Mcmahanrosenkilde2163
Neutralizing anti-drug antibody (NAb) assays often have lower drug tolerance (DT) than trough drug concentrations, potentially under-estimating NAb incidence. To improve DT, drug-specific proteins were coupled to magnetic beads to deplete drug in the sample. To avoid interference from carryover, drug-specific proteins that did not interfere in the NAb assay, such as target or non-blocking anti-drug antibodies, were selected. With the drug depletion step, DT improved by > 10-fold in two competitive ligand binding NAb assays. Analysis of anti-drug antibody positive clinical samples with elevated drug levels demonstrated that NAb incidence was under-estimated without the drug depletion step. However, these NAb-positive samples had low titer and no impact on drug concentrations.Rheumatoid arthritis is an autoimmune disorder causing joint deformity and work disability. Several drugs are available to deal with the disease including conventional drugs; biological drugs such as TNFα inhibitors, B cell-targeted drugs, T cell co-stimulation inhibitors, interleukin-6 inhibitors, and interleukin-1 inhibitors; and kinase inhibitory drugs. In spite of the broad spectrum of drugs available, the disease remains uncontrolled in a number of patients and there is a need for new drugs with better efficacy and universal response rate. The failure of the available drugs to control the disease can be owed to the complex pathogenesis with complementary pathways of disease progression. The blockade of one pathway cannot supersede pathogenesis through other complementary pathways. Janus kinase (JAK) and Bruton's tyrosine kinase (BTK) are the two important mediators of disease which control a number of signaling pathways involved in rheumatoid arthritis pathogenesis. In this study, using the computer-aided drug designing techniques (virtual screening, molecular docking, and molecular dynamics studies), we have designed piperidinyl dipyrrolopyridine-based dual inhibitors of Janus kinase and Bruton's tyrosine kinase. Dual JAK and BTK inhibitors seem promising to fight the complex pathogenesis of the disease at multiple fronts and can be the future drug for patients unresponsive to current remedies.
To evaluate the current evidence for the effectiveness of transarterial embolization (TAE) in treatment of symptomatic hepatic hemangiomas.
A systematic literature review was conducted in PubMed, CINAHL and Scopus databases to identify studies of hepatic hemangiomas treated with transarterial embolization. Main outcome was defined as the mean difference between pre- and post-TAE hemangioma diameters. Treatment agents were categorized as Lipiodol based [bleomycin (L + BE), pingyangmycin (L + PYG) or ethanol (L + ethanol)] and non-Lipiodol based (polyvinyl-alcohol-only). Conventional random-effect meta-analysis technique was applied to analyze data.
Of 3080 initially inspected publications, 21 studies were included in the meta-analysis comprising of 1450 patients with total of 1871 hemangiomas (36.2% male, mean age 46.3 ± 3.6years). One hundred and twenty-six, 1666, 41 and 38 lesions were treated with L + BE, L + PYG, L + ethanol and PVA, respectively. Median follow-up time after embolization was 12months with Lipiodol is safe and associated with reduced size of hemangiomas resulting in symptoms alleviation.A woman with an upper extremity brachioaxillary arteriovenous dialysis graft presented with a 9-month history of profound ipsilateral arm swelling and numbness secondary to chronic axillosubclavian vein occlusion. Previous endovascular and open venous recanalization attempts were unsuccessful. A totally percutaneous extra-anatomic venous bi-bypass was created to salvage the dialysis access circuit and reconstruct the deep venous system. Using overlapping Viabahn stent-grafts, two parallel bypasses were created from the arteriovenous graft and brachial vein, respectively, to the brachiocephalic vein. The hemodialysis graft regained function. Upper extremity symptoms resolved within 48 h. This is the first reported percutaneous double-barrel technique of extra-anatomic venous bypass creation for simultaneous management of a failed dialysis access and chronic venous occlusive disease.
To search for abscopal effects (AE) distant to the site of radiation after sequential Yittrium-90 (Y-90) radioembolization (RE) of liver malignancies.
In this retrospective analysis, all patients treated by RE between 2007 and 2018 (n = 907) were screened for the following setting/conditions sequential RE of left and right liver lobe in two sessions, liver-specific MRI (MRI1) acquired max. 10days before or after first RE (RE1), liver-specific MRI (MRI2) acquired with a minimum time interval of 20days after MRI1, but before second RE (RE2). No systemic tumor therapies between MRI1 and MRI2. No patients with liver cirrhosis. Metastases > 5mm in untreated liver lobes were compared in MRI1 and MRI2 and rated as follows same size or larger in MRI2 = no abscopal effect (NAE); > 30% shrinkage without Y-90 contamination in SPECT/CT = abscopal effect (AE).
Ninety six of 907 patients met aforementioned criteria. Median time-frame between RE1 and MRI2 was 34 (20-64) days. These 96 cases had 765 metastases which were evaluable (median 5(1-40) metastases per patient). Four patients could be identified with at least one shrinking metastasis of the untreated site one patient with breast cancer (3 metastases 0 NAE; 3 AE), one patient with prostate cancer (6 metastases 3 NAE; 3 metastases > 30% shrinkage but possible Y-90 contamination) and two patients with shrinkage of one metastasis each but less than 30%.
