Natural inhibitors of carcinogenesis

Previous collaborative work by our group has led to the discovery of several plant isolates and derivatives with activities in in vivo models of cancer chemoprevention, including deguelin, resveratrol, bruceantin, brassinin, 4'-bromoflavone, and oxomate. Using a panel of in vitro bioassays to monitor chromatographic fractionation, a diverse group of plant secondary metabolites has been identified as potential cancer chemopreventive agents from mainly edible plants. Nearly 50 new compounds have been isolated as bioactive principles in one or more in vitro bioassays in work performed over the last five years. Included among these new active compounds are alkaloids, flavonoids, stilbenoids, and withanolides, as well as a novel stilbenolignan and the first representatives of the norwithanolides, which have a 27-carbon atom skeleton. In addition, over 100 active compounds of previously known structure have been obtained. Based on this large pool of potential cancer chemopreventive compounds, structure-activity relationships are discussed in terms of the quinone reductase induction ability of flavonoids and withanolides and the cyclooxygenase-1 and -2 inhibitory activities of flavanones, flavones and stilbenoids. Several of the bioactive compounds were found to be active when evaluated in a mouse mammary organ culture assay, when used as a secondary discriminator in our work. The compounds (2 S)-abyssinone II, (2 S)-2',4'-dihydroxy-2"-(1-hydroxy-1-methylethyl)dihydrofuro[2,3- h]-flavanone, 3'-[gamma-hydroxymethyl-( E)-gamma-methylallyl]-2,4,2',4'-tetrahydroxychalcone 11'- O-coumarate, isolicoflavonol, isoliquiritigenin, and ixocarpalactone A are regarded as promising leads as potential cancer chemopreventive agents.     

Differential activation of kinases in ex vivo and in vivo irradiated mice lymphocytes

Various kinases, such as tyrosine, protein kinase C (PKC) and MAP kinase, play important role in the cellular response to radiation, but little is known about the specific response in the whole animal. Most studies, except a few, are based on single cells. There is a paucity of data where signaling following whole body irradiation is concerned. In this study a comparison has been made between the activities of these kinases following ex vivo and in vivo irradiation. Tyrosine kinase activity showed no difference in the lymphocytes irradiated ex vivo or in vivo. A significant differential dose-dependent response could be observed in PKC activity. PKC was seen to be activated at the higher dose, i.e., 1 Gy in, in vivo irradiated lymphocytes, whereas in ex vivo irradiated lymphocytes, PKC was seen to be activated at the lower dose, i.e., 0.1 Gy. MAP kinase activity was seen to decrease with an increasing dose in ex vivo irradiated lymphocytes. In vivo MAP kinase activity was seen to increase as the dose increased, with maximum activation at 3 Gy. These kinases are being used to manipulate the tumor response to radiotherapy. Thus it is essential to study the behavior of the above kinases in the whole animal because the difference in response of a single cell to the whole animal may be different.     

Chemotherapy-induced and/or radiation therapy-induced oral mucositis--complicating the treatment of cancer

The term mucositis is coined to describe the adverse effects of radiation and chemotherapy treatments. Mucositis is one of the most common adverse reactions encountered in radiation therapy for head and neck cancers, as well as in chemotherapy, in particular with drugs affecting DNA synthesis (S-phase-specific agents such as fluorouracil, methotrexate, and cytarabine). Mucositis may limit the patient's ability to tolerate chemotherapy or radiation therapy, and nutritional status is compromised. It may drastically affect cancer treatment as well as the patient's quality of life. The incidence and severity of mucositis will vary from patient to patient. It will also vary from treatment to treatment. It is estimated that there is 40% incidence of mucositis in patients treated with standard chemotherapy and this will not only increase with the number of treatment cycles but also with previous episodes. Similarly, patients who undergo bone marrow transplantation and who receive high doses of chemotherapy have a 76% chance of getting mucositis. Patients receiving radiation, in particular to head and neck cancers, have a 30% to 60% chance. The exact pathophysiology of development is not known, but it is thought to be divided into direct and indirect mucositis. Chemotherapy and/or radiation therapy will interfere with the normal turnover of epithelial, cells leading to mucosal injury; subsequently, it can also occur due to indirect invasion of Gram-negative bacteria and fungal species because most of the cancer drugs will cause changes in blood counts. With the advancement in cytology, a more precise mechanism has been established. With this understanding, we can select and target particular mediators responsible for the mucositis. Risk factors such as age, nutritional status, type of malignancy, and oral care during treatment will play important roles in the development of mucositis. Many treatment options are available to prevent and treat this condition, but none of them can completely prevent or treat mucositis. More and more pathological methods are being developed to understand this condition so that better therapeutic regimens can be selected. Emphasis also should be made in assessing the patient's psychologic condition, particular depressive disorders. This is important because treatment with antidepressants will not only contribute in lifting depression but also reduces pain somatization. Although mucositis is rarely life-threatening, it will interfere with treatment of cancer to a great extent.     

