| 1. |
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| 2. |
- Mullins, N., et al.
(författare)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 3. |
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| 4. |
- Jonsson, Lina, 1982, et al.
(författare)
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Characterisation of age and polarity at onset in bipolar disorder
- 2021
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Ingår i: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 219:6, s. 659-669
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Tidskriftsartikel (refereegranskat)abstract
- Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (beta = -0.34 years, s.e. = 0.08), major depression (beta = -0.34 years, s.e. = 0.08), schizophrenia (beta = -0.39 years, s.e. = 0.08), and educational attainment (beta = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
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| 5. |
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| 6. |
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| 7. |
- da Silva, R., et al.
(författare)
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Oxygen, sulfur, and iron radial abundance gradients of classical Cepheids across the Galactic thin disk
- 2023
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 678, s. A195-A195
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Tidskriftsartikel (refereegranskat)abstract
- Context. Classical Cepheids (CCs) are solid distance indicators and tracers of young stellar populations. Dating back to the beginning of the 20th century, they have been safely adopted to trace the rotation, kinematics, and chemical enrichment history of the Galactic thin disk.Aims. The main aim of this investigation is to provide iron, oxygen, and sulfur abundances for the largest and most homogeneous sample of Galactic CCs analyzed so far (1118 spectra of 356 objects). The current sample, containing 70 CCs for which spectroscopic metal abundances are provided for the first time, covers a wide range in galactocentric distances, pulsation modes, and pulsation periods.Methods. Optical high-resolution spectra with a high signal-to-noise ratio that were collected with different spectrographs were adopted to provide homogeneous estimates of the atmospheric parameters (effective temperature, surface gravity, and microturbulent velocity) that are required to determine the abundance. Individual distances were based either on trigonometric parallaxes by the Gaia Data Release 3 (Gaia DR3) or on distances based on near-infrared period-luminosity relations.Results. We found that iron and α-element radial gradients based on CCs display a well-defined change in the slope for galactocentric distances larger than ~12 kpc. We also found that logarithmic regressions account for the variation in [X/H] abundances from the inner to the outer disk. Radial gradients for the same elements, but based on open clusters covering a wide range in cluster ages, display similar trends. This means that the flattening in the outer disk is an intrinsic feature of the radial gradients because it is independent of age. Empirical evidence indicates that the S radial gradient is steeper than the Fe radial gradient. The difference in the slope is a factor of two in the linear fit (−0.081 vs. −0.041 dex kpc−1) and changes from −1.62 to −0.91 in the logarithmic distance. Moreover, we found that S (explosive nucleosynthesis) is underabundant on average when compared with O (hydrostatic nucleosynthesis). The difference becomes clearer in the metal-poor regime and for the [O/Fe] and [S/Fe] abundance ratios. We performed a detailed comparison with Galactic chemical evolution models and found that a constant star formation efficiency for galactocentric distances larger than 12 kpc accounts for the flattening observed in both iron and α-elements. To further constrain the impact of the predicted S yields for massive stars on radial gradients, we adopted a toy model and found that the flattening in the outermost regions requires a decrease of a factor of four in the current S predictions.Conclusions. CCs are solid beacons for tracing the recent chemical enrichment of young stellar populations. Sulfur photospheric abundances, when compared with other α-elements, have the key advantage of being a volatile element. Therefore, stellar S abundances can be directly compared with nebular sulfur abundances in external galaxies.
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| 8. |
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| 9. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 10. |
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| 11. |
- Biancari, Fausto, et al.
(författare)
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Multicenter study on postcardiotomy venoarterial extracorporeal membrane oxygenation
- 2020
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Ingår i: Journal of Thoracic and Cardiovascular Surgery. - : Elsevier BV. - 0022-5223 .- 1097-685X. ; 159:5, s. 1844-1854
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The aim of this study was to identify the risk factors associated with early mortality after postcardiotomy venoarterial extracorporeal membrane oxygenation. Methods: This is an analysis of the postcardiotomy extracorporeal membrane oxygenation registry, a retrospective multicenter cohort study including 781 patients aged more than 18 years who required venoarterial extracorporeal membrane oxygenation for cardiopulmonary failure after cardiac surgery from 2010 to 2018 at 19 cardiac surgery centers. Results: After a mean venoarterial extracorporeal membrane oxygenation therapy of 6.9 ± 6.2 days, hospital and 1-year mortality were 64.4% and 67.2%, respectively. Hospital mortality after venoarterial extracorporeal membrane oxygenation therapy for more than 7 days was 60.5% (P = .105). Centers that had treated more than 50 patients with postcardiotomy venoarterial extracorporeal membrane oxygenation had a significantly lower hospital mortality than lower-volume centers (60.7% vs 70.7%, adjusted odds ratio, 0.58; 95% confidence interval, 0.41-0.82). The postcardiotomy extracorporeal membrane oxygenation score was derived by assigning a weighted integer to each independent pre–venoarterial extracorporeal membrane oxygenation predictors of hospital mortality as follows: female gender (1 point), advanced age (60-69 years, 2 points; ≥70 years, 4 points), prior cardiac surgery (1 point), arterial lactate 6.0 mmol/L or greater before venoarterial extracorporeal membrane oxygenation (2 points), aortic arch surgery (4 points), and preoperative stroke/unconsciousness (5 points). The hospital mortality rates according to the postcardiotomy extracorporeal membrane oxygenation score was 0 point, 45.6%; 1 point, 40.5%; 2 points, 51.1%; 3 points, 57.8%; 4 points, 70.7%; 5 points, 68.3%; 6 points, 77.5%; and 7 points or more, 89.7% (P < .0001). Conclusions: Age, female gender, prior cardiac surgery, preoperative acute neurologic events, aortic arch surgery, and increased arterial lactate were associated with increased risk of early mortality after postcardiotomy venoarterial extracorporeal membrane oxygenation. Center experience with postcardiotomy venoarterial extracorporeal membrane oxygenation may contribute to improved results.
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| 12. |
- Biancari, Fausto, et al.
(författare)
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Postcardiotomy Venoarterial Extracorporeal Membrane Oxygenation in Patients Aged 70 Years or Older
- 2019
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Ingår i: Annals of Thoracic Surgery. - : Elsevier BV. - 0003-4975 .- 1552-6259. ; 108:4, s. 1257-1264
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Forskningsöversikt (refereegranskat)abstract
- Background: There is uncertainty whether venoarterial extracorporeal membrane oxygenation (VA-ECMO) should be used in older patients with cardiopulmonary failure after cardiac surgery. Methods: This was a retrospective multicenter study of 781 patients who required postcardiotomy VA-ECMO for cardiopulmonary failure after adult cardiac surgery from 2010 to 2018 at 19 cardiac surgery centers. A parallel systematic review with meta-analysis of the literature was performed. Results: The hospital mortality in the overall Postcardiotomy Venoarterial Extracorporeal Membrane Oxygenation (PC-ECMO) series was 64.4%. A total of 255 patients were 70 years old or older (32.7%), and their hospital mortality was significantly higher than in younger patients (76.1% vs 58.7%; adjusted odds ratio, 2.199; 95% confidence interval [CI], 1.536 to 3.149). Arterial lactate level greater than 6 mmol/L before starting VA-ECMO was the only predictor of hospital mortality among patients 70 years old or older in univariate analysis (82.6% vs 70.4%; P =.029). Meta-analysis of current and previous studies showed that early mortality after postcardiotomy VA-ECMO was significantly higher in patients aged 70 years or older compared with younger patients (odds ratio, 2.09; 95% CI, 1.59 to 2.75; 5 studies including 1547 patients; I2, 5.9%). The pooled early mortality rate among patients aged 70 years or older was 78.8% (95% CI, 74.1 to 83.5; 6 studies including 617 patients; I2, 41.8%). Two studies reported 1-year mortality (including hospital mortality) of 79.9% and 75.6%, respectively, in patients 70 years old or older. Conclusions: Advanced age should not be considered a contraindication for postcardiotomy VA-ECMO. However, in view of the high risk of early mortality, meaningful scrutiny is needed before using VA-ECMO after cardiac surgery in older patients.
