk for psychological distress from an unexpected diagnosis of infertility. A phenomenological approach examined the mental health experiences and perceptions of infertility-related mental health care of young women with DOR. Women diagnosed with DOR by age 35 in the United States who experienced emotional distress during infertility were recruited from infertility-specific social media and via snowball sampling. Participants completed a demographic survey and semi-structured individual interview that was audio-recorded, transcribed verbatim, and analyzed using a phenomenological approach. Ten women ages 27-41 completed the study. On average, participants were 30 years of age at the time of DOR diagnosis (age range 25-35), primarily Caucasian (90%), and married (90%). Two main themes were found: (1) Young women with DOR feel like a "forgotten community" coping with an invisible disease; and (2) Not all fertility clinics are created equal. Participants perceived their diagnosis as devastating and hopeless and urged others to find a provider with ample experience treating patients with DOR. This study helped to understand how young women with DOR perceive their mental health and identified a significant need for advancing towards more holistic infertility healthcare that encompasses both physical and mental health.
Assuntos
Infertilidade , Reserva Ovariana , Feminino , Humanos , Estados Unidos , Adulto , Saúde Mental , Envelhecimento , EmoçõesRESUMO
OBJECTIVES: To analyze and synthesize the reported psychometric properties of the Fertility Quality of Life (FertiQoL) instrument and describe its implications for use in practice and research in men and women with infertility. METHODS: A systematic literature search was performed to identify all articles using the FertiQoL tool. PubMed, CINAHL, and PsycINFO were searched from September 2006 through May 2022. Studies were eligible for inclusion if they reported psychometric data on the original FertiQoL tool using a sample population of individuals with infertility. Sample size, country of origin, and psychometric data were documented for each study. RESULTS: The initial search revealed 153 articles that had utilized the FertiQoL. Following abstract, title, and full-text screenings, 53 articles reported psychometric data and met criteria for inclusion. The FertiQoL is a sound measurement with satisfactory reliability and validity. Studies indicated adequate reliability in the overall scale ([Formula: see text]), as well as the core Emotional, Mind/Body, Social, and Relational scales ([Formula: see text]) and two optional Tolerability and Environment fertility treatment subscales ([Formula: see text]). Although the Relational subscale exhibited slightly lower reliability in several studies, the internal consistency for the measurement as a whole was satisfactory. Results also indicate adequate: 1) face and content validity with extensive professional and patient feedback during development; 2) convergent validity with general quality of life, depression, and anxiety measurements; and 3) structural validity using both confirmatory and exploratory factor analyses. CONCLUSION: The FertiQoL tool is the most commonly used instrument to measure the impact of fertility issues on quality of life in men and women with infertility. Understanding the impact of infertility on quality of life provides valuable insight into the areas of infertility-related care that need to be prioritized, such as mental health or relational stressors. While the instrument has been used in different patient populations with infertility and available in multiple translations, it is necessary to understand the updated psychometric properties and the implications for its use. This review shows that the FertiQoL is reliable and valid for cross-cultural use among individuals with various etiologies of infertility.
Assuntos
Infertilidade , Qualidade de Vida , Masculino , Humanos , Feminino , Qualidade de Vida/psicologia , Psicometria , Reprodutibilidade dos Testes , Fertilidade , Infertilidade/terapia , Infertilidade/psicologia , Inquéritos e QuestionáriosRESUMO
AIMS: Explore the knowledge, experiences, preferences, and concerns related to fertility preservation as an option for building a biological family among women with cystic fibrosis. DESIGN: Convergent mixed methods study design. METHODS: We recruited women with cystic fibrosis of childbearing age in the United States through cystic fibrosis centres, snowball sampling, and social media. Participants completed an anonymous survey about fertility and fertility preservation (n = 50). We also conducted audio-recorded, semi-structured interviews with a subset of women to gain a better understanding of their perspectives (n = 20). We transcribed the interviews verbatim and analysed them using thematic analysis. RESULTS: For the quantitative arm, 78% of women indicated that they would like to have a child in the future; however, 74% reported never having had conversations about fertility preservation with their providers. For the qualitative arm, four major themes emerged: (1) Women with cystic fibrosis have inadequate knowledge about fertility and fertility preservation; (2) fertility is a low priority area for the cystic fibrosis care team; (3) women with cystic fibrosis recommend that the cystic fibrosis care team provide specific fertility resources; and (4) providers and literature lack information on fertility and cystic fibrosis. Integrated findings identified that while the majority of women with cystic fibrosis want to become mothers in the future, including post-lung transplantation, they have not received education on fertility preservation, and there is a general lack of knowledge on the topic of fertility in cystic fibrosis. CONCLUSION: Women with cystic fibrosis desire to have children but have little knowledge about fertility preservation, and cystic fibrosis providers do not initiate family planning discussions. IMPACT: Findings from the study support that additional education is needed for women with cystic fibrosis who are considering parenthood. Clinical care models should include early, regular, and thoughtful discussions about reproductive health issues, including fertility preservation.
