Biomedical subjects

Y Kitamura

Publications and source records attributed to Y Kitamura.

At least 271 records · Page 15Linked to original sources

PubMed1997

Neurotrophin-3 expression in human pancreatic cancers.

Some neurotrophic factors stimulate process outgrowth in peripheral and/or central nerve fibres. There is no published report that has focused on the expression of neurotrophic factors in human pancreatic cancer except basic fibroblast growth factor. This study was therefore designed to examine the mRNA and protein levels of neurotrophin-3 (NT-3), which is one of the representative neurotrophic factors. The mRNA level for NT-3 was first investigated in eight pancreatic cancers and two samples of normal pancreas, using reverse transcription-polymerase chain reaction (RT-PCR). NT-3 protein expression was then studied in 47 human pancreatic cancers, using a monoclonal antibody against human NT-3 protein. There was a notable difference in the level of NT-3 mRNA between normal and pancreatic carcinoma tissues, with no evident difference in the expression of the beta-actin gene. Immunohistochemically, 34 of 47 pancreatic cancers (72 per cent) were mildly to markedly immunoreactive for NT-3 in the cytoplasma. Immunoreactivity was usually more pronounced at the infiltrative margins of the tumours. These observations suggest that pancreatic carcinoma overexpresses NT-3.

Adult↗

PubMed1997

Cell growth and differentiation of a novel mouse Ito (fat-storing) cell line transformed by a temperature-sensitive mutant of simian virus 40.

A novel mouse Ito (fat-storing) cell line (A640-IS) was established by transformation with a temperature-sensitive mutant of simian virus 40 (SV40) and the relationships between the expression of SV40 large T antigen and the growth, differentiation, and functions of A640-IS cells were investigated. A640-IS cells expressed large T antigen when cultured at 33 degrees C. At this temperature, the cells grew actively, assumed a fibroblastic shape, and showed few Ito cell characteristics. In contrast, when large T-antigen expression was inhibited by culture at 39 degrees C, the cells did not grow but differentiated into Ito cells as assessed by both morphological and functional characteristics. Expression of the transcription factor SCL (stem cell leukemia), which plays a role in the development and differentiation of blood cells, was observed at both 33 degrees C and 39 degrees C, although expression was greater at 33 degrees C. Therefore, opposite patterns of cell growth and the functions of differentiated cells occurred at 33 degrees C and 39 degrees C in this novel Ito cell line. Transforming growth factor beta1 stimulated A640-IS cells to produce fibronectin, collagen type III, and laminin. This unique Ito cell line provides a useful model to address important questions regarding the nature of these cells.

Adipocytes↗

PubMed1997

In vivo hypoxia-induced neuronal damage with an enhancement of neuronal nitric oxide synthase immunoreactivity in hippocampus.

Although it is well known that brain ischemia is dominantly caused by hypoxia and hypoglycemia, it is still unclear how hypoxia participates in ischemia. We studied the changes in neuronal nitric oxide synthase (nNOS) and the effect of the NOS inhibitor NG-nitro-L-arginine (NNA) on hypoxia. In vivo hypoxia (5% O2/95% N2 for 30 min) induced mild degenerative neuronal changes (shrunken and eosinophilic somata with picnotic nuclei) in neurons of the CA3, the hilus of the dentate gyrus (DG) and the DG, but not in the CA1. At 3 and 7 days after hypoxia, levels of nNOS protein were significantly enhanced to 153 and 209%, but iNOS protein could not be detected. The numbers of nNOS-immunopositive neurons were significantly enhanced to 145 and 191% in the CA3, 145 and 178% in the hilus of the DG, and 243 and 387% in the DG after 3 and 7 days, respectively. In contrast, no statistical difference was determined in the CA1. We further examined the effect of NNA administered at 5 min and 3, 6, and 24 h after hypoxia. Administration of NNA (0.1 and 1 mg/kg, i.p.) significantly decreased the number of damaged neurons in the hilus of the DG and the DG. However, higher doses of NNA (10 mg/kg, i.p.) did not prevent damage. These results suggest that hypoxia alone induces enhancement of nNOS protein and nNOS immunoreactivity in neurons of the hippocampus and that NNA has biphasic effects against hypoxia-induced neuronal damage in the hilus of the DG and the DG.

