Given a context passage, generate a question from the passage such that its answer is shortest continous span from the passage.

Ex Input:
Bone, as well as the lung and liver, is among the sites of predilection for cancer metastasis. The bone stores large amounts of growth factors such as insulin-like growth factors and transforming growth factor-b, and provides fertile soil for metastatic cancer cells by continuously releasing these bone-stored growth factors, which are a consequence of osteoclastic bone resorption. Metastatic cancer cells in turn produce osteoclast-stimulating cytokines such as parathyroid hormone-related protein( PTH-rP), prostaglandin E2.(PGE2), and various interleukins(ILs). These cancer-produced osteoclast-stimulating cytokines bind to their cognitive receptors and promote the expression of ligands for the receptor activators of nuclear factor kB (RANKL)in osteoblasts. RANKL then binds to its receptor RANK, expressed in pre-osteoclasts, stimulates mature osteoclast formation, and subsequently, osteoclastic bone resorption. This vicious cycle between metastatic cancer cells and osteoclasts is critical to the development and progression of bone metastases. In addition, it is likely that metastatic cancer cells are influenced by bone environments(or niche)and acquire additional capacities such as an epithelial-mesenchymal transition(EMT), allowing them to be resistant to chemotherapy or apoptosis, to survive in a dormant state, or to aggressively spread to distant organs including lung and liver. Thus, the bone can serve as transit port. Disrupting this cycle by inhibiting osteoclastic bone resorption, antagonizing bone-derived growth factors, and neutralizing RANKL or PTH-rP, should be a promising therapeutic intervention for bone metastases. Bisphosphonates(BP)are specific inhibitors of osteoclasts, and have been shown to significantly reduce skeletal-related events(SRE)associated with bone metastasis. Denosumab is a neutralizing monoclonal antibody to RANKL and has recently been found to inhibit SRE more effectively than BP. Further understanding of the crosstalk communication between metastatic cancer cells and bone at the molecular level should lead us to design novel, more effective and specific treatments for cancer patients with bone metastases.

Ex Output:
To the ligand of which receptors does Denosumab (Prolia) bind?

Ex Input:
Electronic book publishing has many of the same risks and opportunities as electronic music publishing. By delivering text direct to the user's computer screen, the e-book could cut down costs, and allow creators to deal directly with their audience, bypassing traditional publishers and readers. But it also raises the possibility of mass piracy . Phil Rance, founder and managing director of Online Originals, a London-based e-book publisher, sums it up. "No one wants Napster to happen to books." Indeed, the most popular MP3 have put the frighteners on an industry that generally operates some way behind the "bleeding edge". The Mata Group, a leading US-based market researcher, says publishers are far too concerned about protecting their rights, "We believe all the recent legal control over Napster is like putting a finger in a river that is already overflowing. Publishers need to deal with reality and come up with new ways to develop wide electronic distribution , asking the question: 'How can we use the certainty of wide distribution to our advantage?'" At the moment, most publishers would like to limit the use of e-books to the person who bought them, or to the computer used to download them. If that can be done, e-books become just an extra income stream in a publishing industry that would continue to operate the way it does today, according to Terry Robinson, business manager for Adobe's e-paper group. "If you've cracked digital rights aspect, you've cracked the market," he says. Robert Nichols, Books Director at BOL agrees, "Rights management is absolutely important. Publishers just say that 'until copyright is secure, we're not going to talk'."

Ex Output:
What do publishers care most about e-books?

Ex Input:
Nestin is a unique intermediate filament protein. While it is robustly expressed in developing brain, postnatal expression is limited to the brain's subventricular zone (SVZ) and endothelial cells. Reexpression occurs, however, under several pathological conditions, including injury and neoplasia. We hypothesized that nestin would be a sensitive marker of early neoplasia after transplacental exposure of rats to ethylnitrosourea (ENU). Rats of various ages were administered bromodeoxyuridine (BudR) before sacrifice, and brain sections were examined for proliferative cells and several immunohistochemical markers, including nestin. Additional rats were examined after a stab wound injury to assess the expression of two of these markers, GFAP and nestin, in reactive astrocytes. All ENU-induced brain tumors (n = 9) were classified as gliomas (astrocytomas or oligoastrocytomas) based on their histology and immunophenotype. Nestin expression was noted in all tumors examined and was present in tumor cells as well as endothelial cells. During tumor development, we consistently noted nestin-expressing cells bearing multiple processes distributed throughout brain parenchyma. Both single cells and multiple cell clusters were observed as early as postnatal day 30 in all ENU-exposed brains examined (n = 11). Such distinctive nestin-expressing cells were not seen in nestin-stained control brains or ENU-exposed brains stained for GFAP or vimentin, nor was such a cell seen in a stab wound model used to assess reactive astrocytosis. While the number of these clusters was highly variable among rats, their size increased between 30 and 90 days. The data suggest that these nestin-expressing cells represent an early stage of the neoplastic process. It remains to be determined whether these cells become apparent at 30 days of age due to "dedifferentiation" of a local resident astrocyte or astrocyte precursor cell or migration of a relatively undifferentiated precursor/stem cell from the SVZ.

Ex Output:
Which intermediate filament (IF) protein can be used as a non-specific marker of the neuronal precursor cells of the subventricular zone?