The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is characterized by expression of Bcr-abl, a tyrosine kinase oncogene. Clinical outcomes in CML were revolutionized by development of Bcr-abl-targeted tyrosine kinase inhibitors (TKIs), but CML is not cured by these agents. CML leukemia stem cells (LSCs) are relatively TKI insensitive and persist even in remission. LSC persistence results in relapse upon TKI discontinuation, or drug resistance or blast crisis (BC) during prolonged treatment. We hypothesize that increased expression of Fas-associated phosphatase 1 (Fap1) in CML contributes to LSC persistence and BC. As Fap1 substrates include Fas and glycogen synthase kinase-3ß (Gsk3ß), increased Fap1 activity in CML is anticipated to induce Fas resistance and stabilization of ß-catenin protein. Resistance to Fas-induced apoptosis may contribute to CML LSC persistence, and ß-catenin activity increases during BC. In the current study, we directly tested the role of Fap1 in CML LSC persistence using in an in vivo murine model. In TKI-treated mice, we found that inhibiting Fap1, using a tripeptide or small molecule, prevented TKI resistance, BC and relapse after TKI discontinuation; all events observed with TKI alone. In addition, Fap1 inhibition increased Fas sensitivity and decreased ß-catenin activity in CD34(+) bone marrow cells from human subjects with CML. Therapeutic Fap1 inhibition may permit TKI discontinuation and delay in progression in CML.

Near-threshold production of the multistrange Xi- hyperon.

The yield for the multistrange Xi(-) hyperon has been measured in 6A GeV Au+Au collisions via reconstruction of its decay products pi(-) and Lambda, the latter also being reconstructed from its daughter tracks of pi(-) and p. The measurement is rather close to the threshold for Xi(-) production and therefore provides an important test of model predictions. The measured yield for Xi(-) and Lambda are compared for several centralities. In central collisions the Xi(-) yield is found to be in excellent agreement with statistical and transport model predictions, suggesting that multistrange hadron production approaches chemical equilibrium in high baryon density nuclear matter.

Comparison of source images for protons, pi-'s, and lambda's in 6A GeV Au+Au collisions.

Source images are extracted from two-particle correlations constructed from strange and nonstrange hadrons produced in 6A GeV Au+Au collisions. Very different source images result from pp vs p Lambda vs pi(-)pi(-) correlations. Scaling by transverse mass can describe the apparent source size ratio for p/pi(-) but not for Lambda/pi(-) or Lambda/p. These observations suggest important differences in the space-time emission histories for protons, pions, and neutral strange baryons produced in the same events.

Longitudinal flow of protons from (2-8)A GeV central Au+Au collisions.

Rapidity distributions of protons from central 197Au+197Au collisions measured by the E895 Collaboration in the energy range from (2-8)A GeV at the Brookhaven AGS are presented. Longitudinal flow parameters derived using a thermal model including collective longitudinal expansion are extracted from these distributions. The results show an approximately linear increase in the longitudinal flow velocity, (L), as a function of the logarithm of beam energy.

Model-independent source imaging using two-pion correlations in (2 to 8)a GeV Au+Au collisions.

We report a particle source imaging analysis based on two-pion correlations in high multiplicity Au+Au collisions at beam energies between 2A and 8A GeV. We apply the imaging technique introduced by Brown and Danielewicz, which allows a model-independent extraction of source functions with useful accuracy out to relative pion separations of about 20 fm. The extracted source functions have Gaussian shapes. Values of source functions at zero separation are almost constant across the energy range under study. Imaging results are found to be consistent with conventional source parameters obtained from a multidimensional Hanburg-Brown-Twiss analysis.

Directed flow of lambda hyperons in (2-6 )A GeV Au+Au collisions.

Directed flow measurements for Lambda hyperons are presented and compared to those for protons produced in the same Au+Au collisions (2A, 4A, and 6A GeV; b<5-6 fm). The measurements indicate that Lambda hyperons flow consistently in the same direction but with smaller magnitudes. A strong positive flow [for Lambdas] has been predicted in calculations which include the influence of the Lambda-nucleon potential. The experimental flow ratio Lambda/p is in qualitative agreement with expectations (approximately 2/3) from the quark counting rule at 2A GeV but is found to decrease with increasing beam energy.