Animals↗

PubMed1997

Endocrine cells in hepatobiliary cystadenomas and cystadenocarcinomas.

We investigated the distribution of endocrine cells in hepatobiliary cystadenoma (n = 5, two associated with mesenchymal stroma) and cystadenocarcinoma (n = 3) immunohistochemically. In normal livers (n = 20) and livers affected by hepatolithiasis (n = 15) used as controls, endocrine cells revealed by chromogranin immunostaining were located exclusively in normal or proliferating intrahepatic peribiliary glands. In the eight cases of hepatobiliary cystadenoma and cystadenocarcinoma, endocrine cells were present in four cases (50%) (1 cystadenoma, 1 cystadenoma with mesenchymal stroma, and 2 cystadenocarcinomas). Endocrine cells tended to be located beneath and among the columnar epithelial cells. Intrahepatic peribiliary glands were located in the vicinity of cystadenoma or cystadenocarcinoma in six (75%) of the eight cases, and they frequently showed cystic dilatation and contained endocrine cells. Intrahepatic peribiliary glands were located in the vicinity of the endocrine cells in all cystadenomas and cystadenocarcinomas that were positive for endocrine cells. These data show that about 50% of hepatobiliary cystadenomas and cystadenocarcinomas contain endocrine cells and suggest that hepatobiliary cystadenoma and cystadenocarcinoma may originate from intrahepatic peribiliary glands.

Aged↗

PubMed1997

Effect of IL-6 on tumor cell invasion of vascular endothelial monolayers.

The effect of interleukin-6 (IL-6) on the invasive capacity of B16-F1 mouse melanoma cells into vascular endothelial monolayers was examined, and an in vitro assay system for the quantitative determination of tumor cell invasiveness, using confocal microscopy with a fluorescence image analyzer, was developed. First, the invasive capacity of B16-F1 mouse melanoma cells against bovine vascular endothelial monolayers was estimated; then, the gap junctional intercellular communication (GJIC) of endothelial cells was examined. Treatment of endothelial cells with IL-6 resulted in a remarkable increase in the invasion of tumor cells into the endothelial monolayer, which was found to be significant from 25 ng/ ml, and peaked at levels of more than 50 ng/ml. This stimulatory effect of IL-6, which was observed from 3 h after the initiation of treatment and lasted for up to 24 h, was abolished by the addition of the anti-IL-6 antibody. Although phase-contrast microscopy did not reveal any morphological changes in the endothelial cells following treatment with 25-200 ng/ml IL-6 for 24 h, the GJIC was observed to be significantly decreased. These findings indicate that the invasive capacity of tumor cells into endothelial cells is affected by IL-6.

Analysis of Variance↗

PubMed1997

Identification of motor and sensory brain activities during unilateral finger movement: spatiotemporal source analysis of movement-associated magnetic fields.

We investigated the movement-related cortical fields (MRCFs) recorded by magnetoencephalography (MEG) to identify the motor and sensory brain activities at the instant of the unilateral finger movement using six normal subjects. We focused our investigation on the source analysis of the events tightly linked to movement onset, and we used brain electric source analysis (BESA) to model the sources generating MRCFs during the interval from 200 ms before to 150 ms after the movement onset. Four sources provided satisfactory solutions for MRCF activities in this interval. Sources 1 and 2, which were located in the pre-central regions in the hemisphere contralateral and ipsilateral to the moved finger, respectively, generated the readiness fields (RF), but source 1 was predominant just before movement onset. The motor field (MF), the peak of which was just after movement onset, was mainly generated by source 1. Sources 3 and 4 were located in the post-central regions in the hemisphere contralateral and ipsilateral to the moved finger, respectively. The first motor evoked field (MEF-I), the peak of which was about 80 ms after the movement, was mainly generated by source 3, but with the participation of sources 1, 2 and 4. The results indicated that the activities of both pre -and post-central regions in bilateral hemispheres were related to voluntary movements, although the predominant areas varied over time. This is the first noninvasive study to clarify the complex spatiotemporal activities relating movements in humans using a multi-channel MEG system.

Adult↗

PubMed1997

Endocrine cells in intraductal papillary-mucinous neoplasms of the pancreas. A histochemical and immunohistochemical study.

