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Natural killer cells (NK) are the "professional killer" of tumors and play a crucial role in anti-tumor immunotherapy. NK cell desensitization is a key mechanism of tumor immune escape. Dysregulated NKG2D-NKG2DL signaling is a primary driver of this desensitization process. However, the factors that regulate NK cell desensitization remain largely uncharacterized. Here, we present the first report that circular RNA circARAP2 (hsa_circ_0069396) is involved in the soluble MICA (sMICA)-induced NKG2D endocytosis in the NK cell desensitization model. CircARAP2 was upregulated during NK cell desensitization and the loss of circARAP2 alleviated NKG2D endocytosis and NK cell desensitization. Using Chromatin isolation by RNA purification (ChIRP) and RNA pull-down approaches, we identified that RAB5A, a molecular marker of early endosomes, was its downstream target. Notably, transcription factor CTCF was an intermediate functional partner of circARAP2. Mechanistically, we discovered that circARAP2 interacted with CTCF and inhibited the recruitment of CTCF-Polycomb Repressive Complex 2 (PRC2) to the promoter region of RAB5A, thereby erasing histone H3K27 and H3K9 methylation suppression to enhance RAB5A transcription. These data demonstrate that inhibition of circARAP2 effectively alleviates sMICA-induced NKG2D endocytosis and NK cell desensitization, providing a novel target for therapeutic intervention in tumor immune evasion.
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Fator de Ligação a CCCTC , Antígenos de Histocompatibilidade Classe I , Células Matadoras Naturais , RNA Circular , Proteínas rab5 de Ligação ao GTP , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Humanos , Fator de Ligação a CCCTC/metabolismo , Fator de Ligação a CCCTC/genética , RNA Circular/genética , RNA Circular/metabolismo , Proteínas rab5 de Ligação ao GTP/metabolismo , Proteínas rab5 de Ligação ao GTP/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Endocitose , Endossomos/metabolismo , Camundongos , AnimaisRESUMO
BACKGROUND: A higher difference in estimated glomerular filtration rate by cystatin C versus creatinine (eGFRDiff = eGFRCys - eGFRCreat) is associated with decreased frailty risk. Since eGFRCreat is influenced by muscle more than eGFRCys, muscle mass may explain this association. Previous work could not account for this when considering regional muscle measures by imaging. Deuterated creatine (D3Cr) dilution measures whole body muscle mass (kilograms). We aimed to determine whether eGFRDiff is associated with D3Cr muscle mass and whether muscle mass explains the association between eGFRDiff and frailty. METHODS: Cross-sectional analysis within the multicenter MrOS Study at Year 14 (visit 4). 490 men of the original cohort of 5994 MrOS participants (aged ≥65 at enrollment) were included. Exposure was eGFRDiff (= eGFRCys - eGFRCreat), calculated using CKD-EPI equations 2012/2021. Primary outcome was D3Cr muscle mass. Secondary outcome was phenotypic pre-frailty (one or two criteria) and frailty (≥three criteria) including the following: weight loss, weakness, slow gait, physical activity, poor energy. The association of eGFRDiff with D3Cr muscle mass was examined by linear regression, that with prefrailty / frailty by multinomial logistic regression. RESULTS: Mean ± SD age was 84 ± 4 years, eGFRCreat 68 ± 16, eGFRCys 52 ± 16, eGFRDiff -15 ± 12 mL/min/1.73 m2 and D3Cr muscle mass 24 ± 4 kg. For each SD increment in eGFRDiff, D3Cr muscle mass was 1.4 kg higher on average, p < 0.0001 (fully adjusted). Higher eGFRDiff was associated with lower odds of frailty (OR = 0.63 95% CI [0.45;0.89]), but this was partially attenuated and insignificant after additionally adjusting for D3Cr muscle mass (OR = 0.85 95% CI [0.58; 1.24]). CONCLUSIONS: Higher eGFRDiff is associated with lower odds of frailty among late-life men. D3Cr muscle mass accounts for some of this association. This suggests that non-GFR determinants of creatinine and cystatin C, such as muscle mass, play a role in explaining the association of eGFRDiff with frailty. Future studies are needed to confirm.
