De Novo Fibrillary Glomerulonephritis (FGN) in a Renal Transplant with Chronic Hepatitis C.

Chronic hepatitis C viremia (HepC) has been associated with numerous renal manifestations both in native kidneys and in the setting of renal transplantation. Glomerulonephritis (GN) of the renal allograft in the setting of HepC most commonly manifests as type 1 membranoproliferative GN (MPGN), either representing recurrence of the original disease or arising de novo. Other GNs were reported after transplantation in the patient with HepC including membranous nephropathy and thrombotic microangiopathy, as well as an enhanced susceptibility to transplant glomerulopathy. We describe the first case of de novo fibrillary GN in a renal transplant patient with HepC where the primary renal disease was biopsy proven type 1 MPGN. We discuss this relationship in detail

Potential Tools for Eradicating HIV Reservoirs in the Brain: Development of Trojan Horse Prodrugs for the Inhibition of P-Glycoprotein with Anti-HIV-1 Activity

Combination antiretroviral therapy is the mainstay of HIV treatment, lowering plasma viral levels below detection. However, eradication of HIV is a major challenge due to cellular and anatomical viral reservoirs that are often protected from treatment by efflux transporters, such as P-glycoprotein (P-gp) at the blood–brain barrier (BBB). Herein we described a Trojan horse approach to therapeutic evasion of P-gp based on a reversibly linked combination of HIV reverse transcriptase and protease inhibitors. Potent inhibition of P-gp efflux in cells, including human brain endothelial cells, was observed with the linked heterodimeric compounds. In vitro regeneration of active monomeric drugs was observed in a reducing environment with these dimeric prodrugs, with the superior leaving group promoting more facile release from the tether. These release trends were mirrored in the efficacy of the in cyto anti-HIV-1 activity of the Trojan horse heterodimers

How robust are cross-country comparisons of PISA scores to the scaling model used?

The Programme for International Student Assessment (PISA) is an important international study of 15‐olds' knowledge and skills. New results are released every 3 years, and have a substantial impact upon education policy. Yet, despite its influence, the methodology underpinning PISA has received significant criticism. Much of this criticism has focused upon the psychometric scaling model used to create the proficiency scores. The aim of this article is to therefore investigate the robustness of cross‐country comparisons of PISA scores to subtle changes to the underlying scaling model used. This includes the specification of the item‐response model, whether the difficulty and discrimination of items are allowed to vary across countries (item‐by‐country interactions) and how test questions not reached by pupils are treated. Our key finding is that these technical choices make little substantive difference to the overall country‐level results

How robust are cross-country comparisons of PISA scores to the scaling model used?

The Programme for International Student Assessment (PISA) is an important international study of 15‐olds' knowledge and skills. New results are released every 3 years, and have a substantial impact upon education policy. Yet, despite its influence, the methodology underpinning PISA has received significant criticism. Much of this criticism has focused upon the psychometric scaling model used to create the proficiency scores. The aim of this article is to therefore investigate the robustness of cross‐country comparisons of PISA scores to subtle changes to the underlying scaling model used. This includes the specification of the item‐response model, whether the difficulty and discrimination of items are allowed to vary across countries (item‐by‐country interactions) and how test questions not reached by pupils are treated. Our key finding is that these technical choices make little substantive difference to the overall country‐level results

Grain legume yields are as stable as other spring crops in long-term experiments across northern Europe

Grain legumes produce high-quality protein for food and feed, and potentially contribute to sustainable cropping systems, but they are grown on only 1.5% of European arable land. Low temporal yield stability is one of the reasons held responsible for the low proportion of grain legumes, without sufficient quantitative evidence. The objective of this study was to compare the yield stability of grain legumes with other crop species in a northern European context and accounting for the effects of scale in the analysis and the data. To avoid aggregation biases in the yield data, we used data from long-term field experiments. The experiments included grain legumes (lupin, field pea, and faba bean), other broad-leaved crops, spring, and winter cereals. Experiments were conducted in the UK, Sweden, and Germany. To compare yield stability between grain legumes and other crops, we used a scale-adjusted yield stability indicator that accounts for the yield differences between crops following Taylor's Power Law. Here, we show that temporal yield instability of grain legumes (30%) was higher than that of autumn-sown cereals (19%), but lower than that of other spring-sown broad-leaved crops (35%), and only slightly greater than spring-sown cereals (27%). With the scale-adjusted yield stability indicator, we estimated 21% higher yield stability for grain legumes compared to a standard stability measure. These novel findings demonstrate that grain legume yields are as reliable as those of other spring-sown crops in major production systems of northern Europe, which could influence the current negative perception on grain legume cultivation. Initiatives are still needed to improve the crops agronomy to provide higher and more stable yields in future.Peer reviewe

Chimeric Antigen Receptor-Redirected Regulatory T Cells Suppress Experimental Allergic Airway Inflammation, a Model of Asthma

