RESUMO
BACKGROUND: No guidelines exist regarding physicians' duty to inform former patients about novel genetic tests that may be medically beneficial. Research on the feasibility and efficacy of disseminating information and patient opinions on this topic is limited. METHODS: Adult patients treated at our institution from 1950 to 2010 for medullary thyroid cancer, pheochromocytoma, or paraganglioma were included if their history suggested being at-risk for a hereditary syndrome but genetic risk assessment would be incomplete by current standards. A questionnaire assessing behaviors and attitudes was mailed 6 weeks after an information letter describing new genetic tests, benefits, and risks was mailed. RESULTS: Ninety-seven of 312 (31.1%) eligible patients with an identified mailing address returned the questionnaire. After receiving the letter, 29.2% patients discussed genetic testing with their doctor, 39.3% considered pursuing genetic testing, and 8.5% underwent testing. Nearly all respondents (97%) indicated that physicians should inform patients about new developments that may improve their or their family's health, and 71% thought patients shared this responsibility. Most patients understood the letter (84%) and were pleased it was sent (84%), although 11% found it upsetting. CONCLUSIONS: Patients believe it is important for physicians to inform them of potentially beneficial developments in genetic testing. However, physician-initiated letters to introduce new information appear inadequate alone in motivating patients to seek additional genetic counseling and testing. Further research is needed regarding optimal methods to notify former patients about new genetic tests and corresponding clinical and ethical implications.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Carcinoma Neuroendócrino/genética , Comunicação , Testes Genéticos , Paraganglioma/genética , Feocromocitoma/genética , Papel do Médico , Neoplasias da Glândula Tireoide/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Aconselhamento Genético/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Inquéritos e QuestionáriosRESUMO
PURPOSE AND INTRODUCTION: A growing number of cancer patients are older adults aged 65 years and older. Patients with cancer are at increased risk for developing osteoporosis, falls, and fractures. We sought to identify the incidence of fractures in older adults who underwent cancer care between January 2013 and December 2015. METHODS: A comprehensive geriatric assessment was performed, and bone densitometry was measured at baseline, with a 2-year follow-up. RESULTS: In this study, among 304 patients with gastrointestinal, urologic, breast, lung, and gynecologic cancers we evaluated, and who completed the bone density testing (n = 199), 80% had osteoporosis or low bone mass (osteopenia). There was a higher prevalence of osteoporosis in cancer patients (40 vs. 16%, p = 0.05) than in population studies. Vitamin D insufficiency (< 30 ng/ml) was identified in 49% of tested cases (n = 245). Risk factors for low bone mass or osteoporosis were advanced age (p = 0.05), malnutrition (p = 0.04), and frailty (p = 0.01). Over the following 2 years (median follow-up 18 months), there was an incidence of fractures of 110 per 1000 person-years, or 2.8 times higher than reported in individuals without cancer. Risk factors for fractures included advanced age (70-79 vs. 60-69 years, p = 0.05) and frailty (p = 0.03). CONCLUSION: Most older cancer patients studied have osteoporosis or low bone mass, resulting in an almost 3-fold increase in fracture risk as compared to epidemiologic studies. Bone health issues are commonly seen in older cancer patients, we recommend universal bone density testing. The initiation of antiresorptive treatment when findings are of osteopenia or osteoporosis will reduce the risk of fractures.
Assuntos
Fraturas Ósseas/etiologia , Avaliação Geriátrica/métodos , Neoplasias/complicações , Deficiência de Vitamina D/complicações , Idoso , Idoso de 80 Anos ou mais , Feminino , Hospitais , Humanos , Masculino , Neoplasias/patologia , Fatores de Risco , TexasRESUMO
The RET proto-oncogene, a tyrosine kinase receptor, is widely known for its essential role in cell survival. Germ line missense mutations, which give rise to constitutively active oncogenic RET, were found to cause multiple endocrine neoplasia type 2, a dominant inherited cancer syndrome that affects neuroendocrine organs. However, the mechanisms by which RET promotes cell survival and prevents cell death remain elusive. We demonstrate that in addition to cytoplasmic localization, RET is localized in the nucleus and functions as a tyrosine-threonine dual specificity kinase. Knockdown of RET by shRNA in medullary thyroid cancer-derived cells stimulated expression of activating transcription factor 4 (ATF4), a master transcription factor for stress-induced apoptosis, through activation of its target proapoptotic genes NOXA and PUMA. RET knockdown also increased sensitivity to cisplatin-induced apoptosis. We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. Moreover, chromatin immunoprecipitation assays revealed that ATF4 occupancy increased at the NOXA promoter in TT cells treated with tyrosine kinase inhibitors or the ATF4 inducer eeyarestatin as well as in RET-depleted TT cells. Together these findings reveal RET as a novel dual kinase with nuclear localization and provide mechanisms by which RET represses the proapoptotic genes through direct interaction with and phosphorylation-dependent inactivation of ATF4 during the pathogenesis of medullary thyroid cancer.
Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Apoptose , Proteínas Proto-Oncogênicas c-ret/metabolismo , Fator 4 Ativador da Transcrição/química , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Cisplatino/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Inibidores de Proteínas Quinases/farmacologia , Proteólise/efeitos dos fármacos , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Treonina/metabolismo , Transcrição Gênica/efeitos dos fármacosRESUMO
The 2015 Santa Fe Bone Symposium was a venue for healthcare professionals and clinical researchers to present and discuss the clinical relevance of recent advances in the science of skeletal disorders, with a focus on osteoporosis and metabolic bone disease. Symposium topics included new developments in the translation of basic bone science to improved patient care, osteoporosis treatment duration, pediatric bone disease, update of fracture risk assessment, cancer treatment-related bone loss, fracture liaison services, a review of the most significant studies of the past year, and the use of telementoring with Bone Health Extension for Community Healthcare Outcomes, a force multiplier to improve the care of osteoporosis in underserved communities.
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Doenças Ósseas Metabólicas , Osteoporose , California , HumanosRESUMO
Two independent events--the identification of activating mutations of the RET proto-oncogene, a receptor tyrosine kinase, in medullary thyroid carcinoma, and the recognition that small organic molecules could bind to and inhibit phosphorylation of signaling molecules, thereby inactivating the pathway-led to the recognition that kinase inhibitors could be used to treat medullary thyroid carcinoma (MTC). The introduction of these compounds into clinical practice has transformed the treatment of metastatic MTC and provided insight into the mechanisms by which RET causes C-cell transformation. This chapter will review the progress in this field over the past 7 years.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Carcinoma Neuroendócrino/enzimologia , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Predisposição Genética para Doença , Humanos , Terapia de Alvo Molecular , Mutação , Seleção de Pacientes , Fenótipo , Inibidores de Proteínas Quinases/efeitos adversos , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Resultado do TratamentoRESUMO
Procalcitonin (PCT) is expressed in nonthryoidal tissues of humans during severe infections. Serum PCT levels are measured to diagnose and guide therapy, and there is some evidence that PCT may also contribute to the pathogenesis of sepsis. We tested whether disruption of the gene encoding PCT in mice affected the course of sepsis. Mice with exons 2-5 of the gene encoding calcitonin/calcitonin gene-related polypeptide α (Calca) knocked out and congenic C57BL/6J control mice were challenged with aerosolized Streptococcus pneumoniae or Pseudomonas aeruginosa, or injected intraperitoneally with S. pneumoniae. There were no significant differences in the survival of knockout and control mice in the two pneumonia models, and no significant differences in weight loss, splenic bacterial counts, or blood leukocyte levels in the peritoneal sepsis model. To verify disruption of the Calca gene in knockout mice, the absence of calcitonin in the serum of knockout mice and its presence and inducibility in control mice were confirmed. To evaluate PCT expression in nonthyroidal tissues of control mice, transcripts were measured in multiple organs. PCT transcripts were not significantly expressed in liver or spleen of control mice challenged with aerosolized P. aeruginosa or intraperitoneal endotoxin, and were expressed in lung only at low levels, even though serum IL-6 rose 3,548-fold. We conclude that mice are not an ideal loss-of-function model to test the role of PCT in the pathogenesis of sepsis because of low nonendocrine PCT expression during infection and inflammation. Nonetheless, our studies demonstrate that nonendocrine PCT expression is not necessary for adverse outcomes from sepsis.