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To assess the independent and combined relationships among objectively measured sedentary time (ST), light intensity PA (LPA), and moderate-to-vigorous intensity PA (MVPA) with muscle mass and fat mass (FM) and how theoretical displacement of these inter-dependent behaviours relates to body composition in oldest-old men. A total of 1046 men participating in the year 14 visit of the prospective Osteoporotic Fractures in Men (MrOS) cohort study with complete data for accelerometry, dual x-ray absorptiometry, and deuterated creatine dilution (D3Cr) muscle mass were included in the analysis (84.0 ± 3.8 yrs.). Single, partition, and isotemporal substitution models were used to assess the interrelationships between PA intensities and ST with body composition measures, while controlling for relevant confounders. Replacing 30-min of ST with 30-min of MVPA was associated with lower FM (ß =-0.17, p < 0.001) and higher D3Cr muscle mass, although this was of borderline significance (ß = 0.07, p = 0.05). Replacing 30-min of ST for LPA was associated with lower FM (ß =-0.15, p < 0.001), but there was no effect on D3Cr muscle mass (p > 0.05). Exchanging ST with any intensity of PA is associated with benefits for FM in oldest-old adult men, although substitution with MVPA may be more beneficial than LPA for maintaining/improving skeletal muscle mass.
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Absorciometria de Fóton , Acelerometria , Composição Corporal , Exercício Físico , Músculo Esquelético , Comportamento Sedentário , Humanos , Masculino , Exercício Físico/fisiologia , Idoso de 80 Anos ou mais , Músculo Esquelético/fisiologia , Estudos Prospectivos , CreatinaRESUMO
The N6-methyladenosine (m6A) RNA modification plays essential roles in multiple biological processes, including stem cell fate determination. To explore the role of the m6A modification in pluripotent reprogramming, we used RNA-seq to map m6A effectors in human iPSCs, fibroblasts, and H9 ESCs, as well as in mouse ESCs and fibroblasts. By integrating the human and mouse RNA-seq data, we found that 19 m6A effectors were significantly upregulated in reprogramming. Notably, IGF2BPs, particularly IGF2BP1, were among the most upregulated genes in pluripotent cells, while YTHDF3 had high levels of expression in fibroblasts. Using quantitative PCR and Western blot, we validated the pluripotency-associated elevation of IGF2BPs. Knockdown of IGF2BP1 induced the downregulation of stemness genes and exit from pluripotency. Proteome analysis of cells collected at both the beginning and terminal states of the reprogramming process revealed that the IGF2BP1 protein was positively correlated with stemness markers SOX2 and OCT4. The eCLIP-seq target analysis showed that IGF2BP1 interacted with the coding sequence (CDS) and 3'UTR regions of the SOX2 transcripts, in agreement with the location of m6A modifications. This study identifies IGF2BP1 as a vital pluripotency-associated m6A effector, providing new insight into the interplay between m6A epigenetic modifications and pluripotent reprogramming.
