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1.
Carbohydr Polym ; 259: 117741, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33674001

RESUMO

Polysialic acid (polySia) is a linear polysaccharide comprised of N-acetylneuraminic acid residues and its over-expression in cancer cells has been correlated with poor clinical prognosis. An assay has been developed for quantitative analysis of cellular polySia expression. This was achieved by extracting and purifying released polySia from glycoproteins by mild acid hydrolysis and optimised organic extraction. The polySia was further hydrolysed into Sia monomers, followed by fluorescent labelling and quantitative analysis. The assay was qualified utilising endoneuraminidase-NF to remove polySia from the surface of C6-ST8SiaII cancer cells (EC50 = 2.13 ng/mL). The result was comparable to that obtained in a polySia-specific cellular ELISA assay. Furthermore, the assay proved suitable for evaluation of changes in polySia expression following treatment with a small molecule inhibitor of polysialylation. Given the importance of polySia in multiple disease states, notably cancer, this is a potentially vital tool with applications in the fields of drug discovery and glycobiology.


Assuntos
Cromatografia de Fase Reversa , Ácidos Siálicos/análise , Animais , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Cromatografia por Troca Iônica , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Ensaio de Imunoadsorção Enzimática , Glicosídeo Hidrolases/metabolismo , Ratos , Ácidos Siálicos/metabolismo , Sialiltransferases/antagonistas & inibidores , Sialiltransferases/metabolismo
3.
Best Pract Res Clin Anaesthesiol ; 34(3): 517-528, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33004163

RESUMO

Angina pectoris is defined as substernal chest pain that is typically exacerbated by exertion, stress, or other exposures. There are various methods of treatment for angina. Lifestyle modification and pharmacological management are considered as conservative treatments. If these medications do not result in the resolution of pain, more invasive approaches are an option, like coronary revascularization. Refractory angina (RA) is differentiated from acute or chronic angina based on the persistence of symptoms despite conventional therapies. Overall, the prevalence of RA is estimated to be 5%-15% in patients with coronary artery disease, which can account for up to 1,500,000 current cases and 100,000 new cases in the United States per year. Spinal cord stimulation treatment is a viable option for patients who are suffering from RA pain and are either not candidates for revascularization surgery or are currently not being well managed on more traditional treatments. Many studies show a positive result.

4.
Neurol Ther ; 9(2): 301-315, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32785879

RESUMO

Hereditary variant transthyretin amyloidosis (ATTRv) is a rare genetic defect that affects about 5000-10,000 people worldwide, causing amyloidosis secondary to misfolding of mutant transthyretin (TTR) protein fibrils. TTR mutations can cause protein deposits in many extracellular regions of organs, but those deposits in cardiac and axonal cells are the primary cause of this clinical syndrome. Treatment options are limited, but new drugs are being developed. Patisiran, a novel drug, is a liposomal siRNA against TTR that specifically targets this protein, reducing the accumulation of TTR in tissues, with subsequent improvement in both neuropathy and cardiac function. Patisiran is likely to serve as a prototype for the development of further intelligent drug solutions for use in targeted therapy. In this review we summarize the evidence currently available on the treatment of polyneuropathy in people with ATTRv with patisiran. We review the evidence on its efficacy, safety, and indications of use, citing novel and seminal papers on these subjects.

5.
Psychopharmacol Bull ; 50(3): 76-96, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32733113

RESUMO

Purpose of Review: This is a comprehensive review of the literature regarding the use of Lofexidine for opiate withdrawal symptoms. It covers the background and necessity of withdrawal programs and the management of withdrawal symptoms and then covers the existing evidence of the use of Lofexidine for this purpose. Recent Findings: Opiate abuse leads to significant pain and suffering. However, withdrawal is difficult and often accompanied by withdrawal symptoms and renewed cravings. These symptoms are driven mostly by signaling in the locus coeruleus and the mesolimbic system and a rebound increase in noradrenaline, producing symptoms such as anxiety, gastrointestinal upset, and tension. Lofexidine, an alpha-2 agonist, can be used to manage acute withdrawal symptoms before starting maintenance treatment with either methadone or buprenorphine. Lofexidine, if FDA approved for management of withdrawal symptoms and has been proved to be both effective and safe. Summary: Opiate addiction is increasing and plaguing the western world and specifically the U.S. It takes a large toll on both a personal and societal level and carries a high cost. Withdrawal is difficult, both related to withdrawal symptoms and renewed cravings. Lofexidine has been shown to be effective in reducing the former and could potentially aid in recovery and withdrawal.

