Biomedical subjects

Hiroyuki Yamamoto

Publications and source records attributed to Hiroyuki Yamamoto.

At least 73 records · Page 4Linked to original sources

PubMed2004

Involvement of peripheral mechanism in the verapamil-induced potentiation of morphine analgesia in mice.

Morphine's analgesic actions are thought to be mediated through both the central and peripheral nervous systems. L-type calcium channel blockers have been reported to potentiate the analgesic effects of morphine, but the locus of this interaction is not known. In this experiment, we examined the site of verapamil-induced potentiation of morphine analgesia in mice using the quaternary opioid receptor antagonist naloxone-methiodide (NLX-M). Subcutaneous injections of morphine increased locomotor activity and serum corticosterone level, which are mediated by the central nervous system. These central effects were not antagonized by 0.1 mg/kg of NLX-M, whereas this dose of NLX-M partially antagonized the analgesic effect of morphine. Treatment with verapamil potentiated morphine analgesia in a dose-dependent manner. The verapamil-induced potentiation of morphine analgesia was abolished by pretreatment with NLX-M (0.1 and 1 mg/kg). These findings suggest that peripheral mechanisms partially contribute to morphine analgesia and mediate the potentiation of morphine analgesia by verapamil.

Analgesics, Opioid↗

PubMed2004

Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status.

In sporadic colorectal tumours the BRAFV600E is associated with microsatellite instability (MSI-H) and inversely associated to KRAS mutations. Tumours from hereditary non-polyposis colorectal cancer (HNPCC) patients carrying germline mutations in hMSH2 or hMLH1 do not show BRAFV600E, however no consistent data exist regarding KRAS mutation frequency and spectrum in HNPCC tumours. We investigated KRAS in 158 HNPCC tumours from patients with germline hMLH1, hMSH2 or hMSH6 mutations, 166 MSI-H and 688 microsatellite stable (MSS) sporadic carcinomas. All tumours were characterized for MSI and 81 of 166 sporadic MSI-H colorectal cancer (CRCs) were analysed for hMLH1 promoter hypermethylation. KRAS mutations were observed in 40% of HNPCC tumours, and the mutation frequency varied upon the mismatch repair gene affected: 48% (29/61) in hMSH2, 32% (29/91) in hMLH1 and 83% (5/6) in hMSH6 (P = 0.01). KRAS mutation frequency was different between HNPCC, MSS and MSI-H CRCs (P = 0.002), and MSI-H with hMLH1 hypermethylation (P = 0.005). Furthermore, HNPCC CRCs had more G13D mutations than MSS (P < 0.0001), MSI-H (P = 0.02) or MSI-H tumours with hMLH1 hypermethylation (P = 0.03). HNPCC colorectal and sporadic MSI-H tumours without hMLH1 hypermethylation shared similar KRAS mutation frequency, in particular G13D. In conclusion, we show that depending on the genetic/epigenetic mechanism leading to MSI-H, the outcome in terms of oncogenic activation may be different, reinforcing the idea that HNPCC, sporadic MSI-H (depending on the hMLH1 status) and MSS CRCs, may target distinct kinases within the RAS/RAF/MAPK pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Electrophysiological characteristic of corticoaccumbens synapses in rat mesolimbic system reconstructed using organotypic slice cultures.

The nucleus accumbens (NAc) is a component of the mesolimbic system involved in drug dependence. Activity of nucleus accumbens neurons is modulated by glutamatergic afferents from the prefrontal cortex and by dopaminergic afferents from the ventral tegmental area (VTA). In the present study, we reconstructed the mesolimbic system using organotypic slice cultures and examined the effects of dopaminergic agents on synaptic activity in the prefrontal cortex-nucleus accumbens synapses. A slice of each of the prefrontal cortex, nucleus accumbens and ventral tegmental area in newborn rat, was arranged on a multi-electrode dish (MED) filled with culture medium so that they contacted each other, termed a 'triple culture'. Extracellular recording using microelectrodes on the multi-electrode dish showed that a single electrical stimulation of the prefrontal cortex slice evoked field excitatory postsynaptic potential, and that population spikes occurred spontaneously in the nucleus accumbens area of the triple culture. The amplitude of evoked field excitatory postsynaptic potentials and the frequency of spontaneous population spikes were decreased by glutamatergic antagonists, D(-)-2-amino-5-phosphonovaleric acid and 6-cyano-7-nitroquinoxaline-2,3-dione. The D1-like receptor agonist SKF38393, but not the D2-like receptor agonist quinpirole, reduced both the amplitude of field excitatory postsynaptic potential and frequency of spontaneous population spikes. Cocaine depressed field excitatory postsynaptic potential and this depression was reversed by D1-like receptor antagonist SCH23390, but not by D2-like receptor antagonist sulpiride. These results suggest that evoked field excitatory postsynaptic potentials and spontaneous population spikes were driven by glutamatergic neurons and were subject to exogenous and endogenous dopaminergic modulation in the triple culture that was similar to that shown in in vivo.

