971. Mobocertinib in patients with EGFR exon 20 insertion-positive non-small cell lung cancer (MOON) : an international real-world safety and efficacy analysisOliver Illini, Felix Carl Saalfeld, Petros Christopoulos, Michaël Duruisseaux, Anders Vikström, Nir Peled, Ingel Demedts, Elizabeth Dudnik, Anna Eisert, Urška Janžič, Katja Mohorčič, Marija Ivanović, Sayed M. S. Hashemi, 2024, izvirni znanstveni članek Povzetek: EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24–45). The response rate in treatment-naïve patients was 27% (95% CI, 8–58). The median progression-free and overall survival was 5 months (95% CI, 3.5–6.5) and 12 months (95% CI, 6.8–17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity. Ključne besede: medicina, non-small cell lung cancer, EGFR exon 20 inhibitors, mobocertinib, real-world data, exon 20 insertion Objavljeno v DiRROS: 19.06.2024; Ogledov: 196; Prenosov: 120
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972. New insights in ATP synthesis as therapeutic target in cancer and angiogenic ocular diseasesCornelis J. F. van Noorden, Bahar Yetkin-Arik, Paola Serrano Martinez, Noëlle Bakker, Mathilda E. van Breest Smallenburg, Reinier O. Schlingemann, Ingeborg Klaassen, Bernarda Majc, Anamarija Habič, Urban Bogataj, Katrin S. Galun, Miloš Vittori, Mateja Erdani-Kreft, Metka Novak, Barbara Breznik, Vashendriya V. V. Hira, 2024, pregledni znanstveni članek Povzetek: Lactate and ATP formation by aerobic glycolysis, the Warburg effect, is considered a hallmark of cancer. During angiogenesis in non-cancerous tissue, proliferating stalk endothelial cells (ECs) also produce lactate and ATP by aerobic glycolysis. In fact, all proliferating cells, both non-cancer and cancer cells, need lactate for the biosynthesis of building blocks for cell growth and tissue expansion. Moreover, both non-proliferating cancer stem cells in tumors and leader tip ECs during angiogenesis rely on glycolysis for pyruvate production, which is used for ATP synthesis in mitochondria through oxidative phosphorylation (OXPHOS). Therefore, aerobic glycolysis is not a specific hallmark of cancer but rather a hallmark of proliferating cells and limits its utility in cancer therapy. However, local treatment of angiogenic eye conditions with inhibitors of glycolysis may be a safe therapeutic option that warrants experimental investigation. Most types of cells in the eye such as photoreceptors and pericytes use OXPHOS for ATP production, whereas proliferating angiogenic stalk ECs rely on glycolysis for lactate and ATP production. Ključne besede: aerobic glycolysis, anaerobic glycolysis, angiogenesis, ATP synthesis, cancer cells, cancer stem cells, endothelial cells, energy metabolism, eye diseases, oxidative phosphorylation, pericytes, retina, Warburg effect Objavljeno v DiRROS: 18.06.2024; Ogledov: 218; Prenosov: 140
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973. The truncated moment problem on reducible cubic curves I : Parabolic and circular type relationsSeonguk Yoo, Aljaž Zalar, 2024, izvirni znanstveni članek Povzetek: In this article we study the bivariate truncated moment problem (TMP) of degree $2k$ on reducible cubic curves. First we show that every such TMP is equivalent after applying an affine linear transformation to one of 8 canonical forms of the curve. The case of the union of three parallel lines was solved by the second author (2022), while the degree 6 cases by the first author (2017). Second we characterize in terms of concrete numerical conditions the existence of the solution to the TMP on two of the remaining cases concretely, i.e., a union of a line and a circle, and a union of a line and a parabola. In both cases we also determine the number of atoms in a minimal representing measure. Ključne besede: truncated moment problems, K-moment problems, K-representing measure, minimal measure, moment matrix extensions Objavljeno v DiRROS: 18.06.2024; Ogledov: 170; Prenosov: 126
