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1.
Sci Rep ; 10(1): 4326, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152475

RESUMO

For successful tracheal reconstruction, tissue-engineered artificial trachea should meet several requirements, such as biocompatible constructs comparable to natural trachea, coverage with ciliated respiratory mucosa, and adequate cartilage remodeling to support a cylindrical structure. Here, we designed an artificial trachea with mechanical properties similar to the native trachea that can enhance the regeneration of tracheal mucosa and cartilage through the optimal combination of a two-layered tubular scaffold and human induced pluripotent stem cell (iPSC)-derived cells. The framework of the artificial trachea was fabricated with electrospun polycaprolactone (PCL) nanofibers (inner) and 3D-printed PCL microfibers (outer). Also, human bronchial epithelial cells (hBECs), iPSC-derived mesenchymal stem cells (iPSC-MSCs), and iPSC-derived chondrocytes (iPSC-Chds) were used to maximize the regeneration of tracheal mucosa and cartilage in vivo. After 2 days of cultivation using a bioreactor system, tissue-engineered artificial tracheas were transplanted into a segmental trachea defect (1.5-cm length) rabbit model. Endoscopy did not reveal granulation ingrowth into tracheal lumen. Alcian blue staining clearly showed the formation of ciliated columnar epithelium in iPSC-MSC groups. In addition, micro-CT analysis showed that iPSC-Chd groups were effective in forming neocartilage at defect sites. Therefore, this study describes a promising approach for long-term functional reconstruction of a segmental tracheal defect.

2.
Cancer Discov ; 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188705

RESUMO

Although mutations in the RNA splicing factor SF3B1 are frequent in multiple cancers, their functional effects and therapeutic dependencies are poorly understood. Here we characterize 98 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations, identifying hundreds of cryptic 3' splice sites common and specific to different cancer types. Regulatory network analysis revealed that the most common SF3B1 mutation activates MYC via effects conserved across human and mouse cells. SF3B1 mutations promote decay of transcripts encoding the PP2A phosphatase subunit PPP2R5A, increasing c-MYC S62 and BCL2 S70 phosphorylation which, in turn, promote MYC protein stability and impair apoptosis, respectively. Genetic PPP2R5A restoration or pharmacologic PP2A activation impaired SF3B1-mutant tumorigenesis elucidating a therapeutic approach to aberrant splicing by mutant SF3B1.

3.
Int J Dent Hyg ; 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32196912

RESUMO

OBJECTIVE: High stress levels experienced by medical professionals is a well-established phenomenon in current literature. However, there are few studies focusing on stress experienced in the field of oral health or on the sense of coherence (SOC) that helps to actively respond to job stress. The purpose of this study was to analyze if there is an association between SOC and job stress among dental hygienists in Korea. METHODS: A cross-sectional study was conducted on a convenience sample of 441 dental hygienists in the Seoul Gyeonggi province, Korea. The independent variable was SOC which had three dimensions: comprehensibility, manageability, and meaningfulness. The dependent variable was job stress, which was evaluated using the Korean Occupational Stress Scale Short Form. Confounding factors were age, marital status, educational background, type of hospital, and work experience. The Chi-square test and t-test measures were used for bivariate analysis. Multiple logistic regression analysis was performed to confirm the association between SOC and job stress. The collected data were statistically analyzed using SPSS version 22.0. RESULTS: The SOC score showed a significant difference in relation to the job stress score. The SOC score was high when the job stress was low (P < .001). Overall SOC scores showed an inverse correlation with job stress. CONCLUSION: This study reports that a higher SOC is associated with lower job stress in Korean dental hygienists. Since a higher SOC in dental hygienists indicated that they could cope with job stress more positively, it is important to increase their SOC.

