Pancreatic cancer belongs to the incurable family of solid cancers. Despite of a recent better understanding its molecular biology, and an increased number of clinical trials, there is still a lack ...for innovative targeted therapies to fight this deadly malignancy. PI3K/Akt signalling is one of the most commonly deregulated signalling pathways in cancer, which explains the massive attention from many pharmaceutical companies over the ten past years on these signalling molecules. The already developed small molecule inhibitors are currently under clinical trial in various cancer types. Class I PI3Ks have 4 isoforms for which the role in physiology starts to be well described in the literature. Data are more unclear for their differential involvement in oncogenesis. In this review, we will discuss about the cognitive and therapeutic potential of targeting this signalling pathway and in particular Class I PI3K isoforms for pancreatic cancer treatment. Isoform-specificity of PI3K inhibitors are currently designed to achieve the same goal as pan-PI3K inhibitors but without potential adverse effects. We will discuss if such strategy is relevant in pancreatic adenocarcinoma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Several aspects of past culture, including historical trends, are inferred from time-based patterns observed in archaeological artifacts belonging to different periods. The presence and ...variation of these objects provides important clues about the Neolithic revolution and given their relative abundance in most archaeological sites, ceramic potteries are significantly helpful in this purpose. Nonetheless, most available pottery is fragmented, leading to missing morphological information. Currently, the reassembly of fragmented objects from a collection of thousands of mixed fragments is a daunting and time-consuming task done almost exclusively by hand, which requires the physical manipulation of the fragments. To overcome the challenges of manual reconstruction and improve the quality of reconstructed samples, we present IberianGAN, a customized Generative Adversarial Network (GAN) tested on an extensive database with complete and fragmented references. We trained the model with 1072 samples corresponding to Iberian wheel-made pottery profiles belonging to archaeological sites located in the upper valley of the Guadalquivir River (Spain). Furthermore, we provide quantitative and qualitative assessments to measure the quality of the reconstructed samples, along with domain expert evaluation with archaeologists. The resulting framework is a possible way to facilitate pottery reconstruction from partial fragments of an original piece.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Increased PI 3-kinase (PI3K) signaling in pancreatic ductal adenocarcinoma (PDAC) correlates with poor prognosis, but the role of class I PI3K isoforms during its induction remains unclear. Using ...genetically engineered mice and pharmacological isoform-selective inhibitors, we found that the p110α PI3K isoform is a major signaling enzyme for PDAC development induced by a combination of genetic and nongenetic factors. Inactivation of this single isoform blocked the irreversible transition of exocrine acinar cells into pancreatic preneoplastic ductal lesions by oncogenic Kras and/or pancreatic injury. Hitting the other ubiquitous isoform, p110β, did not prevent preneoplastic lesion initiation. p110α signaling through small GTPase Rho and actin cytoskeleton controls the reprogramming of acinar cells and regulates cell morphology in vivo and in vitro. Finally, p110α was necessary for pancreatic ductal cancers to arise from Kras-induced preneoplastic lesions by increasing epithelial cell proliferation in the context of mutated p53. Here we identify an in vivo context in which p110α cellular output differs depending on the epithelial transformation stage and demonstrate that the PI3K p110α is required for PDAC induced by oncogenic Kras, the key driver mutation of PDAC. These data are critical for a better understanding of the development of this lethal disease that is currently without efficient treatment.
Abstract
Self-perception of ethnicity is a complex social trait shaped by both, biological and non-biological factors. We developed a comprehensive analysis of ethnic self-perception (ESP) on a large ...sample of Latin American mestizos from five countries, differing in age, socio-economic and education context, external phenotypic attributes and genetic background. We measured the correlation of ESP against genomic ancestry, and the influence of physical appearance, socio-economic context, and education on the distortion observed between both. Here we show that genomic ancestry is correlated to aspects of physical appearance, which in turn affect the individual ethnic self-perceived ancestry. Also, we observe that, besides the significant correlation among genomic ancestry and ESP, specific physical or socio-economic attributes have a strong impact on self-perception. In addition, the distortion among ESP and genomic ancestry differs across age ranks/countries, probably suggesting the underlying effect of past public policies regarding identity. Our results indicate that individuals’ own ideas about its origins should be taken with caution, especially in aspects of modern life, including access to work, social policies, and public health key decisions such as drug administration, therapy design, and clinical trials, among others.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The PI3K pathway is highly active in human cancers. The four class I isoforms of PI3K are activated by distinct mechanisms leading to a common downstream signaling. Their downstream redundancy is ...thought to be responsible for treatment failures of PI3K inhibitors. We challenged this concept, by mapping the differential phosphoproteome evolution in response to PI3K inhibitors with different isoform-selectivity patterns in pancreatic cancer, a disease currently without effective therapy. In this cancer, the PI3K signal was shown to control cell proliferation. We compared the effects of LY294002 that inhibit with equal potency all class I isoenzymes and downstream mTOR with the action of inhibitors with higher isoform selectivity toward PI3Kα, PI3Kβ, or PI3Kγ (namely, A66, TGX-221 and AS-252424). A bioinformatics global pathway analysis of phosphoproteomics data allowed us to identify common and specific signals activated by PI3K inhibitors supported by the biological data. AS-252424 was the most effective treatment and induced apoptotic pathway activation as well as the highest changes in global phosphorylation-regulated cell signal. However, AS-252424 treatment induced reactivation of Akt, therefore decreasing the treatment outcome on cell survival. Reversely, AS-252424 and A66 combination treatment prevented p-Akt reactivation and led to synergistic action in cell lines and patient organoids. The combination of clinically approved α-selective BYL-719 with γ-selective IPI-549 was more efficient than single-molecule treatment on xenograft growth. Mapping unique adaptive signaling responses to isoform-selective PI3K inhibition will help to design better combinative treatments that prevent the induction of selective compensatory signals.
