Biomedical subjects

K Kashiwagi

Publications and source records attributed to K Kashiwagi.

At least 37 records · Page 2Linked to original sources

PubMed2001

Dual action of nitric oxide on purely isolated retinal ganglion cells.

PURPOSE: The role of nitric oxide (NO) in the survival of retinal ganglion cells (RGCs) was investigated. METHODS: RGCs were purely isolated from postnatal Sprague-Dawley rats by 2-step panning and were cultured in chemically defined serum free medium. An NO releaser, S-nitroso-N-acetylpenicillamine (SNAP: 500 microM, 250 microM, 100 microM, 10 microM, 1 microM, 100 nM, and 10 nM), an NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide potassium salt (c-PTIO: 100 microM, 33 microM, 10 microM, 1 microM), mixture of 100 microM SNAP and 33 microM c-PTIO, N(G)-nitro-L-arginine methyl ester (L-NAME: 10 mM, 5 mM, 500 microM, 100 microM or 10 microM), or their vehicles were added to the medium of pure RGC culture for 48 hr. Survival rates of small and large RGCs were determined separately by flow cytometry. RESULTS: At > or = 100 microM, SNAP significantly reduced RGC survival in a concentration dependent manner. At < or = 41 microM, SNAP significantly increased survival, particularly of large RGCs. c-PTIO and L-NAME reduced the survival rates concentration-dependently. A mixture of 100 microM SNAP and 33 microM c-PTIO significantly improved RGC survival compared with when they were added on their own. CONCLUSIONS: These results indicate that NO exhibits neuroprotective and neurotoxic actions on RGCs and that low concentrations of NO may be beneficial for the survival of neonatal RGCs in vitro.

Animals↗

PubMed2001

Matrix metalloproteinases in human diabetic and nondiabetic vitreous.

PURPOSE: To compare matrix metalloproteinase (MMP) activities in human vitreous samples from patients with diabetic retinopathy (DR) and other vitreoretinal diseases, and to investigate the factors influencing the MMP activities in human DR vitreous samples. METHODS: Thirty-one diabetic and 17 nondiabetic vitreous samples (from nine patients with macular holes and eight patients with epiretinal membranes) were examined. Samples collected at the time of pars plana vitrectomy were subjected to substrate zymography to conduct a quantitative analysis of MMP activity. Immunoblotting against antihuman MMP-1, 2, and 9 was performed to identify MMP in vitreous samples. The effects of posterior vitreous detachment (PVD), vitreous hemorrhage, proliferative membrane, traction detachment, and cystoid macular edema on MMP activities were investigated. RESULTS: All vitreous samples from both DR and non-DR patients showed a single band at the position of 72 kD, corresponding to MMP-2. Another band at 99 kD, corresponding to MMP-9, was detected significantly more often in DR samples than in non-DR samples: 45.2% and 0%, respectively (P = 0.0007). The number of samples showing a band from MMP-9 was significantly higher in partial PVD samples than in complete PVD samples: 66.7% and 15.4%, respectively (P = 0.001). CONCLUSION: The results indicated that MMP-9 may be involved in DR and that partial PVD may be related to the MMP-9 activity in DR.

Adult↗

PubMed2001

Cystoid macular edema associated with topical latanoprost in glaucomatous eyes with a normally functioning blood-ocular barrier.

PURPOSE: To study prospectively using optical coherence tomography (OCT) whether topical latanoprost induces retinal disorders, such as cystoid macular edema, in patients with glaucoma and a normally functioning blood-ocular barrier. METHODS: Sixty-eight eyes of 38 patients with glaucoma and no history of intraocular surgery, uveitis, or laser trabeculoplasty were studied. Before initiation of latanoprost treatment and after 1, 3, and 6 months of treatment, OCT images were taken, and the following tests were performed: visual acuity examination, fundus ophthalmoscopy, intraocular pressure measurement, and fundus color photography. To evaluate retinal thickness in the fovea accurately. OCT scanning was repeated six times, and the smallest value was used as the retinal thickness in the fovea. RESULTS: Latanoprost ophthalmic solution did not influence retinal thickness in the fovea at any investigated time points compared with the time before instillation, and no changes were observed in visual acuity, ophthalmoscopic findings, and fundus photographs. The intraocular pressure was reduced significantly at all investigated time points compared with the time before instillation. CONCLUSIONS: It is unlikely that topical latanoprost induces retinal disorders, such as cystoid macular edema, in glaucomatous eyes with a normally functioning blood-ocular barrier.

