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ID PMID Title PublicationDate abstract
31333185 [Treatment of Periprosthetic Distal Femoral Fractures]. 2019 PURPOSE OF THE STUDY Periprosthetic distal femoral fractures (PDFF) constitute an unpleasant complication in patients with a total knee replacement (TKR). The incidence reported in literature is 0.3-2.5 %. The number of periprosthetic knee fractures has been increasing due to the ageing of population, a growing number of implants, a longer life expectancy of patients, a more intensive physical activity of patients, and osteoporosis. Most of these fractures are treated surgically, non-surgical treatment is reserved solely for patients unable to undergo a surgery for general health conditions. MATERIAL AND METHODS Our retrospective study evaluated the group of patients with PDFF who were treated at out department in the period 2007- 2016 and 2,975 primary TKR were performed. The total number of patients with PDFF was 56. The mean age of patients with PDFF was 77 years (56-94 years) and at the time of fracture the mean age was 71 years in men and 78 years in women. The average time from the TKR to periprosthetic fracture was 8.2 years (0-20 years). The fractures were assessed using the Su classification modified by Krbec. RESULTS A primary TKR was performed in 46 cases for gonarthrosis, in 6 cases for rheumatoid arthritis and in 4 cases for secondary, post-traumatic gonarthrosis. The average incidence of periprosthetic distal femoral fractures was 5-6 cases per year. Women represented 86 %, men 14 %. Su Type I fracture was diagnosed in 25 % of cases, Su Type II fractures in 71 %, and Su Type III fractures 4 %. 52 patients with PDFF were treated surgically, in 4 cases conservative treatment was opted for. The average treatment time of PDFF to healing by callus formation was 6.6 months (3-12 months). Mortality during the first 3 months after osteosynthesis of PDFF was 9 %. A failure of osteosynthesis of PDFF was reported in 4 cases. DISCUSSION Multiple classification systems were developed to assess these fractures. The most appropriate we consider the classification of Su et al. classifying the PDFF into 3 groups, namely based on the height of the fracture line relative to the femoral component. Osteosynthesis by retrograde femoral nail is indicated for periprosthetic fractures, with sufficient bone mass in distal femur, which allows stable distal fixation. The new generation of anatomically shaped angular stable implants gives us yet another option for osteosynthesis of PDFF. Many studies point at the advantages of these implants in osteoporotic bone as against the conventional plates. CONCLUSIONS The number of PDFF has been increasing. The main methods of internal osteosynthesis continue to be the angular stable plates and the retrograde femoral nail. Preoperative planning is important to determine the type and dimensions of the existing femoral component and to distinguish whether or not it has come loose. The choice of the implant may depend on the bone mass available for distal fixation. The retrograde femoral nail is usually the most suitable method of treatment for proximal PDFF (Su Type I). The angular stable plates can be used for PDFF originating at the femoral component (Su Type II and Type III). Very distal fractures classified as Su Type III with a loose femoral component require a revision surgery with a TKR with stems. The surgeon should be prepared for a revision surgery if the intraoperative finding is more complicated than anticipated based on the preoperative radiograph. Key words:total knee arthroplasty, periprosthetic fracture, osteosynthesis.
31277230 Synergy between Auranofin and Celecoxib against Colon Cancer In Vitro and In Vivo through 2019 Jul 3 Recent study suggests that auranofin (AF), a US Food and Drug Administration (FDA)-approved drug for treatment of rheumatoid arthritis, has selective anticancer activity in various experimental models. Its clinical applications in cancer treatment, however, have been hampered due in part to its relatively moderate activity as a single agent. In this study, we performed a high-throughput screening of the FDA-approved drug library for clinical compounds that potentiate the anticancer activity auranofin, and unexpectedly identified an anti-inflammatory drug celecoxib (CE) that potently enhanced the therapeutic activity of AF in vitro and in vivo. Mechanistically, AF/CE combination induced severe oxidative stress that caused ROS-mediated inhibition of hexokinase (HK) and a disturbance of mitochondrial redox homeostasis, resulting in a significant decrease of ATP generation. The CE-induced ROS increase together with AF-medicated inhibition of thioredoxin reductase cause a shift of Trx2 to an oxidized state, leading to degradation of MTCO2 and dysfunction of the electron transport chain. Our study has identified a novel drug combination that effectively eliminates cancer cells in vivo. Since AF and CE are FDA-approved drugs that are currently used in the clinic, it is feasible to translate the findings of this study into clinical applications for cancer treatment.
