The association between acute kidney injury and outcomes in cancer patients receiving immune checkpoint inhibitor therapy: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICPIs) are a novel therapeutic approach to cancer treatment that have changed the landscape of cancer therapy but also have some considerable drawbacks. Acute kidney injury (AKI) is one of these potential complications that may have effects on patient outcomes. In this review, we assessed the effect of AKI on mortality outcomes in cancer patients receiving this immunotherapy. Methods: We performed a systematic review and meta-analysis of prospective, retrospective, randomized and non-randomized studies, which examined the effects of AKI in cancer patients receiving immune checkpoint inhibitors. We searched through PubMed, Medline, Web of Science, Scopus and Cochrane Library databases. Results: Seven studies were included in the final analysis, with a total number of patients of 761. Overall, the risk of death was higher in patients that developed AKI during ICPI treatment [hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.05-1.92, P = 0.02; heterogeneity χ2 = 11.68, I2 = 66%, P = 0.02] compared with patients that did not develop AKI. In addition, there was a trend to a better survival in those with less severe AKI patients compared with those with more severe AKI (HR 1.35, 95% CI 0.99-1.83, P = 0.05). Lastly, it was seen that patients with persistent kidney dysfunction (non-recovery) had an increased risk for all-cause mortality (HR 2.93, 95% CI 1.41-6.08, P = 0.004; heterogeneity χ2 = 0.53, I2 = 0%, P = 0.47). Conclusions: Development of AKI in patients with cancer receiving immune checkpoint inhibitors is associated with increased risk of mortality.

Non-thermal disruption of ß-adrenergic receptor-activated Ca2+ signalling and apoptosis in human ES-derived cardiomyocytes by microwave electric fields at 2.4 GHz.

The ubiquity of wireless electronic-device connectivity has seen microwaves emerge as one of the fastest growing forms of electromagnetic exposure. A growing evidence-base refutes the claim that wireless technologies pose no risk to human health at current safety levels designed to limit thermal (heating) effects. The potential impact of non-thermal effects of microwave exposure, especially in electrically-excitable tissues (e.g., heart), remains controversial. We exposed human embryonic stem-cell derived cardiomyocytes (CM), under baseline and beta-adrenergic receptor (ß-AR)-stimulated conditions, to microwaves at 2.4 GHz, a frequency used extensively in wireless communication (e.g., 4G, Bluetooth™ and WiFi). To control for any effect of sample heating, experiments were done in CM subjected to matched rates of direct heating or CM maintained at 37 °C. Detailed profiling of the temporal and amplitude features of Ca2+ signalling in CM under these experimental conditions was reconciled with the extent and spatial clustering of apoptosis. The data show that exposure of CM to 2.4 GHz EMF eliminated the normal Ca2+ signalling response to ß-AR stimulation and provoked spatially-clustered apoptosis. This is first evidence that non-thermal effects of 2.4 GHz microwaves might have profound effects on human CM function, responsiveness to activation, and survival.

UPLC-MS/MS method for the quantification of MCI-77, a novel sigma-1 receptor ligand, and its application to pharmacokinetic studies.

Sigma-1 receptors are involved in pain modulation, particularly in cases of nerve injury and neuropathic pain. High-affinity ligands with improved pharmacokinetic profiles are needed to further investigate the properties of these receptors and their potential as a therapeutic target. The novel compound MCI-77 is one such selective sigma-1 receptor ligand, and the purpose of this study was to characterize its preclinical pharmacokinetic parameters. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify MCI-77 in mouse plasma and brain homogenate. The method was validated for sensitivity, selectivity, linearity, accuracy, precision, stability, and dilution integrity. The method has a linearity range of 2-200 ng/mL, a short run-time of 3.2 min, and requires a low sample volume of 25 µL. A simple protein precipitation procedure was used for compound extraction. Samples were run on an Acquity UPLC BEH C18 column (1.7 µm, 2.1 × 50 mm) following a gradient elution method using a mobile phase consisting of water containing 0.1% (v/v) formic acid and acetonitrile. The method was applied to the analysis of plasma and brain homogenate samples from preclinical pharmacokinetic studies in CD-1 mice. MCI-77 exhibited high systemic clearance (8.5 ± 0.3 L/h/kg) and extensive tissue distribution indicated by a high volume of distribution (20.1 ± 0.3 L/kg). The concentration levels were consistently higher in brain samples than in plasma (brain/plasma AUC ratio 2.9), indicating its ability to cross the blood-brain barrier.

Pharmacokinetics of Eleven Kratom Alkaloids Following an Oral Dose of Either Traditional or Commercial Kratom Products in Rats.

