Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 105
Filtrar
1.
ACS Chem Biol ; 16(2): 334-343, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33439620

RESUMO

mRNA-based therapies and vaccines constitute a disruptive technology with the potential to revolutionize modern medicine. Chemically modified 5' cap structures have provided access to mRNAs with superior translational properties that could benefit the currently flourishing mRNA field. Prime examples of compounds that enhance mRNA properties are antireverse cap analog diastereomers that contain an O-to-S substitution within the ß-phosphate (ß-S-ARCA D1 and D2), where D1 is used in clinically investigated mRNA vaccines. The compounds were previously found to have high affinity for eukaryotic translation initiation factor 4E (eIF4E) and augment translation in vitro and in vivo. However, the molecular basis for the beneficial "thio-effect" remains unclear. Here, we employed multiple biophysical techniques and captured 11 cap analog-eIF4E crystallographic structures to investigate the consequences of the ß-O-to-S or -Se substitution on the interaction with eIF4E. We determined the SP/RP configurations of ß-S-ARCA and related compounds and obtained structural insights into the binding. Unexpectedly, in both stereoisomers, the ß-S/Se atom occupies the same binding cavity between Lys162 and Arg157, indicating that the key driving force for complex stabilization is the interaction of negatively charged S/Se with positively charged amino acids. This was observed for all structural variants of the cap and required significantly different conformations of the triphosphate for each diastereomer. This finding explains why both ß-S-ARCA diastereomers have higher affinity for eIF4E than unmodified caps. Binding affinities determined for di-, tri-, and oligonucleotide cap analogs suggested that the "thio-effect" was preserved in longer RNAs. Our observations broaden the understanding of thiophosphate biochemistry and enable the rational design of translationally active mRNAs and eIF4E-targeting drugs.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33041477

RESUMO

This paper presents the results of compartment fire experiments on four 12.8 m long composite floor beams with various end support conditions. Specimens were constructed as partially-composite beams, consisting of W18×35 steel beams and 83 mm thick lightweight concrete slabs cast on top of 76 mm deep ribbed steel deck units. Test variables included two types of simple shear connections (shear-tab and welded-bolted double-angle connections) and the presence or absence of slab continuity over the girders. Each specimen was subjected to gravity loading using hydraulic actuators and 4000 kW compartment fires produced using natural gas-fueled burners. This study evaluated the characteristics of the fire loading and thermal and structural responses of the specimens. The test results indicated that there were significant effects of thermal restraints on the behavior and failure modes of the specimens with simple shear connections. The specimens resisted gravity loads at large vertical displacements near midspan (approximately a ratio of span length over 20) without collapse under fire loading. However, various limit states and vulnerabilities to fires were observed, including local buckling of steel beams near supports, flexural failure (yielding of steel beams and concrete fracture near restrained end supports), and connection failure (weld shear or bolt shear) during heating and cooling which could lead to partial or total collapse of the floor system.

3.
Mod Pathol ; 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661296

RESUMO

Fibroma of tendon sheath (FTS) is an uncommon benign fibroblastic/myofibroblastic neoplasm that typically arises in the tenosynovial tissue of the distal extremities. Histologically, it is a well-circumscribed proliferation of spindle cells within collagenous stroma with peripheral slit-like vessels. Most examples are relatively hypocellular and more densely collagenous than nodular fasciitis; however, a cellular variant has been described, which has considerable morphologic overlap with nodular fasciitis and has been shown to harbor USP6 translocations in a subset of cases. The incidence of these rearrangements and the identity of the USP6 fusion partners have not been described in detail. In this study we evaluate 13 cases of cellular fibroma of tendon sheath by anchored multiplex PCR/next generation sequencing in order to detect potential gene fusions. Nucleic acids of adequate quality were obtained in 11 cases, demonstrating gene fusions in 7/11 (64%), all of which involve USP6 with a variety of partners, including PKM, RCC1, ASPN, COL1A1, COL3A1, and MYH9. Some unusual histomorphologic findings were present in a subset of cases including palisading growth pattern, epithelioid cells, and osteoclast-like multinucleated giant cells, particularly in the tumors with PKM and ASPN gene partners. Overall, the findings support a biologic relationship between cellular fibroma of tendon sheath and other lesions within the spectrum of USP6-rearranged neoplasms, particularly nodular fasciitis.