4.
J Neurosci ; 40(11): 2200-2214, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047055

RESUMO

The dentate gyrus (DG) in the hippocampus may play key roles in remembering distinct episodes through pattern separation, which may be subserved by the sparse firing properties of granule cells (GCs) in the DG. Low intrinsic excitability is characteristic of mature GCs, but ion channel mechanisms are not fully understood. Here, we investigated ionic channel mechanisms for firing frequency regulation in hippocampal GCs using male and female mice, and identified Kv4.1 as a key player. Immunofluorescence analysis showed that Kv4.1 was preferentially expressed in the DG, and its expression level determined by Western blot analysis was higher at 8-week than 3-week-old mice, suggesting a developmental regulation of Kv4.1 expression. With respect to firing frequency, GCs are categorized into two distinctive groups: low-frequency (LF) and high-frequency (HF) firing GCs. Input resistance (R in) of most LF-GCs is lower than 200 MΩ, suggesting that LF-GCs are fully mature GCs. Kv4.1 channel inhibition by intracellular perfusion of Kv4.1 antibody increased firing rates and gain of the input-output relationship selectively in LF-GCs with no significant effect on resting membrane potential and R in, but had no effect in HF-GCs. Importantly, mature GCs from mice depleted of Kv4.1 transcripts in the DG showed increased firing frequency, and these mice showed an impairment in contextual discrimination task. Our findings suggest that Kv4.1 expression occurring at late stage of GC maturation is essential for low excitability of DG networks and thereby contributes to pattern separation.SIGNIFICANCE STATEMENT The sparse activity of dentate granule cells (GCs), which is essential for pattern separation, is supported by high inhibitory inputs and low intrinsic excitability of GCs. Low excitability of GCs is thought to be attributable to a high K+ conductance at resting membrane potentials, but this study identifies Kv4.1, a depolarization-activated K+ channel, as a key ion channel that regulates firing of GCs without affecting resting membrane potentials. Kv4.1 expression is developmentally regulated and Kv4.1 currents are detected only in mature GCs that show low-frequency firing, but not in less mature high-frequency firing GCs. Furthermore, mice depleted of Kv4.1 transcripts in the dentate gyrus show impaired pattern separation, suggesting that Kv4.1 is crucial for sparse coding and pattern separation.

5.
J Vis Exp ; (156)2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32090989

RESUMO

The use of biocompatible materials for circumferential esophageal reconstruction is a technically challenging task in rats and requires an optimal implant technique with nutritional support. Recently, there have been many attempts at esophageal tissue engineering, but the success rate has been limited due to difficulty in early epithelization in the special environment of peristalsis. Here, we developed an artificial esophagus that can improve the regeneration of the esophageal mucosa and muscle layers through a two-layered tubular scaffold, a mesenchymal stem cell-based bioreactor system, and a bypass feeding technique with modified gastrostomy. The scaffold is made of polyurethane (PU) nanofibers in a cylindrical shape with a three-dimensional (3D) printed polycaprolactone strand wrapped around the outer wall. Prior to transplantation, human-derived mesenchymal stem cells were seeded into the lumen of the scaffold, and bioreactor cultivation was performed to enhance cellular reactivity. We improved the graft survival rate by applying surgical anastomosis and covering the implanted prosthesis with a thyroid gland flap, followed by temporary nonoral gastrostomy feeding. These grafts were able to recapitulate the findings of initial epithelialization and muscle regeneration around the implanted sites, as demonstrated by histological analysis. In addition, increased elastin fibers and neovascularization were observed in the periphery of the graft. Therefore, this model presents a potential new technique for circumferential esophageal reconstruction.

6.
Cell Death Differ ; 27(2): 573-586, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31243342

RESUMO

MyoD functions as a master regulator to induce muscle-specific gene expression and myogenic differentiation. Here, we demonstrate a positive role of Protein arginine methyltransferase 7 (Prmt7) in MyoD-mediated myoblast differentiation through p38MAPK activation. Prmt7 depletion in primary or C2C12 myoblasts impairs cell cycle withdrawal and myogenic differentiation. Furthermore, Prmt7 depletion decreases the MyoD-reporter activities and the MyoD-mediated myogenic conversion of fibroblasts. Together with MyoD, Prmt7 is recruited to the Myogenin promoter region and Prmt7 depletion attenuates the recruitment of MyoD and its coactivators. The mechanistic study reveals that Prmt7 methylates p38MAPKα at the arginine residue 70, thereby promoting its activation which in turn enhances MyoD activities. The arginine residue 70 to alanine mutation in p38MAPKα impedes MyoD/E47 heterodimerization and the recruitment of Prmt7, MyoD and Baf60c to the Myogenin promoter resulting in blunted Myogenin expression. In conclusion, Prmt7 promotes MyoD-mediated myoblast differentiation through methylation of p38MAPKα at arginine residue 70.

7.
Cell Death Differ ; 27(1): 15-28, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31000813

RESUMO

Cellular senescence is implicated in aging or age-related diseases. Sonic hedgehog (Shh) signaling, an inducer of embryonic development, has recently been demonstrated to inhibit cellular senescence. However, the detailed mechanisms to activate Shh signaling to prevent senescence is not well understood. Here, we demonstrate that Protein arginine methyltransferase 7 (PRMT7) promotes Shh signaling via GLI2 methylation which is critical for suppression of cellular senescence. PRMT7-deficient mouse embryonic fibroblasts (MEFs) exhibited a premature cellular senescence with accompanied increase in the cell cycle inhibitors p16 and p21. PRMT7 depletion results in reduced Shh signaling activity in MEFs while PRMT7 overexpression enhances GLI2-reporter activities that are sensitive to methylation inhibition. PRMT7 interacts with and methylates GLI2 on arginine residues 225 and 227 nearby a binding region of SUFU, a negative regulator of GLI2. This methylation interferes with GLI2-SUFU binding, leading to facilitation of GLI2 nuclear accumulation and Shh signaling. Taken together, these data suggest that PRMT7 induces GLI2 methylation, reducing its binding to SUFU and increasing Shh signaling, ultimately leading to prevention of cellular senescence.

8.
Cell Death Dis ; 10(12): 903, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31787756

RESUMO

Endoplasmic reticulum (ER) stress signaling plays a critical role in the control of cell survival or death. Persistent ER stress activates proapoptotic pathway involving the ATF4/CHOP axis. Although accumulating evidences support its important contribution to cardiovascular diseases, but its mechanism is not well characterized. Here, we demonstrate a critical role for PRMT1 in the control of ER stress in cardiomyocytes. The inhibition of PRMT1 augments tunicamycin (TN)-triggered ER stress response in cardiomyocytes while PRMT1 overexpression attenuates it. Consistently, PRMT1 null hearts show exacerbated ER stress and cell death in response to TN treatment. Interestingly, ATF4 depletion attenuates the ER stress response induced by PRMT1 inhibition. The methylation-deficient mutant of ATF4 with the switch of arginine 239 to lysine exacerbates ER stress accompanied by enhanced levels of proapoptotic cleaved Caspase3 and phosphorylated-γH2AX in response to TN. The mechanistic study shows that PRMT1 modulates the protein stability of ATF4 through methylation. Taken together, our data suggest that ATF4 methylation on arginine 239 by PRMT1 is a novel regulatory mechanism for protection of cardiomyocytes from ER stress-induced cell death.

9.
Nature ; 574(7777): 273-277, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578525

RESUMO

Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia1,2. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex3, concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis.


Assuntos
Processamento Alternativo/genética , Carcinogênese/genética , Epigênese Genética , Leucemia Mieloide Aguda/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Proteínas de Ligação a DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Isocitrato Desidrogenase/genética , Masculino , Mutação/genética , RNA Polimerase II/metabolismo , Fatores de Processamento de Serina-Arginina/genética , Transcriptoma
10.
Nature ; 574(7778): 432-436, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597964

RESUMO

SF3B1 is the most commonly mutated RNA splicing factor in cancer1-4, but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here we integrated pan-cancer splicing analyses with a positive-enrichment CRISPR screen to prioritize splicing alterations that promote tumorigenesis. We report that diverse SF3B1 mutations converge on repression of BRD9, which is a core component of the recently described non-canonical BAF chromatin-remodelling complex that also contains GLTSCR1 and GLTSCR1L5-7. Mutant SF3B1 recognizes an aberrant, deep intronic branchpoint within BRD9 and thereby induces the inclusion of a poison exon that is derived from an endogenous retroviral element and subsequent degradation of BRD9 mRNA. Depletion of BRD9 causes the loss of non-canonical BAF at CTCF-associated loci and promotes melanomagenesis. BRD9 is a potent tumour suppressor in uveal melanoma, such that correcting mis-splicing of BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppresses tumour growth. Our results implicate the disruption of non-canonical BAF in the diverse cancer types that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies.