Kratom, Mitragyna speciosa Korth., is being widely consumed in the United States for pain management and the reduction of opioid withdrawal symptoms. The central nervous system (CNS) active alkaloids of kratom, including mitragynine, 7-hydroxymitragynine, and numerous additional compounds, are believed to derive their effects through opioid receptor activity. There is no literature describing the systemic exposure of many of these alkaloids after the consumption of kratom. Therefore, we have developed and validated a bioanalytical method for the simultaneous quantitation of 11 kratom alkaloids (mitragynine, 7-hydroxymitragynine, corynantheidine, speciogynine, speciociliatine, paynantheine, corynoxine, corynoxine-B, mitraphylline, ajmalicine, and isospeciofoline) in rat plasma. The validated method was used to analyze oral pharmacokinetic study samples of lyophilized kratom tea (LKT) and a marketed product, OPMS liquid shot, in rats. Among the 11 alkaloids, only mitragynine, 7-hydroxymitragynine, speciociliatine, and corynantheidine showed systemic exposure 8 h postdose, and the dose-normalized systemic exposure of these four alkaloids was higher (1.6-2.4-fold) following the administration of the commercial OPMS liquid. Paynantheine and speciogynine levels were quantifiable up to 1 h postdose, whereas none of the other alkaloids were detected. In summary, the method was successfully applied to quantify the exposure of individual kratom alkaloids after an oral dose of traditional or commercial products. This information will contribute to understanding the role of each alkaloid in the overall pharmacology of kratom and elucidating the pharmacokinetic differences between traditional and commercial kratom products.

Application of survival classification and regression tree analysis for identification of subgroups of risk in patients with heart failure and reduced left ventricular ejection fraction.

The aim of this study was to identify by classification and regression tree (CART) analysis groups of patients with different survival patterns in a population of patients with heart failure and reduced left ventricular ejection fraction (HFrEF) by using standard methods of heart function assessment, as well as well as utilizing non-traditional approaches for determining hydration and nutritional status in HF patients-lung ultrasonography (LUS) and bioimpedance spectroscopy (BIS) analysis. Eligible patients with a left ventricular ejection fraction (LVEF) below 45% were identified via the daily echocardiography assessments. LUS was performed with patients in the supine position, for a total of 28 sites per complete examination. The hydration state and the body composition were assessed using a portable whole-body BIS device. Our study included 151 patients (69.2% males) with a mean age of 67.1 years. During the follow-up 53 (35.1%) patients died. Using the CART algorithm, we identified five groups based on serum sodium, the severity of NYHA class, serum urea and systolic blood pressure. When comparing the two models, the model derived from the CART analysis showed better predictive power than the conventional Cox model (c-index 0.790, 95% CI 0.723-0.857 vs. 0.736, 95%CI 0.664-0.807, p < 0.05). The application of CART analysis allowed us to identify different groups of risk for all-cause mortality in patients with HFrEF. The use of this type of modelling showed better prediction capabilities over that of using more conventional statistical approach.ClinicalTrials.gov Identifier: NCT02764073.

Preclinical pharmacokinetic study of speciociliatine, a kratom alkaloid, in rats using an UPLC-MS/MS method.

Speciociliatine is a minor indole alkaloid found in kratom, a southeast Asian medicinal plant, used for centuries to increase energy, enhance mood, and mitigate pain and opioid dependence. An ultra-performance liquid chromatography tandem mass spectrometry method was developed and validated to quantify speciociliatine in rat plasma. The quantitation range was 3-600 ng/mL. The validated method was applied to a preclinical pharmacokinetic study in male Sprague-Dawley rats after 2.5 mg/kg intravenous (I.V.) and 20 mg/kg oral (P.O.) dosing. The plasma was analyzed to obtain concentration-time profiles and results were subjected to non-compartmental analysis to determine pharmacokinetic parameters including volume of distribution (6.2 ± 2.3 L/kg I.V.), clearance (0.7 ± 0.2 L/hr/kg), and absolute oral bioavailability (20.7 %). Speciociliatine had higher systemic exposure and lower clearance compared to the other kratom alkaloids mitragynine and corynantheidine. The speciociliatine pharmacokinetic parameters described here will help to better understand the overall effects reported with kratom product use.

Bioanalytical method development and pharmacokinetics of MCI-92, a sigma-1 receptor ligand.

