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Biomedical subjects

H Weinstein

Publications and source records attributed to H Weinstein.

At least 109 records · Page 6Linked to original sources
PubMed1988

Failure patterns and survival in pediatric soft tissue sarcoma.

We retrospectively analyzed 44 patients with localized soft tissue sarcomas who were seen and treated at the JCRT, DFCI, and TCH between 1970-1984. Patients with rhabdomyosarcoma were excluded. Primary tumors were located in the following sites: extremities 19 (43%), head and neck 9 (20%), and trunk 16 (37%). Median follow-up for survivors was 7.7 years (range 24 mo-16 years). Surgery was the initial aspect of treatment for all patients. All patients also received post-operative irradiation, 43 at presentation and one at local relapse, and 26 received adjuvant chemotherapy. Radiation was delivered to a dose of 4000 cGy (median) followed by a boost to a median dose of 5760 cGy (range 4500-7000 cGy). Actuarial 5- and 10-year disease-free survivals (DFS) were 70% and 59% while the actuarial 5- and 10-year overall survivals (OS) were both 75%. All parameters were assessed for significance by univariate analysis. OS was significantly affected by presenting stage when analyzed according to both the Intergroup Rhabdomyosarcoma Staging System (IRS) and the American Joint Committee on Cancer system (AJCC). For the IRS, OS at 10 years was 100% for Stage I, 72% for Stage II, and 54% for Stage III (p = 0.04). For the AJCC, OS at 10 years was 100% for Stage I and 65% for Stage II and III (p = 0.05). Primary site, histology, and use of adjuvant chemotherapy did not influence OS or DFS. Fourteen patients failed: 8 local, 1 distant, and 5 combined local and distant. There was no LF among the 9 pts. with primary lesions less than 5 cm compared to 11/29 (39%) whose tumor was greater than 5 cm (p = 0.04). Pts. with gross residual disease had a local DFS of 42%, but those with no residual or microscopic residual had a local DFS of 71% (p = 0.02). In conclusion, childhood STS has an excellent OS (75% at 10 years). Tumor size and residual tumor after surgery strongly predicted for local failure. Of interest, the pattern of failure is predominantly local in our series. This suggests that more aggressive local treatment is indicated in management of children with STS. Higher doses of irradiation as used for adult STS are probably indicated for patients with gross residual disease.

Adolescent↗
PubMed1988

Role of primary and secondary protein structure in neurotransmitter receptor activation mechanisms.

A proton transfer triggered by a ligand interacting with the receptor had been suggested as the initial step in the activation of a receptor for the neurotransmitter serotonin (5-hydroxy-tryptamine; 5-HT). To evaluate the role of the receptor macromolecule in modulating the primary molecular event in ligand-mediated activation, the process of proton transfer was analysed in the environment of a protein model for the 5-HT receptor. In the absence of a detailed receptor structure, the enzyme actinidin was chosen as the model for the receptor based on criteria obtained from structure-activity considerations on the ligands. The first simulation of a mechanism for receptor activation was performed on this model using methods of theoretical chemistry to study the effect of specific structural elements. The premise is that the role of the elements of secondary structure of soluble proteins (e.g. actinidin) in determining structure-function relations in these macromolecules is maintained when these elements are part of membrane-bound receptor proteins. Results from the calculations of the effects of the six alpha helices of actinidin on the proton transfer process from the imidazolium side chain of His 162 to the thiol side chain of Cys 25 in the protein show that the helices contribute in different ways to modulate the energy of proton transfer. The largest helix, A1, opposes the proton transfer through the effect of the helix dipole. The charged residues (primary structure) in helix A3 favor the proton transfer, and mask the effect of its helix dipole (secondary structure) which opposes the transfer. The direction of the proton transfer simulated for the activation mechanism is opposite to that assumed in the catalytic process of the thiol protease, and the entire protein environment opposes the transfer. This supports the specific role of the ligand in triggering the proton transfer as a response to its binding.

Computer Graphics↗
PubMed1988

Stage IA and IIA supradiaphragmatic Hodgkin's disease: prognostic factors in surgically staged patients treated with mantle and paraaortic irradiation.