31213783 Effects of teriparatide in Chinese and Caucasian women with osteoporosis: bridging study o 2019 OBJECTIVE: To bridge the efficacy and compare the safety of the 24-week teriparatide treatment in a Chinese osteoporosis study (NCT00414973) to a large international trial (FPT, NCT00670501) to determine whether long-term results from the international study were applicable to Chinese patients. METHODS: In this post-hoc analysis, a propensity score matching method was used to select patients with similar baseline characteristics. Patients were female with osteoporosis at high risk of fracture, aged ≥55 years, and had no history of rheumatoid arthritis or corticosteroid use. Outcomes included percentage changes in lumbar-spine bone mineral density (LS-BMD) from baseline to 24 weeks, safety in matched-pair patients, and long-term percentage changes in LS-BMD and fragility fracture incidence in the matched fracture prevention trial (FPT) population. The determination of the acceptability of bridging results was based on the International Conference on Harmonization E5 guidelines. RESULTS: A total number of 228 patients from each study were matched and paired. Patients were similar at baseline (P-values >0.33) except for ethnicity (98% Caucasian for FPT). For changes in LS-BMD from baseline to week 24, treatment with teriparatide showed significantly greater increases (P-values <0.001; least-squares mean difference: 5.0% in the Chinese study and 5.4% in FPT) than comparator (calcitonin/placebo). The safety profiles over 24 weeks were similar between two studies. For matched-pair FPT patients, long-term changes in LS-BMD were significantly greater (least-squares mean difference: 11.5%, P<0.001) and the fragility fracture rate was marginally lower in the teriparatide group compared with the placebo group (13.1% vs 22.3%, P=0.070). CONCLUSION: Assuming similar pharmacokinetic profiles for teriparatide between populations, comparable increases in LS-BMD and consistent safety profiles within 24 weeks of the treatment suggest long-term LS-BMD results from the FPT may be applicable to Chinese population.
31068198 Plasma VCAM1 levels correlate with disease severity in Parkinson's disease. 2019 May 8 BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor and non-motor symptoms. There is increasing evidence that PD pathology is accompanied by an inflammatory response. This is highly relevant for understanding disease progression and the development of novel neuroprotective therapies. OBJECTIVE: Assessing potential dysregulation of a panel of inflammatory mediators in the peripheral blood mononuclear cells (PBMCs) and plasma of PD patients and in the context of clinical outcome metrics. METHODS: We performed a screening of selected cell-surface chemokine receptors and adhesion molecules in PBMCs from PD patients and age-matched healthy controls in a flow cytometry-based assay. ELISA was used to quantify VCAM1 levels in the plasma of PD patients. Lymphocytic chemotactic ability was assessed using a modified Boyden chamber assay. RESULTS: VLA4 expression was significantly downregulated on CD3+ T cells, CD56+ NK cells, and CD3+/CD56+ NK-T cells from PD patients; further, an increase of the soluble VLA4 ligand VCAM1 in patient plasma was noted. sVCAM1 in PD patients was even higher than reported for patients with multiple sclerosis, neuromyelitis optica, and rheumatoid arthritis. sVCAM1 levels correlated with the disease stage (Hoehn and Yahr scale) and motor impairment. Chemoattraction with SDF-1α revealed impaired motility of lymphocytes from PD patients relative to controls. CONCLUSION: Our data provides evidence for a functional dysregulation of the sVCAM1-VLA4 axis in PD. Further studies evaluating the therapeutic potential of this axis are warranted.
31018627 Effect of Topically Applied Wikstroemia dolichantha Diels on the Development of Atopic Der 2019 Apr 23 Plants of the genus Wikstroemia are traditionally used to treat inflammatory diseases like bronchitis and rheumatoid arthritis. In the present study, the anti-atopic effects of an EtOH extract of Wikstroemia dolichantha (WDE) on oxazolone- and DNCB (2,4-dinitrochlorobenzene)-induced dermatitis in mice were investigated. Both ears of BALB/c mice were exposed to oxazolone, and dorsal skins of SKH-1 hairless mice were sensitized with DNCB to induce acute eczematous atopic skin lesions. 1% WDE was applied daily to oxazolone- and DNCB-induced AD mice for two or three weeks, respectively. Total IL-4 and IgE concentrations in serum, transepidermal water loss (TEWL) and skin hydration were assessed. High-performance liquid chromatography/mass spectrometry (HPLC/MS) was used to determine the composition of WDE. Dermal application of 1% WDE grossly and histopathologically improved oxazolone- and DNCB-induced AD skin symptoms. Epidermal thickness and mast cell infiltration were significantly lower in animals treated with WDE than in vehicle controls. Furthermore, in addition to reducing DNCB-induced increases in serum IL-4 (interleukin 4) and IgE (immunoglobulin E) levels, WDE also decreased TEWL and increased skin hydration (indicative of improved skin barrier function). The four flavonoids taxifolin, aromadendrin, padmatin and chamaejasmine were tentatively identified in WDE by HPLC-DAD/QTOF-MS. The above results show WDE protected against oxazolone- and DNCB-induced AD in mice by down-regulating the T(H)2-associated cytokine IL-4 and improving skin barrier function and suggest WDE might be useful for the management of atopic dermatitis.
