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Colon cancer with DNA mismatch repair (MMR) defects reveals indistinguishable clinical and pathologic aspects, including better prognosis and reduced response to 5-fluorouracil (5-FU)-based chemotherapy. There has been no consensus for p53 as a prognostic marker in colorectal cancer. This study investigated the clinical implication of MSI-H/MMR-D and p53 expression in R0-resected colon cancer patients who received adjuvant oxaliplatin/5-FU/leucovorin (FOLFOX) therapy. We analyzed 135 patients, who had been treated by adjuvant chemotherapy containing 5-FU and oxaliplatin (FOLFOX) after curative resection (R0) for colon adenocarcinoma between May 2004 and November 2007. Tumor expression of the MMR proteins, MLH1 and MSH2, was detected by immunohistochemistry (IHC) in surgically resected tumor specimens. MSI was analyzed by polymerase chain reaction (PCR) amplification using fluorescent dye-labeled primers specific for microsatellite loci. Tumors with MMR defects were defined as those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Expression patterns of p53 were determined in a semiquantitative manner by light microscopy. There were 13 (9.6%) patients with stage II, 108 (80%) with stage III, and 14 (10.4%) with stage IV. Fourteen patients with stage IV (10.3%) had metastases to liver only, all of whom underwent complete metastasectomy for liver metastases. In total, 134 tumor specimens were genotyped, 115 specimens were tested by IHC and 113 cases had both genotyping and IHC results available for analysis. Genotyping results demonstrated that 12 (9.0%) cases were MSI-H and 122 (91.0%) were MSI-L/S. By IHC, 11 (9.6%) patients were MMR-D and 104 (90.4%) were MMR-I. The methods were in agreement in 108 patients (94.7%). We assessed 114 patients for p53 expression by immunostaining. MMR status was not significantly associated with DFS ( P = 0.56) or OS ( P = 0.61) in patients with colon cancer ( n = 135) receiving adjuvant FOLFOX. According to p53 status, there was also no significant difference for DFS ( P = 0.11) and OS ( P = 0.94). For patients with genotyping/IHC agreement ( n = 108), there was no difference in DFS ( P = 0.57) and OS ( P = 0.98) between patients with MSI-H/MMR-D and MSI-L/S/MMR-I tumors. The MMR status or p53 positivity was not significantly associated with outcomes to FOLFOX as adjuvant chemotherapy in colon cancer patients with R0 resection. Adding oxaliplatin in adjuvant chemotherapy may overcome negative impact of 5-FU on colon cancers with MSI-H/MMR-D. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Preparation regimens for morning colonoscopy are suboptimal. The aim of this study was to test the efficacy and tolerance of a split-dose magnesium citrate–low-volume (2 liters) polyethylene glycol (PEG) regimen for morning colonoscopy.METHODS:A total of 232 patients were randomly assigned to receive 4 liters PEG (day before procedure; group 1, n=79), 2 liters PEG (day before procedure) followed by another 2 liters PEG (day of procedure; group 2, n=80), or magnesium citrate (250 ml, day before procedure) followed by 2 liters PEG (day of procedure; group 3, n=73). The quality of bowel cleansing, tolerability, and adverse effects in group 3 were compared with those in groups 1 and 2.RESULTS:Satisfactory bowel preparation was more frequently reported for group 3 than for group 1 (75% vs. 51%, P=0.001) and was similar to that for group 2 (75% vs. 76%, P=0.896). A significantly greater proportion of patients in group 3 graded their overall satisfaction as satisfactory compared with group 1 (43% vs. 23%, P=0.010), and the proportion was similar to that in group 2 (43% vs. 35%, P=0.133). Patients in group 3 were more willing to repeat the same preparation regimen, if necessary, than those in group 1 (93% vs. 48%, P<0.001) or group 2 (93% vs. 62%, P<0.001).CONCLUSIONS:The split-dose magnesium citrate–low-volume (2 liters) PEG regimen was more efficient than and preferred to the conventional regimen of 4 liters of PEG, and it was equally efficient as, but, again, preferred to the split-dose (2+2 liters) regimen for morning colonoscopy. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Colonic spasm, a relatively common problem during colonoscopy, may interfere with intubation and examination. This study was conducted to compare the effect of warm water consumption before unsedated colonoscopy on the incidence of spasm, pain, and technical difficulties. In addition, we studied the associations between attributes of patients and the degree of pain experienced by them during procedures undertaken after warm water consumption.METHODS:A prospective, randomized, controlled, and investigator-blinded study was conducted in which three groups of patients underwent unsedated colonoscopies. Those randomized to group A (n=64) were instructed to drink 2 l of warm water and 90 ml of sodium phosphate (NaP) solution before colonoscopy. For comparison, those randomized to groups B (n=64) and C (n=64) were instructed to drink 2 l of cold water and 90 ml of NaP solution, or 90 ml of NaP solution without any additional water, respectively. Patient demographics, procedure-related factors, and degree of spasm, pain, and technical difficulty were assessed.RESULTS:Ileal intubation and withdrawal times were significantly shorter for group A than for groups B and C (P<0.001 and P<0.001, respectively). There was no significant difference between groups in the degree of spasm reported by the endoscopist. The level of pain at the sigmoid colon and splenic flexure during colonoscopy was lower for group A than for groups B and C on both advancement and withdrawal of the colonoscope (P<0.001 and P<0.001, respectively). The level of discomfort 2 h after the completion of endoscopy was lower for group A than for the other groups. (P=0.001). A subgroup analysis showed that warm water consumption was especially beneficial for patients <40 years of age and for those with irritable bowel syndrome. A multivariate analysis showed that warm water consumption before colonoscopy (odds ratio (OR) 0.22; 95% confidence interval (CI): 0.09–0.48 vs. the cold water group and OR 0.34; 95% CI: 0.16–0.73 vs. the no water group) was an independent factor for the reduction of pain during colonoscopy.CONCLUSIONS:The intake of warm water before unsedated colonoscopy reduces procedure-related pain and technical difficulty, especially in patients who are young or have irritable bowel syndrome, even though it does not improve the frequency of visible spasmodic events. [ABSTRACT FROM AUTHOR]

