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Article ; Online: Thermal Proteome Profiling Reveals Distinct Target Selectivity for Differentially Oxidized Oxysterols.

Rossetti, Cecilia / Laraia, Luca

ACS chemical biology

2022 Volume 17, Issue 7, Page(s) 1677–1684

Abstract: Oxysterols are produced physiologically by many species; however, their distinct roles in regulating human physiology have not been studied systematically. The role of differing oxidation states and sites in mediating their biological functions is also ... ...

Abstract	Oxysterols are produced physiologically by many species; however, their distinct roles in regulating human physiology have not been studied systematically. The role of differing oxidation states and sites in mediating their biological functions is also unclear. As oxysterols have been associated with atherosclerosis, neurodegeneration, and cancer, a better understanding of their protein targets is desirable. To address this, we mapped the oxysterol interactome with three A- and B-ring oxidized sterols as well as 25-hydroxy cholesterol using thermal proteome profiling, validating selected targets with the cellular thermal shift assay and isothermal dose response fingerprinting. This revealed that the site of oxidation has a profound impact on target selectivity, with each oxysterol possessing an almost unique set of target proteins. Overall, targets clustered in pathways relating to vesicular transport and phosphoinositide metabolism, suggesting that while individual oxysterols bind to a unique set of proteins, the processes they modulate are highly interconnected.
MeSH term(s)	Cholesterol/metabolism ; Humans ; Oxidation-Reduction ; Oxysterols ; Proteome/metabolism ; Sterols
Chemical Substances	Oxysterols ; Proteome ; Sterols ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2022-06-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.2c00383
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Article: Identification of non-conventional small molecule degraders and stabilizers of squalene synthase.

Hoock, Joseph G F / Rossetti, Cecilia / Bilgin, Mesut / Depta, Laura / Enemark-Rasmussen, Kasper / Christianson, John C / Laraia, Luca

Chemical science

2023 Volume 14, Issue 45, Page(s) 12973–12983

Abstract: Squalene synthase (SQS) is an essential enzyme in the mevalonate pathway, which controls cholesterol biosynthesis and homeostasis. Although catalytic inhibitors of SQS have been developed, none have been approved for therapeutic use so far. Herein we ... ...

Abstract	Squalene synthase (SQS) is an essential enzyme in the mevalonate pathway, which controls cholesterol biosynthesis and homeostasis. Although catalytic inhibitors of SQS have been developed, none have been approved for therapeutic use so far. Herein we sought to develop SQS degraders using targeted protein degradation (TPD) to lower overall cellular cholesterol content. We found that KY02111, a small molecule ligand of SQS, selectively causes SQS to degrade in a proteasome-dependent manner. Unexpectedly, compounds based on the same scaffold linked to E3 ligase recruiting ligands led to SQS stabilization. Proteomic analysis found KY02111 to reduce only the levels of SQS, while lipidomic analysis determined that KY02111-induced degradation lowered cellular cholesteryl ester content. Stabilizers shielded SQS from its natural turnover without recruiting their matching E3 ligase or affecting enzymatic target activity. Our work shows that degradation of SQS is possible despite a challenging biological setting and provides the first chemical tools to degrade and stabilize SQS.
Language	English
Publishing date	2023-10-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2559110-1
ISSN	2041-6539 ; 2041-6520
ISSN (online)	2041-6539
ISSN	2041-6520
DOI	10.1039/d3sc04064j
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Article: Perimount MAGNA Ease vs. INSPIRIS Resilia Valve: A PS-Matched Analysis of the Hemodynamic Performances in Patients below 70 Years of Age.

Francica, Alessandra / Tonelli, Filippo / Rossetti, Cecilia / Galeone, Antonella / Perrone, Fabiola / Luciani, Giovanni Battista / Onorati, Francesco

Journal of clinical medicine

2023 Volume 12, Issue 5

Abstract: Background: During the past decade, the Perimount Magna Ease (PME) bioprosthesis has been implanted worldwide for aortic valve replacement (AVR). Recently, the INSPIRIS Resilia (IR) valve has been introduced as the newest generation of pericardial ... ...

Abstract	Background: During the past decade, the Perimount Magna Ease (PME) bioprosthesis has been implanted worldwide for aortic valve replacement (AVR). Recently, the INSPIRIS Resilia (IR) valve has been introduced as the newest generation of pericardial bioprostheses. However, few data have been reported about patients ≤70 years, and no comparisons in terms of hemodynamic performance between these two bioprostheses have been ever reported. Methods: Patients aged <70 years undergoing AVR were considered for comparison between PME ( Results: A total of 122 pairs with similar baseline characteristics were obtained from the PS-matching. The two prostheses showed comparable hemodynamic performances at one year (Gmean: 11.3 ± 3.5 mmHg vs. 11.9 ± 5.4 mmHg; Conclusions: This first PS-matched analysis demonstrated that the newly developed IR valve achieves the same safety and efficacy of the PME valve during mid-term follow-up in patients aged <70 years.
Language	English
Publishing date	2023-03-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm12052077
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Article: Value of Perioperative Chest X-ray for the Prediction of Sternal Wound Complications after Cardiac Surgery in High-Risk Patients: A "Work in Progress" Analysis.