30981187 Ethanol extract of Polyscias fruticosa leaves suppresses RANKL-mediated osteoclastogenesis 2019 Jun BACKGROUND: Many bone-related diseases such as osteoporosis and rheumatoid arthritis are commonly associated with the excessive activity of osteoclasts. Polyscias fruticosa has been used as traditional medicine for the treatment of ischemia and inflammation and also eaten as a salad. However, its effect on the bone related diseases has not been investigated yet. PURPOSE: This study aimed to investigate the effect of ethanol extract of P. fruticosa on RANKL-induced osteoclastogenesis in vitro and LPS-induced bone loss in mouse, and evaluate anti-osteoclastogenic activities of its major constituents. METHODS: BMMs or RAW264.7 cells were treated with ethanol extract from P. fruticose leaves (EEPL), followed by an evaluation of cell viability, RANKL-induced osteoclast differentiation, actin-ring formation, and resorption pits activity. Effects of EEPL on RANKL-induced phosphorylation of MAPKs were evaluated by Western blotting. The expression levels of NFATc1 and c-Fos were evaluated by Western blotting or immunofluorescence assay. The expression levels of osteoclast-specific marker genes were evaluated by Western blotting and reverse transcription-qPCR analysis. A LPS-induced murine bone loss model was used to evaluate the protective effect of EEPL on inflammation-induced bone loss. HPLC analysis was performed to identify the major constituents of EEPL. RESULTS: EEPL significantly inhibited RANKL-induced osteoclast differentiation by decreasing the number of osteoclasts, osteoclast actin-ring formation, and bone resorption. EEPL suppressed RANKL-induced phosphorylation of p38 and JNK MAPKs, as well as the expression of c-Fos and NFATc1. EEPL decreased the expression levels of osteoclast marker genes, including MMP-9, TRAP and CtsK. Mice treated with EEPL significantly protected the mice from LPS-induced osteoclast formation and bone destruction as indicated by micro-CT and histological analysis of femurs. We also identified 3-O-[β-d-glucopyranosyl-(1→4)-β-d-glucuronopyranosyl] oleanolic acid 28-O-β-d-glucopyranosyl ester (1) and quercitrin (3) as the active constituents in EEPL for inhibiting RANKL-induced osteoclast differentiation. CONCLUSION: The results showed that EEPL exerted anti-osteoclastogenic activity in vitro and in vivo by inhibiting RANKL-induced osteoclast differentiation and function, and suggested that EEPL could have beneficial applications for preventing or inhibiting osteoclast-mediated bone diseases.
30843482 The Relationship Between Prolidase Activity and Atrial Electromechanical Changes in Patien 2019 BACKGROUND: Tissue fibrosis increases in the structure of the atrial tissue of atrial fibrillation patients. Prolidase enzyme regulates collagen synthesis. There may be an association between electrocardiography (ECG) findings and prolidase activity. OBJECTIVE: This study investigated the association between atrial conduction time and prolidase activity, a collagen synthesis enzyme, and P-wave dispersion (PWD) in patients with Paroxysmal Atrial Fibrillation (PAF). METHODS: Exclusion criteria included the age of <18 years, heart failure, diabetes, hypertension, hyperlipidemia, malignancy, cerebrovascular disease, chronic respiratory distress, osteoporosis, rheumatoid arthritis, renal disease, cirrhosis, and other types of arrhythmia. Patients diagnosed with PAF within 48 hours were considered to have a definite diagnosis. PWD was calculated using a 12-lead ECG, and inter- and intraatrial electromechanical delay (EMD) was assessed using tissue Doppler imaging and conventional echocardiography. Serum prolidase levels were measured in both groups. RESULTS: A total of 43 patients with PAF (20 female, 23 male; mean age, 46.8 ± 5.7 years) and 42 healthy volunteers (21 female, 21 male; mean age, 43.9 ± 5.1 years) were included in the study. Inter- and intraatrial EMD, PWD, minimum P-wave (Pmin), and maximum P-wave (Pmax) measurements were significantly higher (39.7 ± 2.7, 35.7 ± 2.3, p < 0.001; 13.2 ± 2.6, 8.5 ± 1.9, p < 0.001; 47.1 ± 11, 24.1 ± 7.1, p < 0.001; 69.8 ± 8.8, 66.7 ± 10.2, p < 0.130; 114.8 ± 13, 93.6 ± 8.6, p < 0.001, respectively) and serum prolidase levels were significantly lower in patients with PAF compared to healthy controls (3.96 ± 1.2, 8.5 ± 3.56, p < 0.001). In patients with PAF, correlation analysis showed a negative correlation between prolidase levels and intra- and interatrial EMD, PWD, and Pmax (r = -0.41, p < 0.05; r = -0.54, p < 0.05; r = -0.62, p < 0.05; r = -0.49, p < 0.05, respectively). Interatrial EMD showed a significant positive correlation with intraatrial EMD, Pmax, and PWD in patients with PAF (r = 0.90, p < 0.05; r = 0.574, p < 0.05; r = 0.43, p < 0.05, respectively). Additionally, the level of high-sensitivity C-reactive protein (hs-CRP) was significantly higher in patients with PAF (6.6 ± 8, 1.8 ± 1.6, p < 0.001). CONCLUSION: The decreased plasma prolidase activity in patients with PAF may explain the irregularity of the collagen metabolism of different extracellular components and may indicate the onset of atrial remodeling. Changes in PWD, interatrial EMD, and serum prolidase level may predict PAF before diagnosis.
