Die Rolle des mTOR2-Komplexes bei der Regulation der Natrium- und Kaliumausscheidung im distalen Tubulus der Niere

Der mTOR-Signalweg spielt eine grundlegende Rolle bei der Regulation von zellulären Homöostasemechanismen. Die bisher vorliegenden Daten beziehen sich in erster Linie auf den mTORC1, während der mTORC2 und im Speziellen seine nierenspezifische in-vivo-Funktion relativ unerforscht ist. In-vitro-Experimente mit immortalisierten Nierenepithelzellen deuteten auf eine Beteiligung von mTORC2 bei der Regulation des epithelialen Natriumkanals ENaC durch Phosphorylierung der SGK1 hin. Um die in-vivo-Relevanz dieser in-vitro-Befunde zu erforschen, generierten wir mTORC2-Knockout-Mäuse, bei denen dieser Komplex durch Entfernung des Rictor-Gens im distalen Tubulus der Niere ausgeschaltet wurde. Diese Rictorfl/fl*KspCre-Mäuse (mTORC2-Knockout) waren lebensfähig und zeigten unter Kontrollbedingungen keinerlei phänotypische Auffälligkeiten. Bei Gabe einer Niedrigsalz/Normalkalium-Diät waren die Rictorfl/fl*KspCre -Tiere wie auch die Wildtyp-Tiere, in der Lage ihre Na+-Ausscheidung über den Urin adäquat zu drosseln, während die Gabe einer NS/HK-Diät zu einer moderaten Hyperkaliämie bei den Rictorfl/fl*KspCre -Tieren führte. Die Behandlung mit einer Niedrigsalz/Hochkalium-Diät führte bei den mTORC2-Knockout-Mäusen zu einem fulminantem Gewichtsverlust, einer Hyperkaliämie und einem akuten Nierenversagen innerhalb von vier Tagen. Derselbe Phänotyp konnte nach kontinuierlicher Behandlung mit dem ENaC-Blocker Triamteren beobachtet werden. Immunfluoreszenzmikroskopisch konnte bei den Rictorfl/fl*KspCre-Tieren eine nicht vorhandene Phosphorylierung der SGK1 (an Ser422), PKCα (an Thr657) und Akt (Ser493) nachgewiesen werden. Diese Erkenntnisse bestätigen die lebensnotwendige Rolle von mTORC2 bei der aldosteronvermittelten, distal-tubulären Regulation des Na+- und K+-Haushalts unter klinisch relevanten Bedingungen. Hierbei spielt mTORC2 eine entscheidende Rolle bei der K+-Sekretion unter salzarmen bzw. Salzverlust-Bedingungen

mTORC2 critically regulates renal potassium handling

The mTOR pathway orchestrates cellular homeostasis. The rapamycin-sensitive mTOR complex (mTORC1) in the kidney has been widely studied; however, mTORC2 function in renal tubules is poorly characterized. Here, we generated mice lacking mTORC2 in the distal tubule (Rictorfl/fl Ksp-Cre mice), which were viable and had no obvious phenotype, except for a 2.5-fold increase in plasma aldosterone. Challenged with a low-Na+ diet, these mice adequately reduced Na+ excretion; however, Rictorfl/fl Ksp-Cre mice rapidly developed hyperkalemia on a high-K+ diet, despite a 10-fold increase in serum aldosterone levels, implying that mTORC2 regulates kaliuresis. Phosphorylation of serum- and glucocorticoid-inducible kinase 1 (SGK1) and PKC-α was absent in Rictorfl/fl Ksp-Cre mice, indicating a functional block in K+ secretion activation via ROMK channels. Indeed, patch-clamp experiments on split-open tubular segments from the transition zone of the late connecting tubule and early cortical collecting duct demonstrated that Ba2+-sensitive apical K+ currents were barely detectable in the majority of Rictorfl/fl Ksp-Cre mice. Conversely, epithelial sodium channel (ENaC) activity was largely preserved, suggesting that the reduced ability to maintain K+ homeostasis is the result of impaired apical K+ conductance and not a reduced electrical driving force for K+ secretion. Thus, these data unravel a vital and nonredundant role of mTORC2 for distal tubular K+ handling

