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Steen Jensby posted an update 6 days, 1 hour ago
The formation of the neocortex relies on intracellular and extracellular signaling molecules that are involved in the sequential steps of corticogenesis, ranging from the proliferation and differentiation of neural progenitor cells to the migration and dendrite formation of neocortical neurons. Abnormalities in these steps lead to disruption of the cortical structure and circuit, and underly various neurodevelopmental diseases, including dyslexia and autism spectrum disorder (ASD). In this review, we focus on the axon guidance signaling Slit-Robo, and address the multifaceted roles of Slit-Robo signaling in neocortical development. Recent studies have clarified the roles of Slit-Robo signaling not only in axon guidance but also in progenitor cell proliferation and migration, and the maturation of neocortical neurons. We further discuss the etiology of neurodevelopmental diseases, which are caused by defects in Slit-Robo signaling during neocortical formation.While topotecan (TPT) is a first- and second-line chemotherapeutic drug in treating lung cancer, the development of drug resistance in tumors still reserves as a major obstacle to chemotherapeutic success. Therefore, a better understanding of the mechanisms of topotecan resistance is critical. In this study, the first topotecan-resistant human non-small cell lung cancer (NSCLC) cell line, termed NCI-H460/TPT10, was established from the parental NCI-H460 cell line. NCI-H460/TPT10 cells exhibited a 394.7-fold resistance to TPT, and cross-resistance to SN-38, mitoxantrone, and doxorubicin, compared to parental NCI-H460 cells. Overexpression of ABCG2 localized on the cell membrane, but not ABCB1 or ABCC1, was found in NCI-H460/TPT10 cells, indicating that ABCG2 was likely to be involved in topotecan-resistance. This was confirmed by the abolishment of drug resistance in NCI-H460/TPT10 cells after ABCG2 knockout. Moreover, the involvement of functional ABCG2 as a drug efflux pump conferring multidrug resistance (MDR) was indicated by low intracellular accumulation of TPT in NCI-H460/TPT10 cells, and the reversal effects by ABCG2 inhibitor Ko143. The NCI-H460/TPT10 cell line and its parental cell line can be useful for drug screening and developing targeted strategies to overcome ABCG2-mediated MDR in NSCLC.This article reviews the pathogenetic role of the complement system in myocardial infarction reperfusion injury. The complement activation pathways involved in myocardial tissue injury are identified, as are the complement-derived effector molecules. The results of past anti-complement therapies are reviewed; as the more recent therapeutic concept of complement depletion with humanized CVF described.Doxorubicin (DOX), the first-line chemotherapy for bladder cancer, usually induces side effects. We previously demonstrated that green tea polyphenol EGCG had potent anti-tumor effect in bladder cancer via down regulation of NF-κB. This study aimed to investigate the additive/synergistic effect EGCG and DOX against bladder cancer. Our results demonstrated that the combined use of DOX and EGCG inhibited T24 and SW780 cell proliferation. EGCG enhanced the apoptosis induction effect of DOX in both SW780 and T24 cells and resulted in significant differences. Besides, EGCG promoted the inhibitory effect of DOX against bladder cancer cell migration. In addition, the in vivo results demonstrated that DOX in combination with EGCG showed the most potent anti-tumor effects among DOX, EGCG and DOX+EGCG treatment groups. Further mechanistic studies determined that the combination of DOX and EGCG inhibited phosphorylated NF-κB and MDM2 expression, and up-regulated p53 expression in tumor, as assessed by western blot and immunohistochemistry. Western blot in SW780 cells also confirmed that the combined use of EGCG and DOX caused significant increase in p53, p21, and cleaved-PARP expression, and induced significant inhibition in phosphorylated NF-κB and MDM2. When NF-κB was inhibited, the expression of p53 and p-MDM2 were changed, and the combination of DOX and EGCG showed no obvious effect in transwell migration and cell viability. In conclusion, the novel application of chemotherapy DOX and EGCG demonstrated potent anti-tumor, anti-migration and anti-proliferation effects against bladder cancer. EGCG enhanced the anti-tumor effect of DOX in bladder cancer via NF-κB/MDM2/p53 pathway, suggesting the potential clinical application against bladder cancer patients.Aberrant expression of the transcription factor hematopoietic ally expressed homeobox/proline-rich homeodomain (HHEX/PRH) is implicated in numerous cancers. However, the association of HHEX with breast cancer (BC) remains unclear. In this study, HHEX mRNA and protein expression were analyzed using the Oncomine, UALCAN, GEPIA, TCGAportal, and HPA databases. We evaluated the effect of HHEX on clinicopathological parameters using Kaplan-Meier plotter, OncoLnc, TCGAportal, PROGgeneV2, and BC-GenExMiner. Western blotting was performed to compare the level of HHEX in breast samples of Tientsin Albino 2 mice, human breast precancerous lesions, benign breast tumors, and BC. The correlation between HHEX and cancer stem cells was investigated using the GEO (GSE52327 and GSE94865) and GEPIA datasets. Networks between HHEX and survival-related gene marker sets and microRNAs were analyzed using GEPIA, StarBase, and Cytoscape. Results of this study showed that HHEX expression in BC was significantly lower than those in brewere joined into miRNA-HHEX-mRNA potential regulatory network. The abilities of proliferation, migration and invasion increased in MDA-MB-231 and BT-549 breast cancer cell lines after HHEX down expression and decreased after HHEX overexpression compared them in the control cells. In conclusion, these data suggest that HHEX expression is downregulated in BC and HHEX may regulate the development of BC through the stem cell-related genes.Enamel renal syndrome (ERS) is a rare recessive disorder caused by loss-of-function mutations in FAM20A (family with sequence similarity 20 member A, OMIM #611062). Enamel renal syndrome is characterized by amelogenesis imperfecta, delayed or failed tooth eruption, intrapulpal calcifications, gingival overgrowth and nephrocalcinosis. buy GSK126 Although gingival overgrowth has consistently been associated with heterotopic calcifications the pathogenesis, structure and interactions of the mineral deposits with the surrounding connective tissue are largely unknown. We here report a novel FAM20A mutation in exon 1 (c.358C > T) introducing a premature stop codon (p.Gln120*) and resulting in a complete loss of FAM20A. In addition to the typical oral findings and nephrocalcinosis, ectopic calcified nodules were also seen in the cervical and thoracic vertebrae regions. Histopathologic analysis of the gingiva showed an enlarged papillary layer associated with aberrant angiogenesis and a lamina propria displaying significant changes in its extracellular matrix composition, including disruption of the collagen I fiber network.