TASK DEFINITION: Given a context passage, generate a question from the passage such that its answer is shortest continous span from the passage.
PROBLEM: Molecular abnormalities caused by the hybrid Bcr-Abl gene are causally associated with the development and progression of Philadelphia chromosome-positive (Ph(+)) chronic myelogenous leukemia (CML). Imatinib mesylate (STI571), a specific Bcr-Abl tyrosine-kinase signal-transduction inhibitor, has shown encouraging activity in phase I and II studies of CML. Here, we describe the use of imatinib mesylate to treat 75 patients in blast-phase CML (median age, 53 years; 65 with nonlymphoid and 10 with lymphoid blasts), and compare the results with those of a historical control group treated with standard cytarabine-based therapy. Imatinib mesylate was given as oral doses at 300 to 1000 mg per day and was the first salvage therapy for 47 patients. The objective response rate was 52% (39 of 75 patients: 16 had complete and 3 had partial hematologic response; 12 had hematologic improvement; 7 returned to second chronic phase; and 1 had a complete response in extramedullary blastic disease). Response rates were not different between nonlymphoid and lymphoid groups. The cytogenetic response rate was 16% (12 patients: 5 complete, 3 partial [Ph(+) below 35%], and 4 minor [Ph(+), 34% to 90%]). The estimated median overall survival was 6.5 months; the estimated 1-year survival was 22%. Response to therapy (landmark analysis at 8 weeks) was associated with survival prolongation. Compared with standard cytarabine combinations, imatinib mesylate therapy was less toxic and produced a higher response rate (55% versus 29%, P =.001), longer median survival (7 versus 4 months, P =.04), and lower 4-week induction mortality (4% versus 15%, P =.07). Imatinib mesylate is currently being tested in combination with other drugs to improve the prognosis for blast-phase CML.

SOLUTION: What tyrosine kinase, involved in a Philadelphia- chromosome positive chronic myelogenous leukemia, is the target of Imatinib (Gleevec)?

PROBLEM: Ponds are small bodies of fresh water that usually have no outlet; ponds are often are fed by underground springs. Like lakes, ponds are bordered by hills or low rises so the water is blocked from flowing directly downhill. Lakes are larger bodies of water. Lakes are usually fresh water, although the Great Salt Lake in Utah is just one exception. Water usually drains out of a lake through a river or a stream and all lakes lose water to evaporation. Lakes form in a variety of different ways: in depressions carved by glaciers, in calderas (Figure 1.1), and along tectonic faults, to name a few. Subglacial lakes are even found below a frozen ice cap. As a result of geologic history and the arrangement of land masses, most lakes are in the Northern Hemisphere. In fact, more than 60% of all the worlds lakes are in Canada most of these lakes were formed by the glaciers that covered most of Canada in the last Ice Age (Figure 1.2). Lakes are not permanent features of a landscape. Some come and go with the seasons, as water levels rise and fall. Over a longer time, lakes disappear when they fill with sediments, if the springs or streams that fill them diminish, (a) Crater Lake in Oregon is in a volcanic caldera. Lakes can also form in volcanic craters and impact craters. (b) The Great Lakes fill depressions eroded as glaciers scraped rock out from the landscape. (c) Lake Baikal, ice coated in winter in this image, formed as water filled up a tectonic faults. Lakes near Yellowknife were carved by glaciers during the last Ice Age. or if their outlets grow because of erosion. When the climate of an area changes, lakes can either expand or shrink (Figure 1.3). Lakes may disappear if precipitation significantly diminishes. Large lakes have tidal systems and currents, and can even affect weather patterns. The Great Lakes in the United States contain 22% of the worlds fresh surface water (Figure 1.1). The largest them, Lake Superior, has a tide that rises and falls several centimeters each day. The Great Lakes are large enough to alter the weather system in Northeastern United States by the lake effect, which is an increase in snow downwind of the relatively warm lakes. The Great Lakes are home to countless species of fish and wildlife. Many lakes are not natural, but are human-made. People dam a stream in a suitable spot and then let the water back up behind it, creating a lake. These lakes are called "reservoirs." Click image to the left or use the URL below. URL:

SOLUTION: which of these is not full of fresh water?

PROBLEM: The ESET (also called SETDB1) protein contains an N-terminal tudor domain that mediates protein-protein interactions and a C-terminal SET domain that catalyzes methylation of histone H3 at lysine 9. We report here that ESET protein is transiently upregulated in prehypertrophic chondrocytes in newborn mice. To investigate the in vivo effects of ESET on chondrocyte differentiation, we generated conditional knockout mice to specifically eliminate the catalytic SET domain of ESET protein only in mesenchymal cells. Such deletion of the ESET gene caused acceleration of chondrocyte hypertrophy in both embryos and young animals, depleting chondrocytes that are otherwise available to form epiphyseal plates for endochondral bone growth. ESET-deficient mice are thus characterized by defective long bone growth and trabecular bone formation. To understand the underlying mechanism for ESET regulation of chondrocytes, we carried out co-expression experiments and found that ESET associates with histone deacetylase 4 to bind and inhibit the activity of Runx2, a hypertrophy-promoting transcription factor. Repression of Runx2-mediated gene transactivation by ESET is dependent on its H3-K9 methyltransferase activity as well as its associated histone deacetylase activity. In addition, knockout of ESET is associated with repression of Indian hedgehog gene in pre- and early hypertrophic chondrocytes. Together, these results provide clear evidence that ESET controls hypertrophic differentiation of growth plate chondrocytes and endochondral ossification during embryogenesis and postnatal development.

SOLUTION:
What is the characteristic domain of histone methyltransferases?