Adult↗

PubMed2001

Isopropyl unoprostone increases the activities of matrix metalloproteinases in cultured monkey ciliary muscle cells.

PURPOSE: The mechanism by which the prostaglandin F2alpha-related antiglaucoma compound isopropyl unoprostone (referred to as unoprostone) reduces intraocular pressure is largely unknown. Another prostaglandin F2alpha-related compound, latanoprost, influences the activities of matrix metalloproteinases in ciliary muscle. Unoprostone ophthalmic solution is metabolized to oxidized metabolites, mainly M1 and M2, in the eye. The aim of this study was to investigate whether intraocular metabolites of unoprostone, M1 and M2, change the metalloproteinase activity in cultured monkey ciliary muscle cells. MATERIALS AND METHODS: Monkey ciliary muscle cells and trabecular meshwork cells were grown separately to confluence in monolayer cell cultures. M1 (10 nM, 100 nM, or 1 microM), M2 (10 nM, 100 nM, or 1 microM), 100 nM prostaglandin F2alpha, or vehicle solutions were added to each culture medium for 48 hours. The media were then assayed to measure metalloproteinase activities quantitatively by means of substrate zymography. RESULTS: Compared with the vehicle controls, M1, M2, and prostaglandin F2alpha significantly increased the metalloproteinase-2 activity in cultured ciliary muscle cells in a dose-dependent manner, but did not affect the metalloproteinase-2 activity in cultured trabecular meshwork cells. All experimented prostaglandins slightly increased metalloproteinase-9 activity in ciliary muscle cells, although these changes were not significant. CONCLUSIONS: The current results show that unoprostone influences the metabolism of the extracellular matrix in the ciliary muscle and that remodeling of the extracellular matrix in the ciliary muscle may be a possible mechanism by which unoprostone ophthalmic solution reduces intraocular pressure.

Animals↗

PubMed2001

Iridial pigmentation induced by latanoprost ophthalmic solution in Japanese glaucoma patients.

PURPOSE: To investigate the incidence of iridial pigmentation induced by latanoprost ophthalmic solution in Japanese glaucoma patients by a prospective and observer-masked study. PATIENTS AND METHODS: Sixty-nine eyes of 69 glaucoma patients were included. Patients who had undergone intraocular surgery, laser trabeculoplasty, and laser iridotomy within 12 months before enrollment, and patients with history of uveitis and any changes in antiglaucoma drugs within 6 months before enrollment were excluded. Iridial photographs were taken by one examiner under the same conditions at 1, 3, and 6 months after the initiation of latanoprost treatment. Three glaucoma specialists, masked of patient information, independently assessed the iridial pigmentation. Cases with iridial pigmentation diagnosed by three specialists were categorized as showing a definite increase in iridial pigmentation. RESULTS: A definite increase in iridial pigmentation occurred in 3.5%, 9.7%, and 35.0% of eyes within 1, 3, and 6 months of treatment, respectively. Age, gender, or concomitantly used eyedrops did not significantly influence the incidence of iridial pigmentation within 6 months of instillation. A reduction of intraocular pressure by latanoprost did not differ significantly between patients with and without iridial pigmentation. CONCLUSION: The incidence of iridial pigmentation by latanoprost ophthalmic solution in Japanese patients was higher than previously reported values in pigmented races.

Adult↗

PubMed2001

Properties of a revertant of Escherichia coli viable in the presence of spermidine accumulation: increase in L-glycerol 3-phosphate.

Escherichia coli CAG2242 cells are deficient in the speG gene encoding spermidine acetyltransferase. When these cells were cultured in the presence of 0.5 to 4 mM spermidine, their viability was greatly decreased through the inhibition of protein synthesis by overaccumulation of spermidine. When the cells were cultured with a high concentration of spermidine (4 mM), a revertant strain was obtained. We found that a 55-kDa protein, glycerol kinase, was overexpressed in the revertant and that synthesis of a ribosome modulation factor and the RNA polymerase sigma(38) subunit, factors important for cell viability, was increased in the revertant. Levels of L-glycerol 3-phosphate also increased in the revertant. Transformation of glpFK, which encodes a glycerol diffusion facilitator (glpF) and glycerol kinase (glpK), to E. coli CAG2242 partially prevented the cell death caused by accumulation of spermidine. It was also found that L-glycerol 3-phosphate inhibited spermidine binding to ribosomes and attenuated the inhibition of protein synthesis caused by high concentrations of spermidine. These results indicate that L-glycerol 3-phosphate reduces the binding of excess amounts of spermidine to ribosomes so that protein synthesis is recovered.

Amino Acid Sequence↗

PubMed2001

Polymyositis, pulmonary fibrosis and malignant lymphoma associated with hepatitis C virus infection.

Polymyositis has been associated with various viral infections, and a spectrum of immune-related diseases may occur with hepatitis C (HCV) infection. Both polymyositis and HCV infection may be accompanied by pulmonary fibrosis. An association between polymyositis and malignancy has also been reported. We report a 55-year-old woman accompanied cryoglobulinemia with HCV infection and manifesting polymyositis, pulmonary fibrosis and malignant lymphoma. Steroid therapy was effective to improve interstitial pneumonia, polymyositis, and liver function.

Cryoglobulinemia↗

PubMed2001

Effects of retinal glial cells on isolated rat retinal ganglion cells.

PURPOSE: The effect of retinal glial cells on retinal ganglion cell (RGC) survival was investigated in cocultures of pure, isolated retinal glial cells with pure, isolated RGCs. METHODS: RGCs from 2-day-old rats were cocultured for 48 hours, avoiding direct contact between cell types, with either nonconfluent retinal glial cells from 3-day-old rats or confluent retinal glial cells from 3-day-old, 12-day-old, or 1-year-old rats. Survival of RGCs was evaluated by flow cytometry. Amino acids were determined in culture medium. The effects of glutamate antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione and MK801, a nitric oxide (NO) scavenger, 2-(4-carboxyphenyl)-4,4,5,5tetramethylimidazoline-1-oxyl-3-oxide potassium salt (c-PTIO), and an NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), were examined. RESULTS: Nonconfluent retinal glial cells significantly reduced the survival of small and large RGCs, but confluent retinal glial cells reduced the survival of only small RGCs, regardless of the rat's age at the time of retinal glial cell harvesting. Profiles of some amino acids significantly varied, depending on the culture condition. Cocultures of RGCs with nonconfluent retinal glial cells released significantly more glutamate into the medium than cocultures of RGCs with confluent retinal glial cells or RGCs in pure culture. The glutamate antagonists improved the survival of RGCs cocultured with nonconfluent retinal glial cells, especially when the two were administered in combination, and in the case of large RGCs. c-PTIO and L-NAME, also improved the survival of RGCs cocultured with nonconfluent retinal glial cells. CONCLUSIONS: Adverse effects of retinal glial cells on the survival of RGCs varied by size of the RGCs and retinal glial cell confluence. Glutamate and NO may be involved in retinal glial cell-related antisurvival effects.

Animals↗

PubMed2000

Identification of the putrescine recognition site on polyamine transport protein PotE.

The PotE protein can catalyze both uptake and excretion of putrescine. The K(m) values of putrescine for uptake and excretion are 1.8 and 73 microm, respectively. Uptake of putrescine is dependent on the membrane potential, whereas excretion involves putrescine-ornithine antiporter activity. Amino acids involved in both activities were identified using mutated PotE proteins. It was found that Cys(62), Trp(201), Trp(292), and Tyr(425) were strongly involved in both activities, and that Tyr(92), Cys(210), Cys(285), and Cys(286) were moderately involved in the activities. Mutations of Tyr(78), Trp(90), and Trp(422) mainly affected uptake activity, and the K(m) values for putrescine uptake by these PotE mutants increased greatly, indicating that these amino acids are involved in the high affinity uptake of putrescine by PotE. Mutations of Lys(301) and Tyr(308) mainly affected excretion activity (putrescine-ornithine antiporter activity), and excretion by these mutants was not stimulated by ornithine, indicating that these amino acids are involved in the recognition of ornithine. It was found that the putrescine and ornithine recognition site on PotE is located at the cytoplasmic surface and the vestibule of the pore consisting of 12 transmembrane segments. Based on the results of competition experiments with various putrescine analogues and the disulfide cross-linking of PotE between cytoplasmic loops and the COOH terminus, a model of the putrescine recognition site on PotE consisting of the identified amino acids is presented.

