Biomedical subjects
Publications and source records attributed to J Cho.
Eight 2-alkylaminosubstituted 5,8-dimethoxy-4-methylquinolines and nine 2-alkylaminosubstituted or 2,6-disubstituted 4-methylquinoline-5,8-diones were synthesized and evaluated in vitro cytotoxicity against four human cancer cell lines (HOP62, SK-OV-3, HCT15 and SF295).
OBJECTIVE: To present the MR and angiographic findings of alveolar soft part sarcoma (ASPS). DESIGN AND PATIENTS: MR examinations (12 tumors of 10 patients) of ASPS performed at multiple hospitals were retrospectively reviewed. The tumors were found in the thigh (n=4), lower leg (n=4), femur (n=2, local metastasis), scalp (n=1) and arm (n=1). The MR signal characteristics including signal intensity, homogeneity and signal void of lesions and bony invasion including direct invasion or local metastasis were evaluated. Angiographic findings (n=4) and post-embolotherapy follow-up MR imaging (n=2) findings were also assessed. RESULTS: Local bony metastasis was found in two cases. Seven tumors showed heterogeneous high signal intensity on T - and T2-weighted images with good enhancement. One tumor had a very high signal on T1-weighted images. Eight tumors (67%) showed numerous signal voids in or near the tumors. All four angiographic studies showed numerous enlarged vessels, arteriovenous shunts and delayed washout. Two cases mimicked arteriovenous malformations on angiographic studies but MR images demonstrated solid soft tissue components as well as tortuous vessels. CONCLUSIONS: High signal on T1 -weighted image and numerous signal voids are highly suggestive of ASPS, although they are not universal as has been suggested and arteriovenous malformation should be included in the differential diagnosis. Local bony metastases in ASPS were seen in two cases and should be carefully investigated.
The idiopathic inflammatory bowel diseases (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are related, complex genetic disorders. With the completion of the human genomic sequence, identification of genetic variants contributing to IBD susceptibility can now more systematically be identified. Significant genetic linkages have been observed on chromosomes 16, 12, 14, 19, 6, and 1, of which the linkage to CD on chromosome 16 is the most well-established. For many of the other regions, evidence for linkage has been observed for both CD and UC. Candidate gene association studies have largely focused on genes involved in inflammatory pathways, such as cytokines and cytokine receptors. With greater understanding of genetic differences underlying both disease susceptibility and response to medical therapy, the individualization of medical approaches based on this knowledge may soon be possible in patients with IBD.
Acori graminei rhizoma (AGR) are reported to exhibit a number of pharmacological actions in the central nervous system. The effects of the methanol extract of AGR on excitotoxic neuronal death were evaluated in the present study using cultured rat cortical neurons. Based on the phase-contrast microscopic examinations of cultures and lactate dehydrogenase activities measured in the culture media, the glutamate-induced excitotoxicity was significantly inhibited by the extract. The inhibitory action of the extract was more potent and selective for the N-methyl-D-aspartate (NMDA) receptor-mediated toxicity. The AGR extract competed with [3H]MDL 105,519 for the specific binding to the glycine site of the NMDA receptor with the IC(50) value of 164.7 microg/ml. Modulation of the NMDA receptor activity by the extract was determined using [3H]MK-801 binding studies. The reduction of the binding in the presence of the extract indicated the receptor inactivation by AGR. These results demonstrated that the methanol extract of AGR exhibited protective action against excitotoxic neuronal death, and that the neuroprotective action was primarily due to the blockade of NMDA receptor function by the interaction with the glycine binding site of the receptor.