4.
Hum Pathol ; 103: 14-24, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32679051

RESUMO

A variety of non-neoplastic diseases of the spine, including herniated/sequestered intervertebral discs, synovial cysts, and degenerative or post-traumatic changes, may present as mass lesions. Over the past several years, we have seen a large number of such paraspinal pseudoneoplasms in consultation, referred out of concern for malignancy on the part of the clinician, pathologist, or both. Herein, we report our experience with these specimens, emphasizing the clinical, radiologic, and histopathological features that allow their confident distinction from various mesenchymal tumors. Fifty-eight cases were identified within our consultation archives, referred in consultation to exclude malignancy and diagnosed as non-neoplastic disease involving the intervertebral disc, ligamentum flavum, or paraspinal soft tissues (2006-2019). Available radiologic studies were reviewed by 2 musculoskeletal radiologists. The histologic features of all cases were re-evaluated. Available clinical records were reviewed. The masses occurred in adults (median age 62 years, range 20-86 years) with a male predominance (35 males and 23 females). Sites included lumbar spine (N = 33), thoracic spine (N = 15), cervical spine (N = 6), paraspinal region (N = 3), and sacral spine (N = 1). In 44 cases (76%), the referring pathologist regarded the specimen as representing a benign or malignant neoplasm, either primary or metastatic. Fifteen cases (26%) were sent for second opinion at the request of the treating clinician, following an initial malignant diagnosis. Advanced imaging studies were available for re-review in 37 cases (64%) and showed herniated/extruded disc (N = 17), compression fracture (N = 9), synovial cyst (N = 8), and degenerative joint disease (N = 7). Multiple radiologic findings were seen in 9 patients. Histologically, the specimens showed a spectrum of often florid reactive changes involving degenerating disc material, ligamentum flavum, and bone. Awareness that non-neoplastic spinal processes may form pseudoneoplastic mass lesions, and careful clinical-radiologic-pathologic correlation should allow their confident distinction from potential morphologic mimics.

5.
RNA ; 26(10): 1380-1388, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32513655

RESUMO

Pat1, known as Pdc2 in fission yeast, promotes the activation and assembly of multiple proteins during mRNA decay. After deadenylation, the Pat1/Lsm1-7 complex binds to transcripts containing oligo(A) tails, which can be modified by the addition of several terminal uridine residues. Pat1 enhances Lsm1-7 binding to the 3' end, but it is unknown how this interaction is influenced by nucleotide composition. Here we examine Pat1/Lsm1-7 binding to a series of oligoribonucleotides containing different A/U contents using recombinant purified proteins from fission yeast. We observe a positive correlation between fractional uridine content and Lsm1-7 binding affinity. Addition of Pat1 broadens RNA specificity of Lsm1-7 by enhancing binding to A-rich RNAs and increases cooperativity on all oligonucleotides tested. Consistent with increased cooperativity, Pat1 promotes multimerization of the Lsm1-7 complex, which is potentiated by RNA binding. Furthermore, the inherent ability of Pat1 to multimerize drives liquid-liquid phase separation with multivalent decapping enzyme complexes of Dcp1/Dcp2. Our results uncover how Pat1 regulates RNA binding and higher order assembly by mRNA decay factors.