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974. Evaluating mineral matter dynamics within the peatland as reflected in water compositionValentina Pezdir, Luka Serianz, Mateja Gosar, 2024, izvirni znanstveni članek Povzetek: Peatland hydrology plays an important role in preserving or changing the record in any consideration of past atmospheric deposition records in peat bogs. The Šijec bog, located on the Pokljuka plateau in Slovenia, is one of the largest ombrotrophic peatlands. We sampled the surface pools, pore water, drainage from the peatland, and karst streams not connected to the peatland. Additionally, we sampled the precipitation, as ombrotrophic peatlands receive mineral matter solely from the atmosphere. The results of the evaluation of the chemical and isotopic composition indicated different origins of dissolved mineral matter in different water types. The components originating from the bedrock and surrounding soils (Ca, Mg, Al, Si, Sr) predominated in the streams. The chemical composition of the peatland drainage water revealed the significant removal of major components from the peatland, particularly elements like Al, Fe, and REE, and metals that are readily dissolved in an acidic environment or mobile in their reduced state. Despite their solubility, concentrations of metals (As, Cr, Cu, Fe, Ni, Pb, Ti) and REE in surface pools remained higher than in the drainage due to incomplete elimination from the peatland. The composition of pore water reflects variations among the W and E parts of the peatland, indicating a heterogenous hydrological structure with different dynamics, such as an additional source of water at approximately 90 cm depth in the NW part. The chemical composition and isotope signature (18O and 2H) of pore water additionally indicated a heterogeneous recharge with residence times of less than a year. The overall analysis indicated a predominantly ombrotrophic type and a small part in the NW area of the peatland as a minerotrophic type of peat. Ključne besede: peatland, hydrogeochemistry, isotopes Objavljeno v DiRROS: 18.06.2024; Ogledov: 201; Prenosov: 110
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975. Extending multivariate sub-quasi-copulasDamjana Kokol-Bukovšek, Tomaž Košir, Blaž Mojškerc, Matjaž Omladič, 2024, izvirni znanstveni članek Povzetek: In this paper, we introduce patchwork constructions for multivariate quasi-copulas. These results appear to be new since the kind of approach has been limited to either copulas or only bivariate quasi-copulas so far. It seems that the multivariate case is much more involved, since we are able to prove that some of the known methods of bivariate constructions cannot be extended to higher dimensions. Our main result is to present the necessary and sufficient conditions both on the patch and the values of it for the desired multivariate quasi-copula to exist. We also give all possible solutions. Ključne besede: mathematics, multivariate analysis Objavljeno v DiRROS: 18.06.2024; Ogledov: 199; Prenosov: 101
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976. Best possible upper bounds on the restrained domination number of cubic graphsBoštjan Brešar, Michael A. Henning, 2024, izvirni znanstveni članek Povzetek: A dominating set in a graph $G$ is a set $S$ of vertices such that every vertex in $V(G) \setminus S$ is adjacent to a vertex in $S$. A restrained dominating set of $G$ is a dominating set $S$ with the additional restraint that the graph $G - S$ obtained by removing all vertices in $S$ is isolate-free. The domination number $\gamma(G)$ and the restrained domination number $\gamma_{r}(G)$ are the minimum cardinalities of a dominating set and restrained dominating set, respectively, of $G$. Let $G$ be a cubic graph of order $n$. A classical result of Reed [Combin. Probab. Comput. 5 (1996), 277-295] states that $\gamma(G) \le \frac{3}{8}n$, and this bound is best possible. To determine a best possible upper bound on the restrained domination number of $G$ is more challenging, and we prove that $\gamma_{r}(G) \le \frac{2}{5}n$. Ključne besede: domination, restrained domination, cubic graphs Objavljeno v DiRROS: 18.06.2024; Ogledov: 166; Prenosov: 148
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977. Generalized noncooperative Schrödinger-Kirchhoff-type systems in ${\mathbb R}^N$Nabil Chems Eddine, Dušan Repovš, 2024, izvirni znanstveni članek Povzetek: We consider a class of noncooperative Schrödinger-Kirchhof-type system, which involves a general variable exponent elliptic operator with critical growth. Under certain suitable conditions on the nonlinearities, we establish the existence of infinitely many solutions for the problem by using the limit index theory, a version of concentration-compactness principle for weighted-variable exponent Sobolev spaces and the principle of symmetric criticality of Krawcewicz and Marzantowicz. Ključne besede: concentration–compactness principle, critical points theory, critical Sobolev exponents, generalized capillary operator, limit index theory, p-Laplacian, p(x)-Laplacian, Palais–Smale condition, Schrödinger-Kirchhoff-type problems, weighted exponent spaces Objavljeno v DiRROS: 17.06.2024; Ogledov: 168; Prenosov: 113
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978. High burden of clonal mast cell disorders and hereditary ▫$α-tryptasemia$▫ in patients who need Hymenoptera venom immunotherapyPeter Korošec, Gunter Sturm, Jonathan J. Lyons, Tinkara Pirc Marolt, Manca Svetina, Mitja Košnik, Mihaela Zidarn, Mark Kačar, Nina Frelih, Nika Lalek, Ajda Demšar Luzar, Samo Zver, Matevž Škerget, Ewa Czarnobilska, Wojciech Dyga, Sanja Popović-Grle, Miroslav Samaržija, Lisa Arzt-Gradwohl, Urban Čerpes, Grzegorz Porebski, Branko Pevec, Eva Schadelbauer, Peter Kopač, Julij Šelb, Matija Rijavec, 2024, izvirni znanstveni članek Povzetek: Background
In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT.
Methods
1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms.
Results
285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3–4 vs. 11% [n = 78 of 709] with Grade 1–2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3–4 vs. 0.001% [n = 78] in Grade 1–2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01).
Conclusions
By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT. Ključne besede: anaphylaxis, hereditary α-tryptasemia, hypersensitivity, immunotherapy, mast cell, mastocytosis, venom Objavljeno v DiRROS: 17.06.2024; Ogledov: 251; Prenosov: 166
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979. Multisensory mechanisms of gait and balance in Parkinson's disease : an integrative reviewStiven Roytman, Rebecca Paalanen, Giulia Carli, Uroš Marušič, Prabesh Kanel, Teus van Laar, Nicolaas I. Bohnen, 2025, pregledni znanstveni članek Povzetek: Understanding the neural underpinning of human gait and balance is one of the most pertinent challenges for 21st-century translational neuroscience due to the profound impact that falls and mobility disturbances have on our aging population. Posture and gait control does not happen automatically, as previously believed, but rather requires continuous involvement of central nervous mechanisms. To effectively exert control over the body, the brain must integrate multiple streams of sensory information, including visual, vestibular, and somatosensory signals. The mechanisms which underpin the integration of these multisensory signals are the principal topic of the present work. Existing multisensory integration theories focus on how failure of cognitive processes thought to be involved in multisensory integration leads to falls in older adults. Insufficient emphasis, however, has been placed on specific contributions of individual sensory modalities to multisensory integration processes and cross-modal interactions that occur between the sensory modalities in relation to gait and balance. In the present work, we review the contributions of somatosensory, visual, and vestibular modalities, along with their multisensory intersections to gait and balance in older adults and patients with Parkinson's disease. We also review evidence of vestibular contributions to multisensory temporal binding windows, previously shown to be highly pertinent to fall risk in older adults. Lastly, we relate multisensory vestibular mechanisms to potential neural substrates, both at the level of neurobiology (concerning positron emission tomography imaging) and at the level of electrophysiology (concerning electroencephalography). We hope that this integrative review, drawing influence across multiple subdisciplines of neuroscience, paves the way for novel research directions and therapeutic neuromodulatory approaches, to improve the lives of older adults and patients with neurodegenerative diseases. Ključne besede: aging, gait, balance, encephalography, functional magnetic resonance imaging, multisensory integration Objavljeno v DiRROS: 17.06.2024; Ogledov: 206; Prenosov: 232
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