For patients with metastatic pancreatic cancer that are not eligible for surgery, signal-targeted therapies have so far failed to significantly improve survival. These therapeutic options have been ...tested in phase II/III clinical trials mostly in combination with the reference treatment gemcitabine. Innovative therapies aim to annihilate oncogenic dependency, or to normalize the tumoural stroma to allow immune cells to function and/or re-vascularisation to occur. Large scale transcriptomic and genomic analysis revealed that pancreatic cancers display great heterogeneity but failed to clearly delineate specific oncogene dependency, besides oncogenic Kras. Beyond these approaches, proteomics appears to be an appropriate approach to classify signal dependency and to identify specific alterations at the targetable level. However, due to difficulties in sampling, proteomic data for this pathology are scarce. In this review, we will discuss the current state of clinical trials for targeted therapies against pancreatic cancer. We will then highlight the most recent proteomic data for pancreatic tumours and their metastasis, which could help to identify major oncogenic signalling dependencies, as well as provide future leads to explain why pancreatic tumours are intrinsically resistant to signal-targeted therapies. We will finally discuss how studies on phosphatidylinositol-3-kinase (PI3K) signalling, as the paradigmatic pro-tumoural signal downstream of oncogenic Kras in pancreatic cancer, would benefit from exploratory proteomics to increase the efficiency of targeted therapies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The expression of facial asymmetries has been recurrently related with poverty and/or disadvantaged socioeconomic status. Departing from the developmental instability theory, previous approaches ...attempted to test the statistical relationship between the stress experienced by individuals grown in poor conditions and an increase in facial and corporal asymmetry. Here we aim to further evaluate such hypothesis on a large sample of admixed Latin Americans individuals by exploring if low socioeconomic status individuals tend to exhibit greater facial fluctuating asymmetry values. To do so, we implement Procrustes analysis of variance and Hierarchical Linear Modelling (HLM) to estimate potential associations between facial fluctuating asymmetry values and socioeconomic status. We report significant relationships between facial fluctuating asymmetry values and age, sex, and genetic ancestry, while socioeconomic status failed to exhibit any strong statistical relationship with facial asymmetry. These results are persistent after the effect of heterozygosity (a proxy for genetic ancestry) is controlled in the model. Our results indicate that, at least on the studied sample, there is no relationship between socioeconomic stress (as intended as low socioeconomic status) and facial asymmetries.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Images depicting dark skin tones are significantly underrepresented in the educational materials used to teach primary care physicians and dermatologists to recognize skin diseases. This could ...contribute to disparities in skin disease diagnosis across different racial groups. Previously, domain experts have manually assessed textbooks to estimate the diversity in skin images. Manual assessment does not scale to many educational materials and introduces human errors. To automate this process, we present the Skin Tone Analysis for Representation in EDucational materials (STAR-ED) framework, which assesses skin tone representation in medical education materials using machine learning. Given a document (e.g., a textbook in .pdf), STAR-ED applies content parsing to extract text, images, and table entities in a structured format. Next, it identifies images containing skin, segments the skin-containing portions of those images, and estimates the skin tone using machine learning. STAR-ED was developed using the Fitzpatrick17k dataset. We then externally tested STAR-ED on four commonly used medical textbooks. Results show strong performance in detecting skin images (0.96 ± 0.02 AUROC and 0.90 ± 0.06 F
score) and classifying skin tones (0.87 ± 0.01 AUROC and 0.91 ± 0.00 F
score). STAR-ED quantifies the imbalanced representation of skin tones in four medical textbooks: brown and black skin tones (Fitzpatrick V-VI) images constitute only 10.5% of all skin images. We envision this technology as a tool for medical educators, publishers, and practitioners to assess skin tone diversity in their educational materials.
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