No abstract

Copper is an element required for cell proliferation and angiogenesis. Human prostate cancer xenografts with increased 64Cu radioactivity were visualized previously by PET using 64CuCl2 as a radiotracer (64CuCl2 PET). This study aimed to determine whether the increased tumor 64Cu radioactivity was due to increased cellular uptake of 64Cu mediated by human copper transporter 1 (hCtr1) or simply due to nonspecific binding of ionic 64CuCl2 to tumor tissue. In addition, the functional role of hCtr1 in proliferation of prostate cancer cells and tumor growth was also assessed. Methods A lentiviral vector encoding short-hairpin RNA specific for hCtr1 (Lenti-hCtr1-shRNA) was constructed for RNA interference–mediated knockdown of hCtr1 expression in prostate cancer cells. The degree of hCtr1 knockdown was determined by Western blot, and the effect of hCtr1 knockdown on copper uptake and proliferation were examined in vitro by cellular 64Cu uptake and cell proliferation assays. The effects of hCtr1 knockdown on tumor uptake of 64Cu were determined by PET quantification and tissue radioactivity assay. The effects of hCtr1 knockdown on tumor growth were assessed by PET/CT and tumor size measurement with a caliper. Results RNA interference–mediated knockdown of hCtr1 was associated with the reduced cellular uptake of 64Cu and the suppression of prostate cancer cell proliferation in vitro. At 24 h after intravenous injection of the tracer 64CuCl2, the 64Cu uptake by the tumors with knockdown of hCtr1 (4.02 ± 0.31 percentage injected dose per gram [%ID/g] in Lenti-hCtr1-shRNA-PC-3 and 2.30 ± 0.59 %ID/g in Lenti-hCtr1-shRNA-DU-145) was significantly lower than the 64Cu uptake by the control tumors without knockdown of hCtr1 (7.21 ± 1.48 %ID/g in Lenti-SCR-shRNA-PC-3 and 5.57 ± 1.20 % ID/g in Lenti-SCR-shRNA-DU-145, P < 0.001) by PET quantification. Moreover, the volumes of prostate cancer xenograft tumors with knockdown of hCtr1 (179 ± 111 mm3 for Lenti-hCtr1-shRNA-PC-3 or 39 ± 22 mm3 for Lenti-hCtr1-shRNA-DU-145) were significantly smaller than those without knockdown of hCtr1 (536 ± 191 mm3 for Lenti-SCR-shRNA-PC-3 or 208 ± 104 mm3 for Lenti-SCR-shRNA-DU-145, P < 0.01). Conclusion Overall, data indicated that hCtr1 is a promising theranostic target, which can be further developed for metabolic imaging of prostate cancer using 64CuCl2 PET/CT and personalized cancer therapy targeting copper metabolism.

Newly discovered peloidal limestone from the summit of Mount Qomolangma (Mount Everest) contains skeletal fragments of trilobites, ostracods and crinoids. They are small pebble-sized debris interbedded in micritic bedded limestone of the Qomolangma Formation, and are interpreted to have been derived from a bank margin and redeposited in peri-platform environments. An exposure of the Qomolangma detachment at the base of the first step (8520 m), on the northern slope of Mount Qomolangma was also found. Non-metamorphosed, strongly fractured Ordovician limestone is separated from underlying metamorphosed Yellow Band by a sharp fault with a breccia zone. The 40 Ar-39 Ar ages of muscovite from the Yellow Band show two-phase metamorphic events of approximately 33.3 and 24.5 Ma. The older age represents the peak of a Barrovian-type Eo-Himalayan metamorphic event and the younger age records a decompressional high-temperature Neo-Himalayan metamorphic event. A muscovite whole-rock 87 Rb-86 Sr isochron of the Yellow Band yielded 40.06 ± 0.81 Ma, which suggests a Pre-Himalayan metamorphism, probably caused by tectonic stacking of the Tibetan Tethys sediments in the leading margin of the Indian subcontinent. Zircon and apatite grains, separated from the Yellow Band, gave pooled fission-track ages of 14.4 ± 0.9 and 14.4 ± 1.4 Ma, respectively. These new chronologic data indicate rapid cooling of the hanging wall of the Qomolangma detachment from approximately 350°C to 130°C during a short period .

The Cretaceous Langshan Formation, which crops out along the northern portion of the Lhasa block, is composed mainly of grey or grey-black fine-grained limestones, argillaceous limestones and a few thin-bedded siltstones and silty mudstones. From specimens collected and/or photographed in the field, combined with a revision of taxa previously recorded from the Langshan Formation, four rudist taxa are recognized: (1) Auroradiolites gen. nov.; (2) Eoradiolites cf. davidsoni; (3) Magallanesia rutogensis sp. nov.; and (4) Sellaea sp. We propose Auroradiolites gen. nov. for the grouping of SW Asian to Pacific radiolitid species formerly attributed to Eoradiolites and characterized by a compact (non-celluloprismatic) outer shell layer. The new genus is represented in the Langshan Formation by A. biconvexus (Yang et al., 1982), including several other synonymized taxa. Taxonomic confusion in the literature has resulted from the varied appearance of the strongly developed ligamentary infolding in such forms: in the right valve, it has a forked inner termination, but common transverse sections through both valves show the latter juxtaposed against its broad, rounded counterpart in the left valve, giving the combined terminations a bulb-shaped appearance. Associated Eoradiolites cf. davidsoni is of smaller size and, by contrast, shows the celluloprismatic structure of the outer shell layer. The recently described canaliculate polyconitid genus, Magallanesia Sano et al., 2014, is represented by M. rutogensis sp. nov., which differs from the type species in possessing more numerous and ventrally extended canals in the left valve. Possibly belonging with the latter species are isolated right valves, similar to Horiopleura, but containing tabulae. A probable Sellaea sp. is represented by poorly preserved right valves nevertheless showing typical features, including a very thin outer shell layer and an erect posterior myophoral wall, separating off a broad posterior ectomyophoral cavity. Based on the presence of Magallanesia and the orbitolinid record, this rudist fauna is probably no older than late Albian, while a younger age cannot be excluded. Both Magallanesia and Auroradiolites are characteristic of a SW Asian/central Pacific faunal province, while the other two genera are more widely distributed.