30738949 Feature extraction for phenotyping from semantic and knowledge resources. 2019 Mar OBJECTIVE: Phenotyping algorithms can efficiently and accurately identify patients with a specific disease phenotype and construct electronic health records (EHR)-based cohorts for subsequent clinical or genomic studies. Previous studies have introduced unsupervised EHR-based feature selection methods that yielded algorithms with high accuracy. However, those selection methods still require expert intervention to tweak the parameter settings according to the EHR data distribution for each phenotype. To further accelerate the development of phenotyping algorithms, we propose a fully automated and robust unsupervised feature selection method that leverages only publicly available medical knowledge sources, instead of EHR data. METHODS: SEmantics-Driven Feature Extraction (SEDFE) collects medical concepts from online knowledge sources as candidate features and gives them vector-form distributional semantic representations derived with neural word embedding and the Unified Medical Language System Metathesaurus. A number of features that are semantically closest and that sufficiently characterize the target phenotype are determined by a linear decomposition criterion and are selected for the final classification algorithm. RESULTS: SEDFE was compared with the EHR-based SAFE algorithm and domain experts on feature selection for the classification of five phenotypes including coronary artery disease, rheumatoid arthritis, Crohn's disease, ulcerative colitis, and pediatric pulmonary arterial hypertension using both supervised and unsupervised approaches. Algorithms yielded by SEDFE achieved comparable accuracy to those yielded by SAFE and expert-curated features. SEDFE is also robust to the input semantic vectors. CONCLUSION: SEDFE attains satisfying performance in unsupervised feature selection for EHR phenotyping. Both fully automated and EHR-independent, this method promises efficiency and accuracy in developing algorithms for high-throughput phenotyping.
30633369 Characterization of the Effect of Renal Impairment on Upadacitinib Pharmacokinetics. 2019 Jun Upadacitinib is a novel selective Janus kinase 1 inhibitor developed for treatment of rheumatoid arthritis and other autoimmune diseases. The objective of this study was to assess the pharmacokinetics and safety of a single upadacitinib dose in subjects with normal renal function and in subjects with renal impairment. A total of 24 subjects between the ages of 18 and 75 years were assigned to 1 of 4 renal function groups based on estimated glomerular filtration rate (normal, mild, moderate, severe; N = 6/group). A single 15-mg dose of upadacitinib extended-release formulation was administered under fasting conditions. Serial plasma and urine samples were assayed to evaluate the effect of renal impairment on upadacitinib exposure through regression analysis and analysis of covariance. The primary analysis was the regression analysis of upadacitinib exposures versus estimated glomerular filtration rate. The point estimates for upadacitinib plasma exposure ratios (90% confidence interval [CI]) in subjects with mild, moderate, and severe renal impairment were 1.18 (90%CI, 1.06-1.32), 1.33 (90%CI, 1.11-1.59), and 1.44 (90%CI, 1.14-1.82) for area under the plasma concentration-time curve and 1.06 (90%CI, 0.92-1.23), 1.11 (90%CI, 0.88-1.40), and 1.14 (90%CI, 0.84-1.56) for maximum observed plasma concentration, respectively, relative to subjects with normal renal function based on the regression analysis. The analysis of covariance categorical analysis provided consistent results. Upadacitinib was well tolerated by all subjects, and no safety issues were identified in subjects with renal impairment. Renal impairment has a limited effect on upadacitinib pharmacokinetics. This is in agreement with the known limited role of urinary excretion in upadacitinib elimination. Based on the limited impact on exposure, no dose adjustment is necessary for upadacitinib in subjects with impaired renal function.
