Poorly differentiated clusters (PDC) in colorectal cancer: Does their localization in tumor matter?

Poorly differentiated clusters (PDC) are aggregates of at least five neoplastic cells lacking evidence of glandular differentiation. By definition, they can be present at the invasive front (peripheral PDC or pPDC) and within the tumor stroma (central PDC or cPDC). In colorectal cancer (CRC), PDC are considered adverse prognosticators and seem to reflect epithelial mesenchymal transition (EMT). In this study, we have investigated the immuno-expression of two EMT-related proteins, E-cadherin and \u3b2-catenin, in PDC of primary CRCs and matched liver metastases. pPDC always showed nuclear \u3b2-catenin staining and diffusely reduced/absence of E-cadherin expression as opposed cPDC which showed nuclear \u3b2-catenin immunoreactivity and E-cadherin expression in about 50% of cases. In addition, the pattern of \u3b2-catenin and E-cadherin expression differed between PDC and the main tumor, and between primary CRC and liver metastasis (LM), in a percentage of cases. A discordant pattern of \u3b2-catenin and E-cadherin expression between pPDC and cPDC, between main tumor and cPDC, and between primary CRC and LM, confirms that EMT is a dynamic and reversible process in CRC. On the overall, this suggests that pPDC and cPDC are biologically different. We may advocate that PDC develop at the tumor center (cPDC) and then some of them migrate towards the tumor periphery while progressively completing EMT process (pPDC). Based on these results, PDC presence and counting may have different prognostic relevance if the assessment is done at the invasive front of the tumor or in the intratumor stroma

The mood stabilizing properties of AF3581, a novel potent GSK-3β inhibitor

Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzymeand highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients

Morphology and Molecular Features of Rare Colorectal Carcinoma Histotypes

Several histopathological variants of colorectal carcinoma can be distinguished, some associated with specific molecular profiles. However, in routine practice, ninety/ninety-five percent of all large bowel tumors are diagnosed as conventional adenocarcinoma, even though they are a heterogeneous group including rare histotypes, which are often under-recognized. Indeed, colorectal cancer exhibits differences in incidence, location of tumor, pathogenesis, molecular pathways and outcome depending on histotype. The aim is therefore to review the morphological and molecular features of these rare variants of intestinal carcinomas which may hold the key to differences in prognosis and treatment

Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

Fragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models; however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show an increased number of GFAP positive cells, likely astrocytes, increased spontaneous network activity, and depolarizing GABAergic transmission. Cortical brain organoid models show an increased number of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development

Diagnosis, treatment and prevention of pediatric obesity: consensus position statement of the Italian Society for Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics

The Italian Consensus Position Statement on Diagnosis, Treatment and Prevention of Obesity in Children and Adolescents integrates and updates the previous guidelines to deliver an evidence based approach to the disease. The following areas were reviewed: (1) obesity definition and causes of secondary obesity; (2) physical and psychosocial comorbidities; (3) treatment and care settings; (4) prevention.The main novelties deriving from the Italian experience lie in the definition, screening of the cardiometabolic and hepatic risk factors and the endorsement of a staged approach to treatment. The evidence based efficacy of behavioral intervention versus pharmacological or surgical treatments is reported. Lastly, the prevention by promoting healthful diet, physical activity, sleep pattern, and environment is strongly recommended since the intrauterine phase

Correlation between microsatellite instability status and grading assessed by the counting of poorly differentiated clusters in colorectal cancer

Not availabl

KRAS, NRAS, BRAF mutations and high counts of poorly differentiated clusters of neoplastic cells in colorectal cancer: observational analysis of 175 cases

A novel grading system based on the counting of poorly differentiated clusters (PDC) of neoplastic cells at the invasive margin and in the tumour stroma was recently introduced among the histological parameters predictive of adverse clinical outcome in colorectal cancer (CRC). The aim of this study was to correlate the histological grade based on PDC and the mutational status of KRAS, NRAS and BRAF genes in 175 consecutive CRCs. The highest PDC count under the objective lens of a 720 microscopic field in each tumour was considered for grading assessment, so that PDC counts <5, 5-9 and 6510 PDCs were defined grade 1, grade 2 and grade 3, respectively. Hotspots mutations were identified using the MassArray platform. Overall, there were 42 (24%) mutated tumours. Mutational status was significantly associated with high pT stage (p\u200a=\u200a0.0021), advanced pTNM stage (p\u200a=\u200a0.0018), nodal metastases (p\u200a=\u200a0.006), tumour budding (p\u200a=\u200a0.022) and high PDC grade (p\u200a=\u200a0.0022). KRAS mutations were significantly associated with PDC grade (p\u200a=\u200a0.0379), while BRAF mutations were associated with PDC-G3 although statistical significance was not reached. No significant associations were found between NRAS and PDC. The significant association between mutated KRAS and PDC grade suggests that KRAS mutations may be involved in the formation of PDC

HOXB13 expression in metastatic prostate cancer

not presen

Prognostic relevance of histopathological features in signet ring cell carcinoma of the colorectum

Signet ring cell carcinoma (SRCC) is a rare variant of colorectal cancer (CRC), by definition composed of at least 50\uc2&nbsp;% of neoplastic cells showing signet ring cell morphology. Colorectal SRCC is mainly characterized by aggressive clinical behavior, high pTNM stage and microsatellite instability (MSI). We assessed the prognostic value of several histopathological parameters (histological grade, venous invasion, lymphovascular invasion, MSI, mucin content, tumour budding, pTNM stage) in terms of disease free survival (DFS) and cancer specific survival (CSS) in a series of 32 SRCCs. We confirm that pTNM stage at diagnosis is relevant for predicting DFS and CSS in SRCC. In addition, we show on haematoxylin and eosin or immunohistochemically stained (CD34, podoplanin) sections that venous invasion and lymphovascular invasion are significantly associated with shorter DFS and CSS in SRCC. Notably, venous invasion assed by immunohistochemistry had the highest risk ratio and proved to be the only independent prognostic variable. Finally, we show that histological grade, as assessed on the percentage of formed glands, has prognostic relevance in SRCC as high-grade tumours (&lt;50\uc2&nbsp;% of glands) had significantly shorter CSS compared to low-grade tumours. This remained an independent variable at multivariate analysis. If our findings are confirmed in further studies, venous invasion as assessed by immunohistochemistry and histological Tgrade might be added to guidelines for SRCC reporting as significant prognostic factors