No abstract

The physiological role of an orphan G protein-coupled receptor, LGR5, was investigated by targeted deletion of this seven-transmembrane protein containing a large N-terminal extracellular domain with leucine-rich repeats.LGR5 null mice exhibited 100% neonatal lethality characterized by gastrointestinal tract dilation with air and an absence of milk in the stomach. Gross and histological examination revealed fusion of the tongue to the floor of oral cavity in the mutant newborns and immunostaining of LGR5 expression in the epithelium of the tongue and in the mandible of the wild-type embryos. The observed ankyloglossia phenotype provides a model for understanding the genetic basis of this craniofacial defect in humans and an opportunity to elucidate the physiological role of the LGR5 signaling system during embryonic development.The leucine-rich repeat-containing, G protein-coupled receptors (LGRs) designated LGR4 through LGR8 are structurally similar to receptors for gonadotropins and thyrotropin (11,12). These receptors are characterized by a large N-terminal extracellular domain containing leucine-rich repeats followed by a seven-transmembrane region. Phylogenetic analyses showed three LGR subgroups: the glycoprotein hormone receptors; the subgroup of LGR4, LGR5, and LGR6; and a third subgroup represented by LGR7 and LGR8 recently found to be receptors for the relaxin family ligands (13,15,23). Evolutionary analyses suggested that these three subgroups of LGRs existed before the divergence of vertebrates and invertebrates (10). LGR5, also known as GPR49, HG38, or FEX, is a large protein consisting of 18 extracellular leucine-rich repeats together with a seven-transmembrane region (8,12,17). UnlikeLGRs in the other two subgroups, the ligands and physiological functions for the LGR4, LGR5, and LGR6 genes are unclear.Ankyloglossia is a rare human craniofacial defect associated with difficulties in an infant's ability to breast-feed and defective speech articulation (6,16,18). In patients with this disorder, the lingual frenulum, which attaches the tongue to the floor of the oral cavity, extends to the tip of the tongue, thereby preventing optimal tongue movement. Limitation of tongue movement may vary from very mild to complete fusion of the tongue to the floor of the mouth. Ankyloglossia in breastfeeding infants can cause ineffective latch, inadequate milk transfer, and maternal nipple pain, resulting in slower weight gain and untimely weaning. Some cases of ankyloglossia are associated with cleft palate (CPX; MIM 303400; OMIM database, Johns Hopkins University, Baltimore, Md.) and are inherited as an X-linked disorder caused by mutations in TBX22, a T-box transcription factor gene located in Xq21 (3).In an attempt to elucidate the physiological roles of the subgroup of orphan LGRs consisting of LGR4, LGR5, and LGR6, we performed gene deletion experiments with LGR5 using a mouse model. Here, we report that the LGR5 null mice exhibit neonatal lethality associated with ankyloglossia characterized by fusion of the ...

MicroRNA-7 (miR-7) has been reported to be a tumor suppressor in all malignancies including colorectal cancer (CRC). However, its significance for CRC clinical outcomes has not yet been explored. The potential for miR-7 to act as a tumor suppressor by coordinately regulating the epidermal growth factor receptor (EGFR) signaling pathway at several levels was examined. We investigated the tumor inhibitory effect of miR-7 in CRC, with particular focus on the relationship between miR-7 and the EGFR pathway. Quantitative reverse transcription-PCR was used to evaluate miR-7 expression in 105 CRC cases to determine the clinicopathologic significance of this miRNA. The regulation of EGFR by miR-7 was examined with miR-7 precursor-transfected cells. Furthermore, we investigated whether miR-7 suppresses proliferation of CRC cells in combination with cetuximab, a monoclonal antibody against EGFR. Multivariate analysis indicated that low miR-7 expression was an independent prognostic factor for poor survival (P = 0.0430). In vitro assays showed that EGFR and RAF-1 are direct targets of miR-7, which potently suppressed the proliferation of CRC cells, and, interestingly, that the growth inhibitory effect of each of these was enhanced by cetuximab. miR-7 is a meaningful prognostic marker. Furthermore, these data indicate that miR-7 precursor, alone or in combination with cetuximab, may be useful in therapy against CRC.

BackgroundThe aim of this study was to investigate the effects of Rikkunshito on ghrelin secretion and on cisplatin-induced anorexia in humans.MethodsThe study was performed as a crossover design, and ten unresectable or relapsed gastric cancer patients were randomly divided into two groups. Group A (n = 5) was started on Rikkunshito (2.5 g three times daily, orally) from the first course of chemotherapy and followed by a second course without Rikkunshito. A treatment with reversed order was performed for Group B (n = 5). All patients received combined chemotherapy with S-1 plus cisplatin. The primary endpoint was the amount of oral intake, and the categories of scales of anorexia, nausea, and vomiting; secondary endpoints included the plasma concentration of acylated ghrelin.ResultsIn the Rikkunshito-on period, no decrease of the plasma concentration of acylated ghrelin induced by cisplatin was observed. The average oral intake in the Rikkunshito-on period was significantly larger than that in the Rikkunshito-off period, and the grade of anorexia was significantly lower in the Rikkunshito-on period than in the Rikkunshito-off period.ConclusionRikkunshito appeared to prevent anorexia induced by cisplatin, resulting in effective prophylactic administration of chemotherapy with cisplatin, and patients could continue their treatments on schedule.

Fast isochoric heating of a pre-compressed plasma core with a high-intensity short-pulse laser is an attractive and alternative approach to create ultra-high-energy-density states like those found in inertial confinement fusion (ICF) ignition sparks. Laser-produced relativistic electron beam (REB) deposits a part of kinetic energy in the core, and then the heated region becomes the hot spark to trigger the ignition. However, due to the inherent large angular spread of the produced REB, only a small portion of the REB collides with the core. Here, we demonstrate a factor-of-two enhancement of laser-to-core energy coupling with the magnetized fast isochoric heating. The method employs a magnetic field of hundreds of Tesla that is applied to the transport region from the REB generation zone to the core which results in guiding the REB along the magnetic field lines to the core. This scheme may provide more efficient energy coupling compared to the conventional ICF scheme.