A total of 315 pathologically staged (PS) patients with IA and IIA Hodgkin's disease (HD) were treated with mantle and paraaortic irradiation, and evaluated for freedom-from-first relapse (FFR), survival, prognostic factors, and long-term complications. The 14-year actuarial FFR and survival were 82% and 93%, respectively, with a median follow-up time of 9 years. Mediastinal size was the only factor that predicted for a lower FFR, P less than .001. Forty-nine patients have developed recurrent HD. Thirty-six patients are disease-free following retreatment and only 13 patients have died of HD. Patients with mixed cellularity (MC) histology were more likely to relapse below the diaphragm (11%) as compared with patients with nodular sclerosis (NS) (5.1%) or lymphocyte predominant (LP) (3.6%) histology. These relapses were often associated with bulky pelvic nodal adenopathy and salvage treatment with chemotherapy alone often failed to control recurrent disease. Alternative diagnostic and therapeutic recommendations are presented for these patients. Thyroid abnormalities represented the most common long-term complication with an actuarial risk at 16 years of 37%. Major complications were rare. Mantle and paraaortic irradiation is associated with a high FFR and a low risk of complications and should remain standard treatment for early-stage HD.

Adolescent↗
PubMed1988

Bone marrow transplantation for constitutional pure red cell aplasia.

Constitutional pure red cell aplasia (CPRCA) is a syndrome of failed erythropoiesis usually diagnosed within the first year of life. Four patients with CPRCA received transplants with marrow from their HLA-identical, mixed lymphocyte culture-nonreactive siblings. All patients were resistant to corticosteroid therapy and were dependent on regular red cell transfusions for at least 5 years. Three patients were conditioned with procarbazine, antithymocyte globulin, cyclophosphamide, and busulfan, and one was conditioned with antithymocyte serum, cyclophosphamide, and busulfan. Three patients promptly had successful engraftments with establishment of donor hematopoiesis. One patient initially rejected his graft but received a successful retransplant. All patients are currently alive with Karnofsky performance scores of 100 and normal erythropoiesis of donor origin. Despite a history of multiple transfusions, bone marrow transplantation is a potentially curative therapy for patients with CPRCA.

Adolescent↗
PubMed1987

Wide-field radiation therapy alone or with chemotherapy for Hodgkin's disease in relapse from combination chemotherapy.

Nineteen patients with Hodgkin's disease who relapsed primarily in nodal sites after intensive combination chemotherapy were retreated with wide-field radiation therapy alone or with additional chemotherapy between January 1971 and December 1984. Six patients presented in second relapse and 13 patients in first relapse. Seven patients were treated with combination chemotherapy and radiation therapy and twelve patients were treated with radiation therapy alone. Radiation therapy field sizes and doses were similar to those recommended for early-stage Hodgkin's disease patients treated with radiation therapy alone. The 5-year actuarial freedom from relapse (FFR) and survival following retreatment were 48% and 69%, respectively. Twelve patients are currently disease-free 12 to 172 months following retreatment. Wide-field radiation therapy alone or with additional chemotherapy should be considered for patients with advanced Hodgkin's disease who relapse in nodal sites after initial combination chemotherapy.

Actuarial Analysis↗
PubMed1987

A molecular model for activation of a 5-hydroxytryptamine receptor.

The extension of a model proposed previously for molecular recognition at a serotonin (5-hydroxytryptamine (5-HT) ) receptor makes possible the formulation of a molecular mechanism of receptor activation. The activation mechanism proposed here is based on the changes induced in the drug and in a model receptor by the interaction mimicking the formation of a drug-receptor complex. This mechanism was simulated by quantum mechanical calculations of molecular interactions between 5-HT and a model for a receptor represented by an imidazolium-ammonia complex that serves as a proton transfer model (PTM). The movement of the proton in the PTM is promoted by the interaction with 5-HT, suggesting a process by which 5-HT can trigger the activation of the receptor. The elements of the activation mechanism revealed by the results of the simulation are: (a) the electrostatic alignment between the PTM and 5-HT, which guides the recognition of 5-HT by the PTM; (b) the contraction of the distance between the hydrogen bonded components of the PTM, induced by the interaction of 5-HT with the PTM, which leads to a decrease in the barrier to proton transfer in the PTM; (c) an additional decrease of the barrier to proton transfer produced by the negative electrostatic potential of 5-HT, which stabilizes the transition state; and (d) the increased preference for product over reactant in the interaction complex between 5-HT and the PTM, which constitutes a driving force for the proton transfer process. According to this model, compounds that activate the 5-HT receptor should bind in a mode that induces the changes described above in the PTM and thus triggers the proton transfer.

