TY  - JOUR
A1  - Haertle, Larissa
A1  - Buenache, Natalia
A1  - Cuesta Hernández, Hipólito Nicolás
A1  - Simicek, Michal
A1  - Snaurova, Renata
A1  - Rapado, Inmaculada
A1  - Martinez, Nerea
A1  - López-Muñoz, Nieves
A1  - Sánchez-Pina, José María
A1  - Munawar, Umair
A1  - Han, Seungbin
A1  - Ruiz-Heredia, Yanira
A1  - Colmenares, Rafael
A1  - Gallardo, Miguel
A1  - Sanchez-Beato, Margarita
A1  - Piris, Miguel Angel
A1  - Samur, Mehmet Kemal
A1  - Munshi, Nikhil C.
A1  - Ayala, Rosa
A1  - Kortüm, Klaus Martin
A1  - Barrio, Santiago
A1  - Martínez-López, Joaquín
T1  - Genetic alterations in members of the proteasome 26S subunit, AAA-ATPase (PSMC) gene family in the light of proteasome inhibitor resistance in multiple myeloma
JF  - Cancers
N2  - For the treatment of Multiple Myeloma, proteasome inhibitors are highly efficient and widely used, but resistance is a major obstacle to successful therapy. Several underlying mechanisms have been proposed but were only reported for a minority of resistant patients. The proteasome is a large and complex machinery. Here, we focus on the AAA ATPases of the 19S proteasome regulator (PSMC1-6) and their implication in PI resistance. As an example of cancer evolution and the acquisition of resistance, we conducted an in-depth analysis of an index patient by applying FISH, WES, and immunoglobulin-rearrangement sequencing in serial samples, starting from MGUS to newly diagnosed Multiple Myeloma to a PI-resistant relapse. The WES analysis uncovered an acquired PSMC2 Y429S mutation at the relapse after intensive bortezomib-containing therapy, which was functionally confirmed to mediate PI resistance. A meta-analysis comprising 1499 newly diagnosed and 447 progressed patients revealed a total of 36 SNVs over all six PSMC genes that were structurally accumulated in regulatory sites for activity such as the ADP/ATP binding pocket. Other alterations impact the interaction between different PSMC subunits or the intrinsic conformation of an individual subunit, consequently affecting the folding and function of the complex. Interestingly, several mutations were clustered in the central channel of the ATPase ring, where the unfolded substrates enter the 20S core. Our results indicate that PSMC SNVs play a role in PI resistance in MM.
KW  - Multiple Myeloma
KW  - drug resistance
KW  - proteasome inhibitors
KW  - immunoglobulin rearrangement
KW  - ATPase activity
KW  - PSMC2
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305013
SN  - 2072-6694
VL  - 15
IS  - 2
ER  - 
TY  - JOUR
A1  - Kurotschka, Peter Konstantin
A1  - Fulgenzio, Chiara
A1  - Da Cas, Roberto
A1  - Traversa, Giuseppe
A1  - Ferrante, Gianluigi
A1  - Massidda, Orietta
A1  - Gágyor, Ildikó
A1  - Aschbacher, Richard
A1  - Moser, Verena
A1  - Pagani, Elisabetta
A1  - Spila Alegiani, Stefania
A1  - Massari, Marco
T1  - Effect of fluoroquinolone use in primary care on the development and gradual decay of Escherichia coli resistance to fluoroquinolones: a matched case-control study
JF  - Antibiotics
N2  - The reversibility of bacterial resistance to antibiotics is poorly understood. Therefore, the aim of this study was to determine, over a period of five years, the effect of fluoroquinolone (FQ) use in primary care on the development and gradual decay of Escherichia coli resistance to FQ. In this matched case–control study, we linked three sources of secondary data of the Health Service of the Autonomous Province of Bolzano, Italy. Cases were all those with an FQ-resistant E. coli (QREC)-positive culture from any site during a 2016 hospital stay. Data were analyzed using conditional logistic regression. A total of 409 cases were matched to 993 controls (FQ-sensitive E. coli) by the date of the first isolate. Patients taking one or more courses of FQ were at higher risk of QREC colonization/infection. The risk was highest during the first year after FQ was taken (OR 2.67, 95%CI 1.92–3.70, p < 0.0001), decreased during the second year (OR 1.54, 95%CI 1.09–2.17, p = 0.015) and became undetectable afterwards (OR 1.09, 95%CI 0.80–1.48, p = 0.997). In the first year, the risk of resistance was highest after greater cumulative exposure to FQs. Moreover, older age, male sex, longer hospital stays, chronic obstructive pulmonary disease (COPD) and diabetes mellitus were independent risk factors for QREC colonization/infection. A single FQ course significantly increases the risk of QREC colonization/infection for no less than two years. This risk is higher in cases of multiple courses, longer hospital stays, COPD and diabetes; in males; and in older patients. These findings may inform public campaigns and courses directed to prescribers to promote rational antibiotic use.
KW  - drug resistance
KW  - bacterial
KW  - antimicrobial resistance
KW  - anti-bacterial agents
KW  - primary care
KW  - quinolones
KW  - fluoroquinolones
KW  - information storage and retrieval
KW  - Escherichia coli
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-278771
SN  - 2079-6382
VL  - 11
IS  - 6
ER  - 
TY  - JOUR
A1  - Peindl, Matthias
A1  - Göttlich, Claudia
A1  - Crouch, Samantha
A1  - Hoff, Niklas
A1  - Lüttgens, Tamara
A1  - Schmitt, Franziska
A1  - Pereira, Jesús Guillermo Nieves
A1  - May, Celina
A1  - Schliermann, Anna
A1  - Kronenthaler, Corinna
A1  - Cheufou, Danjouma
A1  - Reu-Hofer, Simone
A1  - Rosenwald, Andreas
A1  - Weigl, Elena
A1  - Walles, Thorsten
A1  - Schüler, Julia
A1  - Dandekar, Thomas
A1  - Nietzer, Sarah
A1  - Dandekar, Gudrun
T1  - EMT, stemness, and drug resistance in biological context: a 3D tumor tissue/in silico platform for analysis of combinatorial treatment in NSCLC with aggressive KRAS-biomarker signatures
JF  - Cancers
N2  - Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRAS\(^{G12C}\) or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-β. To investigate further determinants of drug response, we tested several drugs in combination with a KRAS\(^{G12C}\) inhibitor in KRAS\(^{G12C}\) mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures.
KW  - EMT
KW  - drug resistance
KW  - invasion
KW  - stemness
KW  - 3D lung tumor tissue models
KW  - KRAS biomarker signatures
KW  - boolean in silico models
KW  - targeted combination therapy
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270744
SN  - 2072-6694
VL  - 14
IS  - 9
ER  -