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Background It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. Methods In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1–10.8)]. Results In this extended analysis, M1, S1 and T1–T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P Conclusion Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.

Contains fulltext : 232930.pdf (Publisher’s version ) (Closed access) BACKGROUND: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. METHODS: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to

Inhibiting MYC has long been considered unfeasible, although its key role in human cancers makes it a desirable target for therapeutic intervention. One reason for its perceived undruggability was the fear of catastrophic side effects in normal tissues. However, we previously designed a dominant-negative form of MYC called Omomyc and used its conditional transgenic expression to inhibit MYC function both in vitro and in vivo. MYC inhibition by Omomyc exerted a potent therapeutic impact in various mouse models of cancer, causing only mild, well-tolerated, and reversible side effects. Nevertheless, Omomyc has been so far considered only a proof of principle. In contrast with that preconceived notion, here, we show that the purified Omomyc mini-protein itself spontaneously penetrates into cancer cells and effectively interferes with MYC transcriptional activity therein. Efficacy of the Omomyc mini-protein in various experimental models of non-small cell lung cancer harboring different oncogenic mutation profiles establishes its therapeutic potential after both direct tissue delivery and systemic administration, providing evidence that the Omomyc mini-protein is an effective MYC inhibitor worthy of clinical development.

ImportanceAlthough IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation. ObjectiveTo derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide. Design, Setting, and ParticipantsWe derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan. Main Outcomes and MeasuresCox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R-D(2) measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. ResultsThe study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R-D(2) (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (Delta C, 0.04; 95% CI, 0.03-0.04 and Delta C, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R-D(2) (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. Conclusions and RelevanceIn this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research.

Breast cancer is a leading cause of cancer mortality in women due to the high frequency of metastatic disease, which, despite advances in therapeutic options, is still essentially incurable. The role of Myc in promoting tumorigenesis is beyond doubt, but there are contradictory reports in the literature on its role in the metastatic process. Using a Myc dominant negative termed Omomyc, we have demonstrated in various mouse models that Myc inhibition is a safe and effective therapeutic approach against several types of cancer, regardless of the tissue of origin or the driver oncogenic lesion. So far, Omomyc has only been tested in primary tumors. However, since many steps of the metastatic cascade have been reported to depend on Myc, we hypothesized that Omomyc could be extremely effective in both the prevention and treatment of metastasis too. Here we show that Omomyc expression has a dramatic effect on colony formation capacity in human breast cancer cell lines representative of all the molecular subtypes of the disease. In MDA-MB-231 cells, not only did it impair their proliferation but also migration, invasion and their capacity to induce angiogenesis, key aspects of the metastatic process. We demonstrate that, in vivo, Omomyc reduces the growth of orthotopically-implanted human breast cancer cells in immunocompromised mice, induces regression of established metastases after primary tumor resection and impairs the development of lung metastases after tail vein injection. In the immunocompetent MMTV-PyMT transgenic model, Omomyc expression dramatically delays the formation and growth of mammary fat pad tumors, thereby preventing the appearance of lung metastases. When the purified Omomyc mini-protein is administered exogenously, we observe remarkable growth inhibition in vitro that recapitulates transgenic expression of Omomyc. Intravenous administration of the mini-protein reduces lung colonization and tumor growth in vivo. We have demonstrated for the first time the applicability of Omomyc against metastasis, challenging the pre-established notion that Myc inhibition could potentiate, rather than inhibit, invasion. Finally, we have validated the use of the purified Omomyc mini-protein as the first directly-deliverable Omomyc-based drug for the treatment of metastatic breast cancer, providing a new therapeutic opportunity for patients suffering from this dreadful and incurable disease. Citation Format: Daniel Massó-Vallés, Marie-Eve Beaulieu, Toni Jauset, Erika Serrano, Sandra Martínez-Martín, Laia Foradada, Virginia Castillo, Francisco Castillo, Génesis Martín, Sílvia Casacuberta-Serra, Mariano F. Zacarias-Fluck, Antonio Luque-García, Marta Escorihuela, Jonathan R. Whitfield, Joaquín Arribas, Laura Soucek. Translating Myc inhibition to the clinic in metastatic breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1823.

