Non-migratory tumorigenic intrinsic cancer stem cells ensure breast cancer metastasis by generation of CXCR4(+) migrating cancer stem cells.

Although the role of metastatic cancer stem cells (mCSCs) in tumor progression has been well documented, our study reveals a hitherto unidentified role of tumorigenic intrinsic CSCs (iCSCs) in breast cancer metastasis. We show that unlike highly migratory mCSCs residing in the breast tumor disseminating/peripheral regions, iCSCs populate the inner mass of the tumor and are non-migratory. However iCSCs, via paracrine signaling, induce conversion of non-stem cancer cells to CSCs that (i) are identical to the previously reported mCSCs, and (ii) in contrast to iCSCs, express chemokine receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), which is crucial for their metastatic potential. These mCSCs also demonstrate high in vivo tumorigenicity. Physical non-participation of iCSCs in metastasis is further validated in vivo, where only mCSCs are found to exist in the metastatic sites, lymph nodes and bone marrow, whereas the primary tumor retains both iCSCs and mCSCs. However, iCSCs ensure metastasis since their presence is crucial for deliverance of highly metastatic CXCR4(+) mCSCs to the migrating fraction of cells. Cumulatively, these results unveil a novel role of iCSCs in breast cancer metastasis as parental regulators of CXCR4(+) mCSCs, and highlight the therapeutic requisite of targeting iCSCs, but not CXCR4(+) mCSCs, to restrain breast cancer metastasis from the root by inhibiting the generation of mCSCs from iCSCs. Considering the pivotal role of iCSCs in tumor metastasis, the possibility of metastasis to be a 'stem cell phenomena' is suggested.

Dis-organizing centrosomal clusters: specific cancer therapy for a generic spread?

Cancer is a leading cause of mortality and the annual incidence of new cancer cases is rising worldwide. Due to the frequent development of resistance and the side effects of established anti-cancer drugs, the quest for new drugs with improved therapeutic features goes on. In contrast to cytotoxic chemotherapy of the past, the concept of targeted chemotherapy attempts to increase specificity of therapy by attacking tumor-related mechanisms. A novel emerging treatment concept represents the inhibition of centrosomal clustering. The centrosome regulates mitotic spindle formation assuring uniform separation of chromosomes to daughter cells. Many tumors contain supernumerary centrosomes, which contribute to aneuploidy induction via multipolar mitotic spindle formation. As spindle multipolarity leads to cell death, tumor cells developed centrosomal clustering mechanism to prevent multipolar spindle formation by coalescence of multiple centrosomes into two functional spindle poles. Inhibition of centrosome clustering represents a novel strategy for drug development and leads to the formation of multipolar spindles and subsequent cell death. In the present review, we report advances in understanding the biology of centrosomal clustering as well as enlist compounds capable of inducing the formation of multipolar spindles such as indolquinolizines, integrin-linked kinase inhibitors (QLT-0267), noscapinoids (EM011), phthalamide derivatives (TC11), griseofulvin, phenanthridines (PJ-34), CCC1-01, CW069 GF-15, colcemid, nocodazole, paclitaxel, and vinblastine. We also present in silico result of compounds that bind to γ-tubulin under the ambit of centrosomal clustering inhibition. We observed maximum binding efficacy in GF-15, CW069, paclitaxel and larotaxel with GF-15 exhibiting least energy of -8.4 Kcal/mol and 0.7 µM Pki value.

IGFBP-5 enhances epithelial cell adhesion and protects epithelial cells from TGFß1-induced mesenchymal invasion.

TGFß1 is a major fibrotic factor and its actions involve induction of epithelial cell death, together with the stimulation and transdifferentiation of fibroblasts into collagen- and fibronectin-secreting myofibroblasts. These actions of TGFß1 are also consistent with a pro-metastatic role, by aiding epithelial cell escape through mesenchymal tissues. Recently IGFBP-5 has been described as a pro-fibrotic (pro-metastatic?) agent and the aim of this study was to compare and contrast the actions of IGFBP-5 with TGFß1. We used NMuMG cells and cloned stable epithelial and mesenchymal lines from the parent cells. TGFß1 induced apoptosis and/or EMT in the epithelial cells, whereas it enhanced mesenchymal cell survival and migration. IGFBP-5, in contrast, enhanced both cell-cell and cell-ECM adhesion and also improved wound closure in epithelial cells whereas, in mesenchymal cells, IGFBP-5 decreased adhesion and migration. Furthermore, IGFBP-5 was able to antagonise the actions of TGFß1. In a co-culture model simulating epithelial-mesenchymal boundaries, IGFBP-5 was able to antagonise the disruptive transgressions induced by TGFß1. Overall, these findings suggest that IGFBP-5 is important in maintaining epithelial-mesenchymal boundaries and thus may limit metastasis and fibrosis by inducing an orderly repair mechanism, very distinct from the fibrotic disruption induced by TGFß1. A role for IGFBP-5 in the inhibition of metastasis is supported by immunohistochemical studies of breast cancer microarrays, where we show that elevated IGFBP-5 expression is associated with increased disease-free survival.