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To examine age-related changes in the morphology of intestinal brush border membrane (BBM; microvilli) and specific activities of intestinal BBM enzymes including alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (gamma-GT), and disacchridase, four groups of Wistar rats were sacrificed at 2.5 wk, 5 wk, 5 mon and 23 mon. In an electron microscopic examination, morphologically a less dense BBM structure in the duodenum of rats aged 23 mon was observed than that of rats aged 5 mon. Specific activity of ALP in the duodenum from 5-mon-old rats was significantly higher than from rats aged 2.5 wk and 23 mon. The mucosal tissues from 5-wk-old rats had significantly higher specific activity of gamma-GT than did tissues from the other ages. In sucrase and maltase specific activities, 5-mon-old rats had higher activities of these enzymes than other age groups, especially 2.5-wk- and 23-mon-old rats. There was also a significant effect of site on intestinal BBM enzyme activities in post-weanling rats. Regional gradients of ALP and gamma-GT along the entire small intestine (duodenum > jejunum > ileum) were remarkable. Disaccharidase activities peaked in the jejunum and declined toward both the duodenum and ileum. Taken together the result obtained here suggested that 5-mon-old rats had the most elevated intestinal function. This result also strongly indicated that the structure of the intestinal BBM and development of intestinal BBM enzymes in Wistar rate were markedly influenced by age during the postnatal period.
OBJECTIVE: To investigate the short- and long-term clinician and angiographic outcome of stenting or angioplasty for chronic total coronary artery occlusion. METHODS: A total of 95 patients with successful percutaneous transluminal coronary angioplasty (PTCA) for total occlusion coronary artery were identified out of 358 patients undergoing PTCA for chronic total occlusion. Patients were classified into two groups: Group A had selective stenting after successful PTCA and Group B only had PTCA. Clinical cardiac events including acute myocardial infarction (AMI) angina, death, repeat revascularization and angiographic variables were followed and analyzed. RESULTS: A total of 85 of 95 patients (89%) completed clinical and angiographic follow-up. In group A (n = 42), 1 patient experienced an AMI while in group B, 2 patients experienced AMI and 1 died. In group A, the restenosis rate was 29%, reocclusion rate was 12% and recanularization rate was 19%, as compared to 58%, 22% and 45% respectively in group B (P < 0.001, P < 0.05 and P < 0.001, respectively). CONCLUSIONS: Selective stent improves short- and long-term clinical and angiographic outcomes and is recommended in cases of chronic total occlusion independent of the primary PTCA results.
Head-direction (HD) cells are neurons that signal a rat's directional heading in the horizontal plane. Evidence suggests that the lateral mammillary nucleus (LMN) may play an important role in generating the HD signal. Here, we examined the role of LMN in the HD circuit by comparing the effects of unilateral and bilateral LMN lesions on the activity of HD cells in the anterodorsal thalamus (AD). HD cells were recorded from AD in freely behaving rats. In the middle of the recording session, the rat received either bilateral or unilateral lesions of LMN. Immediately after the lesion, we continued recording the same HD cell in AD that had been recorded before the lesion. Additional cells were recorded from lesioned animals for up to 3 weeks after the lesion. We found that bilateral lesions of LMN permanently abolish HD cells in AD. After bilateral lesions, AD exhibits unusual rhythmic oscillations and velocity-correlated spike activity. Unilateral lesions of LMN did not abolish HD cells in AD. After unilateral lesions, the firing properties of HD cells in AD become more similar to those of HD cells in the intact hemisphere of LMN. We discuss the implications of these findings for understanding the role of LMN in the HD circuit.
Quantitative studies of the binding of neomycin B to RRE constructs are carried out to determine the relationship between non-Watson Crick base-paired elements in the RNA and aminoglycoside binding. The RRE region contains two unpaired domains containing a single base bulge and a bubble structure, respectively. Deletion of the single base bulge has no effect on neomycin binding as the site of aminoglycoside binding is localized to the bubble region. Converting the bubble region into an A-form duplex gradually abolishes neomycin B binding in 3-5-fold steps in affinity over a 75-fold range. Thus, the binding of aminoglycoside is favored at domains in RNA that are nonduplex in nature, but aminoglycoside binding is only graded-specific in that affinities are enhanced gradually as the structure further deviates from a duplex form. It is likely that high-affinity aminoglycoside binding does not occur in duplex RNA because the major groove is too narrow to allow for aminoglycoside access and that structural perturbations that allow widening of the groove facilitate access. However, these interactions are only graded-specific with respect to both aminoglycoside structure and RNA domain structure.