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| 13. |
- Calvert, Clara, et al.
(författare)
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Changes in preterm birth and stillbirth during COVID-19 lockdowns in 26 countries
- 2023
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Ingår i: Nature Human Behaviour. - : Springer Nature. - 2397-3374. ; 7:4, s. 529-544
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Tidskriftsartikel (refereegranskat)abstract
- Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways.
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| 14. |
- Combs, Stephanie E., et al.
(författare)
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ESTRO ACROP guideline for target volume delineation of skull base tumors
- 2021
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Ingår i: Radiotherapy and Oncology. - : Elsevier. - 0167-8140 .- 1879-0887. ; 156, s. 80-94
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: For skull base tumors, target definition is the key to safe high-dose treatments because surrounding normal tissues are very sensitive to radiation. In the present work we established a joint ESTRO ACROP guideline for the target volume definition of skull base tumors.Material and methods: A comprehensive literature search was conducted in PubMed using various combinations of the following medical subjects headings (MeSH) and free-text words: “radiation therapy” or “stereotactic radiosurgery” or “proton therapy” or “particle beam therapy” and “skull base neoplasms” “pituitary neoplasms”, “meningioma”, “craniopharyngioma”, “chordoma”, “chondrosarcoma”, “acoustic neuroma/vestibular schwannoma”, “organs at risk”, “gross tumor volume”, “clinical tumor volume”, “planning tumor volume”, “target volume”, “target delineation”, “dose constraints”. The ACROP committee identified sixteen European experts in close interaction with the ESTRO clinical committee who analyzed and discussed the body of evidence concerning target delineation.Results: All experts agree that magnetic resonance (MR) images with high three-dimensional spatial accuracy and tissue-contrast definition, both T2-weighted and volumetric T1-weighted sequences, are required to improve target delineation. In detail, several key issues were identified and discussed: i) radiation techniques and immobilization, ii) imaging techniques and target delineation, and iii) technical aspects of radiation treatments including planning techniques and dose-fractionation schedules. Specific target delineation issues with regard to different skull base tumors, including pituitary adenomas, meningiomas, craniopharyngiomas, acoustic neuromas, chordomas and chondrosarcomas are presented.Conclusions: This ESTRO ACROP guideline achieved detailed recommendations on target volume definition for skull base tumors, as well as comprehensive advice about imaging modalities and radiation techniques.
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| 15. |
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| 16. |
- Dorofte, Luiza, 1982-, et al.
(författare)
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Low level of interobserver concordance in assessing histological subtype and tumor grade in patients with penile cancer may impair patient care
- 2022
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Ingår i: Virchows Archiv. - : Springer. - 0945-6317 .- 1432-2307. ; 480:4, s. 879-886
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Tidskriftsartikel (refereegranskat)abstract
- Differentiation between penile squamous cell carcinoma patients who can benefit from limited organ-sparing surgery and those at significant risk of lymph node metastasis is based on histopathological prognostic factors including histological grade and tumor histological subtype. We examined levels of interobserver and intraobserver agreement in assessment of histological subtype and grade in 207 patients with penile squamous cell carcinoma. The cases were assessed by seven pathologists from three hospitals located in Sweden and Italy. There was poor to moderate concordance in assessing both histological subtype and grade, with Fleiss kappas of 0.25 (range: 0.02-0.48) and 0.23 (range: 0.07-0.55), respectively. When choosing HPV-associated and non-HPV-associated subtypes, interobserver concordance ranged from poor to good, with a Fleiss kappa value of 0.36 (range: 0.02-0.79). A re-review of the slides by two of the pathologists showed very good intraobserver concordance in assessing histological grade and subtype, with Cohen's kappa values of 0.94 and 0.91 for grade and 0.95 and 0.84 for subtype. Low interobserver concordance could lead to undertreatment and overtreatment of many patients with penile cancer, and brings into question the utility of tumor histological subtype and tumor grade in determining patient treatment in pT1 tumors.
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| 17. |
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| 18. |
- Fiorentino, M., et al.
