Original Article

The pancreas taken from the frog (Rana nigromaculata) was fixed in 1% OsO_4 and sliced into ultrathin sections for electron microscopic studies. The following observations were made: 1. A great \u27number of minute granules found in the cytoplasm of a pancreatic cell were called the microsomes, which were divided into two types, the C-microsome and S-microsome. 2. Electron microsopic studies of the ergastoplasm showed that it is composed of the microsome granules and A-substance. The microsomes were seen embedded in the A-substance which was either filamentous or membranous. The membranous structure, which was called the Am-membrane, was seen to form a sac, with a cavity of varying sizes, or to form a lamella. 3. The Am-membrane has close similarity to α-cytomembrane of Sjostrand, except that the latter is rough-surfaced. It was deduced that the Am-membrane, which is smooth-surfaced, might turn into the rough-surfaced α-cytomembrane. 4. There was the Golgi apparatus in the supranuclear region of a pancreatic cell. It consisted of the Golgi membrane, Golgi vacuole and. Golgi vesicle. 5. The mitochondria of a pancreatic cell appeared like long filaments, and some of them were seen to ramify. 6. The membrane of mitochondria, i. e. the limiting membrane, consisted of the Ammembrane. The mitochondria contained a lot of A-substances, as well as the C-microsomes and S-microsomes. When the mitochondria came into being, there appeared inside them chains of granules, which appeared like strips of beads, as the outgrowths of the A-substance and the microsome granules attached to the Am-membrane. They are the so-called cristae mitochondriales. 7. The secretory granules originate in the microsomes. They came into being when the microsomes gradually thickened and grew in size as various substances became adhered to them. Some of the secretory granules were covered with a membrane and appeared like what they have called the intracisternal granule of Palade.It seemed that this was a phenomenon attendant upon the dissolution and liqutefaction of the secretory granule. 8. Comparative studies were made of the ergastoplasm of the pancreatic cells from the frogs in hibernation, the frogs artificially hungered, the frogs which were given food after a certain period of fasting, the frogs to which pilocarpine was given subcutaneously, and the very young, immature frogs. The studies revealed that the ergastoplasm of the pancreatic cells greatly varied in form with the difference in nutritive condition and with different developmental stages of the cell. The change in form and structure occured as a result of transformation of the microsomes and A-substance. The ergastoplasm, even after it has come into being, might easily be inactivated if nutrition is defective. The ergastoplasm is concerned in the secretory mechanism, which is different from the secretory phenomenon of the secretory granules. It would seem that structurally the mitochondria have no direct relation to this mechanism

Antitumor effects of antiretroviral therapy

n/

HIV protease inhibitors as new treatment options for Kaposi's sarcoma

A reduced incidence and regression of Kaposi's sarcoma (KS) and other tumours has been reported in Acquired Immune Deficiency Syndrome (AIDS) patients treated with antiretroviral combination therapies containing Human Immunodeficiency Virus (HIV) protease inhibitors (PIs) such as indinavir or saquinavir. Indeed, evidence indicates that although PIs were designed to selectively inhibit the HIV protease activity, they can interfere with several cellular pathways and can inhibit tumour growth. In particular, our recent results indicate that doses of indinavir or saquinavir similar to those employed to treat AIDS patients can induce regression of experimental KS by directly blocking two fundamental steps of KS initiation and progression: new blood vessel formation (angiogenesis) and KS tumour cell invasion. This is because indinavir or saquinavir inhibit the activation of matrix metalloproteinase-2 (MMP-2), a basement membrane-degrading enzyme, which is required for the progression of most tumours. Based on these results, a multicentre clinical trial is now starting in Italy, which will assess PI effects on the progression of KS in HIV-uninfected individuals (classical KS)

The formation of new blood vessels in Kaposi’s sarcoma.

Abnormal and intense new blood vessel formation is a general feature of all clinical-epidemiological forms of Kaposi’s sarcoma (KS). This chapter summarizes key aspects of the scientific literature regarding the genesis of new vessels in KS lesions, in an effort to draw a unifying view of KS initiation and progression

Inhibition of MMP-9 expression by ritonavir or saquinavir is associated with inactivation of the AKT/Fra-1 pathway in cervical intraepithelial neoplasia cells

A reduced incidence and decreased clinical progression of uterine cervical intraepithelial neoplasia (CIN) has been observed in women infected with human immunodeficiency virus (HIV) treated with HIV-protease inhibitors (PIs). The HIV-PIs saquinavir (SQV) and ritonavir (RTV) have been demonstrated to efficiently inhibit invasion of human primary CIN cells by downregulating the expression of matrix metalloproteinase (MMP)-9. The present study further investigated the molecular mechanisms underlying the activity of SQV and RTV in CIN. The results of the present study indicate that the treatment of human primary CIN cells with SQV or RTV directly impairs events leading to MMP-9 expression, including the phosphorylation of AKT and the nuclear localisation of the Fos-related antigen transcription factor. In addition, neither SQV nor RTV affected the expression of human papilloma virus proteins, such as E6 or E7. In view of the important role that the AKT/Fra-1/MMP-9 signalling pathway serves in CIN progression to invasive cervical carcinoma, these data further support the use of HIV-PIs in the treatment of CIN in women infected with HIV and women who are not infected with HIV. Furthermore, the present study identified a molecular mechanism underlying the anti-invasive effects of SQV/RTV, providing useful information for the development of SQV/RTV derivatives, which may be employed as novel anticancer drugs

IFN-gamma induces endothelial cells to proliferate and to invade the extracellular matrix in response to the HIV-1 Tat protein: implications for AIDS-Kaposi's sarcoma pathogenesis

Previous studies indicated that the Tat protein of HIV functions as a progression factor in Kaposi's sarcoma (KS), an angioproliferative disease common and aggressive in HIV-1-infected individuals (AIDS-KS). In particular, Tat that is released by infected cells stimulates the growth and invasion of spindle cells of endothelial origin derived from KS lesions (KS cells). Other work suggested that inflammatory cytokines may act as initiating factors in KS since they induce normal endothelial cells to acquire the same phenotype and functional features of KS cells, including the responsiveness to Tat. In this study, we show that among the inflammatory cytokines increased in AIDS-KS lesions, IFN-gamma alone is sufficient to induce endothelial cells to proliferate and to invade the extracellular matrix in response to Tat. This is because IFN-gamma up-regulates the expression and activity of the receptors for Tat identified as the integrins alpha5beta1 and alpha(v)beta3. These results suggest that, by triggering Tat effects, IFN-gamma plays a major role in AIDS-KS pathogenesis