Assuntos
Estabilidade de RNA/genética , Proteínas de Ligação a RNA/genética , RNA/genética , Proteínas de Saccharomyces cerevisiae/genética , Schizosaccharomyces/genética , Fatores de Transcrição/genética , Citoplasma/genética , RNA Mensageiro/genética , Proteínas Recombinantes/genética , Saccharomyces cerevisiae/genética
6.
Int J Surg Pathol ; : 1066896920927794, 2020 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-32484057

RESUMO

Chondroblastoma is a rare benign tumor of immature cartilage cells that generally occurs in an epiphyseal location of skeletally immature individuals. However, a few studies have reported cases in older patients. The purpose of this study was to evaluate the clinical, radiographic, and pathologic features of chondroblastoma in an adult population. The pathology archives of our institution were searched for cases of chondroblastoma diagnosed in patients ≥25 years of age. Of 14 patients identified, 8 were male and 6 were female with a median age of 34 years (range = 29-54 years). Most lesions occurred in short bones of hands and feet (N = 7, 50%), followed by the long tubular bones (N = 4, 28%). All demonstrated typical histologic features of chondroblastoma, but more extensive calcification, necrosis, and degenerative changes were also seen. At follow-up (median = 73.5 months), 2 patients (17%) had local recurrence. None had metastasis. In summary, chondroblastoma in adults tends to involve the short bones of the hands and feet and demonstrate histologic changes associated with long-standing growth of a benign tumor.

7.
Mod Pathol ; 33(11): 2169-2185, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32467650

RESUMO

Pathologists are responsible for rapidly providing a diagnosis on critical health issues. Challenging cases benefit from additional opinions of pathologist colleagues. In addition to on-site colleagues, there is an active worldwide community of pathologists on social media for complementary opinions. Such access to pathologists worldwide has the capacity to improve diagnostic accuracy and generate broader consensus on next steps in patient care. From Twitter we curate 13,626 images from 6,351 tweets from 25 pathologists from 13 countries. We supplement the Twitter data with 113,161 images from 1,074,484 PubMed articles. We develop machine learning and deep learning models to (i) accurately identify histopathology stains, (ii) discriminate between tissues, and (iii) differentiate disease states. Area Under Receiver Operating Characteristic (AUROC) is 0.805-0.996 for these tasks. We repurpose the disease classifier to search for similar disease states given an image and clinical covariates. We report precision@k = 1 = 0.7618 ± 0.0018 (chance 0.397 ± 0.004, mean ±stdev ). The classifiers find that texture and tissue are important clinico-visual features of disease. Deep features trained only on natural images (e.g., cats and dogs) substantially improved search performance, while pathology-specific deep features and cell nuclei features further improved search to a lesser extent. We implement a social media bot (@pathobot on Twitter) to use the trained classifiers to aid pathologists in obtaining real-time feedback on challenging cases. If a social media post containing pathology text and images mentions the bot, the bot generates quantitative predictions of disease state (normal/artifact/infection/injury/nontumor, preneoplastic/benign/low-grade-malignant-potential, or malignant) and lists similar cases across social media and PubMed. Our project has become a globally distributed expert system that facilitates pathological diagnosis and brings expertise to underserved regions or hospitals with less expertise in a particular disease. This is the first pan-tissue pan-disease (i.e., from infection to malignancy) method for prediction and search on social media, and the first pathology study prospectively tested in public on social media. We will share data through http://pathobotology.org . We expect our project to cultivate a more connected world of physicians and improve patient care worldwide.

8.
Head Neck Pathol ; 14(1): 33-42, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31950469

RESUMO

Biphenotypic sinonasal sarcoma is an anatomically restricted low-grade malignant neoplasm with dual neural and myogenic differentiation composed of a monotonous population of spindled cells with herringbone/fascicular architecture. These tumors demonstrate a unique immunoprofile with relatively consistent S100-protein and actin expression in conjunction with more variable desmin, myogenin and myoD1 staining. SOX10 is uniformly negative. Genetically, the majority of tumors harbor PAX3-MAML3 fusions, with alternate PAX3 partners including FOXO1, NCOA1, NCOA2 and WWTR1. Although the differential diagnosis of BSNS is broad, careful morphologic inspection together with targeted ancillary studies is often sufficient to arrive at the correct diagnosis. As these tumors have significant local recurrence rates but lack metastatic potential, awareness and accurate diagnosis of this rare and newly described neoplasm is critical for appropriate management.


