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

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

PROBLEM: With the recent introduction of inhibitors of mammalian target of rapamycin (mTOR) in oncology, distinct cutaneous and oral adverse events have been identified. In fact, stomatitis and rash are documented as the most frequent and potentially dose-limiting side effects. Clinically, mTOR inhibitor-associated stomatitis (mIAS) more closely resembles aphthous stomatitis than oral mucositis due to conventional anticancer therapies. While most cases of mIAS are mild to moderate and self-limiting, more severe and persistent mIAS can become a dose-limiting toxicity. Small ulcerations may cause significant pain and mucosal sensitivity may occur in the absence of clinical changes. Use of clinical assessment tools that are primarily driven by ulceration size may underestimate mIAS, and assessment should include patient-reported outcomes. This article provides an up-to-date review of the clinical presentation, terminology, pathogenesis, assessment and management of mIAS and other mTOR inhibitor-associated oral adverse events. In addition, areas of future research are considered.

SOLUTION: What does mTOR stands for?

PROBLEM: Treatment of CLL patients with conventional cytotoxic agents is often combined with significant toxicity that prevents broad application especially in elderly patients. In addition, relapse frequently occurs after application of conventional chemotherapy in CLL. Recently several new chemo-free treatment options have been introduced within clinical trials. Among them are monoclonal antibodies, most of them targeting the CD20 molecule: besides the licensed drugs rituximab and ofatumumab obinutuzumab, although in combination with chemotherapy, has recently shown high clinical efficacy in front-line treatment of elderly patients with CLL. Lenalidomide as monotherapy has demonstrated clinical efficacy in patients with relapsed disease and first data within clinical trials have been generated in the front-line setting. A promising class of novel agents has been designed to block aberrant signaling from the B-cell receptor. Ibrutinib acts by inhibiting the Bruton's tyrosine kinase (BTK) while idelalisib represents a first-in-class specific inhibitor of the phosphoinositol-3 kinase (PI3K) delta isoform. Another class of drugs with potential impact for chemo-free treatment strategies in CLL are the BH3-mimetic inhibitors of the Bcl-2 family of pro-survival proteins. Other interesting candidate drugs that are currently explored for CLL patients include small modular immunopharmaceutical (SMIP) proteins (e. g. TRU-016), CDK inhibitors (e. g. dinaciclib), HDAC inhibitors and others. Given all these novel agents and targets, chemo-free or at least chemo-reduced concepts may become reality in the near future for our patients suffering from CLL.

SOLUTION:
What is the name of Bruton's tyrosine kinase inhibitor that can be used for treatment of chronic lymphocytic leukemia?