(författare)
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Immunohistochemical Expression of BRCA1 in Prostate Cancer
- 2009
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Ingår i: Laboratory Investigation. - : Nature Publishing Group. - 0023-6837 .- 1530-0307. ; 22, s. 169A-169A
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: BRCA1 is a multifunctional protein involved in DNA repair, gene transcription and the regulation of cell-cycle check-points. While germline mutations of BRCA1 are rare in prostate cancer and seem to play a limited role in tumor susceptibility, BRCA1 expression has not been investigated to date.Design: We analyzed the immunohistochemical expression of BRCA1 in paraffin embedded samples from 524 men with prostate cancer belonging to the Physicians’ Health Study and the Swedish Watchful Waiting cohorts of prostate cancer patients. High density tissue micro-arrays (TMA) including at least three tumor cores for each case were utilized for the immunohistochemical staining with the monoclonal MS110 antibody specific for the N-terminus of the 220 kDa BRCA1 protein. Cases were scored as negative or positive for BRCA1 immunostaining. The Ki67 proliferation index was also assessed on the same TMAs and evaluated by quantitative image analysis.Results: A positive nuclear immunostaining for BRCA1 was revealed in 62 of 524 (11.9%) patients while normal prostate control cores were all negative. BRCA1 positive tumors were associated with 4 times greater proliferation rate compared to BRCA1 negative tumors (p ∼ 0.0003). In addition, we found a linear trend such that tumors with greater number of TMA cores expressing BRCA1 had stronger extent of proliferation. Men with BRCA1 positive tumors had a slightly higher Gleason’s score (mean 7.5) compared to those negative for BRCA1 (mean 7) No significant correlation was found between BRCA1 staining and cancer-specific death.Conclusions: BRCA1 protein is expressed in a small subset of prostate cancers characterized by high proliferation index but not in normal prostate tissue. Expression of BRCA1 might be acquired in selected tumors to prevent DNA damage in actively replicating cells. A different role independent of germline mutations might be disclosed for BRCA1 as cell cycle regulator in prostate cancer.
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| 19. |
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| 20. |
- KC, Ashish, 1982-, et al.
(författare)
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Changes in preterm birth and stillbirth during COVID-19 lockdowns in 26 countries.
- 2023
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Ingår i: Nature human behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 7:4, s. 529-544
-
Tidskriftsartikel (refereegranskat)abstract
- Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways.
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| 21. |
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| 22. |
- Maverakis, Emanual, et al.
(författare)
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International consensus criteria for the diagnosis of Raynaud's phenomenon.
- 2014
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411. ; 48-49:Jan 31, s. 60-65
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Tidskriftsartikel (refereegranskat)abstract
- Vasoconstriction accompanied by changes in skin color is a normal physiologic response to cold. The distinction between this normal physiology and Raynaud's phenomenon (RP) has yet to be well characterized. In anticipation of the 9th International Congress on Autoimmunity, a panel of 12 RP experts from 9 different institutes and four different countries were assembled for a Delphi exercise to establish new diagnostic criteria for RP. Relevant investigators with highly cited manuscripts in Raynaud's-related research were identified using the Web of Science and invited to participate. Surveys at each stage were administered to participants via the on-line SurveyMonkey software tool. The participants evaluated the level of appropriateness of statements using a scale of 1 (extremely inappropriate) through 9 (extremely appropriate). In the second stage, panel participants were asked to rank rewritten items from the first round that were scored as "uncertain" for the diagnosis of RP, items with significant disagreement (Disagreement Index > 1), and new items suggested by the panel. Results were analyzed using the Interpercentile Range Adjusted for Symmetry (IPRAS) method. A 3-Step Approach to diagnose RP was then developed using items the panelists "agreed" were "appropriate" diagnostic criteria. In the final stage, the panel was presented with the newly developed diagnostic criteria and asked to rate them against previous models. Following the first two iterations of the Delphi exercise, the panel of 12 experts agreed that 36 of the items were "appropriate", 12 items had "uncertain" appropriateness, and 13 items were "inappropriate" to use in the diagnostic criteria of RP. Using an expert committee, we developed a 3-Step Approach for the diagnosis of RP and 5 additional criteria for the diagnosis of primary RP. The committee came to an agreement that the proposed criteria were "appropriate and accurate" for use by physicians to diagnose patients with RP.
