A Study of Rb Gene in Oral Squamous Cell Carcinoma

Thefirsttumorsuppressorgenemolecularlyisolatedistheretinoblastoma(Rb).ThedeletionofRbplaysanessentialroleinRetinoblastoma[1].TheosteosarcomaisalsoassociatedwiththedoublelossoftheRbgene[2].AbnormalitiesinthestructureandexpressionoftheRbgenehadbeenidentifiedinsmallcellcanceroflung[3]andbreastcancers[4].ThesefindingssuggestthattheRbgeneisapleiotropicsuppressorgene.Oralsquamouscellcarcinomaisthecommonmalignanttumor,whichaccountsfor80%ofthetotalofmalignanttumorsinoralmaxillofacialregion.Theprog…     

Hydrophobic Bombyx mori Silk Fibroin: Routes to Functionalization with Alkyl Chains

Bombyx mori silk fibroin (SF) is a very versatile biopolymer due to its biocompatibility and exceptional mechanical properties which make possible its use as a functional material in several applications. SF can be modified with a large variety of chemical approaches which endow the material with tailored chemical–physical properties. Here, a systematic investigation of different routes is reported to graft long alkyl chains on SF based on both liquid- and solid-phase, aiming to modulate its hydrophobic behavior. The liquid phase method involves direct activation of SF tyrosine residues via diazo coupling and cycloaddition reactions, generating hydrophobic materials insoluble in any common solvent. The solid phase approach consists of the chemical modification of drop-casted SF films by esterification of hydroxyl groups of serine, threonine, and tyrosine SF residues with acyl chlorides of fatty acids. For the solid-state functionalization, a new class of hydrophobic pendant groups is synthesized, based on triple esters of gallic acid anhydrides, that are reacted with the biopolymer to further enhance its resulting hydrophobic features.     

Rat Jejunal Permeability and Metabolism of μ-Selective Tetrapeptides in Gastrointestinal Fluids from Humans and Rats

Purpose. To study intestinal transport and metabolism of three new -selective tetrapeptide enkephalin analogues, LEF537, LEF553 and TAPP These peptides are stabilized against enzymatic hydrolysis by having a D-aminoacid in position 2 and a blocked COOH-terminal. Methods. We used a single-pass perfusion technique to study the transport of the peptides in rat jejunum. To reduce luminal and/or brush-border metabolism during the perfusion we used protease inhibitors (Pefabloc^® SC, bestatin and thiorphan). The rate of metabolism was studied by incubations in rat jejunal homogenate, rat jejunal fluid and human gastric and jejunal fluid with and without these inhibitors. Results. The jejunal permeabilities (P_eff) of the peptides were 0.43–0.78 10^–4 cm/s without inhibitors and 0.09–0.45 10^–4 cm/s in presence of the inhibitors. All three peptides were rather rapidly degraded by enzymes in rat jejunal homogenate with half-lives of between 11.9 ± 0.5 and 31.7 ± 1.5 min. The addition of inhibitors to the homogenate prolonged the half-lives substantially for LEF553 (167 ± 35 min) and TAPP (147 ± 2 min), but only slightly for LEF537 (16.4 ± 0.5 min). LEF553 and TAPP were both hydrolyzed in rat and human jejunal fluid, while LEF537 was metabolized less in these fluids. When LEF553 and TAPP were incubated with intestinal fluid in the presence of inhibitors, metabolism was almost completely inhibited. There was no metabolism for any of the peptides in human gastric juice. Conclusions. The replacement of the terminal free carboxylic group with an amide group did not increase the stability of the peptides in jejunal tissue enough to allow successful oral drug delivery.     

The pharmacokinetics of high-dose epirubicin and of the cardioprotector ADR-529 given together with cyclophosphamide, 5-fluorouracil,and tamoxifen in metastatic breast-cancer patients

A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-m silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i.v. administration of different doses of ADR-529 (600–1000 mg/m²) together with different doses of epirubicin (E, 60–100 mg/m²), fixed-dose cyclophosphamide (C, 600 mg/m²), fixed-dose 5-fluorouracil (F, 600 mg/m²), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m². We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity.     

Hypotheses: Melatonin/steroid combination contraceptives will prevent breast cancer

Summary The use of the conventional combination oral contraceptives (containing ethinyl-estradiol and a progestin) is associated with reduced risk of ovarian and endometrial cancer. However, prolonged use of these pills before first term pregnancy apparently increases the risk of pre menopausal breast cancer. We propose that the pineal gland hormone melatonin, combined with a progestin, as a new and novel oral contraceptive combination might prevent breast cancer in long term users. This hypothesis is based on the assumption that women have a propensity to develop breast cancer which correlates with number of ovulatory cycles over their lifetime. In evolution, the phylogenetic point at which women became sensitive to breast cancer evolved at a transfer point of the mechanism of ovulation from seasonal ovulation, which is still common in many mammalian species, to the current human pattern of continuous ovulatory cycles. We suggest that melatonin/ovariansteroid contraceptive will restore the lost mechanism of endogenous anovulation, and thus, by preventing continuous epithelial breast cell proliferation, will reduce the risk of breast cancer in long-term users.     