Assuntos
Fibrose Cística , Preservação da Fertilidade , Transplante de Pulmão , Criança , Serviços de Planejamento Familiar , Feminino , Fertilidade , HumanosRESUMO
BACKGROUND: Neuroticism is associated with the onset and maintenance of a number of mental health conditions, as well as a number of deleterious outcomes (e.g. physical health problems, higher divorce rates, lost productivity, and increased treatment seeking); thus, the consideration of whether this trait can be addressed in treatment is warranted. To date, outcome research has yielded mixed results regarding neuroticism's responsiveness to treatment, perhaps due to the fact that study interventions are typically designed to target disorder symptoms rather than neuroticism itself. The purpose of the current study was to explore whether a course of treatment with the unified protocol (UP), a transdiagnostic intervention that was explicitly developed to target neuroticism, results in greater reductions in neuroticism compared to gold-standard, symptom focused cognitive behavioral therapy (CBT) protocols and a waitlist (WL) control condition. METHOD: Patients with principal anxiety disorders (N = 223) were included in this study. They completed a validated self-report measure of neuroticism, as well as clinician-rated measures of psychological symptoms. RESULTS: At week 16, participants in the UP condition exhibited significantly lower levels of neuroticism than participants in the symptom-focused CBT (t(218) = -2.17, p = 0.03, d = -0.32) and WL conditions(t(207) = -2.33, p = 0.02, d = -0.43), and these group differences remained after controlling for simultaneous fluctuations in depression and anxiety symptoms. CONCLUSIONS: Treatment effects on neuroticism may be most robust when this trait is explicitly targeted.
Assuntos
Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental , Neuroticismo , Resultado do Tratamento , Adulto , Escalas de Graduação Psiquiátrica Breve , Feminino , Humanos , Masculino , Fenótipo , Autorrelato , Listas de EsperaRESUMO
RATIONALE: The mechanisms driving atherothrombotic risk in individuals with JAK2 V617F ( Jak2 VF) positive clonal hematopoiesis or myeloproliferative neoplasms are poorly understood. OBJECTIVE: The goal of this study was to assess atherosclerosis and underlying mechanisms in hypercholesterolemic mice with hematopoietic Jak2 VF expression. METHODS AND RESULTS: Irradiated low-density lipoprotein receptor knockout ( Ldlr-/-) mice were transplanted with bone marrow from wild-type or Jak2 VF mice and fed a high-fat high-cholesterol Western diet. Hematopoietic functions and atherosclerosis were characterized. After 7 weeks of Western diet, Jak2 VF mice showed increased atherosclerosis. Early atherosclerotic lesions showed increased neutrophil adhesion and content, correlating with lesion size. After 12 weeks of Western diet, Jak2 VF lesions showed increased complexity, with larger necrotic cores, defective efferocytosis, prominent iron deposition, and costaining of erythrocytes and macrophages, suggesting erythrophagocytosis. Jak2 VF erythrocytes were more susceptible to phagocytosis by wild-type macrophages and showed decreased surface expression of CD47, a "don't-eat-me" signal. Human JAK2VF erythrocytes were also more susceptible to erythrophagocytosis. Jak2 VF macrophages displayed increased expression and production of proinflammatory cytokines and chemokines, prominent inflammasome activation, increased p38 MAPK (mitogen-activated protein kinase) signaling, and reduced levels of MerTK (c-Mer tyrosine kinase), a key molecule mediating efferocytosis. Increased erythrophagocytosis also suppressed efferocytosis. CONCLUSIONS: Hematopoietic Jak2 VF expression promotes early lesion formation and increased complexity in advanced atherosclerosis. In addition to increasing hematopoiesis and neutrophil infiltration in early lesions, Jak2 VF caused cellular defects in erythrocytes and macrophages, leading to increased erythrophagocytosis but defective efferocytosis. These changes promote accumulation of iron in plaques and increased necrotic core formation which, together with exacerbated proinflammatory responses, likely contribute to plaque instability.
