Biomedical subjects

S M Cohen

Publications and source records attributed to S M Cohen.

At least 127 records · Page 7Linked to original sources

PubMed1996

A hierarchy of cross-regulation involving Notch, wingless, vestigial and cut organizes the dorsal/ventral axis of the Drosophila wing.

Short-range interaction between dorsal and ventral cells establishes an organizing center at the dorsal/ventral compartment boundary that controls growth and patterning of the wing. We report here that the dorsal/ventral organiser is built though a hierarchy of regulatory interactions involving the Notch and wingless signal transduction pathways and the vestigial gene. wingless and vestigial are activated in cells adjacent to the dorsal/ventral boundary by a Notch-dependent signal. vestigial is initially expressed under control of an early dorsal/ventral boundary enhancer that does not depend on wingless activity. Similarly, activation of wingless does not require vestigial function, showing that wingless and vestigial are parallel targets of the Notch pathway. Subsequently, vestigial is expressed in a broad domain that fills the wing pouch. This second phase of vestigial expression depends on Wingless function in cells at the dorsal/ventral boundary. In addition, the Notch and Wingless pathways act synergistically to regulate expression of cut in cells at the dorsal/ventral boundary. Thus Wingless can act locally, in combination with Notch, to specify cell fates, as well as at a distance to control vestigial expression. These results suggest that secreted Wingless protein mediates both long-range and short-range patterning activities of the dorsal/ventral boundary.

Animals↗

PubMed1996

Distinct mitogenic and cell fate specification functions of wingless in different regions of the wing.

Patterning and proliferation are coordinately controlled in the development of Drosophila imaginal discs. Localized expression of decapentaplegic (dpp) at the anterior-posterior and wingless (wg) at the dorsal-ventral compartment boundaries controls growth of the wing with respect to the A/P and D/V axes. The growth-promoting effects of these organizers are thought to be indirect, since growth is dispersed throughout the disc, and is not localized near the sources of wg or dpp. wg has also been implicated in proximal-distal patterning of the wing hinge. In this report, we present evidence that wg is principally required for local cell proliferation in the hinge. Loss of wg expression leads to a local reduction in cell division, resulting in the deletion of a distinct set of wing hinge structures. Ectopic activation of the wg pathway in cells of the wing hinge leads to overproliferation without repatterning, indicating that wg acts as a mitogen in this part of the disc. By contrast, overexpression of wg in the wing blade leads to repatterning and only secondarily to proliferation. These results suggest that the Wg signal elicits very different responses in different regions of the wing imaginal disc.

Alleles↗

PubMed1996

Mad acts downstream of Dpp receptors, revealing a differential requirement for dpp signaling in initiation and propagation of morphogenesis in the Drosophila eye.

Decapentaplegic (Dpp), a member of the TGF-beta family of cytokines, has been implicated in many patterning processes in Drosophila, including the initial steps of pattern formation in the developing eye. We show that the Mothers against dpp (Mad) gene is required for dpp signaling during eye development. Clonal analysis demonstrates a cell-autonomous function for Mad and genetic interactions indicate that Mad is an essential component of the signal transduction pathway downstream of the Dpp receptors in responding cells. Mad-mediated dpp signaling is absolutely required for the initiation of the morphogenetic furrow in the eye, but has only a minor role in its subsequent propagation across the eye disc. We also present evidence for the repression of wingless transcription by dpp signaling.

Alleles↗

PubMed1996

On the safety of 5-[125I]iodo-2'-deoxyuridine--Preclinical evaluation in swine.

To increase tumor incorporation and minimize hepatic degradation of radio-IUdR, compartmental administration routes are being considered as an alternative to intravenous (i.v.) injections. Although there are significant data on the biodistribution and some reports on radiotoxicity of i.v.-administered 125IUdR, similar results for other routes of delivery are not available. We have undertaken a series of experiments intended to examine radiation effects of 125IUdR after intravesical (3 swine; eight 3 mCi doses at 4-day intervals), intracarotid (3 swine; two 10 mCi doses at 2-week intervals), and intra-aortic (5 swine, single dose of 10 mCi) administration in a swine model. Liver, renal functions, and complete blood counts were monitored throughout the duration of the experiment. Pharmacokinetics, systemic distribution of radioactivity and metabolites were measured. The normal tissue 125IUdR uptake and histology were determined after necropsy. No adverse systemic effects were identified. Clinical observations, laboratory data, and necropsy results were within normal range.

