Tissue-specific inhibition of embryonic neural cell proliferation by rat brain extract

Summary The effect of rat brain tissue extract on the proliferative activity of chicken embryonic neural tube and other tissues was studied. Only tissue-specific inhibitory action was found to be similar to substances of the chalone group.     

Erythropoietic stimulation enhances,and erythropoietic inhibition suppresses,multidirectional differentiation in 5-day transient endogenous spleen colonies

Summary Transient endogenous spleen colonies were found to be composed of either erythroid, granuloid or megakaryocytic cells, or mixtures of these cell types. Independently of the directions of differentiation of the colonies their formation was uniformly stimulated by bleeding and almost completely prevented by hypertransfusion. It is suggested that cells which form these colonies constitute a separate class of pluripotential hemopoietic progenitors, whose differentiation in either direction passes the stage sensitive to erythropoiesis-modulating factors.Acknowledgments. I am indebted to Drs C. Szczylik and J. Grzybowski for fruitful discussions and to Ms Elzbieta Rychowiecka for expert technical assistance. This work was supported in part by grant 10.5 from Polish Academy of Sciences.     

Lithium suppresses hibernation in the Turkish hamster

Daily uptake of lithium salt (LiCl) in the drinking water at a rate of over 100 micrograms/g b.wt (or 2.4 mEq/kg) reduced or suppressed natural torpidity (hibernation) in the Turkish hamster (Mesocricetus brandti). The data indicate a direct influence of lithium on clock-related functions controlling the hibernation process rather than indirect effects by preventing gonadal regression and thereby also hibernation.     

Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI-1

Genetic alterations causing oncogenic activation of the RET gene are recognized as pathogenic events in papillary and medullary thyroid carcinomas. Inhibition of Ret oncoprotein functions could thereby represent a specific therapeutic approach. We previously described the inhibitory activity of the 2-indolinone derivative RPI-1 (formerly Cpd1) on the tyrosine kinase activity and transforming ability of the products of the RET/PTC1 oncogene exogenously expressed in murine cells. In the present study, we investigated the effects of RPI-1 in the human papillary thyroid carcinoma cell line TPC-1 spontaneously harboring the RET/PTC1 rearrangement. Treatment with RPI-1 inhibited cell proliferation and induced accumulation of cells at the G2 cell cycle phase. In treated cells, Ret/Ptc1 tyrosine phosphorylation was abolished along with its binding to Shc and phospholipase C, thereby indicating abrogation of constitutive signaling mediated by the oncoprotein. Activation of JNK2 and AKT was abolished, thus supporting the drug inhibitory efficacy on downstream pathways. In addition, cell growth inhibition was associated with a reduction in telomerase activity by nearly 85%. These findings in a cellular context relevant to the pathological function of RET oncogenes support the role of Ret oncoproteins as useful targets for therapeutic intervention, and suggest RPI-1 as a promising candidate for preclinical development in the treatment of thyroid tumors expressing RET oncogenes.Received 31 December 2002; received after revision 21 February 2003; accepted 10 April 2003     

Strychnine-resistant inhibition in the retina

Zusammenfassung Konvulsive Dosen von Strychnin (0,25–0,8 mg/kg) erhöhten die Inipulsaktivität von Einzelfasern im N. opticus der Katze; die Hemmungsphasen in den on- und off-Antworten blieben jedoch bei 68 von 69 untersuchten Fasereinheiten erhalten. Die Ergebnisse beweisen die Existenz einer strychninresistenten Hemmung in der Retina.     

Excessive proliferation of epithelium of the rabbit cornea

Zusammenfassung Die Schädigung der Basalmembran durch eine Stichverletzung hat eine Proliferation und Einwanderung von Corneaepithelien zur Folge. Eigenartigerweise sind bei diesem Prozess keine Mitosen nachweisbar, was darauf hinzuweisen scheint, dass Amitosen experimentell verfolgt werden können.

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This research was supported in part by grants from the National Research Council (Canada) and the National Cancer Institute of Canada.     

Strategies for the inhibition of serine proteases

Serine proteases have been shown to play a multifarious role in health and disease. As a result, there has been considerable interest in the design and development of synthetic inhibitors of these enzymes. In view of their diverse roles in biological processing events, one of the great challenges in such endeavours has been the need to produce compounds with exquisite selectivity. Inhibitor design has been broadly guided by the use of either peptide- or heterocyclic-based compounds, designed to exploit the known substrate specificity characteristics of individual enzymes. This review describes the thinking and strategies employed in such efforts. Received 8 August 2000; received after revision 16 November 2000; accepted 17 November 2000     

Concerning the ionic basis of presynaptic inhibition

Summary The superfused rat cuneate nucleus has been used to investigate the sensitivity of primary afferent terminals and of evoked primary afferent depolarization (PAD) to alterations in extracellular K⁺ and Cl^– ion levels. Results indicate that PAD is caused by an efflux of Cl^– from primary afferent terminals rather than by an increase in extracellular K⁺.     