11.
Exp Mol Med ; 51(10): 119, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601786

RESUMO

The sodium leak channel NALCN is a key player in establishing the resting membrane potential (RMP) in neurons and transduces changes in extracellular Ca2+ concentration ([Ca2+]e) into increased neuronal excitability as the downstream effector of calcium-sensing receptor (CaSR). Gain-of-function mutations in the human NALCN gene cause encephalopathy and severe intellectual disability. Thus, understanding the regulatory mechanisms of NALCN is important for both basic and translational research. This study reveals a novel mechanism for NALCN regulation by arginine methylation. Hippocampal dentate granule cells in protein arginine methyltransferase 7 (PRMT7)-deficient mice display a depolarization of the RMP, decreased threshold currents, and increased excitability compared to wild-type neurons. Electrophysiological studies combined with molecular analysis indicate that enhanced NALCN activities contribute to hyperexcitability in PRMT7-/- neurons. PRMT7 depletion in HEK293T cells increases NALCN activity by shifting the dose-response curve of NALCN inhibition by [Ca2+]e without affecting NALCN protein levels. In vitro methylation studies show that PRMT7 methylates a highly conserved Arg1653 of the NALCN gene located in the carboxy-terminal region that is implicated in CaSR-mediated regulation. A kinase-specific phosphorylation site prediction program shows that the adjacent Ser1652 is a potential phosphorylation site. Consistently, our data from site-specific mutants and PKC inhibitors suggest that Arg1653 methylation might modulate Ser1652 phosphorylation mediated by CaSR/PKC-delta, leading to [Ca2+]e-mediated NALCN suppression. Collectively, these data suggest that PRMT7 deficiency decreases NALCN methylation at Arg1653, which, in turn, decreases CaSR/PKC-mediated Ser1652 phosphorylation, lifting NALCN inhibition, thereby enhancing neuronal excitability. Thus, PRMT7-mediated NALCN inhibition provides a potential target for the development of therapeutic tools for neurological diseases.

12.
Sci Rep ; 9(1): 12997, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506521

RESUMO

Pathogenic variants in the human SCN5A gene encoding the a-subunit of the principle Na+ channel (Nav1.5) are associated with long QT syndrome (LQTS) 3. LQT3 patients display variable responses to Na+ channel blockers demanding for the development of variant-specific therapeutic strategies. Here we performed a combined electrophysiological analysis with in silico simulation of variant channel to elucidate mechanisms of therapeutic responsiveness. We identified a novel SCN5A variant (A1656D) in a LQTS patient with a distinct response to mexiletine resulting in suppression of non-sustained ventricular tachycardia and manifestation of premature atrial contraction. Patch clamp analysis revealed that A1656D variant exerted gain-of-function effects including hyperpolarizing shift of the voltage-dependence of activation, depolarizing shift in the voltage-dependence of inactivation, and slowing of fast inactivation. Among ranolazine, flecainide, and mexiletine, only mexiletine restored inactivation kinetics of A1656D currents. In silico simulation to assess the effect of A1656D variant on ventricular cardiac cell excitation predicted a prolonged action potential which is consistent with the prolonged QT and non-sustained ventricular tachycardia of the patient. It also predicted that only mexiletine suppressed the prolonged action potential of human ventricular myocytes expressing A1656D. These data elucidate the underlying mechanism of the distinct response to mexiletine in this patient.

13.
J Ginseng Res ; 43(3): 402-407, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31308812

RESUMO

Background: To investigate the neurobiological evidence supporting the adaptogenic effects of Korean Red Ginseng in reducing the harmful consequences of stress using a double-blind, placebo-controlled trial. Method: Sixty-three subjects with high stress levels were randomized to receive an orally administered, double-blind, 6-week treatment with Korean Red Ginseng (n = 32) or placebo (n = 31). All participants underwent a comprehensive psychological evaluation using Beck Depression Inventory and Stress Response Inventory, cognitive evaluation using the continuous performance test, biological evaluation by measuring blood levels of lipids, catecholamines, inflammation markers, and heart rate variability at baseline and after 6 weeks. Results: At baseline, both groups showed no significant differences in age, sex, years of education, Beck Depression Inventory, and Stress Response Inventory. After 6 weeks, triglyceride levels were significantly increased within the normal limit in theKorean Red Ginseng group (F = 4.11, p = 0.048), and the epinephrine level was decreased in this group (F = 4,35, p = 0.043). The triglyceride increase was significantly associated with epinephrine decrease (B = -0.087, p = 0.041), suggesting that Korean Red Ginseng may stabilize the sympathetic nervous system. In addition, we detected a significant group by time effect in the visually controlled continuous performance test, suggesting positive effects of Korean Red Ginseng on cognition. Conclusion: Korean Red Ginseng might help to stabilize the sympathetic nervous system and improve cognition in individuals with high stress.