Administration, Intravesical↗

PubMed1996

A novel nonopioid action of enkephalins: competitive inhibition of the mammalian brain high affinity L-proline transporter.

The high affinity L-proline transporter (PROT) is a member of the family of Na+ (and Cl-)-dependent plasma membrane transport proteins that comprises transporters for several neurotransmitters, osmolytes, and metabolites. The brain-specific expression of PROT in a subset of putative glutamatergic pathways implies a specialized function for this novel transporter and its presumed natural substrate L-proline in excitatory synaptic transmission. However, definitive studies of the physiological role(s) of high affinity L-proline uptake have been precluded by the lack of specific uptake inhibitors. Here, we report that Leu- and Met-enkephalin and their des-tyrosyl derivatives potently and selectively inhibited high affinity L-proline uptake in rat hippocampal synaptosomes and in PROT-transfected HeLa cells. High concentrations of the opiate receptor antagonist naltrexone did not block the inhibitory actions of these peptides, arguing against an involvement of opioid receptors. Des-tyrosyl-Leu-enkephalin elevated the apparent K(m) of L-proline transport in transfected HeLa cells without altering the V(max). PROT-transfected HeLa cells did not accumulate [3H]Leu-enkephalin above background levels, demonstrating that enkephalins are not substrates for PROT. These findings indicate that enkephalins competitively inhibit mammalian brain PROT through a direct interaction with the transporter protein at or near the L-proline binding site. The high potency and specificity of des-tyrosyl-Leu-enkephalin make this compound a useful tool for elucidating the structure-function properties and physiological role(s) of PROT.

Amino Acid Transport Systems, Neutral↗

PubMed1996

Radiolabeled iododeoxyuridine: safety evaluation.

UNLABELLED: The emphasis of radiolabeled iododeoxyuridine (*IUdR) research at our institution to date has been to assess its safety as a potential therapeutic agent. Toward this goal, we have performed preclinical and clinical studies, using various routes of administration, to detect adverse changes in normal tissues in both humans and animals. As IUdR is rapidly dehalogenated by the liver, the intravenous route is unlikely to be successful in therapeutic efforts. We have therefore focused our attention on more "protected" routes: intra-arterial and intravesicular administration. METHODS: Studies were performed in farm pigs after multiple administrations of [125I]IUdR into the aorta, carotid artery and bladder. IUdR and metabolites were measured in venous blood samples at appropriate time intervals after administration, after which histologic examination of tissues was performed. Studies in human have been performed after intra-arterial administration of [123I]IUdR in patients with liver metastases and intravesicular administration in patients with bladder carcinoma, initially using [123I]IUdR and currently using both [123I]IUdR and [125I]IUdR. Blood samples for pharmacokinetics and metabolite analysis and tissue for autoradiography (when feasible) have been obtained. RESULTS: To date, no evidence of adverse effects on normal tissue or alteration of hematologic or metabolic indices have been seen in pigs or humans. When instilled in the bladder, there is little leakage of IUdR in the circulation. CONCLUSION: When [125I]IUdR is used as a therapeutic agent, we anticipate little or no effect on normal tissues.

Administration, Intravesical↗

PubMed1995

Cell proliferation in the bladder and implications for cancer risk assessment.

Chemicals can increase carcinogenic risk by either directly damaging DNA or increasing cell replication or they can do both. These effects have different implications for a biologically-based extrapolation from rodent bioassays to humans. 2-Acetylaminofluorene (2-AAF) administered at low doses to mice for a lifetime has a different dose-response for the liver (approximately linear) compared to the urinary bladder (apparent no effect dose of 45 ppm with a sigmoidal dose response at 60-150 ppm), which can be explained if carcinogen metabolism, DNA adduct formation and cell proliferation effects are considered. In contrast to 2-AAF and other genotoxic chemicals, chemicals which form calculi in the urine do not generally damage DNA directly but increase cell proliferation dramatically by eroding the bladder surface, leading to regenerative hyperplasia. This occurs only at doses at which calculi form; lower doses do not produce calculi and, therefore, do not increase cell proliferation or cause tumors. Extrapolation to humans from the rodent bioassay should be dependent on dose requirements for formation of calculi rather than any type of statistical extrapolation to lower doses. Saccharin and other sodium salts administered at high doses to rats also produce bladder cancer by increasing cell proliferation. These salts do not affect mice, hamsters, guinea pig or monkeys. Based on dose and mechanistic considerations, saccharin and these other sodium salts are unlikely to be human carcinogens. Extrapolation to possible human cancer risk requires biological determinations rather than simply using statistical formulations.