Animals↗

PubMed2004

Synthesis of enzymatically crosslinkable peptide-poly(L-lysine) conjugate and creation of bio-inspired hybrid fibers.

Poly(L-lysine)s having an Nepsilon-substituted tetrapeptide, Lys-Gly-Tyr-Gly, were synthesized by the coupling of the protected tetrapeptide active ester, Boc-Lys(Z)-Gly-Tyr(Bzl)-Gly (4-hydroxyphenyl)dimethylsulfonium methylsulfate and Nepsilon-group of the poly(L-lysine) side chain. The Nepsilon-substituted tetrapeptide functions as the substrate of tyrosinase and is responsible for the enzyme-mediated interpolymer cross-linking. The degree of Nepsilon-substitution (DS) was mostly controlled by changing the stoichiometry between the Nepsilon-amino groups of the parent poly(L-lysine) and the protected tetrapeptide active ester. Two kinds of samples having DS values of 8.6 and 18 mol-% were prepared. The resulting cationic Nepsilon-(Lys-Gly-Tyr-Gly)-poly(L-lysine) (abbreviated as PLL(GYGK)) was spun into hybrid fibers with the anionic polysaccharide gellan via a polyionic complexation reaction at the interface between aqueous solutions of the two polymers. The mechanical strengths of the PLL(GYGK)-gellan hybrid fibers were superior to those of the original poly(L-lysine)-gellan fibers. The mechanical strength of the hybrid fibers further increased upon the tyrosinase-mediated cross-linking reaction of the PLL(GYGK). This result indicates that the covalent cross-bridge formation between the Nepsilon-substituted peptides significantly contributed to reinforcement of the hybrid fibers. The present study affords a new methodology for reinforcement inspired by a biological process.

Biomimetic Materials↗

PubMed2004

Novel mutations in the cellular retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata albescens: evidence of interfamilial genetic heterogeneity and fundus changes in heterozygotes.

OBJECTIVE: To evaluate the molecular genetic defects associated with retinitis punctata albescens (RPA) in 5 patients from 3 families with this disease. METHODS: We examined 3 probands and 2 clinically affected relatives with RPA. Clinical examinations included best-corrected visual acuity, visual field testing, electroretinography, dilated fundus examination, and fundus photography. Leukocyte DNA was analyzed for mutations in the exons of the genes encoding cellular retinaldehyde-binding protein 1 (RLBP1), 11-cis-retinol dehydrogenase (RDH5), interphotoreceptor retinoid-binding protein (RBP3), and photoreceptor all-trans-retinol dehydrogenase (RDH8). Not all patients were evaluated for mutations in each gene. The exons were individually amplified and screened for mutations by single-stranded conformational polymorphism analysis or direct genomic sequencing. RESULTS: The 3 probands had similar clinical findings, including a history of poor night vision, the presence of punctate white deposits in the retina, and substantially reduced or absent rod responses on electroretinogram testing. One of the probands (patient 2:III:2) had 2 novel mutations in the RLBP1 gene (Arg151Trp and Gly31[2-base pair deletion], [GGA-->G-]). Segregation analysis showed that the 2 mutations were allelic and that the patient was a compound heterozygote. Both parents of the proband manifested round white deposits in the retina. The other 2 probands had no detected pathogenic mutations in RLBP1 or in the other 3 genes evaluated. CONCLUSIONS: The identification of novel RLBP1 mutations in 1 of our 3 probands, all with RPA, is further evidence of genetic (nonallelic) heterogeneity in this disease. The presence of round white deposits in the retina may be observed in those heterozygous for RLBP1. Clinical Relevance Patients with a clinical presentation of RPA can have genetically different mutations. Drusen-like lesions may be observed in heterozygotes in families with this disease and a mutation in RLBP1.

Adult↗

PubMed2004

Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation.

BRAF, a serine/threonine kinase of the RAF family, is a downstream transducer of the RAS-regulated MAPK pathway and signals upstream of MEK1/2 kinases. Recently, activating mutations within BRAF have been reported in a high percentage of melanomas and colorectal carcinomas and shown to have oncogenic capabilities. Further, their association to mismatch-repair-deficient tumors has suggested the involvement of the RAS/RAF pathway in the tumorigenesis of microsatellite-unstable colon cancers, and that RAS and RAF mutations are alternative genetic events. We determined whether colorectal mismatch-repair-deficient tumors with BRAF mutations show a specific genotype when compared with tumors with wild-type BRAF, and whether they can be associated with a particular clinicopathological feature. Here, we report a striking association of BRAF, but not of APC, KRAS2, AXIN2, and TP53 mutations, with proximal mismatch-repair-deficient colon tumors and MLH1 hypermethylation. Our results support the hypothesis that proximal and distal colorectal tumors with mismatch repair deficiency harbor different genetic alterations, and we suggest that the involvement of the RAS/RAF pathway in colorectal tumorigenesis is differentially modulated according to tumor location and MLH1 inactivation.

Adaptor Proteins, Signal Transducing↗

PubMed2004

A case of systemic lupus erythematosus with postpartum hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome and concomitant high phosphatidylserine-dependent anti-prothrombin antibody levels.

In August 1994, a 19-year-old woman presented to her dermatologist with a slight fever, arthralgia, and a butterfly rash. Discoid lupus erythematosus was suspected, and serological testing yielded positive results for antinuclear antibody. She was diagnosed with systemic lupus erythematosus without organ failure and was treated with only nonsteroidal antiinflammatory drugs. She became pregnant in June 2001, at age 26. In November her obstetrician noted that she had severe hypertension, edema of the low limbs, and proteinuria. On admission, she was diagnosed with severe preeclampsia, and cesarean section was performed. On hospital day 3 the patient developed sudden epigastric pain and vomiting. Laboratory tests revealed thrombocytopenia, liver dysfunction, and microangiopathic hemolytic anemia, leading to a diagnosis of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Plasma exchange was performed for 5 days. The thrombocytopenia, liver dysfunction, and proteinuria diminished quickly. Later testing revealed a high titer of plasma phosphatidylserine-dependent anti-prothrombin antibody. This case is useful for exploring the relations between SLE, HELLP syndrome, and anti-prothrombin antibody.

Journal Article↗

PubMed2004

Prediction of postoperative visual outcome based on hole configuration by optical coherence tomography in eyes with idiopathic macular holes.

PURPOSE: To evaluate whether an index based on hole configuration can be used to predict visual outcome in eyes with idiopathic macular holes. DESIGN: Prospective interventional case series. METHODS: Thirty-five eyes of 32 patients with idiopathic stage 2 or 3 macular hole were enrolled in this study. The best-corrected visual acuity (BCVA), cross-sectional image of the macular hole by optical coherence tomography (OCT), and retinal thickness in the central (<1000 microm), inner (1000 to 2220 microm), and outer ring areas (2220 to 3450 microm) as defined by the OCT retinal mapping program were evaluated preoperatively and at 1, 3, 6, and 12 months postoperatively. The change in retinal thickness of the inner ring area at the 6-month postoperative period was used to evaluate the degree of preoperative retinal deformation. The macular hole index (MHI) (ratio of hole height to base diameter of hole) was calculated and correlated with minimum diameter of hole, base diameter of hole, the postoperative decrease in macular thickness, and the postoperative BCVA. The postoperative BCVA was further evaluated in two patient-matched groups. RESULTS: Retinal thickness values in the inner ring area were decreased at the 1-month postoperative period. MHI significantly correlated with the postoperative decrease in macular thickness in the inner ring area at 6 months (correlation coefficient = -0.632, P = .030, Spearman analysis) and with the postoperative BCVA (P = .013, multiple regression analysis). Postoperative BCVA in the MHI >/=0.5 group was better than that in the MHI <0.5 group (P = .032, Mann-Whitney test). CONCLUSIONS: The MHI is a ratio easily calculated from OCT transverse images of the macular area. The MHI represents the preoperative configuration of a macular hole and is a prognostic factor for visual outcome.