The endocrine cells in intraductal papillary-mucinous neoplasms (IPN) of the pancreas have rarely been investigated. In the normal pancreatic ducts of normal pancreases (n = 5) there were a few endocrine cells: argyrophil in 5 (100%), chromogranin A in (100%), pancreatic polypeptide (PP) in 3 (60%), and insulin in 7 (20%). These endocrine cells were scattered, and located in the basal portions of pancreatic ducts. In IPN of the pancreas (n = 9), there were many endocrine cells: argyrophil in 7 (78%), argentaffin in 8 (89%), chromogranin A in 8 (89%), PP in 7 (78%), serotonin in 7 (78%), insulin in 4 (44%), and gastrin in 5 (56%). In invasive ductal adenocarcinoma of the pancreas (n = 6), many endocrine cells were also detected: argyrophil cells in (67%), chromogranin A in 3 (50%), insulin in 3 (50%), glucagon in 4 (67%), and somatostatin in 3 (50%). In positive cases, endocrine cells were situated under or among the neoplastic cells and the proportion of endocrine cells in IPN was less than 5% of the total neoplastic cell population. These data show that normal pancreatic ducts contain endocrine cells and that IPN frequently contain argyrophil, argentaffin, chromogranin A, and hormone-containing endocrine cells. These data also suggest that endocrine differentiation occurs during neoplastic transformation and progression of IPN of the pancreas.

Adenocarcinoma, Mucinous↗

PubMed1997

Expression of pancreatic digestive enzymes in normal and pathologic epithelial cells of the human gastrointestinal system.

Pancreatic digestive enzymes have rarely been reported in human nonpancreatic organs. We examined their expression in the epithelial cells of the nonpancreatic gastrointestinal organs, looking for pancreatic alpha-amylase, trypsin, chymotrypsin and pancreatic lipase. Western blotting, enzyme assay and pancreatic alpha-amylase mRNA were also used in selected specimens. In normal tissues, immunoreactivity of one or more of these enzymes was frequently noted in cells of the salivary glands, stomach, duodenum, large pancreatic ducts, extrahepatic bile ducts and gall bladder. The epithelium of the normal oesophagus, small intestine and colon were consistently negative for these enzymes. In pathologic tissues, immunoreactivity for one or more enzymes was present in epithelial cells of pleomorphic adenomas of the salivary glands, oesophageal squamous cell carcinoma, gastric adenoma and adenocarcinoma, pancreatic adenocarcinoma, cholecystitis, adenocarcinoma of the gall bladder and extrahepatic bile duct, and colon adenoma and adenocarcinoma. Western blotting showed a specific band of each enzyme in some specimens of normal stomach. In situ hybridization for pancreatic alpha-amylase mRNA showed specific signals in the normal stomach, but not in the normal colon. Reverse transcriptase polymerase chain reaction analysis for pancreatic alpha-amylase mRNA revealed specific signals in the normal stomach. Enzyme assay revealed that the stomach and gall bladder showed these activities. The data suggest that pancreatic digestive enzymes are produced by several epithelial cell types of the nonpancreatic gastrointestinal organs, that the organs positive for pancreatic enzyme have a common cell lineage, and that neoplasms continue to express or neoexpress these enzymes after neoplastic transformation.

Adult↗

PubMed1997

Ultrastructural identification of the c-kit-expressing interstitial cells in the rat stomach: a comparison of control and Ws/Ws mutant rats.

Interstitial cells in the circular muscle layer of the stomach of the Ws/Ws mutant rat, which lacks c-kit-expressing cells, and its siblings have been studied by electron microscopy. In the sibling control rats, two types of interstitial cells are found lying in close association with nerve bundles. Cells of the first type are characterized by electron-dense cytoplasm containing abundant mitochondria, granular endoplasmic reticulum, and Golgi apparatus. Intermediate filaments are richly distributed throughout the perinuclear region and the cell processes. Caveolae, subsurface cisterns, and indistinct basal lamina are observed along the cell membrane. The most conspicuous feature of this cell type is the existence of many large gap junctions that interconnect with the same type of cell, smooth muscle cells, or cells of the second type. Cells of the second type show an ultrastructure similar to fibroblasts, viz., a well-developed Golgi apparatus and granular endoplasmic reticulum whose cisterns often show a dilated form and contain flocculent material. Unlike typical fibroblasts, however, cells of this type also form many gap junctions with cells of the first type and smooth muscle cells. Both types of cells are observed in close apposition to nerve varicosities. Since cells of the first type are absent in the Ws/Ws mutant rat, we concluded that they correspond to c-kit-expressing cells and to interstitial cells of Cajal.