6.
Psychopharmacol Bull ; 50(3): 97-118, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32733114

RESUMO

Purpose of Review: Opioid medications are a pillar of acute and chronic analgesia, though their use is often accompanied by side-effects, such as opioid-induced constipation. Unfortunately, tolerance rarely develops to this untoward side effect. This review presents the background, evidence, and indications for the use of Naldemedine (Brand name Symproic 0.2 mg tablets) to treat opioid-induced constipation. Recent Findings: Opioids are often used for the treatment of acute and chronic analgesia. Outside of the central effect they exert, they also interact with peripheral receptors, resulting in opioid-induced constipation, the commonest of side effects of chronic opioid usage. Complications include colonic distention, ileus, perforation, and can progress to other serious bowel complications, which can result in hospitalization and fatal events.For the most part, laxatives and other anti-constipation therapies are often inefficient and require intervention directed at the root cause, such as peripheral mu receptor agonists, including methylnaltrexone, naloxegol, and naldemedine. Naldemedine is the most recent to gain FDA approval of the group.An antagonist of Mu, Kappa, and Delta peripheral receptors, Naldemedine, is the only drug to counteract all three receptor classes. It was shown to be both safe and effective when compared with placebo. No data exists to compare its efficacy to that of other members of the group. Summary: Opioids are frequently used in the management of acute and chronic pain. The most common of the side effects is opioid-induced constipation, secondary to the peripheral activity of opioids. Naldemedine is an FDA-approved, once-daily oral tablet that counteracts this side effect by antagonizing mu, kappa, and delta-opioid receptors and has been shown to be safe and effective. Further investigation including head-to-head clinical trials are required to evaluate the relative efficacy of naldemedine compare with other peripheral opiate receptor antagonists.

7.
Educ Prim Care ; 31(3): 188-191, 2020 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-32267816

RESUMO

There is an increased focus on engagement with quality improvement (QI) strategies within the undergraduate setting. Reflecting on the recent integration of a QI Project (QIP) within our medical school curriculum, we assessed the value of establishing early familiarity with QI principles.

8.
Pain Ther ; 9(1): 145-160, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32107725

RESUMO

PURPOSE OF REVIEW: This is a comprehensive literature review of the available evidence and techniques of foot injections for chronic pain conditions. It briefly describes common foot chronic pain syndromes and then reviews available injection techniques for each of these syndromes, weighing the available evidence and comparing the available approaches. RECENT FINDINGS: Foot and ankle pain affects 20% of the population over 50 and significantly impairs mobility and ability to participate in activities of daily living (ADLs), as well as increases fall risk. It is commonly treated with costly surgery, at times with questionable efficacy. Injection therapy is challenging when the etiology is anatomical or compressive. Morton's neuroma is a budging of the interdigital nerve. Steroid, alcohol, and capsaicin injections provide some benefit, but it is short lived. Hyaluronic acid (HA) injection provided long-term relief and could prove to be a viable treatment option. Achilles tendinopathy (AT) is most likely secondary to repeat tendon stress-platelet-rich-plasma (PRP) and prolotherapy have been trialed for this condition, but more evidence is required to show efficacy. Similar injections were trials for plantar fasciitis and achieved only short-term relief; however, some evidence suggests that PRP injections reduce the frequency of required therapy. Tarsal tunnel syndrome, a compressive neuropathy carries a risk of permanent neural injury if left untreated. Injection therapy can provide a bridge to surgery; however, surgical decompression remains the definitive therapy. When the etiology is inflammatory, steroid injection is more likely to provide benefit. This has been shown in several studies for gout, as well as osteoarthritis of the foot and ankle and treatment-refractory rheumatoid arthritis. HA showed similar benefit, possibly due to anti-inflammatory effects. Stem cell injections may provide the additional benefit of structure restoration. Chronic foot pain is common in the general population and has significant associated morbidity and disability. Traditionally treated with surgery, these are costly and only somewhat effective. Injections provide an effective alternative financially and some evidence exists that they are effective in pain alleviation. However, current evidence is limited and the benefit described from injection therapy has been short-lived in most cases. Further studies in larger populations are required to evaluate the long-term effects of these treatments.

9.
Sci Transl Med ; 10(454)2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111643

RESUMO

Pharmacological inhibition of uncontrolled cell growth with small-molecule inhibitors is a potential strategy for treating glioblastoma multiforme (GBM), the most malignant primary brain cancer. We showed that the synthetic small-molecule KHS101 promoted tumor cell death in diverse GBM cell models, independent of their tumor subtype, and without affecting the viability of noncancerous brain cell lines. KHS101 exerted cytotoxic effects by disrupting the mitochondrial chaperone heat shock protein family D member 1 (HSPD1). In GBM cells, KHS101 promoted aggregation of proteins regulating mitochondrial integrity and energy metabolism. Mitochondrial bioenergetic capacity and glycolytic activity were selectively impaired in KHS101-treated GBM cells. In two intracranial patient-derived xenograft tumor models in mice, systemic administration of KHS101 reduced tumor growth and increased survival without discernible side effects. These findings suggest that targeting of HSPD1-dependent metabolic pathways might be an effective strategy for treating GBM.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Metabolismo Energético , Glioblastoma/metabolismo , Glioblastoma/patologia , Tiazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chaperonina 60/metabolismo , Ciclo do Ácido Cítrico/efeitos dos fármacos , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Glioblastoma/genética , Glicólise/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Invasividade Neoplásica , Estresse Fisiológico/efeitos dos fármacos , Análise de Sobrevida , Transcrição Genética/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Stem Cell Reports ; 8(1): 125-139, 2017 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-28076755