31654585 Promotion of a quality standard for Porana sinensis Hemsl. based on the efficacy-oriented 2020 Feb Multicompound determination for the quality control of traditional Chinese medicine (TCM) may often be inadequate, since these compounds may not be associated with, or fully represent, the clinical effects of TCM. Moreover, the individual contributions of each constituent to the pharmacological effect are often not considered. In China, Porana sinensis is widely used as a substitute for Erycibe sources to treat joint pain and rheumatoid arthritis. The existing quality control methods for P. sinensis neither consider the individual contributions of various compounds nor control the actual quality associated with different clinical efficacies. In the present study, a novel efficacy-oriented approach, named the effect-constituent index (ECI), was established for P. sinensis. Analyses of the spectrum-effect relationship and components in rat plasma were conducted to systematically and scientifically select quality markers. Quantitative analysis of multicomponents via a single marker method was introduced to enhance the practical application value of the established ECI. The established ECI shows a good ability to distinguish and predict the bioeffect-based quality of P. sinensis. The present study also provides a reference for the establishment and application of ECI as a quality control method for TCMs.
31607028 [Expression and clinical significance of CCL18 in bronchoalveolar lavage fluid of connecti 2019 Oct 15 Objective: To explore the expression and clinical significance of chemokine ligand 18 (CCL18) in Bronchoalveolar Lavage Fluid (BALF) of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). Methods: From January 2016 to June 2017, BALF of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD group), patients with dermatomyositis-associated interstitial lung disease (DM-ILD group), and patients with primary Sjögren syndrome-associated interstitial lung disease (pSS-ILD group) of Peking University People's Hospital were collected. According to the prognosis of each group of patients during hospitalization, they were divided into the discharged and the died. Besides, 30 patients without ILD served as a control group. Levels of CCL18 in BALF of all patients were tested by enzyme linked immunosorbent assay (ELISA). Cells in BALF of RA-ILD group, DM-ILD group and pSS-ILD group were collected and analyzed by absolute different cell counts. Results of high-resolution CT (HRCT) of these three groups were scored. In addition, the area under the curve (AUC) of CCL18 in predicting mortality during hospitalization was calculated. Results: A total of 38 patients with RA-ILD, 54 patients with DM-ILD, and 35 patients with pSS-ILD were enrolled. Levels of CCL18 of those discharged patients of RA-ILD, DM-ILD, and pSS-ILD groups were 8.27(3.62, 14.36), 11.04 (5.86, 17.38), 5.25(2.68, 8.21) μg/L, respectively, which were all significantly higher than that of the control group [2.54(1.26, 3.66) μg/L, all P<0.05]. Furthermore, levels of CCL18 of those deceased patients of RA-ILD and DM-ILD groups were 18.28 (13.82, 22.39), 18.81 (16.29, 22.90) μg/L, which were significantly higher than that of the discharged patients of same group (all P<0.05). Levels of CCL18 were positively correlated with lymphocyte percentage in BALF of RA-ILD, DM-ILD and pSS-ILD groups (r=0.4356, 0.4029, 0.3939, respectively, all P<0.05). Besides, levels of CCL18 were significantly correlated with HRCT scores of RA-ILD and DM-ILD groups (r=0.4242, 0.3319, respectively, both P<0.05). Areas under the curve (AUCs) of CCL18 to predict mortality during hospitalization of RA-ILD and DM-ILD groups were 0.860, 0.851, respectively. Conclusions: Levels of CCL18 are elevated in BALF of CTD-ILD patients, and may be correlated with the severity and prognosis during hospitalization. CCL18 might be served as an indicator of the severity and prognosis of CTD-ILD.
31443172 Pathogenic and Therapeutic Relevance of JAK/STAT Signaling in Systemic Lupus Erythematosus 2019 Aug 15 Four Janus kinases (JAKs) (JAK1, JAK2, JAK3, TYK2) and seven signal transducers and activators of transcription (STATs) (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) mediate the signal transduction of more than 50 cytokines and growth factors in many different cell types. Located intracellularly and downstream of cytokine receptors, JAKs integrate and balance the actions of various signaling pathways. With distinct panels of STAT-sensitive genes in different tissues, this highly heterogeneous system has broad in vivo functions playing a crucial role in the immune system. Thus, the JAK/STAT pathway is critical for resisting infection, maintaining immune tolerance, and enforcing barrier functions and immune surveillance against cancer. Breakdowns of this system and/or increased signal transduction may lead to autoimmunity and other diseases. Accordingly, the recent development and approval of the first small synthetic molecules targeting JAK molecules have opened new therapeutic avenues of potentially broad therapeutic relevance. Extensive data are now available regarding the JAK/STAT pathway in rheumatoid arthritis. Dysregulation of the cytokines is also a hallmark of systemic lupus erythematosus (SLE), and targeting the JAK/STAT proteins allows simultaneous suppression of multiple cytokines. Evidence from in vitro studies and animal models supports a pivotal role also in the pathogenesis of cutaneous lupus and SLE. This has important therapeutic implications, given the current paucity of targeted therapies especially in the latter. Herein, we summarize the currently available literature in experimental SLE, which has led to the recent promising Phase II clinical trial of a JAK inhibitor.
