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1.
Nat Commun ; 12(1): 4917, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389714

RESUMO

APOBEC3A is a cytidine deaminase driving mutagenesis in tumors. While APOBEC3A-induced mutations are common, APOBEC3A expression is rarely detected in cancer cells. This discrepancy suggests a tightly controlled process to regulate episodic APOBEC3A expression in tumors. In this study, we find that both viral infection and genotoxic stress transiently up-regulate APOBEC3A and pro-inflammatory genes using two distinct mechanisms. First, we demonstrate that STAT2 promotes APOBEC3A expression in response to foreign nucleic acid via a RIG-I, MAVS, IRF3, and IFN-mediated signaling pathway. Second, we show that DNA damage and DNA replication stress trigger a NF-κB (p65/IkBα)-dependent response to induce expression of APOBEC3A and other innate immune genes, independently of DNA or RNA sensing pattern recognition receptors and the IFN-signaling response. These results not only reveal the mechanisms by which tumors could episodically up-regulate APOBEC3A but also highlight an alternative route to stimulate the immune response after DNA damage independently of cGAS/STING or RIG-I/MAVS.


Assuntos
Citidina Desaminase/genética , Dano ao DNA , Regulação da Expressão Gênica , Imunidade/genética , Proteínas/genética , Transdução de Sinais/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Citidina Desaminase/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células THP-1 , Fator de Transcrição RelA/metabolismo , Regulação para Cima , Vírus/crescimento & desenvolvimento
2.
Eur J Pharm Biopharm ; 157: 108-120, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33068736

RESUMO

Glioblastoma is a malignant brain tumour with a median survival of 14.6 months from diagnosis. Despite maximal surgical resection and concurrent chemoradiotherapy, reoccurrence is inevitable. To try combating the disease at a stage of low residual tumour burden immediately post-surgery, we propose a localised drug delivery system comprising of a spray device, bioadhesive hydrogel (pectin) and drug nanocrystals coated with polylactic acid-polyethylene glycol (NCPPs), to be administered directly into brain parenchyma adjacent to the surgical cavity. We have repurposed pectin for use within the brain, showing in vitro and in vivo biocompatibility, bio-adhesion to mammalian brain and gelling at physiological brain calcium concentrations. Etoposide and olaparib NCPPs with high drug loading have shown in vitro stability and drug release over 120 h. Pluronic F127 stabilised NCPPs to ensure successful spraying, as determined by dynamic light scattering and transmission electron microscopy. Successful delivery of Cy5-labelled NCPPs was demonstrated in a large ex vivo mammalian brain, with NCPP present in the tissue surrounding the resection cavity. Our data collectively demonstrates the pre-clinical development of a novel localised delivery device based on a sprayable hydrogel containing therapeutic NCPPs, amenable for translation to intracranial surgical resection models for the treatment of malignant brain tumours.

5.
ANZ J Surg ; 89(4): 367-371, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30791194

RESUMO

BACKGROUND: Definitive chemoradiation for oesophageal squamous cell carcinoma (SCC) is the first-line treatment in many centres. However, it is not without morbidity. We assess outcomes for patients treated with definitive chemoradiotherapy and radiotherapy. METHODS: A retrospective review of a prospectively maintained database (Radiotherapy Department, Canterbury District Health Board) was undertaken. All patients who underwent definitive radiotherapy for oesophageal SCC between October 1996 and April 2015 were included. RESULTS: Sixty patients underwent chemoradiotherapy with curative intent and 17 underwent definitive radiotherapy with curative intent. Median age was 69 years (44-84 years) for those undergoing chemoradiotherapy and 73 years (36-85 years) for those who underwent definitive radiotherapy. Tumour location in all patients was upper third in 14 (18%), middle third in 39 (51%), lower third in 22 (29%) cases and junctional tumour in two (3%). Staging information was complete for 73 of 77 patients (stage I 16/77 (21%), stage II 40/77 (52%), stage III 17/77 (22%)). Median dose of external beam radiotherapy for those who underwent definitive chemotherapy was 50.4 Gy (30-63 Gy) and 60 Gy (50-64 Gy) for definitive radiotherapy. Median length of follow-up was 39 months (range 4-120 months). Strictures developed in 58% of all patients (52% chemoradiotherapy and 76% definitive radiotherapy). Twenty-four (32%) patients were dilated and 14 (18%) stented. The chemoradiotherapy group had higher 5-year survival than definitive radiotherapy group (34% versus 6%, P = 0.0034). CONCLUSION: Oesophageal SCC treated with chemoradiation has a 5-year survival rate of 34%. Post-treatment strictures occur in 52% of patients with chemoradiotherapy and 76% with definitive radiotherapy.


