Integral membrane proteins carry out essential functions in the cell, and their activities are often modulated by specific protein-lipid interactions in the membrane. Here, we elucidate the intricate role of cardiolipin (CDL), a regulatory lipid, as a stabilizer of membrane proteins and their complexes. Using the in silico-designed model protein TMHC4_R (ROCKET) as a scaffold, we employ a combination of molecular dynamics simulations and native mass spectrometry to explore the protein features that facilitate preferential lipid interactions and mediate stabilization. We find that the spatial arrangement of positively charged residues as well as local conformational flexibility are factors that distinguish stabilizing from non-stabilizing CDL interactions. However, we also find that even in this controlled, artificial system, a clear-cut distinction between binding and stabilization is difficult to attain, revealing that overlapping lipid contacts can partially compensate for the effects of binding site mutations. Extending our insights to naturally occurring proteins, we identify a stabilizing CDL site within the E. coli rhomboid intramembrane protease GlpG and uncover its regulatory influence on enzyme substrate preference. In this work, we establish a framework for engineering functional lipid interactions, paving the way for the design of proteins with membrane-specific properties or functions.

• MeSH
• DNA-Binding Proteins MeSH
• Endopeptidases metabolism   chemistry   genetics   MeSH
• Escherichia coli metabolism   genetics   MeSH
• Cardiolipins * metabolism   chemistry   MeSH
• Membrane Proteins * metabolism   chemistry   genetics   MeSH
• Protein Engineering * MeSH
• Escherichia coli Proteins * metabolism   chemistry   genetics   MeSH
• Molecular Dynamics Simulation MeSH
• Protein Binding MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Open surgery is widely regarded as the standard treatment for spinal dural arteriovenous fistulas (SDAVFs). However, endovascular treatment (EVT) with liquid embolic agents has emerged as an alternative. While N-butyl cyanoacrylate is often preferred for its superior penetration into draining vein, this study aims to assess the effectiveness of an embolization-first strategy using Onyx, drawing on 20 years of clinical experience. METHODS: A retrospective analysis included 50 patients treated between 2004 and 2024. Only patients undergoing EVT as the first-line therapy for SDAVF were included. RESULTS: Overall, EVT achieved complete occlusion in 38 (76%) cases, with an additional 6 (12%) requiring adjuvant surgery resulting in definitive cure. In the remaining 6 (12%) patients, embolization of the feeding artery and fistula nidus led to permanent clinical improvement (n = 4, 66%) or stability (n = 2, 33%), supported by indirect fistula signs regression on follow-up magnetic resonance imaging. Onyx was solely used in 84% of EVTs, achieving a complete occlusion rate of 83%. Clinical improvement or stabilization was observed in 46 (92%) patients, with no recurrences in successfully treated patients. There was no EVT-related complication. Follow-up magnetic resonance imagings showed regression of perimedullary varices and regression or stability of myelopathy in all cases (n = 50, 100%). CONCLUSIONS: The embolization-first strategy, with adjuvant surgery when necessary, can achieve outcomes nearing those of purely surgical approaches. Based on our long-term experience, EVT with Onyx can result in complete and permanent cure of SDAVF in more than 80% of cases.

• MeSH
• Central Nervous System Vascular Malformations * therapy   diagnostic imaging   MeSH
• Dimethyl Sulfoxide * therapeutic use   MeSH
• Adult MeSH
• Endovascular Procedures methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Polyvinyls * therapeutic use   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Tantalum * therapeutic use   MeSH
• Embolization, Therapeutic * methods   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Antagonists with a long residence time at the receptors are desired for the possibility of reducing daily doses and side effects. KH-5 (1-{2-[4-(hexyloxy)benzoyloxy]ethyl}-1-methyl-1,2,3,6-tetrahydropyridin-1-ium iodide) is the long-acting M1-preferring bitopic muscarinic antagonist with a half-life at muscarinic receptors of up to five hours. The binding of 2-hexyloxy and 3-hexyloxy analogues of KH-5 was simulated in silico, compounds were synthesized and their binding and antagonistic properties were measured experimentally in CHO cells expressing individual subtypes of muscarinic acetylcholine receptors. The overall binding affinities of the new compounds were similar to their respective parent compounds. Shifting the hexyloxy chain to ortho and meta positions led to a decrease in potency at the M1 receptor but an increase in potency at the M2 receptor and abolition of long-term antagonism. Preservation of the para position of the hexyloxy chain is essential for the further development of M1-preferring antagonists. Modifications of the basic centre may be the way to improve the geometry of antagonists towards long residence times to obtain the desired long-acting muscarinic antagonists in the future. The additional challenge for further development is the low metabolic stability of compounds.