This article reports the conclusions of the second part of a consensus expert conference on the nomenclature of renal replacement therapy (RRT) techniques currently utilized to manage acute kidney injury and other organ dysfunction syndromes in critically ill patients. A multidisciplinary approach was taken to achieve harmonization of definitions, components, techniques, and operations of the extracorporeal therapies. The article describes the RRT techniques in detail with the relevant technology, procedures, and phases of treatment and key aspects of volume management/fluid balance in critically ill patients. In addition, the article describes recent developments in other extracorporeal therapies, including therapeutic plasma exchange, multiple organ support therapy, liver support, lung support, and blood purification in sepsis. This is a consensus report on nomenclature harmonization in extracorporeal blood purification therapies, such as hemofiltration, plasma exchange, multiple organ support therapies, and blood purification in sepsis., 0, SCOPUS: re.j, info:eu-repo/semantics/published

This article reports the conclusions of a consensus expert conference on the basic principles and nomenclature of renal replacement therapy (RRT) currently utilized to manage acute kidney injury (AKI). This multidisciplinary consensus conference discusses common definitions, components, techniques, and operations of the machines and platforms used to deliver extracorporeal therapies, utilizing a "machine-centric" rather than a "patient-centric" approach. We provide a detailed description of the performance characteristics of membranes, filters, transmembrane transport of solutes and fluid, flows, and methods of measurement of delivered treatment, focusing on continuous renal replacement therapies (CRRT) which are utilized in the management of critically ill patients with AKI. This is a consensus report on nomenclature harmonization for principles of extracorporeal renal replacement therapies. Devices and operations are classified and defined in detail to serve as guidelines for future use of terminology in papers and research., 0, SCOPUS: re.j, info:eu-repo/semantics/published

Introduction and Hypothesis: Breast cancer is a leading cause of cancer mortality in women due to the high frequency of metastatic disease, which, despite advances in therapeutic options, is still essentially incurable. The role of Myc in promoting tumorigenesis is beyond doubt, but there are contradictory reports in the literature on its role in the metastatic process. Using a Myc dominant negative termed Omomyc, we have demonstrated in various mouse models that Myc inhibition is a safe and effective therapeutic approach against several types of cancer, regardless of the tissue of origin or the driver oncogenic lesion. So far, Omomyc has only been tested in primary tumors. However, since many steps of the metastatic cascade have been reported to depend on Myc, we hypothesized that Omomyc could be extremely effective in both the prevention and treatment of metastasis too. Methods: We induced transgenic expression of Omomyc in a panel of 11 breast cancer cell lines and analyzed its effect on clonogenic capacity, proliferation, cell cycle progression, angiogenesis, migration, and invasion. To characterize the effect of Omomyc expression in vivo, we performed prevention and intervention studies in several mouse models of metastatic breast cancer: an orthotopic human cell line-derived model with surgical resection, a human cell line-derived lung colonization model, and the MMTV-PyMT transgenic model. Omomyc expression was induced at different stages of the disease, and tumor burden and metastatic spread were compared between groups at different time points. In parallel to this systemic modeling of Myc inhibition by transgenic expression of Omomyc, we are also validating the therapeutic utility of Omomyc-derived peptides as a pharmacologic approach. To this aim, we assessed the cell-penetrating capacity of the peptides in MDA-MB-231 cells by confocal microscopy and flow cytometry. To enhance its activity and to target metastases in vivo, Omomyc was conjugated with a metastasis-targeting sequence, and its efficacy compared with the one exerted by Omomyc alone in vitro. We selected the fusion peptide for in vivo studies and treated the orthotopic and lung colonization mouse models by several routes of administration. Results: Here we show that Omomyc expression has a dramatic effect on colony formation capacity in human breast cancer cell lines representative of all the molecular subtypes of the disease. In MDA-MB-231 cells, not only did it impair their proliferation but also migration, invasion, and their capacity to induce angiogenesis, key aspects of the metastatic process. We demonstrate that, in vivo, Omomyc reduces the growth of orthotopically implanted human breast cancer cells in immunocompromised mice, induces regression of established metastases after primary tumor resection, and impairs the development of lung metastases after tail vein injection. In the immunocompetent MMTV-PyMT transgenic model, Omomyc expression dramatically delays the formation and growth of mammary fat pad tumors, thereby preventing the appearance of lung metastases. When the Omomyc peptide is administered exogenously, we observe remarkable growth inhibition that recapitulates transgenic expression of Omomyc. When conjugated with a metastasis-targeting sequence, its cell-penetrating capacity is increased and causes abundant cell death in vitro. In vivo, treatment with the fusion peptide reduces growth of mammary primary tumors and lung metastases. Conclusions: We have demonstrated for the first time the applicability of Omomyc against metastasis, challenging the pre-established notion that Myc inhibition could potentiate, rather than inhibit, invasion. Finally, we have validated a metastasis-targeting fusion peptide as the first directly deliverable Omomyc-based drug for the treatment of metastatic breast cancer, providing a new therapeutic opportunity for patients suffering from this dreadful and incurable disease. Citation Format: Daniel Massó-Vallés, Marie-Eve Beaulieu, Toni Jauset, Erika Serrano, Sandra Martínez-Martín, Laia Foradada, Virginia Castillo, Sílvia Casacuberta-Serra, Mariano F. Zacarias-Fluck, Génesis Martín, Antonio Luque-García, Marta Escorihuela, Jonathan R. Whitfield, Joaquín Arribas, Laura Soucek. Targeting Myc in metastatic breast cancer by Omomyc: From proof of principle to pharmacologic approach [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B16.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are currently treated with trastuzumab, an anti-HER2 antibody. About 30% of these tumors express a group of HER2 fragments collectively known as p95HER2. Our previous work indicated that p95HER2-positive tumors are resistant to trastuzumab monotherapy. However, recent results showed that tumors expressing the most active of these fragments, p95HER2/611CTF, respond to trastuzumab plus chemotherapy. To clarify this discrepancy, we analyzed the response to chemotherapy of cell lines transfected with p95HER2/611CTF and patient-derived xenografts (n = 7 mice per group) with different levels of the fragment. All statistical tests were two-sided. p95HER2/611CTF-negative and positive tumors showed different responses to various chemotherapeutic agents, which are particularly effective on p95HER2/611CTF-positive cells. Furthermore, chemotherapy sensitizes p95HER2/611CTF-positive patient-derived xenograft tumors to trastuzumab (mean tumor volume, trastuzumab alone: 906 mm(3), 95% confidence interval = 1274 to 538 mm(3); trastuzumab+doxorubicin: 259 mm(3), 95% confidence interval = 387 to 131 mm(3); P < .001). This sensitization may be related to HER2 stabilization induced by chemotherapy in p95HER2/611CTF-positive cells.