Cellular therapy with chimeric antigen receptor (CAR)-redirected cytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. We explored a regulatory T cell (Treg)-based therapy in the treatment of allergic airway inflammation, a model for asthma, which is characterized by an airway hyper-reactivity (AHR) and a chronic, T helper-2 (Th2) cell-dominated immune response to allergen. To restore the immune balance in the lung, we redirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma, closely mimicking the clinical situation. Adoptively transferred CAR Tregs accumulated in the lung and in tracheobronchial lymph nodes, reduced AHR and diminished eosinophilic airway inflammation, indicated by lower cell numbers in the bronchoalveolar lavage fluid and decreased cell infiltrates in the lung. CAR Treg cells furthermore prevented excessive pulmonary mucus production as well as increase in allergen-specific IgE and Th2 cytokine levels in exposed animals. CAR Tregs were more efficient in controlling asthma than non-modified Tregs, indicating the pivotal role of specific Treg cell activation in the affected organ. Data demonstrate that lung targeting CAR Treg cells ameliorate key features of experimental airway inflammation, paving the way for cell therapy of severe allergic asthma

The roles of the human ATP-binding cassette transporters P-glycoprotein and ABCG2 in multidrug resistance in cancer and at endogenous sites: future opportunities for structure-based drug design of inhibitors

The ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp) and ABCG2 are multidrug transporters that confer drug resistance to numerous anti-cancer therapeutics in cell culture. These findings initially created great excitement in the medical oncology community, as inhibitors of these transporters held the promise of overcoming clinical multidrug resistance in cancer patients. However, clinical trials of P-gp and ABCG2 inhibitors in combination with cancer chemotherapeutics have not been successful due, in part, to flawed clinical trial designs resulting from an incomplete molecular understanding of the multifactorial basis of multidrug resistance (MDR) in the cancers examined. The field was also stymied by the lack of high-resolution structural information for P-gp and ABCG2 for use in the rational structure-based drug design of inhibitors. Recent advances in structural biology have led to numerous structures of both ABCG2 and P-gp that elucidated more clearly the mechanism of transport and the polyspecific nature of their substrate and inhibitor binding sites. These data should prove useful helpful for developing even more potent and specific inhibitors of both transporters. As such, although possible pharmacokinetic interactions would need to be evaluated, these inhibitors may show greater effectiveness in overcoming ABC-dependent multidrug resistance in combination with chemotherapeutics in carefully selected subsets of cancers. Another perhaps even more compelling use of these inhibitors may be in reversibly inhibiting endogenously expressed P-gp and ABCG2, which serve a protective role at various blood-tissue barriers. Inhibition of these transporters at sanctuary sites such as the brain and gut could lead to increased penetration by chemotherapeutics used to treat brain cancers or other brain disorders and increased oral bioavailability of these agents, respectively

Inhibition of P-Glycoprotein-Mediated Paclitaxel Resistance by Reversibly Linked Quinine Homodimers

P-glycoprotein (P-gp), an ATP-dependent drug efflux pump, has been implicated in multidrug resistance of several cancers as a result of its overexpression. In this work, rationally designed second-generation P-gp inhibitors are disclosed, based on dimerized versions of the substrates quinine and quinidine. These dimeric agents include reversible tethers with a built-in clearance mechanism. The designed agents were potent inhibitors of rhodamine 123 efflux in cultured cancer cell lines that display high levels of P-gp expression at the cell surface and in transfected cells expressing P-gp. The quinine homodimer Q2, which was tethered by reversible ester bonds, was particularly potent (IC50 ≈ 1.7 μM). Further studies revealed that Q2 inhibited the efflux of a range of fluorescent substrates (rhodamine 123, doxorubicin, mitoxantrone, and BODIPY-FL-prazosin) from MCF-7/DX1 cells. The reversibility of the tether was confirmed in experiments showing that Q2 was readily hydrolyzed by esterases in vitro (t½ ≈ 20 h) while demonstrating high resistance to nonenzymatic hydrolysis in cell culture media (t½ ≈ 21 days). Specific inhibition of [125I]iodoarylazidoprazosin binding to P-gp by Q2 verified that the bivalent agent interacted specifically with the drug binding site(s) of P-gp. Q2 was also an inhibitor of verapamil-stimulated ATPase activity. In addition, low concentrations of Q2 stimulated basal P-gp ATPase levels. Finally, Q2 was shown to inhibit the transport of radiolabeled paclitaxel (Taxol) in MCF-7/DX1 cells, and it completely reversed the P-gp-mediated paclitaxel resistance phenotype

Chimeric Antigen Receptor-Redirected Regulatory T Cells Suppress Experimental Allergic Airway Inflammation, a Model of Asthma

Cellular therapy with chimeric antigen receptor (CAR)-redirected cytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. We explored a regulatory T cell (Treg)-based therapy in the treatment of allergic airway inflammation, a model for asthma, which is characterized by an airway hyper-reactivity (AHR) and a chronic, T helper-2 (Th2) cell-dominated immune response to allergen. To restore the immune balance in the lung, we redirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma, closely mimicking the clinical situation. Adoptively transferred CAR Tregs accumulated in the lung and in tracheobronchial lymph nodes, reduced AHR and diminished eosinophilic airway inflammation, indicated by lower cell numbers in the bronchoalveolar lavage fluid and decreased cell infiltrates in the lung. CAR Treg cells furthermore prevented excessive pulmonary mucus production as well as increase in allergen-specific IgE and Th2 cytokine levels in exposed animals. CAR Tregs were more efficient in controlling asthma than non-modified Tregs, indicating the pivotal role of specific Treg cell activation in the affected organ. Data demonstrate that lung targeting CAR Treg cells ameliorate key features of experimental airway inflammation, paving the way for cell therapy of severe allergic asthma