Animals↗

PubMed1995

Distinguishable functions for engrailed and invected in anterior-posterior patterning in the Drosophila wing.

Subdivision of the limb primordia into compartments initiates pattern formation in the developing limbs. Interaction between distinctly specific cells in adjacent compartments leads to localized expression of the secreted signalling molecules Wingless (Wg) or Decapentaplegic (Dpp), which in turn organize pattern and control growth of the limbs. The homeobox gene engrailed has been implicated in specification of posterior cell fate, whereas the LIM/homeobox gene, apterous, specifies dorsal fate. Removing apterous activity causes a complete transformation from dorsal to ventral fate and leads to the formation of an ectopic dorsal-ventral boundary organizer. By contrast, removing engrailed activity causes incomplete morphological transformation from posterior to anterior fate in the wing, and fails to produce an ectopic anterior-posterior organizer (reviewed in ref.2). Complete transformation can only be effected by simultaneously eliminating activity of engrailed and its homologue invected. Here we show that invected functions principally to specify posterior cell fate. Thus establishment of the anterior-posterior organizer and control of compartment identity are genetically distinguishable, and invected may perform a discrete subset of functions previously ascribed to engrailed.

Animals↗

PubMed1995

Delaney reform.

Explore the source record for details and available documents.

Animals↗

PubMed1995

Rodent bladder tumors do not always predict for humans.

Dr. David Clayson, 20 years ago, suggested that chemicals which lead to the formation of calculi in rodents might pose an artifact with respect to extrapolation to potential carcinogenic risk to humans. We reviewed what has been learned about the role of calculi in urinary bladder carcinogenesis in the ensuing 20 years, along with several examples. Formation of microcrystalluria and amorphous precipitate also poses problems in interpretation and examples are described. The chemicals producing these solid urinary materials are non-genotoxic, with marked increase in cell proliferation being the mode of action by which they are able to produce cancer in long-term rodent bioassays.

Animals↗

PubMed1995

Signal transduction by cAMP-dependent protein kinase A in Drosophila limb patterning.

Interaction between distinctly specified cells in adjacent compartments establishes organizing centres that control growth and specify cell fate in the developing limbs of Drosophila. Localized expression of the secreted Hedgehog protein (Hh) by cells in the posterior compartment induces expression of the secreted signalling molecules decapentaplegic (dpp) or wingless (wg) in nearby anterior cells. wg and dpp in turn organize spatial pattern in the wing and leg imaginal discs. The Hh signal is thought to act by antagonizing the ability of the patched (ptc) gene product to repress wg and dpp expression. Here we present evidence that removing activity of the gene encoding cyclic AMP-dependent protein kinase A (pka) is functionally equivalent to removing ptc activity or to providing cells with the Hh signal. These findings suggest that cyclic AMP-dependent protein kinase A is a component of the signal transduction pathway through which Hh and Ptc direct localized expression of dpp (or wg) and establish the compartment boundary organizer.

Alleles↗

PubMed1995

Branch retinal arterial occlusions in multifocal retinitis with optic nerve edema.

OBJECTIVE: To determine the natural history and visual prognosis of patients with branch retinal arterial occlusions secondary to multifocal retinitis. METHODS: Cases were reviewed for seven patients who exhibited multifocal retinitis and branch retinal arterial occlusion. The average age of the patients was 27 years (age range, 14 to 19 years). RESULTS: Six patients had systemic illnesses associated with their ocular findings. Four patients were scratched by a cat or exposed to a cat with fleas within 1 month of symptoms. Three of these patients were tested and had positive cat-scratch disease titers. At presentation, five patients complained of a scotoma, and two noted blurred vision. On examination, visual acuity was 20/25 or better in all but one eye. Five patients had vitritis, which was bilateral in three. Four patients exhibited optic nerve edema, which was bilateral in two. White intraretinal infiltrates were present in all patients, and were bilateral in five. The six patients who were examined within 1 week of symptoms had a white retinal infiltrate at the site of vascular occlusion. The retinal findings resolved in 2 to 6 weeks and did not recur. The final visual acuity was 20/20 OU in all patients. CONCLUSIONS: Branch retinal arterial occlusions represent a complication of multifocal retinitis and idiopathic optic nerve edema. The arterial occlusions are probably caused by a focus of retinitis. This self-limited disorder has an excellent visual prognosis and may be related to cat-scratch disease.

