Differential expression of cyclooxygenases in hypertrophic scar and keloid tissues

Hypertrophic scar (HS) and keloid (KL) are two forms of an abnormal cutaneous scarring process, mainly characterized by excessive extracellular matrix deposition and fibroblast proliferation. Despite the increased understanding of the molecular and cellular events leading to HS and KL, the pathogenesis of these lesions remains poorly understood. A pivotal role in the formation of abnormal scars has been ascribed to transforming growth factor-β, whose activity appears to be mediated through a link with pathways acting via cyclooxygenases (COX-1 and COX-2). To date, there is no report on the in vivo expression of COX-1 and COX-2 in human HS and KL tissues. Therefore, using immunohistochemistry and Western blot analysis, we investigated 36 cases of KL, 32 cases of HS, and 25 cases of normal skin in order to define the localization and distribution of COX-1 and COX-2 in the tissues of these scar lesions and the overlying epidermis. The results mainly show the following: (a) a significant overexpression of COX-1 in HS tissues and the overlying epidermis as compared with normal skin and KL tissues and (b) a significant overexpression of COX-2 in KL tissue and the overlying epidermis in contrast to normal skin and HS tissues. Our data support the hypothesis that both COXs are involved in the pathogenesis of scar lesions in different ways and, particularly, COX-1 in the formation of HS and COX-2 in the formation of KL. In addition, the overexpression of COX-1 and COX-2 in the epidermis overlying HS and KL tissues, respectively, underlines the importance of epithelial- mesenchymal interactions in the pathogenesis of scar lesion

Analysis of microbiome in gastrointestinal stromal tumors: Looking for different players in tumorigenesis and novel therapeutic options

Preclinical forms of gastrointestinal stromal tumor (GIST), small asymptomatic lesions, called microGIST, are detected in approximately 30% of the general population. Gastrointestinal stromal tumor driver mutation can be already detected in microGISTs, even if they do not progress into malignant cancer; these mutations are necessary, but insufficient events to foster tumor progression. Here we profiled the tissue microbiota of 60 gastrointestinal specimens in three different patient cohorts—micro, low-risk, and high-risk or metastatic GIST—exploring the compositional structure, predicted function, and microbial networks, with the aim of providing a complete overview of microbial ecology in GIST and its preclinical form. Comparing microGISTs and GISTs, both weighted and unweighted UniFrac and Bray–Curtis dissimilarities showed significant community-level separation between them and a pronounced difference in Proteobacteria, Firmicutes, and Bacteroidota was observed. Through the LEfSe tool, potential microbial biomarkers associated with a specific type of lesion were identified. In particular, GIST samples were significantly enriched in the phylum Proteobacteria compared to microGISTs. Several pathways involved in sugar metabolism were also highlighted in GISTs; this was expected as cancer usually displays high aerobic glycolysis in place of oxidative phosphorylation and rise of glucose flux to promote anabolic request. Our results highlight that specific differences do exist in the tissue microbiome community between GIST and benign lesions and that microbiome restructuration can drive the carcinogenesis process

Three cases of bone metastases in patients with gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. Tumor resection is the treatment of choice for localized disease. Tyrosine kinase inhibitors (imatinib, sunitinib) are the standard therapy for metastatic or unresectable GISTs. GISTs usually metastasize to the liver and peritoneum. Bone metastases are uncommon. We describe three cases of bone metastases in patients with advanced GISTs: two women (82 and 54 years of age), and one man (62 years of age). Bones metastases involved the spine, pelvis and ribs in one patient, multiple vertebral bodies and pelvis in one, and the spine and iliac wings in the third case. The lesions presented a lytic pattern in all cases. Two patients presented with multiple bone metastases at the time of initial diagnosis and one patient after seven years during the follow-up period. This report describes the diagnosis and treatment of the lesions and may help clinicians to manage bones metastases in GIST patients

Language and reading impairments are associated with increased prevalence of non-right handedness

Funding: Royal Society - UF150663, RGF\EA\180141; Wellcome Trust - 217065/Z/19/Z; H2020 European Research Council - 694189; NWO - 451-15-017; National Health and Medical Research Council - 1173896; Canadian Institute for Health Research - MOP-133440.Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6–19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06–1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.Publisher PDFPeer reviewe

The role of fundamental solution in Potential and Regularity Theory for subelliptic PDE

In this survey we consider a general Hormander type operator, represented as a sum of squares of vector fields plus a drift and we outline the central role of the fundamental solution in developing Potential and Regularity Theory for solutions of related PDEs. After recalling the Gaussian behavior at infinity of the kernel, we show some mean value formulas on the level sets of the fundamental solution, which are the starting point to obtain a comprehensive parallel of the classical Potential Theory. Then we show that a precise knowledge of the fundamental solution leads to global regularity results, namely estimates at the boundary or on the whole space. Finally in the problem of regularity of non linear differential equations we need an ad hoc modification of the parametrix method, based on the properties of the fundamental solution of an approximating problem

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits

Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET

<p>Abstract</p> <p>Background</p> <p>Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT, while RAD001 (everolimus) inhibits mTOR. We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging.</p> <p>Methods</p> <p>Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm³). Small animal PET (GE Explore tomography) was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment.</p> <p>Results</p> <p>After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm³) and the treatments began at day 38 after cell injection. Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for everolimus alone. The baseline FDG uptake was positive in all animals. FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3 vs 0.</p> <p>Conclusions</p> <p>As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism. The integration of everolimus in GIST treatment merits further investigation.</p

The Insulin Receptor Substrate 1 (Irs1) in Intestinal Epithelial Differentiation and in Colorectal Cancer

Colorectal cancer (CRC) is associated with lifestyle factors that affect insulin/IGF signaling, of which the insulin receptor substrate 1 (IRS1) is a key transducer. We investigated expression, localization and pathologic correlations of IRS1 in cancer-uninvolved colonic epithelium, primary CRCs with paired liver metastases and in vitro polarizing Caco2 and HT29 cells. IRS1 mRNA and protein resulted higher, relative to paired mucosa, in adenomas of familial adenomatous polyposis patients and in CRCs that overexpressed c-MYC, ß-catenin, InsRß, and IGF1R. Analysis of IRS1 immunostaining in 24 cases of primary CRC with paired colonic epithelium and hepatic metastasis showed that staining intensity was significantly higher in metastases relative to both primary CRC (P<0.01) and colonic epithelium (P<0.01). Primary and metastatic CRCs, compared to colonic epithelium, contained significantly higher numbers of IRS1-positive cells (P = 0.013 and P = 0.014, respectively). Pathologic correlations in 163 primary CRCs revealed that diffuse IRS1 staining was associated with tumors combining differentiated phenotype and aggressive markers (high Ki67, p53, and ß-catenin). In Caco 2 IRS1 and InsR were maximally expressed after polarization, while IGF1R was highest in pre-polarized cells. No nuclear IRS1 was detected, while, with polarization, phosphorylated IRS1 (pIRS1) shifted from the lateral to the apical plasma membrane and was expressed in surface cells only. In HT29, that carry mutations constitutively activating survival signaling, IRS1 and IGF1R decreased with polarization, while pIRS1 localized in nuclear spots throughout the course. Overall, these data provide evidence that IRS1 is modulated according to CRC differentiation, and support a role of IRS1 in CRC progression and liver metastatization

Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10−8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits