Biomedical subjects
Publications and source records attributed to M Rubenstein.
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Malacoplakia is a granulomatous disease of unknown cause often associated with a coliform urinary infection. It is occasionally a self-limiting disease with diverse clinical presentations and roentgenographic appearances. The importance of a differential diagnosis which considers malignancy is emphasized. A rare instance of malacoplakia involving prostatic tissue is reported.
Doses of sodium salicylate greater than 100 mug/ml increased the generation time of baby hamster kidney (BHK 21) cells in culture from 16 to 35 hr. Exposure to similar doses of salicylate for 18-44 hr resulted in a marked reduction of RNA synthesis. The species of RNA synthesized in the presence of sodium salicylate appeared to be similar to those synthesized by normal cells in the absence of sodium salicylate. Sodium salicylate did not alter the oxidative phosphorylation of BHK cells.
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Hypothyroidism was induced in guinea pigs by various methods. Using a new technique, electrodes were permanently implanted and action potentials aroused by different sound stimuli recorded and measured. The results obtained before and during the hypometabolic state were analysed and compared with those obtained after replacement therapy. A tentative attempt was made to extrapolate the changes in pattern and magnitude of the action potentials caused by the experimentally induced hypothyroidism, to the hearing disorders observed in patients with thyroid deficiency.
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The staging of renal cell carcinoma was initiated in the United States with the systems of Flocks and Robson. The development of the TNM system began in Europe, evolved through several stages and is now being employed throughout the world. The predictive value of the current TNM system is supported by patient survival data. Practitioners treating renal cell carcinoma are encouraged to utilize the TNM classification.
Antisense oligonucleotides (oligos) are now in clinical trials for the treatment of a variety of diseases. However, concern is sometimes expressed as to the toxicity of such compounds, particularly those with phosphorothioated backbones. We have previously reported (J. Surg. Oncol. 62, 194, 1996) our experience in treating nude mice bearing human PC-3 prostate tumors with phosphorothioated antisense oligos directed against mRNA encoding transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor (EGFR). This therapy resulted in a 75% (9/12) response rate for the intralesional treatment and a 100% (3/3) response rate for the systemic administration utilizing Alzet diffusion pumps. In the current study, athymic nude rats bearing orthotopically implanted LNCaP tumors, whose establishment was confirmed by the expression of human PSA, were implanted subcutaneously with Alzet diffusion pumps and treated systemically for 14 days with a total of 1 mg of each oligo (2 mg total). Controls consisted of five untreated rats similarly inoculated with LNCaP cells, but which did not receive antisense oligos. After 2 weeks the rats were sacrificed and serum samples were evaluated for BUN, creatinine, LDH and SGOT. Lungs, kidneys, livers, spleens and prostates were also removed for pathologic evaluation. There were no serum marker differences between groups nor was there histologic evidence of oligo toxicity seen in any evaluated tissue. Of interest was the observation that the livers and spleens, as well as prostates, of treated animals revealed mild lymphocytic infiltration compared to controls. We conclude that at this level of administration, there is no toxicity associated with 14-day oligo treatment.
The purpose of this research was to describe the changes in marker expression and histologic morphology following androgen deprivation in malignant and benign human prostates. Fourteen patients receiving pre-radical prostatectomy total androgen deprivation had pre- and post-androgen deprivation evaluation of marker expression and histologic morphology (both malignant and benign). Marker expression was significantly reduced for serum (p < 0.0001) and tissue (p < 0.004) PSA as well as bcl-2 expression (p < 0.008). There were significant histologic increases in vacuolization (p < 0.001), pyknosis (p < 0.04), fibrosis (p < 0.01) and lymphocytic infiltration (p < 0.008) in the malignant tissue. There were significant increases in squamous metaplasia (p < 0.0002), fibrosis (p < 0.0005), basal cell hypertrophy (p < 0.0005) and lymphocytic infiltration (p < 0.0002) in the benign tissue. Androgen deprivation therapy produces significant changes in marker expression and morphology in prostate specimens. At times these iatrogenic changes can be confusing. Clinicians and pathologists must be aware of these changes.
OBJECTIVE: We examined the short- and long-term temporal stability of tic counts to estimate the minimum length of videotape needed for a reliable index of overall tic activity and determined the interrater reliability and validity of tic counts based on prolonged videotape segments (> 10 minutes). METHOD: Motor and phonic tic counts and clinician ratings were performed on 43 patients with Tourette's syndrome (TS), aged 7 to 50 years. Short-term stability was estimated by determining the mean interval-to-interval correlation of sequential equal-length segments from 30-minute videotape recordings of 20 subjects. Long-term stability was determined by correlating tic counts at 1-week (N = 14) and 2-week intervals (N = 11). In addition, tic counts were correlated with the most widely used clinical ratings of TS. RESULTS: The short-term stability data indicated that estimates of motor and phonic tic frequencies should be based on videotape counts of at least 5 minutes' duration. Tic counts also were highly reliable and were significantly correlated with clinical ratings with the Yale Global Tic Severity Scale and the Clinical Global Impression Scale for Tourette Syndrome. CONCLUSIONS: Standardized videotape tic counts can provide highly reliable, stable measures of tic frequencies that are moderately correlated with selected global ratings of tic severity.