A commercial aluminum foil was used to braze alumina plates in air. Although the outer surface of the aluminum oxidizes in air, the majority of the aluminum underneath remains unoxidized during brazing, allowing the ceramic pieces to be joined together with adequate strength. Joint strength testing and subsequent examination of the fracture surfaces of the joints indicate that the joints are inherently ductile, even after long-term, high-temperature air exposure. [ABSTRACT FROM AUTHOR]

CD1d is a major histocompatibility complex (MHC) class I-related molecule that functions in glycolipid antigen presentation to distinct subsets of T cells that express natural killer receptors and an invariant T-cell receptor-α chain (invariant NKT cells)1-3. The acquisition of glycolipid antigens by CD1d occurs, in part, in endosomes through the function of resident lipid transfer proteins, namely saposins4-10. Here we show that microsomal triglyceride transfer protein (MTP), a protein that resides in the endoplasmic reticulum of hepatocytes and intestinal epithelial cells (IECs) and is essential for lipidation of apolipoprotein B11,12, associates with CD1d in hepatocytes. Hepatocytes from animals in which Mttp (the gene encoding MTP) has been conditionally deleted, and IECs in which Mttp gene products have been silenced, are unable to activate invariant NKT cells. Conditional deletion of the Mttp gene in hepatocytes is associated with a redistribution of CD1d expression, and Mttp-deleted mice are resistant to immunopathologies associated with invariant NKT cell-mediated hepatitis and colitis. These studies indicate that the CD1d-regulating function of MTP in the endoplasmic reticulum is complementary to that of the saposins in endosomes in vivo. [ABSTRACT FROM AUTHOR]

Abstract Alopecia induced by aging or side effects of medications affects millions of people worldwide and impairs the quality of life; however, there is a limit to the current medications. Here, we identify a small transdermally deliverable 5‐mer peptide (GLYYF; P5) that activates adiponectin receptor 1 (AdipoR1) and promotes hair growth. P5 sufficiently reproduces the biological effect of adiponectin protein via AMPK signaling pathway, increasing the expression of hair growth factors in the dermal papilla cells of human hair follicle. P5 accelerates hair growth ex vivo and induces anagen hair cycle in mice in vivo. Furthermore, we elucidate a key spot for the binding between AdipoR1 and adiponectin protein using docking simulation and mutagenesis studies. This study suggests that P5 could be used as a topical peptide drug for alleviating pathological conditions, which can be improved by adiponectin protein, such as alopecia.

Abstract Glycine transporters (GlyT1 and GlyT2) that regulate levels of brain glycine, an inhibitory neurotransmitter with co‐agonist activity for NMDA receptors (NMDARs), have been considered to be important targets for the treatment of brain disorders with suppressed NMDAR function such as schizophrenia. However, it remains unclear whether other amino acid transporters expressed in the brain can also regulate brain glycine levels and NMDAR function. Here, we report that SLC6A20A, an amino acid transporter known to transport proline based on in vitro data but is understudied in the brain, regulates proline and glycine levels and NMDAR function in the mouse brain. SLC6A20A transcript and protein levels were abnormally increased in mice carrying a mutant PTEN protein lacking the C terminus through enhanced β‐catenin binding to the Slc6a20a gene. These mice displayed reduced extracellular levels of brain proline and glycine and decreased NMDAR currents. Elevating glycine levels back to normal ranges by antisense oligonucleotide‐induced SLC6A20 knockdown, or the competitive GlyT1 antagonist sarcosine, normalized NMDAR currents and repetitive climbing behavior observed in these mice. Conversely, mice lacking SLC6A20A displayed increased extracellular glycine levels and NMDAR currents. Lastly, both mouse and human SLC6A20 proteins mediated proline and glycine transports, and SLC6A20 proteins could be detected in human neurons. These results suggest that SLC6A20 regulates proline and glycine homeostasis in the brain and that SLC6A20 inhibition has therapeutic potential for brain disorders involving NMDAR hypofunction.