The emerging role of galectins in high-fatality cancers

Although we witnessed considerable progress in the prevention and treatment of cancer during the past few decades, a number of cancers remain difficult to treat. The main reasons for this are a lack of effective biomarkers necessary for an early detection and inefficient treatments for cancer that are diagnosed at late stages of the disease. Because of their alarmin-like properties and their protumorigenic role during cancer progression, members of the galectin family are uniquely positioned to provide information that could be used for the exploration of possible avenues for the treatment of high fatality cancer (HFC). A rapid overview of studies that examined the expressions and functions of galectins in cancer cells reveals that they play a central role in at least three major features that characterize HFCs: (1) induction of systemic and local immunosuppression, (2) chemoresistance of cancer cells, and (3) increased invasive behavior. Defining the galectinome in HFCs will also lead to a better understanding of tumor heterogeneity while providing critical information that could improve the accuracy of biomarker panels for a more personalized treatment of HFCs. In this review, we discuss the relevance of the galectinome in HFC and its possible contribution to providing potential solutions.     

Pharmacological inhibition of store-operated calcium entry in MDA-MB-468 basal A breast cancer cells: consequences on calcium signalling,cell migration and proliferation

Store-operated Ca²⁺ entry is a pathway that is remodelled in a variety of cancers, and altered expression of the components of store-operated Ca²⁺ entry is a feature of breast cancer cells of the basal molecular subtype. Studies of store-operated Ca²⁺ entry in breast cancer cells have used non-specific pharmacological inhibitors, complete depletion of intracellular Ca²⁺ stores and have mostly focused on MDA-MB-231 cells (a basal B breast cancer cell line). These studies compared the effects of the selective store-operated Ca²⁺ entry inhibitors Synta66 and YM58483 (also known as BTP2) on global cytosolic free Ca²⁺ ([Ca²⁺]_CYT) changes induced by physiological stimuli in a different breast cancer basal cell line model, MDA-MB-468. The effects of these agents on proliferation as well as serum and epidermal growth factor (EGF) induced migration were also assessed. Activation with the purinergic receptor activator adenosine triphosphate, produced a sustained increase in [Ca²⁺]_CYT that was entirely dependent on store-operated Ca²⁺ entry. The protease activated receptor 2 activator, trypsin, and EGF also produced Ca²⁺ influx that was sensitive to both Synta66 and YM58483. Serum-activated migration of MDA-MB-468 breast cancer cells was sensitive to both store-operated Ca²⁺ inhibitors. However, proliferation and EGF-activated migration was differentially affected by Synta66 and YM58483. These studies highlight the need to define the exact mechanisms of action of different store-operated calcium entry inhibitors and the impact of such differences in the control of tumour progression pathways.     

Concerning the ionic basis of presynaptic inhibition.

The superfused rat cuneate nucleus has been used to investigate the sensitivity of primary afferent terminals and of evoked primary afferent depolarization (PAD) to alterations in extracellular K+ and Cl- ions levels. Results indicate that PAD is caused by an efflux of Cl- from primary afferent terminals rather than by an increase in extracellular K+.     

On the specific inhibition of adrenal steroid biosynthesis

Zusammenfassung Der Einfluss von Su-4885 (Metopiron®), Su-8000, Su-9055 und Su-10'603 auf die Corticosteroid-Biosynthese wurdein vitro und teilsin vivo untersucht. Ausser den bekannten Hemmeffekten auf die 11- und 17-Hydroxylierung wurden davon unabhängig auch solche auf die Bildung von Aldosteron, 18-Hydroxy- und 19-Hydroxycorticosteron beobachtet.     

Specifity of the immunological inhibition of the parathyroid hormone activity

Résumé Des préparations hormonales de parathyroïde humaine, bovine et porcine furent traitées par des sérums anti PTH spécifiques et non spécifiques. Les expériences in vitro et in vivo ont montré que l'inhibition de l'activité biologique du PTH se produit seulement sous l'influence des sérums spécifiques. L'inactivation immunologique n'inhibe jamais complètement l'activité du PTH.