Apigenin inhibits TNFα/IL-1α-induced CCL2 release through IKBK-epsilon signaling in MDA-MB-231 human breast cancer cells - Fig 7

<p><b>A. IKBKe transcription in MDA-MB-231 cells ± TNFα ± Apigenin.</b> The data represent normalized expression and are expressed as the Mean ± S.E.M., n = 3. The significance of differences between the Ctrl and TNFα groups and TNFα vs. TNFα + Apigenin were determined by a Students t-test *p<0.05. <b>Figure 7B.</b> Protein expression of <b>IKBKe</b>/GAPDH with TNFα ± Apigenin at 24 hours.</p

NF-kB PCR microarray tabulated data on MDA-MB-231 cells ± TNFα ± Apigenin.

<p>The data displays differential transcription as Log2 (Fc) for controls vs. TNFα (Left Panel) and TNFα vs. TNFα + Apigenin (Right Panel) in MDA-MB-231 cells treated for 24 hours. The data show no significant changes at P < .05 for either analysis, with non-significant differences for only IL-1α.</p

NF-kB PCR microarray assessment on MDA-MB-231 cells ± TNFα ± Apigenin.

<p>The data displays differential transcription for controls vs. TNFα (A) and TNFα vs. TNFα + Apigenin (B) in MDA-MB-231 cells treated for 24 hours. The data show no significant changes at P < .05 for either analysis, with non-significant differences for only IL-1α.</p

Characterization of Clinically Relevant Fungi via SERS Fingerprinting Assisted by Novel Chemometric Models

Nonculture-based tests are gaining popularity and upsurge in the diagnosis of <b>invasive fungal infections (IFI)</b> fostered by their main asset, the reduced analysis time, which enables a more rapid diagnosis. In this project, three different clinical isolates of relevant filamentous fungal species were discriminated by using a rapid (less than 5 min) and sensitive <b>surface-enhanced Raman scattering (SERS)</b>-based detection method, assisted by chemometrics. The holistic evaluation of the SERS spectra was performed by employing appropriate chemometric toolsclassical and <b>fuzzy principal component analysis (FPCA)</b> in combination with <b>linear discriminant analysis (LDA)</b> applied to the first relevant principal components. The efficiency of the proposed robust algorithm is illustrated on the data set including three fungal isolates (<i>Aspergillus fumigatus</i> sensu stricto, cryptic <i>A. fumigatus</i> complex species, and <i>Rhizomucor pusillus</i>) that were isolated from patient materials. The accurate and reliable discrimination between species of common fungal pathogen strains suggest that the developed method has the potential as an alternative, spectroscopic-based routine analysis tool in IFI diagnosis

Progress of Hepatitis C elimination in Viennese people living with HIV after two decades of increasing cure rates

Interferon(IFN)-based hepatitis C virus (HCV) therapy has been replaced by direct-acting antivirals (DAAs). We assessed temporal trends in patient characteristics, transmission risks, treatment initiation, and cure rates in eras of IFN, restricted DAA-access, and unrestricted DAA-access in Viennese HCV/HIV-coinfected patients (HIV/HCV). Consecutive HIV/HCV-coinfected patients starting HCV treatment at the Vienna General Hospital between 2002 and 2020 were retrospectively enrolled. Of all N = 508 HIV/HCV, 78% (398/508) were male and the mean age was 41.8 ± 9.5 years. ‘People-who-inject-drugs’ (PWID) accounted for 61% (311/508), while 31% (156/508) were ‘men who have sex with men’ (MSM). In the IFN-era, restricted DAA-era and unrestricted DAA-era, N = 152, N = 129, and N = 227 HCV treatments were started and 49% (74/152), 95% (122/129), and 88% (200/227) achieved sustained virologic response, respectively. Treatment during the IFN-era was a strong predictor for virologic non-response (aOR 12.69; 6.93–23.24) and loss-to-follow-up (aOR 6.12; 2.99–12.54), while virologic non-response was less common in ‘MSM’ (aOR 0.28; 0.13–0.62). Ninety three percent (50/54) of the observed HCV reinfections occurred in the unrestricted DAA-era. A substantial increase in ‘MSM’ transmission was observed since 2010 with 66% (107/161) in the DAA-era versus 15% (49/330) prior to the DAA-era. HCV cure rates in Viennese HIV patients increased from 49% in the IFN-era to 88–95% in the DAA-era. MSM-related risk behaviour and reinfections became the key challenges towards HCV elimination in HIV-coinfected patients.</p

Transjugular intrahepatic portosystemic shunts (TIPS) for the prevention of variceal re-bleeding – A two decades experience

