Biological Stoichiometry in Human Cancer

A growing tumor in the body can be considered a complex ecological and evolutionary system. A new eco-evolutionary hypothesis (the "Growth Rate Hypothesis", GRH) proposes that tumors have elevated phosphorus (P) demands due to increased allocation to P-rich nucleic acids, especially ribosomal RNA, to meet the protein synthesis demands of accelerated proliferation.We determined the elemental (C, N, P) and nucleic acid contents of paired malignant and normal tissues from colon, lung, liver, or kidney for 121 patients. Consistent with the GRH, lung and colon tumors were significantly higher (by approximately two-fold) in P content (fraction of dry weight) and RNA content and lower in nitrogen (N):P ratio than paired normal tissue, and P in RNA contributed a significantly larger fraction of total biomass P in malignant relative to normal tissues. Furthermore, patient-specific differences for %P between malignant and normal tissues were positively correlated with such differences for %RNA, both for the overall data and within three of the four organ sites. However, significant differences in %P and %RNA between malignant and normal tissues were not seen in liver and kidney and, overall, RNA contributed only approximately 11% of total tissue P content.Data for lung and colon tumors provide support for the GRH in human cancer. The two-fold amplification of P content in colon and lung tumors may set the stage for potential P-limitation of their proliferation, as such differences often do for rapidly growing biota in ecosystems. However, data for kidney and liver do not support the GRH. To account for these conflicting observations, we suggest that local environments in some organs select for neoplastic cells bearing mutations increasing cell division rate ("r-selected," as in colon and lung) while conditions elsewhere may select for reduced mortality rate ("K-selected," as in liver and kidney)

Dicer Is Associated with Ribosomal DNA Chromatin in Mammalian Cells

Background: RNA silencing is a common term for pathways utilizing small RNAs as sequence-specific guides to repress gene expression. Components of the RNA silencing machinery are involved in different aspects of chromatin function in numerous organisms. However, association of RNA silencing with chromatin in mammalian cells remains unclear. Methodology/Principal Findings: Immunostaining of mitotic chromosomes with antibodies visualizing either endogenous or ectopically expressed Dicer in mammalian cells revealed association of the protein with ribosomal DNA (rDNA) repeats. Chromatin immunoprecipitations and bisulfite sequencing experiments indicated that Dicer is associated with transcribed regions of both active and silenced genes in rDNA arrays of interphase chromosomes. Metabolic labeling of the mouse embryonic stem (ES) cells lacking Dicer did not reveal apparent defect in rRNA biogenesis though pre-rRNA synthesis in these cells was decreased, likely as a consequence of their slower growth caused by the loss of miRNAs. We analyzed in detail chromatin structure of rDNA but did not find any epigenetic changes at rDNA loci in Dicer 2/2 ES cells. Instead, we found that rDNA methylation is rather low in primary tissues, contrasting with rDNA methylation patterns in transformed cell lines. Conclusion/Significance: We found that Dicer, a key component of RNA silencing pathways, can be detected in association with rDNA chromatin in mammalian cells. The role of this particular localization of Dicer is not readily apparent since th

Prediction of 89Zr production using the Monte Carlo code FLUKA

The widely used Monte Carlo simulation code FLUKA has been utilized to prototype a solid target for the production of 89Zr, by irradiation of a metallic 89Y target foil in a 16.5 MeV proton biomedical cyclotron, through the reaction 89Y(p, n)89Zr. Simulations were performed with and without an Al energy degrader. In the setup of the geometry of the target, state of the art support tools, like SimpleGeo, were used for accurate, detailed modeling. The results permitted a quick assessment of all possible radionuclidic contaminants and confirmed that the use of an energy degrader avoids production of the most important impurity, 88Zr. The estimated value for the activity produced in one hour of irradiation at 20 A is 384+42 MBq; this is encouraging, indicating possible production of clinically significant amounts of activity with the relatively simple target setup adopted. Initial experimental tests gave results in excellent agreement with simulations, confirming the usefulness and accuracy of FLUKA as a tool for the design and optimization of targets for the production of PET radionuclides

Radiosurgery Using Tomotherapy for Patients with Brain Oligo-metastasis: A Retrospective Analysis on Feasibility and Tolerance

Aim: Aim of the study was to evaluate feasibility and toxicities of exclusive radiosurgery using tomotherapy in patients with brain oligo-metastases. Patients and Methods: Between 2008 and 2013 68 patients underwent stereotactic radiosurgery (SRS). Mean patient age was 63 years. Brain was the only site involved in 32 patients, while 36 had extracranial disease. Pre-SRS MRI 56 patients had sovratentorial lesions, 10 subtentorial and 2 patients had both. Fifty-two patients had 1 brain lesion, 11 had 2, and 5 patients had three. All patients underwent SRS using Tomotherapy. The median delivered dose was 18 Gy. Results: After a mean follow-up of 13 months, 14 patients were alive, while 54 patients had died. Two patients had complete response, 32 had partial response, 21 stable disease and 13 disease progression. Overall response rate was 80.9%. One- and two-year overall survival were 41,2% and 24,7%, while local control 61.5% and 37.7%. Toxicity was acceptable. Conclusion: SRS using tomotherapy has been proven feasible as non-invasive exclusive treatment for oligometastatic patients with good prognostic score