Search PubMed⌕ Search

Biomedical subjects

T J Lynch

Publications and source records attributed to T J Lynch.

At least 73 records · Page 4Linked to original sources
PubMed1993

Extrapleural pneumonectomy in the setting of a multimodality approach to malignant mesothelioma.

The use of extrapleural pneumonectomy in a multimodality treatment setting for malignant pleural mesothelioma is described, presenting first the right-sided approach and then the left-sided. This technique used in a multimodality approach with CAP chemotherapy (cyclophosphamide 600 mg/m2, doxorubicin 60 mg/m2, cisplatin 75 mg/m2) 5 cycles at 3-week intervals, and radiotherapy (55 Gy radiation to sites of previous bulky disease or residual disease) to treat 44 patients with malignant pleural mesothelioma resulted in improved operative mortality and decreased length of hospital stay.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Management of malignant pleural effusions.

Malignant pleural effusions (MPEs) are a common complication of advanced malignancies, particularly lung and breast cancer. They are caused by a variety of mechanisms including tumor obstruction of lymphatic flow, spread of malignant cells via the systemic circulation, and tumor invasion of the pulmonary arterioles. Therapy is determined by tumor histology, stage of malignancy, and a careful assessment of a patient's performance status and comorbid diseases. A number of approaches have been used to treat patients with MPE ranging from thoracentesis to pleurectomy. Tube thoracostomy drainage followed by application of a sclerosing agent is the most common strategy. Effective sclerosing agents include quinacrine, talc, bleomycin, tetracycline and Corynebacterium parvum. Results from a recent multicenter randomized trial suggest that bleomycin may be superior in terms of control of effusion at 30 days. Further randomized studies are ongoing to determine the optimal method of draining the pleural space and the most effective sclerosing agent. Thoracoscopy using video-assisted techniques is a promising new approach to MPEs both for diagnosis and treatment. The application of biological agents such as interleukin-2, the interferons, and novel chemotherapeutic agents are experimental approaches that are under investigation.

Bleomycin↗
PubMed1993

Immunotoxin therapy of small-cell lung cancer. N901-blocked ricin for relapsed small-cell lung cancer.

Despite its initial chemosensitivity, small-cell lung cancer (SCLC) is rarely cured with chemotherapy alone, and fewer than 5% of patients are alive at 5 years. Immunotoxin therapy appears to offer promise in treating the minimal residual disease that remains after induction chemotherapy. We have studied N901-bR in patients with relapsed SCLS. N901-bR consists of the N901 monoclonal antibody (MoAb) and blocked ricin, an altered ricin molecule in which the galactose binding sites of the ricin B-chain which mediate nonspecific binding of the toxin are blocked through the covalent binding of ligands. N901 is an anti-NCAM (CD56) MoAb which binds to SCLC tumors and cell lines, cardiac muscle, natural killer (NK) cells, and peripheral nerve. N901-bR showed a 2.7 log greater in vitro cytotoxicity to the CD56-positive cell line SE-2 than to the antigen-negative Namalwa cell line. Nineteen patients with relapsed antigen-negative Namalwa cell line. Nineteen patients with relapsed and/or refractory SCLC have been entered into a phase I study at doses ranging from 5 to 40 micrograms/kg/day given as a 7-day continuous infusion. The dose-limiting toxicity is capillary leak syndrome observed in two thirds of the patients treated at 40 micrograms/kg/day. One patient at the maximum tolerated dose, 30 micrograms/kg/day x 7 days, has achieved a partial response to N901-bR. No patient has developed clinically significant peripheral or central neuropathy. We plan to begin a phase II study of N901-bR following induction chemotherapy in patients with SCLC.

Antibodies, Monoclonal↗
PubMed1993

Multimodality therapy of patients with stage IIIA, N2 non-small-cell lung cancer. Impact of preoperative chemotherapy on resectability and downstaging.