Animals↗

PubMed1997

Effects of chitin and chitosan particles on BALB/c mice by oral and parenteral administration.

Chitin and chitosan were administered orally and parenterally into mice and their toxicity was investigated. When 5 mg of chitin were injected intraperitoneally every 2 weeks over a 12-week period, the mice were apparently normal, but histologically, many macrophages with hyperplasia were observed in the mesenterium and foreign-body giant-cell-type polykaryocytes were observed in the spleen. The polykaryocytes were also observed in the spleen of the mice injected subcutaneously with 5 mg of chitin, but no other changes were observed. When 5 mg of chitosan were injected intraperitoneally, the body weights of the mice decreased significantly and inactivity was observed in the fifth week. Histologically, many macrophages with hyperplasia were observed in the mesenterium. Subcutaneous injection of 5 mg of chitosan did not evoke the general and cellular abnormalities. Oral administration of 5% chitosan via a casein diet caused mouse body weights to decrease and also decreased the number of Bifidobacterium and Lactobacillus in normal flora of the intestinal tract. These results indicate that special care should be taken in the clinical use of chitin and chitosan over a long time period.

Administration, Oral↗

PubMed1997

Alterations in acetylcholine, NMDA, benzodiazepine receptors and protein kinase C in the brain of the senescence-accelerated mouse: an animal model useful for studies on cognitive enhancers.

The senescence-accelerated mouse (SAMP8) is a useful murine model of accelerated aging and learning deficiency. We examined bindings of [3H]pirenzepine, [3H]dizocilpine (MK-801), [3H]flunitrazepam, [3H]8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and [3H]phorbol 12,13-dibutylate (PDBu) in SAMP8 brains, and compared them to those of SAMR1 (control). In the hippocampus of SAMP8 at 12 months, bindings of [3H]pirenzepine, [3H]MK-801, [3H]flunitrazepam, [3H]8-OH-DPAT and [3H]PDBu were significantly lower than those in SAMR1. In the cerebral cortex, bindings of [3H]pirenzepine, [3H]flunitrazepam and [3H]8-OH-DPAT were higher in SAMP8 than in SAMR1 at 12 months. [3H]PDBu binding was decreased in both the fractions of the membrane and cytosol in the hippocampus of SAMP8. The neurochemical findings presented here support behavioral and pharmacological findings that SAMP8 is a useful model of learning dysfunction and anxiety-deficiency. The usefulness of SAMP8 in studies on cognitive enhancers is also discussed.

Aging↗

PubMed1997

5-Hydroxytryptamine-induced Ca2+ -independent cGMP formation is mediated by nitric oxide in a nitric oxide synthase-independent manner in NG108-15 cells.

A novel pathway of 5-hydroxytryptamine (5-HT)-induced cGMP formation, which does not require Ca2+ and is distinct from the 5-HT, receptor-mediated pathway, is reported to exist in NG108-15 cells. Although the possible involvement of undefined 5-HT receptors and membrane-bound guanylyl cyclase is suggested. the mechanism is not clarified in detail in this Ca2+ -independent cGMP formation. In the present study, we investigated the activation mechanism of guanylyl cyclase activity. 5-HT-induced Ca2+ -independent cGMP formation was not observed in the cell membrane preparation. In intact cells, the 5-HT-induced Ca2+ -independent cGMP formation was inhibited by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazolin-1-oxyl 3-oxide (carboxyPTIO), a nitric oxide (NO)-specific trapper, and by 3,7-bis(dimethylamino)-phenothiazinium chloride (methylene blue), a cytosolic guanylyl cyclase-specific inhibitor, suggesting the involvement of NO and cytosolic guanylyl cyclase. Ca2+ -independent cGMP formation was not inhibited by 1,2-bis(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA-AM), N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), and various arginine-derivative nitric oxide synthase (NOS) inhibitors. Our findings suggest that 5-HT stimulation results in the generation of NO followed by cGMP formation in an NOS-independent manner in NG108-15 cells.