Amino Acid Sequence↗

PubMed2000

Antioxidative galloyl esters as enzyme inhibitors of p-hydroxybenzoate hydroxylase.

Gallic acid and its esters were evaluated as enzyme inhibitors of recombinant p-hydroxybenzoate hydroxylase (PHBH), a NADPH-dependent flavin monooxygenase from Pseudomonas aeruginosa. n-Dodecyl gallate (DG) (IC(50)=16 microM) and (-)-epigallocatechin-3-O-gallate (EGCG) (IC(50)=16 microM), a major component of green tea polyphenols, showed the most potent inhibition, while product-like gallic acid did not inhibit the enzyme significantly (IC(50)>250 microM). Inhibition kinetics revealed that both DG and EGCG inhibited PHBH in a non-competitive manner (K(I)=18.1 and 14.0 microM, respectively). The enzyme inhibition was caused by specific binding of the antioxidative gallate to the enzyme, and by scavenging reactive oxygen species required for the monooxygenase reaction. Molecular modeling predicted that EGCG binds to the enzyme in the proximity of the FAD binding site via formation of three hydrogen bonds.

4-Hydroxybenzoate-3-Monooxygenase↗

PubMed2000

Increase in cap- and IRES-dependent protein synthesis by overproduction of translation initiation factor eIF4G.

The role of eIF4G during the initiation of protein synthesis was studied using mouse mammary carcinoma FM3A cells and FM4G cells that overproduce an N-terminally truncated form of eIF4G, which lacks the binding site of poly(A)-binding protein. An increase in eIF4G was correlated with an increase in protein synthesis and RNA helicase activity. Translation of mRNAshaving both short and long 5'-untranslated regions (5'-UTR) increased significantly in FM4G cells compared to that in FM3A cells. Both full-length and N-terminally truncated eIF4G transfectants of NIH3T3 cells formed colonies in soft agar and increased the saturation density of cell growth, indicating that both eIF4Gs function similarly. We also found that an internal ribosome entry site (IRES) exists in the 5'-UTR of ornithinedecarboxylase mRNA and that IRES-dependent protein synthesis increased in FM4G cells. Our results indicate that an increase in eIF4G contributes to the formation of active eIF4F similarly to that caused by an increase in eIF4E, as well as to a stimulation of IRES-dependent protein synthesis.

3T3 Cells↗

PubMed2000

Polyamines: mysterious modulators of cellular functions.

In recent years the functions of polyamines (putrescine, spermidine, and spermine) have been studied at the molecular level. Polyamines can modulate the functions of RNA, DNA, nucleotide triphosphates, proteins, and other acidic substances. A major part of the cellular functions of polyamines can be explained through a structural change of RNA which occurs at physiological concentrations of Mg(2+) and K(+) because most polyamines exist in a polyamine-RNA complex within cells. Polyamines were found to modulate protein synthesis at several different levels including stimulation of special kinds of protein synthesis, stimulation of the assembly of 30 S ribosomal subunits and stimulation of Ile-tRNA formation. Effects of polyamines on ion channels have also been reported and are gradually being clarified at the molecular level.

Animals↗

PubMed2000

Properties of a polyamine transporter regulated by antizyme.

The regulation of polyamine transport by antizyme, a protein that is involved in the rapid degradation of ornithine decarboxylase (ODC), was studied in FM3A mouse cells overproducing ODC. Both artificial (Z1) and natural antizymes not only inhibited polyamine uptake but also stimulated polyamine excretion. The properties of the polyamine transporter regulated by antizyme were characterized. The uptake of radiolabelled polyamines was inhibited by excess acetylpolyamines and a protonophore, CCCP (carbonyl cyanide m-chlorophenylhydrazone), whereas the excretion of radiolabelled polyamines was stimulated by unlabelled polyamines, acetylpolyamines and CCCP in the medium. Furthermore, it is shown that polyamines and acetylpolyamines are excreted from cells. On the basis of the results, it is discussed how antizyme regulates polyamine transport negatively.

