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Biomedical subjects

R Weisman

Publications and source records attributed to R Weisman.

At least 19 recordsLinked to original sources
PubMed2005

[Immunohistochemistry study of EGFR expression in head and neck squamous cell carcinoma].

EGFR is an important transmembrane receptor member of the family of tyrosine kinases, that translates signals from both outside and inside the cell and plays a key role in numerous proceses that affect tumour development, growth, progresion, differentiation, inhibition of apoptosis and metastasis. Immunohistochemistry studies have shown that 40-80% of head and neck squamous cell carcinomas express EGFR and it has been suggested as a potential independent prognostic parameter. The objective of this study is to evaluate by immunohistochemistry the expresi6n of EGFR in a series of Head and Neck Squamous Cell Carcinoma and correlate it to clinico-pathological features and prognostic significance. We investigated expression of EGFR in 44 samples. There was a high expression in 41% of the cases. Even if we have not found that the expression of EGFR correlated with the prognosis of these patients the presence of EGFR is very important because there are chemical agents or drugs that can inhibit its activity.

Aged↗
PubMed2004

The fission yeast TOR proteins and the rapamycin response: an unexpected tale.

The TOR proteins are known as key regulators of cell growth in response to nutritional and mitogenic signals and as targets for the immunosuppressive and anti-cancerous drug rapamycin. The fission yeast Schizosaccharomyces pombe has two TOR homologues, tor1+ and tor2+. Despite their structural similarity, these genes have distinct functions: tor1+ is required under starvation, extreme temperatures, and osmotic or oxidative stress conditions, whereas tor2+ is required under normal growth conditions. Surprisingly, rapamycin does not seem to inhibit the S. pombe TOR-related functions. Rapamycin specifically inhibits sexual development in S. pombe, and this seems to stem from direct inhibition of the S. pombe FKBP12 homologue. Why S. pombe cells are resistant to rapamycin during the growth phase is as yet unclear and awaits further analysis of the TOR-dependent signaling pathways.

Antifungal Agents↗
PubMed2001

Rapamycin blocks sexual development in fission yeast through inhibition of the cellular function of an FKBP12 homolog.

FKBP12 is a ubiquitous and a highly conserved prolyl isomerase that binds the immunosuppressive drugs FK506 and rapamycin. Members of the FKBP12 family have been implicated in many processes that include intracellular protein folding, transport, and assembly. In the budding yeast Saccharomyces cerevisiae and in human T cells, rapamycin forms a complex with FKBP12 that inhibits cell cycle progression by inhibition of the TOR kinases. We reported previously that rapamycin does not inhibit the vegetative growth of the fission yeast Schizosaccharomyces pombe; however, it specifically inhibits its sexual development. Here we show that disruption of the S. pombe FKBP12 homolog, fkh1(+), at its chromosomal locus results in a mating-deficient phenotype that is highly similar to that obtained by treatment of wild type cells with rapamycin. A screen for fkh1 mutants that can confer rapamycin resistance identified five amino acids in Fkh1 that are critical for the effect of rapamycin in S. pombe. All five amino acids are located in the putative rapamycin binding pocket. Together, our findings indicate that Fkh1 has an important role in sexual development and serves as the target for rapamycin action in S. pombe.

Amino Acid Sequence↗
PubMed2000

The fission yeast TOR homolog, tor1+, is required for the response to starvation and other stresses via a conserved serine.

Targets of rapamycin (TORs) are conserved phosphatidylinositol kinase-related kinases that are involved in the coordination between nutritional or mitogenic signals and cell growth. Here we report the initial characterization of two Schizosaccharomyces pombe TOR homologs, tor1(+) and tor2(+). tor2(+) is an essential gene, whereas tor1(+) is required only under starvation and other stress conditions. Specifically, Deltator1 cells fail to enter stationary phase or undergo sexual development and are sensitive to cold, osmotic stress, and oxidative stress. In complex with the prolyl isomerase FKBP12, the drug rapamycin binds a conserved domain in TORs, FRB, thus inhibiting some of the functions of TORs. Mutations at a conserved serine within the FRB domain of Saccharomyces cerevisiae TOR proteins led to rapamycin resistance but did not otherwise affect the functions of the proteins. The S. pombe tor1(+) exhibits different features; substitution of the conserved serine residue, Ser(1834), with arginine compromises its functions and has no effect on the inhibition that rapamycin exerts on sexual development in S. pombe.

