1. Ranking as a procedure for selecting a replacement variable in the score predicting the survival of patients treated with curative intent for colorectal liver metastasesIrena Plahuta, Matej Mencinger, Iztok Peruš, Tomislav Magdalenić, Špela Turk, Aleks Brumec, Stojan Potrč, Arpad Ivanecz, 2023, original scientific article Abstract: Background and Objectives: The issue of a missing variable precludes the external validation of many prognostic models. For example, the Liverpool score predicts the survival of patients undergoing surgical therapy for colorectal liver metastases, but it includes the neutrophil–lymphocyte ratio, which cannot be measured retrospectively.
Materials and Methods: We aimed to find the most appropriate replacement for the neutrophil–lymphocyte ratio. Survival analysis was performed on data representing 632 liver resections for colorectal liver metastases from 2000 to 2020. Variables associated with the Liverpool score, C-reactive protein, albumins, and fibrinogen were ranked. The rankings were performed in four ways: The first two were based on the Kaplan-Meier method (log-rank statistics and the definite integral ��
between two survival curves). The next method of ranking was based on univariate and multivariate Cox regression analyses.
Results: The ranks were as follows: the radicality of liver resection (rank 1), lymph node infiltration of primary colorectal cancer (rank 2), elevated C-reactive protein (rank 3), the American Society of Anesthesiologists Classification grade (rank 4), the right-sidedness of primary colorectal cancer (rank 5), the multiplicity of colorectal liver metastases (rank 6), the size of colorectal liver metastases (rank 7), albumins (rank 8), and fibrinogen (rank 9).
Conclusions: The ranking methodologies resulted in almost the same ranking order of the variables. Elevated C-reactive protein was ranked highly and can be considered a relevant replacement for the neutrophil–lymphocyte ratio in the Liverpool score. These methods are suitable for ranking variables in similar models for medical research.
Keywords: colorectal cancer, liver metastases, inflammation, ranking, survival
Published in DKUM: 07.04.2025; Views: 0; Downloads: 5
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2. The endocannabinoid system in asthma patients and the effect of cannabinoids in the modulation of inflammatory responseCarina Esteves Pinto Kozmus, 2021, doctoral dissertation Abstract: Asthma is a chronic inflammatory condition characterised by intermittent and reversible airflow obstruction caused by inflammation, bronchospasm, and increased airway secretions. Questions about the endocannabinoid system’s function in asthma pathogenesis have arisen as evidence grows, demonstrating it is a native modulator of immune functions. The main goal of this study was to genetically characterise the endocannabinoid system in naive asthma patients and determine if there is a relationship between endogenous cannabinoids and their inflammatory response. We studied a case-control cohort of 353 patients with mild/moderate persistent asthma and 276controls. The mRNA expression levels of the selected genes were quantified in peripheral blood mononuclear cells (PBMCs) and N-acylethanolamines (NAEs) quantified from plasma samples. Our results revealed that the genes for CB1 (CNR1) andCB2 (CNR2), along with genes for the enzymes NAPE-PLD (NAPEPLD), Abhd4(ABHD4) and MAGL (MGLL) were up-regulated in asthma patients and associated with their clinical and inflammatory condition. In addition, two of the genotyped polymorphisms located in the CNR2 gene were also associated with worse clinical symptoms. Palmitoylethanolamide (PEA) levels were lower and significantly different between allergic asthma patients and the control group and associated with worse clinical symptoms. Furthermore, our findings indicate that asthma patients with highCNR1mRNA expression levels at the time of diagnosis, treated with LTA, have better treatment response, while asthma patients with highCNR1mRNA expression levels, treated with ICS, had worse treatment response. Long-term ICS or LTRA therapy reduced mRNA expression ofCNR1together withIL4andIL5.It is evident from these findings that the endocannabinoid system plays a role in asthma, but it is not possible to determine whether this up-regulation is a cause or a result of the condition. Nonetheless, our findings add to a better understanding of the endocannabinoid system’s significance in asthma pathogenesis.
Keywords: Asthma, Endocannabinoid system, Cannabinoids, Inflammation, Molecular genetics
Published in DKUM: 18.03.2024; Views: 251; Downloads: 20
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3. Cleavage-mediated regulation of Myd88 signaling by inflammasome-activated caspase-1Monika Avbelj, Iva Hafner Bratkovič, Duško Lainšček, Mateja Manček Keber, Tina Tinkara Peternelj, Gabriela Panter, Steven P. Treon, Boris Gole, Uroš Potočnik, Roman Jerala, 2022, original scientific article Abstract: Coordination among multiple signaling pathways ensures an appropriate immune response, where a signaling pathway may impair or augment another signaling pathway. Here, we report a negative feedback regulation of signaling through the key innate immune mediator MyD88 by inflammasome-activated caspase-1. NLRP3 inflammasome activation impaired agonist- or infection-induced TLR signaling and cytokine production through the proteolytic cleavage of MyD88 by caspase-1. Site-specific mutagenesis was used to identify caspase-1 cleavage site within MyD88 intermediary segment. Different cleavage site location within MyD88 defined the functional consequences of MyD88 cleavage between mouse and human cells. LPS/monosodium urate–induced mouse inflammation model corroborated the physiological role of this mechanism of regulation, that could be reversed by chemical inhibition of NLRP3. While Toll/interleukin-1 receptor (TIR) domain released by MyD88 cleavage additionally contributed to the inhibition of signaling, Waldenström’s macroglobulinemia associated MyD88L265P mutation is able to evade the caspase-1-mediated inhibition of MyD88 signaling through the ability of its TIRL265P domain to recruit full length MyD88 and facilitate signaling. The characterization of this mechanism reveals an additional layer of innate immunity regulation.
Keywords: Myeloid differentiation factor 88, Myd88, caspase-1, inflammasomes, regulation, innate immunity, inflammation
Published in DKUM: 16.08.2023; Views: 561; Downloads: 50
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