Ardigò, Andrea / Francica, Alessandra / Veraldi, Gian Franco / Tropea, Ilaria / Tonelli, Filippo / Rossetti, Cecilia / Onorati, Francesco / Faggian, Giuseppe

Journal of clinical medicine

2021 Volume 10, Issue 2

Abstract: Background: Sternal wound complications are serious events that occur after cardiac surgery. Few studies have investigated the predictive value of chest X-ray radiological measurements for sternal complications.: Methods: Several perioperative ... ...

Abstract	Background: Sternal wound complications are serious events that occur after cardiac surgery. Few studies have investigated the predictive value of chest X-ray radiological measurements for sternal complications. Methods: Several perioperative radiological measurements at chest X-ray and clinical characteristics were computed in 849 patients deemed at high risk for sternal dehiscence (SD) or More than Grade 1 Surgical Site Infection (MG1-SSI). Multivariable analysis identified independent predictors, whilst receiver operating characteristics (ROC) curve analyses highlighted cut-off values of radiological measurements for the prediction of both complications. Results: SD occurred in 8.8% of the patients, MG1-SSI in 6.8%. Chronic obstructive pulmonary disease (COPD) was the only independent predictor for SD (Odds Ratio, O.R. 12.1; Conclusion: PSH and iPSH at preoperative chest X-ray may act as indicators of high risk for sternal wound complications, allowing for early preventative measures.
Language	English
Publishing date	2021-01-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm10020207
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Article: Cardioplegia between Evolution and Revolution: From Depolarized to Polarized Cardiac Arrest in Adult Cardiac Surgery.

Francica, Alessandra / Tonelli, Filippo / Rossetti, Cecilia / Tropea, Ilaria / Luciani, Giovanni Battista / Faggian, Giuseppe / Dobson, Geoffrey Phillip / Onorati, Francesco

Journal of clinical medicine

2021 Volume 10, Issue 19

Abstract: Despite current advances in perioperative care, intraoperative myocardial protection during cardiac surgery has not kept the same pace. High potassium cardioplegic solutions were introduced in the 1950s, and in the early 1960s they were soon recognized ... ...

Abstract	Despite current advances in perioperative care, intraoperative myocardial protection during cardiac surgery has not kept the same pace. High potassium cardioplegic solutions were introduced in the 1950s, and in the early 1960s they were soon recognized as harmful. Since that time, surgeons have minimized many of the adverse effects by lowering the temperature of the heart, lowering K
Language	English
Publishing date	2021-09-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm10194485
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Article ; Online: Short-term outcome of adenosine-lidocaine-magnesium polarizing cardioplegia in humans.

Francica, Alessandra / Vaccarin, Arianna / Dobson, Geoffrey Phillip / Rossetti, Cecilia / Gardellini, Jacopo / Faggian, Giuseppe / Onorati, Francesco

European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery

2021 Volume 61, Issue 5, Page(s) 1125–1132

Abstract: Objectives: Hyperkalaemic depolarized myocardial arrest is the cornerstone of myocardial protection, although some potassium-related cytotoxicity has been demonstrated. Polarized arrest has gained interest because of a reported better myocardial ... ...