Assuntos
Quimiorradioterapia/efeitos adversos , Constrição Patológica/induzido quimicamente , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/radioterapia , Radioterapia/efeitos adversos , Adulto , Assistência ao Convalescente/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Quimiorradioterapia/mortalidade , Terapia Combinada , Constrição Patológica/patologia , Constrição Patológica/terapia , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/etiologia , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nova Zelândia/epidemiologia , Radioterapia/mortalidade , Dosagem Radioterapêutica , Estudos Retrospectivos , Stents/efeitos adversos , Taxa de Sobrevida
7.
Prim Care ; 45(2): 193-212, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29759120

RESUMO

New and existing rheumatic disease is frequently encountered in the primary care setting. The number of medications used to treat various rheumatic conditions continues to increase. Some medications have very specific indications, whereas others have increasing off-label uses. Regardless of the indication, the medications used in rheumatology have variable dosing recommendations, significant side effects, recommended monitoring parameters, and potential medication interactions. Clinicians need to be aware of the potential uses as well as possible pitfalls associated with medications used in rheumatology.


Assuntos
Antirreumáticos/uso terapêutico , Atenção Primária à Saúde/organização & administração , Doenças Reumáticas/tratamento farmacológico , Antirreumáticos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Reumatologia
8.
Mil Med ; 182(11): e2108-e2111, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29087892

RESUMO

Chikungunya virus (CHIKV) is an arthropod-borne alphavirus initially endemic to Central and East Africa but now spreading to Asia, Europe, and most recently the Western hemisphere. CHIKV infection initially presents as an acute, nonspecific febrile syndrome with rash and polyarthralgia, later leading to a chronic arthritis clinically similar to rheumatoid arthritis. We report a case of an active duty military member infected with CHIKV while deployed to Central America, who developed chronic arthritis. Active duty military members are at higher risk of contracting CHIKV because of deployment to countries with a high prevalence of this mosquito-borne illness. Severe chronic arthritis can result from CHIKV, resulting in serious impact on fitness for military duty.


Assuntos
Febre de Chikungunya/complicações , Militares , Sinovite/etiologia , Adulto , Animais , Artralgia/etiologia , Artrópodes/patogenicidade , Artrópodes/virologia , Vírus Chikungunya/patogenicidade , Exantema/etiologia , Febre/etiologia , Guatemala , Humanos , Masculino , Sinovite/diagnóstico por imagem , Sinovite/virologia , Ultrassonografia/métodos
9.
Arthritis Care Res (Hoboken) ; 69(10): 1519-1525, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-27998042

RESUMO

OBJECTIVE: Limited literature exists on the sonographic appearance of the posterior tibialis tendon (PTT) and the peroneus brevis tendon (PBT) entheses. We determined the anatomic features and best imaging techniques of normal PTT and PBT using musculoskeletal ultrasound and compared these findings to subjects with inflammatory arthritis. METHODS: Adult subjects were enrolled as healthy controls (HCs), rheumatoid arthritis (RA) patients, or spondyloarthropathy (SpA) patients. Bilateral PTT and PBT entheses were imaged longitudinally, comparing 2 angles of insonation: perpendicular to the skin surface and 45° cephalad. Images were scored on semiquantitative scales assessing pathology. RESULTS: A total of 78 subjects were enrolled (37 HC, 21 RA, and 20 SpA). Complete enthesis visualization was achieved more frequently in the perpendicular than in the cephalad view for the PBT (76.3% versus 58.7%), but more frequently in the cephalad view for the PTT (58.0% versus 19.6%). RA and SpA subjects had higher rates of PTT fiber disruption (P < 0.001), PTT tenosynovial effusion (P < 0.001), and Doppler signal (P < 0.001) than HCs. No significant differences existed at the PBT enthesis. In multivariate analysis, RA and SpA subjects were found to be 5.1 times (P < 0.001) and 3.6 times (P < 0.001) more likely to exhibit ultrasound-detected pathology, respectively, than HCs. CONCLUSION: The perpendicular transducer aim is optimal for imaging the PBT, while the cephalad transducer orientation was more effective for evaluation of the PTT. Unlike distal PBT imaging, PTT imaging distinguished healthy and disease states, with both RA and SpA patients showing features of PTT enthesopathy. Distal PTT imaging is a useful technique for musculoskeletal ultrasound.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Entesopatia/diagnóstico por imagem , Espondiloartropatias/diagnóstico por imagem , Tendões/diagnóstico por imagem , Ultrassonografia Doppler , Adulto , Idoso , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Transdutores , Ultrassonografia Doppler/instrumentação , Ultrassonografia Doppler/métodos
11.
Bioanalysis ; 8(6): 487-95, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26916197