Protocol of the IntenSify-Trial:An open-label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab-paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy

Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab-paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab-paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab-paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2) and cobicistat (150 mg) are fixed, three dose levels of nab-paclitaxel (75, 100, and 125 mg/m2) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT-Nr. 2019-001439-29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab-paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large-scale clinical study.</p

Inference for the Unit-Gompertz distribution based on record data

Practically record values are applied in situations concerning meteorology, hydrology, and sports events. A keen interest of a sports statistician may be to predict the future record value for a specific event. There are practical situations in which the record values from the available data are lost due to specific reasons. This need for record values stimulates us to construct the probability model that predicts the future record value and provides an estimation procedure in case of censored data. In the present study, the mechanism of sample moments of lower record values using the Type-II censoring is developed by assuming that the record characteristics follow the Unit Gompertz distribution. Utilizing this mechanism, the moments of lower record values are evaluated and tabulated for the specific values of the parameters. These tabulated values are applied to estimate the location and scale parameters of the underlying distribution by the method of ordered least squares. Furthermore, the point prediction and prediction interval for future record values are produced. Finally, the methodology is applied to real-life data to explain the procedure as well as show the effectiveness of forecasting out-of-sample data through the samplemoments of the lower record values, depending on the characteristicparameters of the Unit Gompertz distribution

Vagueness in Communication: A Corpus Driven Study of Academic Discourse

The present research paper aims to analyze one of the most frequently used vague words, namely "thing," as employed by Pakistani students in their undergraduate assignments and essays. The data was collected from the Pakistan National Corpus of English (PNCE) and analyzed using the Antconc corpus software. The objective is to determine whether the word "thing" is utilized as a vague noun, for meta-discourse, or in any other capacity in order to understand how effectively Pakistani students communicate. This study yields several conclusions, with the primary one being that the word "thing" is consistently employed both in a discussive and non-discussive manner. It often serves as a placeholder for various objects, which are subsequently elucidated in preceding or subsequent statements by the students. The frequent use of this word also lends legitimacy to its usage by Pakistani students. However, it is important to note that the recurrent use of the word "thing" poses a risk of creating confusion in written work due to its repetitive nature

Socioeconomic and geographical inequalities in delivery by cesarean section among women in Bangladesh, 2004–2017

Abstract Background There is a dearth of evidence on the trends and inequalities in utilizing cesarean section (CS) among women in Bangladesh. Hence, this study aimed to estimate the socioeconomic and geographical inequalities in delivery by CS among Bangladeshi women from 2004 to 2017. Methods Data from Bangladesh Demographic and Health Survey 2004, 2007, 2011, 2014, and 2017 were analyzed using the WHO’s Health Equity Assessment Toolkit (HEAT) software. Inequalities were measured using four summary measures: Difference (D), Population Attributable Risk (PAR), Population Attributable Fraction (PAF), and Ratio (R). Socioeconomic inequalities were assessed using two equity dimensions: household wealth status, and level of education, while geographical disparities were measured using two equity dimensions: place of residence, and sub-national regions. For each measure, point estimates and their 95% confidence intervals were reported. Results An increasing trend in the prevalence (weighted) of CS in Bangladesh use was found from 4.50% in 2004 to 32.73% in 2017 We found significant socioeconomic inequalities in CS in every survey point, with a higher concentration of CS among the rich (in 2017, PAR = 28.57; 95% CI: 26.69–30.46) indicating a pro-rich inequality, and higher educated (in 2017, PAF = 23.97; 95% CI: 12.26–35.68) sub-groups. We also identified significant geographical disparities in CS with a higher concentration of CS among people from urban areas (in 2017, PAR = 10.99; 95% CI: 10.19–11.79), and a coastal region (Khulna division) (in 2017, PAF: 30.48 (95% CI: 18.66–42.30). Conclusion We observed both socioeconomic and geographical inequalities in CS exist in Bangladesh, though the trends of these inequalities were curved over time. Thus, it is important to comprehend these pro-rich and geographical inequalities better and implement appropriate interventions and policies to alleviate them