Alteration of brain monoamines & EEG wave pattern in rat model of Alzheimer's disease & protection by Moringa oleifera.

BACKGROUND & OBJECTIVES: The monoaminergic systems which exert a modulatory role in memory processing, are disturbed in Alzheimer's disease (AD) and Moringa oleifera (MO) has been shown to exert its effect in CNS by altering the brain monoamines. The present study aims to see whether chronic oral treatment of ethanolic extract of MO leaves can alter the brain monoamines (norepinephrine, dopamine and serotonin) in distinct areas of brain in rat model of AD caused by intracerebroverticle (ICV) infusion of colchicine and hence can provide protection against monoaminergic deficits associated with AD. METHODS: Rats were given ICV infusion of colchicine (15 microg/5microl) and MO leaf alcoholic extract was given in various doses. The effective dose was standardized by radial arm maze (RAM) training. From the selected dose of 250 mg/kg body weight, the biochemical estimations and EEG studies were performed. RESULTS: Stereotaxic ICV infusion of colchicine significantly impaired the RAM performance together with decrease in norepinephrine (NE) level in cerebral cortex (CC), hippocampus (HC) and caudate nucleus (CN). Dopamine (DA) and serotonin (5-HT) levels were decreased in CC, HC and CN. The EEG studies showed a decrease in beta and alpha waves and increase in biphasic spike wave pattern in experimental Alzheimer rat model. Treatment with MO extract markedly increased the number of correct choices in a RAM task with variable alteration of brain monoamines. The EEG studies showed an increase in beta waves and a decrease in spike wave discharges. INTERPRETATION & CONCLUSION: Our results showed that brain monoamines were altered discreetly in different brain areas after colchicine infusion in brain. After treatment with MO, leaf extract the monoamine levels of brain regions were restored to near control levels. Our findings indicated that MO might have a role in providing protection against AD in rat model by altering brain menoamine levels and electrical activity.

Inhibitory role of Acorus calamus in ferric chloride-induced epileptogenesis in rat.

The roots and rhizomes of Acorus calamus (Family: Araceae) have been used in the ancient systems of medicine for the treatment of various neurological disorders. Of the various methods used for inducing experimental epileptic models, the intracortical administration of ferric chloride (FeCl(3)) into sensorimotor cortex induces recurrent seizures and epileptic discharge similar to human post-traumatic epilepsy through the generation of free radicals. The present study focuses on the effect of Acorus calamus on the behavioral, electroencephalographic, and antioxidant changes in FeCl(3)-induced rat epileptogenesis. Topical administration of FeCl(3) (5 microL; 100 mM) into the sensorimotor cortex of rats showed an increase in the wet dog shake behavior, spike wave discharges together with an significant increase in antioxidant enzyme activity, such as superoxide dismutase and catalase, resulting in an increase in the level of lipid peroxidation in cerebral cortex. Pretreatment with Acorus calamus (200 mg/kg b.w., p.o. for 14 days) and also diazepam (DZ, 20 mg/kg b.w., i.p.) decreased the WDS behavior, spike wave discharges with single isolated positive waves, and a significant decrease in activity of superoxide dismutase and level of lipid peroxidation was observed in cerebral cortex with respect to those observed in FeCl(3)-induced epileptic group. Data presented in this study clearly show that Acorus calamus possesses the ability for preventing the development of FeCl(3)-induced epileptogenesis by modulating antioxidant enzymes, which in turn exhibit the potentiality of Acorus calamus to be developed as an effective anti-epileptic drug.

Multiple brain haemorrhages in falciparum malaria.

A young male with multiple intracerebral haemorrhages with presence of P. falciparum in peripheral smear and normal coagulation profile without features of encephalopathy managed successfully with antimalarial has been reported. The rarity of the clinical presentation has been highlighted and its possible pathogenesis discussed.