RESUMO

The 9th GCCClosed Forum was held just prior to the 2015 Workshop on Recent Issues in Bioanalysis (WRIB) in Miami, FL, USA on 13 April 2015. In attendance were 58 senior-level participants, from eight countries, representing 38 CRO companies offering bioanalytical services. The objective of this meeting was for CRO bioanalytical representatives to meet and discuss scientific and regulatory issues specific to bioanalysis. The issues selected at this year's closed forum include CAPA, biosimilars, preclinical method validation, endogenous biomarkers, whole blood stability, and ELNs. A summary of the industry's best practices and the conclusions from the discussion of these topics is included in this meeting report.


Assuntos
Biomarcadores/análise , Medicamentos Biossimilares/análise , Avaliação Pré-Clínica de Medicamentos/métodos , Biomarcadores/sangue , Registros Eletrônicos de Saúde , Laboratórios , Sociedades Médicas , Estudos de Validação como Assunto
13.
J Clin Rheumatol ; 21(6): 314-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26267716

RESUMO

Calcium pyrophosphate dihydrate deposition (CPPD) disease is a common etiology of crystalline arthropathy; however, it can manifest in multiple patterns such as acute calcium pyrophosphate (CPP) crystal arthritis, osteoarthritis with CPPD, and chronic CPP crystal inflammatory arthritis. Tumoral or tophaceous-like CPPD is a rare manifestation that is occasionally mistaken for gouty tophus or a soft tissue malignancy. Dual-energy computed tomography (DECT) is a new imaging modality currently utilized in assessing monosodium urate crystal deposition; however, its value in CPPD is uncertain. We describe a case using DECT to diagnose tumoral CPPD mimicking tophaceous gout versus recurrence of a previous synovial sarcoma. The imaging findings on DECT prevented unnecessary surgery to assess for possible malignancy, allowing for the prompt diagnosis of tumoral CPPD. Further studies should be performed to determine the role of DECT in assessing for crystalline deposition disease other than gout.


Assuntos
Condrocalcinose , Gota/diagnóstico , Sarcoma Sinovial/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Articulação do Punho/diagnóstico por imagem , Condrocalcinose/diagnóstico , Condrocalcinose/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Articulação do Punho/patologia
14.
Ann Pharmacother ; 48(11): 1406-14, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25070396

RESUMO

BACKGROUND: Contradictory evidence exists regarding statin use and risk of osteoporotic fractures. OBJECTIVE: The study objective was to examine the effect of statins on fracture risk in a Military Healthcare System (MHS) with similar access and standard of health care for its beneficiaries. METHODS: This is a retrospective study of patients enrolled in an MHS encompassing the period from October 1, 2003, to March 1, 2010. Statin users were defined as those receiving a statin for ≥90 days in Fiscal Year 2005, whereas nonusers were defined as individuals not receiving a statin throughout the study period. A propensity score-matched cohort of statin users and nonusers was created using 42 variables. The outcomes were identified using ICD-9-CM codes in the follow-up period (October 1, 2006, to March 1, 2010). In all, 4 outcomes were examined: all fractures, femoral neck fractures, upper-extremity fractures, and lower-extremity fractures. RESULTS: Of 46 249 patients, 6967 pairs of statin users and nonusers were matched. Statin users had a lower risk of femoral neck fracture in comparison to nonusers (odds ratio=0.58, 95% CI=0.36-0.94) but similar risk of all fractures, lower-extremity fractures, and upper-extremity fractures. CONCLUSIONS: In this cohort of patients managed in an MHS, statin use was associated with a lower risk of femoral neck fractures, but not all fractures, upper-extremity fractures, or lower-extremity fractures.


