Is response guided therapy dead? Low cure rates in patients with detectable hepatitis C virus at week 4 of treatment

Background

Historically, chronic hepatitis C virus (HCV) treatment was response-guided. Clinical trials with sofosbuvir indicated on-treatment virologic response was not predictive of sustained virologic response (SVR) and hence response-guided therapy (RGT) was abandoned. The purpose of this study is to examine the association between on-treatment 4-week HCV RNA and SVR in patients treated in real-world practice.

Methods

The study is a retrospective analysis of consecutive patients started on treatment with a sofosbuvir-containing regimen, January 1, 2014 through August 20, 2014, for HCV genotype 1–6 infection. Patients were treated by HCV specialists at 6 centers in the Project ECHO (Extension for Community Healthcare Outcomes) HCV Collaborative or in the community by primary care clinicians mentored by HCV specialists through Project ECHO. Patients were included if they were over 18 years, had evidence of chronic HCV, and were started on a sofosbuvir-containing regimen. The aspartate aminotransferase:platelet ratio index (APRI) was used to estimate fibrosis. The main outcome measures were 4-week HCV RNA and SVR.

Results

Overall SVR was 82.5 %. At week 4, HCV RNA was detected in 27.4 % of patients. Stepwise multivariable logistic-regression analyses identified APRI > 1.0, male sex, genotype 3, and detectable on treatment 4-week HCV RNA as independent predictors of failure to achieve SVR.

Conclusions

In a real-world setting, a significant proportion of sofosbuvir treated patients have detectable on-treatment 4-week HCV RNA. Detectable on-treatment 4-week HCV RNA is associated with virologic failure. More data are needed to formulate guidance for RGT with newly available HCV therapies.

     

Decreased proportions of CD4 + IL17+/CD4 + CD25 + CD127− and CD4 + IL17+/CD4 + CD25 + CD127 − FoxP3+ T cells in children with autoimmune thyroid diseases*

Until now, altered balance of Th1 and Th2 immune cells has been postulated to play an important role in the pathogenesis of autoimmune thyroid diseases (AITD). However, recent studies on thyroid diseases have suggested a new role for Th17 cells that have been classified as a new lineage, distinct from Th1, Th2 and Treg cells. Despite wide interest, the role of Th17 cells in the pathogenesis of inflammatory and autoimmune diseases is still debated. The aim of the study was to estimate the proportions of Th17/Treg T cells in peripheral blood from patients with Graves’ disease (GD; n?=?29, mean age 15.4?±?5.1 years), Hashimoto’s thyroiditis (HT; n?=?39, mean age 15.2?±?4.1 years) and in healthy controls (n?=?49, mean age 14.8?±?3 years). Polychromatic flow cytometry and several fluorochrome-conjugated monoclonal antibodies were applied to delineate Th17 and Treg cells. The analysis of Th17/Treg T cell proportions in peripheral blood from patients with Graves’ disease revealed significantly lower ratios of CD4?+?IL17+/CD4?+?CD25?+?CD127???(p?p?p?p?R?=?0.71, p?R?=?0.72, p?R?=?0.66, p?相似文献   

Mixture toxicity of flubendazole and fenbendazole to Daphnia magna

Nowadays, residual amounts of many pharmaceuticals can be found in various environmental compartments including surface and ground waters, soils and sediments as well as biota. Even though they undergo degradability, their environmental discharge is relatively continuous, thus they may be regarded as quasi-persistent contaminants, and are also frequently regarded as emerging organic pollutants. Benzimidazoles, especially flubendazole (FLU) and fenbendazole (FEN), represent two anthelmintic drugs belonging to this group. Although their presence in environmental matrices has been reported, there is relatively little data concerning their (eco)toxicological impact. Furthermore, no data is available on their mixture toxicity. FLU and FEN have been found to have a strong impact on an environmentally important non-target organism – Daphnia magna. Moreover, these compounds are usually present in the environment as a part of pharmaceutical mixtures. Therefore, there is a need to evaluate their mixture toxicity, which was the main aim of this study. Single substance toxicity tests were carried out in parallel with mixture studies of FLU and FEN, with the application of two well established concepts of Concentration Addition (CA) and Independent Action (IA). As a result, both models (CA and IA) were found to underestimate the toxicity of mixtures, however CA yielded more accurate predictions.     

Saponins as chemosensitizing substances that improve effectiveness and selectivity of anticancer drug—Minireview of in vitro studies

Triterpene saponins (saponosides) are found in higher plants and display a wide range of biological and pharmacological activities. The antitumor effects of saponins have been proved by their cytotoxic, cytostatic, proapoptotic, and anti‐invasive effects in many cellular models. Saponins hold great potential for being developed into chemopreventive and chemotherapeutic drugs. A promising way of reducing the adverse effects of chemotherapy without attenuating its efficiency is provided by the combined application of chemotherapeutic agents and saponosides in subtoxic concentrations. Until recently, saponosides were primarily used as adjuvants that enhance the effect of vaccines. In cancer therapy, saponins are applied in combination with immunotoxins because they increase the selectivity of given immunotoxins against cancer cells and therefore inure normal cells to the cytotoxic effects of immunotoxins. Significantly, certain saponins have been identified that drastically enhance the efficacy of many chemotherapeutic agents, including cisplatin, paclitaxel, doxorubicin, docetaxel, mitoxantrone, and cyclophosphamide. Moreover, saponins used in combination therapy enhance the sensitivity of chemoresistant tumor cells to clinically used chemotherapeutic agents. This review sheds light on the molecular mechanisms underlying cancer co–treatment with saponins and chemotherapy, with a particular focus on modulation of the cell signaling pathways associated with the promotion and progression of cancer cell proliferation, apoptosis, and metastasis.     