Animals↗

PubMed2000

Human CD8 and CD4 T cell epitopes of epithelial cancer antigens.

Recent human tumor immunology research has identified several genes coding immunogenic peptides recognized by CD8 cytotoxic T lymphocytes (CTLs) in melanoma tumors. Very recently, CD4 T cell antigenic epitopes were also determined in certain melanoma tumors. The use of these peptides in conjunction with human immunotherapy could prove to be of great benefit. However, such peptides in clinically common tumors of epithelial cell origin, such as of the stomach, colon, lung, etc., have not yet been determined extensively. We describe for the first time an HLA-A31 (A*31012)-restricted natural antigenic peptide recognized by the CD8 CTL TcHST-2 of gastric signet ring cell carcinoma cell line HST-2. We also identified the HLA-DRB1*08032-restricted peptide recognized by the CD4 T cell line TcOSC-20 of squamous cell carcinoma OSC-20 derived from the oral cavity. The antigenic peptide of HST-2, designated F4.2, is composed of 10 amino acid residues with two anchor motif residues necessary for binding to HLA-A31 molecules. The synthetic F4.2 peptide enhanced the reactivity of TcHST-2 against HST-2 cells. Furthermore, introduction of an expression minigene coding F4.2 peptide to HLA-A31(+) cells conferred cytotoxic susceptibility to TcHST-2 on the cells. Some stomach cancer lines into which the HLA-A31 gene had been introduced, such as MKN28-A31-2, were lysed by TcHST-2, suggesting the presence of F4.2 peptide in at least some HLA-A31(+) stomach cancers. Furthermore, F4.2 peptide induced an F4.2 peptide-specific CTL response in at least 30-40% of HLA-A31(+) peripheral blood lymphocytes from gastric cancer patients, suggesting that F4.2 peptide could be used as a cancer vaccine for gastric tumors. The natural antigenic peptide of OSC-20 was also determined using acid extraction and biochemical separation and by mass spectrometry. Consequently, OSC-20 peptide was designated as the 6-1-5 peptide, an HLA-DRB1*08032-restricted 16-mer peptide with two possible anchor motifs. It has an amino acid sequence identical to that of human alpha-enolase, suggesting that it was derived from the processed parental alpha-enolase protein. We are presently attempting to determine the genes that code tumor rejection antigens recognized by HLA-A24- and A26-restricted T cells, including those of pulmonary and pancreatic carcinomas. The search for these antigenic peptides may lead to the identification of immunogenic peptide antigens that would be suitable for clinical use in commonly occurring epithelial cancers.

Amino Acid Sequence↗

PubMed2000

A chylous cyst of the mesentery: report of a case.

A case is presented of an adult chylous cyst of the mesentery that was preoperatively diagnosed to be a pancreatic cystadenoma. A 66-year-old asymptomatic male was followed up for 15 months under the diagnosis of a benign pancreatic cyst. On October 1997, computed tomography showed a 45 x 40 mm cystic mass in the upper abdomen which came in contact with the pancreas. Endoscopic ultrasonography revealed a multilocular mass with a 7 x 4 mm elevated lesion. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography revealed the cystic mass to be unrelated to the pancreatic duct. The preoperative diagnosis was a pancreatic cystadenoma or cystadenocarcinoma. A laparotomy showed a 50 x 40 mm cystic mass containing chylous fluid, that arose from the mesentery of the upper part of the jejunum. The pathological diagnosis was a chylous cyst of the mesentery. The preoperative diagnosis in this case was very difficult because the chylous cyst appeared to be attached to the pancreas and this phenomenon is considered to be extremely rare.

Aged↗

PubMed2000

Ultrasound biomicroscopic study of ciliary body thickness in eyes with narrow angles.