Sigma-1 receptors are found throughout the nervous system and play a role in regulating nociception. They are highly expressed in nerve injury, making them a potential target for the treatment of neuropathic pain. Although sigma-1 receptor antagonists have been shown to have anti-nociceptive and anti-allodynic effects, improved selectivity of these ligands is needed to further investigate their potential to treat neuropathic pain. MCI-92 is a novel, selective sigma-1 receptor ligand developed to address this need. A sensitive and rapid ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of MCI-92 in mouse plasma and brain homogenate. A structural analog of the analyte, MCI-147, was used as the internal standard (IS). The chromatographic separation was achieved on an Acquity UPLC BEH C18 column using a mobile phase consisting of water acidified with 0.1 % v/v formic acid and acetonitrile with gradient elution over 3.2 min. The method was linear over a concentration range of 1-200 ng/mL. Multiple reaction monitoring in the positive ionization mode was used for the mass spectrometric quantitation using m/z transitions 369.2 > 126.0 for MCI-92 and 448.9 > 350.1 for the IS. The method was successfully applied to the analysis of plasma and brain samples obtained in the course of oral and intravenous pharmacokinetic studies in CD-1 mice. MCI-92 showed a high volume of distribution (11.3 ± 0.6 L/kg) and rapid clearance (6.1 ± 0.8 L/h/kg) from systemic circulation. The concentration of the MCI-92 was higher in the brain than in plasma throughout all terminal time points, indicating high blood-to-brain partitioning and slow brain clearance.

Regulatory sampling of industrial hemp plant samples (Cannabis sativa L.) using UPLC-MS/MS method for detection and quantification of twelve cannabinoids.

BACKGROUND: In 2018, the Farm Bill mandated the United States Department of Agriculture to develop regulations governing the cultivation, processing, and marketing of industrial hemp. Industrial hemp is defined as Cannabis sativa L. with a total Δ-9-tetrahydrocannabinol (Δ-9-THC) content ≤0.3%. Therefore, for hemp to become an agricultural commodity, it is important to regulate production by developing standard methods for sampling and testing of the plant material. METHODS: An ultra-performance liquid chromatography-tandem mass spectrometry analytical method for the quantification of twelve cannabinoids was developed. The method was applied to a regulatory sampling trial of three hemp varieties cultivated for cannabidiol (CBD) production. Two samples were taken from 28 plants with one sample being flower only while the other was a composite sample that included flowers, leaves, and stems. RESULTS: The assay method was validated for specificity, range, repeatability, reproducibility, and recovery in accordance with all applicable standards for analytical methods. The results of the regulatory study indicated a significant decrease in the concentration of total Δ-9-THC and total CBD of 0.09% and 1.32%, respectively, between a flower only and a composite sample. CONCLUSIONS: There are many factors that may influence reported total Δ-9-THC content in industrial hemp. A robust analytical method was developed to analyze hemp samples in a trial regulatory study. The results indicate that the way hemp is sampled and analyzed may influence the legality of a crop, which could have negative economic and legal consequences.

Bioanalytical method development and validation of corynantheidine, a kratom alkaloid, using UPLC-MS/MS, and its application to preclinical pharmacokinetic studies.

Corynantheidine, a minor alkaloid found in Mitragyna speciosa (Korth.) Havil, has been shown to bind to opioid receptors and act as a functional opioid antagonist, but its unique contribution to the overall properties of kratom remains relatively unexplored. The first validated bioanalytical method for the quantification of corynantheidine in rat plasma is described. The method was linear in the dynamic range from 1-500 ng/mL, requires a small plasma sample volume (25 µL), and a simple protein precipitation method for extraction of the analyte. The separation was achieved with Waters BEH C18 2.1 × 50 mm column and the 3-minute gradient of 10 mM ammonium acetate buffer (pH = 3.5) and acetonitrile as mobile phase. The method was validated in terms of accuracy, precision, selectivity, sensitivity, recovery, stability, and dilution integrity. It was applied to the analysis of the male Sprague Dawley rat plasma samples obtained during pharmacokinetic studies of corynantheidine administered both intravenously (I.V.) and orally (P.O.) (2.5 mg/kg and 20 mg/kg, respectively). The non-compartmental analysis performed in Certara Phoenix® yielded the following parameters: clearance 884.1 ±â€¯32.3 mL/h, apparent volume of distribution 8.0 ±â€¯1.2 L, exposure up to the last measured time point 640.3 ±â€¯24.0 h*ng/mL, and a mean residence time of 3.0 ±â€¯0.2 h with I.V. dose. The maximum observed concentration after a P.O. dose of 213.4 ±â€¯40.4 ng/mL was detected at 4.1 ±â€¯1.3 h with a mean residence time of 8.8 ±â€¯1.8 h. Absolute oral bioavailability was 49.9 ±â€¯16.4 %. Corynantheidine demonstrated adequate oral bioavailability, prolonged absorption and exposure, and an extensive extravascular distribution. In addition, imaging mass spectrometry analysis of the brain tissue was performed to evaluate the distribution of the compound in the brain. Corynantheidine was detected in the corpus callosum and some regions of the hippocampus.