Assuntos
Neoplasias dos Seios Paranasais/patologia , Sarcoma/diagnóstico , Sarcoma/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Diagnóstico Diferencial , Humanos , Neoplasias dos Seios Paranasais/diagnóstico , Neoplasias dos Seios Paranasais/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
9.
Aesthet Surg J ; 40(4): 413-429, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-30951166

RESUMO

BACKGROUND: PrabotulinumtoxinA is a 900-kDa botulinum toxin type A produced by Clostridium botulinum. OBJECTIVES: The authors sought to investigate the efficacy and safety of prabotulinumtoxinA compared to onabotulinumtoxinA and placebo for the treatment of glabellar lines. METHODS: This was a 150-day, multicenter, double-blind, controlled, single-dose Phase III study. Adult patients (n = 540) with moderate to severe glabellar lines at maximum frown as assessed by the investigator on the validated 4-point Glabellar Line Scale (0 = no lines, 1 = mild, 2 = moderate, 3 = severe), who also felt that their glabellar lines had an important psychological impact, were enrolled. Patients were randomized 5:5:1 to receive a single treatment (0.1 mL injected into each of 5 glabellar sites) of 20 U prabotulinumtoxinA (n = 245), 20 U onabotulinumtoxinA (n = 246), or placebo (n = 49). The primary efficacy endpoint was the proportion of responders (patients with a Glabellar Line Scale score of 0 or 1 at maximum frown by investigator assessment) on day 30. RESULTS: Responder rates for the primary efficacy endpoint were 87.2%, 82.8%, and 4.2% in the prabotulinumtoxinA, onabotulinumtoxinA, and placebo groups, respectively. The absolute difference between prabotulinumtoxinA and onabotulinumtoxinA groups was 4.4% (95% confidence interval [-1.9, 10.8]). Given that the lower bound of the 95% confidence interval for the difference was less than -10.0%, noninferiority of prabotulinumtoxinA vs onabotulinumtoxinA was concluded. Five patients (3 prabotulinumtoxinA, 1.2%; 1 onabotulinumtoxinA, 0.4%; 1 placebo, 2.0%) experienced serious adverse events, none of which were study drug related. CONCLUSIONS: A single treatment of 20 U prabotulinumtoxinA was safe and effective and noninferior to 20 U onabotulinumtoxinA for the treatment of moderate to severe glabellar lines.

10.
Cell Host Microbe ; 26(6): 739-747.e4, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31830442

RESUMO

Primate lentiviruses encode a Vif protein that counteracts the host antiviral APOBEC3 (A3) family members. The adaptation of Vif to species-specific A3 determinants is a critical event that allowed the spillover of a lentivirus from monkey reservoirs to chimpanzees and subsequently to humans, which gave rise to HIV-1 and the acquired immune deficiency syndrome (AIDS) pandemic. How Vif-A3 protein interactions are remodeled during evolution is unclear. Here, we report a 2.94 Å crystal structure of the Vif substrate receptor complex from simian immunodeficiency virus isolated from red-capped mangabey (SIVrcm). The structure of the SIVrcm Vif complex illuminates the stage of lentiviral Vif evolution that is immediately prior to entering hominid primates. Structure-function studies reveal the adaptations that allowed SIVrcm Vif to antagonize hominid A3G. These studies show a partitioning between an evolutionarily dynamic specificity determinant and a conserved protein interacting surface on Vif that enables adaptation while maintaining protein interactions required for potent A3 antagonism.


Assuntos
Produtos do Gene vif , Vírus da Imunodeficiência Símia , Desaminase APOBEC-3G/metabolismo , Síndrome de Imunodeficiência Adquirida , Animais , Cercocebus , Cristalografia , Evolução Molecular , Produtos do Gene vif/química , Produtos do Gene vif/genética , HIV-1/genética , HIV-1/metabolismo , Hominidae , Interações Hospedeiro-Patógeno , Humanos , Lentivirus/genética , Lentivirus/metabolismo , Doenças dos Macacos/virologia , Pan troglodytes , Primatas , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/metabolismo , Produtos do Gene vif do Vírus da Imunodeficiência Humana/química , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genética , Produtos do Gene vif do Vírus da Imunodeficiência Humana/ultraestrutura
11.
Proc Natl Acad Sci U S A ; 116(47): 23512-23517, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31690658

RESUMO

Pat1 is a hub for mRNA metabolism, acting in pre-mRNA splicing, translation repression, and mRNA decay. A critical step in all 5'-3' mRNA decay pathways is removal of the 5' cap structure, which precedes and permits digestion of the RNA body by conserved exonucleases. During bulk 5'-3' decay, the Pat1/Lsm1-7 complex engages mRNA at the 3' end and promotes hydrolysis of the cap structure by Dcp1/Dcp2 at the 5' end through an unknown mechanism. We reconstitute Pat1 with 5' and 3' decay factors and show how it activates multiple steps in late mRNA decay. First, we find that Pat1 stabilizes binding of the Lsm1-7 complex to RNA using two conserved short-linear interaction motifs. Second, Pat1 directly activates decapping by binding elements in the disordered C-terminal extension of Dcp2, alleviating autoinhibition and promoting substrate binding. Our results uncover the molecular mechanism of how separate domains of Pat1 coordinate the assembly and activation of a decapping messenger ribonucleoprotein (mRNP) that promotes 5'-3' mRNA degradation.


Assuntos
Proteínas Serina-Treonina Quinases/fisiologia , Estabilidade de RNA , RNA Fúngico/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Schizosaccharomyces pombe/fisiologia , Schizosaccharomyces/metabolismo , Sequência de Aminoácidos , Sequência Conservada , Modelos Moleculares , Complexos Multiproteicos , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Mapeamento de Interação de Proteínas , Capuzes de RNA/metabolismo , Proteínas Recombinantes/metabolismo , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos
12.
Urol Case Rep ; 27: 101009, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31516836

RESUMO

Penile cancer is normally discovered in an early stage due to its visibility to the patient. This case report demonstrates a morbidly obese patient with a locally advanced penile cancer hidden by fatty tissue. Biopsy showed P16-positive tumor cells, which responded to concurrent chemo-radiotherapy with no evidence of disease at 24 months of follow-up. We also review the significance of p16-positive cell biology.

13.
Case Rep Gastrointest Med ; 2019: 8175376, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275668

RESUMO

A 30-year-old female underwent vertical sleeve gastrectomy. Postoperatively, hypercupremia and elevated ceruloplasmin were identified. Further testing revealed normal blood levels of transaminases, alkaline phosphatase, and albumin. She stopped ingestion of multivitamins, began a copper-free multivitamin, and then began a low copper diet, but with no improvement in hypercupremia. Protein electrophoresis was normal with no M-spike. Urinary copper excretion was normal at 0.24 micromol/24 hours (normal: < 0.55), and there were no Kayser-Fleischer rings on slit lamp examination. Two years postoperatively, she lost 44% of excess preoperative weight and she began zinc sulfate before meals twice daily (115 mg elemental Zinc/day). At 2 months and 8 months later, plasma copper and ceruloplasmin had essentially normalized. Increased production of ceruloplasmin could have been a response to significant weight loss or the presence of nonalcoholic steatohepatitis. The mechanism of zinc's beneficial effect is uncertain but may be related to suppressing hepatic synthesis of or secretion of ceruloplasmin.