Amino Acid Sequence↗
PubMed1999

Timing and classifying brief acoustic stimuli by songbirds and humans.

The durations of animals' brief vocalizations provide conspecifics with important recognition cues. In the present experiments, zebra finches and humans (trained musicians) were rewarded for responding after S+ (standard) auditory signals from 56 to 663 ms and not for responding after shorter or longer S- (comparison) durations from 10 to 3684 ms. With either a single standard (Experiment 1) or multiple standards (Experiment 2), both zebra finches and humans timed brief signals to about the same level of accuracy. The results were in qualitative agreement with predictions from scalar timing theory and its connectionist implementation in both experiments. The connectionist model provides a good quantitative account of temporal gradients with a single standard (Experiment 1) but not with multiple standards (Experiment 2).

Adult↗
PubMed1999

Quantitation of the change in GADD153 messenger RNA level as a molecular marker of tumor response in head and neck cancer.

Cells injured by exposure to cisplatin (cDDP) undergo a cellular injury response that shares characteristics with responses produced by many other injurious agents. We sought to determine whether the increase of the message of the "growth arrest and DNA damage-inducible" gene, GADD153, could be used to assess the extent of the cellular injury response in model systems and in patients with head and neck cancer after treatment with cDDP. The mRNA levels of GADD153, a gene highly transcriptionally activated by cDDP damage, were increased in a transient, concentration-dependent manner by cDDP when human UMSCC10b head and neck carcinoma cells were treated with cDDP both in vitro and when grown as tumor xenografts in nude mice. There was a good correlation between the change in level of GADD153 mRNA and UMSCC10b cell kill by cDDP in vitro (r = 0.98). The magnitude of the increase was proportionally reduced in UMSCC10b sublines that were 3- or 6-fold resistant to cDDP. GADD153 mRNA levels were measured in biopsies obtained before and 24 h after treatment with cDDP from 32 patients with stage III/IV head and neck cancer. There was a relationship between the increase in GADD153 mRNA levels and the response rate. Seven of the 32 patients had no response and no increase in GADD153 mRNA level. Among the eight patients who attained a partial response, the increase in GADD153 message ranged from 0.7-2.5-fold. In contrast, 17 of 32 patients had a complete response, and this was accompanied by a 2-9-fold induction of GADD153. The mean increase in the complete responders (3.8+/-2.2-fold) differed significantly from that for the partial responders (1.6+/-0.9) and nonresponders (0.8+/-0.5; P <0.05); the difference between the partial responders and nonresponders was also significant (P <0.05). An increase of GADD153 mRNA of 1.75-fold or higher predicted a complete response, with a sensitivity of 94% and a specificity of 87%. We conclude that the magnitude of the increase in GADD153 mRNA is a promising candidate for service as an intermediate marker of head and neck tumor response to cDDP. The fact that the change in GADD153 mRNA reflects the actual extent of injury sustained by the tumor makes it particularly attractive as a potential marker. One strength of this approach is that it can provide a measure of the effectiveness of therapy as early as 24-48 h after the first dose of treatment.

Animals↗
PubMed1998

Frequency-range discriminations: special and general abilities in zebra finches (Taeniopygia guttata) and humans (Homo sapiens).

The acoustic frequency ranges in birdsongs and human speech can provide important pitch cues for recognition. Zebra finches and humans were trained to sort contiguous frequencies into 3 or 8 ranges, based on associations between the ranges and reward. The 3-range task was conducted separately in 3 spectral regions. Zebra finches discriminated 3 ranges in the medium and high spectral regions faster than in the low region and discriminated 8 ranges with precision. Humans discriminated 3 ranges in all 3 spectral regions to the same modest standard and acquired only a crude discrimination of the lowest and highest of 8 ranges. The results indicate that songbirds have a special sensitivity to the pitches in conspecific songs and, relative to humans, have a remarkable general ability to sort pitches into ranges.

Acoustic Stimulation↗
PubMed1998

The fission yeast mitotic regulator win1+ encodes an MAP kinase kinase kinase that phosphorylates and activates Wis1 MAP kinase kinase in response to high osmolarity.