To assess the effect of neoadjuvant platinum-based chemotherapy on resectability, stage of disease at resection, and patterns of recurrence and survival in patients with IIIA, N2 non-small-cell lung cancer, we examined the first 60 patients treated with neoadjuvant chemotherapy followed by attempted resection in our institution. Of 67 patients identified, 7 patients were ineligible because of comorbidities, 3 patients refused chemotherapy, and 1 consented but died before treatment. Fifty-six received neoadjuvant chemotherapy. Complications of chemotherapy were minor, with no deaths. Fifty-four patients had thoracotomy; 75% (n = 42) had complete resection and 25% (n = 14) had unresectable lesions. One postoperative death occurred (2%). Pathologic review of specimens and nodal groups revealed that 41% (n = 23) were downstaged, 39% (n = 22) remained stage IIIA, and 19% (n = 11) progressed. Squamous histologic type was predictive of resectability, 18 of 20 patients having resectable squamous cell tumors (p < 0.05). Actuarial survivals at 1 and 2 years were 74% and 52%, respectively. In patients with resectable tumors survivals at 1 and 2 years were 85% and 67%, respectively. For those with unresectable lesions, survivals were 43% and 14%. Relapse-free survivals at 1 and 2 years for patients with resectable lesions were 70% and 42%, respectively. Relapses were local in 25% (n = 4), at a distant site only in 50% (n = 8), combined local and distant in 25% (n = 4). Distant relapse occurred in the central nervous system only in 7 of 8 patients (88%). Complete resectability was highly predictive of improved survival (p < 0.0002). Weight loss did not affect resectability but was associated with decreased survival (p < 0.003). Neoadjuvant chemotherapy appears to improve resectability and to pathologically downstage N2 non-small-cell lung cancer from stage IIIA. Multiinstitutional randomized trials are needed to further demonstrate the efficacy of this approach.

Adenocarcinoma↗
PubMed1993

Regional pharmacokinetics educational program.

An educational program for hospital pharmacists in and near Vermont is described and its impact on departmental clinical practice evaluated. Pharmacists were instructed by practitioners from a single institution in basic pharmacokinetics, practice guidelines for aminoglycoside therapy, and use of a computer program for aminoglycoside dosage determination. Participants completed a multiple-choice precourse test, a similar postcourse test, and a third test six months after class completion. Test scores were compared with those from a control group of pharmacists. Pharmacy directors from study group hospitals completed questionnaires measuring aminoglycoside clinical services before and six months after the program. Compared with the control group, participants scored higher on the postcourse tests. Results from the questionnaire indicate that the program affected clinical practice in almost all participating pharmacy departments. A consistent pharmacokinetic strategy for reviewing aminoglycoside dosages and evaluating serum aminoglycoside concentrations is now practiced in most Vermont hospitals. An educational program originating in one hospital can expand pharmacists' knowledge and influence departmental clinical practice throughout a region.

Aminoglycosides↗
PubMed1992

Continuous-infusion cisplatin, 5-fluorouracil, and bolus methotrexate in the treatment of advanced non-small cell lung cancer.

BACKGROUND: Cisplatin and 5-fluorouracil have noted synergy in preclinical systems. The authors combined methotrexate with infusional cisplatin and 5-fluorouracil in an attempt to produce a regimen with improved activity in advanced NSCLC: METHODS: Twenty-six ambulatory patients with previously untreated non-small cell lung cancer were treated with continuous-infusion cisplatin (25 mg/m2/day for 5 days), 5-fluorouracil (800 mg/m2/day for 5 days), and intermediate-dose methotrexate (200 mg/m2 on days 15, 22), followed by leucovorin rescue (PFM regimen). RESULTS: Patients received a median of four cycles of therapy. Two patients had a complete response, and 10 had a partial response (overall response rate, 46.2% or 12 of 26). The median time to treatment failure was 22.5 weeks; the median survival was 55 weeks from the start of chemotherapy. There were no toxic deaths attributed to chemotherapy. Thrombocytopenia was the only Grade 4 toxicity (27%). Grade 1/4 and 2/4 peripheral neuropathy occurred in 17 of 26 patients (66%) and was associated with a cumulative cisplatin dose of more than 300 mg/m2. CONCLUSIONS: PFM (using continuous-infusion cisplatin) produced a high response rate but resulted in an high incidence of low-grade peripheral neuropathy.

Adult↗
PubMed1992

Middle-ear transmission: acoustic versus ossicular coupling in cat and human.

Otologic surgeons consider the action of sound pressure on the cochlear windows to be of major importance in certain cases of middle-ear pathology, yet previously published network models of mammalian middle ears do not include such a mechanism. A unified middle-ear model is developed in which it is assumed that the difference of acoustic pressures acting on the windows adds to the ossicular-chain pressure to produce cochlear input. From a network model of the cat middle-ear cavities we estimate the contributions of pressures on the cochlear windows for both normal and abnormal cat ears. For the human ear we use the model of Kringlebotn (1988) and measurements of Békésy (1947). We determine that the pressure difference across the cochlear windows is negligibly small in normal cat and human ears. Thus, it is a reasonable approximation to ignore this mechanism in normal ears. For ears with a drastically altered tympanic membrane and/or ossicular chain, acoustic coupling to the cochlear windows can--to a considerable extent--explain residual hearing in human. The model predicts hearing levels for type IV tympanoplastic reconstructions that agree with the best results obtained surgically.