31914413 A highly selective inhibitor of interleukin-1 receptor-associated kinases 1/4 (IRAK-1/4) d 2020 Feb 7 Interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-4, as well as transforming growth factor β-activated kinase 1 (TAK1), are protein kinases essential for transducing inflammatory signals from interleukin receptors. IRAK family proteins and TAK1 have high sequence identity within the ATP-binding pocket, limiting the development of highly selective IRAK-1/4 or TAK1 inhibitors. Beyond kinase activity, IRAKs and TAK1 act as molecular scaffolds along with other signaling proteins, complicating the interpretation of experiments involving knockin or knockout approaches. In contrast, pharmacological manipulation offers the promise of targeting catalysis-mediated signaling without grossly disrupting the cellular architecture. Recently, we reported the discovery of takinib, a potent and highly selective TAK1 inhibitor that has only marginal activity against IRAK-4. On the basis of the TAK1-takinib complex structure and the structure of IRAK-1/4, here we defined critical contact sites of the takinib scaffold within the nucleotide-binding sites of each respective kinase. Kinase activity testing of takinib analogs against IRAK-4 identified a highly potent IRAK-4 inhibitor (HS-243). In a kinome-wide screen of 468 protein kinases, HS-243 had exquisite selectivity toward both IRAK-1 (IC(50) = 24 nm) and IRAK-4 (IC(50) = 20 nm), with only minimal TAK1-inhibiting activity (IC(50) = 0.5 μm). Using HS-243 and takinib, we evaluated the consequences of cytokine/chemokine responses after selective inhibition of IRAK-1/4 or TAK1 in response to lipopolysaccharide challenge in human rheumatoid arthritis fibroblast-like synoviocytes. Our results indicate that HS-243 specifically inhibits intracellular IRAKs without TAK1 inhibition and that these kinases have distinct, nonredundant signaling roles.
31678520 Transferosomes as nanocarriers for drugs across the skin: Quality by design from lab to in 2020 Jan 5 Transferosomes, also known as transfersomes, are ultradeformable vesicles for transdermal applications consisting of a lipid bilayer with phospholipids and an edge activator and an ethanol/aqueous core. Depending on the lipophilicity of the active substance, it can be encapsulated within the core or amongst the lipid bilayer. Compared to liposomes, transferosomes are able to reach intact deeper regions of the skin after topical administration delivering higher concentrations of active substances making them a successful drug delivery carrier for transdermal applications. Most transferosomes contain phosphatidylcholine (C18) as it is the most abundant lipid component of the cell membrane, and hence, it is highly tolerated for the skin, decreasing the risk of undesirable effects, such as hypersensitive reactions. The most common edge activators are surfactants such as sodium deoxycholate, Tween® 80 and Span® 80. Their chain length is optimal for intercalation within the C18 phospholipid bilayer. A wide variety of drugs has been successfully encapsulated within transferosomes such as phytocompounds like sinomenine or apigenin for rheumatoid arthritis and leukaemia respectively, small hydrophobic drugs but also macromolecules like insulin. The main factors to develop optimal transferosomal formulations (with high drug loading and nanometric size) are the optimal ratio between the main components as well as the critical process parameters for their manufacture. Application of quality by design (QbD), specifically design of experiments (DoE), is crucial to understand the interplay among all these factors not only during the preparation at lab scale but also in the scale-up process. Clinical trials of a licensed topical ketoprofen transferosomal gel have shown promising results in the alleviation of symptons in orthreothritis with non-severe skin and subcutaneous tissue disorders. However, the product was withdrawn from the market which probably was related to the higher cost of the medicine linked to the expensive manufacturing process required in the production of transferosomes compared to other conventional gel formulations. This example brings out the need for a careful formulation design to exploit the best properties of this drug delivery system as well as the development of manufacturing processes easily scalable at industrial level.
