TASK DEFINITION: In this task, you are given a passage which has a question and the context. You have to generate an answer to the question based on the information present in the context.
PROBLEM: Context: With the advent of new and more efficient anti-androgen drugs targeting androgen receptor (AR) in breast cancer (BC) is becoming an increasingly important area of investigation. This would potentially be most useful in triple negative BC (TNBC), where better therapies are still needed. The assessment of AR status is generally performed on the primary tumor even if the tumor has already metastasized. Very little is known regarding discrepancies of AR status during tumor progression. To determine the prevalence of AR positivity, with emphasis on TNBCs, and to investigate AR status during tumor progression, we evaluated a large series of primary BCs and matching metastases and recurrences.', 'AR status was performed on 356 primary BCs, 135 matching metastases, and 12 recurrences using a next-generation Tissue Microarray (ngTMA). A commercially available AR antibody was used to determine AR-status by immunohistochemistry. AR positivity was defined as any nuclear staining in tumor cells ≥1 %. AR expression was correlated with pathological tumor features of the primary tumor. Additionally, the concordance rate of AR expression between the different tumor sites was determined.', 'AR status was positive in: 87 % (307/353) of primary tumors, 86.1 % (105/122) of metastases, and in 66.7 % (8/12) of recurrences. TNBC tested positive in 11.4 %, (4/35) of BCs. A discrepant result was seen in 4.3 % (5/117) of primary BC and matching lymph node (LN) metastases. Three AR negative primary BCs were positive in the matching LN metastasis, representing 17.6 % of all negative BCs with lymph node metastases (3/17). Two AR positive primary BCs were negative in the matching LN metastasis, representing 2.0 % of all AR positive BCs with LN metastases (2/100). No discrepancies were seen between primary BC and distant metastases or recurrence (n\u2009=\u200917).\Question: Is androgen receptor status highly conserved during tumor progression of breast cancer?

SOLUTION: Most primary (87 %) and metastasized (86.1 %) BCs are AR positive including a significant fraction of TNBCs (11.4 %). Further, AR status is highly conserved during tumor progression and a change only occurs in a small fraction (4.1 %). Our study supports the notion that targeting AR could be effective for many BC patients and that re-testing of AR status in formerly negative or mixed type BC's is recommended.

PROBLEM: Context: An intact and fully functional multiprotein DNA replication complex (DNA synthesome) from human as well as from murine mammary carcinoma cells was first isolated and characterized in our laboratory. The human cell synthesome supports the in vitro origin-specific simian virus 40 (SV40) DNA replication reaction in the presence of the viral large T-antigen using a semiconservative mechanism and has been shown to contain all the proteins and enzymes required to support DNA synthesis. We are currently using the DNA synthesome as a unique model for analyzing the mechanism of action of anticancer drugs affecting DNA replication. The purpose of this study was to further investigate the mechanism of action of ara-C using the DNA synthesome isolated from the human breast cancer cell line MDA MB-468.', 'Synthesome-mediated SV40 DNA replication was performed in the presence of various concentrations of ara-CTP (the active metabolite of ara-C) and the types of daughter DNA molecules produced were analyzed lusing neutral and alkaline gel electrophoresis. We also examined the effect of ara-C on intact MDA MB-468 cell DNA synthesis and on cell proliferation. In addition, we studied the effect of ara-CTP on the activity of some of the synthesome target proteins (the DNA polymerases alpha and delta).', 'Full-length daughter DNA molecules were obtained in the presence of low concentrations of ara-CTP while at higher concentrations, there was an inhibition of full-length daughter DNA synthesis. The findings suggest that specifically the initiation phase of DNA synthesis was inhibited by ara-CTP since the production of the short Okazaki fragments was suppressed at all concentrations of the drug above 10 microM. In addition, it was found that the IC50 of ara-CTP for inhibition of synthesome-mediated in vitro DNA replication was comparable to that required to inhibit intact cell DNA synthesis. Further experimentation has shown that ara-CTP preferentially inhibits the activity of the synthesome-associated DNA polymerase alpha enzyme while the DNA polymerase delta seems to be resistant to the inhibitory effect of that drug.\Question: Does ara-C affect formation of cancer cell DNA synthesome replication intermediates?

SOLUTION: Our results indicate that ara-C's action on DNA replication is mediated primarily through DNA polymerase alpha and suggest that this enzyme plays a key role in DNA synthetic initiation events. The results also provide definitive support for the use of the DNA synthesome as a unique and powerful model for analyzing the mechanism of action of anticancer drugs which directly affect DNA replication.

PROBLEM: Context: During endoscopic or open carpal tunnel release, a palmar fat pad is visualized immediately proximal to the distal end of the transverse carpal ligament (TCL). Visualization of the fat pad allows anticipation of complete release of the TCL without unnecessary distal dissection that could risk iatrogenic injury. This study defines the anatomic relationship of the distal edge of the TCL to the fat pad, the superficial palmar arch, and the motor branch of the median nerve.', 'Eighteen fresh-frozen cadaver hands were dissected, and the proximal aspect of the palmar fat pad, the distal edge of the TCL, the superficial palmar arch, and the motor branch of the median nerve were identified. An electronic caliper was used to measure distances between each structure along the axis of the radial border of the ring finger. A subset of 8 hands was radiographically imaged with fingers flexed and extended (wrist neutral) to determine if finger positioning influenced measurements between marked structures.', 'The proximal aspect of the palmar fat pad is 2.0 mm proximal to the distal edge of the TCL. The distal end of the TCL, as measured along the axis of the radial border of the ring finger is 12.7 mm from the most proximal aspect of the palmar arch and 6.5 mm from the nearest aspect of the motor branch. Flexing the fingers decreases the distance between the distal end of the TCL and the fat pad while not markedly affecting the distance between the TCL and the palmar arch or the motor branch.\Question: Is the palmar fat pad a reliable intraoperative landmark during carpal tunnel release?

SOLUTION:
The palmar fat pad is a reliable anatomic landmark during carpal tunnel release. When dividing the TCL from proximal to distal, visualization of the proximal aspect of the fat pad indicates that the distal edge of the TCL is within approximately 2 mm and indicates that distal dissection beyond this extent is unnecessary.