Aged↗

PubMed2004

Down-regulation of inducible nitric oxide synthase by lysophosphatidic acid in human respiratory epithelial cells.

Viral infection generally results in the activation of inducible nitric oxide synthase (iNOS or NOS2) in respiratory epithelial cells by inflammatory cytokines. Activated NOS2 catalyzes synthesis of nitric oxide (NO), which in excess can cause cellular injury. On the other hand, lysophosphatidic acid (LPA), a lipid mediator released from epithelial cells, platelets, and fibroblasts in injured tissue, functions in repair of cell injury. However, details of the mechanism for repair by LPA remain unknown. We demonstrated one effect of LPA favoring repair, specifically inhibition by LPA of cytokine-induced NOS2 protein and mRNA expression by human respiratory epithelial cells in vitro. NO production by LPA-treated, cytokine-stimulated cells was also reduced. These decreases were prevented by Rho kinase inhibition with Y-27632. Thus, down-regulation by LPA of cytokine-induced increases in NOS2 activity is likely to involve a Rho-dependent signaling pathway. Harmful biologic effects of NO in viral respiratory infection might be modified by therapeutic manipulations involving LPA or Rho.

Cell Line↗

PubMed2004

A glycosylated byssal precursor protein from the green mussel Perna viridis with modified dopa side-chains.

Foot tissue of the green mussel Perna viridis contains a variety of byssal precursor proteins with the unusual redox-active amino acid, Dopa (-beta-3,4-dihydroxyphenyl-alpha-alanine). Eight proteins were detectable in acidic extracts of the Perna foot by a redox cycling assay with nitroblue tetrazolium. In one of these, however, P. viridis foot protein-1 (Pvfp-1), activity was not due to Dopa, but to another redox-active derivative. Based on specific colorimetric derivatization with Arnow's reagent, ninhydrin and phenylisothiocyanate (Edman), mass spectrometry, the redox-active derivative in Pvfp-1 is not consistent with any known modification. Another uncommon modification of Pvfp-1 involves O-glycosylation of threonine by mannose, glucose or fucose. As in previously characterized fp-1s, the primary sequence of the Pvfp-1 (apparent mass 89 kDa) has two consensus decapeptide motifs; one is APPKPX1TAX2K and the other is APPPAX1TAX2K, where P is Pro/Hyp, and X1 and X2 are difucosylated threonine and a redox sensitive derivative of tyrosine or Dopa, respectively. Of these two unusual residues, X2 is unique to Pvfp-1, whereas O-glycosylated Thr has been previously detected in freshwater mussel fp-1. The sequence homology of Pvfp-1 with the common structural motifs of the fp-1 protein family strongly suggests that the Pvfp-1 functions as the byssal coating (lacquer) protein.

Adhesiveness↗

PubMed2004

Observation of iron silicide formation by plan-view transmission electron microscopy.

The formation and the phase transitions of iron silicide by solid-phase epitaxy have been investigated by means of plan-view transmission electron microscopy, which enables us to observe a clean interface between Fe and Si. Layers of Fe were deposited on Si (100) at room temperature in an ultrahigh vacuum chamber. The sample was annealed in the electron microscope at a temperature between 673 and 1073 K. After annealing at 673 K, FeSi crystallites were formed with various orientations. When the annealing temperature was increased to 973 K, we found that the crystallites suddenly started to coalesce into grains of several hundreds of nanometers in size and polycrystalline beta-FeSi2 was formed. These phase transitions were also confirmed with electron energy-loss spectroscopy.

Crystallography↗

PubMed2004

Purification and functional characterization of insecticidal sphingomyelinase C produced by Bacillus cereus.

