Perlecan, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway

BACKGROUND: Genetic studies associated the CAPB locus with familial risk of brain and prostate cancers. We have identified HSPG2 (Perlecan) as a candidate gene for CAPB. Previously we have linked Perlecan to Hedgehog signaling in Drosophila. More recently, we have demonstrated the importance of Hedgehog signaling in humans for advanced prostate cancer. RESULTS: Here we demonstrate Perlecan expression in prostate cancer, and its function in prostate cancer cell growth through interaction and modulation of Sonic Hedgehog (SHH) signaling. Perlecan expression in prostate cancer tissues correlates with a high Gleason score and rapid cell proliferation. Perlecan is highly expressed in prostate cancer cell lines, including androgen insensitive cell lines and cell lines selected for metastatic properties. Inhibition of Perlecan expression in these cell lines decreases cell growth. Simultaneous blockade of Perlecan expression and androgen signaling in the androgen-sensitive cell line LNCaP was additive, indicating the independence of these two pathways. Perlecan expression correlates with SHH in tumor tissue microarrays and increased tumor cell proliferation based on Ki-67 immunohistochemistry. Inhibition of Perlecan expression by siRNA in prostate cancer cell lines decreases SHH signaling while expression of the downstream SHH effector GLI1 rescues the proliferation defect. Perlecan forms complexes with increasing amounts of SHH that correlate with increasing metastatic potential of the prostate cancer cell line. SHH signaling also increases in the more metastatic cell lines. Metastatic prostate cancer cell lines grown under serum-starved conditions (low androgen and growth factors) resulted in maintenance of Perlecan expression. Under low androgen, low growth factor conditions, Perlecan expression level correlates with the ability of the cells to maintain SHH signaling. CONCLUSION: We have demonstrated that Perlecan, a candidate gene for the CAPB locus, is a new component of the SHH pathway in prostate tumors and works independently of androgen signaling. In metastatic tumor cells increased SHH signaling correlates with the maintenance of Perlecan expression and more Perlecan-SHH complexes. Perlecan is a proteoglycan that regulates extracellular and stromal accessibility to growth factors such as SHH, thus allowing for the maintenance of SHH signaling under growth factor limiting conditions. This proteoglycan represents an important central regulator of SHH activity and presents an ideal drug target for blocking SHH effects

Caregiver-Assisted Coping Skills Training for Lung Cancer: Results of a Randomized Clinical Trial

Lung cancer is one of the most common cancers in the U.S. and is associated with high levels of symptoms including pain, fatigue, shortness of breath, and psychological distress. Caregivers as well as patients are adversely affected. However, previous studies of coping skills training (CST) interventions have not been tested in patients with lung cancer nor systematically included caregivers

Influence of taste disorders on dietary behaviors in cancer patients under chemotherapy

<p>Abstract</p> <p>Objectives</p> <p>To determine the relationship between energy and nutrient consumption with chemosensory changes in cancer patients under chemotherapy.</p> <p>Methods</p> <p>We carried out a cross-sectional study, enrolling 60 subjects. Cases were defined as patients with cancer diagnosis after their second chemotherapy cycle (n = 30), and controls were subjects without cancer (n = 30). Subjective changes of taste during treatment were assessed. Food consumption habits were obtained with a food frequency questionnaire validated for Mexican population. Five different concentrations of three basic flavors --sweet (sucrose), bitter (urea), and a novel basic taste, umami (sodium glutamate)-- were used to measure detection thresholds and recognition thresholds (RT). We determine differences between energy and nutrient consumption in cases and controls and their association with taste DT and RT.</p> <p>Results</p> <p>No demographic differences were found between groups. Cases showed higher sweet DT (6.4 vs. 4.4 μmol/ml; p = 0.03) and a higher bitter RT (100 vs. 95 μmol/ml; <it>p </it>= 0.04) than controls. Cases with sweet DT above the median showed significant lower daily energy (2,043 vs.1,586 kcal; p = 0.02), proteins (81.4 vs. 54 g/day; <it>p </it>= 0.01), carbohydrates (246 vs.192 g/day; <it>p </it>= 0.05), and zinc consumption (19 vs.11 mg/day; <it>p </it>= 0.01) compared to cases without sweet DT alteration. Cases with sweet DT and RT above median were associated with lower completion of energy requirements and consequent weight loss. There was no association between flavors DT or RT and nutrient ingestion in the control group.</p> <p>Conclusion</p> <p>Changes of sweet DT and bitter RT in cancer patients under chemotherapy treatment were associated with lower energy and nutrient ingestion. Taste detection and recognition thresholds disorders could be important factors in malnutrition development on patients with cancer under chemotherapy treatment.</p

Leadership that facilitates the successful implementation of Lean Six Sigma

Researchers have identified leadership as a critical success factor for Lean Six Sigma implementation. It is essential to understand leadership behaviours that facilitate the use of Lean Six Sigma. This paper aims to identify leadership styles from the literature that can facilitate Lean Six Sigma implementation, which in turn broaden the current understanding of the suitable leadership styles. Also, the authors aim to explore how leadership styles can enhance Lean Six Sigma operations. The authors systematically reviewed the literature on leadership styles and Lean Six Sigma. The results determined the leadership styles that can enable the use of Lean Six Sigma successfully. These leadership styles are as follows: situational (task-oriented or relation-oriented behaviour), transformational, servant, authentic, empowering, and distributed leadership. The authors provide a better understanding for practitioners and researchers from existing literature on how leaders' behaviours can enhance Lean Six Sigma implementation. It is not clear which style is the most dominant and effective. There is a lack in interpreting how these leadership styles linked to Lean Six Sigma implementation. There is a lack of empirical evidence most of the studies depended on a theoretical base. Very few studies have focused on leadership styles and Six Sigma success; to the best of the authors' knowledge only one paper has studied this. Also, there is scarcity in papers that addressed leadership styles that facilitate Lean Six Sigma implementation. This paper initiates a call to study Lean Six Sigma rather than focus only on either Lean or Six Sigma. This proposition guides future research based on the view that Lean management can share underlying assumptions with Lean Six Sigma characteristics. However, the mean limitation of this review is the use of specific keywords and database to identify studies

Raiders of the Lost Scrolls: The Right of Scholarly Access to the Content of Historic Documents

In Section I of this article, I will describe the events that led to the current controversy. In Section II, I will discuss whether the content of historic documents can be classified as cultural property. In Section III, I will consider whether control of the content of these documents interferes with intellectual freedom. In Section IV, I will discuss the intellectual property arguments raised by owners and interpreters of the Scrolls. Finally, in Section V, I will propose standards for access to, and preservation of, historic documents

The manager

Free to read As Indigenous CEOs, we train non-Indigenous doctors in cultural safety, and rely on them to integrate Aboriginal health workers into the multidisciplinary team