Peritoneal dialysis (PD) is a form of renal replacement therapy whose repeated use can alter dialytic function through induction of epithelial–mesenchymal transition (EMT) and fibrosis, eventually ...leading to PD discontinuation. The peritoneum from Cav1−/− mice showed increased EMT, thickness, and fibrosis. Exposure of Cav1−/− mice to PD fluids further increased peritoneal membrane thickness, altered permeability, and increased the number of FSP‐1/cytokeratin‐positive cells invading the sub‐mesothelial stroma. High‐throughput quantitative proteomics revealed increased abundance of collagens, FN, and laminin, as well as proteins related to TGF‐β activity in matrices derived from Cav1−/− cells. Lack of Cav1 was associated with hyperactivation of a MEK‐ERK1/2‐Snail‐1 pathway that regulated the Smad2‐3/Smad1‐5‐8 balance. Pharmacological blockade of MEK rescued E‐cadherin and ZO‐1 inter‐cellular junction localization, reduced fibrosis, and restored peritoneal function in Cav1−/− mice. Moreover, treatment of human PD‐patient‐derived MCs with drugs increasing Cav1 levels, as well as ectopic Cav1 expression, induced re‐acquisition of epithelial features. This study demonstrates a pivotal role of Cav1 in the balance of epithelial versus mesenchymal state and suggests targets for the prevention of fibrosis during PD.
Synopsis
Peritoneal dialysis (PD) has major advantages vs. hemodialysis but leads to inflammation and injury to the PM. This study identifies MEK/ERK1/2 signaling as playing a central role in EMT and fibrosis occurring during PD, and caveolin‐1 as an important regulator of these events.
Caveolin‐1 (Cav1) limits the occurrence of EMT and fibrosis during peritoneal dialysis.
Absence of Cav1 is associated to hyper‐activation of the MEK‐ERK‐Snail‐1 axis, which affects the SMAD2‐3/SMAD1‐5‐8 balance.
MEK inhibition prevents EMT, fibrosis, and altered peritoneal membrane function in the peritoneum of Cav1−/− mice undergoing peritoneal dialysis.
Treatment of human peritoneal dialysis patient‐derived mesothelial cells with drugs increasing Cav1 levels, as well as ectopic Cav1 expression, induce re‐acquisition of epithelial features.
Peritoneal dialysis (PD) has major advantages vs. hemodialysis but leads to inflammation and injury to the PM. This study identifies MEK/ERK1/2 signaling as playing a central role in EMT and fibrosis occurring during PD, and caveolin‐1 as an important regulator of these events.
Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms ...(SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we measured these BMD-associated microRNAs in trabecular bone from osteoporotic hip fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblast-expressed microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone disorders.
The accuracy of the provisional estimation of the Biopharmaceutics Classification System (BCS) is heavily influenced by the permeability measurement. In this study, several theoretical and ...experimental models currently employed for BCS permeability classification have been analysed. The experimental models included the in situ rat intestinal perfusion, the ex vivo rat intestinal tissue in an Ussing chamber, the MDCK and Caco‐2 cell monolayers, and the parallel artificial membrane (PAMPA). The theoretical models included the octanol–water partition coefficient and the QSPeR (Quantitative Structure‐Permeability Relationship) model recently developed. For model validation, a dataset of 43 compounds has been recompiled and analysed for the suitability for BCS permeability classification in comparison with the use of human intestinal absorption and oral bioavailability values. The application of the final model, based on a majority voting system showed a 95.3% accuracy for predicting human permeability. Finally, the present approach was applied to the 186 orally administered drugs in immediate‐release dosage forms of the WHO Model List of Essential Medicines. The percentages of the drugs that were provisionally classified as BCS Class I and Class III was 62.4%, suggesting that in vivo bioequivalence (BE) may potentially be assured with a less expensive and more easily implemented in vitro dissolution test, ensuring the efficiency and quality of pharmaceutical products. The results of the current study improve the accuracy of provisional BCS classification by combining different permeability models.
In silico prediction of human oral bioavailability is a relevant tool for the selection of potential drug candidates and for the rejection of those molecules with less probability of success during ...the early stages of drug discovery and development. However, the high variability and complexity of oral bioavailability and the limited experimental data in the public domain have mainly restricted the development of reliable in silico models to predict this property from the chemical structure. In this study we present a KNIME automated workflow to predict human oral bioavailability of new drug and drug-like molecules based on five machine learning approaches combined into an ensemble model. The workflow is freely accessible and allows the quick and easy prediction of oral bioavailability for new molecules. Users do not require any knowledge or advanced experience in machine learning or statistical modeling to automatically obtain their predictions, increasing the potential use of the present proposal.