Assuntos
Calcitonina/metabolismo , Deleção de Genes , Precursores de Proteínas/metabolismo , Sepse/patologia , Animais , Carga Bacteriana , Calcitonina/sangue , Calcitonina/genética , Peptídeo Relacionado com Gene de Calcitonina , Éxons , Interleucina-6/metabolismo , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peritonite/microbiologia , Peritonite/patologia , Infecções Pneumocócicas/metabolismo , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/patologia , Precursores de Proteínas/genética , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/patogenicidade , Sepse/genética , Sepse/microbiologia , Índice de Gravidade de Doença , Baço/microbiologia , Streptococcus pneumoniae/patogenicidadeRESUMO
Bone health and maintenance of bone integrity are important components of comprehensive cancer care. Many patients with cancer are at risk for therapy-induced bone loss, with resultant osteoporotic fractures, or skeletal metastases, which may result in pathologic fractures, hypercalcemia, bone pain, and decline in motility and performance status. Effective screening and timely interventions are essential for reducing bone-related morbidity. Management of long-term bone health requires a broad knowledge base. A multidisciplinary health care team may be needed for optimal assessment and treatment of bone-related issues in patients with cancer. Since publication of the previous NCCN Task Force Report: Bone Health in Cancer Care in 2009, new data have emerged on bone health and treatment, prompting NCCN to convene this multidisciplinary task force to discuss the progress made in optimizing bone health in patients with cancer. In December 2012, the panel members provided didactic presentations on various topics, integrating expert judgment with a review of the key literature. This report summarizes issues surrounding bone health in cancer care presented and discussed during this NCCN Bone Health in Cancer Care Task Force meeting.
Assuntos
Osso e Ossos/fisiopatologia , Terapia Neoadjuvante/efeitos adversos , Neoplasias/complicações , Osteoporose/fisiopatologia , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Densidade Óssea , Cálcio/administração & dosagem , Suplementos Nutricionais , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Neoplasias/patologia , Osteoporose/induzido quimicamente , Osteoporose/complicações , Osteoporose/epidemiologia , Medição de Risco , Vitamina D/administração & dosagemRESUMO
Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast-mediated bone resorption and reduction of osteoblast-mediated bone formation. However, the molecular mechanisms underlying the differentiation and activity of osteoclasts and osteoblasts within a myelomatous microenvironment remain unclear. Here, we demonstrate that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions. CIITA upregulates the secretion of osteolytic cytokines from osteocytes through acetylation at histone 3 lysine 14 in the promoter of TNFSF11 (encoding RANKL) and SOST (encoding sclerostin), leading to enhanced osteoclastogenesis and decreased osteoblastogenesis. In turn, myeloma cell-secreted 2-deoxy-D-ribose, the product of thymidine catalyzed by the function of thymidine phosphorylase, upregulates CIITA expression in osteocytes through the STAT1/IRF1 signaling pathway. Our work thus broadens the understanding of myeloma-induced osteolysis and indicates a potential strategy for disrupting tumor-osteocyte interaction to prevent or treat patients with myeloma bone disease.