Frames in contestation: gendering domestic violence policies in five central and eastern European countries.

The article looks at the translation of international norms on domestic violence to the national level in five Central and Eastern European countries. It argues that translation brings a concept of domestic violence, which stretches gender equality ideas underpinning international norms so as to be easier to endorse by mainstream policy actors, and results in policies framed in degendered individual rights terms. The potential for keeping gender equality in focus is then guaranteed by gendering policy processes through empowerment of gender equality actors at all stages. Absence of ownership of the policy by gender equality actors risks co-optation by frames contesting gender equality.

Changes in the histological spectrum of glomerular diseases in the past 16 years in the North-Eastern region of Romania.

BACKGROUND: The aim of this study was to describe the findings of renal biopsies from a large nephrology center in Iasi, Romania, performed between 2005 and 2010. We compared these findings with our previous ones, from 1995 to 2004, as well as with similar reports. METHODS: We studied retrospectively 239 renal biopsies. The indications for renal biopsy were categorized into: nephrotic syndrome, acute nephritic syndrome, asymptomatic urinary abnormalities, acute kidney injury, and chronic kidney disease of unknown etiology. RESULTS: During the past 16 years, a gradual increase in the annual number of renal biopsies/per million population (p.m.p.)/year was observed, although this incidence remained lower than in other European countries. Nephrotic syndrome was the indication for renal biopsy in over 50% of cases. Glomerulonephritis (GN) was the main histological diagnosis in 91% of cases, of which 56% were primary GN and 35% were secondary GN. The frequency of various types of primary GN was: membranoproliferative GN (MPGN) - 29.3%, membranous nephropathy (MN) -27.5%, focal segmental glomerulosclerosis (FSGS) - 17.2%, mesangial GN (including IgAN) -13.7%, crescentic GN - 9.4%, and minimal change disease (MCD) - 2.5%. Compared to the previously reported period (1994-2004), we observed a significant decrease in the frequency of MPGN and significant increases in the frequency of FSGS and, particularly MN - which more than doubled. CONCLUSION: We report significant changes in the histological spectrum of GN in North-Eastern Romania in 2005-2010, compared to the previously reported 10-yrs. These changes seem to be following a trend that has also been observed in Western countries a few decades ago, and which may have a socioeconomic explanation.

Europeanization in making policies against domestic violence in Central and Eastern Europe.

This article looks at how Europe matters in the development of policies against domestic violence, a gender equality field outside the core European Union (EU) conditionality criteria. By analyzing the concrete workings and uses of Europe's domestic violence policy-making in five Central and Eastern European countries, it identifies three mechanisms of Europeanization in the field and shows how together they work to expand the reach of the EU to this policy realm. The findings point toward an understanding of Europeanization based on social learning and dynamic, interactive processes of constructing what membership in the EU means in terms of domestic violence policy processes.

Entrance effects at nanopores of nanocapsules functionalized with poly(ethylene glycol) and their flow through nanochannels.

We studied the effect of poly(ethylene glycol) (PEG) on the extrusion of large, multilamellar nanocapsules (also called liposomes or vesicles) through nanochannels with a length of 6 microm. For the generation of the nanocapsules, we used a lipid mixture with lecithin consisting of saturated and unsaturated fatty acids (dipalmitoylphosphatidylcholine (DPPC) and dioleoylphosphatidylcholine (DOPC)), cholesterol, and 2-8 mol % PEG linked to a lipid anchor (distearoylphosphatidylethanolamine (DSPE)) or the plain lipid anchor without PEG. An increase in PEG leads to a decrease of the critical tension for nanocapsule rupture (lysis tension) between 20-30%, whereas the pure lipid anchor does not produce any differences. We interpret these findings to be produced by a partial intrusion of the polymeric chain into the phospholipid bilayer of the nanocapsule which weakens its tensile strength. We evaluate statistically the discrepancies of lysis tensions found for different channels widths (50-100 nm) and two or four channels in series. Comparing our results on the flow resistance of either nanocapsules or pure water with lubrication theory, we find that the calculated viscous forces are not sufficient to account for the measured friction of nanocapsules. This shows that the nanocapsules are decelerated in the nanochannels by van der Waals interactions between channel and capsule walls and the intermediate water layer. The strength of these forces is 24 times higher for PEG and 94 times higher for the pure lipid anchor than the respective calculated viscous forces alone, showing that nanocapsule flow in nanochannels cannot be considered under the classical continuum assumption of the intermediate water layer.