Mauritian Endemic Medicinal Plant Extracts Induce G2/M Phase Cell Cycle Arrest and Growth Inhibition of Oesophageal Squamous Cell Carcinoma in Vitro.

Terrestrial plants have contributed massively to the development of modern oncologic drugs. Despite the wide acceptance of Mauritian endemic flowering plants in traditional medicine, scientific evidence of their chemotherapeutic potential is lacking. This study aimed to evaluate the in vitro tumor cytotoxicity of leaf extracts from five Mauritian endemic medicinal plants, namely Acalypha integrifolia Willd (Euphorbiaceae), Labourdonnaisia glauca Bojer (Sapotaceae), Dombeya acutangula Cav. subsp. rosea Friedmann (Malvaceae), Gaertnera psychotrioides (DC.) Baker (Rubiaceae), and Eugenia tinifolia Lam (Myrtaceae). The cytotoxicities of the extracts were determined against six human cancer cell lines, including cervical adenocarcinoma, colorectal carcinoma, oesophageal adenocarcinoma, and oesophageal squamous cell carcinoma. The potent extracts were further investigated using cell cycle analysis and reverse phase protein array (RPPA) analysis. The antioxidant properties and polyphenolic profile of the potent extracts were also evaluated. Gas chromatography mass spectrometry (GC-MS) analyses revealed the presence of (+)-catechin and gallocatechin in E. tinifolia and L. glauca, while gallic acid was detected in A. integrifolia. L. glauca, A. integrifolia, and E. tinifolia were highly selective towards human oesophageal squamous cell carcinoma (KYSE-30) cells. L. glauca and E. tinifolia arrested KYSE- 30 cells in the G2/M phase, in a concentration-dependent manner. RPPA analysis indicated that the extracts may partly exert their tumor growth-inhibitory activity by upregulating the intracellular level of 5'AMP-activated kinase (AMPK). The findings highlight the potent antiproliferative activity of three Mauritian endemic leaf extracts against oesophageal squamous cell carcinoma and calls for further investigation into their chemotherapeutic application.

Postimpact earliest Paleogene warming shown by fish debris oxygen isotopes (El Kef, Tunisia).

Greenhouse warming is a predicted consequence of the Chicxulub impact, but supporting data are sparse. This shortcoming compromises understanding of the impact's effects, and it has persisted due to an absence of sections that both contain suitable material for traditional carbonate- or organic-based paleothermometry and are complete and expanded enough to resolve changes on short time scales. We address the problem by analyzing the oxygen isotopic composition of fish debris, phosphatic microfossils that are relatively resistant to diagenetic alteration, from the Global Stratotype Section and Point for the Cretaceous/Paleogene boundary at El Kef, Tunisia. We report an ~1 per mil decrease in oxygen isotopic values (~5°C warming) beginning at the boundary and spanning ~300 centimeters of section (~100,000 years). The pattern found matches expectations for impact-initiated greenhouse warming.

Targeting the EGF receptor in ovarian cancer with the tyrosine kinase inhibitor ZD 1839 ("Iressa").

The modulating effects of the orally active epidermal growth factor receptor-specific tyrosine kinase inhibitor ZD 1839 ("Iressa") on cell growth and signalling were evaluated in four ovarian cancer cell lines (PE01, PE04, SKOV-3, OVCAR-5) that express the epidermal growth factor receptor, and in A2780, which is epidermal growth factor receptor-negative. Transforming growth factor-alpha stimulated growth was completely inhibited by concentrations of ZD 1839 > or =0.3 microM in the epidermal growth factor receptor-expressing cell lines, as were transforming growth factor-alpha stimulated phosphorylation of the epidermal growth factor receptor and downstream components of the MAP kinase and PI-3 kinase signalling cascades. Growth inhibition in the absence of added transforming growth factor-alpha was also observed which could be consistent with suppression of action of autocrine epidermal growth factor receptor-activating ligands by ZD 1839. In support of this, transforming growth factor-alpha, EGF and amphiregulin mRNAs were detected by RT-PCR in the epidermal growth factor receptor-expressing cell lines. ZD 1839 inhibited growth of the PE04 ovarian cancer xenograft at 200 mg kg(-1)day(-1). These data lend further support to the view that targeting the epidermal growth factor receptor in ovarian cancer could have therapeutic benefit.

Expression of erbB-4/HER-4 growth factor receptor isoforms in ovarian cancer.

Immunohistochemical expression of erbB4 protein was identified in 93% (49 of 53) of ovarian cancers using the HFR-1 antibody (targeted to the cytoplasmic domain of the erbB4 receptor) and in 89% (47 of 53) of ovarian cancers using the H4.77.16 antibody (targeted to the extracellular domain). Tumors of serous histology were more likely to express a higher level of erbB4 than endometrioid tumors, and for stage III serous tumors, long-term survival was associated with moderate to high coexpression of erbB4 and erbB2. Within ovarian cancer cell lines, high erbB4 expression was associated with cisplatin resistance. Using reverse transcription-PCR, the presence of multiple isoforms of erbB4 mRNA was identified in both ovarian primary tumors and cell lines. Splice variants in the juxtamembrane (JM-a and JM-d) and cytoplasmic (CT-a and CT-b) regions were identified in mRNA of both cell lines and primary tumors. The use of an anti-erbB4 blocking antibody suggested that erbB4 was not the mediator of the growth stimulatory effects of neuregulin in ovarian cancer cells and indeed could potentially antagonize this effect.