Animals↗

PubMed1997

Tissue inhibitor of metalloproteinase-1 in the liver of patients with chronic liver disease.

BACKGROUND/AIMS: Tissue inhibitor of metalloproteinase (TIMP)-1 is an important regulator of matrix metalloproteinase activity. To clarify the changes in TIMP-1 in diseased livers, we measured TIMP-1 concentrations in liver tissue samples from patients with chronic liver disease. The relationship between serum and liver levels of TIMP-1 was also examined in some patients. METHODS: The subjects were 68 patients who underwent liver biopsy. The liver TIMP-1 concentration was measured using an enzyme immunoassay after the extraction of TIMP-1 with 2 M guanidine. RESULTS: As compared with the controls (n=10), the liver TIMP-1 level was increased 2.2-fold in the 24 chronic active hepatitis 2A patients, 2.9-fold in the 10 chronic active hepatitis 2B patients and 4.1-fold in the six liver cirrhosis patients, but no significant increase was observed among the 18 chronic persistent hepatitis patients. The liver TIMP-1 levels were closely correlated with the histological degrees of periportal necrosis, portal inflammation, and liver fibrosis. When the localization of TIMP-1 was examined immunohistochemically, TIMP-1 was stained mainly in hepatocytes, and the intensity was stronger in the livers of chronic active hepatitis and liver cirrhosis patients than in those of the chronic persistent hepatitis patients. The serum TIMP-1 and liver TIMP-1 levels were significantly correlated, indicating that serum TIMP-1 could reflect the change of liver TIMP-1 in patients with chronic liver disease. CONCLUSION: Liver TIMP-1 concentration increases with progression of the liver disease, when the degradation of extracellular matrix proteins is decreased, resulting in the development of liver fibrosis.

Adult↗

PubMed1997

Possible involvement of ADP-ribosylation of particular enzymes in cell death induced by nitric oxide-donors in human neuroblastoma cells.

To clarify the mechanisms of nitric oxide (NO)-induced cell death in human neuronal cells, we examined effects of NO donors such as sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) on activities of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and poly(ADP-ribose) polymerase (PARP) in human neuroblastoma cell line, SH-SY5Y. SNP-induced [32P]ADP-ribosylation of 113-kDa and 37-kDa proteins in SH-SY5Y cells. Treatment with PARP inhibitors such as 3-aminobenzamide and 1,5-isoquinolinediol partially prevented SNAP-induced cell death of SH-SY5Y. In purified GAPDH (37-kDa protein), SNP- and SNAP-induced enhancement of [32P]ADP-ribosylation, and inhibition of GAPDH activity. These results suggest that NO-induced cell death in human neuroblastoma SH-SY5Y cells possibly involves in covalent modifications such as ADP-ribosylation in PARP and GAPDH.

Adenosine Diphosphate Ribose↗

PubMed1997

Effects of kyotorphin (L-tyrosyl-L-arginine) ON[3H]NG-nitro-L-arginine binding to neuronal nitric oxide synthase in rat brain.

L-Tyrosyl-L-arginine (kyotorphin) is known as an endogenous analgesic neuropeptide. We examined whether kyotorphin and other arginine-containing neuropeptides were endogenous substrates for neuronal nitric oxide synthase (NOS) in the rat brain. Cytosol fractions of the rat cerebellum contained higher concentrations of neuronal NOS (nNOS) than endothelial NOS. In rat cerebellar cytosol, the binding activity of [3H]NG-nitro-L-arginine (NNA) was inhibited equally by L-arginine (L-Arg), kyotorphin, and L-leucyl-L-Arg (a kyotorphin receptor antagonist). Binding activities were inhibited to lesser degrees by fibronectin active fragments, bradykinin, and dynorphin A, but were not inhibited by L-tyrosyl-D-Arg or substance P. Interestingly, the inhibition of [3H]NNA binding by kyotorphin was attenuated by inhibitors of kyotorphin-hydrolyzing peptidases (KTPases) such as bestatin and arphamenine B. These results suggest that kyotorphin is degraded to L-Arg by KTPases, which in turn may act as substrate for nNOS.

