The purple membrane of Halobacterium halobium contains the protein bacteriorhodopsin which resembles the visual pigment, rhodopsin, in many aspects. The isomeric configurations of its chromophore, retinal, were studied by a combination of methylene chloride extraction and analysis by high-pressure liquid chromatography. The light-adapted form bR570LA yields solely all-trans-retinal, while the dark-adapted form of bacteriorhodopsin, bR560DA, yields a mixture of 13-cis and all-trans with a ratio of similar to 1;1. The photointermediate M412 in a membrane modified by ether at high NaCl concentration also yields an approximately 1:1 mixture of 13-cis-and all-trans-retinals, while a similar M405 species produced by illumination in 2 M guanidine hydrochloride at high pH yields mainly 13-cis-retinal. These results indicate that the photochemical cycle of bR570LA may involve an isomerization of the retinal chromophore from the all-trans to the 13-cis form.
Purpose: Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1. Stimulation of this receptor in vitro results in up-regulation of activated extracellular signal-regulated kinase (ERK). Furthermore, a xenograft model of melanoma treated with riluzole, an oral GRM1 blocking agent, showed decreased tumor growth compared with the untreated controls. We have now completed a phase 0 trial of riluzole in patients with melanoma. Experimental Design: Patients enrolled on this trial underwent a pretreatment biopsy, took 200 mg of oral riluzole per day for 14 days, and then underwent resection of their remaining tumor. We compared the levels of pERK and pAKT in the pretreatment and post-treatment samples and assessed the metabolic activity of pretreatment and posttreatment tumors using fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. Results: We accrued 12 patients and all expressed GRM1. We found a significant decrease in pAKT and/or pERK in post-treatment tumor samples as compared with pretreatment samples in 4 (34%) patients. These four patients had a significant decrease in FDG-PET intensity post-treatment as well. Two other patients had a clinical response with no corresponding metabolic response; five patients had similar pretreatment and post-treatment FDG-PET scan findings; and one patient had progressive disease. Conclusions: Our data show that glutamate blockade with riluzole can inhibit signaling through the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways and suppress the metabolic activity of melanoma. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma, and targeting this pathway may be an effective therapy. Recently, our group described a heretofore unknown component of melanoma pathogenesis. A transgenic murine model of melanoma was developed by the ectopic expression of metabotropic glutamate receptor 1 (GRM1) in melanocytes (1-3). These mice spontaneously develop melanocytic lesions indistinguishable from human melanoma. We have expanded these original studies and have now shown that more than 60% of human melanomas express GRM1 and that activation of this receptor results in activation of the mitogen-activated protein kinase (MAPK) pathway in a B-Raf-and N-Rasindependent fashion (1). In preclinical studies, we have shown that the ectopic expression of GRM1 in melanocytes is transforming and that inhibition of GRM1 signaling in vitro and in vivo results in cell cycle arrest and subsequent apoptosis in human melanoma (2).We have now translated our findings into the clinic and have completed a phase 0 trial of riluzole in patients with stage III and IV melanoma. Riluzole (2-amino-6-trifluoromethoxybenzothiazole) is a noncompetitive GRM1 receptor antagonist that has been shown to be safe and effective in patients with amylotropic lateral sclerosis (ALS; refs. 4-7). Rilu...
Results: I -uptake was noted in 25% of NIS-expressing tumors (two of eight). The remaining cases did not show NIS expression or activity. Thyroid I -uptakes were decreased to <2.8% at 24 h in T 3 -treated patients and 1/100 normal with T 3 /MMI. Uptake (2.9%) was calculated in a peribronchial metastasis on 131 I dosimetry scans at 4 h with disappearance of the signal by 24 h. We estimated a therapeutic dose of 3000 cGy could be achieved in this metastasis with 100 mCi of 131 I if the tumor exhibited the same dynamics as the T 3 /MMI-suppressed thyroid.Conclusions: This is the first article of in vivo, scintigraphically detected, NIS-mediated I -accumulation in human BCM. T 3 /MMI down-regulation of thyroid NIS makes 131 I-radioablation of BCM possible with negligible thyroid uptake and radiation damage.
Our evaluation of discrepancy rates was unusual in that we included interpretations of sonograms, on which residents and the attending radiologist had a higher rate of agreement (99.5%). Because of the high agreement in the interpretation of sonograms, the overall discrepancy rate was 3.8%. However, if only body CT scan interpretations were evaluated, our results were closer to the rates reported in previously published studies. Major discrepancies led to a change in patient treatment but did not lead to any increase in patient morbidity or to any quantifiable increase in the length of the hospital stay.
Single-photon emission computed tomography (SPECT) imaging with n-isopropyliodoamphetamine (IMP) was performed on 11 patients with bipolar mania, 21 acute schizophrenics, and 15 healthy control subjects. Subjects were evaluated with neuropsychological tests and psychiatric rating scales. SPECT brain studies were blindly evaluated to assess the degree of radiopharmaceutical uptake in three neuroanatomical regions of interest in each hemisphere. All the control subjects, 1 manic patient, and 1 schizophrenic patient had normal brain SPECT uptake patterns. The scans of all others were read as abnormal. Hypofrontality was noted in some schizophrenics and maniacs. A significant increase in tracer uptake in temporal lobes was observed in both patient groups, more prominently in the manic patients. Increased and decreased basal ganglia uptake was also observed in patients. Both manic and schizophrenic patients showed cortical tracer heterogeneity of varying degree. The patterns of cerebral SPECT uptake seen in these acute psychoses were not specific for a diagnosis, but may be associated with dimensions of psychopathology. Because the patterns are different from those seen in cerebrovascular disease and the dementias, they may prove to be helpful in differential diagnosis.
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