14.
Exp Mol Med ; 51(7): 81, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31316050

RESUMO

Chloride intracellular channel 1 (CLIC1) is a promising therapeutic target in cancer due to its intrinsic characteristics; it is overexpressed in specific tumor types and its localization changes from cytosolic to surface membrane depending on activities and cell cycle progression. Ca2+ and reactive oxygen species (ROS) are critical signaling molecules that modulate diverse cellular functions, including cell death. In this study, we investigated the function of CLIC1 in Ca2+ and ROS signaling in A549 human lung cancer cells. Depletion of CLIC1 via shRNAs in A549 cells increased DNA double-strand breaks both under control conditions and under treatment with the putative anticancer agent chelerythrine, accompanied by a concomitant increase in the p-JNK level. CLIC1 knockdown greatly increased basal ROS levels, an effect prevented by BAPTA-AM, an intracellular calcium chelator. Intracellular Ca2+ measurements clearly showed that CLIC1 knockdown significantly increased chelerythrine-induced Ca2+ signaling as well as the basal Ca2+ level in A549 cells compared to these levels in control cells. Suppression of extracellular Ca2+ restored the basal Ca2+ level in CLIC1-knockdown A549 cells relative to that in control cells, implying that CLIC1 regulates [Ca2+]i through Ca2+ entry across the plasma membrane. Consistent with this finding, the L-type Ca2+ channel (LTCC) blocker nifedipine reduced the basal Ca2+ level in CLIC1 knockdown cells to that in control cells. Taken together, our results demonstrate that CLIC1 knockdown induces an increase in the intracellular Ca2+ level via LTCC, which then triggers excessive ROS production and consequent JNK activation. Thus, CLIC1 is a key regulator of Ca2+ signaling in the control of cancer cell survival.

15.
Br Dent J ; 227(1): 25-29, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31300776

RESUMO

Head and neck cancer is the eighth most common cancer in the UK. Management may include surgery, chemotherapy, radiotherapy or a combination of these. A multidisciplinary approach is required, with the dental team forming an integral part of the patient pathway. Prior to commencement of cancer therapy, patients should have a dental assessment and urgent treatment should be provided as necessary. This article presents the case of a 49-year-old male with previous T4N0M0 squamous cell carcinoma of the pharynx. Surgery, chemotherapy and radiotherapy had been provided four years prior to presentation. The patient had significant post-operative complications of cancer therapy which were significantly affecting his quality of life. The patient underwent dental treatment, including preventive care, periodontal therapy and restorative care, with the multidisciplinary dental team. This case illustrates that oral assessment and urgent dental treatment should start prior to cancer treatment. Post-operative regular dental follow-ups should be instigated for monitoring and maintenance.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Assistência Odontológica , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida
16.
Inorg Chem ; 58(14): 9341-9350, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31241335

RESUMO

We have employed a range of ultrafast X-ray spectroscopies in an effort to characterize the lowest energy excited state of [Fe(dcpp)2]2+ (where dcpp is 2,6-(dicarboxypyridyl)pyridine). This compound exhibits an unusually short excited-state lifetime for a low-spin Fe(II) polypyridyl complex of 270 ps in a room-temperature fluid solution, raising questions as to whether the ligand-field strength of dcpp had pushed this system beyond the 5T2/3T1 crossing point and stabilizing the latter as the lowest energy excited state. Kα and Kß X-ray emission spectroscopies have been used to unambiguously determine the quintet spin multiplicity of the long-lived excited state, thereby establishing the 5T2 state as the lowest energy excited state of this compound. Geometric changes associated with the photoinduced ligand-field state conversion have also been monitored with extended X-ray absorption fine structure. The data show the typical average Fe-ligand bond length elongation of ∼0.18 Å for a 5T2 state and suggest a high anisotropy of the primary coordination sphere around the metal center in the excited 5T2 state, in stark contrast to the nearly perfect octahedral symmetry that characterizes the low-spin 1A1 ground state structure. This study illustrates how the application of time-resolved X-ray techniques can provide insights into the electronic structures of molecules-in particular, transition metal complexes-that are difficult if not impossible to obtain by other means.