Animals↗

PubMed1997

NG-nitro-L-[3H]arginine binding properties of neuronal nitric oxide synthase in rat brain.

NG-Nitro-L-arginine (L-NNA), a derivative of L-arginine (L-Arg), is known as a pseudosubstrate and inhibitor for nitric oxide synthase (NOS). To clarify the regulatory mechanism of substrate-binding domain in neuronal NOS (nNOS), we examined the characteristics of NG-nitro-L-[3H]Arg (L-[3H]NNA) binding using the cytosolic fraction and purified nNOS from the rat cerebellum, in comparison with L-[14C]citrulline formation from L-[14C]Arg. The L-[3H]NNA binding was inhibited by L-NNA > NG-methyl-L-Arg > diphenyleneiodonium > L-Arg, but was not inhibited by L-citrulline and D-Arg. Thus, L-NNA seems to bind the substrate-binding domain in the nNOS with high affinity rather than L-Arg. Even in the absence of NADPH, tetrahydrobiopterin (BH4) and Ca2+, the L-[3H]NNA binding activity was observed in the cerebellar cytosol, although L-[14C]citrulline could not be produced from L-[14C]Arg. L-[3H]NNA binding was increased by BH4 alone and was markedly enhanced by NADPH plus BH4 (NADPH/BH4), but not by Ca2+/CaM. In contrast, L-[14C]citrulline was formed only in the presence of NADPH/BH4 and Ca2+. Similar results were obtained in purified nNOS. These results suggest that L-[3H]NNA seems to bind the substrate-binding domain in the nNOS but the binding affinity of L-Arg was lower than the affinity of L-NNA. Although the substrate binding is necessary to BH4 and NADPH, Ca2+/CaM are further necessary for the formation of NO and L-citrulline.

Animals↗

PubMed1997

In vivo hypoxia-induced neuronal damage in dentate gyrus of rat hippocampus: changes in NMDA receptors and the effect of MK-801.

Hypoxia is a major cause of ischaemia-induced neuronal damage. In the present study, we examined the effects of in vivo hypoxia on N-methyl-D-aspartate receptors (NMDAR) in the rat hippocampus. This model of in vivo hypoxia involved placing rats in a hypoxic chamber containing 5% O2 and 95% N2 for 30 min. In the hippocampus, neuronal cells in the CA3, the hilus of the dentate gyrus and the dentate gyrus (DG) were damaged. In the CA1, which is known to be vulnerable to ischaemic damage, neuronal cells did not show hypoxia-induced damage. In vivo hypoxia-induced damage caused morphological changes in neuronal cells, such as shrunken, spindle or triangular shapes accompanied by pyknotic nuclei, but did not induce the loss of neuronal cells. On the other hand, the number of binding sites for [3H]-1-[1-(2-thienyl)cyclohexyl]-3,4-piperidine hydrochloride (TCP) gradually decreased on and after 7 days, and then maximally decreased by 25% at 21 days after hypoxia. The number of NMDAR1-immunopositive cells was decreased by 22% in the DG, but was unchanged in the CA3. Furthermore, we examined the effect of a non-competitive NMDA antagonist, (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,b] cyclohepten-5,10-imine hydrogen maleate (MK-801), on against in vivo hypoxia. The administration of MK-801 (3 mg/kg, i.p.), 30 min before hypoxia treatment, partly protected against neuronal damage in the DG, but not in the CA3. These results suggest that hypoxia-induced neuronal damage in the DG involves, in part, the activation of NMDAR.

Animals↗

PubMed1997

A case of pleomorphic adenoma of the epiglottis. Bilateral vocal-cord paralysis after YAG laser surgery.

Pleomorphic adenoma of the larynx is a rare disorder, and until recently has been treated mainly by approaches involving pharyngotomy. We encountered a case of pleomorphic adenoma originating from the laryngeal surface of the epiglottis and removed it using a YAG laser through a suspension laryngoscope. This case was complicated by delayed-onset bilateral vocal-cord paralysis, the causes of which are also discussed.

Adenoma, Pleomorphic↗