Assuntos
Mieloma Múltiplo , Osteólise , Humanos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Proteínas Nucleares , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteócitos/metabolismo , Osteólise/metabolismo , Osteólise/patologia , Osteólise/prevenção & controle , Ligante RANK/metabolismo , Transativadores , Microambiente TumoralRESUMO
Activating transcription factor 4 (ATF4) is a crucial mediator of the integrated stress response and a negative regulator of RET tyrosine kinase receptor in medullary thyroid carcinoma (MTC). However, the impact of genomic abnormalities in the ATF4 locus on MTC pathogenesis and response to tyrosine kinase inhibitor therapy remains unknown. Here, we evaluated ATF4 copy number variation and protein levels, with overall survival and response to TKIs in a clinical cohort of fifty-nine sporadic primary MTC. We assessed the somatic RETM918T mutation by sequencing, ATF4 copy number by a real-time polymerase chain reaction, and ATF4 protein levels using immunohistochemistry. This MTC cohort comprised 45 (76%) stage IV patients with a median follow-up of 100 months (interquartile range: 58-134 months). Somatic RETM918T was present in 23/57 (40%) tumors. Mono-allelic (36%; 21/59) and bi-allelic (5%; 3/59) loss of ATF4 was identified and was associated with low ATF4 protein expression (0-20%). Kaplan-Meier curves highlight low ATF4 protein or ATF4 loss alone had a significant negative impact on median survival compared to high protein expression (P<0.001) or diploid ATF4 (P=0.011), respectively. The combination of somatic RETM918T and low ATF4 protein levels further decreased overall survival. Both allelic loss and protein reduction were associated with worse overall survival (HR=3.79, 4.06 +RETM918T , and HR=10.64, 11.66 +RETM918T , respectively). Additionally, all 4 of the 11 patients treated with TKIs with a progressive disease by RECIST had low tumor ATF4 protein, with the two partial responder's tumors having high ATF4 protein. These findings suggest that ATF4 may predict response to tyrosine kinase inhibitors, serve as a prognostic marker for personalized care, and a therapeutic target in MTC.
RESUMO
Gain-of-function point mutations in the receptor tyrosine kinase RET, a driver oncogene in medullary thyroid carcinoma (MTC), prevent apoptosis through inhibition of ATF4, a critical transcriptional regulator of endoplasmic reticulum stress. However, the critical regulatory mechanisms driving RET-dependent oncogenesis remain elusive, and there is a clinical need to identify a transcriptional RET inhibitor. Here, we found that RET depletion decreased IGFBP2 and VEGFR2 mRNA and protein expression in MTC cells. IGFBP2 knockdown decreased cell survival and migration of MTC cells. In patients, IGFBP2 expression increased in metastatic MTC, and high IGFBP2 associated with poor overall survival. VEGFR2 protein levels were positively associated with RET expression in primary tumors, and VEGF-mediated increased cell viability was RET dependent. The small-molecule ONC201 treatment of MTC cells caused apoptotic cell death, decreased transcription of RET, VEGFR2, IGFBP2, increased mRNA levels of ATF4, and ATF4 target genes including DDIT3, BBC3, DUSP8, MKNK2, KLF9, LZTFL1, and SESN2 Moreover, IGFBP2 depletion increased ONC201-induced cell death. ONC201 inhibited tumor growth at a well-tolerated dose of 120 mg/kg/week administered by oral gavage and decreased MTC xenograft cell proliferation and angiogenesis. The protein levels of RET, IGFBP2, and VEGFR2 were decreased in ONC201-treated xenografts. Our study uncovered a novel ONC201 mechanism of action through regulation of RET and its targets, VEGFR2 and IGFBP2; this mechanism could be translated into the clinic and represent a promising strategy for the treatment of all patients with MTC, including those with TKI-refractory disease and other cancer with RET abnormalities.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Imidazóis/uso terapêutico , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Estudos RetrospectivosRESUMO
Cancer patients are at risk for adverse events involving bone. Metastasis of cancer to bone and primary bone tumors can compromise the integrity of bone. Various cancer therapies cause long-term skeletal disorders, particularly bone loss, osteomalacia, and avascular necrosis. Cancer therapies that include chemotherapy, glucocorticoids, hormonal agents, and newer targeted therapies can affect bone in several ways. With the improved effectiveness of cancer treatment, more cancer patients are surviving longer and may experience fractures as a long-term complication of bone loss. Prevention of bone loss through early detection and appropriate use of anti-osteoporosis treatment may decrease bone loss and fractures. This article reviews causative risk factors, mechanisms, and prevention and treatment strategies for cancer therapy-related bone loss in hematologic and specific solid malignancies.
