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  • 1
    Online Resource
    Online Resource
    The Spliceosome: A New Therapeutic Target in Chronic Myeloid Leukaemia
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 19 ( 2022-09-27), p. 4695-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 19 ( 2022-09-27), p. 4695-
    Abstract: RNA splicing factors are frequently altered in cancer and can act as both oncoproteins and tumour suppressors. They have been found mutated or deregulated, justifying the growing interest in the targeting of splicing catalysis, splicing regulatory proteins, and/or specific, key altered splicing events. We recently showed that the DNA methylation alterations of CD34+CD15− chronic myeloid leukaemia (CML) cells affect, among others, alternative splicing genes, suggesting that spliceosome actors might be altered in chronic-phase (CP)-CML. We investigated the expression of 12 spliceosome genes known to be oncogenes or tumour suppressor genes in primary CP-CML CD34+ cells at diagnosis (n = 15). We found that CP-CML CD34+ cells had a distinct splicing signature profile as compared with healthy donor CD34+ cells or whole CP-CML cells, suggesting: (i) a spliceosome deregulation from the diagnosis time and (ii) an intraclonal heterogeneity. We could identify three profile types, but there was no relationship with a patient’s characteristics. By incubating cells with TKI and/or a spliceosome-targeted drug (TG003), we showed that CP-CML CD34+ cells are both BCR::ABL and spliceosome dependent, with the combination of the two drugs showing an additive effect while sparing healthy donors cells. Our results suggest that the spliceosome may be a new potential target for the treatment of CML.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14194695
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 2
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    Conditional Knockdown of Osteopontin Inhibits Breast Cancer Skeletal Metastasis
    MDPI AG ; 2019
    In:  International Journal of Molecular Sciences Vol. 20, No. 19 ( 2019-10-04), p. 4918-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 20, No. 19 ( 2019-10-04), p. 4918-
    Abstract: High osteopontin (OPN) expression is linked to breast cancer bone metastasis. In this study we modulated osteopontin levels conditionally and investigated any related antineoplastic effects. Therefore, we established cell clones from human breast cancer MDA-MB-231 cells, in which the expression of OPN is regulated by the Tet-Off tet-off system. These cells, which conditionally express a specific miRNA targeting OPN, were used for in vitro studies as well as for a bone metastasis model in nude rats. Changes in whole-genome expression elicited by conditional OPN knockdown and vesicle formation were also analyzed. The alkylphosphocholine erufosine was used for combination therapy. Conditional OPN knockdown caused mild anti-proliferative, but more intensive anti-migratory and anti clonogenic effects, as well as partial and complete remissions of soft tissue and osteolytic lesions. These effects were associated with specific gene and protein expression modulations following miRNA-mediated OPN knockdown. Furthermore, high levels of OPN were detected in vesicles derived from rats harboring breast cancer skeletal metastases. Finally, the combination of OPN inhibition and erufosine treatment caused an additive reduction of OPN levels in the investigated breast cancer cells. Thus, knockdown of OPN alone or in combination with erufosine is a promising strategy in breast cancer skeletal metastasis treatment.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms20194918
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 3
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    A Proteomics-Based Analysis Reveals Predictive Biological Patterns in Fabry Disease
    MDPI AG ; 2020
    In:  Journal of Clinical Medicine Vol. 9, No. 5 ( 2020-05-02), p. 1325-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 9, No. 5 ( 2020-05-02), p. 1325-
    Abstract: Background: Fabry disease (FD) is an X-linked progressive lysosomal disease (LD) due to glycosphingolipid metabolism impairment. Currently, plasmatic globotriaosylsphingosine (LysoGb3) is used for disease diagnosis and monitoring. However, this biomarker is inconstantly increased in mild forms and in some female patients. Materials and Methods: We applied a targeted proteomic approach to explore disease-related biological patterns that might explain the disease pathophysiology. Forty proteins, involved mainly in inflammatory and angiogenesis processes, were assessed in 69 plasma samples retrieved from the French Fabry cohort (FFABRY) and from 83 healthy subjects. For predictive performance assessment, we also included other LD samples (Gaucher, Pompe and Niemann Pick C). Results: The study yielded four discriminant proteins that include three angiogenesis proteins (fibroblast growth factor 2 (FGF2), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor C (VEGFC)) and one cytokine interleukin 7 (IL-7). A clear elevation of FGF2 and IL-7 concentrations was observed in FD compared to other LD samples. No correlation was observed between these proteins and globotriaosylsphingosine (LysoGb3). A significant correlation exists between IL-7 and residual enzyme activity in a non-classical phenotype. This highlights the orthogonal biological information yielded by these proteins that might help in stratifying Fabry patients. Conclusion: This work highlights the potential of using proteomics approaches in exploring FD and enhancing FD diagnosis and therapeutic monitoring performances.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm9051325
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2662592-1
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  • 4
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    A Robust One-Step Recombineering System for Enterohemorrhagic Escherichia coli