Assuntos
Fraturas Ósseas/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Militares , Razão de Chances , Pontuação de Propensão , Estudos Retrospectivos , Risco
15.
Mil Med ; 178(3): e367-71, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23707127

RESUMO

BACKGROUND: Guillain-Barré syndrome (GBS) is a potentially life-threatening autoimmune disease causing demyelination of peripheral nerves. Multiple variants of GBS exist, with acute motor and sensory axonal neuropathy (AMSAN) being the most severe. GBS typically does not occur in the setting of other autoimmune diseases; however, few case reports do exist describing the occurrence. METHODS: We describe a patient with acute motor and sensory deficits and thrombocytopenia, ultimately diagnosed with concurrent AMSAN and immune thrombocytopenic purpura (ITP). RESULTS: A 75-year-old woman presented with new onset diplopia and gait instability, however, was found to have a severe thrombocytopenia. Corticosteroids were initiated for ITP and intravenous immunoglobulin for apparent GBS. Nerve conduction studies and her clinical course indicated that she likely had AMSAN. Although her platelet count recovered, her neurologic status remained poor, prompting therapy with plasmapheresis with subsequent mild improvement. CONCLUSION: A review of the literature revealed eleven previous cases of concurrent GBS and ITP; however, we report the first case of concurrent AMSAN and ITP. Among these cases, trends were noted to include sex, preceding infections, and cranial nerve involvement.


Assuntos
Ataxia/etiologia , Doenças do Sistema Nervoso Periférico/complicações , Púrpura Trombocitopênica Idiopática/complicações , Idoso , Feminino , Humanos
16.
Br J Clin Pharmacol ; 73(2): 232-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21834938

RESUMO

AIMS: The objectives of this phase 1 study were to confirm the tolerability of single ascending subcutaneous doses of PP 1420 in healthy subjects, to assess its adverse effects and to investigate the drug's pharmacokinetics and dose proportionality. METHODS: This was a double-blind, placebo-controlled, randomized study. There were three dosing periods. Each subject (n= 12) was randomized to receive one dose of placebo and two ascending doses of PP 1420, given as a subcutaneous injection. Blood samples were taken over 24 h to assess pharmacokinetics. Standard safety and laboratory data were collected. The primary endpoint was the tolerability of PP 1420. The secondary endpoint was exposure to PP 1420 as assessed by C(max) and AUC(0,∞). RESULTS: PP 1420 was well tolerated by all subjects with no serious adverse effects. Following single subcutaneous doses of PP 1420 at 2, 4 and 8 mg to male subjects, C(max) was reached at a median t(max) of approximately 1 h post dose (range 0.32-2.00 h). Thereafter, plasma concentrations of PP 1420 declined with geometric mean apparent terminal elimination t(1/2) ranging from 2.42-2.61 h (range 1.64-3.95 h) across all dose levels. CONCLUSIONS: Subcutaneous PP 1420 was well tolerated in healthy human subjects at single doses between 2-8 mg, with no tolerability issues arising. Where observed, adverse events were not serious, and there was no evidence of a dose-relationship to frequency of adverse events. The results therefore support the conduct of clinical trials to investigate efficacy, tolerability and pharmacokinetics during repeated dosing.


Assuntos
Depressores do Apetite/farmacocinética , Apetite/efeitos dos fármacos , Obesidade/prevenção & controle , Polipeptídeo Pancreático/análogos & derivados , Receptores de Neuropeptídeo Y/agonistas , Adolescente , Adulto , Depressores do Apetite/efeitos adversos , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Polipeptídeo Pancreático/efeitos adversos , Polipeptídeo Pancreático/farmacocinética , Reino Unido , Adulto Jovem
17.
Acta Biomater ; 7(4): 1535-41, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21187168

RESUMO

Highly oriented poly(glycolic acid) (PGA) fibres with an initial tensile strength of 1.1 GPa and different lamellar morphologies were prepared and studied during degradation in aqueous media at 37°C. A combination of small- and wide-angle X-ray scattering was used to study the structural changes during degradation and to generate two structural models of highly oriented PGA fibres with different lamellar morphologies. It is shown that as a result of crystallisation during degradation PGA crystals grow preferentially along the (110) and (020) directions of the crystal lattice or perpendicular to the orientation direction of the fibres. (1)H nuclear magnetic resonance measurements revealed three phases within the fibres with different relaxation times: (1) a mobile amorphous phase with a short relaxation time; (2) a semi-rigid phase with an intermediate relaxation time; (3) a rigid crystalline phase with a longer relaxation time. It is shown that the mobile amorphous phase degrades very rapidly and that it plays only a small role in the tensile mechanical behaviour of the fibres during degradation. It is shown that semi-rigid chains connecting crystalline domains are responsible for transferring the stress between crystalline domains and carrying the tensile deformation. It is proposed that once these tie molecules degrade considerably the oriented fibres very rapidly lose their strength retention.


