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Biological properties of circRNA_015350/006696 in neurons and astrocytes under hypoxic conditions
No full textDie circRNAs sind eine Gruppe der nicht-kodierenden RNAs, die erst vor kurzem entdeckt wurde. Viele der biologischen Funktionen von circRNAs sind noch nicht vollständig bekannt. Derzeit wird angenommen, dass circRNAs unter anderem als miRNA-Schwamm, RNA-binding protein (RBP)-Schwamm, Transkriptionsregulatoren oder als Translationsvorlagen fungieren können. Zudem wurden circRNAs in allen Arten von Zellen nachgewiesen und sind an vielen physiologischen und pathophysiologischen Prozessen beteiligt.
Man kann daher vermuten, dass circRNAs auch am ischämischen Schlaganfall beteiligt sind. Suresh L. Mehta und seine Kollegen entdeckten, dass sich Expressionsmuster von circRNAs im Gehirn von Mäusen nach einer transienten fokalen Ischämie signifikant veränderten und identifizierten sechs vielversprechende circRNA-Kandidaten. Die circRNAs circ_008018, circ_015350 und circ_016128 werden in diesem Kontext hochreguliert, während circ_011137, circ_001729 und circ_006696 herunterreguliert werden. Die Expressionsniveaus dieser circRNAs in bestimmten Zelltypen sind jedoch bislang noch nicht untersucht worden, insbesondere auch nicht die Interaktion zwischen bestimmten Zelltypen in Bezug auf die circRNA-Expression.
In der hier vorliegenden Arbeit wurden die Expressionsniveaus von zweien dieser circRNAs in Neuronen und Astrozyten untersucht, nämlich circ_015350 und circ_006696. Unter hypoxischen Bedingungen veränderten sich die Expressionsniveaus der circRNAs in den verschiedenen Zelltypen unterschiedlich: circ-15350 wurde hochregruliert, wohingegen circ_006696 herunterreguliert wurde. Es ist daher anzunehmen, dass circ_015350 und circ_006696 möglicherweise eine wichtige Rolle im Rahmen der Resistenz gegenüber hypoxischen Noxen für diese Zelltypen sein könnten. Vor dem Hintergrund der „Schwammfunktion“ von solchen circRNAs wurde im weiteren Verlauf dieser Arbeit eine Interaktion mit ausgewählten miRNAs postuliert. Nach Analyse der Datenbank „miRDB“ konnten FISH-Experimente eine Co-Lokalisation von circ_015350 mit miR-27b-3p und miR-27a-3p bzw. von circ_006696 mit miR-145-5P bestätigen. Die hier vorliegenden Ergebnisse unterstützen daher die Hypothese, dass circ_015350 bzw. circ_006696 vielversprechende Kandidaten für zukünftige Therapieansätze beim ischämischen Schlaganfall sein könnten.CircRNAs are a group of non-coding RNAs that have only recently been discovered. Many of the biological functions of circRNAs are not yet fully understood. It is currently assumed that circRNAs can act as miRNA sponges, RNA-binding protein (RBP) sponges, transcriptional regulators or translation templates, among other things. In addition, circRNAs have been detected in all types of cells and are involved in many physiological and pathophysiological processes.
It can therefore be assumed that circRNAs are also involved in ischaemic stroke. Suresh L. Mehta and his colleagues discovered that expression patterns of circRNAs in the brain of mice changed significantly after transient focal ischaemia and identified six promising circRNA candidates. The circRNAs circ_008018, circ_015350 and circ_016128 are upregulated in this context, while circ_011137, circ_001729 and circ_006696 are downregulated. However, the expression levels of these circRNAs in certain cell types have not yet been investigated, nor has the interaction between certain cell types in terms of circRNA expression.