Abstract	Objectives: Hyperkalaemic depolarized myocardial arrest is the cornerstone of myocardial protection, although some potassium-related cytotoxicity has been demonstrated. Polarized arrest has gained interest because of a reported better myocardial protection in preclinical studies. The goal of this study was to analyse the quality of myocardial protection and hospital outcome after normokalaemic adenosine-lidocaine-magnesium (ALM) blood polarizing cardioplegia, compared to hyperkalaemic blood Buckberg depolarizing cardioplegia, in elective routine adult cardiac surgery. Methods: One thousand consecutive elective adult cardiac patients [627 undergoing ALM-polarizing cardioplegia (ALM-POL) vs 373 Buckberg depolarized cardioplegia (BUCK-DEPOL)] who were operated on were analysed. Perioperative leakage of high-sensitivity troponin I (Hs-TnI), peripheral lactate, inotropic and vasoactive daily requirement [maximal vasoactive inotropic score (VISMAX)], hospital mortality and morbidity were collected and compared in the overall population and in the propensity score (PS) matched population (206 pairs). Results: A significantly lower leakage of Hs-TnI during hospitalization was detected in patients receiving ALM-POL versus those receiving BUCK-DEPOL (group time P < 0.001 for overall population and PS matched pairs). The maximum value of postoperative Hs-TnI was also lower after ALM-POL (P < 0.001 in both cohorts), and spontaneous recovery of sinus rhythm at aortic declamping was higher (P < 0.001 in favour of ALM-POL). Maximal VISMAX during hospitalization was significantly higher after BUCK-DEPOL in both cohorts (P = 0.019 for overall population; P = 0.031 for PS matched population), with significantly higher VISMAX on the day of surgery in BUCK-DEPOL PS matched patients (P = 0.042). No other significant differences in hospital morbidity and mortality were found. Conclusions: Despite comparable short-term clinical outcomes, ALM-POL cardioplegia proved superior in terms of quality of myocardial protection compared to BUCK-DEPOL cardioplegia in elective routine adult cardiac surgery.
MeSH term(s)	Adenosine ; Adult ; Cardioplegic Solutions/therapeutic use ; Heart Arrest, Induced/adverse effects ; Humans ; Lidocaine ; Magnesium
Chemical Substances	Cardioplegic Solutions ; Lidocaine (98PI200987) ; Magnesium (I38ZP9992A) ; Adenosine (K72T3FS567)
Language	English
Publishing date	2021-11-09
Publishing country	Germany
Document type	Journal Article
ZDB-ID	639293-3
ISSN	1873-734X ; 1010-7940 ; 1567-4258
ISSN (online)	1873-734X
ISSN	1010-7940 ; 1567-4258
DOI	10.1093/ejcts/ezab466
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Article: Correction to: Exploring the peptide retention mechanism in molecularly imprinted polymers

Rossetti, Cecilia / Odd Gøran Ore / Börje Sellergren / Trine Grønhaug Halvorsen / Léon Reubsaet

Analytical and bioanalytical chemistry. 2018 Feb., v. 410, no. 5

2018

Abstract: The authors would like to call the reader’s attention to the fact that unfortunately due to the file formatting during the exporting of the data matrix from the program Unscrambler (used for the development of the statistical model) to the Word office ... ...

Abstract	The authors would like to call the reader’s attention to the fact that unfortunately due to the file formatting during the exporting of the data matrix from the program Unscrambler (used for the development of the statistical model) to the Word office file.
Keywords	molecular imprinting ; peptides ; polymers ; statistical models
Language	English
Dates of publication	2018-02
Size	p. 1607-1608.
Publishing place	Springer Berlin Heidelberg
Document type	Article
Note	Published Erratum
ISSN	1618-2642
DOI	10.1007/s00216-017-0797-5
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Article: Transapical Transcatheter Aortic Valve Replacement: A Real-World Early and Mid-Term Outcome of a Third-Level Centre.

Francica, Alessandra / Tonelli, Filippo / Saran, Alberto / Pesarini, Gabriele / Vendramin, Igor / Tabbì, Rocco / Rossetti, Cecilia / Luciani, Giovanni Battista / Ribichini, Flavio L / Onorati, Francesco

Journal of clinical medicine

2022 Volume 11, Issue 14

Abstract: Background: Transapical transcatheter aortic valve replacement (TA-TAVR) is generally considered to be associated with higher morbidity compared with transfemoral-TAVR. However, TA-TAVR remains a feasible alternative for patients who are unsuitable for ... ...

Abstract	Background: Transapical transcatheter aortic valve replacement (TA-TAVR) is generally considered to be associated with higher morbidity compared with transfemoral-TAVR. However, TA-TAVR remains a feasible alternative for patients who are unsuitable for TF-TAVR. It has been shown that outcomes after TAVR are linked to the operator's expertise. Therefore, the purpose of this study is to report short- and mid-term outcomes after TA-TAVR performed by an expert Heart-Team of a third-level centre. Methods: From 2015 to 2022, 154 consecutive patients underwent TA-TAVR. The outcomes were analysed according to the VARC-3 criteria. Kaplan-Meier curves were estimated for major clinical events at mid-term follow-up. Results: The mean age of the population was 79.3 years and the STS risk-score of mortality was 4.2 ± 3.6%. Periprocedural mortality was 1.9%. Acute kidney injury and prolonged ventilation occurred in 1.9%. Incidence of stroke was 0.6%. Pacemaker implantation rate was 1.9%. Freedom from cardiovascular mortality was 75.7%, and 60.2% at 3 and 5 years. Freedom from stroke was 92.3% and 88.9% at 3 and 5 years, respectively; freedom from endocarditis was 94.4% and 90.8% at 3 and 5 years, respectively. Conclusion: TA-TAVR may be considered a safe and effective alternative approach in patients unsuitable for TF-TAVR, especially when performed by a proficient Heart-Team.
Language	English
Publishing date	2022-07-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm11144158
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Article: Exploring the peptide retention mechanism in molecularly imprinted polymers

Rossetti, Cecilia / Odd Gøran Ore / Börje Sellergren / Trine Grønhaug Halvorsen / Léon Reubsaet

Analytical and bioanalytical chemistry. 2017 Sept., v. 409, no. 24

2017

Abstract: Molecularly imprinted polymers (MIPs) have been used as useful sorbents in solid-phase extraction for a wide range of molecules and sample matrices. Their unique selectivity can be fine-tuned in the imprinting process and is crucial for the extraction of ...