17.
Spec Care Dentist ; 39(4): 435-440, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31120566

RESUMO

Cold agglutinin disease (CAD) is a rare variant of autoimmune hemolytic anemia, characterized by the destruction of red blood cells by autoantibodies following exposure to cold temperatures. This case is of a 75-year-old male who presented to a dedicated hematology dental clinic. The dental management over a 3-year period is described, whereby the patient had extraction and periodontal disease management with considerations for medical, social and dental risk assessments and treatment modifications. The principles are applicable to patients with other hematological disorders.


Assuntos
Anemia Hemolítica Autoimune , Idoso , Autoanticorpos , Humanos , Masculino
18.
Nature ; 567(7749): 521-524, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30867592

RESUMO

Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2. For the 50% of patients with histiocytosis who have BRAFV600 mutations3-5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.


Assuntos
Azetidinas/uso terapêutico , Transtornos Histiocíticos Malignos/tratamento farmacológico , Transtornos Histiocíticos Malignos/enzimologia , Histiocitose/tratamento farmacológico , Histiocitose/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Piperidinas/uso terapêutico , Azetidinas/farmacologia , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/patologia , Histiocitose/genética , Histiocitose/patologia , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mutação , Piperidinas/farmacologia , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética
19.
Cancer Cell ; 35(3): 369-384.e7, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30799057

RESUMO

RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated in cancer. We systematically interrogated RBP dependencies in human cancers using a comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains of 490 classical RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for maintaining RNA splicing and AML survival. Genetic or pharmacologic targeting of one key member of this network, RBM39, repressed cassette exon inclusion and promoted intron retention within mRNAs encoding HOXA9 targets as well as in other RBPs preferentially required in AML. The effects of RBM39 loss on splicing further resulted in preferential lethality of spliceosomal mutant AML, providing a strategy for treatment of AML bearing RBP splicing mutations.


Assuntos
Redes Reguladoras de Genes , Marcação de Genes/métodos , Leucemia Mieloide Aguda/patologia , Proteômica/métodos , Proteínas de Ligação a RNA/genética , Regulação para Cima , Processamento Alternativo , Animais , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Células HL-60 , Proteínas de Homeodomínio/genética , Humanos , Células Jurkat , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Camundongos , Transplante de Neoplasias , Prognóstico , Proteínas de Ligação a RNA/metabolismo , Análise de Sequência de RNA/métodos , Análise de Sobrevida
20.
BMJ Open ; 9(1): e024116, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30782727

RESUMO

OBJECTIVE: This study aimed to calculate the distance patients travel to dental clinics, the rate of bypassing nearby dental clinics and the distance covered when bypassing nearby dental clinics, and explored factors associated with patients' spatial access to dental clinics. DESIGN: A secondary data analysis. SETTING: Korea Health Panel. PARTICIPANTS: We included users of dental care services from 2008 to 2011. A total of 2375 patients and 15 978 dental visits were analysed. PRIMARY OUTCOME MEASURES: Korea Health Panel data (2008-2011) were used to geocode patients' and healthcare facilities' addresses. The distance travelled was calculated using road network information. To analyse the panel data, we adopted a generalised estimating equation: geographical measures on the choice of dental care facility were examined based on sex, age, educational level, equivalent income, treatment details and regional classification. RESULTS: The median distance travelled to a dental clinic was 1.8 km, which is farther for rural (8.4 km) than for urban (1.5 km) patients. The bypass rate was 58.9%. Patients bypassing nearby dental clinics travelled 9.6 times farther for dental care (p<0.001). Unlike bypass distance, travel distance was not associated with equivalent income. People with higher education and those with implants/orthodontic treatment were more likely to bypass nearby dental clinics and travelled 1.27 times and 1.17 times farther (p<0.01), respectively. CONCLUSIONS: Given the spatial barrier to available dental resources, factors associated with spatial access were mostly the same between travel and bypass distance except for equivalent income. The findings of this study suggest that spatial distance acts as a utilisation barrier and demands additional opportunity cost. At the same time, patients' preferences for services also increase their willingness to bypass nearby dental clinics and travel greater distances.


Assuntos
Clínicas Odontológicas , Acesso aos Serviços de Saúde , Viagem , Adulto , Idoso , Implantes Dentários , Escolaridade , Feminino , Mapeamento Geográfico , Humanos , Renda , Masculino , Pessoa de Meia-Idade , Ortodontia , República da Coreia , População Rural , População Urbana , Adulto Jovem
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