Assuntos
Antineoplásicos/efeitos adversos , Doenças Ósseas Metabólicas/etiologia , Reabsorção Óssea/etiologia , Neoplasias/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/metabolismo , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/prevenção & controle , Humanos , Neoplasias/metabolismo , Fatores de RiscoRESUMO
The multiple endocrine neoplasia (MEN) workshops had their beginnings at Queen's University in Kingston, Ontario in June, 1984. This initial meeting brought clinicians and scientists together to focus on mapping the gene for multiple endocrine neoplasia type 2 (MEN2). These efforts culminated in the identification of the RET protooncogene as the causative gene a decade later. Over the next 35 years there were a total of 16 international workshops focused on the several MEN syndromes. Importantly, these workshops were instrumental in efforts to define the molecular basis for multiple endocrine neoplasia type 1 (MEN1), MEN2, von Hippel-Lindau disease (VHL), Carney Complex, hereditary pheochromocytoma and hyperparathyroidism. In this same spirit some 150 scientists and clinicians met at MD Anderson Cancer Center March 26-29, 2019, Houston, TX for the 16th Multiple Endocrine Neoplasia (MEN) Workshop. Appropriate to its location in a cancer center, the workshop focused on important issues in the causation and treatment of malignant aspects of the MEN syndromes: medullary thyroid carcinoma, pancreatic neuroendocrine tumors, malignant pheochromocytoma and parathyroid carcinoma. Workshops at the meeting focused on a better understanding of how the identified molecular defects in these genetic syndromes lead to transformation, how to apply targeted kinase inhibitors and immunotherapy to treat these tumors and important clinical management issues. This issue of Endocrine-Related Cancer describes these discussions and recommendations.
RESUMO
Forty years ago, physicians caring for the J-kindred, a 100+ member family with multiple endocrine neoplasia type 2A (MEN2A), hypothesized that early thyroidectomy based on measurement of the biomarker calcitonin could cure patients at risk for development of medullary thyroid carcinoma (MTC). We re-evaluated 22 family members with proven RET proto-oncogene mutations (C634G) who underwent thyroidectomy and central lymphadenectomy between 1972 and 1994 based on stimulated calcitonin abnormalities. Current disease status was evaluated by serum calcitonin measurement and neck ultrasound in 18 of the 22 prospectively screened patients. The median age of the cohort at thyroidectomy was 16.5 years (range 9-24). The median duration of follow-up at the time of examination was 40 years (range 21-43) with a median current age of 52 years (range 34-65). Fifteen of the 18 patients had no detectable serum calcitonin (<2 pg/mL). Three had detectable serum calcitonin measurements, inappropriately elevated following total thyroidectomy. None of the 16 patients imaged had an abnormal ultrasound. Survival analysis shows no MTC-related deaths in the prospectively screened patients, whereas there were many in prior generations. Early thyroidectomy based on biomarker testing has rendered 15 of 18 MEN2A patients (83%) calcitonin-free with a median follow-up period of 40 years. There have been no deaths in the prospectively screened and thyroidectomized group. We conclude that early thyroidectomy and central lymph node dissection is an effective prophylactic treatment for hereditary MTC.
Assuntos
Neoplasia Endócrina Múltipla/cirurgia , Tireoidectomia/métodos , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Proto-Oncogene Mas , Fatores de Tempo , Adulto JovemRESUMO
The 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) held in Houston, TX, USA, focused on emerging topics in the pathogenesis and therapy of malignant endocrine tumors associated with MEN syndromes. With MEN-2 syndromes, the most common malignancy is medullary thyroid carcinoma (MTC). In the spirit of the original MEN meeting workshop model, the conference included didactic lectures and interactive working groups of clinicians and researchers focused on the state of science in MTC and ongoing challenges or unmet needs in the understanding of MTC and to develop strategies to address these issues.
Assuntos
Carcinoma Neuroendócrino/etiologia , Neoplasia Endócrina Múltipla/complicações , Neoplasias da Glândula Tireoide/etiologia , Carcinoma Neuroendócrino/patologia , Humanos , Neoplasias da Glândula Tireoide/patologiaRESUMO
BACKGROUND: In the face of the COVID-19 pandemic, cancer care has had to adapt rapidly given the Centers for Disease Control and Prevention and the American College of Surgeons (ACS) issuing recommendations to postpone nonurgent surgeries. METHODS: An institutional multidisciplinary group of Head and Neck Surgical Oncology, Surgical Endocrinology, and Medical Endocrinology devised Surgical Triaging Guidelines for Endocrine Surgery during COVID-19, aligned with phases of care published by the ACS. RESULTS: Phases of care with examples of corresponding endocrine cases are outlined. Most cases can be safely postponed with active surveillance, including most differentiated and medullary thyroid cancers. During the most acute phase, all endocrine surgeries are deferred, except thyroid tumors requiring acute airway management. CONCLUSIONS: These guidelines provide context for endocrine surgery within the spectrum of surgical oncology, with the goal of optimal individualized multidisciplinary patient care and the expectation of significant resource diversion to care for patients with COVID-19.
Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Doenças do Sistema Endócrino/cirurgia , Seleção de Pacientes , Pneumonia Viral/epidemiologia , Triagem , Algoritmos , COVID-19 , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Doenças do Sistema Endócrino/patologia , Humanos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Guias de Prática Clínica como Assunto , SARS-CoV-2RESUMO
The active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), can suppress disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Calcium appears to be a critical component of 1,25(OH)(2)D(3)-mediated suppression of EAE, as complete disease prevention only occurs with a concomitant increase in serum calcium levels. Calcitonin (CT) is a peptide hormone released in response to acute increases in serum calcium, which led us to explore its importance in 1,25(OH)(2)D(3)-mediated suppression of EAE. Previously, we discovered that co-administration of pharmacological doses of CT enhanced the suppressive effect of 1,25(OH)(2)D(3) on EAE, suggesting CT may play a role in 1,25(OH)(2)D(3)-mediated suppression of EAE. To determine the importance of CT in EAE we have utilized a mouse strain in which the gene encoding CT and its alternative splice product, calcitonin gene related peptide-alpha (CGRP), have been deleted. Deletion of the CT/CGRP gene had no effect on EAE progression. Furthermore, treatment with 1,25(OH)(2)D(3) suppressed EAE in CT/CGRP knock-out mice equal to that in wild type mice. Therefore, we conclude that CT is not necessary for 1,25(OH)(2)D(3)-mediated suppression of EAE.
Assuntos
Calcitonina/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Vitamina D/análogos & derivados , Animais , Calcitonina/uso terapêutico , Cálcio/análise , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Encefalomielite Autoimune Experimental/prevenção & controle , Feminino , Hipercalcemia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vitamina D/farmacologia , Vitamina D/uso terapêuticoRESUMO
Medullary thyroid carcinoma (MTC) is an uncommon malignancy of hereditary and sporadic presentation. Mutations in the RET proto-oncogene are involved in the pathogenesis of familial MTC and >50% of the sporadic cases. Currently, there is no effective treatment for recurrent or metastatic MTC. We report here a rapid response to a sorafenib (RET and RAF kinase and vascular endothelial growth factor receptor inhibitor)--based regimen in a patient with sporadic MTC who had advanced, progressive disease and a novel RET kinase aberration at exon 11 shown in tumor tissue.
Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma Medular/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Piridinas/uso terapêutico , Quinolonas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Sequência de Aminoácidos , Carcinoma Medular/enzimologia , Linhagem Celular Tumoral , Éxons , Humanos , Masculino , Dados de Sequência Molecular , Niacinamida/análogos & derivados , Compostos de Fenilureia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret/genética , Sorafenibe , Neoplasias da Glândula Tireoide/enzimologiaRESUMO
Medullary thyroid carcinoma (MTC) originates from the C cells of the thyroid gland, which secrete calcitonin. Lymph node and distant metastases are frequently present at diagnosis. Activating mutations of RET, a driver oncogene in MTC that encodes a tyrosine kinase receptor, prevents apoptosis through inhibition of ATF4, a key transcriptional regulator of endoplasmic reticulum (ER) stress. We hypothesized that the combination of a tyrosine kinase inhibitor (TKI) and an ATF4 inducer promotes cell death by triggering catastrophic oxidative stress and apoptotic cell death. Here, we report that the ER-associated protein degradation (ERAD) inhibitor eeyarestatin sensitized MTC cells to the TKIs, sunitinib and vandetanib, thereby leading to synergistic upregulation of ATF4 expression, accumulation of reactive oxygen species, and subsequent cell death. Genome-wide analysis of ATF4 interaction sites by chromatin immunoprecipitation (ChIP) sequencing revealed that among ATF4 target genes was KLF9 (Kruppel-like factor 9), which induces MTC apoptosis. ChIP assays revealed that ATF4 occupancy at the KLF9 promoter was increased in MTC cells treated with eeyarestatin or vandetanib alone and was further enhanced in cells treated with both drugs, leading to increased KLF9 transcription. Depletion of ATF4 by shRNA led to downregulation of KLF9 expression and prevented oxidative stress-induced cell death. Furthermore, we identified ATF4 target genes (LZTFL1, MKNK2, and SIAH1 with known tumor suppressor function) that were synergistically upregulated with the combination of TKI and ERAD inhibitor. IMPLICATIONS: These findings reveal a combination therapy that induces reactive oxygen species-dependent catastrophic cell death through induction of ATF4 and KLF9 transcriptional activity.