Adolescent↗

PubMed1995

Port site metastases after laparoscopic colorectal surgery for cure of malignancy.

Laparoscopic surgery is excellent for treating benign disease of the colon and rectum, and for palliative operations for malignancy. Its application for cure of colorectal malignancy, however, must be approached with caution. Port site recurrence of tumour is a particular, and increasingly recognized, drawback. This review discusses the evidence to date to support prospective randomized trials of laparoscopic colectomy for cure of carcinoma.

Aged↗

PubMed1995

Comparison of the effects of new specific azasteroid inhibitors of steroid 5 alpha-reductase on canine hyperplastic prostate: suppression of prostatic DHT correlated with prostate regression.

Four new azasteroid inhibitors of steroid 5 alpha-reductase were compared to the benchmark compound finasteride, each at a dose level of 1 mg/kg/day, as well to placebo and to castration, in seven groups of mature male beagle dogs with enlarged prostates. Prostate volumes were measured repetitively by a volume MRI method over 15 weeks of treatment. The study probed the obverse of the familiar relation between DHT and prostate growth, and provides the first documentation of a tight negative correlation between prostate regression and the prostatic concentration of DHT across a range of treatment regimens (r = -0.982). In this first direct comparison study of structure vs. in vivo activity for several azasteroids in the dog model of BPH, relative efficacy for induction of shrinkage of the dog prostate did not correlate at all with the inhibitor's relative activity against the dog 5 alpha-reductase in vitro. On the basis of the relative IC50 values it would not have been predicted that, at the dose tested, the analogue MK-434 (17 beta-benzoyl-4-aza-5 alpha-androst-1-en-3-one) was distinguished from the other inhibitors with respect to the induction of faster and more complete regression (69%) as well as greater reduction in prostatic DHT (95%), both of which approached the castrated dog levels of 75% prostatic shrinkage and > 98% reduction in DHT. Treatment with any one of the five azasteroids induced two- to five-fold increases in prostatic testosterone. However, total androgen was conserved at the placebo control level. Despite the differences noted, each azasteroid tested induced a highly significant decrease in prostatic volume that correlated tightly with a decreased prostatic DHT level in canine spontaneous BPH.

5-alpha Reductase Inhibitors↗

PubMed1995

Quantitative evaluation of glandular and stromal compartments in hyperplastic dog prostates: effect of 5-alpha reductase inhibitors.

The objective of this study was to determine the effects of 2 different 5-alpha reductase inhibitors (finasteride and MK-0434) on the glandular and stromal compartments of hyperplastic canine prostates. In this study, dogs received 1 of the 2 compounds orally, at a dose of 1 mg/kg/day for 16 weeks; control dogs received a placebo. The morphological changes in the glandular and stromal compartments in the prostate were quantitated by a point-counting method on Masson's trichrome-stained sections. Treatment with 5-alpha reductase inhibitors resulted in significant (P < or = 0.05) decreases in mean prostatic volumes, microscopic evidence of prostatic atrophy, and significant (P < or = 0.05) decreases in the absolute volumes of the prostatic glandular and stromal compartments compared to controls. In finasteride-treated dogs, the mean percent change from baseline was: epithelium, -52; lumens, -58; fibrovascular stroma, -41; and smooth muscle, -29. In MK-0434-treated dogs, the mean percent change from baseline was: epithelium, -77; lumens, -58; fibrovascular stroma, -38; and smooth muscle, -42. The effect on the glandular compartment in dogs treated with MK-0434 was slightly greater than in dogs treated with finasteride; however, the effect on the stroma was similar. These results clearly demonstrate that inhibition of 5-alpha reductase enzyme activity affects growth and maintenance of both glandular and stromal compartments of dog hyperplastic prostates. It is likely that the decrease in size of the prostate in finasteride-treated (Proscar) men is due to shrinkage of both glandular and stromal compartments.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1995

Human relevance of animal carcinogenicity studies.