Assuntos
Teste de Materiais/métodos , Ácido Poliglicólico/química , Tampões (Química) , Espectroscopia de Ressonância Magnética , Espalhamento a Baixo Ângulo , Soluções , Resistência à Tração , Difração de Raios X
18.
Biomaterials ; 31(30): 7599-605, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20655107

RESUMO

The synthesis and characterisation of a series of liquid-crystalline aromatic-aliphatic copolyesters are presented. Differential scanning calorimetry showed these polymers have a glass transition temperature in the range 72 degrees C-116 degrees C. Polarised optical microscopy showed each polymer exhibits a nematic mesophase on heating to the molten state at temperatures below 165 degrees C. Melt processing is demonstrated by the production of injection moulded and compression moulded specimens with Young's modulus of 5.7 +/- 0.3 GPa and 2.3 +/- 0.3 GPa, respectively. Wide-angle X-ray scattering data showed molecular orientation is responsible for the increase of mechanical properties along the injection direction. Degradation studies in the temperature range 37 degrees C-80 degrees C are presented for one polymer of this series and a kinetic constant of 0.002 days(-1) is obtained at 37 degrees C assuming a first order reaction. The activation energy (83.4 kJ mol(-1)) is obtained following the Arrhenius analysis of degradation, showing degradation of this material is less temperature sensitive compared with other commercially available biodegradable polyesters. In vitro and in vivo biocompatibility data are presented and it is shown the unique combination of degradative, mechanical and biological properties of these polymers may represent in the future an alternative for medical device manufacturers.


Assuntos
Materiais Biocompatíveis , Hidrocarbonetos Aromáticos/química , Cristais Líquidos/química , Poliésteres , Polímeros , Células 3T3 , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Humanos , Masculino , Teste de Materiais , Camundongos , Estrutura Molecular , Peso Molecular , Poliésteres/síntese química , Poliésteres/química , Poliésteres/metabolismo , Polímeros/síntese química , Polímeros/química , Polímeros/metabolismo , Ratos , Ratos Sprague-Dawley , Espalhamento de Radiação , Estresse Mecânico , Temperatura , Técnicas de Cultura de Tecidos
19.
Expert Rev Cardiovasc Ther ; 7(10): 1193, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19814661

RESUMO

The first orally active nonprostanoid PGI(2) receptor agonist has shown highly positive results in a Phase IIa study for the treatment of pulmonary arterial hypertension.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Receptores de Epoprostenol/agonistas , Ensaios Clínicos Fase II como Assunto , Humanos
20.
PLoS One ; 4(4): e5322, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19390688

RESUMO

BACKGROUND: Secretion of gonadotropin-releasing hormone (GnRH) produced in neurons in the basal forebrain is the primary regulator of reproductive maturation and function in mammals. Peptidergic signals relating to circadian timing and energy balance are an important influence on the reproductive axis. The aim of this study was to investigate the innervation of GnRH neurons by peptidergic neurons. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemistry and confocal microscopy were used to detect appositions of peptidergic fibers (NPY, beta-endorphin, MCH) associated with energy balance and metabolic status in transgenic mice expressing a green fluorescent protein reporter construct in GnRH neurons. The frequency of these appositions was compared to those of vasoactive intestinal peptide (VIP), a hypothalamic neuropeptide likely to convey circadian timing information to the GnRH secretory system. The majority of GnRH neurons (73-87%) were closely apposed by fibers expressing NPY, beta-endorphin, or MCH, and a significant proportion of GnRH neurons (28%) also had close contacts with VIP-ir fibers. CONCLUSIONS/SIGNIFICANCE: It is concluded that GnRH neurons in the mouse receive a high frequency of direct modulatory inputs from multiple hypothalamic peptide systems known to be important in conveying circadian information and signalling energy balance.


Assuntos
Hormônio Liberador de Gonadotropina/metabolismo , Neurônios/metabolismo , Neuropeptídeos/análise , Animais , Ritmo Circadiano , Proteínas de Fluorescência Verde/metabolismo , Hormônios Hipotalâmicos/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos , Microscopia Confocal , Vias Neurais , beta-Endorfina/análise
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