Sideward flow in Au+Au collisions between 2A and 8A GeV

Using the large acceptance Time Projection Chamber of experiment E895 at Brookhaven, measurements of collective sideward flow in Au+Au collisions at beam energies of 2A, 4A, 6A, and 8A GeV are presented in the form of in-plane transverse momentum and the first Fourier coefficient of azimuthal anisotropy v(1). These measurements indicate a smooth variation of sideward flow as a function of beam energy. The data are compared with four nuclear transport models which have an orientation towards this energy range. All four exhibit some qualitative trends similar to those found in the data, although none show a consistent pattern of agreement within experimental uncertainties.

Continued experimental study of the pathogenesis of sporadic bacteriuria in the rat. III.

With reference to a previously published experimental model, the author relates continued experiments with sporadic, experimental hydronephrosis. The experimental animals were as previously, white female rats. The results confirmed the author's assertion that sporadic infection of an experimental hydronephrosis occurs under conditions where ascending infection of the urinary tract is precluded. In these experiments, age and environment of the animals did not influence sporadic infection. In experimental, intravenously induced Escherichia coli bacteremia, however, old age seemed to increase the frequency in the experimental model.

Continued experimental study on the pathogenesis of sporadic bacteriuria in the rat. II.

The previously described experimental model implying ligature of the left ureter in the rat has been used in continued experiments. The present experiments intended to saturate the reticuloendothelial system with dead E. coli, and thereby produce a possible increase in the seeding of bacteria into the experimental locus minoris resistentiae. The results indicate that usage of organic material as E. coli may also stimulate the RES system. Most probably, the incidence of experimental infections in the left ureter is influenced upon by 2 main variables: the size of the experimental bacteremia and the current state of host defence mechanisms.

Continued experimental study on the pathogenesis of sporadic bacteriuria in the rat.

An experimental model implying ligature of the left ureter in the rat has previously (1977) been described by the author. The same model has been used in the experiments which are presented in this paper. The aim has been to study further the hematogenous seeding of bacteria to the hydronephrotic left kidney. The experiments seem to confirm the author's view that sporadic hematogenous infection with intestinal bacteria occasionally takes place and can be demonstrated by this method. Intravenous injection of E. coli showed that the minimal kidney infecting dose amounted to 0.5 ml E. coli 10(6) bacteria per ml. The author found considerable increase of sporadic infection after splenectomy and partial liver resection.

Experimental hydronephrosis. Influence of infection on the histological picture.

The present paper is concerned with a histological examination of 110 pairs of rat kidneys from an experimental investigation on unilateral hydronephrosis previously published. Urine sampled by puncture of the obstructed pelvis remained sterile in cultures from most of the cases, though in 22 of a total of 184 cases growth of bacteria occurred. Intravenous injection of E. coli resulted in substantial growth of the bacteria in similar samples. In 2 cases the untreated control kidney displayed histological evidence of infection. The histology indicated that damage to the renal parenchyma in hydronephrotic kidneys probably predisposes the kidney for hematogenous infection.

An experimental study on the pathogenesis of sporadic bacteriuria in the rat.

An experimental model is used in which one ureter of a rat is ligated with the object of forming a hydronephrosis from which urine specimens can subsequently be collected. Ascending urinary infection from the bladder is excluded by the ligation. The investigations with this experimental model showed that growth of intestinal bacteria occasionally occurred in culture of urine obtained from the occluded renal pelvis. Ascending infection being excluded, these bacteria had in all probability entered the renal pelvis via the hydronephrotic kidney. The frequency of infection seemed to increase with age. Whedronephrotic kidney. The frequency of infection seemed to increase with age. When intravenous injection of E. coli was added to the standard experiment, substantial growth of these bacteria was found in the left upper urinary tract in 16 out of 17 animals thus treated.