Acoustic Stimulation↗
PubMed1992

Multidisciplinary protocol for determining aminoglycoside dosage.

A protocol for determining optimal dosages of aminoglycosides early in therapy is described, and the effectiveness of the protocol is evaluated. The protocol was developed jointly by physicians and pharmacists at a 550-bed hospital to ensure that surgical patients prescribed aminoglycosides were quickly and consistently put on a safe and effective course of therapy. Physicians select an aminoglycoside and calculate a loading dose and initial maintenance dosage by using a nomogram printed on an antimicrobial order form. Nurses are trained to administer and document aminoglycoside doses accurately and to draw blood samples at the correct times. Pharmacists order serum aminoglycoside concentration assays, analyze the results, and recommend changes in dosage when necessary. To evaluate the effectiveness of the dosing protocol, the records of surgical patients treated before and after the protocol was in place were reviewed. Compared with the control group, a higher percentage of patients treated under the protocol were receiving therapeutic, nontoxic dosages of aminoglycosides within 48 hours of the start of therapy. In addition, fewer serum drug concentration tests were ordered per patient under the protocol, and the percentage of concentration determinations useful for analysis was higher. The mean duration of aminoglycoside therapy was identical before and after the protocol was instituted, and nephrotoxic reactions tended to be less common among the protocol patients. An aminoglycoside dosing protocol requiring the cooperation of pharmacists, nurses, and physicians provides a consistent, safe, and effective means of managing aminoglycoside therapy for the hospitalized patient.

Adult↗
PubMed1990

Substrate specificity of Acanthamoeba myosin I heavy chain kinase as determined with synthetic peptides.

Phosphorylation of a single threonine (myosin IA) or serine (myosins IB and IC) in the heavy chains of the Acanthamoeba myosin I isozymes is required for expression of their actin-activated Mg2(+)-ATPase activities. We now report that the synthetic peptide Gly-Arg-Gly-Arg-Ser-Ser-Val-Tyr-Ser, which corresponds to the phosphorylated region of Acanthamoeba myosin IC, is a good substrate for myosin I heavy chain kinase: Km = 54 microM, and Vmax = 15 mumols/min.mg. The same serine is phosphorylated as in the native substrate (residue 6 in the above sequence), and kinase activity with the synthetic peptide as substrate is also stimulated by phosphatidylserine-enhanced autophosphorylation of the kinase. These results indicate that all of the essential sequence determinants of kinase specificity are contained within this 9-residue peptide. With the peptide as substrate, we found that another acidic phospholipid, phosphatidylinositol, also enhances autophosphorylation of the kinase whereas the neutral phospholipids phosphatidylcholine and phosphatidylethanolamine do not. By comparing the Km and Vmax values for a series of synthetic peptide substrates, we established that 1 basic amino acid is essential on the NH2-terminal side of the phosphorylation site, and two are preferable, and that a tyrosine is essential 2 residues away on the COOH-terminal side. There is a slight preference for arginines over lysines. All of these local sequence specificity determinants are present in the three native substrates, Acanthamoeba myosins IA, IB, and IC, and in two Dictyostelium myosin I isozymes that are putative substrates for the kinase. Similar sequences do not occur in the myosins I from intestinal brush border, which is not a substrate for the Acanthamoeba kinase.

Acanthamoeba↗
PubMed1990

Acanthamoeba myosin I heavy chain kinase is activated by phosphatidylserine-enhanced phosphorylation.

The actin-activated Mg2(+)-ATPase activities of myosins I from Acanthamoeba castellanii are fully expressed only when a single amino acid on their heavy chain is phosphorylated by myosin I heavy chain kinase. Here we show that kinase isolated by a procedure designed to minimize its phosphorylation during purification can incorporate up to 7.5 mol of phosphate/mol of enzyme when incubated with ATP, possibly by autophosphorylation. The rate of phosphorylation is enhanced about 20-fold by phosphatidylserine but is unaffected by calcium ions. Phosphorylation increases the rate at which the kinase phosphorylates the regulatory site of myosin I by about 50-fold. These results suggest that (auto?)phosphorylation may regulate the activity of myosin I heavy chain kinase in vivo. The stimulation of kinase phosphorylation by phosphatidylserine (other phospholipids have not yet been tested) is of particular interest because myosin I has been shown to be tightly associated with membranes, especially the plasma membrane.