Abstract	Molecularly imprinted polymers (MIPs) have been used as useful sorbents in solid-phase extraction for a wide range of molecules and sample matrices. Their unique selectivity can be fine-tuned in the imprinting process and is crucial for the extraction of macromolecules from complex matrices such as serum. A relevant example of this is the application of MIPs to peptides in diagnostic assays. In this article the selectivity of MIPs, previously implemented in a quantitative mass-spectrometric assay for the biomarker pro-gastrin-releasing peptide, is investigated. Partial least squares regression was used to generate models for the evaluation and prediction of the retention mechanism of MIPs. A hypothesis on interactions of MIPs with the target peptide was verified by ad hoc experiments considering the relevant peptide physicochemical properties highlighted from the multivariate analysis. Novel insights into and knowledge of the driving forces responsible for the MIP selectivity have been obtained and can be directly used for further optimization of MIP imprinting strategies. Graphical Abstract Applied analytical strategy: the Solid Phase Extraction (SPE) of digested Bovin Serum Albumin (BSA), using Molecularly Imprinted Polymers (MIP), is followed by the liquid chromatography-mass spectrometry (LC-MS) analysis for the identification of the retained peptides. The further application of multivariate analysis allows setting up a Partial Least Square (PLS) model, which describes the peptide retention into the MIP and gives additional knowledge to be used in the optimization of the MIP and the whole SPE method
Keywords	biomarkers ; blood serum ; least squares ; liquid chromatography ; mass spectrometry ; models ; peptides ; physicochemical properties ; polymers ; prediction ; serum albumin ; solid phase extraction ; sorbents
Language	English
Dates of publication	2017-09
Size	p. 5631-5643.
Publishing place	Springer Berlin Heidelberg
Document type	Article
ISSN	1618-2642
DOI	10.1007/s00216-017-0520-6
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Evaluation of affinity-based serum clean-up in mass spectrometric analysis: Plastic vs monoclonal antibodies.

Rossetti, Cecilia / Levernæs, Maren C S / Reubsaet, Léon / Halvorsen, Trine G

Journal of chromatography. A

2016 Volume 1471, Page(s) 19–26

Abstract: Mass spectrometric assays are now of great relevance for trace compound analysis in complex matrices such as serum and plasma samples. Especially in the quantification of low abundant protein-biomarkers, the choice of the sample preparation is crucial. ... ...

Abstract	Mass spectrometric assays are now of great relevance for trace compound analysis in complex matrices such as serum and plasma samples. Especially in the quantification of low abundant protein-biomarkers, the choice of the sample preparation is crucial. In the present paper immunocapture and Molecular Imprinted Polymers (MIPs) have been applied in the determination of pro-gastrin-releasing peptide, a Small Cell Lung Cancer marker. These affinity-based techniques were compared in terms of matrix effect, limits of detection, repeatability and extraction specificity. In addition, protein precipitation was included for comparison as it is a typical sample preparation method of biological matrices. The results highlighted differences in the methods' performance and specificity, strongly affecting the outcome of the mass spectrometric determination. Plastic and monoclonal antibodies confirmed to be sensitive and specific sample preparations able to determine ProGRP at clinical relevant concentration, although only the use of monoclonal antibodies allowed the reliable quantification of ProGRP at reference levels (8pM). In addition better insight in the specificity of the three sample preparation techniques was gained. This might also be of interest for other biological applications.
MeSH term(s)	Antibodies, Monoclonal/metabolism ; Biomarkers, Tumor/blood ; Blood Chemical Analysis/methods ; Chromatography, Liquid ; Humans ; Mass Spectrometry ; Peptides/blood ; Plastics/metabolism ; Protein Precursors/blood ; Sensitivity and Specificity ; Serum/chemistry ; Small Cell Lung Carcinoma/blood
Chemical Substances	Antibodies, Monoclonal ; Biomarkers, Tumor ; Peptides ; Plastics ; Protein Precursors ; gastrin-releasing peptide precursor
Language	English
Publishing date	2016-11-04
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1171488-8
ISSN	1873-3778 ; 0021-9673
ISSN (online)	1873-3778
ISSN	0021-9673
DOI	10.1016/j.chroma.2016.09.069
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