Assuntos
Fator 4 Ativador da Transcrição/genética , Apoptose/efeitos dos fármacos , Degradação Associada com o Retículo Endoplasmático/efeitos dos fármacos , Fatores de Transcrição Kruppel-Like/genética , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Fator 4 Ativador da Transcrição/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Epigenetic changes that cause dysregulated gene expression during progression of androgen-independent prostate cancer (PCa) and metastatic skeletal lesions remain elusive. Here, we explored the role of histone demethylase NO66 in the pathogenesis of PCa and bone metastasis-related skeletal lesions. Tissue and cDNA microarrays of PCa were analyzed for NO66 mRNA and protein levels. We examined the effects of gain and loss of NO66 function on cell viability, colony formation, migration, invasion, and tumor-induced skeletal lesions in femoral bone. RNAseq and ChIPseq were performed to elucidate NO66-target genes in PCa. We report that NO66 levels were upregulated in advanced primary prostate tumors compared to normal tissue or tumors with low Gleason scores. Forced expression of NO66 promoted cell survival and invasion of PCa cells; whereas, knockdown of NO66 resulted in decreased cell survival and increased sensitivity to docetaxel. NO66-overexpressing PC3 cells implanted into the femoral bone of male SCID mice caused massive bone loss and stimulation of mouse osteoclast-promoting genes, including Dickkopf1, Cathepsin K, Nf-kß,; and Calcr, suggesting a role for NO66 in tumor growth in bone and osteoclast activity. Combined RNAseq and ChIP-seq revealed that NO66 activates the survival gene MCL1, the invasion-associated genes IGFBP5 and MMP3, the pro-oncogenic genes CTNNB1 and CCND1, and the epigenetic modifier gene KMT2A in androgen-independent PCa. Our findings uncover the role of NO66 as a key oncogenic driver in PCa, causing osteolytic lesions through upstream epigenetic regulation of key genes for survival, invasion and metastasis, and pro-osteoclastic factors.
Assuntos
Transformação Celular Neoplásica/genética , Dioxigenases/fisiologia , Histona Desmetilases/fisiologia , Osteólise/genética , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Dioxigenases/genética , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Histona Desmetilases/genética , Histonas/metabolismo , Humanos , Masculino , Camundongos , Camundongos SCID , Células NIH 3T3 , Osteólise/patologia , Células PC-3 , Neoplasias de Próstata Resistentes à Castração/metabolismoRESUMO
BACKGROUND: Tumor-induced osteomalacia is a rare paraneoplastic syndrome in which patients develop hypophosphatemia and osteomalacia. METHODS AND RESULTS: Here, we report a unique case of a 42-year-old man who presented to our institution with a 1-year history of pain in his ribs, hips, lower back, and feet. Radiologic examination revealed a decrease in bone density and multiple insufficiency fractures. Laboratory evaluation revealed hypophosphatemia, low serum 1,25 dihydroxy vitamin D3 , and elevated fibroblast growth factor 23 (FGF23). A positron emission tomography/CT scan showed increased uptake in the right mandibular third molar region. Panoramic radiography and CT scanning showed a lytic expansile bone lesion. A mandibular bone biopsy revealed a mixed connective tissue tumor. A right segmental mandibulectomy was performed, followed by microvascular reconstruction. The resection was confirmed by normalization of serum phosphate and FGF23. CONCLUSION: Successful management of this condition was achieved, with complete surgical resection of the tumor and reconstructive surgery.