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Células-Tronco Pluripotentes Induzidas , Humanos , Animais , Camundongos , Células-Tronco Pluripotentes Induzidas/metabolismo , Diferenciação Celular/genética , Epigênese Genética , Fibroblastos/metabolismo , Reprogramação Celular/genéticaRESUMO
Purpose: Adult growth hormone deficiency (AGHD) is often underdiagnosed and undertreated, leading to costly comorbidities. Previously, we developed an algorithm to identify individuals in a commercially insured US population with high, moderate, or low likelihood of having AGHD. Here, we estimate and compare direct medical costs by likelihood level. Patients and Methods: Retrospective, observational analysis using the Truven Health MarketScan database to analyze direct medical costs relating to inpatient and outpatient claims, outpatient prescription claims, medication usage, clinical utilization records, and healthcare expenditures. Patients were categorized into groups based on algorithmically determined likelihoods of AGHD. Likelihood groups were further stratified by age and sex. Trajectories of annual costs (USD) by likelihood level were also investigated. Results: The study cohort comprised 135 million US adults (aged ≥18 years). Individuals ranked as high-likelihood AGHD had a greater burden of comorbid illness, including cardiovascular disease and diabetes, than those ranked moderate- or low-likelihood. Those in the high-likelihood group had greater mean total direct medical monthly costs ($1844.51 [95% confidence interval (CI): 1841.24;1847.78]) than those in the moderate- ($945.65 [95% CI: 945.26;946.04]) and low-likelihood groups ($459.10 [95% CI: 458.95;459.25]). Outpatient visits accounted for the majority of costs overall, although cost per visit was substantially lower than for inpatient services. Costs tended to increase with age and peaked around the time that individuals were assigned a level of AGHD likelihood. Total direct medical costs in individuals with a high likelihood of AGHD exceeded those for individuals with moderate or low likelihood. Conclusion: Understanding the trajectory of healthcare costs in AGHD may help rationalize allocation of healthcare resources.
Growth hormone is an important substance found in the body. Adult growth hormone deficiency (AGHD) is the reduced production of growth hormone unrelated to the normal reduction seen with aging. Untreated AGHD can result in the development of other conditions, known as comorbidities, which can be expensive to manage. Previously, 135 million privately insured people in the US, aged 1864 years, were categorized into groups by their likelihood (high, medium, or low) of having AGHD. This study compared the estimated direct medical costs (eg hospital care and medication) across the different likelihood levels. People with a high likelihood of AGHD had more comorbidities than people with a medium/low likelihood, and an average total direct medical monthly cost of $1844.51, nearly twice as much as those with a medium likelihood ($945.65), and four times as much as those with a low likelihood ($459.10). These costs tended to increase with age, with the highest costs associated with people aged 5059 years and 6064 years. Outpatient costs (for treatments not requiring an overnight hospital stay) accounted for the greatest proportion of total medical costs, ahead of inpatient costs (for treatments requiring an overnight hospital stay) and medication costs. These findings suggest that diagnosing and treating AGHD earlier may help to reduce medical costs over time. Increased testing and treatment will cause an initial increase in the use of healthcare resources, but could improve overall cost effectiveness by reducing the long-term impact of the disease and avoiding unnecessary healthcare use.
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Pluripotent stem cells (PSCs) provide unlimited resources for regenerative medicine because of their potential for self-renewal and differentiation into many different cell types. The pluripotency of these PSCs is dynamically regulated at multiple cellular organelle levels. To delineate the factors that coordinate this inter-organelle crosstalk, we profiled those long non-coding RNAs (lncRNAs) that may participate in the regulation of multiple cellular organelles in PSCs. We have developed a unique strand-specific RNA-seq dataset of lncRNAs that may interact with mitochondria (mtlncRNAs) and polyribosomes (prlncRNAs). Among the lncRNAs differentially expressed between induced pluripotent stem cells (iPSCs), fibroblasts, and positive control H9 human embryonic stem cells, we identified 11 prlncRNAs related to stem cell reprogramming and exit from pluripotency. In conjunction with the total RNA-seq data, this dataset provides a valuable resource to examine the role of lncRNAs in pluripotency, particularly for studies investigating the inter-organelle crosstalk network involved in germ cell development and human reproduction.
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Células-Tronco Pluripotentes Induzidas , Células-Tronco Pluripotentes , RNA Longo não Codificante , Humanos , Diferenciação Celular , Reprogramação Celular , Mitocôndrias/genética , Mitocôndrias/metabolismo , Polirribossomos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
[This corrects the article on p. 714 in vol. 9, PMID: 31105998.].
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Introduction Although there are some recommendations in the literature on the assessments that should be performed in children on recombinant human growth hormone (rhGH) therapy, the level of consensus on these measurements is not clear. The objective of the current study was to identify the minimum dataset (MDS) that could be measured in a routine clinical setting across the world, aiming to minimise burden on clinicians and improve quality of data collection. Methods This study was undertaken by the GH Scientific Study Group (SSG) in GloBE-Reg, a new project that has developed a common registry platform that can support long-term safety and effectiveness studies of drugs. Twelve clinical experts from 7 international endocrine organisations identified by the GloBE-Reg Steering Committee, 2 patient representatives and representatives from 2 pharmaceutical companies with previous GH registry expertise collaborated to develop this recommendation. A comprehensive list of data fields routinely collected by each of the clinical and industry experts for children with GHD was compiled. Each member was asked to determine the: (1) Importance of the data field and (2) Ease of data collection. Data fields that achieved 70% consensus in terms of importance qualified for the MDS, provided <50% deemed the item difficult to collect. Results A total of 246 items were compiled and 27 removed due to redundancies, with 219 items subjected to the grading system. Of the 219 items, 111 achieved at least 70% consensus as important data to collect when monitoring children with GH deficiency (GHD) on rhGH treatment. Sixty-nine of the 219 items were deemed easy to collect. Combining the criteria of importance and ease of data collection, 63 met the criteria for the MDS. Several anomalies to the MDS rule were identified and highlighted for discussion, including whether the patients were involved in current or previous clinical trials, need for HbA1c monitoring, other past medical history, and adherence, enabling formulation of the final MDS recommendation of 43 items; 20 to be completed once, 14 every 6 months and 9 every 12 months. Conclusion In summary, this exercise performed through the GloBE-Reg initiative provides a recommendation of the minimum dataset requirement, collected through real-world data, for the monitoring of safety and effectiveness of rhGH in children with GHD, both for the current daily preparations and the newer long-acting growth hormone.
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Non-coding RNAs (ncRNAs) are defined as RNAs that do not encode proteins, but many ncRNAs do have the ability to regulate gene expression. These ncRNAs play a critical role in the epigenetic regulation of various physiological and pathological processes through diverse biochemical mechanisms. However, the existing screening methods to identify regulatory ncRNAs only focus on whole-cell expression levels and do not capture every ncRNA that targets certain genes. We describe a new method, chromatin-RNA in situ reverse transcription sequencing (CRIST-seq), that can identify all the ncRNAs that are associated with the regulation of any given gene. In this article, we targeted the ncRNAs that are associated with pluripotent gene Sox2, allowing us to catalog the ncRNA regulation network of pluripotency maintenance. This methodology is universally applicable for the study of epigenetic regulation of any genes by making simple changes on the CRISPR-dCas9 gRNAs. Key features This method provides a new technique for screening ncRNAs and establishing chromatin interaction networks. The target gene for this method can be any gene of interest and any site in the entire genome. This method can be further extended to detect RNAs, DNAs, and proteins that interact with target genes. Graphical overview.
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Abstract Traumatic brain injury (TBI) is increasingly recognized, with an incidence of approximately 110 per 100,000 in pediatric populations and 618 per 100,000 in adolescent and adult populations. TBI often leads to cognitive, behavioral, and physical consequences, including endocrinopathies. Deficiencies in anterior pituitary hormones (e.g., adrenocorticotropic hormone, thyroid-stimulating hormone, gonadotropins, and growth hormone [GH]) can negatively impact health outcomes and quality of life post-TBI. This review focuses on GH deficiency (GHD), the most common post-TBI pituitary hormone deficiency. GHD is associated with abnormal body composition, lipid metabolism, bone mineral density, executive brain functions, behavior, and height outcomes in pediatric, adolescent, and transition-age patients. Despite its relatively frequent occurrence, post-TBI GHD has not been well studied in these patients; hence, diagnostic and treatment recommendations are limited. Here, we examine the occurrence and diagnosis of TBI, retrospectively analyze post-TBI hypopituitarism and GHD prevalence rates in pediatric and adolescent patients, and discuss appropriate GHD testing strategies and GH dosage recommendations for these patients. We place particular emphasis on the ways in which testing and dosage recommendations may change during the transition phase. We conclude with a review of the challenges faced by transition-age patients and how these may be addressed to improve access to adequate healthcare. Little information is currently available to help guide patients with TBI and GHD through the transition phase and there is a risk of interrupted care; therefore, a strength of this review is its emphasis on this critical period in a patient's healthcare journey.
