The biology and mechanism of chemoresistance of brain metastases

Primary brain neoplasms and metastases to the brain are generally resistant to systemic chemotherapy. The purpose of theses studies was to determine the mechanism(s) for this resistance. We have developed a model to study the biology of brain metastasis by injecting metastatic K1735 melanoma cells into the carotid artery of syngeneic C3H/HeN or nude mice. The resulting brain lesions are produced in the parenchyma of the brain. Mice with subcutaneous or brain melanoma lesions were treated intravenously with doxorubicin (DXR) (7 mg/kg). The s.c. lesions regressed in most of the mice whereas no therapeutic benefits were produced in mice with brain metastases. The intravenous injection of sodium fluorescine revealed that the blood-brain barrier (BBB) is intact in and around brain metastases smaller than 0.2 mm$\sp2$ but not in larger lesions, implying that the BBB is not a major obstacle for chemotherapy of brain metastases.^ Western blot and FACS analyses revealed that K1735 melanoma brain metastases expressed high levels of P-glycoprotein (P-gp) as compared to s.c. tumors or in vitro cultures. Similarly, K1735 cells from brain metastases expressed higher levels of mdrl mRNA. This increased expression of mdrl was due to adaptation to the local brain environment. We base this conclusion on the results of two studies. First, K1735 cells from brain metastases cultured for 7 days lost the high mdrl expression. Second, in crossover experiments K1735 cells from s.c. tumors (low mdrl expression) implanted into the brain exhibited high levels of mdrl expression whereas cells from brain metastases implanted s.c. lost the high level mdrl expression.^ To investigate the mechanism by which the brain environment upregulates mdrl expression of the K1735 cells we first studied the regulation of P-gp in brain endothelial cells. Since astrocytes are closely linked with the BBB we cocultured brain endothelial cells for 3 days with astrocytes. These endothelial cells expressed high levels of mdrl mRNA and protein whereas endothelial cells cocultured with endothelial cells or fibroblasts did not. We next cocultured K1735 melanoma cells with astrocytes. Here again, astrocytes (but not fibroblasts or tumor cells) uprelated the mdrl expression in K1735 tumor cells. This upregulation inversely correlated with intracellular drug accumulation and sensitivity to DXR.^ The data conclude that the resistance of melanoma brain metastases to chemotherapy is not due to an intact BBB but to the upregulation of the mdrl gene by the organ microenvironment, i.e., the astrocytes. This epigenetic mediated resistance to chemotherapy has wide implications for the therapy of brain metastases. ^

Thermal and Barometric Constraints on the Intrusive and Unroofing History of the Black Mountains: Implications for Timing, Initial Dip, and Kinematics of Detachment Faulting in the Death-Valley Region, California

Unroofing of the Black Mountains, Death Valley, California, has resulted in the exposure of 1.7 Ga crystalline basement, late Precambrian amphibolite facies metasedimentary rocks, and a Tertiary magmatic complex. The Ar-40/Ar-39 cooling ages, obtained from samples collected across the entire length of the range (>55 km), combined with geobarometric results from synextensional intrusions, provide time-depth constraints on the Miocene intrusive history and extensional unroofing of the Black Mountains. Data from the southeastern Black Mountains and adjacent Greenwater Range suggest unroofing from shallow depths between 9 and 10 Ma. To the northwest in the crystalline core of the range, biotite plateau ages from approximately 13 to 6.8 Ma from rocks making up the Death Valley turtlebacks indicate a midcrustal residence (with temperatures >300-degrees-C) prior to extensional unroofing. Biotite Ar-40/Ar-39 ages from both Precambrian basement and Tertiary plutons reveal a diachronous cooling pattern of decreasing ages toward the northwest, subparallel to the regional extension direction. Diachronous cooling was accompanied by dike intrusion which also decreases in age toward the northwest. The cooling age pattern and geobarometric constraints in crystalline rocks of the Black Mountains suggest denudation of 10-15 km along a northwest directed detachment system, consistent with regional reconstructions of Tertiary extension and with unroofing of a northwest deepening crustal section. Mica cooling ages that deviate from the northwest younging trend are consistent with northwestward transport of rocks initially at shallower crustal levels onto deeper levels along splays of the detachment. The well-known Amargosa chaos and perhaps the Badwater turtleback are examples of this "splaying" process. Considering the current distance of the structurally deepest samples away from moderately to steeply east tilted Tertiary strata in the southeastern Black Mountains, these data indicate an average initial dip of the detachment system of the order of 20-degrees, similar to that determined for detachment faults in west central Arizona and southeastern California. Beginning with an initially listric geometry, a pattern of footwall unroofing accompanied by dike intrusion progress northwestward. This pattern may be explained by a model where migration of footwall flexures occur below a scoop-shaped banging wall block. One consequence of this model is that gently dipping ductile fabrics developed in the middle crust steepen in the upper crust during unloading. This process resolves the low initial dips obtained here with mapping which suggests transport of the upper plate on moderately to steeply dipping surfaces in the middle and upper crust.

The Jewish encyclopedia : a descriptive record of the history, religion, literature, and customs of the Jewish people from the earliest time to the present day ; complete in 12 volumes

Isidore Singer, projector and managing ed.

The history of the Jews, from the taking of Jerusalem by Titus, to the present time, comprising a narrative of their wanderings, persecutions, commercial enterprises, literature, manners, customs, and forms of worship : with an account of the various efforts made for their conversion

[James A. Huie]