Histone deacetylase inhibitor enhances the anti-leukemic activity of an established nucleoside analogue

Interest in histone deacetylase (HDAC) inhibitors as antineoplastic agents has been accelerating over the last several years and increasing number of compounds are in or entering clinical trials in humans. Recently, attention has been focused on the ability of HDAC inhibitors to induce perturbations in cell cycle regulatory proteins (e.g. p21CIP1), down regulation of survival signaling pathways (e.g. Raf/MAPkinase/ERK), and disruption of cellular redox state (e.g. reactive oxygen species, ROS). In April 2004 issue of Cancer Research, Maggio et al. report that pre-treatment of human leukemic cells with a histone deacetylase inhibitor, MS-275 significantly enhances the abrogative capacity of an established nucleoside analogue, fludarabine. The study indicates that apart from promoting acetylation of histones and regulation of genes involved in differentiation and apoptosis, MS-275 also induces multiple perturbations in signal transduction, survival and cell cycle regulatory pathways that increase the fludarabine-mediated cell death.     

An unusual case of neonatal anuria

Neonatal anuria is not an uncommon problem in neonates. Here, we report an unusual case of neonatal anuria due to renal tubular dysgenesis, secondary to the use of angiotensin converting enzyme inhibitor (ACEI) during pregnancy. ACEI remains one of the most commonly used antihypertensive drug at present. A greater awareness needs to be created in the medical fraternity especially among pediatricians, gynecologists and internists that ACE inhibitors should not be prescribed during any trimester of pregnancy.     

Diaper dermatitis — An overview

Diaper dermatitis, also know as nappy rash, is an inflammation of the skin covered by nappy. It probably results due to an interaction of multiple factors like increased wetness, elevated pH due to urine, fecal enzymes and microorganisms under the nappy. It manifests as an erythematous rash occurring on the convex surfaces of skin under the nappy. Rashes resembling nappy dermatitis can also be caused by some diseases which may have serious systemic manifestations. Therefore it is essential to differentiate and treat them. The principle of treatment of diaper dermatitis is to keep the skin in the nappy area as dry as possible with frequent nappy change. The superabsorbent disposable diapers are known to reduce the incidence of diaper dermatitis. Barrier creams to protect the infant’s skin and mild topical corticosteroids to reduce the inflammation are mainstays of therapy. The incidence and severity can be reduced by keeping the skin dry under the nappy and protected from irritants and infections.     

Multiple fetuses in fetu:imaging findings

Fetus in fetu is an extremely rare developmental abnormality secondary to abnormal embryogenesis in a diamniotic monochorionic pregnancy. It occurs when a vertebrate fetus is enclosed within the abdomen of a normally developing fetus. This report describes the prospective diagnosis of fetus in fetu by findings on a plain radiograph and CT scan. At surgery, two fetus in fetu were discovered.     

Novel applications of recombinant factor VIIa for the management of pediatric coagulopathic diseases

Recombinant factor VIIa (rFVIIa) was envisioned for the treatment of bleeding in hemophilia patients with inhibitors. In response to tissue factor expressed upon vessel wall injury, rFVIIa amplifies the thrombin burst primarily on membrane surfaces, including activated platelets. Because it is functional at a key point in the clotting cascade, rFVIIa shows promise as a therapeutic option for various bleeding situations. The prothrombin time (PT) is often used as a surrogate to monitor rFVIIa therapy. Using laboratory and clinical measures of outcome, the use of rVIIa as a therapeutic option in treating several different pediatric coagulopathic conditions is described.