Pharmacologic Manipulation of Late SV40 Factor Suppresses Wnt Signaling and Inhibits Growth of Allogeneic and Syngeneic Colon Cancer Xenografts.

Aberrant hyperactivation of Wnt signaling, driven by nuclear ß-catenin in the colonic epithelium, represents the seminal event in the initiation and progression of colorectal cancer (CRC). Despite its established role in CRC tumorigenesis, clinical translation of Wnt inhibitors remains unsuccessful. Late SV40 factor (LSF; encoded by TFCP2) is a transcription factor and a potent oncogene. The current study identified a chemotype, named factor quinolinone inhibitors (FQIs), that specifically inhibits LSF DNA-binding, partner protein-binding, and transactivation activities. The role of LSF and FQIs in CRC tumor growth was examined. Herein, the study showed that LSF and ß-catenin interacted in several CRC cell lines irrespective of their mutational profile, which was disrupted by FQI2-34. FQI2-34 suppressed Wnt activity in CRC cells in a dose-dependent manner. Leveraging both allogeneic and syngeneic xenograft models showed that FQI2-34 suppressed CRC tumor growth, significantly reduced nuclear ß-catenin, and down-regulated Wnt targets such as axis inhibition protein 2 (AXIN-2) and SRY-box transcription factor 9, in the xenograft cells. FQI2-34 suppressed the proliferation of xenograft cells. Adenocarcinomas from a series of stage IV CRC patients revealed a positive correlation between LSF expression and Wnt targets (AXIN-2 and SRY-box transcription factor 9) within the CRC cells. Collectively, this study uncovers the Wnt inhibitory and CRC growth-suppressive effects of these LSF inhibitors in CRC cells, revealing a novel target in CRC therapeutics.

Palliative and end-of-life care in rheumatology: High symptom prevalence and unmet needs.

OBJECTIVES: To determine the extent of end-of-life suffering and predictors of high symptom prevalence in the last one year of life in patients with systemic rheumatic diseases (SRDs) and the extent of supportive care received. METHODS: We identified adult patients with SRDs who died between 1 April 2006 and 1 April 2016. We collected data within 1 year before their death, on the following: (i) cumulative symptom prevalence, (ii) rates of Advance Care Planning (ACP), Do-Not-Resuscitate (DNR) orders and referral to a palliative physician. We analyzed the predictors of total symptom prevalence and palliative physician referral. RESULTS: Of the 161 patients studied, 34.2% had rheumatoid arthritis and 21.6% had systemic lupus erythematosus. Pain (81.4%), anorexia (80.1%) and dyspnea (77%) afflicted the majority of patients. On multivariate analysis, patients of the following profile had higher total symptom prevalence: (i) older age (ß = 0.027, SE = 0.013, p = 0.044); (ii) more comorbidities measured by the Charlson Comorbidity Index (ß = 0.192, SE = 0.159, p = 0.044); (iii) more admissions (ß = 0.263, SE = 0.090, p = 0.004) and (iv) recurrent infections (ß = 0.923, SE = 0.423, p = 0.031). Five patients (3.1%) received ACP and 25 (15.5%) were referred to a palliative physician. The median time between referral to palliative medicine and death was 8 days (IQR0-19). Of the 106 (67.5%) who had DNR orders, the median time between DNR and death was 3 days (IQR 0-10). CONCLUSIONS: Palliative and supportive care is relevant to patients with SRDs at the end-of-life. These patients experienced high physical suffering, particularly those who were elderly, with more comorbidities, hospital admissions and recurrent infections. Rheumatologists and physicians caring for patients with SRDs must be empowered to provide supportive care to these patients at the last phase of life, particularly by facilitating early ACP.

A cross-sectional study to examine the association between dietary patterns and risk of overweight and obesity in Hong Kong Chinese adolescents aged 10-12 years.

OBJECTIVE: To describe the dietary patterns and examine the associations of these patterns with risk of overweight and obesity in Chinese adolescents. METHODS: Baseline data collected between November 2003 and October 2004 from 171 boys and 180 girls aged 10-12 years who participated in the Hong Kong Adolescent Bone Health Cohort Study were analyzed. Dietary intake was assessed using a food frequency questionnaire and dietary pattern calculated using factor analysis. Data on demographic characteristics, weight, height, and Tanner stage were collected. Overweight and obesity were defined using The International Obesity Task Force cutoff values. Cardiovascular fitness expressed as peak oxygen consumption was predicted using the postexercise heart rate by the 3-minute step test and was used as an objective measure of physical activity. Association between dietary patterns and risk of overweight and obesity was examined using multivariate logistic regression with adjustment for demographics, puberty, and physical activity. RESULTS: The mean (SD) age of the study sample was 11.2 (0.6) years and there were 57 (16.2%) participants who were overweight/obese. Three dietary patterns were identified, namely, vegetables-fruits, snacks-beverages, and animal foods, fats, and condiments dominated. There was no significant linear association between each dietary pattern and the risk of overweight and obesity in this sample. Instead, the risk of overweight and obesity in this sample was positively associated with pubertal stage and inversely associated with physical activity. CONCLUSIONS: Pubertal stage and physical activity, but not dietary patterns, were important factors contributing to the risk of overweight and obesity in this population.

Bone mineral status and its relation with dietary estimates of net endogenous acid production in Hong Kong Chinese adolescents.

Diet composition influences net endogenous acid production (NEAP), which may affect bone health. No studies are available to relate dietary estimate of NEAP to bone health in Chinese adolescents. This study examined the association of dietary estimates of NEAP with bone mineral status in Hong Kong Chinese adolescents. Baseline data on 171 boys and 180 girls aged 10-12 years from the Hong Kong Adolescent Bone Health Cohort Study were presented. Weight, height, Tanner stage and dietary intakes by FFQ were collected. NEAP was estimated from diet using Frassetto's method. Bone area (BA), bone mineral content (BMC) and bone mineral apparent density (BMAD) of total hip, lumbar (L1-L4) spine and whole body were estimated by dual-energy X-ray absorptiometry (DXA). No significant association was observed between BMC or BMAD and energy-adjusted NEAP or other nutrients. BA was significantly and positively associated with BMC at all sites in both sexes. Weight was significantly and positively associated with BMC in hip and spine in both sexes. Height was negatively correlated with hip BMC for boys and whole body BMC for girls. Pubertal stage was significantly and positively associated with BMC in all sites in both sexes. Weight and height contributed most of the variability in BMAD at different sites. The results suggest that anthropometric characteristics and pubertal stage are more influential than dietary NEAP in determining bone mineral status of Hong Kong Chinese adolescents. However, the methodological weaknesses regarding the use of DXA and FFQ in the present sample require attention.