The translational initiation codon for thymidylate synthase (TS) mRNA is located in a unique stem-loop structure which contains an internal cytosine-cytosine (CC) bubble. This stem-loop structure is thought to be important in the regulation of TS translation, which is itself an important target for anticancer drugs, such as 5-fluorouracil. Internal bubble or bulge structures are candidate receptors for the aminoglycoside antibiotics. It is shown here that aminoglycosides bind in a specific and saturable fashion with dissociation constants of approximately 1 microM to a TS mRNA site 1 construct and that the binding site for the aminoglycosides is located in the CC bubble region. In fact, the CC bubble, when grafted into other stem-loop structures, confers aminoglycoside binding on them. These studies reveal an additional binding domain for aminoglycosides and also suggest how novel anti-cancer drugs might be designed that affect TS mRNA translation rather than enzyme function.
Forty-three patients with ovarian cancer were entered on this trial and treated with intravenous (iv) cyclophosphamide (C) and doxorubicin (A), and intraperitoneal (ip) cisplatin (DDP), every 21 days for eight cycles. Following iv hydration, the cisplatin was administered through an intraperitoneal catheter in 2 L of 0.9% normal saline with a 4-h dwell. All patients are evaluable for overall and progression-free survival with a median follow-up of 70 months (range: 3-162 months); 39 patients are evaluable for response. All complete responses were surgically confirmed. The median age was 59 (range 28-82 years); 3 patients were stage IC, 5 were IIC, 14 patients were stage III (optimally debulked), 14 patients were stage III (suboptimally debulked), and 7 patients were stage IV. Two patients had received prior alkylator therapy. Six of 8 patients with Stage IC or II remain without evidence of disease at a mean of 12 years following chemotherapy. Of 14 optimally debulked stage III patients, there were 7 complete responses, 3 partial responses, 1 patient with stable disease, and 3 inevaluable patients. Of 14 suboptimally debulked stage III patients there were 4 complete responses, 4 partial responses, 3 with stable disease, 2 progressions on treatment, and 1 inevaluable patient. Five-year progression-free and overall survivals for stage III optimally debulked patients are 21 and 64%, respectively. At 10 years, progression-free and overall survivals for this group are 21 and 29%, respectively. Toxicity included neutropenia (complicated by sepsis in 2 patients), infrequent thrombocytopenia, and mild anemia. Three patients developed transient serum creatinine elevations >2.0 mg/dl; however, decreased creatinine clearance was noted in 93/258 (36%) of evaluable courses which required a cisplatin dose reduction per protocol. Controllable hypomagnesemia, nausea, and emesis were also observed. We conclude that the combination of iv CA and ip DDP is an effective regimen with long-term progression-free and overall survivals that compare favorably with those of other published studies of intravenous or intraperitoneal chemotherapy. This report is unusual in terms of the prolonged follow-up for all patients enrolled. These long-term results lend further support to recently published trials documenting the efficacy of intraperitoneal chemotherapy for patients with this disease.
Crohn"s disease and ulcerative colitis are related complex genetic disorders, with gene-gene and gene-environment interactions that are critical to their pathogenesis. Multiple genetic loci have been implicated through genome-wide searches. Of these, a locus on Crohn"s disease has been definitively established in the pericentromeric region of chromosome 16. Multiple candidate gene studies have been forwarded, and functionally significant variants in immune-associated genes will provide additional insight. Characterization of the genetic variation responsible for causing inflammatory bowel disease will result in development of novel therapeutic approaches as well as in tailoring of specific therapies to individual patients based on their specific molecular pathogenesis.