The Schizosaccharomyces pombe win1-1 mutant has a defect in the G2-M transition of the cell cycle. Although the defect is suppressed by wis1+ and wis4+, which are components of a stress-activated MAP kinase pathway that links stress response and cell cycle control, the molecular identity of Win1 has not been known. We show here that win1+ encodes a polypeptide of 1436 residues with an apparent molecular size of 180 kDa and demonstrate that Win1 is a MAP kinase kinase kinase that phosphorylates and activates Wis1. Despite extensive similarities between Win1 and Wis4, the two MAP kinase kinase kinases have distinct functions. Wis4 is able to compensate for loss of Win1 only under unstressed conditions to maintain basal Wis1 activity, but it fails to suppress the osmosignaling defect conferred by win1 mutations. The win1-1 mutation is a spontaneous duplication of 16 nucleotides, which leads to a frameshift and production of a truncated protein lacking the kinase domain. We discuss the cell cycle phenotype of the win1-1 cdc25-22 wee1-50 mutant and its suppression by wis genes.

Amino Acid Sequence↗
PubMed1997

Rapamycin specifically interferes with the developmental response of fission yeast to starvation.

Rapamycin is a microbial macrolide which belongs to a family of immunosuppressive drugs that suppress the immune system by blocking stages of signal transduction in T lymphocytes. In Saccharomyces cerevisiae cells, as in T lymphocytes, rapamycin inhibits growth and cells become arrested at the G1 stage of the cell cycle. Rapamycin is also an effective antifungal agent, affecting the growth of yeast and filamentous fungi. Unexpectedly, we observed that rapamycin has no apparent effect on the vegetative growth of Schizosaccharomyces pombe. Instead, the drug becomes effective only when cells experience starvation. Under such conditions, homothallic wild-type cells will normally mate and undergo sporulation. In the presence of rapamycin, this sexual development process is strongly inhibited and cells adopt an alternative physiological option and enter stationary phase. Rapamycin strongly inhibits sexual development of haploid cells prior to the stage of sexual conjugation. In contrast, the drug has only a slight inhibitory effect on the sporulation of diploid cells. A genetic approach was applied to identify the signal transduction pathway that is inhibited by rapamycin. The results indicate that either rapamycin did not suppress the derepression of sexual development of strains in which adenylate cyclase was deleted or the cyclic AMP-dependent protein kinase encoded by pka1 was mutated. Nor did rapamycin inhibit the unscheduled meiosis observed in pat1-114 mutants. Overexpression of ras1+, an essential gene for sexual development, did not rescue the sterility of rapamycin-treated cells. However, expression of the activated allele, ras1Val17, antagonized the effect of rapamycin and restored the ability of the cells to respond to mating signals in the presence of the drug. We discuss possible mechanisms for the inhibitory effect of rapamycin on sexual development in S. pombe.

Adenylyl Cyclases↗
PubMed1997

all-trans retinoic acid enhances cisplatin-induced apoptosis in human ovarian adenocarcinoma and in squamous head and neck cancer cells.

Cisplatin exerts its cytotoxicity by inducing apoptosis. Similarly, all-trans retinoic acid (ATRA) causes apoptosis in certain cells. We studied the interaction of cisplatin and ATRA in human ovarian adenocarcinoma cells 2008, in human head and neck squamous carcinoma cells UMSCC10b, and in their respective cisplatin-resistant sub-lines. ATRA enhanced the cytotoxicity of cisplatin. The interaction of the drugs was synergistic in combination index-isobologram analyses (combination index >0.5 at 50% cell survival) in all of the cell lines tested. ATRA inhibited the cellular accumulation of the cisplatin analogue [3H] cis-dichloroethylenediamineplatinum(II) by 22-33% in three of four cell lines tested but did not alter the cellular content of reduced glutathione. The expression of Bcl-2 relative to Bax decreased more after combined treatment with cisplatin and ATRA than after either drug alone. The apoptotic mechanism of cell death was confirmed by demonstrating cleavage of poly(ADP-ribose)polymerase and by morphological analysis. The combined treatment with ATRA and cisplatin induced apoptosis in significantly more cells than either drug alone. We conclude that ATRA enhances the cytotoxicity of cisplatin by facilitating apoptosis in ovarian and head and neck carcinoma cells.