• MeSH
• Muscarinic Antagonists * pharmacology   MeSH
• CHO Cells MeSH
• Cricetulus * MeSH
• Pyridines pharmacology   chemistry   MeSH
• Receptor, Muscarinic M1 metabolism   antagonists & inhibitors   MeSH
• Receptors, Muscarinic metabolism   MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

Radiation therapy manages pancreatic cancer in various settings; however, the proximity of gastrointestinal (GI) luminal organs at risk (OARs) poses challenges to conventional radiation therapy. Proton beam therapy (PBT) may reduce toxicities compared to photon therapy. This consensus statement summarizes PBT's safe and optimal delivery for pancreatic tumors. Our group has specific expertise using PBT for GI indications and has developed expert recommendations for treating pancreatic tumors with PBT. Computed tomography (CT) simulation: Patients should be simulated supine (arms above head) with custom upper body immobilization. For stomach/duodenum filling consistency, patients should restrict oral intake within 3 hours before simulation/treatments. Fiducial markers may be implanted for image guidance; however, their design and composition require scrutiny. The reconstruction field-of-view should encompass all immobilization devices at the target level (CT slice thickness 2-3 mm). Four-dimensional CT should quantify respiratory motion and guide motion mitigation. Respiratory gating is recommended when motion affects OAR sparing or reduces target coverage. Treatment planning: Beam-angle selection factors include priority OAR-dose minimization, water-equivalent-thickness stability along the beam path, and enhanced relative biological effect consideration due to the increased linear energy transfer at the proton beam end-of-range. Posterior and right-lateral beam angles that avoid traversing GI luminal structures are preferred (minimizing dosimetric impacts of variable anatomies). Pencil beam scanning techniques should use robust optimization. Single-field optimization is preferable to increase robustness, but if OAR constraints cannot be met, multifield optimization may be used. Treatment delivery: Volumetric image guidance should be used daily. CT scans should be acquired ad hoc as necessary (at minimum every other week) to assess the dosimetric impacts of anatomy changes. Adaptive replanning should be performed as required. Our group has developed recommendations for delivering PBT to safely and effectively manage pancreatic tumors.

• MeSH
• Radiotherapy Dosage MeSH
• Four-Dimensional Computed Tomography MeSH
• Respiration MeSH
• Immobilization methods   MeSH
• Consensus MeSH
• Organs at Risk * diagnostic imaging   radiation effects   MeSH
• Humans MeSH
• Pancreatic Neoplasms * radiotherapy   diagnostic imaging   MeSH
• Radiotherapy Planning, Computer-Assisted methods   MeSH
• Organ Motion MeSH
• Movement MeSH
• Proton Therapy * methods   adverse effects   standards   MeSH
• Radiation Injuries prevention & control   MeSH
• Radiotherapy, Image-Guided methods   MeSH
• Stomach diagnostic imaging   MeSH
• Fiducial Markers MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Consensus Development Conference MeSH