Extrapolation of results from rodent bioassays involving high-dose exposures to possible carcinogenic risk in humans exposed to low doses is based on the assumptions of species relevance and high- to low-dose extrapolation. For genotoxic chemicals, such as 2-acetylaminofluorene and N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide, these assumptions appear to be appropriate, although the dose response can be greatly modified by cell proliferation effects of these chemicals at high doses. In contrast, nongenotoxic chemicals, such as chemicals causing urinary calculi or sodium saccharin and related sodium and potassium salts, frequently are carcinogenic only at high doses and/or only in specific species. Consequently, for extrapolation of results for nongenotoxic chemicals these assumptions may not be appropriate.

2-Acetylaminofluorene↗

PubMed1995

Laparoscopic colorectal surgery--are we being honest with our patients?

PURPOSE: A survey was undertaken to assess the impact of laparoscopy on the practice of colorectal surgery. METHODS: A total of 1,520 questionnaires were mailed to all members of the American Society of Colon and Rectal Surgeons; 635 (42 percent) surgeons responded, 50 percent, and indicated that one questionnaire represented their entire group practice. RESULTS: Two hundred seventy-eight (47 percent) respondents currently perform laparoscopic colorectal surgery; 62 percent (171) use the laparoscope for < or = 20 percent of their bowel resections. Conversely, only 6 percent (16) use the laparoscope in over 50 percent of resections. The percentage of surgeons who perform various procedures were right colectomy, 78 percent; left colectomy, 57 percent; stoma creations, 52 percent; anterior resection, 44 percent; Hartmann's closure, 42 percent; abdominoperineal resection, 27 percent; rectopexy, 18 percent; and total colectomy, 14 percent. If the preoperative diagnosis is known to be carcinoma, 196 (71 percent) surgeons attempted laparoscopic colorectal surgery, but 55 percent of surgeons (108) operated only for early lesions and 35 percent (68) only for palliation. To enable the procedure to be laparoscopically performed, 87 percent (243) of surgeons stated that they have changed their practice to include routine use of ureteral stents (23 percent), preoperative colonoscopic marking of small lesions (40 percent), or intraoperative colonoscopy. Despite increased use of endoscopy, there were 18 patients in whom the wrong segment of colon was removed. Moreover, nine patients had early local recurrence after resection of colon cancer, nine had early local recurrence after rectal cancer resection, and five had early port-site recurrence. Although 255 (40 percent) surgeons surveyed would themselves undergo laparoscopic colorectal surgery for a rectal villous adenoma, only 38 (6 percent) would have a laparoscopic anterior resection for cancer. CONCLUSIONS: Several important problems exist including early port-site recurrence and a dual surgical standard. Although many surgeons are eager to practice laparoscopic colorectal surgery on their patients with carcinoma, they are reluctant to have the new technique applied to themselves.

Colectomy↗

PubMed1995

Role of urinary physiology and chemistry in bladder carcinogenesis.

Urine is a complex mixture of numerous substances, only some of which are described above. Literally thousands of substances have been identified in normal urine, including a variety of ions, non-ionic substances and macromolecules. Their presence and concentrations are highly variable, dependent on fluid intake and on nutritional, physiological and biochemical influences. Marked diurnal variations exist. Methodologies involved in the collection and analysis of these components can greatly influence the interpretation of the results. The influence of these various parameters in the urine on bladder carcinogenicity can be either direct or indirect. A major difficulty in studying this aspect of urothelial carcinogenesis is that it is essentially impossible to alter only one variable in the urine at a time. Alteration of any one variable results in physiological alteration of several other of the constituents in the urine. In addition, the processes involved in urothelial carcinogenesis frequently involve a complex interaction of multiple variables, such as volume, osmolality, cationic concentration, anionic concentration, quantitative and qualitative differences in protein, and generation of precipitate, crystals or calculi. Thus, it is likely that the actual mechanisms involved in the carcinogenic process with many of these chemicals, particularly those that are non-genotoxic, will involve a complex interaction of several constituents of the urine. Although this poses a formidable obstacle to our understanding in experimental situations as well as in extrapolating to humans, the role of specific factors appears to be discernible and should offer insight into the risk assessment process (Cohen and Ellwein, 1991 a,b and 1992).

Animals↗