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| 23. |
- Mazzeschi, M., et al.
(författare)
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The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer
- 2022
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Ingår i: Journal of Experimental & Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966. ; 41:1
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Tidskriftsartikel (refereegranskat)abstract
- Background In the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs). Methods In this work, we performed a meta-analysis of CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested cell lines, patient-derived organoids and mice with potent ALK inhibitors, already approved for clinical use. Results ALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the dynamic formation of 3D tumor spheroids. Consistently, ALK appeares constitutively phosphorylated in CMS1, and it signals mainly through the AKT axis. Mechanistically, we found that CMS1 cells display several copies of ALKAL2 ligand and ALK-mRNAs, suggesting an autocrine loop mediated by ALKAL2 in the activation of ALK pathway, responsible for the invasive phenotype. Consequently, disruption of ALK axis mediates the pro-apoptotic action of CMS1 cell lines, both in 2D and 3D and enhanced cell-cell adhesion and e-cadherin organization. In agreement with all these findings, the ALK signature encompassing 65 genes statistically associated with worse relapse-free survival in CMS1 subtype. Finally, as a proof of concept, the efficacy of ALK inhibition was demonstrated in both patient-derived organoids and in tumor xenografts in vivo. Conclusions Collectively, these findings suggest that ALK targeting may represent an attractive therapy for CRC, and CMS classification may provide a useful tool to identify patients who could benefit from this treatment. These findings offer rationale and pharmacological strategies for the treatment of CMS1 CRC.
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| 24. |
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| 25. |
- Rong, Y., et al.
(författare)
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High speed optical modulation in Ge quantum wells using quantum confined stark effect
- 2012
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Ingår i: Frontiers of Optoelectronics. - : Springer Science and Business Media LLC. - 2095-2759 .- 2095-2767. ; 5:1, s. 82-89
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Tidskriftsartikel (refereegranskat)abstract
- We focus on the optimization of SiGe material deposition, the minimization of the parasitic capacitance of the probe pads for high speed, low voltage and high contrast ratio operation. The device fabrication is based on processes for standard Si electronics and is suitable for mass-production. We present observations of quantum confinement and quantum-confined Stark effect (QCSE) electroabsorption in Ge quantum wells (QWs) with SiGe barriers grown on Si substrates. Though Ge is an indirect gap semiconductor, the resulting effects are at least as clear and strong as seen in typical III-V QWstructures at similar wavelengths. We also demonstrated a modulator, with eye diagrams of up to 3. 5 GHz, a small driving voltage of 2. 5 V and a modulation bandwidth at about 10 GHz. Finally, carrier dynamics under ultra-fast laser excitation and high-speed photocurrent response are investigated.
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| 26. |
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| 27. |
- Valentino, G, et al.
(författare)
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NMR-Based Plant Metabolomics in Nutraceutical Research: An Overview
- 2020
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Ingår i: Molecules (Basel, Switzerland). - : MDPI AG. - 1420-3049. ; 25:6
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Tidskriftsartikel (refereegranskat)abstract
- Few topics are able to channel the interest of researchers, the public, and industries, like nutraceuticals. The ever-increasing demand of new compounds or new sources of known active compounds, along with the need of a better knowledge about their effectiveness, mode of action, safety, etc., led to a significant effort towards the development of analytical approaches able to answer the many questions related to this topic. Therefore, the application of cutting edges approaches to this area has been observed. Among these approaches, metabolomics is a key player. Herewith, the applications of NMR-based metabolomics to nutraceutical research are discussed: after a brief overview of the analytical workflow, the use of NMR-based metabolomics to the search for new compounds or new sources of known nutraceuticals are reviewed. Then, possible applications for quality control and nutraceutical optimization are suggested. Finally, the use of NMR-based metabolomics to study the impact of nutraceuticals on human metabolism is discussed.
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