Pacienti se zánětlivými autoimunitními revmatickými chorobami (AIIRD) jsou vystaveni zvýšené afinitě k infekcím a jejich komplikacím. Riziko infekce stoupá se závažností orgánového postižení u AIIRD a typem a délkou imunosupresivní terapie. Celé řadě poměrně častých infekcí se dá předcházet očkováním. Očkování u nemocných s AIIRD by mělo být správně načasováno vzhledem k aktivitě choroby a terapie, aby byla dosažena jeho nejoptimálnější efektivita. Zkušenosti získané z klinických sledování, retrospektivní a prospektivní analýzy výskytu infekcí a proočkovanosti populace s AIIRD umožnily vypracovat doporučení pro očkování pod záštitou EULAR (Evropská aliance revmatologických asociací) publikované v roce 2019 a ACR (Americké revmatologické společnosti) z roku 2022. Tato doporučení zohledňují unikátní populaci pacientů s AIIRD včetně jejich terapie. Očkování může být provedeno i v průběhu léčby (kromě depleční terapie cílené na B lymfocyty), nicméně je upřednostněno ve stabilizovaném onemocnění s nižší aktivitou. Načasování očkování v rámci terapie je nutné zvážit tam, kde může být ovlivněna protilátková odpověď farmakologickými vlastnostmi podávané léčby. Očkování živými vakcínami není u imunosuprimovaných pacientů doporučováno.

Patients with inflammatory autoimmune rheumatic diseases (AIIRD) are exposed to an increased affinity for infections and their complications. The risk of infection increases with the severity of organ involvement in AIIRD and the type and duration of immunosuppressive therapy. Number of relatively common infections can be prevented by vaccination. Vaccination in patients with AIIRD should be properly timed with respect to disease activity and therapy to achieve its most optimal effectiveness. The experience gained from clinical surveillance, retrospective and prospective analyzes of the incidence of infections and vaccination coverage of the population with AIIRD allowed the development of vaccination recommendations under the auspices of EULAR (European Alliance of Rheumatology Associations) published in 2019 and ACR (American Society of Rheumatology) in 2022. These recommendations take into account the unique AIIRD patient population including their therapy. Vaccination can also be carried out during treatment (except for depletion therapy targeting B lymphocytes), however, it is preferred in stabilized disease with lower activity. The timing of vaccination within therapy must be considered where the antibody response may be influenced by the pharmacological properties of the treatment being administered. Vaccination with live vaccines is not recommended in immunosuppressed patients.

• MeSH
• Autoimmune Diseases drug therapy   immunology   complications   MeSH
• Immunosuppression Therapy adverse effects   MeSH
• Communicable Diseases immunology   MeSH
• Humans MeSH
• Rheumatic Diseases * drug therapy   immunology   complications   MeSH
• Practice Guidelines as Topic MeSH
• Vaccination * MeSH
• Vaccines classification   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Hormonálně dependentní HER2 negativní karcinom prsu je nejčastějším podtypem tohoto onemocnění. Kombinace hormonální léčby s inhibitory cyklin-dependentních kináz 4 a 6 (CDK 4/6) je v případě metastazujícího onemocnění jednoznačně preferovaným postupem v iniciálních fázích terapie, a to jak u premenopauzálních, tak postmenopauzálních pacientek. Díky této terapii došlo k výraznému zlepšení prognózy pacientek, a to jak ve smyslu prodloužení doby bez známek progrese onemocnění, tak celkového přežívání. Charakteristiky a chování onemocnění u premenopauzálních pacientek se liší od profilu onemocnění u pacientek postmenopauzálních; častěji se jedná o agresivnější onemocnění (vyšší proliferace, nižní exprese hormonálních receptorů, vyšší nádorový grade) s postižením viscerálních orgánů a s výraznějšími symptomy onemocnění. I v těchto případech je preferována kombinace hormonální léčby s inhibitory CDK 4/6 před chemoterapií. Předkládáme kazuistiku mladé premenopauzální pacientky s metastazujícím karcinomem prsu s postižením plic, hrudní dutiny a skeletu, s iniciálně výrazně symptomatickým a agresivním onemocněním, u které bylo dosaženo pomocí kombinace inhibitoru aromatázy a ribociklibu rychlé a dlouhodobé stabilizace onemocnění s výrazným zlepšením kvality života.