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Progesterone secretion is crucial for maintaining pregnancy to parturition in mammalian species, and in cattle the corpus luteum is the primary source of this hormone. This study determined the roles of prolactin (PRL), growth hormone (GH) and luteinizing hormone (LH) in the luteotropic process in beef heifers hypophyseal stalk-transected (HST, n=7) or sham operated (sham operated controls, SOC, n=9) during midgestation. The main finding was that endogenous PRL and GH maintained progesterone secretion in HST heifers in a similar manner to that in SOC throughout pregnancy. Serum PRL averaged 37 vs 187 and GH 2 vs 4 ng/ml in HST heifers compared with SOC, whereas LH abruptly decreased to undetectable levels after HST compared with a modest 0.4 ng/ml in SOC heifers. The second finding was that parturition and lactation occurred in HST heifers with calf delivery induced to occur at the same time as SOC. Milk production in HST animals was severely limited, and postpartum estrus obliterated compared with SOC. The suckling stimulus sustained milk ejection in HST heifers in spite of diminished PRL, GH, thyroid stimulating hormone, thyroxine and tri-iodothyronine secretion. The results suggest that PRL, GH and possibly placental lactogen are luteotropic during pregnancy in cattle.
This study examined the effects of aging on neuropeptide Y (NPY) and NADPH-diaphorase (NADPH-d)-positive neurons of the cerebral cortex in young (3 months) and aged (24 months) Fischer 344 rats by immunohistochemical and histochemical methods. In the aged group, the number of NPY-immunoreactive (IR)/NADPH-d-positive neurons was not significantly changed in all regions of the cerebral cortex compared to the control group. However, the number of NPY-IR/NADPH-d-negative neurons was significantly decreased in frontal association, primary motor, secondary somatosensory, insular, ectorhinal, perirhinal and auditory cortex in the aged group. In the aged rats, about 5-10% of NPY-IR/NADPH-d-positive neurons were dystrophic and scattered within the cerebral cortex. These results suggested that NPY-IR neurons that do not contain NADPH-d are affected by aging and that aging influences NPY-IR/NADPH-d-negative neurons in a region-specific pattern within the cerebral cortex of rats.
A small (40 nucleotides) stem-loop derivative (J6f1) of a specific aminoglycoside-binding RNA aptamer, containing a 3 nt and a 1 nt bulge, has previously been shown to stoichiometrically bind tobramycin with a dissociation constant of approximately 5 nM [Hamasaki, K., Killian, J., Cho, J. and Rando, R. R. (1997) Biochemistry 36, 1367-1371]. This construct can strongly discriminate among similar aminoglycosides with respect to binding. A combination of chemical interference studies, chemical modification studies, and mutational studies are performed to define the aminoglycoside binding site of J6f1. Recognition of the aminoglycoside by J6f1 involves contacts with nucleotide bases, rather than with the phosphate backbone. The binding site 1 comprised of part of the stem-loop region. The two bulges are also essential for high affinity and stoichiometric binding of tobramycin. These bulges are probably important for prying open the double helical region, thereby allowing the aminoglycoside access to the nucleotide bases.
RNA molecules are the functional targets for aminoglycosides. In order to approach an understanding of the rules which underlie aminoglycoside-RNA recognition, high-affinity RNA aptamers have been prepared which discriminate among various aminoglycosides [Wang et al. (1996) Biochemistry 35, 12338-12346]. One of these aptamers, J6, which is 109 nts in length, binds the aminoglycoside tobramycin stoichiometrically with a dissociation constant of 0.77 +/- 0.03 nM. Aminoglycosides, similar in structure to tobramycin, bind with affinities diminished by 10(3)-10(4) compared to tobramycin. Experiments are reported here which are designed to reveal the nature of the tobramycin binding domain of J6. A small (40 nts) stem-loop derivative of J6, containing a 3 nt and a 1 nt bulge, stoichiometrically binds tobramycin with a dissociation constant of approximately 5 nM. This construct can strongly discriminate between similar aminoglycosides with respect to binding. Elimination of either the three or the single nucleotide bulge eliminates specific aminoglycoside binding. The structure of the loop region is also critical. These studies demonstrate that simplified RNA molecules can be generated which bind aminoglycosides specifically and with high affinities.
Six 3-dialkylaminomethyl-1-azaanthraquinones and five 4-dialkylaminomethyl-1-azaanthraquinones were synthesized and evaluated in vitro cytotoxicity against four human cancer cell lines. The compounds retained much of their cytotoxic activity against the multi-drug-resistant cell line (KB-V-1) as shown by resistance index.