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Lesões Encefálicas Traumáticas , Encefalopatia Traumática Crônica , Hormônio do Crescimento Humano , Hipopituitarismo , Humanos , Adulto , Adolescente , Criança , Estudos Retrospectivos , Qualidade de Vida , Hipopituitarismo/diagnóstico , Hipopituitarismo/epidemiologia , Hipopituitarismo/etiologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/epidemiologia , Hormônio do Crescimento , Encefalopatia Traumática Crônica/complicaçõesRESUMO
Protein translation is a critical regulatory event involved in nearly all physiological and pathological processes. Eukaryotic translation initiation factors are dedicated to translation initiation, the most highly regulated stage of protein synthesis. Eukaryotic translation initiation factor 4G2 (eIF4G2, also called p97, NAT1 and DAP5), an eIF4G family member that lacks the binding sites for 5' cap binding protein eIF4E, is widely considered to be a key factor for internal ribosome entry sites (IRESs)-mediated cap-independent translation. However, recent findings demonstrate that eIF4G2 also supports many other translation initiation pathways. In this review, we summarize the role of eIF4G2 in a variety of cap-independent and -dependent translation initiation events. Additionally, we also update recent findings regarding the role of eIF4G2 in apoptosis, cell survival, cell differentiation and embryonic development. These studies reveal an emerging new picture of how eIF4G2 utilizes diverse translational mechanisms to regulate gene expression.
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Fator de Iniciação Eucariótico 4G , Biossíntese de Proteínas , Apoptose , Diferenciação Celular , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Fator de Iniciação Eucariótico 4G/genética , Fator de Iniciação Eucariótico 4G/metabolismo , Processamento de Proteína Pós-Traducional , HumanosRESUMO
Nuclear reprogramming of somatic cells into a pluripotent status has the potential to create patient-specific induced pluripotent stem cells for regenerative medicine. Currently, however, the epigenetic mechanisms underlying this pluripotent reprogramming are poorly understood. To delineate this epigenetic regulatory network, we utilized a chromatin RNA in situ reverse transcription sequencing (CRIST-seq) approach to identify long noncoding RNAs (lncRNAs) embedded in the 3-dimensional intrachromosomal architecture of stem cell core factor genes. By combining CRIST-seq and RNA sequencing, we identified Oct4-Sox2 interacting lncRNA 9 (Osilr9) as a pluripotency-associated lncRNA. Osilr9 expression was associated with the status of stem cell pluripotency in reprogramming. Using short hairpin RNA (shRNA) knockdown, we showed that this lncRNA was required for the optimal maintenance of stem cell pluripotency. Overexpression of Osilr9 induced robust activation of endogenous stem cell core factor genes in fibroblasts. Osilr9 participated in the formation of the intrachromosomal looping required for the maintenance of pluripotency. After binding to the Oct4 promoter, Osilr9 recruited the DNA demethylase ten-eleven translocation 1, leading to promoter demethylation. These data demonstrate that Osilr9 is a critical chromatin epigenetic modulator that coordinates the promoter activity of core stem cell factor genes, highlighting the critical role of pluripotency-associated lncRNAs in stem cell pluripotency and reprogramming.
