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Biomedical subjects

J B Green

Publications and source records attributed to J B Green.

At least 19 recordsLinked to original sources

Responses of embryonic Xenopus cells to activin and FGF are separated by multiple dose thresholds and correspond to distinct axes of the mesoderm.

The potent mesoderm-inducing factors activin and FGF are present as maternally synthesized proteins in embryos of X. laevis. We show that activin can act on explanted blastomeres to induce at least five different cell states ranging from posterolateral mesoderm to dorsoanterior organizer mesoderm. Each state is induced in a narrow dose range bounded by sharp thresholds. By contrast, FGF induces only posterolateral markers and does so over relatively broad dose ranges. FGF can modulate the actions of activin, potentiating them and broadening the threshold-bounded dose windows. Our results indicate that orthogonal gradients of activin and FGF would be sufficient to specify the main elements of the body plan.

Activins

The middle latency auditory evoked potential may be abnormal in dementia.

The P1 potential (50 msec) of the middle latency auditory evoked potential was lacking in 12 of 31 (39%) patients with probable Alzheimer's disease and seven of 12 (58%) demented patients with Parkinson's disease. Component P1 was not present in one normal control subject and one nondemented Parkinson's disease patient. Clinical and experimental evidence suggests that abnormalities of P1 in dementia may be due to cholinergic dysfunction.

Adult

Expression of a Xenopus homolog of Brachyury (T) is an immediate-early response to mesoderm induction.

The Brachyury (T) gene is required for mesoderm formation in the mouse. In this paper we describe the cloning and expression of a Xenopus homolog of Brachyury, Xbra. As with Brachyury in the mouse, Xbra is expressed in presumptive mesodermal cells around the blastopore, and then in the notochord. We show that expression of Xbra occurs as a result of mesoderm induction in Xenopus, both in response to the natural signal and in response to the mesoderm-inducing factors activin A and basic FGF. Expression of Xbra in response to these factors is rapid, and will occur in dispersed cells and in the presence of a protein synthesis inhibitor, indicating that this is an "immediate-early" response to mesoderm induction.

Activins

A Southwest Oncology Group study on the use of a human tumor cloning assay for predicting response in patients with ovarian cancer.

A total of 211 patients with epithelial ovarian cancer (168 with tumors refractory to prior chemotherapy and 43 with no prior chemotherapy) from 33 different Southwest Oncology Group institutions had their tumors sampled and specimens shipped to two central laboratories for drug-sensitivity testing in a human tumor cloning assay. The 168 patients with a prior history of chemotherapy failure (median of four prior chemotherapeutic agents) were treated with the most effective agent(s) found in the cloning assay (23 patients), and those patients whose tumors did not form colonies in vitro or did not manifest any sensitivity to agent(s) were treated with a clinician's choice of agent(s) (101 patients). The remaining 44 of the 168 patients were not treated with chemotherapy because of deteriorating performance status or early death. The complete and partial response rate in patients treated according to assay results was 28% versus 11% for the patients treated according to clinician's choice (P = 0.03). There was no statistically significant difference in survival between the two options (6.25 versus 7 months, respectively). The 43 patients with no history of prior chemotherapy were all treated with standard combination chemotherapy, and their clinical response was compared with their in vitro sensitivity to the same agents. Overall there was a 100% true-positive rate and 100% true-negative rate for the seven evaluable patients. From these data the authors conclude that use of the human tumor cloning assay may increase the response rate but not the survival for selected patients with advanced chemotherapy-refractory ovarian cancer. The study is weakened, however, by the many steps of patient selection necessitated by inadequate tumor colony formation in vitro and the inability to treat all patients (because of early death or a rapid decline in performance status). The assay does appear to be worthy of additional study for predicting response to combination chemotherapy in patients without a prior history of chemotherapy. Finally the use of central chemosensitivity testing laboratories is feasible for testing in vitro predictive assays in a cooperative group setting.

Antineoplastic Combined Chemotherapy Protocols

Esorubicin in advanced endometrial cancer: an ineffective and potentially toxic therapy. A Southwest Oncology Group study.

The Southwest Oncology Group conducted a phase II study of esorubicin treatment in patients with advanced endometrial cancer who had received no prior chemotherapy. Twenty of 31 patients were fully evaluable for response and toxicity. There were no clinical responses to treatment and 60% (12/20) of the patients developed severe or life threatening leukopenia on therapy. One evaluable patient was removed from study after a cumulative dose of 150 mg/M2 due to a reduction in left ventricular ejection fraction on MUGA scan and another developed congestive heart failure several months after discontinuation of treatment. Esorubicin has significant toxicity and limited clinical activity in patients with advanced endometrial cancer.

Antibiotics, Antineoplastic

Growth factors as morphogens: do gradients and thresholds establish body plan?

Theories of morphogenesis have centred around gradients of morphogens interpreted by cells according to preset concentration thresholds. Growth factor proteins have been candidates for such morphogens, and experiments in the frog Xenopus, among other organisms, now show that embryonic cells are capable of interpreting growth factor concentrations according to the models. This opens up questions of whether such mechanisms are sufficient, and-if there are growth factor gradients-which factors are actually used and how.

Animals

Graded changes in dose of a Xenopus activin A homologue elicit stepwise transitions in embryonic cell fate.

The protein XTC-MIF, a Xenopus homologue of activin A and a potent mesoderm-inducing factor, can induce responding animal pole explants to form several different cell types in a dose-dependent manner, higher doses eliciting more dorso-anterior tissues. This graded response, characteristic of classically postulated morphogens, may underlie pattern formation, but the response of intact animal caps to XTC-MIF provides only a crude indication of trends. Here we report the effects of XTC-MIF on dispersed blastomeres rather than intact animal caps. Under these conditions, responding cells distinguish sharply between doses of pure XTC-MIF differing by less than 1.5-fold. Two different response thresholds have been found, defining three cell states. This suggests that XTC-MIF has an instructive effect. Notochord and muscle are both induced in the same narrow dose-range. Mixing treated with untreated cells does not seem to shift the dose thresholds, showing that at least some cells can stably record the received dose of inducing factor.

