Prostate cancer associated with p53 and Rb deficiency arises from the stem/progenitor cell-enriched proximal region of prostatic ducts

Recently, we have shown that prostate epithelium-specific deficiency for p53 and Rb tumor suppressors leads to metastatic cancer, exhibiting features of both luminal and neuroendocrine differentiation. Using stage-by-stage evaluation of carcinogenesis in this model, we report that all malignant neoplasms arise from the proximal region of the prostatic ducts, the compartment highly enriched for prostatic stem/progenitor cells. In close similarity to reported properties of prostatic stem cells, the cells of the earliest neoplastic lesions express stem cell marker stem cell antigen 1 and are not sensitive to androgen withdrawal. Like a subset of normal cells located in the proximal region of prostatic ducts, the early neoplastic cells coexpress luminal epithelium markers cytokeratin 8, androgen receptor, and neuroendocrine markers synaptophysin and chromogranin A. Inactivation of p53 and Rb also takes place in the lineage-committed transit-amplifying and/or differentiated cells of the distal region of the prostatic ducts. However, the resulting prostatic intraepithelial neoplasms never progress to carcinoma by the time of mouse death. Interestingly, in an ectopic transplantation assay, early mutant cells derived from either region of the prostatic ducts are capable of forming neoplasms within 3 months. These findings indicate that p53 and Rb are critically important for the regulation of the prostatic stem cell compartment, the transformation in which may lead to particularly aggressive cancers in the context of microenvironment.     

Mouse models of prostate adenocarcinoma with the capacity to monitor spontaneous carcinogenesis by bioluminescence or fluorescence

The application of Cre/loxP technology has resulted in a new generation of conditional mouse models of prostate cancer. Here, we describe the improvement of the conditional Pten deletion model of prostate adenocarcinoma by combining it with either a conditional luciferase or enhanced green fluorescent protein reporter line. In these models, the recombination mechanism that inactivates the Pten alleles also activates the reporter gene. In the luciferase reporter model, the growth of the primary cancer can be followed noninvasively by bioluminescence imaging (BLI). Surgical castration of tumor-bearing animals leads to a reduced bioluminescence signal corresponding to tumor regression that is verified at necropsy. When castrated animals are maintained, the emergence of androgen depletion-independent cancer is detected using BLI at times varying from 7 to 28 weeks postcastration. The ability to monitor growth, regression, or relapse of the tumor with the use of BLI lead to the collection of tumors at different stages of development. By comparing the distribution of phenotypically distinct populations of epithelial cells in cancer tissues, we noted that the degree of hyperplasia of cells with neuroendocrine differentiation significantly increases in the recurrent cancer relative to the primary cancer, a characteristic which may parallel the appearance of a neuroendocrine phenotype in human androgen depletion-independent cancer. The enhanced green fluorescent protein model, at necropsy, can provide an opportunity to locate or assess tumor volume or to isolate enriched populations of cancer cells from tumor tissues via fluorescence-based technologies. These refined models should be useful in the elucidation of mechanisms of prostate cancer progression, and for the development of approaches to preclinical intervention.     

Effect of bilateral destruction of the subretrofacial area on central inspiratory activity of the respiratory center and on the respiratory response to hypercapnia

Local bilateral destruction with 1 M glutamic acid of neuronal structures located between ventral surface of the medulla oblongata and the retrofacial nucleus (subretrofacial area) in rats increases the amplitude of pulses from the phrenic nerve and lowers respiratory rate. Hypercapnia does not affect the amplitude of phrenic nerve pulses but increases respiratory rate. It is suggested that the amplitude of central respiratory activity is regulated by the central chemoreceptors with participation of neuronal structures located in the subretrofacial area. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 123, No. 5, pp. 491–493, May, 1997     

Seasonal variation in the occurrence of ischemic stroke and subarachnoid hemorrhage in Siberia, Russia. A population-based study

Epidemiological studies on the relationship between stroke occurrence and the seasons in different countries produced inconsistent results and little is known about these associations in a general population. We report a population-based study of 214 patients with first-ever ischemic stroke (IS, data for 1992) and 64 patients with first-ever subarachnoid hemorrhage (SAH) registered in the 25–74 years old population of Oktiabrsky District of Novosibirsk, Russia in 1982–92. IS and SAH incidence in four seasons (winter, spring, summer, autumn) was evaluated by means of a chi-square test. Poisson regression analysis was used to compute the rate ratios (RRs) and corresponding confidence intervals (CIs) for the occurrence ofIS and SAH in winter, spring, and autumn compared with summer. Seasonal variations in the occurrence of IS were significant for the group of young men (25–64 years) and the group of older women (65–74 years) only. The age and sex adjusted RR of the occurrence of IS in winter was 49% greater than in summer (95%CI 1–119%). When men and women were analyzed separately and the rates were adjusted for age, a significantly higher risk of IS was found only in men (RR = 2.48; 95% CI 1.27–4.83) in spring compared with summer. No seasonality was observed for the occurrence of SAH in both men and women. Our findings indicate that there is a significantly greater incidence of ischemic stroke during winter in Siberia, Russia, whereas the incidence of SAH does not show a seasonal variation.     

Developmental defect of the veins of the cranial vault (sinus pericranii) involving the upper eyelid

Two rare observations of sinus pericranii are presented, characterized by a soft intumescence containing venous blood and growing in size if the head is bent or during tension. The condition may be diagnosed by local introduction of a contrast agent into the intumescence. Surgical treatment of this developmental venous defect is recommended.     

The involvement of intracellular calcium in the sensitization of command neurons in the defensive behavior of the edible snail

Examinations carried out on command neurons of defensive behaviour of snail carried out using electrophysiological methods and a chlorotetracycline fluorescent probe have revealed that a single sensitizing action induces alterations of electrical neuronal activity and bound calcium (Ca-C) level in cells. An initial increase of the Ca-c amount (the first 15-20 min after the sensitizing action) coincides in time with depolarization, enhancement of plasma membrane excitability as well as with a decrease of amplitude and duration of the IPSPs induced by sensory stimulations. Repeated pronounced increase of the Ca-c level develops 50-60 min after the sensitizing action and correlates with facilitation of neuronal responses to sensory stimuli. Alteration of the Ca-c level in command neurons of defensive behaviour in the course of sensitization development differed from the previously described Ca-c shifts in the same cells in the course of habituation development in dynamics and direction.     

The clinico-immunological efficacy of dioxidine in the combined treatment of acute abscessing pneumonias in persons who abuse alcohol

The results of clinico-immunologic studies of the efficacy of dioxidin in persons abusing alcohol have demonstrated that unlike antibiotics, dioxidin does not provoke any immunosuppressive disorders. It is recommended that dioxidin should be included into multimodality treatment of patients with acute lung abscesses, abusing alcohol.     

Core-shell silica nanoparticles as fluorescent labels for nanomedicine

Progress in biomedical imaging depends on the development of probes that combine low toxicity with high sensitivity, resolution, and stability. Toward that end, a new class of highly fluorescent core-shell silica nanoparticles with narrow size distributions and enhanced photostability, known as C dots, provide an appealing alternative to quantum dots. Here, C dots are evaluated with a particular emphasis on in-vivo applications in cancer biology. It is established that C dots are nontoxic at biologically relevant concentrations, and can be used in a broad range of imaging applications including intravital visualization of capillaries and macrophages, sentinel lymph node mapping, and peptide-mediated multicolor cell labeling for real-time imaging of tumor metastasis and tracking of injected bone marrow cells in mice. These results demonstrate that fluorescent core-shell silica nanoparticles represent a powerful novel imaging tool within the emerging field of nanomedicine.