Abstract
Strategies for reversing graft failure (GF) after allogeneic stem cell transplant (SCT) depend on the options available in each situation. GF was reported in 16 Spanish institutions from ...January 2006 to July 2011. Primary GF was defined as an absolute neutrophil count (ANC) > 0.5 × 109/L not reached by day + 28 after SCT from peripheral blood (PB) or bone marrow (BM) progenitors and by day + 42 after SCT from unrelated cord blood (UCB) progenitors. Secondary GF was defined as a recurrent ANC < 0.5 × 109/L. Eighty-nine patients with GF were reported, and 80 patients received a second SCT. The 5-year survival probability was 31% (95% confidence interval CI: 18-44%), and the incidences of non-relapse mortality and relapse estimated by competing risks were 47% (95% CI: 36-58%) and 21% (95% CI: 4-28%). The strategy adopted to treat GF was heterogeneous, and no approach could be unequivocally recommended for this situation. The prognosis of patients with GF was poor even after successful recovery from GF.
Background
Accumulated evidence indicates that patients with lung cancer are a vulnerable population throughout the pandemic. Limited information is available in Latin America regarding the impact of ...the pandemic on medical care. The goal of this study was to describe the clinical and social effect of COVID‐19 on patients with thoracic cancer and to ascertain outcomes in those with a confirmed diagnosis.
Materials and Methods
This cohort study included patients with thoracic neoplasms within a single institution between March 1, 2020, and February 28, 2021. All variables of interest were extracted from electronic medical records. During this period, the Depression Anxiety and Stress Scale 21 (DASS‐2) was applied to evaluate and identify more common psychological disorders.
Results
The mean age for the total cohort (n = 548) was 61.5 ± 12.9 years; non‐small cell lung cancer was the most frequent neoplasm (86.9%), advanced stages predominated (80%), and most patients were under active therapy (82.8%). Any change in treatment was reported in 23.9% of patients, of which 78.6% were due to the COVID‐19 pandemic. Treatment delays (≥7 days) were the most frequent modifications in 41.9% of cases, followed by treatment suspension at 37.4%. Patients without treatment changes had a more prolonged progression‐free survival and overall survival (hazard ratio HR 0.21, p < .001 and HR 0.28, p < .001, respectively). The mean DASS‐21 score was 10.45 in 144 evaluated patients, with women being more affected than men (11.41 vs. 9.08, p < .001). Anxiety was reported in 30.5% of cases, followed by depression and distress in equal proportions (18%). Depressed and stressed patients had higher odds of experiencing delays in treatment than patients without depression (odds ratio OR 4.5, 95% confidence interval CI 1.53–13.23, p = .006 and OR 3.18, 95% CI 1.2–10.06, p = .006, respectively).
Conclusion
Treatment adjustments in patients with thoracic malignancies often occurred to avoid COVID‐19 contagion with detrimental effects on survival. Psychological disorders could have a role in adherence to the original treatment regimen.
Implications for Practice
The pandemic has placed an enormous strain on health care systems globally. Patients with thoracic cancers represent a vulnerable population, with increased morbidity and mortality rates. In Mexico, treatment modifications were common during the pandemic, and those who experienced delays had worse survival outcomes. Most treatment modifications were related to a patient decision rather than a lockdown of health care facilities in which mental health impairment plays an essential role. Moreover, the high case fatality rate highlights the importance of improving medical care access. Likewise, to develop strategies facing future threats that may compromise health care systems in non‐developed countries.
Patients with thoracic neoplasms, with cancer symptoms that can mimic those of COVID‐19, might suffer from misdiagnosis or diagnostic delays, leading to detrimental effects on prognosis. This article describes the clinical and social effect of COVID‐19 on patients with thoracic cancer and the outcomes in those with a confirmed diagnosis.
The main aim of this work is the biopharmaceutical characterization of a new hybrid benzodiazepine-dihydropyridine derivative, JM-20, derived with potent anti-ischemic and neuroprotective effects. In ...this study, the p
a and the pH-solubility profile were experimentally determined. Additionally, effective intestinal permeability was measured using three in vitro epithelial cell lines (MDCK, MDCK-MDR1 and Caco-2) and an in situ closed-loop intestinal perfusion technique. The results indicate that JM-20 is more soluble at acidic pH (9.18 ± 0.16); however, the Dose number (Do) was greater than 1, suggesting that it is a low-solubility compound. The permeability values obtained with in vitro cell lines as well as with the in situ perfusion method show that JM-20 is a highly permeable compound (Caco-2 value 3.8 × 10
). The presence of an absorption carrier-mediated transport mechanism was also demonstrated, as well as the efflux effect of P-glycoprotein on the permeability values. Finally, JM-20 was provisionally classified as class 2 according to the biopharmaceutical classification system (BCS) due to its high intestinal permeability and low solubility. The potential good oral absorption of this compound could be limited by its solubility.