Hormone-dependent HER2-negative breast cancer is the most common subtype of this disease. Combination of hormonal therapy with cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors is clearly the preferred approach for metastatic disease in the initial phases of therapy in both premenopausal and postmenopausal patients. This therapy has significantly improved the prognosis of patients, both in terms of prolonged progression-free survival and overall survival. The characteristics and behavior of the disease in premenopausal patients differ from the disease profile in postmenopausal patients; more often it is a more aggressive disease (higher proliferation, lower hormone receptor expression, higher tumor grade) with visceral involvement and more pronounced symptoms. Even in these cases, the combination of hormonal therapy with CDK 4/6 inhibitors is preferred over chemotherapy. We present a case report of a young premenopausal patient with metastatic breast cancer involving the lung, thoracic cavity and skeleton, with initially highly symptomatic and aggressive disease, in whom a combination of aromatase inhibitor and ribociclib achieved rapid and long-term disease stabilization with significant improvement in quality of life.

The ISWI family protein SMARCA5 contains the ATP-binding pocket that coordinates the catalytic Mg2+ ion and water molecules for ATP hydrolysis. In this study, we demonstrate that SMARCA5 can also possess an alternative metal-binding ability. First, we isolated SMARCA5 on the cobalt column (IMAC) to near homogeneity. Examination of the interactions of SMARCA5 with metal-chelating supports showed that, apart from Co2+, it binds to Cu2+, Zn2+ and Ni2+. The efficiency of the binding to the last-listed metal was influenced by the chelating ligand, resulting in a strong preference for Ni-NTA over the Ni-CM-Asp equivalent. To gain insight in the preferential affinity for the Ni-NTA ligand, QM calculations were performed on model systems and metal-ligand complexes with a limited protein fragment of SMARCA5 containing the double-histidine (dHis) motif. The calculations correlated the observed affinity with the relative stability of the d-block metals to tetradentate ligand coordination over tridentate, as well as their overall octahedral coordination capacity. Likewise, binding free energies derived from model imidazole complexes mirrored the observed Ni-NTA/Ni-CM-Asp preferential affinity. Finally, similar calculations on complexes with a SMARCA5 peptide fragment derived from the AlphaFold structural prediction, captured almost accurately the expected relative stability of the TM complexes, and produced a large energetic separation (~10 kcal∙mol-1) between Ni-NTA and Ni-CM-Asp in favour of the former.

• MeSH
• Adenosine Triphosphatases MeSH
• Chromosomal Proteins, Non-Histone metabolism   chemistry   MeSH
• Metals chemistry   metabolism   MeSH
• Quantum Theory MeSH
• Humans MeSH
• Ligands MeSH
• Models, Molecular MeSH
• Chromatin Assembly and Disassembly MeSH
• Protein Binding * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Bolest je častým problémem u hemodialyzovaných pacientů s incidencí v rozmezí od 8 do 82 %. Léčba bolesti u pacientů s chronickým onemocněním ledvin je však často neúčinná a většina jich skutečně uvádí, že jejich bolest je nedostatečně léčena. Dlouhodobá léčba opioidy má nezastupitelnou roli v léčbě některých pacientů se středně silnou až silnou bolestí. Při indikaci opioidů pacientům se selháním ledvin je třeba vzít v úvahu stupeň selhání ledvin, frekvenci dialýzy a farmakokinetiku léků. Stabilita analgezie během dialýzy se u různých analgetik liší. Špatně dialyzovatelné opioidy mají déle trvající analgetický účinek. Farmakologické vlastnosti buprenorfinu mohou být výhodné pro použití u pacientů léčených hemodialýzou. Buprenorfin může být bezpečně podáván pacientům s poruchou funkce ledvin a hemodialyzovaným pacientům, nejlépe v dávkovém rozmezí do 70 μg/h, protože jeho farmakokinetické vlastnosti nejsou ovlivněny

Pain is a common problem in haemodialysis patients, with an incidence ranging from 8 to 82 %. However, pain management in patients with chronic kidney disease is often ineffective and indeed most report that their pain is undertreated. Long-term opioid therapy has an indispensable role in the treatment of some patients with moderate to severe pain. The degree of renal failure, the frequency of dialysis and the pharmacokinetics of the drugs should be taken into account when prescribing opioids to patients with renal failure. The stability of analgesia during dialysis varies between analgesics. Poorly dialyzable opioids have a longer lasting analgesic effect. The pharmacological properties of buprenorphine may be advantageous for use in patients undergoing haemodialysis. Buprenorphine can be safely administered to renally impaired and haemodialysis patients, preferably in a dose range up to 70 μg/h, as its pharmacokinetic properties are not affected.