    MDPI AG ; 2022
    In:  Microorganisms Vol. 10, No. 9 ( 2022-08-23), p. 1689-
    Details
    In: Microorganisms, MDPI AG, Vol. 10, No. 9 ( 2022-08-23), p. 1689-
    Abstract: Enterohemorrhagic Escherichia coli (EHEC) can cause severe diarrheic in humans. To improve therapy options, a better understanding of EHEC pathogenicity is essential. The genetic manipulation of EHEC with classical one-step methods, such as the transient overexpression of the phage lambda (λ) Red functions, is not very efficient. Here, we provide a robust and reliable method for increasing recombineering efficiency in EHEC based on the transient coexpression of recX together with gam, beta, and exo. We demonstrate that the genetic manipulation is 3–4 times more efficient in EHEC O157:H7 EDL933 Δstx1/2 with our method when compared to the overexpression of the λ Red functions alone. Both recombineering systems demonstrated similar efficiencies in Escherichia coli K-12 MG1655. Coexpression of recX did not enhance the Gam-mediated inhibition of sparfloxacin-mediated SOS response. Therefore, the additional inhibition of the RecFOR pathway rather than a stronger inhibition of the RecBCD pathway of SOS response induction might have resulted in the increased recombineering efficiency by indirectly blocking phage induction. Even though additional experiments are required to unravel the precise mechanistic details of the improved recombineering efficiency, we recommend the use of our method for the robust genetic manipulation of EHEC and other prophage-carrying E. coli isolates.
    Type of Medium: Online Resource
    ISSN: 2076-2607
    URL: Article
    DOI: 10.3390/microorganisms10091689
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2720891-6
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  • 5
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    Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer
    MDPI AG ; 2023
    In:  Cancers Vol. 15, No. 2 ( 2023-01-08), p. 418-
    Details
    In: Cancers, MDPI AG, Vol. 15, No. 2 ( 2023-01-08), p. 418-
    Abstract: Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4–82.6), 88.1% (95%-CI, 85.7–90.4), 93.4% (95%-CI, 91.1–95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18–0.41); p 〈 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17–0.50); p 〈 0.0001) of the patient’s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01–0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers15020418
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2527080-1
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  • 6
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    Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 18 ( 2022-09-06), p. 4346-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 18 ( 2022-09-06), p. 4346-
    Abstract: BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I–III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I–III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75−30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p 〈 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10–4.55) p = 0.0269) of the patient’s gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27−9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35−5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21−5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39−6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14184346
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 7
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    Online Resource
    Towards Forensic DNA Phenotyping for Predicting Visible Traits in Dogs
    MDPI AG ; 2021
    In:  Genes Vol. 12, No. 6 ( 2021-06-11), p. 908-
    Details
    In: Genes, MDPI AG, Vol. 12, No. 6 ( 2021-06-11), p. 908-
    Abstract: The popularity of dogs as human companions explains why these pets regularly come into focus in forensic cases such as bite attacks or accidents. Canine evidence, e.g., dog hairs, can also act as a link between the victim and suspect in a crime case due to the close contact between dogs and their owners. In line with human DNA identification, dog individualization from crime scene evidence is mainly based on the analysis of short tandem repeat (STR) markers. However, when the DNA profile does not match a reference, additional information regarding the appearance of the dog may provide substantial intelligence value. Key features of the dog’s appearance, such as the body size and coat colour are well-recognizable and easy to describe even to non-dog experts, including most investigating officers and eyewitnesses. Therefore, it is reasonable to complement eyewitnesses’ testimonies with externally visible traits predicted from associated canine DNA samples. Here, the feasibility and suitability of canine DNA phenotyping is explored from scratch in the form of a proof of concept study. To predict the overall appearance of an unknown dog from its DNA as accurately as possible, the following six traits were chosen: (1) coat colour, (2) coat pattern, (3) coat structure, (4) body size, (5) ear shape, and (6) tail length. A total of 21 genetic markers known for high predicting values for these traits were selected from previously published datasets, comprising 15 SNPs and six INDELS. Three of them belonged to SINE insertions. The experiments were designed in three phases. In the first two stages, the performance of the markers was tested on DNA samples from dogs with well-documented physical characteristics from different breeds. The final blind test, including dogs with initially withheld appearance information, showed that the majority of the selected markers allowed to develop composite sketches, providing a realistic impression of the tested dogs. We regard this study as the first attempt to evaluate the possibilities and limitations of forensic canine DNA phenotyping.