Adenocarcinoma↗
PubMed1996

A multicopy suppressor of a cell cycle defect in S. pombe encodes a heat shock-inducible 40 kDa cyclophilin-like protein.

Cyclophilins are peptidyl-prolyl cis-trans isomerases (PPIases) which have been implicated in intracellular protein folding, transport and assembly. Cyclophilins are also known as the intracellular receptors for the immunosuppressive drug cyclosporin A (CsA). The most common type of cyclophilins are the 18 kDa cytosolic proteins containing only the highly conserved core domain for PPIase and CsA binding activities. The wis2+ gene of the fission yeast Schizosaccharomyces pombe was isolated as a multicopy suppressor of wee1-50 cdc25-22 win1-1, a triple mutant strain which exhibits a cell cycle defect phenotype. Sequence analysis of wis2+ reveals that it encodes a 40 kDa cyclophilin-like protein, homologous to the mammalian cyclophilin 40. The 18 kDa cyclophilin domain (CyP-18) of wis2 is followed by a C-terminal region of 188 amino acids. The C-terminal region of wis2 is essential for suppression of the triple mutant defect. Furthermore this region of the protein is able to confer suppression activity on the 18 kDa S.pombe cyclophilin, cyp1, since a hybrid protein consisting of an 18 kDa S.pombe cyclophilin (cyp1) fused to the C-terminus of wis2 shows suppression activity. We also demonstrate that the level of wis2+ mRNA increases 10- to 20-fold upon heat shock of S.pombe cells suggesting a role for wis2+ in the heat-shock response.

Amino Acid Isomerases↗
PubMed1996

A novel organ preservation protocol for advanced carcinoma of the larynx and pharynx.

OBJECTIVE: To pilot a targeted chemoradiation protocol for patients with advanced carcinoma of the larynx and pharynx that would circumvent upper aerodigestive tract dysfunction related to major oncologic surgery. DESIGN: Weekly intra-arterial infusions of supradose cisplatin (150 mg/m2 per week x 4) rapidly delivered to the tumor bulk, simultaneous intravenous sodium thiosulfate for systemic drug neutralization, and conventional external-beam irradiation (1.80-2.00 Gy per fraction x 35) were used. Between February 1991 and April 1994, 42 patients were treated who would otherwise have required a major resection of the tongue base, pharyngeal wall, or larynx. MAIN OUTCOME MEASURES: Tumor response, toxic effects, disease control above the clavicle, preservation of the larynx, maintenance of oral nutrition, and overall and disease-related 2-year survival. RESULTS: Three complications were related to the weekly transfemoral superselective intra-arterial procedures performed 160 times. Grade 3 to 4 chemotoxic effects were infrequent, occurring in 9 (5.5%) of 160 cycles, and only 1 patient required a radiotherapy break because of severe mucositis. A complete response in the primary site was obtained in 36 (86%) of 42 patients, 2 of whom had residual disease in the neck. Median follow-up was 13 months (range, 3-46 months). To date, there have been 5 recurrences: 2 regional and 3 distant. The 2-year overall and disease-related survival was 64% and 76%, respectively. The rate of disease control above the clavicle at 2 years was 86%. CONCLUSIONS: We believe this chemoradiation protocol represents an effective management scheme for patients with advanced head and neck cancer while minimizing dysfunction and possibly improving survival.

Adolescent↗
PubMed1995

Anticholinergic poisoning associated with herbal tea.

An outbreak of cholinergic poisoning occurred in New York City during a 3-day period. Seven individuals from three families of South American origin were affected. Signs and symptoms of illness included dry skin, hyperthermia, tachycardia, dilated pupils, agitation, and hallucinations. Onset of illness in all cases was temporally associated with consumption of a tea that was labeled "Paraguay Tea" and was purchased from a grocery store specializing in South American foods. Paraguay tea, made from the leaves of the holly, Ilex paraguariensis, contains caffeine and theophylline and is a popular beverage in South America. Samples of the tea analyzed with gas chromatography contained belladonna alkaloids but neither caffeine nor theophylline. An investigation by the New York City Department of Health personnel determined that the tea was from a single lot, imported by one distributor, and sold at one grocery store. Unsold inventories of the tea were quarantined, and no further cases of anticholinergic poisoning were reported.