Acanthamoeba↗
PubMed1990

Partial characterization of a carotenoid droplet ATPase and its possible significance in carotenoid droplet dispersion in goldfish xanthophores.

The dispersion of carotenoid droplets in permeabilized goldfish xanthophores is dependent on ATP, F-actin, and cytosol. We report here that the motor (ATPase, translocator) resides with the permeabilized cell remnants and not in the cytosol. We also report that the carotenoid droplets have an ATPase that is not conventional myosin, dynein, or an ion pump. Its activity appears to correlate with the actin content of the carotenoid droplet preparation. A carotenoid droplet protein of Mr 72,000 (p72) is shown to be labeled by irradiation with 8-azido-ATP with concomitant loss of ATPase activity of the carotenoid droplets. We propose that this protein may be the ATPase responsible for carotenoid droplet dispersion.

Adenosine Triphosphatases↗
PubMed1990

Morphine-induced pupillary fluctuation: physiological evidence against selective action on the Edinger-Westphal nucleus.

In the rat, the predominant pupillary effect of morphine sulfate (30 mg/kg, i.p.) is mydriasis, interrupted periodically by miotic excursions. Using infrared video pupillometry, respirometry and EEG recording, we had previously reported that miotic excursions are always correlated with the onset of EEG bursting, while mydriatic excursions are preceded by respiratory slowing and correlated with EEG burst cessation. In the current study, we found that during morphine-induced EEG bursting and related miosis, delivery of an alerting stimulus to the rat caused an immediate conversion sequence composed of respiratory slowing, burst cessation and mydriatic excursion. We also simulated morphine-induced EEG bursting through non-opioid means by delivering kindling electrical stimuli to the amygdala. When the stimulus was given during morphine-induced mydriasis, the stimulus-induced bursting resulted in a miotic excursion identical to spontaneous morphine-induced miotic excursions. These results indicate 1) that the reticular activating system is involved in morphine-induced mydriatic excursions and 2) that EEG bursting is not simply correlated with morphine-induced miotic excursions, but causes them. Collectively, these results strengthen our hypothesis that the Edinger-Westphal nucleus is not the site in which the selective, receptor-mediated pupillary effects of morphine are initiated.

Amygdala↗
PubMed1989

Purification and characterization of a third isoform of myosin I from Acanthamoeba castellanii.

A third isoform of myosin I has been isolated from Acanthamoeba and designated myosin IC. Peptide maps and immunoassays indicate that myosin IC is not a modified form of myosin IA, IB, or II. However, myosin IC has most of the distinctive properties of a myosin I. It is a globular protein of native Mr approximately 162,000, apparently composed of a single 130-kDa heavy chain and a pair of 14-kDa light chains. It is soluble in MgATP at low ionic strength, conditions favoring filament assembly by myosin II. Myosin IC has high Ca2+- and (K+,EDTA)-ATPase activities. Its low Mg2+-ATPase activity is stimulated to a maximum rate of 20 s-1 by the addition of F-actin if its heavy chain has been phosphorylated by myosin I heavy chain kinase. The dependence of the Mg2+-ATPase activity of myosin IC on F-actin concentration is triphasic; and, at fixed concentrations of F-action, this activity increases cooperatively as the concentration of myosin IC is increased. These unusual kinetics were first demonstrated for myosins IA and IB and shown to be due to the presence of two actin-binding sites on each heavy chain which enable those myosins I to cross-link actin filaments. Myosin IC is also capable of cross-linking F-actin, which, together with the kinetics of its actin-activated Mg2+-ATPase activity, suggests that it, like myosins IA and IB, possesses two independent actin-binding domains.

Acanthamoeba↗
PubMed1989

The localization and sequence of the phosphorylation sites of Acanthamoeba myosins I. An improved method for locating the phosphorylated amino acid.