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Células-Tronco Pluripotentes Induzidas , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Desmetilação do DNA , Células-Tronco Pluripotentes Induzidas/metabolismo , Reprogramação Celular/genética , Cromatina/genética , Cromatina/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismoRESUMO
CONTEXT: Supraphysiological serum insulin-like growth factor-I (IGF-I) concentrations have been a matter of concern in children treated with GH because high IGF-I levels were associated with risk of later disease in former epidemiological studies. OBJECTIVE: To determine whether a single IGF-I measurement reliably reflects lifetime IGF-I exposure we evaluated intraindividual longitudinal tracking of IGF-I and IGF-binding protein-3 (IGFBP-3) levels and we estimated cumulative lifetime exposure to IGF-I in healthy and GH-treated individuals. METHODS: We included 6459 healthy participants (cross-sectional = 5326; longitudinal = 1133) aged 0-76 years (9963 serum samples) and 9 patients born small-for-gestational-age (SGA) with 238 serum samples during GH treatment. Intraindividual tracking of IGF-I and IGFBP-3 (SD score [SDS]) was determined by intraclass correlation coefficients (ICCs). Cumulative lifetime IGF-I exposure was estimated by area under the curve of the predicted SDS trajectory from 0 to 76 years. RESULTS: For IGF-I (SDS), ICCs were 0.50 (95% CI, 0.47-0.53) for male and 0.53 (0.50-0.56) for female participants. Lifetime IGF-I exposure was significantly higher in female (mean 12 723 ± 3691 SD) than in male participants (12 563 ± 3393); P = 0.02. In SGA children, treatment with GH increased the lifetime exposure to IGF-I from 9512 ± 1889 to 11 271 ± 1689, corresponding to an increase in lifetime IGF-I trajectory from -0.89 SD ± 0.57 to -0.35 SD ± 0.49. CONCLUSION: Because IGF-I and IGFBP-3 levels track throughout life, a single measurement reliably reflects lifetime exposure. GH therapy increased the lifetime exposure to IGF-I only slightly and it remained below the average lifetime exposure in the reference population.
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Hormônio do Crescimento Humano , Recém-Nascido Pequeno para a Idade Gestacional , Fator de Crescimento Insulin-Like I , Criança , Feminino , Humanos , Recém-Nascido , Masculino , Estudos Transversais , Retardo do Crescimento Fetal , Hormônio do Crescimento Humano/uso terapêutico , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Fator de Crescimento Insulin-Like I/metabolismoRESUMO
Recurrent spontaneous abortion (RSA) is a highly heterogeneous complication of pregnancy with the underlying mechanisms remaining uncharacterized. Dysregulated decidualization is a critical contributor to the phenotypic alterations related to pregnancy complications. To understand the molecular factors underlying RSA, we explored the role of longnoncoding RNAs (lncRNAs) in the decidual microenvironment where the crosstalk at the fetal-maternal interface occurs. By exploring RNA-seq data from RSA patients, we identified H19, a noncoding RNA that exhibits maternal monoallelic expression, as one of the most upregulated lncRNAs associated with RSA. The paternally expressed fetal mitogen IGF2, which is reciprocally coregulated with H19 within the same imprinting cluster, was also upregulated. Notably, both genes underwent loss of imprinting, as H19 and IGF2 were actively transcribed from both parental alleles in some decidual tissues. This loss of imprinting in decidual tissues was associated with the loss of the H3K27m3 repressive histone marker in the IGF2 promoter, CpG hypomethylation at the central CTCF binding site in the imprinting control center (ICR), and the loss of CTCF-mediated intrachromosomal looping. These data suggest that dysregulation of the H19/IGF2 imprinting pathway may be an important epigenetic factor in the decidual microenvironment related to poor decidualization.
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Histonas , RNA Longo não Codificante , Fator de Ligação a CCCTC/genética , Metilação de DNA/genética , Feminino , Impressão Genômica , Histonas/metabolismo , Humanos , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Mitógenos , Gravidez , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA não Traduzido/genéticaRESUMO
Insulin-like growth factor I receptor (IGF1R) is frequently upregulated in breast cancer. Due to its intrinsic tyrosine kinase activity, aberrant activation of the IGF1R signaling axis may enhance tumor cell proliferation and cancer stemness, causing tumor relapse, metastasis and resistance to chemotherapy. We utilized a chromatin RNA in situ reverse transcription (CRIST) approach to characterize molecular factors that regulate the IGF1R network. We identified lncRNA HULC (Highly Upregulated in Liver Cancer) as a key trans-regulator of IGF1R in breast cancer cells. Loss of HULC suppressed the expression of IGF1R and the activation of its downstream PI3K/AKT pathway, while HULC overexpression activated the axis in breast cancer cells. Using a transcription-associated trap (RAT) assay, we demonstrated that HULC functioned as a nuclear lncRNA and epigenetically activated IGF1R by directly binding to the intragenic regulatory elements of the gene, orchestrating intrachromosomal interactions, and promoting histone H3K9 acetylation. The activated HULC-IGF1R/PI3K/AKT pathway mediated tumor resistance to cisplatin through the increased expression of cancer stemness markers, including NANOG, SOX2, OCT4, CD44 and ALDH1A1. In immunodeficient mice, stimulation of the HULC-IGF1R pathway promoted tumor metastasis. These data suggest that HULC may be a new epigenetic target for IGF1R axis-targeted therapeutic intervention.