During the early ADME profiling the development of simple, interpretable and reliable in silico tools is very important. In this study, rule‐based and QSPR approaches were investigated using a large ...Caco‐2 permeability database. Three permeability classes were determined: high (H), moderate (M) and low (L). The main physicochemical properties related with permeability were ranked as follows: Polar Surface Area (PSA)>Lipophilicity (logP/logD)>Molecular Weight (MW)>number of Hydrogen Bond donors and acceptors>Ionization State>number of Rotatable Bonds>number of Rings. The best rule, based on the combination of PSA‐MW‐logD (3PRule), was able to identify the H, M and L classes with accuracy of 72.2, 72.9 and 70.6 %, respectively. Subsequently, a consensus system based on three voting binary classification trees was constructed. It accurately predicted 78.4/76.1/79.1 % of H/M/L compounds on training and 78.6/71.1/77.6 % on test set. Finally, the 3PRule and multiclassifier were validated with 23 drugs in a Caco‐2 assay. The rule is very useful to improve assay design and prioritize the high absorption candidates. Meanwhile the QSPR model exhibits appropriate classification performance. Due to the simplicity, easy interpretation and accuracy, the 3PRule and consensus model developed here can be used in early ADME profiling.
Guanine-rich sequences found in telomeres and oncogene promoters have the ability to form G-quadruplex structures. In this paper we describe the use of a virtual screening assay to search a database ...of FDA-approved compounds for compounds with the potential to bind G-quadruplex DNA. More than 750 telomerase inhibitors were identified in a literature search as acting through G-quadruplex stabilization, and from evaluation of these compounds, theoretical models capable of discriminating new compounds that bind G-quadruplex DNA were developed. Six compounds predicted to bind to the G-quadruplex structure were tested for their ability to bind to the human telomeric DNA sequence. Prochloroperazine, promazine, and chlorpromazine stabilized the G-quadruplex structure as determined by fluorescence resonance energy transfer techniques. These compounds also bound to promoter sequences of oncogenes such as c-myc and K-ras. Amitriptyline, imipramine, and loxapine were less stabilizing but did bind to the G-quadruplex. The ability of prochloroperazine, promazine, and chlorpromazine to recognize G-quadruplex structures was confirmed using a fluorescent intercalator displacement assay, in which displacement of thiazole orange from G-quadruplex structures was demonstrated. Interestingly, these compounds exhibited selectivity for the G-quadruplex structure as all had poor affinity for the duplex sequence.
Pilot clinical trials have shown the safety of intra-arterial bone marrow mononuclear cells (BMMNCs) in stroke. However, the efficacy of different doses of intra-arterial BMMNCs in patients with ...acute stroke has not been tested in a randomised clinical trial. We aimed to show safety and efficacy of two different doses of autologous intra-arterial BMMNC transplantation in patients with acute stroke.
The IBIS trial was a multicentre phase 2, randomised, controlled, investigator-initiated, assessor-blinded, clinical trial, in four stroke centres in Spain. We included patients (aged 18–80 years) with a non-lacunar, middle cerebral artery ischaemic stroke within 1–7 days from stroke onset and with a National Institutes of Health Stroke Scale score of 6–20. We randomly assigned patients (2:1:1) with a computer-generated randomisation sequence to standard of care (control group) or intra-arterial injection of autologous BMMNCs at one of two different doses (2 × 106 BMMNCs/kg or 5 × 106 BMMNCs/kg). The primary efficacy outcome was the proportion of patients with modified Rankin Scale scores of 0–2 at 180 days in the intention-to-treat population, comparing each BMMNC dose group and the pooled BMMNC group versus the control group. The primary safety endpoint was the proportion of serious adverse events. This trial was registered at ClinicalTrials.gov, NCT02178657 and is completed.
Between April 1, 2015, and May 20, 2021, we assessed 114 patients for eligibility. We randomly assigned 77 (68%) patients: 38 (49%) to the control group, 20 (26%) to the low-dose BMMNC group, and 19 (25%) the high-dose BMMNC group. The mean age of participants was 62·4 years (SD 12·7), 46 (60%) were men, 31 (40%) were women, all were White, and 63 (82%) received thrombectomy. The median NIHSS score before randomisation was 12 (IQR 9–15), with intra-arterial BMMNC injection done a median of 6 days (4–7) after stroke onset. The primary efficacy outcome occurred in 14 (39%) patients in the control group versus ten (50%) in the low-dose group (adjusted odds ratio 2·08 95% CI 0·55–7·85; p=0·28), eight (44%) in the high-dose group (1·89 0·52–6·96; p=0·33), and 18 (47%) in the pooled BMMNC group (2·22 0·72–6·85; p=0·16). We found no differences in the proportion of patients who had adverse events or dose-related events, but two patients had a groin haematoma after cell injection in the low-dose BMMNC group.
Intra-arterial BMMNCs were safe in patients with acute ischaemic stroke, but we found no significant improvement at 180 days on the mRS. Further clinical trials are warranted to investigate whether improvements might be possible at different timepoints.
Instituto de Salud Carlos III co-funded by the European Regional Development Fund/European Social Fund, Mutua Madrileña, and the Regional Ministry of Health of Andalusia.
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