Inhibition of transforming growth factor alpha (TGF-alpha)-mediated growth effects in ovarian cancer cell lines by a tyrosine kinase inhibitor ZM 252868.

The modulating effects of the epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor ZM 252868 on cell growth and signalling have been evaluated in four ovarian carcinoma cell lines PE01, PE04, SKOV-3 and PE01CDDP. Transforming growth factor alpha (TGF-alpha)-stimulated growth was completely inhibited by concentrations > or =0.3 microM in the PE01 and PE04 cell lines and by > or =0.1 microM in SKOV-3 cells. TGF-alpha inhibition of PE01CDDP growth was reversed by concentrations > or =0.1 microM ZM 252868. TGF-alpha-stimulated tyrosine phosphorylation of both the EGF receptor and c-erbB2 receptor in all four cell lines. The inhibitor ZM 252868, at concentrations > or =0.3 microM, completely inhibited TGF-alpha-stimulated tyrosine phosphorylation of the EGF receptor and reduced phosphorylation of the c-erbB2 protein. EGF-activated EGF receptor tyrosine kinase activity was completely inhibited by 3 microM ZM 252868 in PE01, SKOV-3 and PE01CDDP cells. These data indicate that the EGF receptor-targeted TK inhibitor ZM 252868 can inhibit growth of ovarian carcinoma cells in vitro consistent with inhibition of tyrosine phosphorylation at the EGF receptor.

Estrogen regulation of transforming growth factor-alpha in ovarian cancer.

Transforming growth factor alpha (TGFalpha) may be induced by estrogen in estrogen responsive systems and can contribute to the growth-modulatory effects of this hormone. To test whether TGFalpha contributes to estrogen-regulated growth in ovarian cancers, we have compared the effects of 17beta-estradiol (E2) and TGFalpha in a range of ovarian carcinoma cell lines. Addition of E2 to the estrogen receptor (ER)-positive cell lines (PE01, PE04 and PE01CDDP) produced a 2-4 fold increase in TGFalpha protein concentrations in media conditioned by the cells. Both E2 and TGFalpha stimulated the growth of the PE01 and PE04 lines and inhibited the growth of the PE01CDDP line. Furthermore, the E2-mediated growth effects could be reversed by an epidermal growth factor (EGF) receptor-targeted antibody. E2 also down-regulated EGF receptor expression in ER-positive cell lines. In a series of primary ovarian tumors, higher concentrations of ER were associated with an increased percentage of tumors expressing TGFalpha mRNA and a decreased percentage expressing EGF receptor protein. All these data are consistent with E2 increasing production of TGFalpha in ER-positive ovarian cancer and this in turn acting through the EGF receptor to modulate growth in an autocrine manner.

The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer.

The expression of mRNA for the epidermal growth factor (EGF) receptor, EGF and transforming growth factor alpha (TGF-alpha) was determined in 76 malignant, six borderline and 15 benign primary ovarian tumours using the reverse transcriptase-polymerase chain reaction and related to clinical and pathological parameters. Of the malignant tumours, 70% (53/76) expressed EGF receptor mRNA, 31% (23/75) expressed EGF mRNA and 35% (26/75) expressed TGF-alpha mRNA. For the borderline tumours, four of six (67%) expressed EGF receptor mRNA, 1/6 (17%) expressed TGF-alpha mRNA and none expressed EGF mRNA. Finally, 33% (5/15) of the benign tumours expressed EGF receptor mRNA, whereas 40% (6/15) expressed EGF mRNA and 7% (1/15) expressed TGF-alpha mRNA. The presence of the EGF receptor in malignant tumours was associated with that of TGF-alpha (P = 0.0015) but not with EGF (P = 1.00), whereas there was no relationship between the presence of EGF and TGF-alpha (P = 1.00). EGF receptor mRNA expression was significantly and positively associated with serous histology (P = 0.006) but not with stage or grade. Neither EGF nor TGF-alpha showed any link with histological subtype or stage. The survival of patients with malignant tumours possessing EGF receptor mRNA was significantly reduced compared with that of patients whose tumours were negative (P = 0.030 for all malignant tumours; P = 0.007 for malignant epithelial tumours only). In contrast, neither the expression of TGF-alpha nor EGF was related to survival. These data suggest that the presence of EGF receptor mRNA is associated with poor prognosis in primary ovarian cancer.

Effect of human recombinant interferon-alpha on the activity of cis-diamminedichloroplatinum(II) in human non-small cell lung cancer xenografts.