• MeSH
• Buprenorphine * pharmacokinetics   pharmacology   therapeutic use   MeSH
• Chronic Pain * drug therapy   MeSH
• Renal Dialysis MeSH
• Quality of Life MeSH
• Humans MeSH
• Analgesics, Opioid adverse effects   toxicity   MeSH
• Renal Insufficiency * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Bolest je častým problémem u hemodialyzovaných pacientů s incidencí v rozmezí od 8 do 82 %. Léčba bolesti u pacientů s chronickým onemocněním ledvin je však často neúčinná a většina jich skutečně uvádí, že jejich bolest je nedostatečně léčena. Dlouhodobá léčba opioidy má nezastupitelnou roli v léčbě některých pacientů se středně silnou až silnou bolestí. Při indikaci opioidů pacientům se selháním ledvin je třeba vzít v úvahu stupeň selhání ledvin, frekvenci dialýzy a farmakokinetiku léků. Stabilita analgezie během dialýzy se u různých analgetik liší. Špatně dialyzovatelné opioidy mají déle trvající analgetický účinek. Farmakologické vlastnosti buprenorfinu mohou být výhodné pro použití u pacientů léčených hemodialýzou. Buprenorfin může být bezpečně podáván pacientům s poruchou funkce ledvin a hemodialyzovaným pacientům, nejlépe v dávkovém rozmezí do 70 μg/h, protože jeho farmakokinetické vlastnosti nejsou ovlivněny.

Pain is a common problem in haemodialysis patients, with an incidence ranging from 8 to 82%. However, pain management in patients with chronic kidney disease is often ineffective and indeed most report that their pain is undertreated. Long-term opioid therapy has an indispensable role in the treatment of some patients with moderate to severe pain. The degree of renal failure, the frequency of dialysis and the pharmacokinetics of the drugs should be taken into account when prescribing opioids to patients with renal failure. The stability of analgesia during dialysis varies between analgesics. Poorly dialyzable opioids have a longer lasting analgesic effect. The pharmacological properties of buprenorphine may be advantageous for use in patients undergoing haemodialysis. Buprenorphine can be safely administered to renally impaired and haemodialysis patients, preferably in a dose range up to 70 μg/h, as its pharmacokinetic properties are not affected.

• MeSH
• Buprenorphine * pharmacokinetics   pharmacology   therapeutic use   MeSH
• Chronic Pain * drug therapy   MeSH
• Renal Dialysis MeSH
• Quality of Life MeSH
• Humans MeSH
• Analgesics, Opioid pharmacology   toxicity   MeSH
• Renal Insufficiency * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

The FGF system is the most complex of all receptor tyrosine kinase signaling networks with 18 FGF ligands and four FGFRs that deliver morphogenic signals to pattern most embryonic structures. Even when a single FGFR is expressed in the tissue, different FGFs can trigger dramatically different biological responses via this receptor. Here we show both quantitative and qualitative differences in the signaling of one of the FGF receptors, FGFR1c, in response to different FGFs. We provide an overview of the recent discovery that FGFs engage in biased signaling via FGFR1c. We discuss the concept of ligand bias, which represents qualitative differences in signaling as it is a measure of differential ligand preferences for different downstream responses. We show how FGF ligand bias manifests in functional data in cultured chondrocyte cells. We argue that FGF-ligand bias contributes substantially to FGF-driven developmental processes, along with known differences in FGF expression levels, FGF-FGFR binding coefficients and differences in FGF stability in vivo.

• MeSH
• Chondrocytes metabolism   MeSH
• Fibroblast Growth Factors * metabolism   MeSH
• Humans MeSH
• Ligands MeSH
• Receptor, Fibroblast Growth Factor, Type 1 * metabolism   MeSH
• Receptors, Fibroblast Growth Factor * metabolism   MeSH
• Signal Transduction * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH