The differential staurosporine mediated G1 arrest in normal versus tumor cells is dependent on the retinoblastoma and Chk1 proteins

The ability to regulate cell cycle progression is one of the differences that separates normal from tumor cells. A protein, which is frequently mutated or deleted in a majority of tumor cells, is the retinoblastoma protein (pRb). Previously, we reported that normal cells, which have a wild-type Rb pathway, can be reversibly arrested in the G1 phase of the cell cycle by staurosporine (ST), while tumor cells were unaffected by this treatment. As a result, ST may be used to protect normal cells against the toxic affects of chemotherapy. Here we set out to determine the mechanism(s) by which ST can mediate a reversible G1 arrest in pRb positive cells. To this end, we used an isogenic cell model system of normal human mammary epithelial cells (HMEC) with either intact pRb+ (p53-) or p53+ (pRb-) treated with ST. Our results show that pRb+ cells treated with low concentrations of ST, arrested in the G1 phase of the cell cycle; however, in pRb - cells there was no response. This was verified as a true G 1 arrest in pRb+ cells by two different methods for monitoring cell cycle kinetics and in two additional model systems for Rb (i.e. pRb -/- mouse embryo fibroblasts, and downregulation of RB with siRNA). Our results indicated that ST-mediated G1 arrest required pRb, which in turn initiated a cascade of events leading to inhibition of CDK4 and CDK2 activities and up-regulation of p21 protein. Further assessment of this pathway revealed the novel finding that Chk1 expression and activity were required for the Rb-dependent, ST-mediated G1 arrest. In fact, overexpression of Chk1 facilitated recovery from ST-mediated G1 arrest, an effect only observed in RB+ cells. Collectively, our data suggest pRb is able to cooperate with Chk1 to mediate a G1 arrest in pRb+ cells, but not in pRb- cells. The elucidation of this pathway can help identify novel agents that can be used to protect cancer patients against the debilitating affects of chemotherapy, by targeting only the normal proliferating cells in the body that are otherwise destroyed. ^

The American vegetable practice, or, A new and improved guide to health. : Designed for the use of families. : In six parts. Part I. Concise view of the human body, with engraved and wood-cut illustrations. Part II. Glance at the old school practice of physic. Part III. Vegetable materia medica, with colored illustrations. Part IV. Compounds. Part V. Practice of medicine, based upon what are deemed correct physiological and pathological principles. Part VI. Guide for women, containing a simplified treatise on childbirth, with a description of the diseases peculiar to females and infants. /

Errata and advertisement for "New England Depot. D.L. Hale" at end of v. 2.

Plain reasons addressed to the people of Great-Britain, against the (intended) petition to Parliament from the owners and occupiers of land in the county of Lincoln, for leave to export wool. With some remarks on Sir John Dalrymple's treatise, lately published, in favour of a general exportation of wool.

In manuscript, p. iv : [the author] "The Revd. Sheepshanks, rector of St. Johns in Leeds".

Istoricheskīe materīaly o t︠s︡erkvakh i selakh XVI-XVIII st.

Includes bibliographical references.

Hints for Hardinge, : being a series of political essays published originally in the Dublin morning register; with an appendix, containing observations on the report of Mr. Spring Rice's committee on the state of the poor in Ireland, and letters to the editors of the Times, Globe, and Courier. /

Mode of access: Internet.

Lehrbuch der beschreibenden forstbotanik, zum gebrauche bei den vorlesungen an der Königl. forstschule zu Aschaffenburg.

Mode of access: Internet.

Travels in South America.

T.p. vignette.

Lehrbuch der Forst- und Jagdthiergeschichte.

"Vorzüglichste literatur der thiergeschichte": p. [ix]-xii.

Geschichte und beschreibung von Aschaffenburg und dem Spessart.

Mode of access: Internet.

Der Spessart. Versuch einer topographie dieser waldgegend,

Mode of access: Internet.

Correspondence between the Chesapeake and Ohio Canal Company, and the Baltimore and Ohio Rail Road Company. : In relation to the disputes between those companies concerning the right of way for their respective works along the Potomac River.

Thomson, T.R. Railroads,

French furniture and decoration in the XVIIIth century,

Appendix: List of artists and workmen leaving Paris for St. Petersburg in 1716.--Spaendonck, G. van. Salons.--Oudry, J. B. Salons.--List of officials at the Gobelins.--Caffieri, J. Chronological list of his work for the crown.--Oeben and Reisener. Detailed agreement for the Bureau du roi.--Gouthière. Entries in the sale catalogue of the duke d'Aumont.--Duplessis. Entries in the livre-journal of Lazare Duvaux.--List of French cabinet-makers.