Interferons (IFNs) augment the effect of some antitumor agents, including cis-diamminedichloroplatinum(II) (cDDP), in experimental systems. The effect of human recombinant interferon-alpha 2b (rIFN alpha) on the cDDP-dependent growth delay of a human non-small cell lung cancer established as a xenograft in nude mice (NX002) has been investigated. IFN (10(5) IU/mouse, s.c.) as a single agent had no effect on the growth of the xenograft. cDDP (4.2 mg/kg, i.p.) caused a specific growth delay of 0.42, and this delay was significantly enhanced (to 1.08) by concomitant dosing with the otherwise inactive IFN. Possible mechanisms for this supra-additive relationship between IFN and cDDP have been investigated: increased intratumoral accumulation of platinum was seen at late time points (maximally at 36 hr) during the pharmacokinetic beta-phase of cDDP elimination from the plasma of the nude mice. Tumor:plasma platinum concentration ratios at 36-48 hr indicated significantly increased accumulation of platinum in tumors from IFN-treated mice compared to controls (p < 0.05). Scheduling experiments suggest that this IFN-mediated effect can persist for 4 hr. These differences may account for the enhanced antitumor activity of cDDP when coadministered with IFN.

Comparison of desflurane and fentanyl-based anaesthetic techniques for coronary artery bypass surgery.

We have compared, in 51 ASA II and III patients undergoing coronary artery bypass surgery, an inhaled anaesthetic technique based on desflurane, supplemented with low-dose (10 micrograms kg-1) fentanyl, with an i.v. technique using high-dose (50 micrograms kg-1) fentanyl with midazolam for induction. Satisfactory records were available for analysis in 50 patients. There were no differences between groups in operating time, cardiopulmonary bypass time, aortic cross-clamp time or duration of stay in the intensive care unit after surgery. Desflurane maintained mean systemic arterial pressure at the awake level during incision and sternotomy (end-tidal concentrations 3.7% and 4.6%, respectively) but decreased it significantly at all other times. With fentanyl, mean systemic arterial pressure was unchanged from awake values during induction and laryngoscopy but increased significantly at incision and sternotomy by 8% and 12.8%, respectively, to exceed the desflurane group at sternotomy by 20 mm Hg (P < 0.001). With desflurane, heart rate remained at 60-67 beat min-1 at all times before cardiopulmonary bypass. This was always lower than the fentanyl group by 5-15 beat min-1 and the difference was significant at induction, during skin preparation and before aortic cannulation. In comparison with the desflurane group, cardiac index was significantly greater in the fentanyl group at induction, laryngoscopy and during skin preparation, but was significantly less before aortic cannulation. The need for vasodilator intervention was significantly more common in the fentanyl group before, during and after cardiopulmonary bypass and for beta adrenoceptor block before cardiopulmonary bypass.(ABSTRACT TRUNCATED AT 250 WORDS)

Biphasic regulation of adenylate cyclase by cholera toxin in neuroblastoma x glioma hybrid cells is due to the activation and subsequent loss of the alpha subunit of the stimulatory GTP binding protein (GS).

Exposure of neuroblastoma x glioma hybrid (NG108-15) cells to low concentrations of cholera toxin produced a stimulation of both basal and forskolin-amplified adenylate cyclase activity in membranes prepared from these cells. Higher concentrations of cholera-toxin reversed this effect. Mn2+ activation of adenylate cyclase indicated that this effect was not due to a modification of the intrinsic activity of this enzyme. Cholera toxin was demonstrated to produce a concentration and time-dependent loss of GS alpha from membranes of these cells. Loss of GS alpha from membranes of these cells was preceded by its ADP-ribosylation. The effects of cholera toxin were specific for GS alpha, as no alterations in levels of the pertussis toxin-sensitive G-proteins Gi2, Gi3 and Go, were noted in parallel. Equally, no alteration in levels of G-protein beta-subunit were produced by the cholera toxin treatment. These experiments demonstrate that cholera toxin-catalysed ADP-ribosylation does not simply maintain an activated population of GS at the plasma membrane and that alterations in levels of GS at the plasma membrane can modify adenylate cyclase activity.

Airway management in the transfer of the unconscious patient.

Thirty-one consecutive unconscious patients admitted to a specialist neurosurgical centre for computerised axial tomography and further management were reviewed with emphasis upon initial airway management. Fourteen patients had inadequate airway control on arrival and needed immediate intubation. Six of this group developed pulmonary complications. The implications of this are discussed and certain recommendations made.

Australia (hepatitis-associated) antigen in patients attending a venereal disease clinic.

A total of 1,650 patients attending the venereal disease department at St. Mary's Hospital, London, have been tested for Australia antigen. Twenty-three positive results were obtained, or 1.39%, which is more than 10 times the rate noted by others in blood donor populations in the U.K. and U.S.A. The positive rates among female patients and European male heterosexual patients were 0.36% and 0.19% respectively. High rates were obtained for homosexual patients (3.8%) and non-European heterosexual patients (3.1%). The reasons for the higher rates found in these groups merit further study.