Assuntos
Aterosclerose/genética , Eritrócitos/metabolismo , Janus Quinase 2/genética , Macrófagos/metabolismo , Fagocitose , Adulto , Idoso , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Antígeno CD47/genética , Antígeno CD47/metabolismo , Citocinas/genética , Citocinas/metabolismo , Feminino , Hematopoese , Humanos , Ferro/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neutrófilos/metabolismo , c-Mer Tirosina Quinase/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Over the past decade, genomic studies have identified a number of novel and recurrent somatic mutations that affect epigenetic patterning in patients with myeloid malignancies, including myeloproliferative neoplasms, myelodysplastic syndrome, and acute myeloid leukemia. Many of these mutations occur in genes with established roles in the regulation and maintenance of DNA methylation and/or chromatin modifications in hematopoietic stem/progenitor cells. Subsequent genetic and functional studies have revealed that these mutations affect epigenetic patterning in myeloid diseases. In this review, we discuss historical and recent studies implicating epigenetic modifiers in the development and evolution of the various myeloid malignancies and discuss how this knowledge has and will lead to future clinical and biologic insights.
Assuntos
Epigênese Genética , Células-Tronco Hematopoéticas/fisiologia , Leucemia Mieloide/genética , Mutação/genética , Animais , Metilação de DNA , HumanosRESUMO
JAK inhibitor treatment is limited by the variable development of anemia and thrombocytopenia thought to be due to on-target JAK2 inhibition. We evaluated the impact of Jak2 deletion in platelets (PLTs) and megakaryocytes (MKs) on blood counts, stem/progenitor cells, and Jak-Stat signaling. Pf4-Cre-mediated Jak2 deletion in PLTs and MKs did not compromise PLT formation but caused thrombocytosis, and resulted in expansion of MK progenitors and Lin(-)Sca1(+)Kit+ cells. Serum thrombopoietin (TPO) was maintained at normal levels in Pf4-Cre-positive Jak2(f/f) mice, consistent with reduced internalization/turnover by Jak2-deficient PLTs. These data demonstrate that Jak2 in terminal megakaryopoiesis is not required for PLT production, and that Jak2 loss in PLTs and MKs results in non-autonomous expansion of stem/progenitors and of MKs and PLTs via dysregulated TPO turnover. This suggests that the thrombocytopenia frequently seen with JAK inhibitor treatment is not due to JAK2 inhibition in PLTs and MKs, but rather due to JAK2 inhibition in stem/progenitor cells.
Assuntos
Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Trombocitose/metabolismo , Trombopoese/fisiologia , Animais , Plaquetas/citologia , Cruzamentos Genéticos , Deleção de Genes , Regulação Enzimológica da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Megacariócitos/citologia , Camundongos , Transdução de Sinais , Células-Tronco/citologia , Trombopoetina/sangue , Trombopoetina/metabolismoRESUMO
Hygge practices embody joy, peace, mindfulness, coziness, and conviviality. Cystic fibrosis (CF) is a progressive condition with complex therapies and physical limitations. Little is known about how hygge practice may impact individuals living with CF. A qualitative study explored how adults with CF use hygge practices to promote wellness and cope with their disease. A purposive network sample of 15 adults with CF who utilized hygge practices completed semistructured audio-recorded telephone interviews. Recordings were transcribed and analyzed using Colaizzi's thematic analysis approach. Results reveal that hygge practices influenced individuals' aesthetics, attitudes, and activities, deeply impacting the physical and emotional experience of living with CF. Incorporating hygge into CF care may improve psychological well-being and quality of life for members of this community.