31669506 Sentinel biomarkers in HCV positive patients with mixed cryoglobulinemia. 2020 Jan BACKGROUND: Infections, autoimmunity and cancer play a role as determinants of etiology in Hepatitis C virus (HCV) related mixed cryoglobulinemia (MC). Several factors of risk have been suggested as markers of pathogenesis and progression of HCV-related MC into B cell Non-Hodgkin's Lymphoma (B-NHL). Here, we evaluated IgG subclass distribution, free light chains (FLCs) and vascular endothelial growth factor (VEGF) as a new combination of biomarkers. METHODS: We measured IgG1-4 subclasses, FLCs and VEGF levels in sera 53 from HCV-related MC, in comparison with 40 sera from HCV negative patients with rheumatoid arthritis (RA) and 30 from healthy blood donors (HBD). RESULTS: IgG3 levels were significantly higher in HCV-MC patients with a decrement of IgG2 and IgG4; FLC levels significantly increased in both MC and RA patients' groups; serological VEGF was higher in HCV-MC patients than in HBD in correlation with k and λ levels. CONCLUSION: Our results suggest that a specific IgG subclasses pattern together with raised levels of FLCs and VEGF could represent the biomarker "signature" of an inflammation multistage of acquired immune system.
31491986 Animal Models of Inflammation for Screening of Anti-inflammatory Drugs: Implications for t 2019 Sep 5 Inflammation is one of the common events in the majority of acute as well as chronic debilitating diseases and represent a chief cause of morbidity in today's era of modern lifestyle. If unchecked, inflammation leads to development of rheumatoid arthritis, diabetes, cancer, Alzheimer's disease, and atherosclerosis along with pulmonary, autoimmune and cardiovascular diseases. Inflammation involves a complex network of many mediators, a variety of cells, and execution of multiple pathways. Current therapy for inflammatory diseases is limited to the steroidal and non-steroidal anti-inflammatory agents. The chronic use of these drugs is reported to cause severe adverse effects like gastrointestinal, cardiovascular, and renal abnormalities. There is a massive need to explore new anti-inflammatory agents with selective action and lesser toxicity. Plants and isolated phytoconstituents are promising and interesting sources of new anti-inflammatories. However, drug development from natural sources has been linked with hurdles like the complex nature of extracts, difficulties in isolation of pure phytoconstituents, and the yield of isolated compounds in minute quantities that is insufficient for subsequent lead development. Although various in-vivo and in-vitro models for anti-inflammatory drug development are available, judicious selection of appropriate animal models is a vital step in the early phase of drug development. Systematic evaluation of phytoconstituents can facilitate the identification and development of potential anti-inflammatory leads from natural sources. The present review describes various techniques of anti-inflammatory drug screening with its advantages and limitations, elaboration on biological targets of phytoconstituents in inflammation and biomarkers for the prediction of adverse effects of anti-inflammatory drugs. The systematic approach proposed through present article for anti-inflammatory drug screening can rationalize the identification of novel phytoconstituents at the initial stage of drug screening programs.
31409424 Kinetics of MSC-based enzyme therapy for immunoregulation. 2019 Aug 13 BACKGROUND: Mesenchymal stromal cells (MSC) demonstrate innate and regulatory immunologic functions and have been widely explored for cell therapy applications. Mechanisms by which MSCs achieve therapeutic effects are theorized, though appropriate dosing and duration of these mechanisms in vivo warrant deeper investigation. One, rapid immunosuppressive function of MSCs is through ectoenzyme expression of CD73 and CD39 which cooperatively hydrolyze inflammatory, extracellular adenosine triphosphate (ATP) to anti-inflammatory adenosine. Extracellular ATP has a key role in autoimmune and inflammatory diseases, which administered MSCs have the potential to modulate in a timescale that is befitting of shorter acting therapeutic function. METHODS: In vitro experiments were performed to determine the hydrolysis rates of ATP by MSCs. Through kinetic modeling from experimental results, the rate at which a single cell can metabolize ATP was determined. Based on these rates, the ability of MSCs to downregulate inflammatory signaling pathways was prospectively validated using model system parameters with respect to two different mechanisms: extracellular ATP stimulates lymphocytes to suppress proliferation and induce apoptosis and with co-stimulation, it stimulates monocytes to release pro-inflammatory IL-1β. MSCs were co-cultured with immune cells using transwell inserts and compared to immune cell only groups. RESULTS: Hydrolysis of ATP was efficiently modeled by first-order enzyme kinetics. For in vitro culture, the rate at which a single cell can hydrolyize ATP is 8.9 nmol/min. In the presence of extracellular ATP, cocultures of MSCs reduced cytotoxicity and allows for proliferation of lymphocytes while limiting IL-1β secretion from monocytes. CONCLUSIONS: Such use of these models may allow for better dosing predictions for MSCs to be used therapeutically for chronic inflammatory diseases such as rheumatoid arthritis, diabetes, pancreatitis, and other systemic inflammatory response syndromes. For the first time, the effect of MSCs on ATP hydrolysis in immune cell response is quantitatively analyzed on a cell-molecule basis by modeling the hydrolysis as an enzyme-substrate reaction. The results also give insight into MSCs' dynamic response mechanisms to ameliorate effects of extracellular ATP whether it be through positive or negative regulation.