Background, Clinically, cyclosporine (CSA, Neoral) is titrated to concentrations, and not to pharmacological effect. Methods. Intracellular interleukin- (IL) 2 was measured in phorbol myristic acid-ionomycin-stimulated peripheral lymphocytes by flow cytometry, after isolation from 14 renal transplant recipients receiving CSA+prednisone, and double-blind rapamycin (rapamy-cin:placebo=4:1). Results. The proportion (%) of CD4 + IL-2 + lymphocytes corresponding to CSA levels (mean±SD ng/ml) measured preoperatively (T0=0), and on postoperative day 8, before (356±63), and 2 hr after the morning dose (C max =1567±669), decreased from 39±16 to 15±8 and 3±1.6, respectively. Reciprocally, unresponsive lymphocytes (%CD4 + IL-2 - ) increased with increasing CSA levels and predicted an EC 50 of 249 ng/ml (CSA concentration at which CD4 + IL-2 - cells increased by 50% over baseline) in an E max pharmacodynamic model. Conclusions. Clinically, the pharmacological effect of CSA is quantifiable, and lies in the upper end of the predicted range. In our Neoral-treated sample population, C max was associated with the least variable cyclosporine effect. Such information could potentially individualize immunosuppression, and lead to rational dosing strategies.

Metronomic chemotherapy (MCT) is a novel therapeutic strategy for cancer treatment endowed with an antiangiogenic effect. It refers to regular administration of low doses of cytotoxic drugs, with minimal or no drug-free breaks. Previously, we demonstrated the immunomodulating activity of a single low-dose of cyclophosphamide (Cy) and the antitumor effect of MCT with Cy on established rat lymphomas and sarcomas. Here, we examined whether the immune response is responsible for the antitumor effect of MCT with Cy on L-TACB lymphoma. Inbred e rats and nude mice were subcutaneously challenged with L-TACB. After 7 days, they were distributed into two experimental groups: 1) treated animals, which were injected IP with Cy (10 mg/kg body weight) three times per week, and 2) control animals, which received IP saline injections. Exponential growth and decay and tumor doubling time were calculated. Also, serum IL-10 levels were measured. One hundred percent of treated rats showed tumor regression versus 0% of control rats. The increase of tumor-induced IL-10 levels was reverted by the treatment with Cy. On the other hand, there were no tumor regressions, in treated or control nude mice. However, the tumor doubling times of treated nude mice were significantly higher than those of control mice, implying that other antitumor mechanism(s), independent of the adaptive immune response, might be taking place. Our present results indicate that modulation of the immune response would be involved in the antitumor effect of MCT with Cy, because the absence of the specific immune response impairs, at least in part, its therapeutic effect in a lymphoma tumor model.

