24,372 research outputs found

    "Lesion journey" in hidradenitis suppurativa: clinical and ultrasonographic correlations

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    Introduzione: L'idrosadenite suppurativa (HS) è una malattia immuno-mediata che colpisce i follicoli piliferi situati principalmente nelle aree ricche di ghiandole apocrine. Materiali e metodi: È stato condotto uno studio osservazionale prospettico monocentrico finalizzato a correlare i parametri clinici ed ecografici con: l'evoluzione delle lesioni, la probabilità di riacutizzazione o di andare incontro ad un trattamento chirurgico/laser-CO2. Risultati: Sono stati reclutati sessantuno pazienti con un'età media pari a 29,5 ± 7,5 anni che presentavano un numero basale di 127 noduli infiammatori, 43 ascessi e 62 fistole. Dopo un tempo medio di 77,9 settimane, rispettivamente il 40%, 14%, 8% di noduli, ascessi e fistole erano guariti, il 5%, 30%, 29% persistevano privi di infiammazione, il 47%, 33%, 63 % presentava uno stato infiammatorio, e l'8% e il 23% dei noduli e degli ascessi erano evoluti in fistole. Sono stati registrati 137 episodi di flare nelle lesioni acute (noduli + ascessi) e 54 nelle lesioni croniche (fistole), mentre il numero di interventi procedurali è stato rispettivamente pari a 59 e 50. I fattori predittivi associati ad un'evoluzione sfavorevole (stato infiammatorio o cronicizzazione) per ascessi e noduli sono stati: evidenza ecografica di frammenti piliferi intralesionali, elevato segnale Power Doppler (PD) ed edema all'ecografia, profondità della localizzazione ed interessamento genitale; i predittori associati alle fistole sono stati: profondità della localizzazione, edema e dimensioni della lesione. La probabilità che una lesione acuta venisse sottoposta ad un intervento procedurale è stata correlata a: età, presenza di frammenti piliferi, segnale PD, edema e profondità della localizzazione; per le fistole l'unico predittore indipendente è stato la dimensione. I predittori di riacutizzazione della patologia per ascessi e noduli sono stati: giovane età all'esordio, segnale PD, evidenza ecografica di frammenti follicolari, profondità della localizzazione e dimensioni; per le fistole i predittori sono stati: localizzazione ascellare, profondità della localizzazione, edema e dimensione.Background: Hidradenitis suppurativa (HS) is an immune-mediated disorder affecting hair follicles mainly located in the apocrine gland-bearing area. It presents suppurative lesions consisting of nodules, abscesses, and fistulas that exhibit a variable degree of inflammatory activity. Materials and Methods: A prospective, single-center observational study was designed to correlate clinical and ultrasonographic parameters with the "lesions' evolution" at the end of the study, the probability of flaring or undergoing a surgical/CO2-laser intervention. Results: Sixty-one patients (25 males and 36 females) with a mean age of 29.5±7.5 years who had a total baseline number of 127 inflammatory nodules, 43 abscesses, and 62 fistulas were recruited. After a mean follow-up time of 77.9 weeks, 40%, 14%, 8% of nodules, abscesses, and fistulas respectively had healed, 5%, 30%, 29% were free of inflammation, 47%, 33%, 63% had an inflammatory status, and 8% and 23% of nodules and abscesses had evolved into fistulas. There were 137 flare episodes in the acute lesions (nodules + abscesses) and 54 in the chronic lesions (fistulas), while the number of procedural interventions was 59 and 50, respectively. The predictive factors associated with an unfavorable evolution (inflammatory status or chronicity) for abscesses and nodules were: presence of hair tracts, high degree of Power Doppler (PD) and edema on ultrasonography, depth of localization and genital body area; for fistulas the predictors were: depth of localization, edema, and size. The probability of an acute lesion going to procedural intervention correlated with: age, presence of hair tracts, high degree of PD, edema, and depth of localization; for fistulas the only independent predictor was size. The predictors of flare for abscesses and nodules were: young age at disease onset, PD signal, hair tracts, depth of localization, and size; in the case of fistulas the predictors were: axillary localization, depth of localization, edema, and size