Adolescent↗
PubMed1995

Selective intra-arterial infusion of high-dose cisplatin in patients with advanced head and neck cancer results in high tumor platinum concentrations and cisplatin-DNA adduct formation.

A group of 23 patients with advanced head and neck cancer were treated with highly selective intra-arterial (IA) cisplatin 150 mg/m2 delivered rapidly through microcatheters. The systemic effects of cisplatin were neutralized by concurrent administration of sodium thiosulfate. Two-to-threefold higher tumor platinum contents were detected in tumor biopsies after selective IA cisplatin administration compared to historical controls (treated with 100 mg/m2 IA). Cisplatin-induced DNA modification in human tumor biopsies was quantitated using the antiserum NKI-A59. High levels of cisplatin DNA adducts were detected which correlated linearly with the tumor platinum content (r2 = 0.62). The addition of radiotherapy to this high dose intensity cisplatin treatment resulted in a 92% complete response (CR) rate (12 of 13 patients achieved a CR). Since no difference in tumor platinum content was detected between patients receiving or not receiving radiotherapy (13 and 10 patients, respectively), but the response rate was substantially different (12 CR and 1 partial response with radiotherapy versus 6 partial and 4 non-responders without radiotherapy), these data suggest that the high platinum levels achieved by selective IA infusion were sufficient to produce enough interaction with radiotherapy to cause a 92% CR rate. Whether this interaction is additive or synergistic is as yet unclear.

Antineoplastic Agents↗
PubMed1995

Slight renal effect of mercury from amalgam fillings.

The current study was to answer the question: Is enough mercury absorbed from dental amalgam fillings to produce renal damage? One hundred healthy adults (18-44 years old) filled out health questionnaires and voided urine samples. Urine mercury concentration and N-acetyl-beta-glucosaminidase (NAG) were measured. Subjects were grouped into those having amalgam fillings (N = 66) and those without (N = 34). Median (95% Confidence Interval) urine mercury was 1 (1-2) and 0 (0-0.6) ng/ml (P < 0.01) and median urine NAG was 23 (18-27) and 16 (11-18) units (P < 0.05) in the two groups respectively. People with mercury amalgam fillings excreted slightly more mercury than people without them, and have a very small increase in urinary NAG excretion that is probably of no clinical significance. This dose of mercury absorbed from amalgam appears to be too little to be a public health hazard for renal injury.

Acetylglucosaminidase↗
PubMed1995

Classification of frequencies into ranges by songbirds and humans.

We trained songbirds and humans in go/no-go discriminations among 27 tones. In the compact discrimination, S + s formed a contiguous middle range (3080-4040 Hz), and S-s formed contiguous lower (2000-2960 Hz) and upper (4160-5120 Hz) ranges. In the distributed discrimination, S + s were spread across all 3 ranges. Songbirds acquired the compact discrimination more quickly and with higher accuracy than humans. Songbirds acquired the distributed discrimination only after much extended training; humans did not acquire the distributed discrimination. Compact groups (birds and humans) accurately classified test tones spaced 60 Hz from the training tones, but the distributed groups did not. A single reversal in discrimination between tones on the boundary between the lower S- and middle S + ranges did not propagate to all the tones in either range. A neural network model provided an account of the classification of tones in songbirds and humans.

Adolescent↗
PubMed1995

Lateral rhinotomy and medial maxillectomy.

Lateral rhinotomy and medial maxillectomy have evolved in the last 25 years as the treatment of choice for most neoplastic lesions involving the lateral nasal wall. Technical refinements have allowed this procedure to be performed with acceptable and minimal morbidity. This approach has had its widest application in the treatment of inverted papilloma, with a concomitant marked reduction in the recurrence rate of this tumor compared with more limited procedures. Its advantages are the excellent exposure provided, the opportunity to extend the approach to adjacent areas of tumor extension (orbit, cranial vault, frontal and contralateral ethmoid sinus), and en bloc removal of neoplasms. This approach remains the standard of treatment for lateral nasal wall tumors.

Humans↗