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RNA Longo não Codificante , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Cromatina , Cisplatino/metabolismo , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Recidiva Local de Neoplasia/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Receptor IGF Tipo 1/metabolismoRESUMO
OBJECTIVE/DESIGN: Approximately 2.9 million children and adults in the US experience traumatic brain injuries (TBIs) annually, most of which are considered mild. TBI can induce varying consequences on pituitary function, with growth hormone deficiency (GHD) among the more commonly reported conditions. Panels of pediatric and adult endocrinologists, neurologists, physical medicine and rehabilitation specialists, and neuropsychologists convened in February and October 2020 to discuss ongoing challenges and provide strategies for detection and optimal management of patients with mild TBI and GHD. RESULTS: Difficulties include a low rate of seeking medical attention in the population, suboptimal screening tools, cost and complexity of GHD testing, and a lack of consensus regarding when to test or retest for GHD. Additionally, referrals to endocrinologists from other specialists are uncommon. Recommendations from the panels for managing such patients included multidisciplinary guidelines on the diagnosis and management of post-TBI GHD and additional education on long-term metabolic and probable cognitive benefits of GH replacement therapy. CONCLUSION: As patients of all ages with mild TBI may develop GHD and/or other pituitary deficiencies, a multidisciplinary approach to provide education to endocrinologists, neurologists, neurosurgeons, traumatologists, and other providers and guidelines for the early identification and management of persistent mild TBI-related GHD are urgently needed.
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Concussão Encefálica , Lesões Encefálicas , Nanismo Hipofisário , Hormônio do Crescimento Humano , Hipopituitarismo , Adulto , Humanos , Criança , Concussão Encefálica/complicações , Concussão Encefálica/diagnóstico , Concussão Encefálica/terapia , Consenso , Lesões Encefálicas/metabolismo , Hipopituitarismo/diagnóstico , Hipopituitarismo/etiologia , Hipopituitarismo/terapia , Hormônio do CrescimentoRESUMO
Recurrence and biochemical remission rates vary widely among different histological subtypes of pituitary adenoma. In this prospective study, we evaluated 107 consecutive primary pituitary adenomas operated on by a single neurosurgeon including 28 corticotroph, 27 gonadotroph, 24 somatotroph, 17 lactotroph, 5 null-cell and 6 plurihormonal. In each case, we performed direct endoscopic intraoperative inspection of the medial wall of the cavernous sinus, which was surgically removed when invasion was visualized. This was performed irrespective of tumor functional status. Medial wall resection was performed in 47% of pituitary adenomas, and 39/50 walls confirmed pathologic evidence of invasion, rendering a positive predictive value of intraoperative evaluation of medial wall invasion of 78%. We show for the first-time dramatic disparities in the frequency of medial wall invasion among pathological subtypes. Somatotroph tumors invaded the medial wall much more often than other adenoma subtypes, 81% intraoperatively and 69% histologically, followed by plurihormonal tumors (40%) and gonadotroph cell tumors (33%), both with intraoperative positive predictive value of 100%. The least likely to invade were corticotroph adenomas, at a rate of 32% intraoperatively and 21% histologically, and null-cell adenomas at 0%. Removal of the cavernous sinus medial wall was not associated with permanent cranial nerve morbidity nor carotid artery injury, although 4 patients (all Knosp 3-4) experienced transient diplopia. Medial wall resection in acromegaly resulted in the highest potential for biochemical remission ever reported, with an average postoperative day 1 GH levels of 0.96 ug/L and surgical remission rates of 92% based on normalization of IGF-1 levels after surgery (mean = 15.56 months; range 3-30 months). Our findings suggest that tumor invasion of the medial wall of the cavernous sinus may explain the relatively low biochemical remission rates currently seen for acromegaly and illustrate the relevance of advanced intradural surgical approaches for successful and durable outcomes in endonasal pituitary surgery for functional adenomas.