14.
Cell Host Microbe ; 26(1): 86-99.e7, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31253590

RESUMO

The Cullin-RING E3 ligase (CRL) family is commonly hijacked by pathogens to redirect the host ubiquitin proteasome machinery to specific targets. During HIV infection, CRL5 is hijacked by HIV Vif to target viral restriction factors of the APOBEC3 family for ubiquitination and degradation. Here, using a quantitative proteomics approach, we identify the E3 ligase ARIH2 as a regulator of CRL5-mediated APOBEC3 degradation. The CUL5Vif/CBFß complex recruits ARIH2 where it acts to transfer ubiquitin directly to the APOBEC3 targets. ARIH2 is essential for CRL5-dependent HIV infectivity in primary CD4+ T cells. Furthermore, we show that ARIH2 cooperates with CRL5 to prime other cellular substrates for polyubiquitination, suggesting this may represent a general mechanism beyond HIV infection and APOBEC3 degradation. Taken together, these data identify ARIH2 as a co-factor in the Vif-hijacked CRL5 complex that contributes to HIV infectivity and demonstrate the operation of the E1-E2-E3/E3-substrate ubiquitination mechanism in a viral infection context.


Assuntos
Desaminase APOBEC-3G/metabolismo , Proteínas Culina/metabolismo , Infecções por HIV/patologia , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , Ubiquitina-Proteína Ligases/metabolismo , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo , Linfócitos T CD4-Positivos/virologia , Células Cultivadas , Humanos , Modelos Teóricos , Proteólise , Proteoma/análise , Replicação Viral
15.
Biophys J ; 116(8): 1432-1445, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30961890

RESUMO

Human immunodeficiency virus-1 viral infectivity factor (Vif) is an intrinsically disordered protein responsible for the ubiquitination of the APOBEC3 (A3) antiviral proteins. Vif folds when it binds Cullin-RING E3 ligase 5 and the transcription cofactor CBF-ß. A five-protein complex containing the substrate receptor (Vif, CBF-ß, Elongin-B, Elongin-C (VCBC)) and Cullin5 (CUL5) has a published crystal structure, but dynamics of this VCBC-CUL5 complex have not been characterized. Here, we use molecular dynamics (MD) simulations and NMR to characterize the dynamics of the VCBC complex with and without CUL5 and an A3 protein bound. Our simulations show that the VCBC complex undergoes global dynamics involving twisting and clamshell opening of the complex, whereas VCBC-CUL5 maintains a more static conformation, similar to the crystal structure. This observation from MD is supported by methyl-transverse relaxation-optimized spectroscopy NMR data, which indicates that the VCBC complex without CUL5 is dynamic on the µs-ms timescale. Our NMR data also show that the VCBC complex is more conformationally restricted when bound to the antiviral APOBEC3F (one of the A3 proteins), consistent with our MD simulations. Vif contains a flexible linker region located at the hinge of the VCBC complex, which changes conformation in conjunction with the global dynamics of the complex. Like other substrate receptors, VCBC can exist alone or in complex with CUL5 and other proteins in cells. Accordingly, the VCBC complex could be a good target for therapeutics that would inhibit full assembly of the ubiquitination complex by stabilizing an alternate VCBC conformation.


Assuntos
Proteínas Culina/química , Citidina Desaminase/química , Simulação de Dinâmica Molecular , Produtos do Gene vif do Vírus da Imunodeficiência Humana/química , Subunidade beta de Fator de Ligação ao Core/química , Cristalização , Elonguina/química , Humanos , Cinética , Ligação Proteica , Conformação Proteica , Dobramento de Proteína , Relação Estrutura-Atividade , Ubiquitinação
16.
Dermatol Surg ; 45(11): 1381-1393, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30893162