PURPOSE: To determine the ciliary body thickness and other biometric findings in eyes with narrow angles. METHODS: Eighteen otherwise normal eyes with narrow angles in 18 Japanese patients and 18 normal control eyes with open angles in 18 age-matched and sex-matched Japanese patients were studied. A-scan ultrasonography was performed to measure anterior chamber depth, lens thickness, axial length, and relative lens position. Ultrasound biomicroscopy was also performed to obtain measurements of the anterior ocular structures, including anterior chamber depth and ciliary body thickness at sites 1 mm and 2 mm posterior to the scleral spur (positions 1 and 2, respectively). RESULTS: Compared with normal control eyes, the narrow-angle eyes showed a shallower anterior chamber (narrow angle, 1.87 +/- 0.27 mm; control, 2.69 +/- 0.26 mm; P <.0001), a thicker lens (4.97 +/- 0.49 mm, 4.26 +/- 0.53 mm; P <.0001), a more anteriorly located lens (2. 21 +/- 0.13, 2.35 +/- 0.14; P <.0001), a shorter axial length (22.70 +/- 0.97 mm, 23.41 +/- 0.86 mm; P =.012), and a thinner ciliary body (position 1: 454 +/- 107 microm, 602 +/- 86 microm; P <.0001; position 2: 203 +/- 50 microm, 321 +/- 68 microm; P <.0001). Lens thickness was significantly correlated with ciliary body thickness at positions 1 (R(2) = 0.34; P =.0001) and 2 (R(2) = 0.43; P <.0001). Anterior chamber depth was significantly correlated with ciliary body thickness at positions 1 (R(2) = 0.48; P <.0001) and 2 (R(2) = 0.56; P <.0001). CONCLUSION: Thinning of the ciliary body may be one of the important factors associated with the anterior location of the lens, the increased lens thickness, and the decreased anterior chamber depth in eyes with a narrow angle.

Acute Disease↗

PubMed2000

The influence of age, gender, refractive error, and optic disc size on the optic disc configuration in Japanese normal eyes.

PURPOSE: To investigate the influence of age, gender, refractive error, and optic disc size on optic disc configuration in Japanese normal eyes. METHODS: Ninety-two eyes from 92 visually normal Japanese subjects (mean refractive error+/-SD: -1.26+/-2.25 D, range -8 D to +3 D) were examined using a confocal scanning laser tomograph, TopSS. The following disc parameters were investigated: disc size, total or quadrant C/D area ratio and neuroretinal rim area, half-depth area, volume below, and average cup depth. RESULTS: The disc diameter ( mean+/-SD: 1.84+/-0.16 mm) and disc size showed highly significant correlations with the C/D ratio (p<0.001) and the neuroretinal rim area (p<0.001). No other correlation was observed. CONCLUSION: These results indicate that the optic disc diameter and disc size have higher correlations with the optic disc configuration than age, gender, and refractive error in Japanese. These results are similar to those data reported for eyes of Caucasians or Afro Americans, and should be considered when optic discs are evaluated.

Adult↗

PubMed2000

Clinical usefulness of microsatellite instability for the prediction of gastric adenoma or adenocarcinoma in patients with chronic gastritis.

To assess a role of microsatellite instability (MSI) in the development of gastric adenocarcinoma or adenoma from chronic gastritis, we analysed mutations of five microsatellite loci in gastritis, adenoma and adenocarcinoma retrospectively. Gastric mucosa was biopsied from the same area in each patient at different periods and examined for MSI. Only one of 55 patients with chronic gastritis revealed MSI-H phenotype and the other 54 patients showed microsatellite stable (MSS) phenotypes. In six of 17 patients with gastric adenoma or well-differentiated adenocarcinoma, MSI-positive phenotypes were demonstrated. Interestingly, all of six patients showing MSI, including three high-level MSI (MSI-H) cases and three low-level (MSH-L) cases, had already revealed MSI at the stage of chronic gastritis. In two of three MSI-H cases, the identical MSI patterns had been observed at the stage of gastritis 1.5-7 years before the final diagnosis of adenocarcinoma. The adjacent gastritis mucosa within 10 mm from the carcinoma demonstrated MSI as well. MSI was not found in any of 35 patients with Helicobacter pylori infection, but found in one of 30 patients without infection. Moreover, two of three cases of gastric adenoma or well-differentiated adenocarcinoma with MSI-H at the stage of chronic gastritis showed no evidence of Helicobacter pylori infection throughout the observation periods. These results indicate that MSI in biopsy specimens at the stage of chronic gastritis may predict the risk of the progression to adenoma and well-differentiated adenocarcinoma, and that Helicobacter pylori infection itself may not induce MSI directly in the gastric mucosa.

Adenocarcinoma↗