    Genome-wide association mapping of rust resistance in Aegilops longissima

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    The rust diseases, including leaf rust caused by Puccinia triticina (Pt), stem rust caused by P. graminis f. sp. tritici (Pgt), and stripe rust caused by P. striiformis f. sp. tritici (Pst), are major limiting factors in wheat production worldwide. Identification of novel sources of rust resistance genes is key to developing cultivars resistant to rapidly evolving pathogen populations. Aegilops longissima is a diploid wild grass native to the Levant and closely related to the modern bread wheat D subgenome. To explore resistance genes in the species, we evaluated a large panel of Ae. longissima for resistance to several races of Pt, Pgt, and Pst, and conducted a genome-wide association study (GWAS) to map rust resistance loci in the species. A panel of 404 Ae. longissima accessions, mostly collected from Israel, were screened for seedling-stage resistance to four races of Pt, four races of Pgt, and three races of Pst. Out of the 404 accessions screened, two were found that were resistant to all 11 races of the three rust pathogens screened. The percentage of all accessions screened that were resistant to a given rust pathogen race ranged from 18.5% to 99.7%. Genotyping-by-sequencing (GBS) was performed on 381 accessions of the Ae. longissima panel, wherein 125,343 single nucleotide polymorphisms (SNPs) were obtained after alignment to the Ae. longissima reference genome assembly and quality control filtering. Genetic diversity analysis revealed the presence of two distinct subpopulations, which followed a geographic pattern of a northern and a southern subpopulation. Association mapping was performed in the genotyped portion of the collection (n = 381) and in each subpopulation (n = 204 and 174) independently via a single-locus mixed-linear model, and two multi-locus models, FarmCPU, and BLINK. A large number (195) of markers were significantly associated with resistance to at least one of 10 rust pathogen races evaluated, nine of which are key candidate markers for further investigation due to their detection via multiple models and/or their association with resistance to more than one pathogen race. The novel resistance loci identified will provide additional diversity available for use in wheat breeding

    Sociodemographic, nutritional and health status factors associated with adherence to Mediterranean diet in an agricultural Moroccan adult's population

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    Background. Numerous studies have demonstrated beneficial effects of adherence to the Mediterranean diet (MD) on many chronic diseases, including chronic kidney disease (CKD). Objective. The aim of this study was to assess the adherence of a rural population to the Mediterranean diet, to identify the sociodemographic and lifestyle determinants and to analyze the association between adherence to MD and CKD. Material and Methods. In a cross-sectional study, data on sociodemographic, lifestyle factors, clinical, biochemical parameters and diet were collected on a sample of 154 subjects. Adherence to MD was assessed according to a simplified MD score based on the daily frequency of intake of eight food groups (vegetables, legumes, fruits, cereal or potatoes, fish, red meat, dairy products and MUFA/SFA), using the sex specific sample medians as cut-offs. A value of 0 or 1 was assigned to consumption of each component according to its presumed detrimental or beneficial effect on health. Results. According to the simplified MD score, the study data show that high adherence (44.2%) to MD was characterized by intakes high in vegetables, fruits, fish, cereals, olive oil, and low in meat and moderate in dairy. Furthermore, several factors such as age, marital status, education level, and hypertension status were associated with the adherence to MD in the study population. The majority of subjects with CKD have poor adherence to the MD compared to non-CKD with a statistically insignificant difference. Conclusions. In Morocco, maintaining the traditional MD pattern play crucial role for public health. More research is needed in this area to precisely measure this association

    Putative Role of Neutrophil Extracellular Trap Formation in Chronic Myeloproliferative Neoplasms

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    Myeloproliferative neoplasms (MPNs) are hematologic malignancies characterized by gene mutations that promote myeloproliferation and resistance to apoptosis via constitutively active signaling pathways, with Janus kinase 2-signal transducers and the activators of transcription (JAK-STAT) axis as a core part. Chronic inflammation has been described as a pivot for the development and advancement of MPNs from early stage cancer to pronounced bone marrow fibrosis, but there are still unresolved questions regarding this issue. The MPN neutrophils are characterized by upregulation of JAK target genes, they are in a state of activation and with deregulated apoptotic machinery. Deregulated neutrophil apoptotic cell death supports inflammation and steers them towards secondary necrosis or neutrophil extracellular trap (NET) formation, a trigger of inflammation both ways. NETs in proinflammatory bone marrow microenvironment induce hematopoietic precursor proliferation, which has an impact on hematopoietic disorders. In MPNs, neutrophils are primed for NET formation, and even though it seems obvious for NETs to intervene in the disease progression by supporting inflammation, no reliable data are available. We discuss in this review the potential pathophysiological relevance of NET formation in MPNs, with the intention of contributing to a better understanding of how neutrophils and neutrophil clonality can orchestrate the evolution of a pathological microenvironment in MPNs

    Pathogenetic, Prognostic, and Therapeutic Role of Fucosylation in Intrahepatic Cholangiocarcinoma

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    Summary Intrahepatic cholangiocarcinoma (iCCA) is one of the most lethal forms of primary liver cancer. The incidence of iCCA is growing worldwide, and limited therapeutic options exist for this aggressive tumor. Therefore, innovative therapies are imperative to make this disease curable. Aberrant glycosylation, a post-transcriptional modification of proteins, is considered one of the hallmarks of cancer. In this study, I thoroughly investigated the role of fucosylation in cholangiocarcinogenesis. Through the present investigation, I revealed that global fucosylation and members of the fucosylation pathway are ubiquitously upregulated in human iCCA specimens compared to nontumorous surrounding liver tissues and normal biliary cells. Similarly, a profucosylation phenotype was also observed in liver lesions developed in mouse models of iCCA. Moreover, total fucosylation levels significantly correlate with poor patient prognoses. In addition, fucosylation inhibition by 6-alkynylfucose (6AF) administration decreased the proliferation and migration of iCCA cells in a dose-dependent manner. The addition of fucose to the cell culture medium annulled these effects. Furthermore, iCCA cell lines showed decreased NOTCH activity, NOTCH1/Jagged1 interactions, NOTCH receptors, and NOTCH target gene levels after incubation with 6AF or silencing of GDP-L-fucose synthetase (FX) and GDP-fucose transmembrane transporter (SLC35C1), both key players in cellular fucosylation. In the same cells, EGFR, NF-κB p65, and Bcl-xL protein levels decreased, whereas IκBα (a critical cellular NF-kB inhibitor) increased after FX/SLC35C1 knockdown or 6AF administration. Notably, 6AF treatment profoundly suppressed the growth of iCCA cells in the chick chorioallantoic membrane (CAM) assay. In summary, the results from this thesis indicate that human (and mouse) iCCA is characterized by elevated levels of global fucosylation, leading 4 to augmented NOTCH and EGFR/NF-kB activation and increased cell growth and migration. Hence, aberrant fucosylation may contribute to human iCCA pathogenesis and represent a potential novel therapeutic target in this deadly neoplasm

    Human gene-engineered calreticulin mutant stem cells recapitulate MPN hallmarks and identify targetable vulnerabilities

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    Calreticulin (CALR) mutations present the main oncogenic drivers in JAK2 wildtype (WT) myeloproliferative neoplasms (MPN), including essential thrombocythemia and myelofibrosis, where mutant (MUT) CALR is increasingly recognized as a suitable mutation-specific drug target. However, our current understanding of its mechanism-of-action is derived from mouse models or immortalized cell lines, where cross-species differences, ectopic over-expression and lack of disease penetrance are hampering translational research. Here, we describe the first human gene-engineered model of CALR MUT MPN using a CRISPR/Cas9 and adeno-associated viral vector-mediated knock-in strategy in primary human hematopoietic stem and progenitor cells (HSPCs) to establish a reproducible and trackable phenotype in vitro and in xenografted mice. Our humanized model recapitulates many disease hallmarks: thrombopoietin-independent megakaryopoiesis, myeloid-lineage skewing, splenomegaly, bone marrow fibrosis, and expansion of megakaryocyte-primed CD41+ progenitors. Strikingly, introduction of CALR mutations enforced early reprogramming of human HSPCs and the induction of an endoplasmic reticulum stress response. The observed compensatory upregulation of chaperones revealed novel mutation-specific vulnerabilities with preferential sensitivity of CALR mutant cells to inhibition of the BiP chaperone and the proteasome. Overall, our humanized model improves purely murine models and provides a readily usable basis for testing of novel therapeutic strategies in a human setting.Johannes Foßelteder, Gabriel Pabst, Tommaso Sconocchia, Angelika Schlacher, Lisa Auinger, Karl Kashofer, Christine Beham-Schmid, Slave Trajanoski, Claudia Waskow, Wolfgang Schöll, Heinz Sill, Armin Zebisch, Albert Wölfler, Daniel Thomas, and Andreas Reinisc

    Integrative analysis highlights molecular and immune responses of tick Amblyomma americanum to Escherichia coli challenge

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    Ticks are ectoparasites that can transmit various pathogens capable of causing life-threatening illnesses in people and animals, making them a severe public health threat. Understanding how ticks respond to bacterial infection is crucial for deciphering their immune defense mechanisms and identifying potential targets for controlling tick-borne diseases. In this study, an in-depth transcriptome analysis was used to investigate the molecular and immune responses of Amblyomma americanum to infection caused by the microinjection of Escherichia coli. With an abundance of differentially expressed genes discovered at different times, the analysis demonstrated significant changes in gene expression profiles in response to E. coli challenge. Notably, we found alterations in crucial immune markers, including the antimicrobial peptides defensin and microplusin, suggesting they may play an essential role in the innate immune response. Furthermore, KEGG analysis showed that following E. coli exposure, a number of key enzymes, including lysosomal alpha-glucosidase, fibroblast growth factor, legumain, apoptotic protease-activating factor, etc., were altered, impacting the activity of the lysosome, mitogen-activated protein kinase, antigen processing and presentation, bacterial invasion, apoptosis, and the Toll and immune deficiency pathways. In addition to the transcriptome analysis, we constructed protein interaction networks to elucidate the molecular interactions underlying the tick’s response to E. coli challenge. Hub genes were identified, and their functional enrichment provided insights into the regulation of cytoskeleton rearrangement, apoptotic processes, and kinase activity that may occur in infected cells. Collectively, the findings shed light on the potential immune responses in A. americanum that control E. coli infection

    Molecular characterization of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis

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    Background and aims: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. Methods: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. Results: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. Conclusions: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. Lay summary: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC
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