Osteoporosis and its sequelae have been associated with genetic predisposition, aging, nutritional factors, inactivity, substance abuse, and anorexia nervosa. We report three cases of pathologic osteoporotic hip fractures in elderly females with major depression. Biological consequences of depression and mobilization during hospital treatment are discussed as possible mediators of osteoporotic morbidity.
Human derived T98G glioblastoma has long been utilized as an in vitro model for epidermal growth factor receptor (EGFR)-mediated growth regulation. Recently, T98G has been employed to develop new types of therapy directed at limiting EGFR expression such as by administration of antisense oligonucleotides directed against EGFR encoding mRNA. A major limitation to extending this model for in vivo application is that T98G implanted s.c. or intracerebrally has been reported not to grow in nude mice. In an effort to extend this model to permit in vivo studies, we evaluated the use of Matrigel and orthotopic (intracranial) implantation techniques. When equal volumes of Matrigel were mixed with T98G cell suspensions, tumors developed at both flank and orthotopic locations. Four groups of nude mice were inoculated into the flanks with either 10(5), 10(6), 4 x 10(6) or 10(7) T98G cells in a 150 microliters total volume with Matrigel. In 1/5, 3/5, 1/5 and 1/3 mice receiving 10(5), 10(6), 4 x 10(6) and 10(7) cells, respectively, tumors developed 11, 15, 15 and 15 weeks, respectively, following inoculation. Out of 4 mice inoculated orthotopically (intracranially into the frontal lobe) with only 4 x 10(4) cells and Matrigel, 2 developed tumors. However, all mice (4/4) inoculated orthotopically with 4 x 10(5) cells in a 10 microliters total volume with Matrigel developed tumors. Two were identified histologically following a scheduled sacrifice at 36 and 60 days and two more at 103 and 118 days after sacrifice following abnormal behavior. The best tumor establishment efficacy combined orthotopic implantation of 4 x 10(5) T98G cells with Matrigel. These techniques permit the use of T98G glioblastoma as an in vivo model for new forms of therapy.
BACKGROUND: MK 886, a 5-lipoxygenase inhibitor, induces a type 1 "apoptotic" form of programmed cell death in Bcl-2-positive U937 monoblastoid cells. In Ca2+-depleted, nonpermeabilized U937 cells studied with MK 886 in a Ca2+-free medium, an acute increase in Ca2+ occured within 10 to 20 seconds, detected with fura-2 measured with a spectrofluorimeter. METHODS AND RESULTS: The increased fluorescence was nuclear in location, as judged by confocal microscopy. The antioxidant, N-acetyl-L-cysteine, three agents that inhibit mitochondrialfunction at identified sites, antimycin A, atractyloside and cyclosporin A, the L/N-channel inhibitor, loperamide and BAPTA, an intracellular Ca+ chelator preloaded into cells each reduced the extent or prevented the acute MK 886-induced rise in Ca2+, as determined by radiometric detection. Rhodamine-2, a more selective mitochondrial Ca2+ probe, provided no evidence for nuclear Ca2+ originating from that extra-nuclear site or from the endoplasmic reticulum. With 2', 7'-dichloro-dihydrofluorescein-labelled cells to detect reactive oxygen species, MK 886 increased the initial fluorescent signal from a number of intracellular, largely extra-nuclear sites, including mitochondria. Two chemicals that inhibit the function of Bcl-2, HA14-1 and 2-methyl-antimycin A3, reduced the Ca2+ response to MK 886, if pre-incubated with the Bcl-2-positive U937 cells at 37 degrees C for several hours. MK 886 was previously shown to induce reactive oxygen species and a fall in mitochondrial membrane potential in both Bcl-2-positive U937 and in Bcl-2-negative PC-3 prostate and panc-1 pancreatic cancer cells. The latter solid tumor cells undergo an atypical "type 2" PCD without an acute rise in nuclear Ca2+. CONCLUSION: These results are consistent with an MK 886-induced increase of reactive oxygen species from intra-cellular sites including mitochondria which release Ca2+ located primarily at or near nuclei. These events may involve Bcl-2 participating in some form of Ca2+ channel and nuclear Ca2+ binding proteins undergoing conformational changes due to reactive oxygen species. Reasons for the different PCD responses in Bcl-2 positive lympho-hematopoietic compared to Bcl-2-negative solid cancer cell lines, respectively with and without the induced nuclear Ca2+ signal, remain to be defined.