Assuntos
Fibrose Cística , Adulto , Humanos , Fibrose Cística/psicologia , Qualidade de Vida/psicologia , Emoções , Pesquisa QualitativaRESUMO
BACKGROUND: Most males with cystic fibrosis (MwCF) have congenital bilateral absence of the vas deferens and require assisted reproductive technology to conceive, yet many have limited knowledge about how CF affects sexual and reproductive health (SRH). This study evaluates the feasibility, acceptability, and potential effectiveness of telehealth fertility preservation (FP) counseling for MwCF. METHODS: Pre-lung transplant MwCF ≥18 years, recruited from U.S. CF centers, social media, and via snowball sampling, received individualized telehealth counseling. Participants completed intervention feasibility/acceptability one week post-counseling and FP knowledge, care satisfaction, and self-efficacy assessments at baseline and two months post-counseling. We completed acceptability interviews one-week post-counseling and audio-recorded, transcribed, and thematically analyzed results. We descriptively analyzed survey results and conducted pre/post comparisons using paired t-tests. RESULTS: Thirty MwCF (ages 22-49 years) completed counseling. Most were in a relationship (70 %) and White (86.7 %). Telehealth FP counseling was acceptable (M = 4.38/5 ± 0.60), appropriate (M = 4.37/5 ± 0.60), and feasible (M = 4.60/5 ± 0.45) to MwCF. FP knowledge (9.53 vs. 10.40/12; p = .010), care satisfaction (20.23 vs 26.67/32; p<.001), and self-efficacy (22.87 vs 25.20/30; p = .016) improved at two months post-counseling. Despite desiring provider-initiated SRH, wanting children (81 %), and perceiving the CF team as their primary care provider (97 %), 44 % report not receiving information about infertility by the CF team. CONCLUSIONS: Integrating FP counseling into CF care is feasible and acceptable to MwCF and can improve FP knowledge, self-efficacy, and care satisfaction. MwCF desire early and regular provider-initiated SRH education.
RESUMO
Background: Cystic fibrosis (CF) is a rare genetic disease affecting approximately 30,000 people in the United States (US). African American persons with CF are even rarer, comprising approximately 5% of this population. Purpose: The purpose of this study was to explore the lived experiences of African American persons with CF to identify potential disparities in health care. Methods: Descriptive phenomenology was used to explore lived experiences of African American persons with CF over age 18 recruited from CF Foundation-accredited Centers in the US, CF-specific social media, and via snowball sampling. Study data was obtained through telephone interviews that were audio-recorded, transcribed verbatim, and analyzed using Colaizzi's method of thematic analysis. Results: Six men and six women (ages 23-45) completed the study. Interviews revealed three themes: (1) Accepting a Diagnosis of CF; (2) Desiring a Normal Life while Living with an Invisible Disease; and 3) A Slippery Slope of Subtle Racism. Each theme had 2-3 subthemes. Conclusions: It is critical to explore the unique challenges faced by African American persons with CF in order to develop interventions that improve their daily lives and create better futures. Implications for Practice: Findings highlight the unique challenges faced by underrepresented groups with CF and the need to address health inequities to improve care delivery.
Assuntos
Fibrose Cística , Racismo , Feminino , Humanos , Masculino , Negro ou Afro-Americano , Atenção à Saúde , Pesquisa Qualitativa , Estados Unidos , Adulto Jovem , Adulto , Pessoa de Meia-IdadeRESUMO
AIM: To develop a clear definition of infertility-related stress using Rodgers' method of concept analysis. BACKGROUND: Infertility affects approximately 13% of women in the United States. Though poorly defined in the literature, previous studies suggest infertility-related stressors contribute to psychological distress. DESIGN: Rodgers' method of concept analysis guided the review, including sample and setting, literature search, and data analysis. DATA SOURCE: PubMed, CINAHL, and PsycINFO were searched for relevant literature. REVIEW METHODS: Following abstract, title, and text screenings, 21 articles were included and reported using the PRISMA-S checklist. Texts were analyzed and results informed the proposed definition of infertility-related stress. RESULTS: Antecedents included infertility, desire for children, and fear of the unknown. Attributes were identity crisis, social isolation and stigma, sexual stress, and financial strain. Consequences included treatment dropout and marital strain. Anxiety, depression, and decreased quality of life were identified as both attributes and consequences. CONCLUSIONS: Synthesized results informed a proposed definition of infertility-related stress. Improved understanding of infertility-related stress allows for measurement development and facilitates recognition of patients in need of additional support, while potentially reducing the impact on the health and well-being of infertile women.