Study of primary amenorrhoea with special reference to cytogenetic evaluation.

An attempt has been made to find out the proportion of genetic causes in cases of primary amenorrhoea and to analyse different chromosomal pattern. Cases were analysed according to clinical profile, X-ray, laparoscopy/pneumography, hormone profile, USG, Gonadal Biopsy and Cytogenetic study including Sex Chromatin (Barr body) and Karyotyping. Among the 72 cases studied, the aetiological factors were Mullerian duct abnormalities in 27 cases (37.5%) Gonadal agenesis in 13 cases (18.05%). Turner stigmata in 18 cases (25%), Y cell line in 6 cases (8.33%). Delayed menarche in 4 cases (5.55%), systemic disease like Tuberculosis and Idiopathic 2 cases (2.77%) each. Chromosomal aberration was seen in 24 cases (33.33%) and it comes second most common cause of primary amenorrhoea after mullerian duct abnormalities.

Fragile X syndrome a case report of a family.

Fragile X syndrome is the most common of the inherited disorders causing mental retardation. This disorder results from an abnormal expansion in (CGG)n in repeat found in the coding sequence of the FMRI gene, located at Xq 27.3. Previously it was detected by Karyotyping. With the advent of Molecular Biology PCR, has become the best method in the diagnosis of this disorder. This is a case report of a family with this disorder detected by PCR.

Proton transfer reaction of a new orthohydroxy Schiff base in protic solvents at room temperature.

Ground and excited state inter- and intramolecular proton transfer reactions of a new o-hydroxy Schiff base, 7-ethylsalicylidenebenzylamine (ESBA) have been investigated by means of absorption, emission and nanosecond spectroscopy in different protic solvents at room temperature and 77 K. The excited state intramolecular proton transfer (ESIPT) is evidenced by a large Stokes shifted emission (approximately 11000 cm(-1)) at a selected excited energy in alcoholic solvents. Spectral characteristics obtained reveal that ESBA exists in more than one structural form in most of the protic solvents, both in the ground and excited states. From the nanosecond measurements and quantum yield of fluorescence we have estimated the decay rate constants, which are mainly represented by nonradiative decay rates. At 77 K the fluorescence spectra are found to be contaminated with phosphorescence spectra in glycerol and ethylene glycol. It is shown that the fluorescence intensity and nature of the species present are dependent upon the excitation energy.

Effect of cerebellar modulation on rat gastric secretion and enterochromaffin-like cell.

Effect of cerebellar lesion and vestibular stimulation (VS) on the activity and alternation of ECL-cells along with changes in gastric volume and acid secretion was studied. The results suggest that cerebellar lesion caused increased gastric volume and acid secretion and tended to decrease ECL-cell density. On the other hand VS of nodular lesioned rats resulted in decrease of above parameter which became marked only after 21 days of nodular lesion.

Changes of gastroduodenal peroxidase activity of rats by cerebellar modulation.

The effect of vestibulo-cerebellar lesion and its stimulation by rotation on gastric and duodenal peroxidase activity of rats was studied. Vestibulocerebellar lesion by kainic acid produced gastroduodenal ulceration and peroxidase activity of these tissues were decreased. Mucosal thickness of gastric and duodenal tissue were also decreased. It was observed that when vestibulo-cerebellar lesioned rats were subjected to vestibular stimulation, the peroxidase activity was increased together with increased mucosal thickness of gastric and duodenal tissue. At the same time, it was noted that the severity of ulceration was decreased. We conclude that the study of peroxidase activity is a sensitive and potentially useful estimate of gastric and duodenal injury produced by cerebellar lesion that can be valuable in assessing ulcerogenesis and healing.

Alteration in alkaline phosphatase activity of duodenal tissue following vestibulo-cerebellar modulation.

Effect of electrolytic lesion in vestibulo-cerebellar area of male Wistar rats was investigated on duodenal alkaline phosphatase (AP) activity. Histomorphological observations of brain indicated, that extensive lesion restricted to the wide area of nodule including ventral uvula, resulted in significant fall of AP activity at the mucosal brush border within 20 days. A comparative behavioural study in experimental and control groups by openfield test indicated that, sympathoexcitation resulting from vestibulo-cerebellar lesion may contribute to significant alteration of AP activity in duodenum of rats.