Calorimetry↗
PubMed1987

Pharmacological characterization of two 5-hydroxytryptamine receptors coupled to adenylate cyclase in guinea pig hippocampal membranes.

Two 5-hydroxytryptamine (5-HT) receptors mediate stimulation of adenylate cyclase activity in membranes of adult guinea pig hippocampus. The two receptors were characterized with agonists and antagonists and with the aid of computerized curve-fitting procedures. Each receptor mediates about 50% of the maximal response to 5-HT. 5-HT is about 10-fold more potent in eliciting response through one cyclase-linked receptor (RH) than the other (RL). The concentrations of 5-HT that elicit half-maximal response through RH and RL are 43 +/- 6 nM and 414 +/- 53 nM, respectively. 5-Methoxytryptamine (5-MeOT) and 5-HT are approximately equipotent at each receptor. The agonists tryptamine and bufotenine are less potent than 5-HT at both receptors, and each is about 50-fold selective for RH. The two receptors are best discriminated by the agonists 5-carboxamidotryptamine (5-CONH2-T) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), both of which are selective for RH. 5-CONH2-T is about 7-fold more potent than 5-HT at RH. The rank order of agonist potencies at RH (5-CONH2-T greater than 8-OH-DPAT = 5-HT = 5-MeOT greater than bufotenine greater than tryptamine) differs from that at RL (5-HT = 5-MeOT greater than bufotenine greater than tryptamine = 5-CONH2-T greater than 8-OH-DPAT). Spiperone acts as a simple competitive antagonist at RH, with a dissociation constant of 20 nM, but it is at least 100-fold less potent as an antagonist at RL. The relatively low affinities of the selective 5-HT antagonists ketanserin and MDL 72222 for RH and RL indicate that neither receptor may be classified as the 5-HT2 or as the 5-HT3 (i.e., peripheral neuronal) type. The characteristics of RH suggest that it is a functional correlate of the 5-HT1A-binding site in brain. RL appears not to correspond to a known 5-HT-binding site, but it may be homologous to receptors that mediate 5-HT-stimulated adenylate cyclase activity in other systems such as infant rat colliculi. RH and RL may also mediate stimulation of adenylate cyclase activity by 5-HT in hippocampal membranes of adult rat.

5-Methoxytryptamine↗
PubMed1987

Molecular determinants for recognition of triazole and tetrazole analogs of histamine at H2-receptors.

Calculations of molecular structures, relative stabilities of the various tautomers, and molecular electrostatic potentials (MEPs) were used to examine the molecular properties that determine the actions at H2-receptors of histamine analogs in which the imidazole ring was replaced by triazole or tetrazole. The analysis indicates that the most stable tautomer of 3-ethylamine-1,2,4-triazole (EATRI), is also the most similar to the assumed active form of histamine. Differences in the MEP of EATRI and histamine are observed mainly near the N(2) nitrogen of EATRI which is the steric equivalent of the C(4) position of histamine. Because EATRI is recognized at the receptor in spite of these differences, we conclude that the H2-receptor has no selectivity with respect to the electrostatic or steric properties near this position, in agreement with previous observations from structure-activity relations. This conclusion contrasts with the apparent selectivity of the receptor for the reactivity properties of the position equivalent to C(2) in histamine. Thus, the analysis of the tautomeric forms and MEP of the 5-ethylamine-1,2,3,4-tetrazole, which is not recognized by the H2-histamine receptor, suggests that the negative potential near the N(3) nitrogen, which corresponds to C(2) in histamine, is responsible for the inactivity of this molecule. The mechanism of receptor activation by EATRI is analyzed in relation to results from a theoretical simulation of a proposed activation mechanism of H2-histamine receptors. We find that the discriminant property for receptor activation by EATRI should be the relative energy of the ring protonated tautomers, and our results indicate that only the cation in which the ring protonation is on N(1) and N(4) and the side chain is anchored at the negative receptor site can be recognized at the histamine H2-receptor, and can participate in the proposed activation process.