    Type of Medium: Online Resource
    ISSN: 2073-4425
    URL: Article
    DOI: 10.3390/genes12060908
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527218-4
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  • 8
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    Occurrence and Characteristics of Cut Injuries in Hedgehogs in Germany: A Collection of Individual Cases
    MDPI AG ; 2023
    In:  Animals Vol. 14, No. 1 ( 2023-12-22), p. 57-
    Details
    In: Animals, MDPI AG, Vol. 14, No. 1 ( 2023-12-22), p. 57-
    Abstract: The number of European hedgehogs (Erinaceus europaeus) is in long-term decline across Europe. Recently, an additional threat to hedgehogs’ lives has been cutting injuries caused by garden care equipment, but to date, there have been no reliable data on their spatial and temporal occurrence as well as characteristics such as mortality rate. Usually, found injured hedgehogs are admitted to care centres. In this study, data on hedgehogs with cutting injuries were collected from care centres throughout Germany. Over a period of 16 months, data on a total of 370 hedgehogs with cut injuries were reported by 71 care centres. At least 60% of these hedgehogs were found more than 12 h after the accident and at least 47% did not survive as a result of the injury. The comparatively high mortality rate coupled with a possible high number of unreported cases of hedgehogs with laceration injuries show that these accidents pose an additional, serious danger to hedgehogs, both impacting the welfare of individual animals and having a broader effect on the conservation potential of this species. Moreover, the data collected objectify the current discussion on the need for possible technical or political solutions to prevent such injuries.
    Type of Medium: Online Resource
    ISSN: 2076-2615
    URL: Article
    DOI: 10.3390/ani14010057
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2606558-7
    SSG: 23
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  • 9
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    Online Resource
    Impact of Innovative Emotion Training in Preschool and Kindergarten Children Aged from 3 to 6 Years
    MDPI AG ; 2023
    In:  Children Vol. 10, No. 11 ( 2023-11-17), p. 1825-
    Details
    In: Children, MDPI AG, Vol. 10, No. 11 ( 2023-11-17), p. 1825-
    Abstract: Children’s emotional abilities have been shown to be related to academic performance, peer acceptance, and in-school adjustment. The main objective of this study was to evaluate the effect of innovative emotion training designed to promote the emotional abilities of 316 preschool/kindergarten children aged from 3 to 6 years old enrolled in public schools in the first three levels (L1, L2, and L3). Another objective was to examine the transfer effects on language comprehension and mathematics abilities. The emotion training (eight sessions) focused on the identification, comprehension, and expression of emotions and were co-constructed with teachers. Children were tested before and after the training on emotion, language, and mathematics skills. Results showed an improvement in emotional abilities in young children of L1 (3–4 years) and L2 (4–5 years) in the intervention group compared to those in the non-intervention group. Also, although children’s emotion basic abilities were correlated with their language comprehension and mathematics abilities, the nature of this link was not demonstrated to be causal. Findings are discussed in regard to the influence of the level and in regard to links with academic variables.
    Type of Medium: Online Resource
    ISSN: 2227-9067
    URL: Article
    DOI: 10.3390/children10111825
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2732685-8
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  • 10
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    Online Resource
    Finding the Best Lighting Mode for Daguerreotype, Ambrotype, and Tintype Photographs and Their Deterioration on the Cruse Scanner Based on Selected Methods
    MDPI AG ; 2023
    In:  Sensors Vol. 23, No. 4 ( 2023-02-18), p. 2303-
    Details
    In: Sensors, MDPI AG, Vol. 23, No. 4 ( 2023-02-18), p. 2303-
    Abstract: In the digital heritage field, the accurate reproduction of hard-to-photograph items, such as daguerreotypes, ambrotypes, and tintypes, is an ongoing challenge. Industrial contactless sensors offer the potential to improve the quality of scanned images, but their capabilities and limitations have not been fully explored. In our research, a dataset of 48 scans was created using the hi-tech industrial contactless sensor CRUSE. Moreover, 3 rare original photographs were scanned in 16 different modes, the most suitable images were determined by specialists in the restoration, and validated through experiments involving eye-tracking, multiple computer vision, and image processing methods. Our study identified the Cruse scanning modes, which can be utilized to achieve the most accurate digital representation of scanned originals. Secondly, we proposed several methods for highlighting the degradation and minor scratches on photographs that otherwise might not be detected by the restorer’s naked eye. Our findings belong to four overlapping areas, i.e., image understanding, digital heritage, information visualization, and industrial sensors research. We publish the entire dataset under the CC BY-NC 4.0 license. The CRUSE sensor shows promise as a tool for improving the quality of scanned images of difficult-to-photograph items. Further research is necessary to fully understand its capabilities and limitations in this context.
    Type of Medium: Online Resource
    ISSN: 1424-8220
    URL: Article
    DOI: 10.3390/s23042303
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2052857-7
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