Assuntos
Infertilidade Feminina , Criança , Formação de Conceito , Feminino , Humanos , Qualidade de Vida , Estados UnidosRESUMO
The transition to college represents a period of increased risk for developing a range of mental health conditions, highlighting the need for effective preventive interventions delivered in this setting. The purpose of the present study was to explore the feasibility, acceptability, and efficacy of a preventive version of the unified protocol for college students; this intervention, called emotions 101 was provided in a very brief, online course format. Unselected students (N = 243) were randomized to either the course (n = 120) or wait-list (n = 123) condition, and all participants were asked to complete self-report measures of stress, negative affectivity, and quality of life at baseline, 1-month, 6-month, and 8-month follow-up time points. Despite recruitment challenges, once participants enrolled in the course, they were likely to complete it and provide favorable satisfaction ratings and qualitative feedback. With regard to efficacy, there were no significant differences on our primary (emotional) outcomes (i.e., stress, negative affectivity, quality of life) as a function of condition, though individuals randomized to receive the course demonstrated significantly higher grade point averages at the end of their first college semester than those in the wait-list condition. Taken together, the findings from the present study suggest that a very brief, online prevention program for emotional disorders administered in a healthy sample does not significantly impact mental health variables.
Assuntos
Transtornos do Humor , Qualidade de Vida , Universidades , Emoções , Humanos , Transtornos do Humor/prevenção & controle , EstudantesRESUMO
The Unified Protocol for Transdiagnostic Treatment (UP; Barlow et al., 2011) has recently demonstrated statistically equivalent therapeutic effects compared to leading cognitive behavioral therapy (CBT) protocols for anxiety disorders designed to address disorder-specific symptoms (i.e., single-disorder protocols [SDP]); Barlow et al., 2017). Although all treatment protocols included similar evidence-based CBT elements, investigation of those related to symptom improvement in the UP is warranted. Because the UP is unique from the SDPs for its inclusion of mindfulness, the present study evaluated mindfulness as a primary treatment element. We explored whether UP participants, compared to SDP, demonstrated greater improvements in mindfulness from pre- to posttreatment, and whether these improvements predicted posttreatment severity across anxiety disorder diagnoses. Participants were individuals with a principle anxiety disorder (N = 179) randomized to receive either the UP or SDP. Results indicated significant improvements pre- to posttreatment in mindfulness for participants receiving either the UP or SDP. However, at posttreatment, mindfulness scores were significantly greater for the UP condition. At the diagnosis level, posttreatment scores in mindfulness were significantly greater in the UP condition than the respective SDP conditions for principal Generalized Anxiety Disorder (GAD) and Social Anxiety Disorder (SOC). Moreover, results suggest that change in mindfulness is related to posttreatment severity, when moderated by treatment condition, but only for participants with principal GAD. Taken together, the UP is effective in improving mindfulness in a sample with heterogeneous anxiety disorders, but this change seems particularly relevant for reduction in symptom severity for individuals with principal GAD.
Assuntos
Transtornos de Ansiedade , Terapia Cognitivo-Comportamental , Atenção Plena , Fobia Social , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/terapia , Humanos , Resultado do TratamentoRESUMO
Identifying the neural correlates of positive interactions between friendship dyads may provide insights into mechanisms associated with adolescent social development. Forty-eight 14- to 18-year-old typically developing adolescents were video-recorded discussing a shared positive event with a close friend and subsequently viewed clips during an fMRI scan of that friend during the interaction and of an unfamiliar peer in a similar interaction. Adolescents also reported on their positive affect in daily life while with friends using ecological momentary assessment. We used multivariate repeated measures models to evaluate how positive affect with friends in the laboratory and in daily life was associated with neural response to friend and stranger positive and neutral clips. Adolescents who exhibited more positive affect when with friends in the laboratory showed less dorsolateral prefrontal cortex to friend positive clips. More positive affect when with friends in daily life was associated with less bilateral anterior insula response to friend positive clips, but greater left anterior insula response to stranger positive clips. Findings provide information on the role of lateral prefrontal cortex and anterior insula in enjoyment of friendships during adolescence.
Assuntos
Desenvolvimento do Adolescente/fisiologia , Encéfalo/fisiologia , Amigos , Comportamento Social , Adolescente , Emoções/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
The purpose of the current study was to investigate the unique effects of a commonly used skill incorporated into treatment packages for borderline personality disorder (BPD), countering emotion-driven behavioral urges. Individuals with BPD (N = 8) participated in a single-case experimental design, specifically a multiple baseline, in which they were randomly assigned to complete a baseline assessment-only phase of 2 or 4 weeks. Participants then received four sessions of the countering emotional behaviors module from the unified protocol, followed by a 4-week follow-up phase. Throughout the duration of the study, daily data capture was used to assess real-time changes in the frequency of emotionally avoidant behaviors in response to emotional experiences. Symptoms of BPD, depression, and anxiety were also assessed. By follow-up, the majority of patients demonstrated a meaningful reduction (per single-case experimental design guidelines for evaluating improvements) in their use of avoidant behaviors. There was also preliminary evidence that encouraging participants to act counter to avoidant urges is associated with decreases in BPD, depression, and anxiety symptoms, as well as negative affectivity. The countering emotional behaviors skill from the unified protocol indeed engages its putative target of emotionally avoidant behavioral coping, indicating it is an active ingredient in multicomponent treatment packages for BPD, with implications for downstream clinical endpoints such as BPD and depressive and anxiety symptoms. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Assuntos
Transtorno da Personalidade Borderline/terapia , Emoções , Adulto , Afeto , Ansiedade/terapia , Aprendizagem da Esquiva , Depressão/terapia , Feminino , Humanos , Masculino , Adulto JovemRESUMO
OBJECTIVE: Children of depressed parents are at increased risk for psychopathology. One putative mechanism of risk appears to be altered processing of emotion-related stimuli. Although prior work has evaluated how adolescent offspring of depressed parents may show blunted reward processing compared to low-risk youth, there has been less attention to how young children with this familial history may differ from their peers during middle childhood, a period of critical socio-affective development METHOD: The current study evaluated 56 emotionally healthy 6-to 8-year children who were deemed at high-risk (nâ¯=â¯25) or low-risk (nâ¯=â¯31) for depression based on maternal history of depression. Children completed a behavioral reward seeking task in the laboratory and an fMRI paradigm assessing neural response to happy faces, a social reward. RESULTS: Findings demonstrated that high-risk children showed blunted responding to happy faces in the dorsal striatum compared to low-risk children. Further, lower responding in the dorsal striatum and dorsolateral prefrontal cortex was related to lower behavioral reward seeking, but only in high-risk children. CONCLUSION: Function within neural reward regions may be altered in high-risk offspring as young as 6- to 8-years of age. Further, neural reward responding may be linked to lower behavioral response to obtain reward in these high-risk offspring.
Assuntos
Depressão/fisiopatologia , Predisposição Genética para Doença/psicologia , Córtex Pré-Frontal/fisiopatologia , Adolescente , Criança , Pré-Escolar , Depressão/genética , Transtorno Depressivo , Emoções , Expressão Facial , Feminino , Felicidade , Humanos , Imageamento por Ressonância Magnética , Masculino , Recompensa , RiscoRESUMO
PURPOSE: The myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are characterized by the expansion of the erythroid, megakaryocytic, and granulocytic lineages. A common feature of these disorders is the presence of abnormal megakaryocytes, which have been implicated as causative agents in the development of bone marrow fibrosis. However, the specific contributions of megakaryocytes to MPN pathogenesis remain unclear. EXPERIMENTAL DESIGN: We used Pf4-Cre transgenic mice to drive expression of JAK2V617F in megakaryocyte lineage-committed hematopoietic cells. We also assessed the critical role of mutant megakaryocytes in MPN maintenance through cell ablation studies in JAK2V617F and MPLW515L BMT models of MPN. RESULTS: JAK2V617F -mutant presence in megakaryocytes was sufficient to induce enhanced erythropoiesis and promote fibrosis, which leads to a myeloproliferative state with expansion of mutant and nonmutant hematopoietic cells. The increased erythropoiesis was associated with elevated IL6 level, which was also required for aberrant erythropoiesis in vivo. Furthermore, depletion of megakaryocytes in the JAK2V617F and MPLW515L BMT models ameliorated polycythemia and leukocytosis in addition to expected effects on megakaryopoiesis. CONCLUSIONS: Our observations reveal that JAK/STAT pathway activation in megakaryocytes induces myeloproliferation and is necessary for MPN maintenance in vivo. These observations indicate that MPN clone can influence the behavior of the wild-type hematopoietic milieu, at least, in part, via altered production of proinflammatory cytokines and chemokines. Our findings resonate with patients who present with a clinical MPN and a low JAK2V617F allele burden, and support the development of MPN therapies aimed at targeting megakaryocytes.
Assuntos
Janus Quinase 2/metabolismo , Megacariócitos/metabolismo , Megacariócitos/patologia , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Fator de Transcrição STAT5/metabolismo , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Proliferação de Células/fisiologia , Feminino , Humanos , Janus Quinase 2/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transtornos Mieloproliferativos/genética , Mutação Puntual , Fator de Transcrição STAT5/genética , Transdução de SinaisRESUMO
Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2(-/-);Flt3(ITD) progenitors (LSK CD48(+)CD150(-)) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3(ITD) mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus. Re-expression of Gata2 induced differentiation in AML stem cells and attenuated leukemogenesis. TET2 and FLT3 mutations cooperatively induce AML, with a defined leukemia stem cell population characterized by site-specific changes in DNA methylation and gene expression.
Assuntos
Proteínas de Ligação a DNA/genética , Epigênese Genética , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas/genética , Tirosina Quinase 3 Semelhante a fms/genética , Antineoplásicos/uso terapêutico , Diferenciação Celular/genética , Citarabina/uso terapêutico , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Dioxigenases , Doxorrubicina/uso terapêutico , Fator de Transcrição GATA2/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Haploinsuficiência , Mutação , Proteínas Proto-Oncogênicas/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
The treatment of non-small cell lung cancer has evolved dramatically over the past decade with the adoption of widespread use of effective targeted therapies in patients with distinct molecular alterations. In lung squamous cell carcinoma (lung SqCC), recent studies have suggested that DDR2 mutations are a biomarker for therapeutic response to dasatinib and clinical trials are underway testing this hypothesis. Although targeted therapeutics are typically quite effective as initial therapy for patients with lung cancer, nearly all patients develop resistance with long-term exposure to targeted drugs. Here, we use DDR2-dependent lung cancer cell lines to model acquired resistance to dasatinib therapy. We perform targeted exome sequencing to identify two distinct mechanisms of acquired resistance: acquisition of the T654I gatekeeper mutation in DDR2 and loss of NF1. We show that NF1 loss activates a bypass pathway, which confers ERK dependency downstream of RAS activation. These results indicate that acquired resistance to dasatinib can occur via both second-site mutations in DDR2 and by activation of bypass pathways. These data may help to anticipate mechanisms of resistance that may be identified in upcoming clinical trials of anti-DDR2 therapy in lung cancer and suggest strategies to overcome resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Neurofibromina 1/genética , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/genética , Receptores Mitogênicos/genética , Tiazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Análise Mutacional de DNA , Dasatinibe , Receptores com Domínio Discoidina , Relação Dose-Resposta a Droga , Exoma/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Immunoblotting , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neurofibromina 1/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Mitogênicos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas ras/metabolismoRESUMO
UNLABELLED: While genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations which drive squamous cell lung cancer. Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8% of squamous cell lung cancers and cell lines. Squamous lung cancer cell lines harboring DDR2 mutations were selectively killed by knock-down of DDR2 by RNAi or by treatment with the multi-targeted kinase inhibitor dasatinib. Tumors established from a DDR2 mutant cell line were sensitive to dasatinib in xenograft models. Expression of mutated DDR2 led to cellular transformation which was blocked by dasatinib. A squamous cell lung cancer patient with a response to dasatinib and erlotinib treatment harbored a DDR2 kinase domain mutation. These data suggest that gain-of-function mutations in DDR2 are important oncogenic events and are amenable to therapy with dasatinib. As dasatinib is already approved for use, these findings could be rapidly translated into clinical trials. SIGNIFICANCE: DDR2 mutations are present in 4% of lung SCCs, and DDR2 mutations are associated with sensitivity to dasatinib. These findings provide a rationale for designing clinical trials with the FDA-approved drug dasatinib in patients with lung SCCs.