Bacillus cereus isolated from the larvae of Myrmeleon bore was found to secrete proteins that paralyze and kill German cockroaches, Blattela germanica, when injected. One of these active proteins was purified from the culture broth of B. cereus using anion-exchange and gel-filtration chromatography. The purified toxin, with a molecular mass of 34 kDa, was identified as sphingomyelinase C (EC 3.1.4.12) on the basis of its N-terminal and internal amino-acid sequences. A recombinant sphingomyelinase C expressed in Escherichia coli was as potent as the native protein in killing the cockroaches. Site-directed mutagenesis (His151Ala) that inactivated the sphingomyelinase activity also abolished the insecticidal activity, suggesting that the rapid insect toxicity of sphingomyelinase C results from its phospholipid-degrading activity.

Amino Acid Sequence↗

PubMed2004

Role of pharmacokinetic effects in the potentiation of morphine analgesia by L-type calcium channel blockers in mice.

The present study was designed to investigate the pharmacokinetic interaction of morphine with three classes of L-type calcium channel blockers (CCB) and its relationship to morphine-induced mechanical antinociception in mice. The CCB classes were benzothiazepine (diltiazem), dihydropyridine (nimodipine), and phenylalkylamine (verapamil). Each of the three classes of L-type CCB (diltiazem, 40 and 80 mg/kg; nimodipine, 40 mg/kg; verapamil, 40 mg/kg), when administered prior to morphine (4 mg/kg, s.c.), potentiated the analgesic effect of morphine and markedly increased the level of morphine in serum. Pretreatment with diltiazem (40 and 80 mg/kg) and verapamil (40 mg/kg) also increased morphine level in the brain. However, these drugs produced less increase in morphine level in the brain than they produced in serum (i.e., they decreased the brain-to-serum ratio of morphine). Pretreatment with nimodipine (40 mg/kg) did not affect the morphine level in the brain and also decreased the brain-to-serum ratio of morphine. When morphine (3.2-100 mg/kg, s.c.) was injected alone, the brain-to-serum ratio of morphine was constant, regardless of the morphine dose. These results suggest that increases in morphine concentration in peripheral blood may be, at least in part, involved in the ability of L-type CCBs to potentiate the analgesic effect of morphine.

Analgesia↗

PubMed2004

[Beneficial effect of glucocorticosteroids for esophageal varices due to idiopathic portal hypertension following systemic lupus erythematosus].

A 54-year-old female experienced morning stiffness and arthralgia of the hands from November 2001 and consulted her local doctor in January 2002. Hematological data showed liver dysfunction and antinuclear antibody was positive. In February 2002, the patient was admitted to our hospital to investigate these abnormalities of liver function further. The features of arthritis, thrombocytopenia with elevated platelet-associated IgG, positive antinuclear antibody, and anti-DNA antibody lead to a diagnosis of systemic lupus erythematosus. Liver biopsy revealed infiltration of Glisson's capsule by plasma cells, compatible with autoimmune hepatitis. We performed hepatic venography to investigate severe pancytopenia, remarkable splenomegaly and esophageal varices. Wedged hepatic venous pressure was mildly elevated, and hepatic veins displayed sharp angles, smooth walls and development of anastomosis with each other. These findings suggested idiopathic portal hypertension. Cytopenia and liver dysfunction gradually improved on treatment with 40 mg/day prednisolone. Esophageal varices were disappeared, and splenomegaly had improved after 6 months. As autoimmune factors are considered to underlie the development of idiopathic portal hypertension with systemic lupus erythematosus, steroid administration represents a therapeutic option in this condition.

Esophageal and Gastric Varices↗

PubMed2004

[A case of pityriasis rubra pilaris associated with rapidly progressive finger joint destruction].

A 40-year-old female noticed edema of the lower limbs in March 1995. Nephrotic syndrome due to membranous nephropathy was diagnosed and administration of high-dose corticosteroids resulted in incomplete remission. Progressively enlarging, red scaling skin lesions developed concomitantly from the scalp to the extremities. Pityriasis rubra pilaris (PRP) was diagnosed in 1996 in the Department of Dermatology at Sapporo Medical University hospital. Various treatments proved ineffective. Arthritis of the finger joints developed in July 1999, and proteinuria recurred in April 2000. She was admitted to our department in August 2000. Physical examination on admission revealed marked swelling of both distal interphalangeal (DIP) joints and the right fourth proximal interphalangeal (PIP) joint. Results of testing for antinuclear antibody, rheumatoid factor, and HLA-B27 were all negative. Radiography of the hands revealed destruction of the DIP and PIP joints where MRI indicated the presence of synovitis. Bone scintigraphy demonstrated accumulation in bilateral metatarso-phalangeal joints and the left sacroiliac joint. Arthritis associated with PRP was diagnosed, as both PRP and psoriasis represent keratinizing disorders of the skin and clinical features in the present case resembled those of psoriatic arthritis. Despite administration of high-dose corticosteroids, destruction of finger joints progressed rapidly. Administration of cyclosporine in April 2002 improved arthritic symptoms. Cases of PRP accompanied by arthritis need to be accumulated to allow analysis of the pathogenesis and clinical picture of this association.