L-DGE is a spontaneous poorly differentiated murine lymphoma. During tumor growth it develops lymph node metastasis at a low frequency. Gal-1 is an immunomodulatory protein that acts as a regulator of T cell homeostasis and plays an important role in immune tolerance and tumor-immune escape. Overexpression of Gal-1 is associated with tumor progression and metastasis. Based on our previous findings, our aim was to obtain by a divergent selection two L-DGE variants that differ in tumor growth rate in order to study Gal-1 expression as well as their response to Cy. Two selection experiments were carried out. 1) L-DGE was s.c. implanted on 12 BALB/c mice (day 0). On day 14 the tumor displaying the largest volume was chosen as donor for the next passage to 4 mice. This higher-volume-selection was repeated for 25 serial passages, every 14 days and the tumor thus obtained was named L-DGE/M. 2) L-DGE was s.c. implanted on 12 BALB/c mice (day 0). On day 21, the tumor with the lowest growth rate was chosen as a donor and implanted into 6 mice and repeated through 16 serial passages. As a result of this selection L-DGE/L was obtained. We challenged mice (n=20/group) with L-DGE, L-DGE/M and L-DGE/L and studied tumor growth, metastatic capacity, galectin-1 expression and response to a single low dose Cy (25 mg/kg). Tumor volume vs. Time data was adjusted with an exponential curve and the growth rate was calculated. Gal-1 expression was studied by Western Blot in tumor and metastases homogenates. L-DGE/M growth rate was higher than that of L-DGE (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 404.

The analogue of phenylalanine, β-3-thienylalanine (β-3-TA), inhibits the primary and secondary immune responses to sheep red blood cells in CBA mice fed with phenylalanine-free diet. The optimal dose of β-3-TA needed to obtain maximum immunosuppression with minimal toxicity is 250 mg per kg per day. The drug is maximally effective when administered for 7 days, beginning 2 days prior to primary immunization. With these experimental conditions, the antibody titers and the numbers of direct and indirect plaque-forming cells are greatly reduced during the primary and the secondary immune response.

The pleiotropic cytokine IL-6 accelerates the progression of breast cancer in a variety of preclinical models through the activation of the STAT3 (signal transducer and activator of transcription 3) signaling pathway. However, the proportion of breast cancers sensitive to anti-IL-6 therapies is not known. This study evaluates the efficacy of anti-IL-6 therapies using breast cancer patient derived xenografts (PDXs). During the generation of our collection of PDXs, we showed that the successful engraftment of tumor tissue in immunodeficient mice correlates with bad prognosis. Four PDXs out of six were resistant to anti-IL-6 therapies and the expression of IL-6, its receptor or the levels of phospho-STAT3 (the active form of the signal transducer) did not correlate with sensitivity. Using cell cultures established from the PDXs as well as samples from in vivo treatments, we showed that only tumors in which the activation of STAT3 depends on IL-6 respond to the blocking antibodies. Our results indicate that only a fraction of breast tumors are responsive to anti-IL-6 therapies. In order to identify responsive tumors, a functional assay to determine the dependence of STAT3 activation on IL-6 should be performed.

Excerpt To the Editor:Isoprinosine is a synthetic immunopotentiating agent that can enhance interleukin-2 production in vitro, interleukin-2 receptor expression, natural killer cell activity, mitog...

Metal-halide semiconductor perovskites have received great attention for the development of stable and efficient light emitting diodes and lasers, since they combine high charge carrier mobility and light emission spectral-purity with low-cost fabrication methods. Nevertheless, the role of excitons, free carries and trap states in perovskite light emission properties is still unclear due to their interdependence. In this paper we selectively manage trapping and light emission mechanisms by a reversible laser-assisted trap-passivation process performed on a CH3NH3PbBr3 perovskite layer, coupled to the inner modes of a high-quality micro-cavity, which only affects the radiative recombination. We show that photoluminescence is dominated by exciton radiative decay process and that trap states passivation increases the exciton gemination rate by reducing coulombic scattering of free electrons due to the ionized impurities. This picture provides a more general description than the model based on trap states-free Saha thermodynamic equilibrium between photo-generated species. The interdependence of free carries, trap states and excitons in the light emission properties of CH3NH3PbBr3 perovskite thin films and their relationship to device performance is a subject of debate. Here, the authors investigate the role of non-radiative recombination and demonstrate that the photoluminescence is dominated by exciton radiative decay processes.

Hybrid organo-lead halide perovskites are becoming the benchmark material for next generation photovoltaics and a very important player for other applications such as photodetectors and light emitting diodes. Nevertheless, the most important issue hindering the large-scale application of these materials remains their intrinsic instability due to the organic cation. Although the substitution with inorganic cesium (Cs) enhances stability, in most cases solution deposition methods of fully inorganic perovskites result in high surface roughness and poor surface coverage. This work reports on the evaporation of the CsPbBr3 precursor by Single Source Thermal Ablation, showing that just after deposition films consist of a mixture of CsPbBr3, CsPb2Br5, and Cs4PbBr6 due to a vertical composition gradient. We point out that mild post deposition treatments lead to the conversion of CsPb2Br5 and Cs4PbBr6 into CsPbBr3 due to its higher thermodynamic stability. Conversion results into smooth and pinhole-free CsPbBr3 films with good light absorption and emission properties. We demonstrate the suitability of obtained films for planar devices by preparing perovskite-based pure-green light emitting diodes, thus promoting Single Source Thermal Ablation as a promising alternative deposition technique for all-inorganic perovskite-based devices.