Micromolar concentrations of the five-lipoxygenase inhibitor, MK 886 induce a "type 1" (apoptotic, extrinsic, death domain, receptor-dependent, caspase-positive) form of programmed cell death in Bcl-2-positive U937 human monoblastoid and HL-60 myeloid leukemia cells. A "type 2" (intrinsic, mitochondria-dependent, autophagic, in some examples caspase-negative (Panc-1)) form is induced in Panc-1 pancreatic and PC3 prostate cell lines. The latter two lines from epithelial-derived solid human cancers are Bcl-2-negative. Micromolar MK 886 induces an acute rise in Ca2+ in washed, Ca2+-poor U937 and HL60 cells in Ca2+ and Mg2+-free Hank's buffer. In U937 cells, much of the increase, or more properly redistribution, is nuclear in location (HL-60 not tested). No MK-886-induced acute Ca2+ increase developed in Panc-1 or PC3 cells. Bcl-2-positive HeLa cervical cancer cells exhibited an acute MK 886-induced increase in Ca2+. In the U937, PC3 and Panc-1 cells examined, MK-886 rapidly increased oxidative stress and decreased mitochondrial membrane potential, indicating that neither event is directly determinative for the altered distribution of Ca2+ or the form of PCD observed. Inhibition of increased U937 Ca2+ by the anti-oxidant, N-acetyl-L-cysteine, the effects of inhibitors of mitochondrial function including antimycin A, atractyloside, cyclosporin A, the L/N channel blocker loperamide, the intracellular chelator BAPTA and 2 agents, HA-14 and 3-methyl-antimycin A3 that impair Bcl-2 function further define these events. These differences in the Ca2+ response and possibly also the form of PCD that results may depend upon the presence of Bcl-2 or a related protein participating in a juxta-nuclear / nuclear Ca2+ ion channel. The role of mitochondria, the mechanism by which increased oxidative stress initiates the rapid release of Ca2+ from intracellular, possibly juxta-nuclear / nuclear sites or its redistribution to U937 Ca2+ nuclei, and whether this "signal" or possibly even ROS themselves mandate the type of PCD observed, presumably by differential modulation of transcription, remain to be determined. Lastly, these results demonstrate that, as might be expected, "soil" (cell type) trumps "seed" (inciting agent)".
BACKGROUND: Hypoxic cancer cells located beyond the diffusion path of sufficient oxygen are considered a nidus of therapeutic failure. Due to the dependence of many malignantly transformed cells on glycolysis for metabolic energy, inhibiting this and other sources of energy should seriously reduce cell viability and proliferation, additively or even synergistically. MATERIALS AND METHODS: To try and duplicate in vitro some of the features of in vivo cancer cells likely to resist therapy, HeLa cells were incubated with sub-lethal concentrations of 2-deoxy-D-glucose under aerobic, hypoxic or virtually anoxic conditions, verified by increased synthesis of Hif-1alpha, and their replication and survival determined. MK 886, an inhibitor of mitochondrial function was used to estimate participation of that organelle in energy metabolism. RESULTS: Culture of cervical cancer-derived HeLa cells with 2-deoxy-D-glucose under these restrictive conditions did not reduce their proliferation or viability to the expected extent. Their surprisingly robust survival included the anticipated increase in dependence upon glycolysis and implied a likely entrainment of other constitutive and possibly facultative energy sources and pathways. Increased synthesis of Hif-1alpha, increased binding to its consensus sequence and reduced inhibition from MK 886 in cells under oxygen-deficient environments confirmed the presence of restrictive conditions. CONCLUSION: Efforts to suppress HeLa cell survival by reducing glucose consumption and metabolic energy from ambient oxygen may require inhibition of multiple energy sources, possibly not all of them identified. In vitro assessment of agents directed against sources of metabolic energy or of other therapeutic agents against these or additional potential targets should include studies under hypoxia and relative anoxia. In this way, the possible responses of in vivo hypoxic or anoxic cancer cells believed to contribute to therapeutic failure may be estimated.
The records of 115 patients with stage D-2 prostate cancer treated with bilateral orchiectomy were reviewed to determine the effect of this procedure in previously untreated patients and in patients who had prior hormone therapy. Previously untreated patients survived 22.8 months while those who had prior hormone therapy survived 39.3 months (p < 0.001). Bilateral orchiectomy may be of additional clinical benefit in patients with advanced prostate cancer who have had prior hormone therapy.