Adult↗

PubMed2004

[A case of postoperative chestwall recurrence of gastric cancer responding to a combination of radiation, hyperthermia and oral administration of TS-1].

A 77-year-old man diagnosed with advanced gastric cancer underwent total gastrectomy with combined splenectomy and resection of the pancreatic tails in 1996. He was treated with 400 mg/day of UFT for 2 years. Serum CEA level was found to be elevated on July 5, 2001. He complained of left chest pain in December 2001. A 4 cm-sized tumor was detected in the region extending from the subcutaneous region to the left chest wall containing the osteolytic change of the left sixth rib. He was diagnosed with a chest wall metastasis from gastric cancer. He underwent radiotherapy with thermotherapy and was also treated with chemotherapy. TS-1 was administered at 80-100 mg/body/day, twice daily for 3 weeks followed by a 2-week rest interval as 1 cycle. As a results, shrinkage of the tumor was confirmed on February 14, 2002. The tumor was confirmed to have disappeared on April 17, 2002, by chest CT. A complete response of the metastatic tumor was achieved. The patient maintained a complete response for more than 12 months, but died from the chest wall metastasis recurrence and weakness on August 13, 2003. The only observed adverse event, was grade 2 leukopenia.

Adenocarcinoma↗

PubMed2004

[Difficult airway in a child with multiple juvenile xanthogranulomas].

Juvenile xanthogranuloma (JXG) is a benign and self-healing histiocytosis on the skin. A 4-year-old boy with multiple JXG was scheduled for plastic surgery to correct the scar contraction of the neck. The patient was expected to have difficult airway caused by small mouth, limitation of neck movement and numerous nodular lesions located at the face. Initially he underwent resection of the neck scar under local anesthesia with added inhalation anesthesia via mask, and the restricted neck recurvation was improved. One week later, he underwent skin grafting under general anesthesia. We used a spiral tube of 3 mm diameter inserted to the nostril for manual ventilation, and bronchofiberscope-aided tracheal intubation was successfully performed through the laryngeal mask airway under general anesthesia without any problems.

Anesthesia, General↗

PubMed2003

BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency.

Genes from the RAF family are Ras-regulated kinases involved in growth cellular responses. Recently, a V599E hotspot mutation within the BRAF gene was reported in a high percentage of colorectal tumors and significantly associated to defective mismatch repair (MMR). Additionally, BRAF mutations were described only in K-Ras-negative colon carcinomas, suggesting that BRAF/K-Ras activating mutations might be alternative genetic events in colon cancer. We have addressed to what extent the tumorigenic-positive selection exerted by BRAF mutations seen in colorectal MMR-deficient tumors was also involved in the tumorigenesis of gastric cancer. Accordingly, BRAF mutations were detected in 34% (25/74) of colorectal MMR-deficient tumors and in 5% (7/142) of MMR-proficient colorectal cases (P=0.0001). All mutations found in the MSI cases corresponded to the previously reported hotspot V599E. Two D593K and a K600E additional mutations were also detected in three MSS cases. However, only one mutation of BRAF was found within 124 MSS gastric tumors and none in 37 MSI gastric tumors, clearly suggesting that BRAF mutations are not involved in gastric tumorigenesis. Nonetheless, a high incidence of mutations of K-Ras was found within the MSI gastric group of tumors (P=0.0005), suggesting that the activation of K-Ras-dependent pathways contributes to the tumorigenesis of gastric cancers with MMR deficiency. Accordingly, our results show evidences that BRAF mutations characterize colon but not gastric tumors with MMR deficiency and are not involved in the tumorigenesis of gastric cancer of the mutator phenotype pathway.

Amino Acid Substitution↗