Local geometric changes in left ventricular remodeling post-infarction can lead to apparent reduction in scar thickness

Serial reduction in scar thickness has been shown in animal models. We sought whether this reduction in scar thickness may be a result of dilatation of the left ventricle (LV) with stretching and thinning of the wall. Contrast enhanced magnetic resonance imaging (CMRI) was performed to delineate radial scar thickness in 25 patients (age 63±10, 21 men) after myocardial infarction. The LV was divided into 16 segts and the absolute radial scar thickness (ST) and percentage scar to total wall thickness (%ST) were measured. Regional end diastolic (EDV) and end systolic volumes (ESV) of corresponding segments were measured on CMRI. All patients underwent revascularization and serial changes in ST, %ST, and regional volumes were assessed with a mean follow up of 15±5 months. CMRI identified a total of 93 scar segments. An increase in EDV or ESV was associated with a serial reduction inST(versusEDV, r =−0.3, p = 0.01; versusESV, r =−0.3, p = 0.005) and%ST(versusEDV, r =−0.2, p = 0.04; versus ESV, r =−0.3, p = 0.001). For segts associated with a positive increase in EDV (group I) or ESV (group II) there was a significant decrease in ST and %ST, but in those segts with stable EDV (group III) or ESV (group IV) there were no significant changes in ST and %ST (Table).

Remote sensing applied to land use and erosion hazard studies in Jamaica

The northern half of the parish of St. Catherine in Jamaica was selected as a test area to study, by means of remote sensing, the problems of soil erosion in a tropical environment. An initial study was carried out to determine whether eroded land within this environment could be successfully interpreted and mapped from the available 1: 25,000 scale aerial photographs. When satisfied that a sufficiently high percentage of the eroded land could be interpreted on the aerial photographs the main study was initiated. This involved interpreting the air photo cover of the study area for identifying and classifying land use and eroded land, and plotting the results on overlays on topographic base maps. These overlays were then composited with data on the soils and slopes of the study area. The areas of different soil type/slope/land use combinations were then measured, as was the area of eroded land for each of these combinations. This data was then analysed in two ways. The first way involved determining which of the combinations of soil type, slope and land use were most and least eroded and, on the basis of this, to draw up recommendations concerning future land use. The second analysis was aimed at determining which of the three factors, soil type, slope and land use, was most responsible for determining the rate of erosion. Although it was possible to show that slope was not very significant in determining the rate of erosion, it was much more difficult to separate the effects of land use and soil type. The results do, however, suggest that land use is more significant than soil type in determining the rate of erosion within the study area.

In vivo measurement of regional variation in anterior scleral resistance to Schiotz indentation

Purpose: Recent studies indicate that ocular and scleral rigidity is pertinent to our understanding of glaucoma, age related macular degeneration and the development and pathogenesis of myopia. The principal method of measuring ocular rigidity is by extrapolation of data from corneal indentation tonometry (Ko) using Friedenwald’s transformation algorithms. Using scleral indentation (Schiotz tonometry) we assess whether regional variations in resistance to indentation occur in vivo across the human anterior globe directly, with reference to the deflection of Schiotz scale readings. Methods: Data were collected from both eyes of 26 normal young adult subjects with a range of refractive error (mean spherical equivalent ± S.D. of -1.77 D ± 3.28 D, range -10.56 to +4.38 D). Schiotz tonometry (5.5 g & 7.5 g) was performed on the cornea and four scleral quadrants; supero-temporal (ST) and -nasal (SN), infero-temporal (IT) and -nasal (IN) approximately 8 mm posterior to the limbus. Results: Values of Ko (mm3)-1 were consistent with those previously reported (mean 0.0101 ± 0.0082, range 0.0019–0.0304). In regards to the sclera, significant differences (p < 0.001) were found across quadrants with indentation readings for both loads between means for the cornea and ST; ST and SN; ST and IT, ST and IN. Mean (±S.D.) scale readings for 5.5 g were: cornea 5.93 ± 1.14, ST 8.05 ± 1.58, IT 7.03 ± 1.86, SN 6.25 ± 1.10, IN 6.02 ± 1.49; and 7.5 g: cornea 9.26 ± 1.27, ST 11.56 ± 1.65, IT 10.31 ± 1.74, SN 9.91 ± 1.20, IN 9.50 ± 1.56. Conclusions: Significant regional variation was found in the resistance of the anterior sclera to indentation produced by the Schiotz tonometer.