<div><p>Background and aims</p><p>Transjugular intrahepatic portosystemic shunts (TIPS) are used in patients with cirrhosis for the prevention of variceal rebleeding.</p><p>Methods</p><p>We retrospectively evaluated re-bleeding rate, patency, mortality, and transplant-free survival (TFS) in cirrhotic patients receiving TIPS implantation for variceal bleeding between 1994–2014.</p><p>Results</p><p>286 patients received TIPS (n = 119 bare metal stents, n = 167 polytetrafluorethylene (PTFE)-covered stents) for prevention of variceal re-bleeding. Mean age was 55.1 years, median MELD was 11.8, and the main etiology of cirrhosis was alcoholic liver disease (70%). Median follow-up was 821 days. 67 patients (23%) experienced at least one re-bleeding event. Patients with PTFE-TIPS were at significantly lower risk for variceal re-bleeding than patients with bare metal stents (14% vs. 37%, OR:0.259; p<0.001) and had less need for stent revision (21% vs. 37%; p = 0.024). Patients with PTFE stent grafts showed lower mortality than patients with bare stents after 1 year (19% vs. 31%, p = 0.020) and 2 years (29% vs. 40%; p = 0.041) after TIPS implantation. Occurrence of hepatic encephalopathy after TIPS was similar between groups (20% vs. 24%, p = 0.449).</p><p>Conclusions</p><p>PTFE-TIPS were more effective at preventing variceal re-bleeding than bare metal stents due to better patency. Since this tended to translate in improved survival, only covered stents should be implemented for bleeding prophylaxis when TIPS is indicated.</p></div

<i>N</i>^ε‑Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure–Activity Relationships, and Pharmacokinetic Profiling

Transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes. Consequently, this enzyme is considered a promising target for the diagnosis of and therapy for these diseases. In this study, we report on the synthesis and kinetic characterization of <i>N</i>^ε-acryloyllysine piperazides as irreversible inhibitors of TGase 2. Systematic structural modifications on 54 new compounds were performed with a major focus on fluorine-bearing substituents due to the potential of such compounds to serve as radiotracer candidates for positron emission tomography. The determined inhibitory activities ranged from 100 to 10 000 M^–1 s^–1, which resulted in comprehensive structure–activity relationships. Structure–activity correlations using various substituent parameters accompanied by covalent docking studies provide an advanced understanding of the molecular recognition for this inhibitor class within the active site of TGase 2. Selectivity profiling of selected compounds for other transglutaminases demonstrated an excellent selectivity toward transglutaminase 2. Furthermore, an initial pharmacokinetic profiling of selected inhibitors was performed, including the assessment of potential membrane permeability and liver microsomal stability

<i>N</i>^ε‑Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure–Activity Relationships, and Pharmacokinetic Profiling

Transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes. Consequently, this enzyme is considered a promising target for the diagnosis of and therapy for these diseases. In this study, we report on the synthesis and kinetic characterization of <i>N</i>^ε-acryloyllysine piperazides as irreversible inhibitors of TGase 2. Systematic structural modifications on 54 new compounds were performed with a major focus on fluorine-bearing substituents due to the potential of such compounds to serve as radiotracer candidates for positron emission tomography. The determined inhibitory activities ranged from 100 to 10 000 M^–1 s^–1, which resulted in comprehensive structure–activity relationships. Structure–activity correlations using various substituent parameters accompanied by covalent docking studies provide an advanced understanding of the molecular recognition for this inhibitor class within the active site of TGase 2. Selectivity profiling of selected compounds for other transglutaminases demonstrated an excellent selectivity toward transglutaminase 2. Furthermore, an initial pharmacokinetic profiling of selected inhibitors was performed, including the assessment of potential membrane permeability and liver microsomal stability

<i>N</i>^ε‑Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure–Activity Relationships, and Pharmacokinetic Profiling

Transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes. Consequently, this enzyme is considered a promising target for the diagnosis of and therapy for these diseases. In this study, we report on the synthesis and kinetic characterization of <i>N</i>^ε-acryloyllysine piperazides as irreversible inhibitors of TGase 2. Systematic structural modifications on 54 new compounds were performed with a major focus on fluorine-bearing substituents due to the potential of such compounds to serve as radiotracer candidates for positron emission tomography. The determined inhibitory activities ranged from 100 to 10 000 M^–1 s^–1, which resulted in comprehensive structure–activity relationships. Structure–activity correlations using various substituent parameters accompanied by covalent docking studies provide an advanced understanding of the molecular recognition for this inhibitor class within the active site of TGase 2. Selectivity profiling of selected compounds for other transglutaminases demonstrated an excellent selectivity toward transglutaminase 2. Furthermore, an initial pharmacokinetic profiling of selected inhibitors was performed, including the assessment of potential membrane permeability and liver microsomal stability

Re-bleeding rates and re-interventions after TIPS implantation.

<p>(A). Rebleeding rates after TIPS implantation. (B). Bleeding recurrence after TIPS implantation, by type of implanted stent.</p