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Acromegalia , Adenoma , Seio Cavernoso , Neoplasias Hipofisárias , Acromegalia/patologia , Acromegalia/cirurgia , Adenoma/patologia , Adenoma/cirurgia , Seio Cavernoso/patologia , Seio Cavernoso/cirurgia , Humanos , Processos Neoplásicos , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Estudos Prospectivos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Adult growth hormone deficiency (AGHD) is a rare and serious condition associated with significant morbidity, including reduced quality of life, and is underdiagnosed and often missed in patients. Although the onset of AGHD can occur in either childhood or adulthood, adult-onset AGHD is more difficult to identify as it lacks the auxologic signs caused by GHD during childhood, includes symptoms that tend to be nonspecific, and lacks reliable, simple biomarker testing options. A panel of 9 patients with AGHD (3 with childhood onset; 6 with adult onset) was assembled to share their first-hand experiences, to help reveal important areas of need, increase health literacy, and to raise awareness about GHD among patients, caregivers, and healthcare practitioners. Interviews with patients yielded valuable insights from the patient perspective to supplement prior knowledge about AGHD symptomatology, biomarker testing, and treatment outcomes. Some patients described a burdensome and ineffective screening process that sometimes included many visits to different specialists, repeated rounds of biomarker testing, and, in some cases, excessive delays in AGHD diagnosis. All patients expressed frustration with insurance companies that often resist and/or delay treatment authorization and reimbursement and frequently require additional testing to verify the diagnosis, often leading to treatment gaps. These findings emphasize the necessity of more efficient identification and screening of patients with possible AGHD, better recognition by clinicians and insurance providers of the importance of sustained GH replacement therapy during adulthood, and better patient support for accessing and maintaining uninterrupted GH replacement therapy for patients with documented AGHD.
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Objective: Adult growth hormone deficiency (AGHD) is an underdiagnosed disease associated with increased morbidity and mortality. Identifying people who may benefit from growth hormone (GH) therapy can be challenging, as many AGHD symptoms resemble those of aging. We developed an algorithm to potentially help providers stratify people by their likelihood of having AGHD. Design: The algorithm was developed with, and applied to, data in the anonymized Truven Health MarketScan® claims database. Patients. A total of 135 million adults in the US aged ≥18 years with ≥6 months of data in the Truven database. Measurements. Proportion of people with high, moderate, or low likelihood of having AGHD, and differences in demographic and clinical characteristics among these groups. Results: Overall, 0.5%, 6.0%, and 93.6% of people were categorized into groups with high, moderate, or low likelihood of having AGHD, respectively. The proportions of females were 59.3%, 71.6%, and 50.4%, respectively. People in the high- and moderate-likelihood groups tended to be older than those in the low-likelihood group, with 58.3%, 49.0%, and 37.6% aged >50 years, respectively. Only 2.2% of people in the high-likelihood group received GH therapy as adults. The high-likelihood group had a higher incidence of comorbidities than the low-likelihood group, notably malignant neoplastic disease (standardized difference -0.42), malignant breast tumor (-0.27), hyperlipidemia (-0.26), hypertensive disorder (-0.25), osteoarthritis (-0.23), and heart disease (-0.22). Conclusions: This algorithm may represent a cost-effective approach to improve AGHD detection rates by identifying appropriate patients for further diagnostic testing and potential GH replacement treatment.
RESUMO
Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.