Actins

The synthesis and antiallergy activity of 1-(aryloxy)-4-(4-arylpiperazinyl)-2-butanol derivatives.

A series of 1-(aryloxy)-4-(4-arylpiperazinyl)-2-butanol derivatives were prepared and evaluated for antiallergy activity in the passive foot anaphylaxis (PFA) assay in rats. Twenty-seven derivatives had activity equal to or greater than the parent, alpha-(phenoxymethyl)-4-phenyl-1-piperazinepropanol. Six derivatives that possessed greater activity in the PFA than the parent compound were then tested in the guinea pig anaphylaxis (GPA) assay. Five of the derivatives were more potent than the parent (PD50 = 40 mg/kg) in the GPA with alpha-[(4-fluorophenoxy)methyl]-4-(4-fluorophenyl)-1-piperazinepropan ol (PD50 = 3 mg/kg) having the greatest potency.

Animals

Synthesis and antiallergy activity of N-[2-(dimethylamino)ethyl]-4-aryl-1-piperazinecarboxamide derivatives.

A series of N-[2-(dimethylamino)ethyl]-4-aryl-1-piperazinecarboxamides was synthesized and evaluated for antiallergy activity. Several derivatives had activity in the passive foot anaphylaxis (PFA) assay, an IgE-mediated model useful in the detection of compounds possessing antiallergic activity, but no derivative tested had activity at 10 mg/kg in the guinea pig anaphylaxis (GPA) assay. One analogue, N-[2-(dimethylamino)ethyl]-4-(4-fluorophenyl)-1-piperazinecarboxamide , had an IC50 = 310 nM for inhibition of tritiated mepyramine binding to H1 histaminic receptors isolated from guinea pig cerebral cortex.

Anaphylaxis

The biological effects of XTC-MIF: quantitative comparison with Xenopus bFGF.

Mesoderm in Xenopus and other amphibian embryos is induced by signals from the vegetal hemisphere acting on equatorial or animal hemisphere cells. These signals are diffusible and two classes of candidate signal molecule have been identified: the fibroblast growth factor (FGF) and transforming growth factor beta (TGF-beta) types. In this paper, we compare the effects of cloned Xenopus basic FGF (XbFGF) and electophoretically homogeneous XTC-MIF (a TGF-beta-like factor obtained from a Xenopus cell line) on animal pole explants. We find that they have a similar minimum active concentration (0.1-0.2 ng ml-1) but that, nonetheless, XTC-MIF is at least 40 times more active in inducing muscle. In general, we find that the two factors cause inductions of significantly different characters in terms of tissue type, morphology, gene expression and timing. At low concentrations (0.1-1.0 ng ml-1) both factors induce the differentiation of 'mesenchyme' and 'mesothelium' as well as blood-like cells. These latter cells do not, however, react with an antibody to Xenopus globin. This raised the possibility that the identification of red blood cells in other studies on mesoderm induction might have been mistaken, but combinations of animal pole regions with ventral vegetal pole regions confirmed that genuine erythrocytes are formed. The identity of the blood-like cells formed in response to the inducing factors remains unknown. At higher concentrations XTC-MIF induces neural tissue, notochord, pronephros and substantial and often segmented muscle. By contrast, XbFGF only induces significant amounts of muscle above 24 ng ml-1 and even then this is much less than that induced by XTC-MIF. For both factors an exposure of less than 30 min is effective. Competence of animal pole cells to respond to XbFGF is completely lost by the beginning of gastrulation (stage 10) while competence to XTC-MIF is detectable until somewhat later (stage 11). Since animal pole tissue is known to be able to respond to the natural inducer at least until stage 10, and perhaps until stage 10.5, this suggests that bFGF cannot be the sole inducer of mesoderm in vivo. Taken together, these results are consistent with XTC-MIF being a dorsoanterior inducer and XbFGF a ventroposterior inducer, suggesting that body pattern is established by the interaction of two types of inducing signal. This model is discussed in view of the qualitative and quantitative differences between the factors.

Animals

Carboplatin therapy in advanced endometrial cancer.

A phase II study of the effectiveness and toxicity of carboplatin in the treatment of metastatic or locally advanced endometrial cancer was carried out by the Southwest Oncology Group. Thirty-two patients were registered in the study and 23 were fully evaluable for response and toxicity. Carboplatin was administered in a dose of 400 mg/m2 at 28-day intervals without concomitant hydration if blood counts had recovered sufficiently. There were seven responses (two complete and five partial responses) among the 23 evaluable patients, for an overall response rate of 30%. Four (two of two complete responders and two of five partial responders) of the seven responding patients remain alive at 839+ to 987+ days from the start of therapy. The two complete responders and one of the partial responders had small-volume disease, which may have contributed to their prolonged survival. Myelosuppression was the most prominent toxicity encountered. Seventeen of 27 patients evaluable for toxicity developed platelet counts of less than 75 X 10(3)/muL during therapy, but no hemorrhagic complications were encountered. Leukopenia was less prominent, with only nine of 27 patients developing white blood cell counts of less than 3.0 X 10(3)/microL. No important nephrotoxicity or neurotoxicity was observed. Emesis occurred in ten of 27 patients but was not dose-limiting. No unexpected toxicities were encountered. Carboplatin appears to be an active agent in the treatment of endometrial carcinoma.

Aged