Our retrospective study documents AE after RE of liver tumors in 1 out of 96 cases, 3 other cases remain unclear.
Our retrospective study documents AE after RE of liver tumors in 1 out of 96 cases, 3 other cases remain unclear.
Gingival tissue enlargement is a common side effect of antiepileptic medications (e.g. phenytoin and sodium valproate), immunosuppressing drugs (e.g. cyclosporine) and calcium channel blockers (e.g. nifedipine, verapamil, amlodipine) (Murakami et al. 2018, Clin Periodontol 45S17-S27, 2018). The clinical and histological appearances of lesions caused by these drugs are indistinguishable from one another (Murakami et al. 2018, Clin Periodontol 45S17-S27, 2018). Drug-induced gingival enlargement is rarely seen in edentulous patients.
This case presents a 72-year-old female with a history of squamous cell carcinoma of the floor of the mouth treated with surgical excision and fibula-free flap reconstruction. Following the uncovering of osseointegrated implants placed in the fibular-free flap, the patient developed gingival enlargement of the floor of the mouth. Cessation of amlodipine and switching to an alternative medication lead to a resolution of the enlarged tissue.
This case illustrates that gingival enlargement can occur around dental implants, most notably in rehabilitation cases in patients who have had head and neck cancer. Clinicians should be aware of the risk of gingival enlargement in hypertensive patients taking calcium channel blockers prior to implant placement.
This case illustrates that gingival enlargement can occur around dental implants, most notably in rehabilitation cases in patients who have had head and neck cancer. Clinicians should be aware of the risk of gingival enlargement in hypertensive patients taking calcium channel blockers prior to implant placement.
To build a stronger Pichia pastoris P
promoter and to identify putative transcriptional factor binding sites (TFBSs) on P
that affect the activity of the promoter.
A synthetic library of P
was generated by deleting or duplicating putative TFBS motifs in the promoter sequence. CSRE, MIG1, RAP1 and HAP2/3/4 were found to have important effects on P
activity. The P
variant P4 with a putative binding site of RAP1 on the promoter sequence showed a stronger activity compared with that of the wild-type P
and P
, which is the strongest natural P. pastoris promoter that has been reported. This inference was confirmed with EGFP (enhanced green fluorescent protein) and Candida Antarctica lipase B as the reporters.
The role of the transcriptional regulator RAP1 may be important in P
methanol induction. A stronger P
variant can be constructed by the duplication of the putative binding site of RAP1 on the P
promoter sequence. This P
variant has potential value for heterologous protein production, metabolic engineering, and synthetic biology.
The role of the transcriptional regulator RAP1 may be important in PCAT1 methanol induction. A stronger PCAT1 variant can be constructed by the duplication of the putative binding site of RAP1 on the PCAT1 promoter sequence. This PCAT1 variant has potential value for heterologous protein production, metabolic engineering, and synthetic biology.
In general, a sufficient supply of ATP can promote the synthesis of ATP-driven metabolites, but excessive ATP will lead to the inhibition of cell growth. TGF beta inhibitor For enhancing the co-production of glutathione(GSH) and S-adenosylmethionine(SAM), a dynamic ATP regeneration strategy was developed.
The novel ATP regeneration strategy consisting of ATP-sensing riboswitch ydaO motif, polyphosphate kinase (PPK), and Vitreoscilla hemoglobin (VHb) was successfully applied in Escherichia coli. The intracellular ATP level was always around 0.60mg/g dry cell weight during the fermentation process, resulting in significantly enhanced co-production of GSH and SAM. The GSH titer and SAM titer in the strain CGS-2 increased by 137.40% and 82.18% after fermentation for 24h, compared with the control strain.
The ATP regulation strategy is expected to be a favorable tool to improve the efficiency of microbial cell factories. The proposed ATP dynamic regeneration approach may be applicable for cost-effective, high-yield production of ATP-driven metabolites.
The ATP regulation strategy is expected to be a favorable tool to improve the efficiency of microbial cell factories. The proposed ATP dynamic regeneration approach may be applicable for cost-effective, high-yield production of ATP-driven metabolites.
The Spinal Appearance Questionnaire (SAQ), scoliosis specific quality of life questionnaire, was developed to assess the spinal appearance in adolescent idiopathic scoliosis (AIS) patients. The aim of this study is to evaluate the adaptation, validity, and reliability of the Turkish version of the Spinal Appearance Questionnaire (Tr-SAQ).
Tr-SAQ and already validated Turkish SRS-22 were applied to 75AIS patients (56 females) twice within a 2-week interval for test-retest reliability. Validity of the Tr-SAQ was assessed with factor analysis, convergent validity, and discriminant validity. Convergent validity was evaluated by calculating Spearman correlation coefficients between Tr-SAQ and SRS-22 self-image domain. Internal consistency and intraclass correlation coefficient (ICC) were evaluated for the determination of reliability.
Factor analysis indicated that Tr-SAQ had two factors as appearance (items 1-10) and expectations (items 12-15). Convergent validity test showed a significant negative correlation between the Tr-SAQ appearance score and SRS-22 self-image score (Spearman's r = - 0.