Azoles↗
PubMed1986

Molecular determinants for the agonist activity of 2-methylhistamine and 4-methylhistamine at H2-receptors.

A model for drug action at the histamine H2-receptor has been evaluated computationally for the agonists 2- and 4-methylhistamine. Based on molecular properties calculated for molecular structures optimized with ab initio quantum mechanical methods, the activities of these compounds and their potencies relative to histamine are found to be explained by the previously proposed model. Recognized in the N3-H tautomeric form of their monocations, both compounds exhibit a change in ring tautomeric preference when the cationic side chain is neutralized. This change makes possible their participation in a proposed proton relay event that was postulated to initiate the receptor response of H2-agonists. The relative concentrations of the mono- and dication forms of the molecules in equimolar concentrations of histamine and the two derivatives are calculated from the values of the molecular electrostatic potentials at the ring protonation sites. Because the monocation is the species recognized at the H2-receptor, the reduced potency of 2-methylhistamine relative to histamine and to the 4-methyl derivative is explained by the finding that 2-methylhistamine will have the lowest concentration of the recognized species. The rank order of potencies obtained from the ratio of monocationic species of the molecules is in agreement with experimental results.

Methylhistamines↗
PubMed1986

Theoretical studies on the activation mechanism of the histamine H2-receptor: the proton transfer between histamine and a receptor model.

A proposed molecular mechanism for the activation of the H2-receptor of histamine was simulated with ab initio calculations including geometry optimization with several basis sets. The system is modeled by a proton-relay chain produced by the binding of a histamine molecule to a receptor model consisting of an anionic anchoring site, and proton donor and acceptor sites. The anchoring of histamine cation at a negative receptor site is simulated by the interaction with a hydroxyl anion or by calculations on neutral histamine; the proton donor and acceptor sites are modeled by ammonium and ammonia groups, respectively. Results of the calculations reveal that a significant decrease in the barrier for the movement of the proton from the donor site to the N1 nitrogen in the imidazole portion of histamine occurs as a consequence of the neutralization of the side chain and the simultaneous interaction of the N3 nitrogen with the proton acceptor. An increase of the driving force for the proton transfer process is produced by these interactions, as observed from the relative energies of the initial and final steps of the charge relay. The barrier and the driving force depend on the nature of the proton acceptor site. This simulation of the receptor activation mechanism provides the basis for exploration of the partial receptor activation by molecules characterized as partial agonists and the lack of activation by molecules that act as antagonists on this receptor.

Binding Sites↗
PubMed1985

Determinants of molecular reactivity as criteria for predicting toxicity: problems and approaches.

We discuss the physicochemical basis for mechanisms of action of toxic chemicals and theoretical methods that can be used to understand the relation to the structure of these chemicals. Molecular properties that determine the chemical reactivity of the compounds are proposed as parameters in the analysis of such structure-activity relationships and as criteria for predicting potential toxicity. The theoretical approaches include quantitative methods for structural superposition of molecules and for superposition of their reactivity characteristics. Applications to polychlorinated hydrocarbons are used to illustrate both rigid superposition methods, and methods that take advantage of structural flexibility. These approaches and their results are discussed and compared with methods that afford quantitative structural comparisons without direct superposition, with special emphasis on the need for efficient automated methods suitable for rapid scans of large structural data bases. Quantum mechanical methods for the calculation of molecular properties that can serve as reactivity criteria are presented and illustrated. Special attention is given to the electrostatic properties of the molecules such as the molecular electrostatic potential, the electric fields, and the polarizability terms calculated from perturbation expansions. The practical considerations related to the rapid calculation of these properties on relevant molecular surfaces (e.g., solvent- or reagent-accessible surfaces) are discussed and exemplified, stressing the special problems posed by the structural variety of toxic substances and the paucity of information on their mechanisms of action. The discussion leads to a rationale for the use of the combination of theoretical methods to reveal discriminant criteria for toxicity and to analyze the initial steps in the metabolic processes that could yield toxic products.

DDT↗