The actin-activated Mg2+-ATPase activities of Acanthamoeba myosins IA, IB, and IC are expressed only when a single site in their heavy chains is phosphorylated by a myosin I heavy chain-specific kinase. We show that phosphorylation occurs at Ser-315 in the myosin IB heavy chain, Ser-311 in myosin IC, and a threonine residue at a corresponding position in myosin IA whose amino acid sequence is as yet unknown. The most obvious feature common to the three substrates is a basic amino acid(s) 2 or 3 residues before the site of phosphorylation. The phosphorylation site is located between the ATP- and actin-binding sites, which corresponds to the middle of the 50-kDa domain of skeletal muscle myosin subfragment 1. The sequence similarity between the region surrounding the phosphorylation site of myosin I and subfragment 1 is much lower than the average sequence similarity between myosin I and subfragment 1. This is consistent with the hypothesis that the conformation of this region of myosin I differs from that of the corresponding region in skeletal muscle myosin and that phosphorylation converts the conformation of the actomyosin I complex into a conformation comparable to that present in actosubfragment 1 without phosphorylation. The protein sequences obtained in the course of this work led to the conclusion that the myosin I genes previously identified as myosin IB and IL (myosin-like) heavy chains actually are the myosin IC and IB heavy chains, respectively. Finally, we report a modification of the method for monitoring the appearance of 32Pi during sequencing of 32P-labeled peptides that results in almost complete recovery of the radioactivity, thus allowing unequivocal assignment of the position of the phosphorylated residue.

Acanthamoeba↗
PubMed1989

Myosin I is located at the leading edges of locomoting Dictyostelium amoebae.

Movement of a eukaryotic cell along a substrate occurs by extension of lamellipodia and pseudopodia at the anterior and retraction at the posterior of the cell. The molecular and structural mechanisms of these movements are uncertain. Dictyostelium discoideum contains two forms of myosin. Here we show by immunofluorescence microscopy that non-filamentous myosin I occurs at the leading edges of the lamellipodial projections of migrating Dictyostelium amoebae, which are devoid of myosin II, whereas filamentous myosin II is concentrated in the posterior of the cells. On the basis of these locations of the two forms of myosin and their known biochemical and biophysical properties, we suggest that actomyosin I may contribute to the forces that cause extension at the leading edge of a motile cell, while the contraction of actomyosin II at the rear squeezes the cell mass forward. Myosin I isozymes might have similar roles in metazoan cells, for example at the leading edges of neuronal growth cones, and in the extension of lamellipodia and pseudopodia of leukocytes, macrophages and fibroblasts.

Cell Movement↗
PubMed1989

The effect of actin and phosphorylation on the tryptic cleavage pattern of Acanthamoeba myosin IA.

The Mg2+-ATPase activity of Acanthamoeba myosin IA is activated by F-actin only when the myosin heavy chain is phosphorylated at a single residue. In order to gain insight into the conformational changes that may be responsible for the effects of F-actin and phosphorylation on myosin I ATPase, we have studied their effects on the proteolysis of the myosin IA heavy chain by trypsin. Trypsin initially cleaves the unphosphorylated, 140-kDa heavy chain of Acanthamoeba myosin IA at sites 38 and 112 kDa from its NH2 terminus and secondarily at sites 64 and 91 kDa from the NH2 terminus. F-actin has no effect on tryptic cleavage at the 91- and 112-kDa sites, but does protect the 38-kDa site and the 64-kDa site. Phosphorylation (which occurs very near the 38-kDa site) has no detectable effect on the tryptic cleavage pattern in the absence of F-actin or on F-actin protection of the 64-kDa site, but significantly enhances F-actin protection of the 38-kDa site. Protection of the 64-kDa site is probably due to direct steric blocking because F-actin binds to this region of the heavy chain. The protection of the 38-kDa site by F-actin may be the result of conformational changes in this region of the heavy chain induced by F-actin binding near the 64-kDa site and by phosphorylation. The conformational changes in the heavy chain of myosin IA that are detected by alterations in its susceptibility to proteolysis are likely to be related to the conformational changes that are involved in the phosphorylation-regulated actin-activated Mg2+-ATPase activities of Acanthamoeba myosins IA and IB.

Acanthamoeba↗
PubMed1989

Rearrangements of pterinosomes and cytoskeleton accompanying pigment dispersion in goldfish xanthophores.

The cytoskeleton of goldfish xanthophores contains an abundance of unique dense structures (400 nm in diameter) that are absent in goldfish nonpigment cells and are probably remnants of pterinosomes. No major difference in protein composition between xanthophores and nonpigment cells (without these structures) was found that could account for these structures. In xanthophores, these structures are foci of radiating filaments. The addition or withdrawal of ACTH causes a radical rearrangement of the xanthophore cytoskeleton accompanying redistribution of carotenoid droplets, namely, the virtual exclusion of these dense bodies with associated filaments from the space occupied by the carotenoid droplet aggregate vs. a relatively even cytoplasmic distribution of these structures when the carotenoid droplets are dispersed. These changes in cytoskeletal morphology are not accompanied by any major changes in the protein or phosphoprotein composition of the cytoskeleton.

Adrenocorticotropic Hormone↗