A potent analog of 1alpha,25-dihydroxyvitamin D3 selectively induces bone formation

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] is a principal regulator of calcium and phosphorus homeostasis through actions on intestine, kidney, and bone. 1,25(OH)(2)D(3) is not considered to play a significant role in bone formation, except for its role in supporting mineralization. We report here on the properties of 2-methylene-19-nor-(20S)-1alpha,25(OH)(2)D(3) (2MD), a highly potent analog of 1,25(OH)(2)D(3) that induces bone formation both in vitro and in vivo. Selectivity for bone was first demonstrated through the observation that 2MD is at least 30-fold more effective than 1,25(OH)(2)D(3) in stimulating osteoblast-mediated bone calcium mobilization while being only slightly more potent in supporting intestinal calcium transport. 2MD is also highly potent in promoting osteoblast-mediated osteoclast formation in vitro, a process essential to both bone resorption and formation. Most significantly, 2MD at concentrations as low as 10(-12) M causes primary cultures of osteoblasts to produce bone in vitro. This effect is not found with 1,25(OH)(2)D(3) even at 10(-8) M, suggesting that 2MD might be osteogenic in vivo. Indeed, 2MD (7 pmol/day) causes a substantial increase (9%) in total body bone mass in ovariectomized rats over a 23-week period. 1,25(OH)(2)D(3) (500 pmol three times a week) only prevented the bone loss associated with ovariectomy and did not increase bone mass. These results indicate that 2MD is a potent bone-selective analog of 1,25(OH)(2)D(3) potentially effective in treating bone loss diseases.     

Multi-faceted role of HSP40 in cancer

HSP40 (DNAJ) is an understudied family of co-chaperones. The human genome codes for over 41 members of HSP40 family that reside at distinct intracellular locations. Despite their large numbers, little is known about their physiologic roles. Recent research has revealed involvement of some of the DNAJ family members in various types of cancers. In this article we summarize the information about the involvement of human DNAJ family members in various aspects of cancer biology. Furthermore we discuss the potential role of the J domain of DNAJ proteins in cancer biology.     

Hedgehog signaling pathway regulates the growth of ovarian cancer spheroid forming cells

The hedgehog (Hh) pathway has been shown to be activated in numerous malignancies as well as in cancer stem cells. We sought to determine the importance of the Hh pathway in regulating growth and development of ovarian cancer spheroid-forming cells (SFCs). Ovarian cancer cell lines (ES2, TOV112D, OV90, and SKOV3) as well as a normal ovarian epithelial cell line (IOSE80) were grown in non-adherent growth conditions to form SFCs. Western blot analysis was used to determine the expression of Hh pathway proteins SMOH, PTCH, GLI1. SFCs were treated with Hh agonists (SHH and IHH) as well as an Hh inhibitor (cyclopamine) to determine changes in spheroid growth and survival. All ovarian cancer cell lines readily formed spheroids in non-adherent growth conditions while IOSE80 failed to form SFCs. Compared to IOSE80, ovarian cancer cell lines demonstrated significant activation of the Hh pathway as defined by increased expression of intranuclear GLI1. Both Hh agonists demonstrated significant increases in spheroid volume of at least 42-fold for SHH-treated cells and 46-fold for IHH-treated cells. With regard to survival, SFCs were 30-50% more resistant to cyclopamine than their corresponding monolayer cells. Despite this resistance, inhibition of the Hh pathway with cyclopamine prevented further growth of SFCs with a 10-, 5-, and 4-fold restriction in growth for ES2, SKOV3, and TOV112D, respectively. The hedgehog pathway appears to be important in regulating growth of ovarian cancer spheroid-forming cells. The activation and inhibition of this pathway demonstrates significant correlation to enhanced growth and growth restriction, respectively.     

Pleural block: technique for regional anesthesia during percutaneous hepatobiliary drainage

A new technique was used to achieve safe regional anesthesia in seven patients undergoing percutaneous hepatobiliary drainage. The pleural block was administered, and pain was assessed during and after the procedure by means of sensitivity to pin prick, verbal response, electrocardiographic tracings, and blood pressure measurements. In all patients the technique produced relief of somatic pain and did not alter hemodynamic or respiratory status.     

Aspects of the pharmacology of a new anthelmintic: Pyrantel

1. The pharmacological properties of an anthelmintic, pyrantel, and some of its analogues have been described and compared with piperazine in a variety of vertebrate and helminth preparations.2. Pyrantel and its analogues in common with nicotine and decamethonium cause spastic paralysis in chicks and contracture of the chick semispinalis and toad rectus abdominis muscles.3. In the soleus and anterior tibialis muscles of the cat, pyrantel in large amounts caused a short-lived neuromuscular block that was preceded by initial depolarization.4. In preparations from cat and rat, pyrantel showed properties common to both competitive and depolarizing neuromuscular blocking drugs.5. Pyrantel blocked the contracture evoked by transmural stimulation and caused a marked contracture of the worm. Piperazine caused a gradually developing reduction in the responses to transmural stimulation and no contracture.6. Pyrantel and its analogues caused a slowly developing contracture of strip preparations of Ascaris, being more than 100 times more active than acetylcholine in this respect. Piperazine caused a relaxation of Ascaris strip preparations and in common with (+)-tubocurarine blocked the responses to acetylcholine and pyrantel analogues on this preparation.7. Pyrantel caused depolarization and increased spike discharge frequency in single muscle cells of Ascaris, these changes being accompanied by increase in tension. Piperazine, on the other hand, caused hyperpolarization and reduction in spike discharge frequency and relaxation, and antagonized the effects of pyrantel.