Phenylalanine intercalation parameters for liquid-disordered phase domains – a membrane model study

Background

Propensity of phenylalanine (Phe) for nonpolar environments drives its intercalation into phospholipid membranes, which has been implicated in metabolic and neurological disorders. The knowledge of Phe intercalation parameters can be instrumental in understanding various membrane processes triggered by interactions with Phe, in particular the early events leading to the formation of nucleation/docking sites for the self-assembly of Phe amyloid fibrils at the membrane surface.

Results

In this study, we used monolayers of phosphatidylethanolamine (DPPE) and phosphatidylcholine (DPPC) to mimic the membrane outer leaflet. Its initial interaction with Phe was modeled by injecting Phe into the aqueous phase underneath the monolayer. Constant pressure insertion assays augmented with epifluorescence microscopy imaging were used to monitor Phe intercalation. Our primary goal was to determine the Phe intercalation area, A_Phe. Two values were obtained for A_Phe, 33 ± 2 and 48 ± 3 Å².

Conclusions

Phe appeared to discriminate between DPPE and DPPC packing, and use two modes of intercalation. The area of A_Phe 33 ± 2 Å² is consistent with a Phe monomer intercalating into membrane by inserting the phenyl ring nearly normal to the membrane surface. This mode has been found to operate in DPPE membranes. For DPPC membranes however, the value of A_Phe?=?48 ± 3 Å² suggests that, from saline, Phe tends to intercalate as a larger species plausibly dragging along a counterion, Na⁺, in a Na⁺(Phe) complex.

     

Intra- and Extracellular Biosynthesis and Characterization of Iron Nanoparticles from Prokaryotic Microorganisms with Anticoagulant Activity

Background

The use of microorganisms for the synthesis of nanoparticles (NPs) is relatively new in basic research and technology areas.

Purpose

This work was conducted to optimized the biosynthesis of iron NPs intra- and extracellular by Escherichia coli or Pseudomonas aeruginosa and to evaluate their anticoagulant activity.

Study Design/Methods

The structures and properties of the iron NPs were investigated by Ultraviolet–visible (UV-vis) spectroscopy, Zeta potential, Dynamic light scattering (DLS), Field emission scanning electron microscope (FESEM)/ Energy dispersive X-ray (EDX) and transmission electron microscopy (TEM). Anticoagulant activity was determined by conducting trials of Thrombin Time (TT), Activated Partial Prothrombin Time (APTT) and Prothrombin Time (PT).

Results

UV-vis spectrum of the aqueous medium containing iron NPs showed a peak at 275 nm. The forming of iron NPs was confirmed by FESEM/ EDX, and TEM. The morphology was spherical shapes mostly with low polydispersity and the average particle diameter was 23?±?1 nm. Iron NPs showed anticoagulant activity by the activation of extrinsic pathway.

Conclusion

The eco-friendly process of biosynthesis of iron NPs employing prokaryotic microorganisms presents a good anticoagulant activity. This could be explored as promising candidates for a variety of biomedical and pharmaceutical applications.

     

Electrical Behavior of Copper Mine Tailings During EKR with Modified Electric Fields

Electro-kinetic remediation (EKR) with sinusoidal electric field obtained simultaneously with DC/AC voltage reduce the polarization of the EKR with DC voltage. The DC voltage value defines the presence of a periodic polarity reversal of the cell and the electrical charge for electro-kinetic transport. In this case, the AC frequency favors the breaking of polarization conditions resulting from the EKR with DC voltage. However, with high frequencies a negative effect occurs where the tailings behave as a filter circuit, discriminating frequencies of an electric signal. The goal of this work is to analyse the electrical behaviour of tailings in EKR experiments. The conditions selected were: DC/AC voltages: 10/15 and 20/25 V (peak values), and AC voltage frequencies 50–2000 Hz. When the AC frequency reaches 2000 Hz, the copper removal tends to zero, indicating that the tailing behaves as a high-pass filter in which the DC voltage was filtered out.     

Response to anti-SARS-CoV-2 mRNA vaccines in multiple myeloma and chronic lymphocytic leukemia patients

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients have increased morbidity and mortality rates of COVID-19 due to immunosuppression associated with the disease and ongoing therapy. The same immune impairment accompanying CLL and MM also affects suboptimal vaccine response. The study assessed the effectiveness of the humoral and T cell-mediated immunity following mRNA COVID-19 vaccination (using either BNT162b2 or mRNA-1273) in short-term (2-5 weeks after second dose) and long-term follow-up (12 weeks after vaccination). Between March and August 2021, blood samples were obtained from 62 CLL and 60 MM patients from eight different hematology departments in Poland. Total anti-RBD antibodies were detected in 37% MM patients before vaccination, increased to 91% and 94% in short- and long-term follow-up, respectively. In CLL, serological responses were detectable in 21% of patients before vaccination and increased to 45% in the short-term and 71% in long-term observation. We detected a tendency to higher frequencies of specific CD8+ T cells against SARS-CoV-2 after vaccination compared to samples before vaccination in MM patients and no changes in frequencies of specific T cells in CLL patients. Our study provides novel insights into mRNA vaccination efficacy in immunocompromised MM and CLL patients, and our findings highlight that specific CD8+ T cells against SARS-CoV-2 might be induced by vaccination but do not correlate positively with serological responses.