Treatment of Vitamin B12 Deficiency after Gastric Surgery for Severe Obesity

Background: Vitamin B₁₂ deficiency after gastric surgery for obesity is due to a failure of separation of vitamin B₁₂ from protein foodstuffs and to a failure of absorption of crystalline vitamin B₁₂ in the presence of intrinsic factor. The purpose of this study was to determine which of four oral doses of crystalline vitamin B₁₂ was most effective in treating vitamin B₁₂ deficiency in 102 patients. Methods and Results: At time of entry into the study, the patients had a serum vitamin B₁₂ < 100 pmol L ⁻¹, were 29.9 ± 21.7 months post-op, were 37 ± 8 years old and had a body mass index of 30 ± 6 kg m⁻². Eight (8%) had had a vertical banded gastroplasty and 94 (92%) a gastric bypass. For the first 3 months all patients received 350 μg per day of crystalline vitamin B₁₂ and all increased their serum vitamin B₁₂ levels to over 100 pmol L⁻¹. The patients were then assigned to receive for a further 3 month period one of four oral doses of crystalline vitamin B₁₂-100 μg, 250 μg, 350 μg and 600 μg. Serum vitamin B₁₂ levels were greater than 150 pmol L⁻¹ after 6 months in 83.3% of patients who received 100 μg; 92.3% of patients who received 250 μg; 94.7% after 350 μg and 95.2% after 600 μg (p%0.525). Conclusion: At least 350 μg per day is the appropriate oral dose of crystalline vitamin B₁₂ after gastric surgery for obesity to correct low serum vitamin B₁₂ levels in 95% of patients.     

The recent saga of cardiovascular disease and safety of oral contraceptives

This review presents detailed risk estimates from relevant epidemiological and other studies on the comparative safety of second and third generation oral contraceptives (OC). Written with the intention of presenting a repository of the available information, it also discourses briefly into the symptomatology and diagnosis of diseases associated with OC use and presents some of the critical comments made about various epidemiological analyses. A general critique including observations and opinions of various investigators completes the review. We stress that our own opinions on the various studies, or an attempt to adjudge the relative safety of second and third generation OC, are not given since they form the substance of our second paper which completes this symposium.     

Safety of modern oral contraception: the options for women: lessons to be learned

The relatively short history of hormonal contraception has been marked by a series of 'pill scares', all of which--after creating panic among users--were proven to be unfounded in terms of public health impact. The latest pill scare, provoked by regulatory action in the United Kingdom and the Federal Republic of Germany in response to the publication of a series of articles indicating a doubling of risk of deep venous thrombosis in users of oral contraceptives containing third-generation progestins, seems finally settled: both the British and the German Drug Regulatory Authorities have now reverted their verdict. The damage unfortunately stays: hundreds of thousands of women have been compelled to abandon the pill of their choice, often deciding to drop contraception altogether, thereby exposing themselves to unwanted pregnancy and--in a number of cases--to pregnancy termination. This latest episode should be turned into something positive: we need to learn that, in the case of drugs in widespread use, before restrictive action is taken--and except for very rare and specific instances--the scientific community must carry out an exhaustive debate on the reality and importance of the observed effects. Although the public should, in each instance, be properly informed, it is only after this process has been completed that restrictive action should be taken. It is hoped that, after this last episode, all concerned have learned this simple principle and will accept being guided by it from now on.     

高压下滴流床反应器动持液量的测定

在常压－２．０ＭＰａ的系统压力下测定了滴流床中气－液两相并流下流动的动持液量,了气－液流率,液相粘度,填料大小,压力以及床层高度对动持液量的影响。实验结果表明增中液体流率动持流量增加,气体流率增加时,结果相反粘度的增加对动持液量的影响不大,动持液量随填料空隙率的增大而变小。     

Long-term enhancement of REM sleep by the pituitary adenylyl cyclase-activating polypeptide (PACAP) in the pontine reticular formation of the rat

In rats, rapid eye movement (REM) sleep can be elicited by microinjection of vasoactive intestinal polypeptide (VIP) into the oral pontine reticular nucleus (PnO). In the present study, we investigated whether this area could also be a REM-promoting target for a peptide closely related to VIP: the pituitary adenylyl cyclase-activating polypeptide (PACAP). When administered into the posterior part of the PnO, but not in nearby areas, of freely moving chronically implanted rats, PACAP-27 and PACAP-38 (0.3 and 3 pmol) induced a marked enhancement (60-85% over baseline) of REM sleep for 8 h that could be prevented by prior infusion of the antagonist PACAP-(6-27) (3 pmol) into the same site. Moreover, injections of PACAP into the centre of the posterior PnO resulted in REM sleep enhancement which could last for up to 11 consecutive days. Quantitative autoradiography using [125I]PACAP-27 revealed the presence in the PnO of specific binding sites with high affinity for PACAP-27 and PACAP-38 (IC50 = 2.4 and 3.2 nM, respectively), but very low affinity for VIP (IC50 > 1 microM). These data suggest that PACAP within the PnO may play a key role in REM sleep regulation, and provide evidence for long-term (several days) mechanisms involved in such a control. PAC1 receptors which have a much higher affinity for PACAP than for VIP might mediate this long-term action of PACAP on REM sleep.