RESUMO

BACKGROUND: PrabotulinumtoxinA is a 900-kDa botulinum toxin Type A produced by Clostridium botulinum. OBJECTIVE: To investigate the efficacy and safety of prabotulinumtoxinA for the treatment of glabellar lines. MATERIALS AND METHODS: Adult subjects (n = 330 in EV-001; n = 324 in EV-002) with moderate to severe glabellar lines at maximum frown on the 4-point Glabellar Line Scale (GLS; 0 = no lines, 1 = mild, 2 = moderate, and 3 = severe) were enrolled in 1 of 2 identical 150-day, double-blind, placebo-controlled, single-dose, Phase III studies. Subjects were randomized 3:1 to receive 20-U prabotulinumtoxinA or placebo. The primary efficacy end point was the proportion of responders on Day 30 where the investigator and subject independently agreed that a ≥2-point improvement had occurred on the GLS at maximum frown from Day 0. Adverse events (AEs) were evaluated throughout the study. RESULTS: Responder rates in the prabotulinumtoxinA and placebo groups were 67.5% and 1.2% in EV-001 and 70.4% and 1.3% in EV-002; absolute differences between groups were 66.3% and 69.1% in EV-001 and EV-002, respectively (both p < .001). No serious AE in either study was assessed as study drug related. CONCLUSION: In these studies, a single dose of 20-U prabotulinumtoxinA was safe and effective for the treatment of glabellar lines.


Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Técnicas Cosméticas/efeitos adversos , Fármacos Neuromusculares/administração & dosagem , Envelhecimento da Pele/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Toxinas Botulínicas Tipo A/efeitos adversos , Método Duplo-Cego , Feminino , Testa , Humanos , Injeções Subcutâneas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Resultado do Tratamento , Adulto Jovem
17.
Nat Struct Mol Biol ; 26(2): 147-148, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30575809

RESUMO

The original and corrected figures are shown in the accompanying Publisher Correction.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32493764

RESUMO

Heterochromatin is a classic context for studying the mechanisms of chromatin organization. At the core of a highly conserved type of heterochromatin is the complex formed between chromatin methylated on histone H3 lysine 9 and HP1 proteins. This type of heterochromatin plays central roles in gene repression, genome stability, and nuclear mechanics. Systematic studies over the last several decades have provided insight into the biophysical mechanisms by which the HP1-chromatin complex is formed. Here, we discuss these studies together with recent findings indicating a role for phase separation in heterochromatin organization and function. We suggest that the different functions of HP1-mediated heterochromatin may rely on the increasing diversity being uncovered in the biophysical properties of HP1-chromatin complexes.

19.
Nat Struct Mol Biol ; 25(12): 1077-1085, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30518847

RESUMO

5'-3' RNA decay pathways are critical for quality control and regulation of gene expression. Structural and biochemical studies have provided insights into the key nucleases that carry out deadenylation, decapping, and exonucleolysis during 5'-3' decay, but detailed understanding of how these activities are coordinated is only beginning to emerge. Here we review recent mechanistic insights into the control of 5'-3' RNA decay, including coupling between translation and decay, coordination between the complexes and activities that process 5' and 3' RNA termini, conformational control of enzymatic activity, liquid phase separation, and RNA modifications.


Assuntos
Estabilidade de RNA , RNA Mensageiro/química , Regulação da Expressão Gênica , Modelos Moleculares , RNA Mensageiro/metabolismo
20.
J Surg Case Rep ; 2018(11): rjy307, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30473761

RESUMO

Solitary fibrous tumors (SFT) are uncommon fibroblastic mesenchymal neoplasms that display a wide range of histologic behaviors. These tumors, which are estimated to account for 2% of all soft tissue neoplasms, typically follow a benign clinical course. However, it is estimated that 10-30% of SFTs are malignant and demonstrate aggressive behavior with local recurrence and metastasis up to several years after surgical resection. We report a case of SFT arising from the stomach, which is an exceptionally rare finding and has been reported only six times in the literature. Our case was complicated by diagnostic dilemma with GIST, highlighting the challenges of diagnosing and characterizing SFTs. Additionally, this tumor was associated with dedifferentiation into undifferentiated pleomorphic sarcoma. To our knowledge, there are no documented cases of a malignant SFT arising from the stomach to demonstrate dedifferentiation into an undifferentiated pleomorphic sarcoma.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...