31203509 Management of bone health in patients with cancer: a survey of specialist nurses. 2020 Mar BACKGROUND: Patients with cancer can experience bone metastases and/or cancer treatment-induced bone loss (CTIBL), and the resulting bone complications place burdens on patients and healthcare provision. Management of bone complications is becoming increasingly important as cancer survival rates improve. Advances in specialist oncology nursing practice benefit patients through better management of their bone health, which may improve quality of life and survival. METHODS: An anonymised online quantitative survey asked specialist oncology nurses about factors affecting their provision of support in the management of bone metastases and CTIBL. RESULTS: Of 283 participants, most stated that they worked in Europe, and 69.3% had at least 8 years of experience in oncology. The most common areas of specialisation were medical oncology, breast cancer and/or palliative care (20.8-50.9%). Awareness of bone loss prevention measures varied (from 34.3% for alcohol intake to 77.4% for adequate calcium intake), and awareness of hip fracture risk factors varied (from 28.6% for rheumatoid arthritis to 74.6% for age > 65 years). Approximately one-third reported a high level of confidence in managing bone metastases (39.9%) and CTIBL (33.2%). International or institution guidelines were used by approximately 50% of participants. Common barriers to better specialist care and treatment were reported to be lack of training, funding, knowledge or professional development. CONCLUSION: This work is the first quantitative analysis of reports from specialist oncology nurses about the management of bone metastases and CTIBL. It indicates the need for new nursing education initiatives with a focus on bone health management.
31168709 Prevalence, Safety and Long-Term Retention Rates of Biologics in Hong Kong from 2001 to 20 2019 Sep BACKGROUND: Biologic agents were initially introduced as treatment for rheumatoid arthritis (RA) but have since been used for other medical conditions. As new biologics become increasingly widespread in treatment regimens, it is important to understand their safety and utilization in the post-marketing context. PURPOSE: The aim of this study was to investigate long-term prescribing patterns and the safety of biologics in real clinical settings in Hong Kong. METHODS: This was a population-based drug utilization study in Hong Kong using a territory-wide electronic medical database Clinical Data Analysis and Reporting System (CDARS). Patients who received biologic treatments from 2001 to 2015 were identified and their corresponding demographic and clinical details retrieved from CDARS. The annual prevalence of biologic prescriptions, the long-term retention rates and incidence rates of infections associated with biologic treatments were evaluated. RESULTS: A total of 30,298 patients (male: 44%) prescribed biologic treatments were identified from CDARS from 2001 to 2015. The annual prevalence of biologic prescriptions increased from 0.1 to 16.1 per 100 persons for both sexes. Infliximab had the highest first-year retention rate of 95.6% among all biologics and continuously attained the highest retention rate from second to fifth year. The overall incidence rate of serious infections was less than five per 100 person-years. Specifically, the incidence rates of tuberculosis, upper and lower respiratory infections and herpes zoster were 0.52, 3.24, 4.99 and 1.01 per 100 person-years, respectively. CONCLUSION: This population-based study revealed an increasing prevalence of biologic prescribing. Results from the study described the long-term retention rates and incidence rates of serious infections of biologic treatments for all indications, and confirmed the safety of biologic treatments. Since this study provides an overview of all biologic utilization, further studies on cost effectiveness, safety and compliance of treatment in different patient groups are still warranted.
31091813 Immuno-Imaging to Predict Treatment Response in Infection, Inflammation and Oncology. 2019 May 14 BACKGROUND: Molecular nuclear medicine plays a pivotal role for diagnosis in a preclinical phase, in genetically susceptible patients, for radio-guided surgery, for disease relapse evaluation, and for therapy decision-making and follow-up. This is possible thanks to the development of new radiopharmaceuticals to target specific biomarkers of infection, inflammation and tumour immunology. METHODS: In this review, we describe the use of specific radiopharmaceuticals for infectious and inflammatory diseases with the aim of fast and accurate diagnosis and treatment follow-up. Furthermore, we focus on specific oncological indications with an emphasis on tumour immunology and visualizing the tumour environment. RESULTS: Molecular nuclear medicine imaging techniques get a foothold in the diagnosis of a variety of infectious and inflammatory diseases, such as bacterial and fungal infections, rheumatoid arthritis, and large vessel vasculitis, but also for treatment response in cancer immunotherapy. CONCLUSION: Several specific radiopharmaceuticals can be used to improve diagnosis and staging, but also for therapy decision-making and follow-up in infectious, inflammatory and oncological diseases where immune cells are involved. The identification of these cell subpopulations by nuclear medicine techniques would provide personalized medicine for these patients, avoiding side effects and improving therapeutic approaches.