RESUMO

Patients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation. In GSCs, the small-molecule RAD51 inhibitors RI-1 and B02 prevent RAD51 focus formation, reduce DNA DSB repair, and cause significant radiosensitization. We further demonstrate that treatment with these agents combined with radiation promotes loss of stem cells defined by SOX2 expression. This indicates that RAD51-dependent repair represents an effective and specific target in GSCs.


Assuntos
Reparo do DNA , Glioma/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Rad51 Recombinase/genética , Tolerância a Radiação/genética , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Dano ao DNA/efeitos da radiação , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Humanos , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Rad51 Recombinase/antagonistas & inibidores , Rad51 Recombinase/metabolismo , Radiossensibilizantes/farmacologia , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Methods ; 95: 26-37, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26431670

RESUMO

Historically, recombinant membrane protein production has been a major challenge meaning that many fewer membrane protein structures have been published than those of soluble proteins. However, there has been a recent, almost exponential increase in the number of membrane protein structures being deposited in the Protein Data Bank. This suggests that empirical methods are now available that can ensure the required protein supply for these difficult targets. This review focuses on methods that are available for protein production in yeast, which is an important source of recombinant eukaryotic membrane proteins. We provide an overview of approaches to optimize the expression plasmid, host cell and culture conditions, as well as the extraction and purification of functional protein for crystallization trials in preparation for structural studies.


Assuntos
Clonagem Molecular/métodos , Vetores Genéticos/química , Proteínas de Membrana/biossíntese , Pichia/genética , Plasmídeos/química , Saccharomyces cerevisiae/genética , Animais , Arabidopsis/genética , Arabidopsis/metabolismo , Bases de Dados Factuais , Expressão Gênica , Vetores Genéticos/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/genética , Modelos Moleculares , Pichia/metabolismo , Plasmídeos/metabolismo , Regiões Promotoras Genéticas , Ratos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Saccharomyces cerevisiae/metabolismo , Solubilidade
12.
ACS Chem Biol ; 8(3): 626-35, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23240775

RESUMO

For several well-documented reasons, it has been challenging to develop artificial small molecule inhibitors of protein/protein complexes. Such reagents are of particular interest for transcription factor complexes given links between their misregulation and disease. Here we report parallel approaches to identify regulators of a hypoxia signaling transcription factor complex, involving the ARNT subunit of the HIF (Hypoxia Inducible Factor) activator and the TACC3 (Transforming Acidic Coiled Coil Containing Protein 3) coactivator. In one route, we used in vitro NMR and biochemical screening to identify small molecules that selectively bind within the ARNT PAS (Per-ARNT-Sim) domain that recruits TACC3, identifying KG-548 as an ARNT/TACC3 disruptor. A parallel, cell-based screening approach previously implicated the small molecule KHS101 as an inhibitor of TACC3 signaling. Here, we show that KHS101 works indirectly on HIF complex formation by destabilizing both TACC3 and the HIF component HIF-1α. Overall, our data identify small molecule regulators for this important complex and highlight the utility of pursuing parallel strategies to develop protein/protein inhibitors.


Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Tiazóis/farmacologia , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/isolamento & purificação , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Cristalografia por Raios X , Células HEK293 , Humanos , Proteínas Associadas aos Microtúbulos/isolamento & purificação , Proteínas Associadas aos Microtúbulos/metabolismo , Modelos Moleculares , Ligação Proteica/efeitos dos fármacos , Ratos , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Tiazóis/química
13.
Healthc Financ Manage ; 60(9): 124-8, 130, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16977995

RESUMO

Gainsharing gives hospitals and physicians an opportunity to align their economic interests, and gives hospitals a means to improve operational efficiencies and quality of patient care by promoting the development of best practices. The OIG's 2005 advisory opinions on hospital-physician gainsharing suggest that such arrangements are again open for hospitals to consider. Gainsharing arrangements likely to meet with the OIG's approval are those limited arrangements that are tied to specific, identifiable, and verifiable actions and cost savings.


Assuntos
Regulamentação Governamental , Relações Hospital-Médico , Planos de Incentivos Médicos/economia , Administração Financeira de Hospitais/métodos , Qualidade da Assistência à Saúde , Estados Unidos
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