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- Loibl, S., et al.
(författare)
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ESMO Expert Consensus Statements on the management of breast cancer during pregnancy (PrBC)
- 2023
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Ingår i: Annals of Oncology. - 0923-7534. ; 34:10, s. 849-866
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Tidskriftsartikel (refereegranskat)abstract
- The management of breast cancer during pregnancy (PrBC) is a relatively rare indication and an area where no or little evidence is available since randomized controlled trials cannot be conducted. In general, advances related to breast cancer (BC) treatment outside pregnancy cannot always be translated to PrBC, because both the interests of the mother and of the unborn should be considered. Evidence remains limited and/or conflicting in some specific areas where the optimal approach remains controversial. In 2022, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process on this topic to gain insights from a multidisciplinary group of experts and develop statements on controversial topics that cannot be adequately addressed in the current evidence-based ESMO Clinical Practice Guideline. The aim of this consensus-building process was to discuss controversial issues relating to the management of patients with PrBC. The virtual meeting included a multidisciplinary panel of 24 leading experts from 13 countries and was chaired by S. Loibl and F. Amant. All experts were allocated to one of four different working groups. Each working group covered a specific subject area with two chairs appointed: 1. PrBC: incidence, epidemiology, biology and pathology, diagnostic work-up, staging and risk assessment, prognosis (Chairs: Vincent Vandecaveye, Fedro Peccatori). 2. Clinical pharmacology of systemic agents during pregnancy: management of localized disease and (neo) adjuvant therapies, management of systemic disease (Chairs: Giuseppe Curigliano, Peter Schmid). 3. Obstetric care and fetal/newborn follow-up and outcomes: metastases to fetus, management of pregnancy during anticancer therapy, lactation, psychological support (Chairs: Elyce Cardonick, Mathilde van Gerwen). Planning, preparation and execution of the consensus process was conducted according to the ESMO standard operating procedures.
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| 7. |
- Katsyv, Alexander., et al.
(författare)
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Molecular Basis of the Electron Bifurcation Mechanism in the [FeFe]- Hydrogenase Complex HydABC
- 2023
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 145:10, s. 5696-5709
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Tidskriftsartikel (refereegranskat)abstract
- Electron bifurcation is a fundamental energy coupling mechanism widespread in microorganisms that thrive under anoxic conditions. These organisms employ hydrogen to reduce CO2, but the molecular mechanisms have remained enigmatic. The key enzyme responsible for powering these thermodynamically challenging reactions is the electron-bifurcating [FeFe]-hydrogenase HydABC that reduces low-potential ferredoxins (Fd) by oxidizing hydrogen gas (H2). By combining single-particle cryo-electron microscopy (cryoEM) under catalytic turnover conditions with site-directed mutagenesis experiments, functional studies, infrared spectroscopy, and molecular simulations, we show that HydABC from the acetogenic bacteria Acetobacterium woodii and Thermoanaerobacter kivui employ a single flavin mononucleotide (FMN) cofactor to establish electron transfer pathways to the NAD(P)+ and Fd reduction sites by a mechanism that is fundamentally different from classical flavin-based electron bifurcation enzymes. By modulation of the NAD(P)+ binding affinity via reduction of a nearby iron–sulfur cluster, HydABC switches between the exergonic NAD(P)+ reduction and endergonic Fd reduction modes. Our combined findings suggest that the conformational dynamics establish a redox-driven kinetic gate that prevents the backflow of the electrons from the Fd reduction branch toward the FMN site, providing a basis for understanding general mechanistic principles of electron-bifurcating hydrogenases.
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- Kim, Hyunho, 1993-, et al.
(författare)
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Quinone Catalysis Modulates Proton Transfer Reactions in the Membrane Domain of Respiratory Complex I
- 2023
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Ingår i: Journal of the American Chemical Society. - 0002-7863 .- 1520-5126. ; 145:31, s. 17075-17086
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Tidskriftsartikel (refereegranskat)abstract
- Complex I is a redox-driven proton pump that drives electron transport chains and powers oxidative phosphorylation across all domains of life. Yet, despite recently resolved structures from multiple organisms, it still remains unclear how the redox reactions in Complex I trigger proton pumping up to 200 Å away from the active site. Here, we show that the proton-coupled electron transfer reactions during quinone reduction drive long-range conformational changes of conserved loops and trans-membrane (TM) helices in the membrane domain of Complex I from Yarrowia lipolytica. We find that the conformational switching triggers a π → α transition in a TM helix (TM3ND6) and establishes a proton pathway between the quinone chamber and the antiporter-like subunits, responsible for proton pumping. Our large-scale (>20 μs) atomistic molecular dynamics (MD) simulations in combination with quantum/classical (QM/MM) free energy calculations show that the helix transition controls the barrier for proton transfer reactions by wetting transitions and electrostatic effects. The conformational switching is enabled by re-arrangements of ion pairs that propagate from the quinone binding site to the membrane domain via an extended network of conserved residues. We find that these redox-driven changes create a conserved coupling network within the Complex I superfamily, with point mutations leading to drastic activity changes and mitochondrial disorders. On a general level, our findings illustrate how catalysis controls large-scale protein conformational changes and enables ion transport across biological membranes.
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| 9. |
- Malmevik, Josephine, et al.
(författare)
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microRNA and Neurodegenerative Diseases
- 2013
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Ingår i: microRNAs in Toxicology and Medicine. - 9781118401613
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Bokkapitel (refereegranskat)abstract
- During the past decade it has become evident that microRNAs regulate gene expressions and control many developmental and cellular processes in eukaryotic organisms. Recent studies suggest that microRNAs play an important role in toxicogenomics and are likely to play an important role in a range of human diseases including cancer. microRNAs in Toxicology and Medicine is a comprehensive and authoritative compilation of up-to-date developments in this emerging research area, presented by internationally recognized investigators. It focuses on the role of microRNA in biology and medicine with a special emphasis on toxicology. Divided into six parts, topics covered include:- microRNA and toxicology – including environmental toxicants and perturbation of miRNA signaling; microRNA, and Disease States featuring microRNAs in drug-induced liver toxicity, microRNAs and Inflammation the regulatory role of microRNA in mutagenesis, microRNAs and cancer, and the role of microRNAs in tumor progression and therapy, as well as current understanding of microRNAs as therapeutic targets in cancer- microRNAs and disease states- microRNAs and stem cells- microRNAs and genomics- microRNAs and epigenomics- microRNAs and biomarkers – including body fluid microRNAs as toxicological biomarkers, cell-free microRNAs as biomarkers in human diseases, and circulating microRNAs as biomarkers of drug-induced pancreatitismicroRNAs in Toxicology and Medicine is an essential insight into the current trends and future directions of research in this rapidly expanding field for investigators, toxicologists, risk assessors, and regulators in academia, medical settings, industry, and government.
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