In the present work, the expression levels of two of these circRNAs in neurons and astrocytes were investigated, namely circ_015350 and circ_006696. Under hypoxic conditions, the expression levels of the circRNAs in the different cell types changed differently: circ_015350 was upregulated, whereas circ_006696 was downregulated. It can therefore be assumed that circ_015350 and circ_006696 could potentially play an important role in the resistance to hypoxic noxious agents for these cell types. In view of the ‘sponge function’ of such circRNAs, an interaction with selected miRNAs was postulated in the further course of this work. After analysing the ‘miRDB’ database, FISH experiments were able to confirm a co-localisation of circ_015350 with miR-27b-3p and miR-27a-3p and of circ_006696 with miR-145-5P. The results presented here therefore support the hypothesis that circ_015350 and circ_006696 could be promising candidates for future therapeutic approaches for ischaemic stroke.2025-01-0
Role of FOXM1, GPX1, and CCNB1 in cisplatin resistance in malignant thymomas and thymic carcinomas
Get PDFCisplatin resistance in malignant thymomas and thymic carcinomas remains a significant challenge, impairing therapeutic efficacy and patient outcomes. This study investigates the roles of Glutathione Peroxidase 1 (GPX1), Forkhead Box Protein M1 (FOXM1), and Cyclin B1 (CCNB1) in conferring cisplatin resistance within thymic epithelial tumors. We find these proteins FOXM1, GPX1, and CCNB1 as potential regulators in resistance mechanisms. GPX1 mitigates oxidative stress through ROS regulation, FOXM1 facilitates DNA repair and modulates cell cycle progression, and CCNB1 regulates mitotic transitions critical for cell survival under chemotherapeutic pressure. Our findings show the molecular pathways under cisplatin resistance, providing insights into potential biomarkers and therapeutic targets for combating drug resistance in thymic cancers. These discoveries hold promise for advancing precision oncology approaches in the treatment of refractory thymic epithelial malignancies.2025-01-1
The dual role of MTG3 during human mitoribosome biogenesis
No full textMitochondria are the main energy provider of the cell, and because of the endosymbiotic event they arise from, still contain a small independent genome. Only with the vast ATP production through the mitochondrial OXPHOS system, the eukaryotic cell is able to satisfy its enormous energy demand, which is reflected by severe mitochondrial diseases caused by a defective OXPHOS system. Mitochondriopathies are not only caused by dysfunctional OXPHOS subunits, but can also be evoked by an improperly working mitochondrial gene expression machinery, as essential OXPHOS subunits are encoded by the mitochondrial genome. Thus, it is of high importance for the cell to guarantee mitochondrial homeostasis, as well as the efficient operation of the gene expression system, including the mitochondrial ribosome (mitoribosome).
Mitoribosome biogenesis is a complex process, as mitoribosomes consist of components from dual-genetic origin. All mitoribosomal proteins (MRPs) are encoded in the nucleus, synthesized in the cytosol and2025-10-2
Designing politically feasible policies to enhance healthy and sustainable diets – empirical insights.
Get PDFThe adoption of nutrition policy measures to promote healthy and sustainable diets has lagged behind the health, environmental, social, and economic arguments to invest. In recognition of the fact that a lack of political feasibility – I.e., acceptance of a policy solution by a set of decision-makers and the general public – constitutes a key barrier to adoption, this doctoral thesis focuses on generating insights to mitigate this barrier for various promising policy measures. The dissertation consists of four independent research papers and is divided into five parts.
Following CHAPTER 1, which situates the rationale for the undertaking of the dissertation, delineates key theoretical concepts, and presents the various study contexts and objectives, CHAPTER 2 focuses on political feasibility with regard to the adoption of policy ‘packages’ for tackling unhealthy diets. The focus on policy packages, which refers to a suite of policy measures simultaneously adopted to address multi-faceted drivers of dietary behaviors, is situated in the reality that integrated policies are needed – as well as recommended by scientific experts – to realize meaningful shifts in population-level dietary patterns. This section is divided into two papers. The former examines public support for policy packages, with the understanding that it is a key element of political feasibility in liberal democracies in which policymakers must navigate acting in the public interest while maintaining public favor for re-election. Drawing on insights from a conjoint experiment conducted amongst eligible German voters, this study examines how policy packages to tackle unhealthy food environments might be optimally designed and communicated to foster public support. It also examines key individual drivers of support (or lack thereof) for policy packages amongst voters, including various socio-demographic and attitudinal variables that have been shown to influence support for individual nutrition policy measures. The latter paper pivots from a hypothetical policy package to a ‘real-world’ one, focusing on the Promotion of Healthy Eating law adopted in Argentina in 2021, which jointly introduced (1) mandatory front-of-package warning labels on ultra-processed foods (UPFs), (2) restrictions on child-directed marketing of UPFs, and (3) improvements to school food environments, including banning the sale or offering of UPFs and investing in improvements to nutrition education. Drawing on semi-structured interviews with advocates who worked to advance the law through the policy process, this paper gleans key strategies to elevate the political feasibility of a nutrition policy package, particularly in the face of corporate attempts to undermine it.
CHAPTER 3 turns to consider political feasibility in the context of another rapidly growing policy sphere for promoting healthy and sustainable diets – nudging. Once again, it is divided into two papers. The former turns once again to the issue of public support. Namely, drawing on insights gleaned from an online experiment conducted amongst eligible German voters, this study examines opportunities to tinker with the design of nudges aiming to shift behaviors towards healthier and/or more sustainable dietary choices to increase support. This study focuses specifically on default nudges to promote healthy and/or sustainable food choices, which are particularly promising with regard to anticipated effectiveness, but tend to garner the least public support amongst nudging strategies. As in the first paper of CHAPTER 2, this study also examines key drivers of support (or lack thereof) amongst voters, including socio-demographic and attitudinal variables. The second paper hones in on the issue of autonomy, which is key to the acceptance amongst both decision-makers and the public of the legitimacy of nudge strategies. Drawing on a scoping review of food choice nudge studies, this paper introduces a typology of three mechanisms that, when not considered, could unduly intrude upon autonomy: (1) the effort to opt-out, delineated along economic and physical sub-dimensions; (2) affective influence, such as social reference messaging and emotional appeals; and (3) non-transparency, including of the nudge itself and of non-nudged alternative options. This typology can support choice architects to discern how nudges might better protect consumer autonomy, and ultimately better uphold it in pursuit of behavior change.
Finally, CHAPTER 4 synthesizes insights from across all four papers into a final discussion and outlook, followed by APPENDICES.2025-01-1
Structural basis of human mitochondrial RNA processing
Get PDFMitochondrial transcription produces polycistronic transcripts, in which ribosomal RNA (rRNA) and messenger RNA (mRNA) regions are interspersed with transfer RNA (tRNA) sequences. Endonucleolytic cleavages at the 5' and 3' ends of tRNA sequences in polycistronic transcripts are the first critical post-transcriptional steps in mitochondrial gene expression, essential for the release of all functional rRNA, mRNA, and tRNA species. Mitochondrial tRNA 5’ processing is catalyzed by the mitochondrial RNase P (mt-RNase P) complex composed of an endonuclease subunit, PRORP, and two auxiliary subunits forming a tRNA methyltransferase subcomplex, TRMT10C and SDR5C1. As a multi-subunit protein-only RNase P, the human mt-RNase P complex is distinct from the ubiquitous ribonucleoprotein RNase Ps or single-subunit protein-only RNase Ps. The 3’ processing of both mitochondrial and nuclear tRNAs is catalyzed by a common RNase Z enzyme, ELAC2. Recent evidence indicates that ELAC2 may also depend on TRMT10C and SDR5C1 specifically for mitochondrial tRNA processing. Thus, mitochondrial RNases P and Z appear to be compositionally atypical multimeric enzymes, and the molecular underpinnings of their function are not well understood.
This dissertation focuses on structural and mechanistic characterization of human mt-RNase P and Z complexes. First, to understand how mt-RNase P complex carries out tRNA 5’ processing and what role TRMT10C and SDR5C1 play therein, we determined a cryo-electron microscopy structure of human mt-RNase P bound to precursor tRNA. The structure reveals that the subunits TRMT10C and SDR5C1 form a subcomplex that recognizes tRNAs via a sequence-independent mechanism, enabling the recognition of structurally diverse mt-tRNAs. Binding to TRMT10C–SDR5C1 subcomplex distorts the tRNA structure and positions the 9th nucleobase in the methyltransferase active site. The endonuclease PRORP is recruited via interactions with TRMT10C, which stabilize PRORP in an active conformation and ensure precise cleavage at the 5' end of the pre-tRNA. Subsequently, we investigated the mechanism of tRNA 3’ processing and the role of TRMT10C and SDR5C1 in this process through a combination of structural and biochemical studies. We found that TRMT10C and SDR5C1 are specifically required for processing of mt-tRNAs lacking the canonical elbow regions. ELAC2 recognizes nuclear and mitochondrial tRNAs with canonical elbows via direct interactions with the conserved elbow elements. By contrast, most mt-tRNAs, which lack a canonical elbow, depend on compensatory protein-protein interactions between ELAC2 and TRMT10C for processing. Together, these results elucidate the structural and mechanistic basis of the mitochondrial tRNA 5’ and 3’ processing, provide catalytic insights into tRNA-R9 methylation and explain the role of TRMT10C and SDR5C1 in mt-tRNA processing. Furthermore, they highlight the role of TRMT10C–SDR5C1 complex as a general mt-tRNA maturation platform that functions as a mitochondrial tRNA ‘prosthesis’, stabilizing the tertiary fold of mt-tRNAs and compensating for the absence of conserved structural features otherwise necessary for their recognition. This work represents an important milestone towards a complete structural understanding of mitochondrial gene expression and provides a framework for future studies aimed at achieving this goal.2024-12-2
The influence of Raloxifene and Ostarine as a combination therapy of estrogen and androgen receptor modulators on the bone properties of ovariectomised rats
No full textThis study combined two pharmacological classes to investigate their preventive effect on the skeletal system of ovariectomised rats. The osteoanabolic properties of SARM Ostarine and the antiresorptive effect of SERM Raloxifene were examined. They are considered to be a relatively non-toxic alternative to hormone replacement therapy with androgen or oestrogen, with comparable osteoprotective effects. The surgical ovariectomy of three-month-old Sprague Dawley rats results in comparable osteoporotic alterations to those observed in postmenopausal women. A total of 75 animals were subjected to oophorectomy, with 60 of them being divided into four groups. The 15 animals that had not undergone ovariectomy constituted the control group (NON-OVX). The 60 ovariectomised rats were divided into four groups: one group of 15 rats was not subjected to any medication (OVX), while the remaining 45 rats were treated with one of the following three medications: Ostarine (OSTA), Raloxifene (RALO), or a combination of both (OSTA+RALO). The remaining 45 ovariectomised animals were treated with Ostarine (OSTA), Raloxifene (RALO), or a combination of both (OSTA+RALO), with 15 rats in each group. The dosage of the active ingredient Ostarine was 0.4 mg/kg/day, while Raloxifen was administered at a dosage of 8 mg/kg/day. For the combination therapy, the two doses were combined and administered via soya-free feed. Following a 13-week treatment period, the animals were killed, their femora and lumbar vertebrae IV were prepared and their uteri were removed. Additionally, serum samples were collected and analysed for calcium, magnesium, phosphorus, alkaline phosphatase (AP), osteocalcin (OC) and CTX-I levels. The caput femoris and corpus vertebrae were measured using Micro-CT. The mechanical resilience of the bones was evaluated through a biomechanical assessment. Subsequently, the bones were subjected to ashing to determine their organic and inorganic composition, and the femora were examined for their calcium, magnesium, and phosphate content.
Monotherapy with Ostarine resulted in an improvement in certain bone characteristics. An increase was observed in the volumetric parameters as determined by Micro-CT, as well as in the maximum force of the femur as measured by the biomechanical test. The analysis of the serum revealed a significant increase in bone resorption (CTX-I) in the OVX group, accompanied by a notable elevation in biomarkers of bone formation and mineralisation (AP and OC). Similarly, the results of the analysis and additional parameters indicated that the moderate osteoanabole effect of Ostarine was insufficient to prevent bone loss resulting from oestrogen deficiency.
The monotherapy with Raloxifene resulted in a significant reduction in osteoporotic changes in comparison to the OVX group. The Micro-CT analysis revealed an increase in bone mineral density (BMD) of the vertebrae and the majority of the spongiosa parameters of both bones. The biomechanical test revealed an increase in the maximum force and elasticity of the femur. In the ashing, Raloxifene was observed to maintain the inorganic composition and calcium content of the femur at a higher level in comparison to the OVX group. The serum analysis demonstrateted that the anti-resorptive mechanism counteracted the osteoporotic changes. Additionally, a significant reduction in the consequences of estrogen deficiency on body weight and feed intake was observed in comparison to the OVX group.
The combination therapy comprising Ostarine and Raloxifene demonstrated the most pronounced therapeutic efficacy across all outcomes. The combined effect of the SARM and SERM resulted in a significant improvement in both bones when compared to the ovariecto- mised control group. The Micro-CT results demonstrated an increase in bone mineral density (BMD) in the femur and vertebrae, accompanied by a notable improvement in nearly all spongiosa parameters. The biomechanical test revealed an increase in maximum force for both bones, as well as an improvement in the elasticity of the femur. The combination therapy was observed to maintain the inorganic composition of the bone ash. The analysis of the serum revealed clear indications of the synergistic effect of osteoanabolic and antiresorptive actions on turnover. The resorption of bone (CTX-I) was significantly inhibited, while the formation and mineralisation (AP and OC) were increased. It was observed that the minimisation of the negative effects associated with oestrogen deficiency on weight gain and food intake was achieved.
Significant increases in uterine weight were observed in the OSTA and OSTA+RALO groups. It would be advisable to examine this relationship in conjunction with the growth of malignant cells, taking into account the stimulation of uterine androgen receptors. This also applies to the serum phosphorus concentration of the Ostarine treated groups in the context of calcifica- tions. Additionally, an increase in the magnesium content of the femora was observed in the OSTA group.
These adverse effects suggest that the combination therapy of SARM and SERM is only partially effective in preventing the onset and progression of osteoporotic changes. The combination of osteoanabolic and antiresorptive effects resulted in notable therapeutic outcomes in both bone tissues. However, these outcomes are negated when considering the increased uterus weight observed in the Ostarine-treated groups.2025-01-1
Reductive Small Molecule Transformations with Pyrazolate-Based Bimetallic Complexes
No full textThe activation of small molecules (NO, O2, CO, CO2, N2, etc.) is important in a multitude of fields such as biology, medicine and industrial catalysis. Many synthetic catalysts were inspired by the active sites of metalloenzymes, where the synergy between metals can be beneficial for small molecule activation. A series of new complexes supported by a pyrazolate bridged bis-β-diketiminate ligand scaffolds were synthesized to combine the efficiency of the nacnac framework with the cooperativity of bimetallic systems for small molecule activation.
The focus is initially dedicated to the activation of N2 in relation to the redox chemistry of a dinickel(II) dihydride complex and a dinickel(I) complex. The reactivity towards CO of a dinickel(II) complex which features an intramolecular Ni–C bond and agostic interactions and of a dinickel(II) μ-OH complex is subsequently investigated.2025-01-3
Molekulare und elektrophysiologische Untersuchung der Exozytose in der Maus-Cochlea
Get PDFDie Bändersynapsen von cochleären inneren Haarzellen sind hochspezialisiert, um äußerst
präzise und mit höchster Geschwindigkeit eintreffende akustische Signale in einen
neuronalen Kode zu transformieren, der von den Spiralganglion Neuronen (N. cochlearis) über
den Hörnerv an das zentrale Nervensystem geleitet wird. Um den hohen Anforderungen zu
entsprechen, folgen die Bändersynapsen einem spezialisierten Aufbau, der von
konventionellen Synapsen des zentralen Nervensystems abweicht. Eine zentrale Rolle
spielen die präsynaptisch lokalisierten Rab3-interacting molecule (RIM) binding proteins (RIMBPs),
welche über mehrere Domänen sowohl mit den Calcium-Kanälen, als auch RIMs und
Bassoon interagieren, die strukturell und funktionell an der Exozytose von synaptischen
Vesikeln beteiligt sind. Bisher wurde in inneren Haarzellen nur die Funktion von RIM-BP2
untersucht. Dabei wurde entdeckt, dass die genetische Deletion von RIM-BP2 in Mäusen zu
einer auditorische Synaptopathie führt, die durch eine reduzierte Anzahl an synaptischen
Calcium-Kanälen und einer gestörten Exozytose an Bändersynapsen der inneren Haarzellen
hervorgerufen wurde. Ob auch andere RIM-BPs, wie zum Beispiel RIM-BP1 in IHZ eine
Rolle spielen, und welche das sein könnte, ist bislang ungeklärt.
In dieser Arbeit wurden in vivo Hirnstammaudiometrie und in vitro patch-clamp Messungen an
RIM-BP1/2-Doppelknockout Mäusen, sowie eine Expressionsanalyse von RIM-BP1 in
inneren Haarzellen durchgeführt. Dabei zeigen die Ergebnisse der Hirnstammaudiometrie,
dass zusätzlich zu RIM-BP2, auch RIM-BP1 für das periphere Hören der Mäuse wichtig ist
und der Verlust von RIM-BP1 und 2 zusammen eine stärkere auditorische Synaptopathie
hervorruft als die Deletion von RIM-BP2 alleine. Durch elektrophysiologische patch-clamp
Messungen an inneren Haarzellen konnte keine zusätzliche Auswirkung der RIM-BP1
Deletion auf die Amplitude oder die Spanungsabhängigkeit der Calcium-Ströme in inneren
Haarzellen von RIM-BP1/2-Doppelknockout Mäusen gefunden werden. Daher kann
geschlussfolgert werden, dass zwar RIM-BP2, jedoch nicht RIM-BP1 an der Regulation der
Calcium-Kanäle an den Bändersynapsen innerer Haarzellen beteiligt ist. Jedoch wurde eine
Reduktion der Exozytose von RIM-BP1/2-Doppelknockout inneren Haarzellen bei kurzen
Depolarisationszeiten (< 20 ms) gefunden, welche sich signifikant von RIM-BP2-Knockout
inneren Haarzellen unterschied. Dies deutet auf eine Funktion von RIM-BP1 in der
Exozytose von synaptischen Vesikeln aus dem „readily releasable pool“ hin. Insgesamt scheint
RIM-BP2 im Vergleich zu RIM-BP1 trotz der verstärkten Schwerhörigkeit von RIM-BP1/2-
Doppelknockout Mäusen im Vergleich zu RIM-BP2-Knockout Mäusen, an der inneren
Haarzell-Bändersynapse funktionell eine größere Rolle zu spielen.The afferent synapses between inner hair cells (IHC) and spiral ganglion neurons are
specialized to faithfully encode sound with sub-millisecond precision over prolonged
periods of time. Here, I studied the role of Rab3 interacting molecule-binding proteins
(RIM-BP) 1 and 2 – multidomain proteins of the active zone known to directly interact
with RIMs, Bassoon and CaV1.3 – in IHC presynaptic function and hearing. Recordings
of auditory brainstem responses and otoacoustic emissions revealed that genetic
disruption of RIM-BPs 1 and 2 in mice causes a synaptopathic hearing
impairment exceeding that found in mice lacking RIM-BP2. Patch-clamp
recordings from RIM-BP1/2 knockout IHCs indicated a subtle impairment of exocytosis from
the readily releasable pool of synaptic vesicles that had not been observed in RIMBP2
knockout IHCs. In contrast, the reduction of calcium-influx and sustained exocytosis was
similar to that in RIMBP2 knockout IHCs. In conclusion both RIM-BPs are required for
normal sound encoding at the IHC synapse, whereby RIM-BP2 seems to take the
leading role.2024-02-0
Cardiovascular determinants of quality of life in patients with cancer
No full textZiele Fünf Prozent der deutschen Bevölkerung lebt mit der Diagnose einer malignen Erkrankung, die sich – aufgrund höherer Überlebensraten – zu einer chronischen Erkrankung wandelt. Die Aufrechterhaltung der Lebensqualität gewinnt zunehmend an Bedeutung für die Behandlung und Betreuung dieser Patienten, was zu der Suche nach Einflussfaktoren für die Aufrechterhaltung der Lebensqualität führt.
Methoden und Ergebnisse Für diese Studie bewerteten 283 Tumorpatienten ihre Lebensqualität mit einem Fragebogen zur gesundheitsbezogenen Lebensqualität (European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)). Jeder Patient wurde körperlich und mithilfe apparativer Diagnostik (Ruhe-Elektrokardiogramm, Handkraft-Messung und Laboruntersuchungen) untersucht. In einer multiplen logistischen Regression fanden wir vier unabhängige, prädiktive Einflussfaktoren für eine reduzierte Lebensqualität: Alter [Odds Ratio (OR) 0,973, 95 % Konfidenzintervall (KI) 0,950-0,996], das Vorhandensein von Kachexie [OR 2,036, 95 % KI 1,151-3,601], reduzierte Handkraft [OR 0,948, 95 % KI 0,758-1,002] und erhöhte Ruhe-Herzfrequenz [OR 1,888, 95 % KI 1,099-3,242, alle p < 0.05]. In einer univariablen logistischen Regression zeigte sich die Diagnose einer Anämie [OR 1,957, 95 % KI 1,194-3,207, p < 0.05] ebenfalls als Einflussfaktor für reduzierte Lebensqualität.
Zusammenfassung Die identifizierten Einflussfaktoren Alter, Vorhandensein von Kachexie, reduzierte Handkraft und erhöhte Ruhe-Herzfrequenz sowie wahrscheinlich auch die Diagnose der Anämie sind mögliche Ansatzpunkte für die Verbesserung oder Aufrechterhaltung der Lebensqualität bei Tumorpatienten. Es sind prospektive Studien notwendig, um diese Endpunkte zu verifizieren.Aims Five percent of the German population is living with the diagnosis of a malignant disease, which transforms – due to higher survival rates – to a chronic disease. Maintaining quality of life (QoL) has become increasingly important in the treatment and care of these patients, which leads to the quest of finding determinants of QoL to achieve this maintenance.
Methods and results For this study 283 cancer patients assessed their QoL using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 questionnaire. Every patient underwent a physical examination and apparative diagnostics including resting electrocardiogram, hand grip strength as well as blood testing. Using a multivariable logistic regression, we identified four independently predictive determinants of reduced QoL: age [odds ratio (OR) 0.973, 95 % confidence interval (CI) 0.950-0.996], presence of cachexia [OR 2.036, 95 % CI 1.151-3.601], hand grip strength [OR 0.948, 95 % CI 0.758-1.002] and elevated resting heart rate [OR 1.888, 95 % CI 1.099-3.242, all P < 0.05]. Using an univariable logistic regression the diagnosis of anaemia [OR 1.957, 95 % CI 1.194-3.207, P < 0.05] was found to be a determinant of reduced QoL as well.
Conclusions The identified determinants age, presence of cachexia, hand grip strength and elevated resting heart rate as well as most likely the diagnosis of anaemia are possible adjustment points to improve or maintain QoL in cancer patients. Nevertheless, prospective studies are required to verify these endpoints.2024-04-0
Impact of Genetic Variants of the Negative Co-stimulatory T-Cell Inhibitors TIM-3 and LAG-3 on the Outcome of Patients with Sepsis
No full textBackground: Each year, millions of people die from sepsis or its consequences. Sepsis is defined as a life-threatening condition based on a dysregulated immune response to an infection. Thus, investigating the complex pathophysiology of sepsis and improving its diagnosis and treatment are of international significance. Previous studies revealed the fundamental role of negative co-stimulatory T-cell inhibitors like T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3) in the clinical phenotype and outcome of sepsis. TIM-3 and LAG-3 are specific membrane proteins which, upon interacting with their ligands, can lead to T-cell inhibition and restoration of immune homeostasis during sepsis. This study investigated the impact of the functional single nucleotide polymorphisms (SNPs) TIM-3 rs1036199, TIM-3 rs10515746, LAG-3 rs870849 and LAG-3 rs951818 on the outcome of patients with sepsis.
Methods: A total of 712 patients with sepsis were prospectively enrolled from three intensive care units at the University Medical Center Goettingen since 2012. All patients were genotyped, clinically observed for 28 days, and their survival was assessed 90 days after sepsis onset. The primary outcome was the 28- and 90-day mortality. Disease severity and microbiological findings were secondary endpoints.
Results: Kaplan-Meier survival analysis demonstrated a significantly higher 28-day survival for TIM-3 rs1036199 AA homozygous patients compared to C-allele carriers (82% vs. 73%, p = 0.0099) and TIM-3 rs10515746 CC homozygous patients compared to A-allele carriers (82% vs. 74%, p = 0.0202). Furthermore, there was a significantly higher survival rate among the LAG-3 rs951818 AA homozygous patients at 83 %, compared to C-allele carriers at 76 % (p = 0.0476). The TIM-3 rs1036199 AA and rs10515746 CC genotype remained significant predictors for the 28-day mortality in the multivariate Cox regression analysis after adjusting for relevant confounders like age, BMI, etc. (p = 0.0175, HR 0.6703; p = 0.0310, HR = 0.6958). Additionally, it was observed that individuals with the TIM-3 rs1036199 AA genotype exhibited significantly more infections with gram-positive bacteria and Staphylococcus epidermidis in particular (p = 0.0445, p = 0.0295). Concurrently, a higher incidence of Staphylococcus epidermidis infections was detected in the TIM-3 rs10515746 CC homozygotes (p = 0.0313).
Conclusion: This study is the first to demonstrate a positive impact on the outcome of sepsis in patients with the TIM-3 rs1036199 AA and rs10515746 CC genotype. Further research on the pathophysiological mechanisms of sepsis may be key to early identification of at-risk patients and a more personalized approach to sepsis.2024-04-1